BK channel modulators: a comprehensive overview

DEFF Research Database (Denmark)

Nardi, Antonio; Olesen, Søren-Peter

2008-01-01

channels as a potentially attractive target, the design and synthesis of potent and selective BK modulators continue based on novel chemical ideas. A comprehensive overview of BK channel modulators is therefore timely and important to the current medicinal chemist for review, summary, and classification...

Hard Two-Photon Contribution to Elastic Lepton-Proton Scattering: Determined by the OLYMPUS Experiment

OpenAIRE

Henderson, B. S.; Ice, L. D.; Khaneft, D.; O'Connor, C.; Russell, R.; Schmidt, A.; Bernauer, J. C.; Kohl, M.; Akopov, N.; Alarcon, R.; Ates, O.; Avetisyan, A.; Beck, R.; Belostotski, S.; Bessuille, J.

2016-01-01

The OLYMPUS Collaboration reports on a precision measurement of the positron-proton to electron-proton elastic cross section ratio, \\ud R\\ud 2\\ud γ\\ud , a direct measure of the contribution of hard two-photon exchange to the elastic cross section. In the OLYMPUS measurement, 2.01 GeV electron and positron beams were directed through a hydrogen gas target internal to the DORIS storage ring at DESY. A toroidal magnetic spectrometer instrumented with drift chambers and time-of-flight scintillato...

Eficiência e efeito residual de biofertilizantes de rochas com PK e enxofre com Acidithiobacillus em alface Efficiency and residual effect of PK rock biofertilizers with sulfur and Acidithiobacillus on lettuce

Directory of Open Access Journals (Sweden)

Rita de Cássia Matias de Lima

2007-09-01

PB2 and KB2 and 150% the recommended level PB3 and KB3 for SSP and KCl and a control treatment with no P and K (P0K0. The experimental design was a factorial 5² in the randomized block, with four replicates. There was similar performance of the PK rock biofertilizers compared to the mineral fertilizers, especially when the level BP2BK3 was applied. The consecutive crop showed residual effect on lettuce yield (fresh shoot biomass, height, number of leaves, commercial evaluation, and P and K accumulation on shoot dry biomass. The results suggest that P and K rock biofertilizers may be used as an alternative in mineral fertilization.

Novel Mechanism of Plasma Prekallikrein (PK) Activation by Vascular Smooth Muscle Cells: Evidence of the presence of PK Activator

OpenAIRE

Keum, Joo-Seob; Jaffa, Miran A; Luttrell, Louis M; Jaffa, Ayad A.

2014-01-01

The contribution of plasma prekallikrein (PK) to vascular remodeling is becoming increasingly recognized. Plasma PK is activated when the zymogen PK is digested to an active enzyme by activated factor XII (FXII). Here, we present our findings that vascular smooth muscle cells (VSMC) activate plasma PK in the absence of FXII. Extracted plasma membrane and cytosolic fractions of VSMCs activate PK, but the rate of PK activation was greater by the membrane fraction. FXII neutralizing antibody did...

Absorption of 249Bk from the gastrointestinal tract

International Nuclear Information System (INIS)

Zalikin, G.A.; Nisimov, P.G.

1988-01-01

In experimets with albino mongrel female rats a study was made of the absorption of 249 Bk from the gastrointestinal tract after a single per os administration. The bulk of 249 Bk (96 per cent) administered either intravenously or per os was mainly deposited in the skeleton and liver. The value of 249 Bk absorption from the gastrointestinal trat by days 4 and 8 following administration was 0.05 per cent

Mars - Stratigraphy and gravimetry of Olympus Mons and its aureole

Science.gov (United States)

Hiller, K. H.; Neukum, G. P. O.; Janle, P.; Guest, J. E.; Lopes, R. M. C.

1982-01-01

The relative ages of the major geologic units on and around Olympus Mons are considered, together with an interpretation of the gravity anomaly found for this area. The crater data for this investigation have been acquired and interpreted according to the method outlined by Neukum and Hiller (1981). After careful geological mapping, craters clearly identified as impacts are measured and counted. Crater frequency values per sq km for craters greater than or equal to 1 km ('crater retention ages') are read from the individual counts by fitting the Martian cumulative crater production size-frequency distribution to the individual counts. In addition to age dating, the problem of the origin and nature of the aureole materials using gravity data is addressed. This is done by determining whether the line-of-sight gravity extending from Olympus Mons to the northwestern part of the aureole can be explained by the aureole masses alone or whether additional high-density intrusive masses must be assumed in the aureola area.

Agnoprotein Is an Essential Egress Factor during BK Polyomavirus Infection

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Margarita-Maria Panou

2018-03-01

Full Text Available BK polyomavirus (BKPyV; hereafter referred to as BK causes a lifelong chronic infection and is associated with debilitating disease in kidney transplant recipients. Despite its importance, aspects of the virus life cycle remain poorly understood. In addition to the structural proteins, the late region of the BK genome encodes for an auxiliary protein called agnoprotein. Studies on other polyomavirus agnoproteins have suggested that the protein may contribute to virion infectivity. Here, we demonstrate an essential role for agnoprotein in BK virus release. Viruses lacking agnoprotein fail to release from host cells and do not propagate to wild-type levels. Despite this, agnoprotein is not essential for virion infectivity or morphogenesis. Instead, agnoprotein expression correlates with nuclear egress of BK virions. We demonstrate that the agnoprotein binding partner α-soluble N-ethylmaleimide sensitive fusion (NSF attachment protein (α-SNAP is necessary for BK virion release, and siRNA knockdown of α-SNAP prevents nuclear release of wild-type BK virions. These data highlight a novel role for agnoprotein and begin to reveal the mechanism by which polyomaviruses leave an infected cell.

E-KAUPPAPORTAALIN MAHDOLLISUUDET PK-YRITYKSELLE

OpenAIRE

Järvenpää, Juho

2011-01-01

Opinnäytetyön aiheena oli tutkia e-kauppaportaalin mahdollisuuksia ja hyötyjä pk-yritykselle. Opinnäytetyön tarkoituksena oli tarjota pk-yrityksille tietoa, miksi e-kauppaportaalin käyttöönotto olisi varteen otettava vaihtoehto, kun yritys harkitsee verkkokaupan perustamista. Opinnäyte jakaantuu teorioiden ja tutkimusten esittelyyn ja niiden soveltamiseen pk-yrityksen hyväksi. Opinnäytetyössä käytettiin hyväksi Tieken tutkimuksia ja muita e-kauppaan liittyviä tutkimuksia ja teorioita. Opi...

BK Virus-Associated Nephropathy without Viremia in an Adolescent Kidney Transplant Recipient

Directory of Open Access Journals (Sweden)

Kraisoon Lomjansook, M.D.

2017-09-01

Full Text Available BK virus can reactivate in kidney transplant recipients leading to BK virus-associated nephropathy (BKVAN and allograft dysfunction. Pathogenesis begins with viral replication, follows by viruria, viremia and nephropathy. Screening tools recommended for viral detection are urine and blood BK viral load. Viremia has higher positive predictive value than viruria, thus several guidelines recommend using viremia to determine whether renal biopsy, a gold standard for diagnosis of BKVAN is needed. We present a 16-year-old boy who developed BKVAN five months after deceased donor kidney transplantation. He had increased serum creatinine with negative blood BK viral load. BK nephropathy was diagnosed in kidney graft biopsy. The urine showed BK viruria. Immunosuppressant was reduced and ciprofloxacin given. Viruria disappeared and repeated graft biopsy was normal 4 months later. BK viremia was negative through 1 year follow up. We conclude that BKVAN may occur even without viremia and BK viruria may be considered for screening tool.

KCNMA1 encoded cardiac BK channels afford protection against ischemia-reperfusion injury.

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Ewa Soltysinska

Full Text Available Mitochondrial potassium channels have been implicated in myocardial protection mediated through pre-/postconditioning. Compounds that open the Ca2+- and voltage-activated potassium channel of big-conductance (BK have a pre-conditioning-like effect on survival of cardiomyocytes after ischemia/reperfusion injury. Recently, mitochondrial BK channels (mitoBKs in cardiomyocytes were implicated as infarct-limiting factors that derive directly from the KCNMA1 gene encoding for canonical BKs usually present at the plasma membrane of cells. However, some studies challenged these cardio-protective roles of mitoBKs. Herein, we present electrophysiological evidence for paxilline- and NS11021-sensitive BK-mediated currents of 190 pS conductance in mitoplasts from wild-type but not BK-/- cardiomyocytes. Transmission electron microscopy of BK-/- ventricular muscles fibres showed normal ultra-structures and matrix dimension, but oxidative phosphorylation capacities at normoxia and upon re-oxygenation after anoxia were significantly attenuated in BK-/- permeabilized cardiomyocytes. In the absence of BK, post-anoxic reactive oxygen species (ROS production from cardiomyocyte mitochondria was elevated indicating that mitoBK fine-tune the oxidative state at hypoxia and re-oxygenation. Because ROS and the capacity of the myocardium for oxidative metabolism are important determinants of cellular survival, we tested BK-/- hearts for their response in an ex-vivo model of ischemia/reperfusion (I/R injury. Infarct areas, coronary flow and heart rates were not different between wild-type and BK-/- hearts upon I/R injury in the absence of ischemic pre-conditioning (IP, but differed upon IP. While the area of infarction comprised 28±3% of the area at risk in wild-type, it was increased to 58±5% in BK-/- hearts suggesting that BK mediates the beneficial effects of IP. These findings suggest that cardiac BK channels are important for proper oxidative energy supply of

Reactivation of BK polyomavirus in patients with multiple sclerosis receiving natalizumab therapy.

LENUS (Irish Health Repository)

Lonergan, Roisin M

2012-02-01

Natalizumab therapy in multiple sclerosis has been associated with JC polyomavirus-induced progressive multifocal leucoencephalopathy. We hypothesized that natalizumab may also lead to reactivation of BK, a related human polyomavirus capable of causing morbidity in immunosuppressed groups. Patients with relapsing remitting multiple sclerosis treated with natalizumab were prospectively monitored for reactivation of BK virus in blood and urine samples, and for evidence of associated renal dysfunction. In this cohort, JC and BK DNA in blood and urine; cytomegalovirus (CMV) DNA in blood and urine; CD4 and CD8 T-lymphocyte counts and ratios in peripheral blood; and renal function were monitored at regular intervals. BK subtyping and noncoding control region sequencing was performed on samples demonstrating reactivation. Prior to commencement of natalizumab therapy, 3 of 36 patients with multiple sclerosis (8.3%) had BK viruria and BK reactivation occurred in 12 of 54 patients (22.2%). BK viruria was transient in 7, continuous in 2 patients, and persistent viruria was associated with transient viremia. Concomitant JC and CMV viral loads were undetectable. CD4:CD8 ratios fluctuated, but absolute CD4 counts did not fall below normal limits. In four of seven patients with BK virus reactivation, transient reductions in CD4 counts were observed at onset of BK viruria: these resolved in three of four patients on resuppression of BK replication. No renal dysfunction was observed in the cohort. BK virus reactivation can occur during natalizumab therapy; however, the significance in the absence of renal dysfunction is unclear. We propose regular monitoring for BK reactivation or at least for evidence of renal dysfunction in patients receiving natalizumab.

Perbedaan Pemahaman Guru BK Tentang Konseling Kelompok antara Alumni Unnes dan Non-Unnes

Directory of Open Access Journals (Sweden)

Desta Rizky Budiarti

2014-10-01

Full Text Available Tujuan penelitian ini untuk mengetahui gambaran pemahaman guru BK alumni Unnes dan guru BK alumni non-Unnes tentang konseling kelompok, dan perbedaan pemahaman diantara keduanya. Jenis penelitian adalah penelitian survey komparatif. Populasi penelitian ini yaitu guru BK di SMP Negeri se-Kota Semarang. Teknik sampling yang digunakan adalah Cluster Proportional Random Sampling. Metode pengumpulan data menggunakan tes tentang pemahaman konseling kelompok. Analisis datanya menggunakan analisis kuantitatif yang mencakup deskriptif prosentase dan uji beda t-test polled varian. Hasil penelitian menunjukkan bahwa ada perbedaan yang signifikan, dimana pemahaman guru BK alumni Unnes tentang konseling kelompok berada pada kategori sangat tinggi dengan persentase 84,26% dibandingkan dengan guru BK alumni non-Unnes yang memiliki persentase 63,9% berada pada kategori sedang. Simpulan dari penelitian ini, pemahaman guru BK tentang konseling kelompok antara alumni Unnes lebih tinggi daripada guru BK alumni non-Unnes. The purpose of this study to describe the understanding of BK teacher Unnes graduate and BK teacher non - Unnes graduates about group counseling, and understanding the differences between them . This type of research is a comparative survey research. The population of this study are in Junior High School teacher BK as the city of Semarang. The sampling technique used is proportional cluster random sampling. Methods of data collection using test on understanding group counseling. Analysis of the data using descriptive quantitative analysis that includes the percentage and t - test different test variants polled. The results showed that there were significant differences, where the understanding of BK teacher Unnes graduate  abaout  the counseling group in the category with a very high percentage of 84.26 % compared to a BK teacher non - Unnes graduates who have a percentage only 63.9 % are in the medium category. The conclusions of this study

Evaluation of fluoroquinolones for the prevention of BK viremia after renal transplantation.

Science.gov (United States)

Gabardi, Steven; Waikar, Sushrut S; Martin, Spencer; Roberts, Keri; Chen, Jie; Borgi, Lea; Sheashaa, Hussein; Dyer, Christine; Malek, Sayeed K; Tullius, Stefan G; Vadivel, Nidyanandh; Grafals, Monica; Abdi, Reza; Najafian, Nader; Milford, Edgar; Chandraker, Anil

2010-07-01

Nearly 30% of renal transplant recipients develops BK viremia, a prerequisite for BK nephropathy. Case reports have evaluated treatment options for BK virus, but no controlled studies have assessed prophylactic therapies. Fluoroquinolone antibiotics were studied for prevention of BK viremia after renal transplantation. This retrospective analysis evaluated adult renal transplant recipients with at least one BK viral load (blood) between 90 and 400 days after transplantation. Six to 12 months of co-trimoxazole was used for Pneumocystis prophylaxis. In sulfa-allergic/-intolerant patients, 6 to 12 months of atovaquone with 1 month of a fluoroquinolone was used. Fluoroquinolones can inhibit BK DNA topoisomerase. The two groups studied were those that received 30 days of levofloxacin or ciprofloxacin after transplantation and those that did not. The primary endpoint was BK viremia rates at 1 year. Of note, of the 160 patients not receiving fluoroquinolone prophylaxis, 40 received a fluoroquinolone for treatment of a bacterial infection within 3 months after transplantation. Subgroup analysis evaluating these 40 patients against the 120 who had no exposure to fluoroquinolones was completed. A 1-month fluoroquinolone course after transplantation was associated with significantly lower rates of BK viremia at 1 year compared with those with no fluoroquinolone. In the subgroup analysis, exposure to fluoroquinolone for treatment of bacterial infections within 3 months after transplantation was associated with significantly lower 1-year rates of BK viremia. This analysis demonstrates that fluoroquinolones are effective at preventing BK viremia after renal transplantation.

Coronary arterial BK channel dysfunction exacerbates ischemia/reperfusion-induced myocardial injury in diabetic mice.

Science.gov (United States)

Lu, Tong; Jiang, Bin; Wang, Xiao-Li; Lee, Hon-Chi

2016-09-01

The large conductance Ca(2+)-activated K(+) (BK) channels, abundantly expressed in coronary artery smooth muscle cells (SMCs), play a pivotal role in regulating coronary circulation. A large body of evidence indicates that coronary arterial BK channel function is diminished in both type 1 and type 2 diabetes. However, the consequence of coronary BK channel dysfunction in diabetes is not clear. We hypothesized that impaired coronary BK channel function exacerbates myocardial ischemia/reperfusion (I/R) injury in streptozotocin-induced diabetic mice. Combining patch-clamp techniques and cellular biological approaches, we found that diabetes facilitated the colocalization of angiotensin II (Ang II) type 1 receptors and BK channel α-subunits (BK-α), but not BK channel β1-subunits (BK-β1), in the caveolae of coronary SMCs. This caveolar compartmentation in vascular SMCs not only enhanced Ang II-mediated inhibition of BK-α but also produced a physical disassociation between BK-α and BK-β1, leading to increased infarct size in diabetic hearts. Most importantly, genetic ablation of caveolae integrity or pharmacological activation of coronary BK channels protected the cardiac function of diabetic mice from experimental I/R injury in both in vivo and ex vivo preparations. Our results demonstrate a vascular ionic mechanism underlying the poor outcome of myocardial injury in diabetes. Hence, activation of coronary BK channels may serve as a therapeutic target for cardiovascular complications of diabetes.

An evaluation of the Olympus "Quickrate" analyser.

Science.gov (United States)

Williams, D G; Wood, R J; Worth, H G

1979-02-01

The Olympus "Quickrate", a photometer built for both kinetic and end point analysis was evaluated in this laboratory. Aspartate transaminase, lactate dehydrogenase, hydroxybutyrate dehydrogenase, creatine kinase, alkaline phosphatase and gamma glutamyl transpeptidase were measured in the kinetic mode and glucose, urea, total protein, albumin, bilirubin, calcium and iron in the end point mode. Overall, good correlation was observed with routine methodologies and the precision of the methods was acceptable. An electrical evaluation was also performed. In our hands, the instrument proved to be simple to use and gave no trouble. It should prove useful for paediatric and emergency work, and as a back up for other analysers.

OlyMPUS - The Ontology-based Metadata Portal for Unified Semantics

Science.gov (United States)

Huffer, E.; Gleason, J. L.

2015-12-01

The Ontology-based Metadata Portal for Unified Semantics (OlyMPUS), funded by the NASA Earth Science Technology Office Advanced Information Systems Technology program, is an end-to-end system designed to support data consumers and data providers, enabling the latter to register their data sets and provision them with the semantically rich metadata that drives the Ontology-Driven Interactive Search Environment for Earth Sciences (ODISEES). OlyMPUS leverages the semantics and reasoning capabilities of ODISEES to provide data producers with a semi-automated interface for producing the semantically rich metadata needed to support ODISEES' data discovery and access services. It integrates the ODISEES metadata search system with multiple NASA data delivery tools to enable data consumers to create customized data sets for download to their computers, or for NASA Advanced Supercomputing (NAS) facility registered users, directly to NAS storage resources for access by applications running on NAS supercomputers. A core function of NASA's Earth Science Division is research and analysis that uses the full spectrum of data products available in NASA archives. Scientists need to perform complex analyses that identify correlations and non-obvious relationships across all types of Earth System phenomena. Comprehensive analytics are hindered, however, by the fact that many Earth science data products are disparate and hard to synthesize. Variations in how data are collected, processed, gridded, and stored, create challenges for data interoperability and synthesis, which are exacerbated by the sheer volume of available data. Robust, semantically rich metadata can support tools for data discovery and facilitate machine-to-machine transactions with services such as data subsetting, regridding, and reformatting. Such capabilities are critical to enabling the research activities integral to NASA's strategic plans. However, as metadata requirements increase and competing standards emerge

Beyond DNA repair: DNA-PK function in cancer

OpenAIRE

Goodwin, Jonathan F.; Knudsen, Karen E.

2014-01-01

The DNA-dependent protein kinase (DNA-PK) is a pivotal component of the DNA repair machinery that governs the response to DNA damage, serving to maintain genome integrity. However, the DNA-PK kinase component was initially isolated with transcriptional complexes, and recent findings have illuminated the impact of DNA-PK-mediated transcriptional regulation on tumor progression and therapeutic response. DNA-PK expression has also been correlated with poor outcome in selected tumor types, furthe...

Rendimento da alface e atributos químicos de um Latossolo em função da aplicação de biofertilizantes de rochas com fósforo e potássio Lettuce yield and chemical attributes of an Oxisol by application of biofertilizers from phosphate and potash rocks

Directory of Open Access Journals (Sweden)

Rita de Cássia Matias de Lima

2007-06-01

crops the biofertilizers BP, BK, and chemical fertilizers SFS and KCl were effective on lettuce yield. In the first crop the best results were obtained with the treatments SFS700 BK90, SFS700 BK60, and in the consecutive crop applying the treatments BP700 BK90, SFS700 BK60 and SFS700 BK90. In the two crops the positive response of the PK biofertilizers and PK mineral fertilizers was evident. Residual effect was observed when the treatment BP1050 BK90 was applied. Soil pH was not affected by application of PK biofertilizers plus worm-compound, increasing available P and K, especially for available P in the consecutive crop. The PK rock biofertilizers, plus worm-compound, may be applied as an alternative to PK mineral soluble fertilizers.

Bessong, PK

African Journals Online (AJOL)

Bessong, PK. Vol 11, No 2 (2012) - Articles The Accounting Implication of Cultural Dimensions on Financial Reporting: A Study of Selected Manufacturing Companies in Nigeria Abstract PDF · Vol 11, No 2 (2012) - Articles Human Resource Valuation and the Performance of Selected Banks in Nigeria Abstract PDF.

Autographa californica multiple nucleopolyhedrovirus PK-1 is essential for nucleocapsid assembly

Energy Technology Data Exchange (ETDEWEB)

Liang, Changyong, E-mail: cyliang@yzu.edu.cn [College of Bioscience and Biotechnology, Yangzhou University, Yangzhou 225009 (China); Li, Min; Dai, Xuejuan; Zhao, Shuling; Hou, Yanling; Zhang, Yongli; Lan, Dandan [College of Bioscience and Biotechnology, Yangzhou University, Yangzhou 225009 (China); Wang, Yun; Chen, Xinwen [State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071 (China)

2013-09-01

PK-1 (Ac10) is a baculovirus-encoded serine/threonine kinase and its function is unclear. Our results showed that a pk-1 knockout AcMNPV failed to produce infectious progeny, while the pk-1 repair virus could rescue this defect. qPCR analysis demonstrated that pk-1 deletion did not affect viral DNA replication. Analysis of the repaired recombinants with truncated pk-1 mutants demonstrated that the catalytic domain of protein kinases of PK-1 was essential to viral infectivity. Moreover, those PK-1 mutants that could rescue the infectious BV production defect exhibited kinase activity in vitro. Therefore, it is suggested that the kinase activity of PK-1 is essential in regulating viral propagation. Electron microscopy revealed that pk-1 deletion affected the formation of normal nucleocapsids. Masses of electron-lucent tubular structures were present in cell transfected with pk-1 knockout bacmid. Therefore, PK-1 appears to phosphorylate some viral or cellular proteins that are essential for DNA packaging to regulate nucleocapsid assembly. - Highlights: • A pk-1 knockout AcMNPV failed to produce infectious progeny. • The pk-1 deletion did not affect viral DNA replication. • The catalytic domain of protein kinases (PKc) of PK-1 was essential to viral infectivity. • The kinase activity of PK-1 is essential in regulating viral propagation. • PK-1 appears to phosphorylate some viral proteins that are essential for DNA packaging to regulate nucleocapsid assembly.

Infección por virus BK en paciente pediátrico trasplantado renal BK virus infection in a pediatric renal transplant recipient

Directory of Open Access Journals (Sweden)

R. Bonaventura

2005-09-01

Full Text Available El poliomavirus humano BK causa infección primaria asintomática en la niñez, estableciendo latencia principalmente en el tracto urinario. En individuos con alteración en la inmunidad celular se puede producir su reactivación desencadenando patología a nivel renal. Por estas razones es particularmente importante en la población pediátrica trasplantada renal, en la que puede producir la infección primaria cuando el paciente está inmunosuprimido. En nuestro trabajo se realizó el seguimiento de un paciente de 5 años trasplantado renal en octubre de 2003 que 45 días post-trasplante sufrió un deterioro del órgano injertado. Desde la fecha del trasplante hasta junio de 2004 se produjeron 3 episodios de alteración en la función renal, durante los cuales se analizaron muestras de sangre, orina, biopsia renal y líquido de linfocele. Para el diagnóstico difererencial entre rechazo agudo versus causa infecciosa se emplearon técnicas de detección para los virus BK, CMV y ADV, además del estudio citológico del tejido renal. Los resultados obtenidos junto con la clínica del paciente indican un probable caso de infección por BK. La importancia de realizar el diagnóstico diferencial entre rechazo agudo y la infección por BK radica en que la conducta en cuanto a la terapia inmunosupresora es opuesta en cada caso.BK Human Polyomavirus causes an asymptomatic primary infection in children, then establishing latency mainly in the urinary tract. Viral reactivation can lead to renal pathology in individuals with impaired cellular immune response. This is particularly important in pediatric transplant recipients, who can suffer a primary infection when immunosupressed. We followed up the case of a 5 years old patient who received a renal transplant in October 2003, and presented damaged graft 45 days after the intervention. The patient suffered 3 episodes of renal function failure between October 2003 and June 2004. Blood, urine, renal biopsy

Tools for predicting the PK/PD of therapeutic proteins.

Science.gov (United States)

Diao, Lei; Meibohm, Bernd

2015-07-01

Assessments of the pharmacokinetic/pharmacodynamic (PK/PD) characteristics are an integral part in the development of novel therapeutic agents. Compared with traditional small molecule drugs, therapeutic proteins possess many distinct PK/PD features that necessitate the application of modified or separate approaches for assessing their PK/PD relationships. In this review, the authors discuss tools that are utilized to describe and predict the PK/PD features of therapeutic proteins and that are valuable additions in the armamentarium of drug development approaches to facilitate and accelerate their successful preclinical and clinical development. A variety of state-of-the-art PK/PD tools is currently being applied and has been adjusted to support the development of proteins as therapeutics, including allometric scaling approaches, target-mediated disposition models, first-in-man dose calculations, physiologically based PK models and empirical and semi-mechanistic PK/PD modeling. With the advent of the next generation of biologics including bioengineered antibody constructs being developed, these tools will need to be further refined and adapted to ensure their applicability and successful facilitation of the drug development process for these novel scaffolds.

Genetic Diversity, Natural Selection and Haplotype Grouping of Plasmodium knowlesi Gamma Protein Region II (PkγRII): Comparison with the Duffy Binding Protein (PkDBPαRII).

Science.gov (United States)

Fong, Mun Yik; Rashdi, Sarah A A; Yusof, Ruhani; Lau, Yee Ling

2016-01-01

Plasmodium knowlesi is a simian malaria parasite that has been reported to cause malaria in humans in Southeast Asia. This parasite invades the erythrocytes of humans and of its natural host, the macaque Macaca fascicularis, via interaction between the Duffy binding protein region II (PkDBPαRII) and the Duffy antigen receptor on the host erythrocytes. In contrast, the P. knowlesi gamma protein region II (PkγRII) is not involved in the invasion of P. knowlesi into humans. PkγRII, however, mediates the invasion of P. knowlesi into the erythrocytes of M. mulata, a non-natural host of P. knowlesi via a hitherto unknown receptor. The haplotypes of PkDBPαRII in P. knowlesi isolates from Peninsular Malaysia and North Borneo have been shown to be genetically distinct and geographically clustered. Also, the PkDBPαRII was observed to be undergoing purifying (negative) selection. The present study aimed to determine whether similar phenomena occur in PkγRII. Blood samples from 78 knowlesi malaria patients were used. Forty-eight of the samples were from Peninsular Malaysia, and 30 were from Malaysia Borneo. The genomic DNA of the samples was extracted and used as template for the PCR amplification of the PkγRII. The PCR product was cloned and sequenced. The sequences obtained were analysed for genetic diversity and natural selection using MEGA6 and DnaSP (version 5.10.00) programmes. Genetic differentiation between the PkγRII of Peninsular Malaysia and North Borneo isolates was estimated using the Wright's FST fixation index in DnaSP (version 5.10.00). Haplotype analysis was carried out using the Median-Joining approach in NETWORK (version 4.6.1.3). A total of 78 PkγRII sequences was obtained. Comparative analysis showed that the PkγRII have similar range of haplotype (Hd) and nucleotide diversity (π) with that of PkDBPαRII. Other similarities between PkγRII and PkDBPαRII include undergoing purifying (negative) selection, geographical clustering of haplotypes

Genetic Diversity, Natural Selection and Haplotype Grouping of Plasmodium knowlesi Gamma Protein Region II (PkγRII: Comparison with the Duffy Binding Protein (PkDBPαRII.

Directory of Open Access Journals (Sweden)

Mun Yik Fong

Full Text Available Plasmodium knowlesi is a simian malaria parasite that has been reported to cause malaria in humans in Southeast Asia. This parasite invades the erythrocytes of humans and of its natural host, the macaque Macaca fascicularis, via interaction between the Duffy binding protein region II (PkDBPαRII and the Duffy antigen receptor on the host erythrocytes. In contrast, the P. knowlesi gamma protein region II (PkγRII is not involved in the invasion of P. knowlesi into humans. PkγRII, however, mediates the invasion of P. knowlesi into the erythrocytes of M. mulata, a non-natural host of P. knowlesi via a hitherto unknown receptor. The haplotypes of PkDBPαRII in P. knowlesi isolates from Peninsular Malaysia and North Borneo have been shown to be genetically distinct and geographically clustered. Also, the PkDBPαRII was observed to be undergoing purifying (negative selection. The present study aimed to determine whether similar phenomena occur in PkγRII.Blood samples from 78 knowlesi malaria patients were used. Forty-eight of the samples were from Peninsular Malaysia, and 30 were from Malaysia Borneo. The genomic DNA of the samples was extracted and used as template for the PCR amplification of the PkγRII. The PCR product was cloned and sequenced. The sequences obtained were analysed for genetic diversity and natural selection using MEGA6 and DnaSP (version 5.10.00 programmes. Genetic differentiation between the PkγRII of Peninsular Malaysia and North Borneo isolates was estimated using the Wright's FST fixation index in DnaSP (version 5.10.00. Haplotype analysis was carried out using the Median-Joining approach in NETWORK (version 4.6.1.3.A total of 78 PkγRII sequences was obtained. Comparative analysis showed that the PkγRII have similar range of haplotype (Hd and nucleotide diversity (π with that of PkDBPαRII. Other similarities between PkγRII and PkDBPαRII include undergoing purifying (negative selection, geographical clustering of

Instagram-opas pk-yrityksille

OpenAIRE

Seppälä, Marjaana

2016-01-01

Tämän opinnäytetyön aihe on Instagram-opas pienille ja keskisuurille yrityksille. Tarkoituksena on luoda pk-yrityksille sopiva Instagram-opas, jonka sisältöä voidaan hyödyntää Instagram-palvelun käyttöönotossa ja markkinointia suunniteltaessa. Opas toteutetaan Business-to-Consumer (B2C)– kentällä toimivan yrityksen näkökulmasta. Oppaan tarkoituksena on laskea pk-yrityksen kynnystä lähteä mukaan Instagram-palveluun ja lisätä tietämystä palvelun käytöstä. Tässä opinnäytetyössä tarkastella...

Model Informed Pediatric Development Applied to Bilastine: Ontogenic PK Model Development, Dose Selection for First Time in Children and PK Study Design.

Science.gov (United States)

Vozmediano, Valvanera; Sologuren, Ander; Lukas, John C; Leal, Nerea; Rodriguez, Mónica

2017-12-01

Bilastine is an H 1 antagonist whose pharmacokinetics (PK) and pharmacodynamics (PD) have been resolved in adults with a therapeutic oral dose of 20 mg/day. Bilastine has favorable characteristics for use in pediatrics but the PK/PD and the optimal dose in children had yet to be clinically explored. The purpose is to: (1) Develop an ontogenic predictive model of bilastine PK linked to the PD in adults by integrating current knowledge; (2) Use the model to design a PK study in children; (3) Confirm the selected dose and the study design through the evaluation of model predictability in the first recruited children; (4) Consider for inclusion the group of younger children (design an adaptive PK trial in children that was then confirmed using data from the first recruits by comparing observations with model predictions. PK/PD simulations supported the selection of 10 mg/day in 2 to design hence trial continuation. The model successfully predicted bilastine PK in pediatrics and optimally assisted the selection of the dose and sampling scheme for the trial in children. The selected dose was considered suitable for younger children and the forthcoming safety study in children aged 2 to <12 years.

Differential contribution of Ca2+ sources to day and night BK current activation in the circadian clock.

Science.gov (United States)

Whitt, Joshua P; McNally, Beth A; Meredith, Andrea L

2018-02-05

Large conductance K + (BK) channels are expressed widely in neurons, where their activation is regulated by membrane depolarization and intracellular Ca 2+ (Ca 2+ i ). To enable this regulation, BK channels functionally couple to both voltage-gated Ca 2+ channels (VGCCs) and channels mediating Ca 2+ release from intracellular stores. However, the relationship between BK channels and their specific Ca 2+ source for particular patterns of excitability is not well understood. In neurons within the suprachiasmatic nucleus (SCN)-the brain's circadian clock-BK current, VGCC current, and Ca 2+ i are diurnally regulated, but paradoxically, BK current is greatest at night when VGCC current and Ca 2+ i are reduced. Here, to determine whether diurnal regulation of Ca 2+ is relevant for BK channel activation, we combine pharmacology with day and night patch-clamp recordings in acute slices of SCN. We find that activation of BK current depends primarily on three types of channels but that the relative contribution changes between day and night. BK current can be abrogated with nimodipine during the day but not at night, establishing that L-type Ca 2+ channels (LTCCs) are the primary daytime Ca 2+ source for BK activation. In contrast, dantrolene causes a significant decrease in BK current at night, suggesting that nighttime BK activation is driven by ryanodine receptor (RyR)-mediated Ca 2+ i release. The N- and P/Q-type Ca 2+ channel blocker ω-conotoxin MVIIC causes a smaller reduction of BK current that does not differ between day and night. Finally, inhibition of LTCCs, but not RyRs, eliminates BK inactivation, but the BK β2 subunit was not required for activation of BK current by LTCCs. These data reveal a dynamic coupling strategy between BK channels and their Ca 2+ sources in the SCN, contributing to diurnal regulation of SCN excitability. © 2018 Whitt et al.

Outcomes of renal transplant recipients with BK virus infection and BK virus surveillance in the Auckland region from 2006 to 2012.

Science.gov (United States)

Hsiao, Chun-Yuan; Pilmore, Helen L; Zhou, Lifeng; de Zoysa, Janak R

2016-11-06

To evaluate incidence, risk factors and treatment outcome of BK polyomavirus nephropathy (BKVN) in a cohort of renal transplant recipients in the Auckland region without a formal BK polyomavirus (BKV) surveillance programme. A cohort of 226 patients who received their renal transplants from 2006 to 2012 was retrospectively reviewed. Seventy-six recipients (33.6%) had a BK viral load (BKVL) test and 9 patients (3.9%) developed BKVN. Cold ischaemia time (HR = 1.18, 95%CI: 1.04-1.35) was found to be a risk factor for BKVN. Four recipients with BKVN had complete resolution of their BKV infection; 1 recipient had BKVL less than 625 copies/mL; 3 recipients had BKVL more than 1000 copies/mL and 1 had graft failure from BKVN. BKVN has a negative impact on graft function [median estimated glomerular filtration rate (eGFR) 22.5 (IQR 18.5-53.0) mL/min per 1.73 m 2 , P = 0.015), but no statistically significant difference ( P = 0.374) in renal allograft function was found among negative BK viraemia group [median eGFR 60.0 (IQR 48.5-74.2) mL/min per 1.73 m 2 ), positive BK viraemia without BKVN group [median eGFR 55.0 (IQR 47.0-76.0) mL/min per 1.73 m 2 ] and unknown BKV status group [median eGFR 54.0 (IQR 43.8-71.0) mL/min per 1.73 m 2 ]. The incidence and treatment outcomes of BKVN were similar to some centres with BKV surveillance programmes. Recipients with BVKN have poorer graft function. Although active surveillance for BKV has been shown to be effective in reducing incidence of BKVN, it should be tailored specifically to that transplant centre based on its epidemiology and outcomes of BKVN, particularly in centres with limited resources.

Pelaksanaan Asas-Asas BK dalam Pelayanan BK (Ditinjau dari Persepsi Siswa

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Yasinta Nur Miftakhul Jannah

2015-09-01

Full Text Available Penelitian ini didasarkan pada data dan fenomena yang ditemukan di lapangan yang menunjukkan rendahnya pelaksanaan asas-asas bimbingan dan konseling oleh konselor di sekolah. Penelitian ini bertujuan untuk mengetahui gambaran pelaksanaan asas-asas BK dalam pelayanan BK di SMA Negeri se-Kabupaten Pati (ditinjau dari persepsi siswa kelas XI Tahun Ajaran 2014/2015. Populasi penelitian ini adalah siswa kelas XI di SMA Negeri se-Kabupaten Pati. Pengambilan sampel penelitian dilakukan dengan menggunakan teknik proportionale homogen random sampling dengan sampel sebesar 307 siswa kelas XI. Metode pengumpulan data menggunakan skala psikologis dalam bentuk skala persepsi. Metode analisis data menggunakan statistik deskriptif persentase. Hasil dari penelitian menunjukkan, gambaran pelaksanaan asas-asas BK secara umum sudah masuk pada kategori baik dengan persentase sebesar 73,45%. Asas yang paling tinggi pelaksanaannya yaitu asas kegiatan dengan persentase sebesar 79,80%. Asas yang masih tergolong rendah persentase pelaksanaannya yaitu asas kekinian dengan persentase sebesar 68,80% dan asas alih tangan dengan persentase sebesar 69,10%. This research is based on data and phenomena found in a field that shows low  implementation of guidance and counseling principles by counselor at school. This research aims to find out the implementation of guidance and counseling principles in counseling services toward public senior high school throughout Pati Regency (reviewed from grade XI students’ perceptions Academic Year 2014/2015. Population of this research are grade XI public senior high school students throughout Pati Regency. Sampling in this research is done by using proportionale homogen random sampling technique with the number of samples 307 of grade IX. Collecting data method using psychological scale in the form of scale perception. Data analysis method which used is descriptive percentage. The result shows description of the implementation of

Structure of the (0+,1+) mesons Bs0 and Bs1, and the strong coupling constant gBs0BK and gBs1B*K

International Nuclear Information System (INIS)

Wang, Z. G.

2008-01-01

In this article, we take the point of view that the bottomed (0 + ,1 + ) mesons B s0 and B s1 are the conventional bs meson and calculate the strong coupling constants g B s0 BK and g B s1 B*K with the light-cone QCD sum rules. The numerical values of strong coupling constants g B s1 B*K and g B s0 BK are very large and support the hadronic dressing mechanism. Just like the scalar mesons f 0 (980), a 0 (980), D s0 and axial-vector meson D s1 , the (0 + ,1 + ) bottomed mesons B s0 and B s1 may have small bs kernels of the typical bs meson size. The strong couplings to the hadronic channels (or the virtual mesons loops) may result in smaller masses than the conventional bs mesons in the potential quark models and enrich the pure bs states with other components.

Bk and Cf chromatographic separation and 249Bk/248Cm and 249Cf/248Cm elemental ratios determination by inductively coupled plasma quadrupole mass spectrometry

International Nuclear Information System (INIS)

Gourgiotis, A.; Isnard, H.; Nonell, A.; Aubert, M.; Stadelmann, G.; Dupont, E.; AlMahamid, I.; Tiang, G.; Rao, L.; Lukens, W.; Cassette, P.; Panebianco, S.; Letourneau, A.; Chartier, F.

2013-01-01

The French Atomic Energy Commission has carried out several experiments for the study of minor-actinide transmutation processes in high intensity thermal neutron flux. In this context a Cm sample enriched in 248 Cm (97%) was irradiated in a thermal neutron flux at the High Flux Reactor (HFR) of the Laue-Langevin Institute (ILL). The precise and accurate determination of Cf isotope ratios and of 249 Bk/ 248 Cm and 249 Cf/ 248 Cm elemental ratios in the 248 Cm irradiated sample is crucial for the calculation of actinide neutron capture cross-sections.This work describes an analytical procedure for the separation and the isotope ratio measurement of Bk and Cf in the irradiated sample.The Bk and Cf separation is based on a lanthanides separation protocol previously developed by the laboratory. Well-defined retention times for Bk and Cf were obtained by coupling the Ionic Chromatography (IC) with an ICP-QMS. All conditions of element separation by IC and the different steps of the analytical protocol in order to obtain the isotopic and elemental ratios are presented. Relative uncertainties of Cf isotopic ratios range from 0.3% to 0.5% and the uncertainty of the 249 Bk/ 248 Cm and 249 Cf/ 248 Cm elemental ratios are respectively 6.1% and 3.2%.This level of uncertainty for both isotopic and elemental ratios is in perfect agreement with the requirement for transmutation studies. (authors)

Urinary BK virus excretion in children newly diagnosed with acute lymphoblastic leukemia

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Nahid Raeesi

2012-01-01

Conclusion: To demonstrate the role of BK virus in inducing ALL or increasing the number of relapses, prospective studies on larger scale of population and evaluating both serum and urine for BK virus are recommended.

Cholesterol Down-Regulates BK Channels Stably Expressed in HEK 293 Cells

Science.gov (United States)

Deng, Xiu-Ling; Sun, Hai-Ying; Li, Gui-Rong

2013-01-01

Cholesterol is one of the major lipid components of the plasma membrane in mammalian cells and is involved in the regulation of a number of ion channels. The present study investigates how large conductance Ca2+-activated K+ (BK) channels are regulated by membrane cholesterol in BK-HEK 293 cells expressing both the α-subunit hKCa1.1 and the auxiliary β1-subunit or in hKCa1.1-HEK 293 cells expressing only the α-subunit hKCa1.1 using approaches of electrophysiology, molecular biology, and immunocytochemistry. Membrane cholesterol was depleted in these cells with methyl-β-cyclodextrin (MβCD), and enriched with cholesterol-saturated MβCD (MβCD-cholesterol) or low-density lipoprotein (LDL). We found that BK current density was decreased by cholesterol enrichment in BK-HEK 293 cells, with a reduced expression of KCa1.1 protein, but not the β1-subunit protein. This effect was fully countered by the proteasome inhibitor lactacystin or the lysosome function inhibitor bafilomycin A1. Interestingly, in hKCa1.1-HEK 293 cells, the current density was not affected by cholesterol enrichment, but directly decreased by MβCD, suggesting that the down-regulation of BK channels by cholesterol depends on the auxiliary β1-subunit. The reduced KCa1.1 channel protein expression was also observed in cultured human coronary artery smooth muscle cells with cholesterol enrichment using MβCD-cholesterol or LDL. These results demonstrate the novel information that cholesterol down-regulates BK channels by reducing KCa1.1 protein expression via increasing the channel protein degradation, and the effect is dependent on the auxiliary β1-subunit. PMID:24260325

[β-estradiol activates BK(Ca) in mesenteric artery smooth muscle cells of post-menopause women].

Science.gov (United States)

Cheng, Jun; Zeng, Xiao-Rong; Li, Peng-Yun; Lu, Ting-Ting; Tan, Xiao-Qiu; Wen, Jing; Yang, Yan

2012-04-25

The aim of the present study was to study the effect of β-estradiol (β-E(2)) on the large-conductance Ca(2+)-activated potassium (BK(Ca)) channel in mesenteric artery smooth muscle cells (SMCs). The mesenteric arteries were obtained from post-menopause female patients with abdominal surgery, and the SMCs were isolated from the arteries using an enzymatic disassociation. According to the sources, the SMCs were divided into non-hypertension (NH) and essential hypertension (EH) groups. Single channel patch clamp technique was used to investigate the effect of β-E(2) and ICI 182780 (a specific blocker of estrogen receptor) on BK(Ca) in the SMCs. The results showed the opening of BK(Ca) in the SMCs was voltage and calcium dependent, and could be blocked by IbTX. β-E(2) (100 μmol/L) significantly increased open probability (Po) of BK(Ca) in both NH and EH groups. After β-E(2) treatment, NH group showed higher Po of BK(Ca) compared with EH group. ICI 182780 could inhibit the activating effect of β-E(2) on BK(Ca) in no matter NH or EH groups. These results suggest β-E(2) activates BK(Ca) in mesenteric artery SMCs from post-menopause women via estrogen receptor, but hypertension may decline the activating effect of β-E(2) on BK(Ca).

Molecular mapping of qBK1 WD , a major QTL for bakanae disease resistance in rice.

Science.gov (United States)

Lee, Sais-Beul; Hur, Yeon-Jae; Cho, Jun-Hyeon; Lee, Jong-Hee; Kim, Tae-Heon; Cho, Soo-Min; Song, You-Chun; Seo, Young-Su; Lee, Jungkwan; Kim, Tae-Sung; Park, Yong-Jin; Oh, Myung-Kyu; Park, Dong-Soo

2018-01-10

Bakanae or foot rot disease is a prominent disease of rice caused by Gibberella fujikuroi. This disease may infect rice plants from the pre-emergence stage to the mature stage. In recent years, raising rice seedlings in seed boxes for mechanical transplanting has increased the incidence of many seedling diseases; only a few rice varieties have been reported to exhibit resistance to bakanae disease. In this study, we attempted to identify quantitative trait loci (QTLs) conferring bakanae disease resistance from the highly resistant japonica variety Wonseadaesoo. A primary QTL study using the genotypes/phenotypes of the recombinant inbred lines (RILs) indicated that the locus qBK1 WD conferring resistance to bakanae disease from Wonseadaesoo was located in a 1.59 Mb interval delimited on the physical map between chr01_13542347 (13.54 Mb) and chr01_15132528 (15.13 Mb). The log of odds (LOD) score of qBK1 WD was 8.29, accounting for 20.2% of the total phenotypic variation. We further identified a gene pyramiding effect of two QTLs, qBK WD and previously developed qBK1. The mean proportion of healthy plant for 31 F 4 RILs that had no resistance genes was 35.3%, which was similar to that of the susceptible check variety Ilpum. The proportion of healthy plants for the lines with only qBK WD or qBK1 was 66.1% and 55.5%, respectively, which was significantly higher than that of the lines without resistance genes and that of Ilpum. The mean proportion of the healthy plant for 15 F 4 RILs harboring both qBK WD and qBK1 was 80.2%, which was significantly higher than that of the lines with only qBK WD or qBK1. Introducing qBK WD or pyramiding the QTLs qBK WD and qBK1 could provide effective tools for breeding rice with bakanae disease resistance. To our knowledge, this is the first report on a gene pyramiding effect that provides higher resistance against bakanae disease.

Improving the Accuracy of Predicting Maximal Oxygen Consumption (VO2pk)

Science.gov (United States)

Downs, Meghan E.; Lee, Stuart M. C.; Ploutz-Snyder, Lori; Feiveson, Alan

2016-01-01

Maximal oxygen (VO2pk) is the maximum amount of oxygen that the body can use during intense exercise and is used for benchmarking endurance exercise capacity. The most accurate method to determineVO2pk requires continuous measurements of ventilation and gas exchange during an exercise test to maximal effort, which necessitates expensive equipment, a trained staff, and time to set-up the equipment. For astronauts, accurate VO2pk measures are important to assess mission critical task performance capabilities and to prescribe exercise intensities to optimize performance. Currently, astronauts perform submaximal exercise tests during flight to predict VO2pk; however, while submaximal VO2pk prediction equations provide reliable estimates of mean VO2pk for populations, they can be unacceptably inaccurate for a given individual. The error in current predictions and logistical limitations of measuring VO2pk, particularly during spaceflight, highlights the need for improved estimation methods.

PENGGUNAAN PAKAN BERBASIS BUNGKIL KOPRA PADA PEMBESARAN IKAN BANDENG DI TAMBAK

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Usman Usman

2016-04-01

diberi pakan komersil. Sementara retensi lemak tertinggi terjadi pada ikan yang diberi pakan PK, diikuti berturut-turut yang diberi pakan BK-65 dan BK-55. Pakan berbasis bungkil kopra layak digunakan sebagai pakan alternatif dalam pembesaran ikan bandeng tradisional (+ di tambak.

Impact of two different commercial DNA extraction methods on BK virus viral load

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Massimiliano Bergallo

2016-03-01

Full Text Available Background and aim: BK virus, a member of human polyomavirus family, is a worldwide distributed virus characterized by a seroprevalence rate of 70-90% in adult population. Monitoring of viral replication is made by evaluation of BK DNA by quantitative polymerase chain reaction. Many different methods can be applied for extraction of nucleic acid from several specimens. The aim of this study was to assess the impact of two different DNA extraction procedure on BK viral load. Materials and methods: DNA extraction procedure including the Nuclisens easyMAG platform (bioMerieux, Marcy l’Etoile, France and manual QIAGEN extraction (QIAGEN Hilden, Germany. BK DNA quantification was performed by Real Time TaqMan PCR using a commercial kit. Result and discussion: The samples capacity, cost and time spent were compared for both systems. In conclusion our results demonstrate that automated nucleic acid extraction method using Nuclisense easyMAG was superior to manual protocol (QIAGEN Blood Mini kit, for the extraction of BK virus from serum and urine specimens.

The RAI DBS experiment with Olympus

Science.gov (United States)

Castelli, Enzo

The Italian broadcasting network (RAI) has studied the development of a national DBS service in an effort to outline a proposal for a space segment configuration compatible with development of new services, including HDTV. Proposals so far considered feature the integration of RAI's channel on Olympus in a future operational system and after extensive experimental use. Contents of the experimental program are discussed, and need for a broadcasting standard which considers projected introduction of HDTV is noted. The debate between RAI and consumer electronic industries on the use of broadcasting standards is outlined. The position of RAI in the context of HDTV and DBS is defined and the issue of determining the most effective transmission standard during the experimental stage is raised. It is pointed out that, in the absence of new production facilities for HDTV, the maximum quality which MAC will yield will be that of PAL since programs must be produced in PAL and then converted into MAC. Two alternatives for strategy on the use of broadcasting standards for DBS are offered. Finally, technical experiments and a market survey are discussed.

Pharmacological consequences of the coexpression of BK channel α and auxiliary β subunits

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Yolima P. Torres

2014-10-01

Full Text Available Coded by a single gene (Slo1, KCM and activated by depolarizing potentials and by a rise in intracellular Ca2+ concentration, the large conductance voltage- and Ca+2-activated K+ channel (BK is unique among the superfamily of K+ channels. BK channels are tetramers characterized by a pore-forming α subunit containing seven transmembrane segments (instead of the six found in voltage-dependent K+ channels and a large C terminus composed of two regulators of K+ conductance domains (RCK domains, where the Ca2+-binding sites reside. BK channels can be associated with accessory β subunits and, although different BK modulatory mechanisms have been described, greater interest has recently been placed on the role that the β subunits may play in the modulation of BK channel gating due to its physiological importance. Four β subunits have currently been identified (i.e., β1, β2, β3 & β4 and despite the fact that they all share the same topology, it has been shown that every β subunit has a specific tissue distribution and that they modify channel kinetics as well as their pharmacological properties and the apparent Ca+2 sensitivity of the α subunit in different ways. Additionally, different studies have shown that natural, endogenous and synthetic compounds can modulate BK channels through β subunits. Considering the importance of these channels in different pathological conditions, such as hypertension and neurological disorders, this review focuses on the mechanisms by which these compounds modulate the biophysical properties of BK channels through the regulation of β subunits, as well as their potential therapeutic uses for diseases such as those mentioned above.

Pharmacological consequences of the coexpression of BK channel α and auxiliary β subunits.

Science.gov (United States)

Torres, Yolima P; Granados, Sara T; Latorre, Ramón

2014-01-01

Coded by a single gene (Slo1, KCM) and activated by depolarizing potentials and by a rise in intracellular Ca(2+) concentration, the large conductance voltage- and Ca(2+)-activated K(+) channel (BK) is unique among the superfamily of K(+) channels. BK channels are tetramers characterized by a pore-forming α subunit containing seven transmembrane segments (instead of the six found in voltage-dependent K(+) channels) and a large C terminus composed of two regulators of K(+) conductance domains (RCK domains), where the Ca(2+)-binding sites reside. BK channels can be associated with accessory β subunits and, although different BK modulatory mechanisms have been described, greater interest has recently been placed on the role that the β subunits may play in the modulation of BK channel gating due to its physiological importance. Four β subunits have currently been identified (i.e., β1, β2, β3, and β4) and despite the fact that they all share the same topology, it has been shown that every β subunit has a specific tissue distribution and that they modify channel kinetics as well as their pharmacological properties and the apparent Ca(2+) sensitivity of the α subunit in different ways. Additionally, different studies have shown that natural, endogenous, and synthetic compounds can modulate BK channels through β subunits. Considering the importance of these channels in different pathological conditions, such as hypertension and neurological disorders, this review focuses on the mechanisms by which these compounds modulate the biophysical properties of BK channels through the regulation of β subunits, as well as their potential therapeutic uses for diseases such as those mentioned above.

Pharmacological consequences of the coexpression of BK channel α and auxiliary β subunits

Science.gov (United States)

Torres, Yolima P.; Granados, Sara T.; Latorre, Ramón

2014-01-01

Coded by a single gene (Slo1, KCM) and activated by depolarizing potentials and by a rise in intracellular Ca2+ concentration, the large conductance voltage- and Ca2+-activated K+ channel (BK) is unique among the superfamily of K+ channels. BK channels are tetramers characterized by a pore-forming α subunit containing seven transmembrane segments (instead of the six found in voltage-dependent K+ channels) and a large C terminus composed of two regulators of K+ conductance domains (RCK domains), where the Ca2+-binding sites reside. BK channels can be associated with accessory β subunits and, although different BK modulatory mechanisms have been described, greater interest has recently been placed on the role that the β subunits may play in the modulation of BK channel gating due to its physiological importance. Four β subunits have currently been identified (i.e., β1, β2, β3, and β4) and despite the fact that they all share the same topology, it has been shown that every β subunit has a specific tissue distribution and that they modify channel kinetics as well as their pharmacological properties and the apparent Ca2+ sensitivity of the α subunit in different ways. Additionally, different studies have shown that natural, endogenous, and synthetic compounds can modulate BK channels through β subunits. Considering the importance of these channels in different pathological conditions, such as hypertension and neurological disorders, this review focuses on the mechanisms by which these compounds modulate the biophysical properties of BK channels through the regulation of β subunits, as well as their potential therapeutic uses for diseases such as those mentioned above. PMID:25346693

Symmetric Moeller/Bhabha luminosity monitor for the OLYMPUS experiment

Energy Technology Data Exchange (ETDEWEB)

Capozza, Luigi; Maas, Frank; Perez Benito, Roberto; Rodriguez Pineiro, David [Helmholtz-Institut Mainz, Mainz (Germany); GSI Helmholtzzentrum fuer Schwerionenforschung GmbH, Darmstadt (Germany); O' Connor, Colton [Massachusetts Institute of Technology, Cambridge, MA (United States); Diefenbach, Juergen; Glaeser, Boris [Institut fuer Kernphysik, Mainz (Germany); Khaneft, Dmitry [Johannes Gutenberg-Universitaet Mainz, Mainz (Germany); Helmholtz-Institut Mainz, Mainz (Germany); Ma, Yue [GSI Helmholtzzentrum fuer Schwerionenforschung GmbH, Darmstadt (Germany)

2015-07-01

The OLYMPUS experiment is motivated by the discrepancy between the proton electric to magnetic form factor ratio measured using unpolarized and polarized electron scattering. This discrepancy can be explained by a two-photon exchange (TPE) contribution in lepton-hadron scattering. Measuring the ratio of electron-proton and positron-proton elastic scattering cross sections the contribution of the TPE can be determined. For this purpose, very precise measurements of the relative luminosity have to be performed. The symmetric Moeller/Bhabha luminosity monitor, made of calorimetric lead fluoride (PbF{sub 2}) Cherenkov detectors, provides precise data from counting coincidences Moeller and Bhabha events. High sensitivity to the geometrical acceptance and alignment requires accurate study of systematic uncertainties.

Validation of the second-generation Olympus colonoscopy simulator for skills assessment.

Science.gov (United States)

Haycock, A V; Bassett, P; Bladen, J; Thomas-Gibson, S

2009-11-01

Simulators have potential value in providing objective evidence of technical skill for procedures within medicine. The aim of this study was to determine face and construct validity for the Olympus colonoscopy simulator and to establish which assessment measures map to clinical benchmarks of expertise. Thirty-four participants were recruited: 10 novices with no prior colonoscopy experience, 13 intermediate (trainee) endoscopists with fewer than 1000 previous colonoscopies, and 11 experienced endoscopists with more than 1000 previous colonoscopies. All participants completed three standardized cases on the simulator and experts gave feedback regarding the realism of the simulator. Forty metrics recorded automatically by the simulator were analyzed for their ability to distinguish between the groups. The simulator discriminated participants by experience level for 22 different parameters. Completion rates were lower for novices than for trainees and experts (37 % vs. 79 % and 88 % respectively, P variable stiffness function ( P = 0.004), number of sigmoid N-loops ( P = 0.02); size of sigmoid N-loops ( P = 0.01), and time to remove alpha loops ( P = 0.004). Out of 10, experts rated the realism of movement at 6.4, force feedback at 6.6, looping at 6.6, and loop resolution at 6.8. The Olympus colonoscopy simulator has good face validity and excellent construct validity. It provides an objective assessment of colonoscopic skill on multiple measures and benchmarks have been set to allow its use as both a formative and a summative assessment tool. Georg Thieme Verlag KG Stuttgart. New York.

Identification of the new isotope sup 2 sup 4 sup 1 Bk

CERN Document Server

Asai, M; Ichikawa, S; Nagame, Y; Nishinaka, I; Akiyama, K; Toyoshima, A; Kaneko, T; Sakama, M; Haba, H; Oura, Y; Kojima, Y; Shibata, M

2003-01-01

A new neutron-deficient berkelium isotope sup 2 sup 4 sup 1 Bk produced in the sup 2 sup 3 sup 9 Pu( sup 6 Li, 4n) reaction has been identified using a gas-jet coupled on-line isotope separator. Cm K and L X-rays associated with the EC decay of sup 2 sup 4 sup 1 Bk were observed in the mass-241 fraction, and three gamma transitions were attributed to the EC decay of sup 2 sup 4 sup 1 Bk through X-gamma coincidences. The half-life of sup 2 sup 4 sup 1 Bk was determined to be 4.6+-0.4 min which is 1/2-1/4 of that of theoretical predictions. The half-life value and the observed gamma transitions can be consistently explained as a consequence of the allowed EC transition of pi 7/2 sup + [633] -> nu 7/2 sup + [624]. (orig.)

Renovascular BK(Ca) channels are not activated in vivo under resting conditions and during agonist stimulation

DEFF Research Database (Denmark)

Magnusson, Linda; Sørensen, Charlotte Mehlin; Braunstein, Thomas Hartig

2006-01-01

We investigated the role of large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels for the basal renal vascular tone in vivo. Furthermore, the possible buffering by BK(Ca) of the vasoconstriction elicited by angiotensin II (ANG II) or norepinephrine (NE) was investigated. The possible activation.......3 nmol/min) did not have any effect. Renal injection of ANG II (1-4 ng) or NE (10-40 ng) produced a transient decrease in RBF. These responses were not affected by preinfusion of TEA or IBT. Renal infusion of the BK(Ca) opener NS-1619 (90.0 nmol/min) did not affect basal RBF or the response to NE......, there is no indication for a major role for BK(Ca) channels in the control of basal renal tone in vivo. Furthermore, BK(Ca) channels do not have a buffering effect on the rat renal vascular responses to ANG II and NE. The fact that NS-1619 attenuates the ANG II response indicates that the renal vascular BK(Ca) channels...

Ethanol modulation of mammalian BK channels in excitable tissues: molecular targets and their possible contribution to alcohol-induced altered behavior

Directory of Open Access Journals (Sweden)

Alex M. Dopico

2014-12-01

Full Text Available In most tissues, the function of calcium- and voltage-gated potassium (BK channels is modified in response to ethanol concentrations reached in human blood during alcohol intoxication. In general, modification of BK current from ethanol-naïve preparations in response to brief ethanol exposure results from changes in channel open probability without modification of unitary conductance or change in BK protein levels in the membrane. Protracted and/or repeated ethanol exposure, however, may evoke changes in BK expression. The final ethanol effect on BK open probability leading to either BK current potentiation or BK current reduction is determined by an orchestration of molecular factors, including levels of activating ligand (cytosolic calcium, BK subunit composition and posttranslational modifications, and the channel’s lipid microenvironment. These factors seem to allosterically regulate a direct interaction between ethanol and a recognition pocket of discrete dimensions recently mapped to the channel-forming (slo1 subunit. Type of ethanol exposure also plays a role in the final BK response to the drug: in several central nervous system regions (e.g., striatum, primary sensory neurons, and supraoptic nucleus, acute exposure to ethanol reduces neuronal excitability by enhancing BK activity. In contrast, protracted or repetitive ethanol administration may alter BK subunit composition and membrane expression, rendering the BK complex insensitive to further ethanol exposure. In neurohypophysial axon terminals, ethanol potentiation of BK channel activity leads to a reduction in neuropeptide release. In vascular smooth muscle, however, ethanol inhibition of BK current leads to cell contraction and vascular constriction.

Large conductance Ca2+-activated K+ (BK channel: Activation by Ca2+ and voltage

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RAMÓN LATORRE

2006-01-01

Full Text Available Large conductance Ca2+-activated K+ (BK channels belong to the S4 superfamily of K+ channels that include voltage-dependent K+ (Kv channels characterized by having six (S1-S6 transmembrane domains and a positively charged S4 domain. As Kv channels, BK channels contain a S4 domain, but they have an extra (S0 transmembrane domain that leads to an external NH2-terminus. The BK channel is activated by internal Ca2+, and using chimeric channels and mutagenesis, three distinct Ca2+-dependent regulatory mechanisms with different divalent cation selectivity have been identified in its large COOH-terminus. Two of these putative Ca2+-binding domains activate the BK channel when cytoplasmic Ca2+ reaches micromolar concentrations, and a low Ca2+ affinity mechanism may be involved in the physiological regulation by Mg2+. The presence in the BK channel of multiple Ca2+-binding sites explains the huge Ca2+ concentration range (0.1 μM-100 μM in which the divalent cation influences channel gating. BK channels are also voltage-dependent, and all the experimental evidence points toward the S4 domain as the domain in charge of sensing the voltage. Calcium can open BK channels when all the voltage sensors are in their resting configuration, and voltage is able to activate channels in the complete absence of Ca2+. Therefore, Ca2+ and voltage act independently to enhance channel opening, and this behavior can be explained using a two-tiered allosteric gating mechanism.

Cholesterol tuning of BK ethanol response is enantioselective, and is a function of accompanying lipids.

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Chunbo Yuan

Full Text Available In the search to uncover ethanol's molecular mechanisms, the calcium and voltage activated, large conductance potassium channel (BK has emerged as an important molecule. We examine how cholesterol content in bilayers of 1,2-dioleoyl-3-phosphatidylethanolamine (DOPE/sphingomyelin (SPM and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylethanolamine (POPE/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylserine (POPS affect the function and ethanol sensitivity of BK. In addition, we examine how manipulation of cholesterol in biological membranes modulates ethanol's actions on BK. We report that cholesterol levels regulate the change in BK channel open probability elicited by 50 mM ethanol. Low levels of cholesterol (<20%, molar ratio supports ethanol activation, while high levels of cholesterol leads to ethanol inhibition of BK. To determine if cholesterol affects BK and its sensitivity to ethanol through a direct cholesterol-protein interaction or via an indirect action on the lipid bilayer, we used the synthetic enantiomer of cholesterol (ent-CHS. We found that 20% and 40% ent-CHS had little effect on the ethanol sensitivity of BK, when compared with the same concentration of nat-CHS. We accessed the effects of ent-CHS and nat-CHS on the molecular organization of DOPE/SPM monolayers at the air/water interface. The isotherm data showed that ent-CHS condensed DOPE/SPM monolayer equivalently to nat-CHS at a 20% concentration, but slightly less at a 40% concentration. Atomic force microscopy (AFM images of DOPE/SPM membranes in the presence of ent-CHS or nat-CHS prepared with LB technique or vesicle deposition showed no significant difference in topographies, supporting the interpretation that the differences in actions of nat-CHS and ent-CHS on BK channel are not likely from a generalized action on bilayers. We conclude that membrane cholesterol influences ethanol's modulation of BK in a complex manner, including an interaction with the channel protein

Efficacy of levofloxacin in the treatment of BK viremia: a multicenter, double-blinded, randomized, placebo-controlled trial.

Science.gov (United States)

Lee, Belinda T; Gabardi, Steven; Grafals, Monica; Hofmann, R Michael; Akalin, Enver; Aljanabi, Aws; Mandelbrot, Didier A; Adey, Deborah B; Heher, Eliot; Fan, Pang-Yen; Conte, Sarah; Dyer-Ward, Christine; Chandraker, Anil

2014-03-01

BK virus reactivation in kidney transplant recipients can lead to progressive allograft injury. Reduction of immunosuppression remains the cornerstone of treatment for active BK infection. Fluoroquinolone antibiotics are known to have in vitro antiviral properties, but the evidence for their use in patients with BK viremia is inconclusive. The objective of the study was to determine the efficacy of levofloxacin in the treatment of BK viremia. Enrollment in this prospective, multicenter, double-blinded, placebo-controlled trial occurred from July 2009 to March 2012. Thirty-nine kidney transplant recipients with BK viremia were randomly assigned to receive levofloxacin, 500 mg daily, or placebo for 30 days. Immunosuppression in all patients was adjusted on the basis of standard clinical practices at each institution. Plasma BK viral load and serum creatinine were measured monthly for 3 months and at 6 months. At the 3-month follow-up, the percentage reductions in BK viral load were 70.3% and 69.1% in the levofloxacin group and the placebo group, respectively (P=0.93). The percentage reductions in BK viral load were also equivalent at 1 month (58% versus and 67.1%; P=0.47) and 6 months (82.1% versus 90.5%; P=0.38). Linear regression analysis of serum creatinine versus time showed no difference in allograft function between the two study groups during the follow-up period. A 30-day course of levofloxacin does not significantly improve BK viral load reduction or allograft function when used in addition to overall reduction of immunosuppression.

Diagnosis of BK viral nephropathy in the renal allograft biopsy: role of fluorescence in situ hybridization.

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Wang, Zhen; Portier, Bryce P; Hu, Bo; Chiesa-Vottero, Andres; Myles, Jonathan; Procop, Gary W; Tubbs, Raymond R

2012-09-01

Early recognition of BK viral nephropathy is essential for successful management. Our aim in this study was to evaluate a novel fluorescence in situ hybridization (FISH) assay for detection of BK virus in renal transplant biopsies in the context of standard detection methods. Renal allograft biopsies (n = 108) were analyzed via H&E, immunohistochemistry (IHC) for simian virus 40, and FISH for BK virus. BK virus was detected in 16 (14.8%) cases by H&E, 13 (12%) cases by IHC, 18 (16.6%) cases by FISH, and 19 (17.6%) cases by real-time PCR; 24 of 108 showed a discrepancy in ≥1 testing modalities. Comparison of H&E, IHC, and FISH showed no statistical difference in detection of BK virus. However, performing comparisons between the different tissue-based assays in the context of plasma or urine real-time PCR results showed significant improvement in detection of BK by FISH over H&E (P = 0.02) but not IHC (P = 0.07). This novel FISH-based approach for BK virus identification in renal allograft biopsy tissue mirrored real-time PCR results and showed superior performance to detection of inclusions by H&E. Therefore, use of FISH for BK virus detection in the setting of renal allograft biopsy is a useful and sensitive detection method and could be adopted in any laboratory that currently performs FISH analysis. Copyright © 2012 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Identification of pyrolysis products of the new psychoactive substance 2-amino-1-(4-bromo-2,5-dimethoxyphenyl)ethanone hydrochloride (bk-2C-B) and its iodo analogue bk-2C-I.

Science.gov (United States)

Texter, Kelly B; Waymach, Rachel; Kavanagh, Pierce V; O'Brien, John E; Talbot, Brian; Brandt, Simon D; Gardner, Elizabeth A

2018-01-01

2-Amino-1-(4-bromo-2,5-dimethoxyphenyl)ethanone hydrochloride (bk-2C-B) has recently emerged as a new psychoactive substance (NPS). It is most commonly consumed orally, although there are indications that it might also be ingested by inhalation or 'smoking'. Information about the stability of bk-2C-B when exposed to heat is unavailable and the potential for pyrolytic degradation and formation of unknown substances available for inhalation prompted an investigation using a simulated 'meth pipe' scenario. Twelve products following pyrolysis of bk-2C-B were detected and verified by organic synthesis of the corresponding standards. In addition, 2-amino-1-(4-iodo-2,5-dimethoxyphenyl)ethanone hydrochloride (bk-2C-I) was characterized for the first time and subjected to pyrolysis as well. Similar products were formed, which indicated that the replacement of the bromo with the iodo substituent did not affect the pyrolysis pattern under the conditions used. Two additional products were detected in the bk-2C-I pyrolates, namely 1-(2,5-dimethoxyphenyl)-ethanone and 1-iodo-4-ethenyl-5-methoxyphenol. The potential ingestion of pyrolysis products with unknown toxicity adds an element of concern. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Time-resolved resonance Raman spectroscopy of intermediates of bacteriorhodopsin: The bK(590) intermediate.

Science.gov (United States)

Terner, J; Hsieh, C L; Burns, A R; El-Sayed, M A

1979-07-01

We have combined microbeam and flow techniques with computer subtraction methods to obtain the resonance Raman spectrum of the short lived batho-intermediate (bK(590)) of bacteriorhodopsin. Comparison of the spectra obtained in (1)H(2)O and (2)H(2)O, as well as the fact that the bK(590) intermediate shows large optical red shifts, suggests that the Schiff base linkage of this intermediate is protonated. The fingerprint region of the spectrum of bK(590), sensitive to the isomeric configuration of the retinal chromophore, does not resemble the corresponding region of the parent bR(570) form. The resonance Raman spectrum of bK(590) as well as the spectra of all of the other main intermediates in the photoreaction cycle of bacteriorhodopsin are discussed and compared with resonance Raman spectra of published model compounds.

Molecular Mechanisms Underlying Renin-Angiotensin-Aldosterone System Mediated Regulation of BK Channels

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Zhen-Ye Zhang

2017-09-01

Full Text Available Large-conductance calcium-activated potassium channels (BK channels belong to a family of Ca2+-sensitive voltage-dependent potassium channels and play a vital role in various physiological activities in the human body. The renin-angiotensin-aldosterone system is acknowledged as being vital in the body's hormone system and plays a fundamental role in the maintenance of water and electrolyte balance and blood pressure regulation. There is growing evidence that the renin-angiotensin-aldosterone system has profound influences on the expression and bioactivity of BK channels. In this review, we focus on the molecular mechanisms underlying the regulation of BK channels mediated by the renin-angiotensin-aldosterone system and its potential as a target for clinical drugs.

Surveillance of polyomavirus BK in relation to immunosuppressive therapy in kidney transplantation

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Cristina Costa

2012-03-01

Full Text Available Introduction. Reactivation of polyomavirus BK in kidney transplant recipients has been associated to the development of nephropathy (polyomavirus-associated nephropathy, PVAN, possibly leading to the loss of the transplanted organ. Immunosuppression is the condicio sine qua non for the onset of PVAN; however, a lower incidence of BK viremia has been reported with low-level tacrolimus based immunosuppressive protocols in comparison to cyclosporine A.Aim of this study was to compare the two immunosuppressive protocols. Methods. Virological monitoring of BK was performed in 468 consecutive renal transplant patients over a period of 3 years (2370 urine e 2370 serum specimens: in particular, 1780 specimens from 362 patients treated with tacrolimus and 590 from 106 treated with cyclosporine A. Results. BK viremia was evidenced in 124 (7.0% and 12 (2.0% specimens from 40 (11.0% and 11 (10.4% patients treated with tacrolimus and cyclosporine A, respectively; similarly, BK viruria in 289 (16.2% and 58 (9.8% specimens from 67 (18.5% and 27 (25.5% patients, being the difference of incidence highly significant (p <0.0001 for both viremia and viruria at comparison between specimens and not significant for patients. No case of PVAN was diagnosed at histophatology evaluation. Conclusions. The incidence of viremia and viruria was similar to that previously reported. Our results evidenced that with low-level tacrolimus-based protocols the overall incidence of reactivation in renal transplant patients is not significantly different and there is no increased risk of PVAN, nevertheless the higher incidence of episodes of reactivation.

Physiologically-based PK/PD modelling of therapeutic macromolecules.

Science.gov (United States)

Thygesen, Peter; Macheras, Panos; Van Peer, Achiel

2009-12-01

Therapeutic proteins are a diverse class of drugs consisting of naturally occurring or modified proteins, and due to their size and physico-chemical properties, they can pose challenges for the pharmacokinetic and pharmacodynamic studies. Physiologically-based pharmacokinetics (PBPK) modelling has been effective for early in silico prediction of pharmacokinetic properties of new drugs. The aim of the present workshop was to discuss the feasibility of PBPK modelling of macromolecules. The classical PBPK approach was discussed with a presentation of the successful example of PBPK modelling of cyclosporine A. PBPK model was performed with transport of the cyclosporine across cell membranes, affinity to plasma proteins and active membrane transporters included to describe drug transport between physiological compartments. For macromolecules, complex PBPK modelling or permeability-limited and/or target-mediated distribution was discussed. It was generally agreed that PBPK modelling was feasible and desirable. The role of the lymphatic system should be considered when absorption after extravascular administration is modelled. Target-mediated drug disposition was regarded as an important feature for generation of PK models. Complex PK-models may not be necessary when a limited number of organs are affected. More mechanistic PK/PD models will be relevant when adverse events/toxicity are included in the PK/PD modelling.

Persepsi Guru BK Tentang Kompetensi Konselor di Sekolah Dasar Swasta Kota Semarang

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Restu Setyoningtyas

2014-10-01

Full Text Available Tujuan penelitian ini adalah untuk mengetahui tentang persepsi guru BK tentang kompetensi konselor di sekolah dasar swasta Kota Semarang. Penelitian ini bersifat kuantitatif, responden penelitian adalah guru BK sekolah dasar swasta, teknik pengumpulan data berupa skala psikologi dan dokumentasi. Analisis data menggunakan Analisis Deskriptif Persentase. Hasil penelitian menunjukkan persepsi guru BK tentang kompetensi konselor mendapatkan hasil yang positif. Kompetensi pedagogik yaitu positif, kepribadian yaitu kurang positif, sosial yaitu kurang positif, profesional yaitu cukup positif. Kesimpulan dari penelitian ini adalah persepsi guru BK tentang kompetensi konselor di sekolah dasar swasta Kota Semarang pada umumnya positif. The purpose of this research is determine perception guidance and counseling teacher about counselor competence in private elementary school on Semarang city. This research is quantitative. Respondens is guidance and counseling teacher from private elementary school, techniques of data collection are psychology scale and documentation. The data analysis using Analysis Descriptive Percentage. Result showed that research is perception  guidance and counseling teacher about counselor competence is positive. Pedagogic competence is positive, personality is not positive enough, social is not positive enough, professional is positive enough. The conclusion of this research is perception guidance and counseling teacher about counselor competence in private elementary school on Semarang city in general is positive.

PK/DB: database for pharmacokinetic properties and predictive in silico ADME models.

Science.gov (United States)

Moda, Tiago L; Torres, Leonardo G; Carrara, Alexandre E; Andricopulo, Adriano D

2008-10-01

The study of pharmacokinetic properties (PK) is of great importance in drug discovery and development. In the present work, PK/DB (a new freely available database for PK) was designed with the aim of creating robust databases for pharmacokinetic studies and in silico absorption, distribution, metabolism and excretion (ADME) prediction. Comprehensive, web-based and easy to access, PK/DB manages 1203 compounds which represent 2973 pharmacokinetic measurements, including five models for in silico ADME prediction (human intestinal absorption, human oral bioavailability, plasma protein binding, blood-brain barrier and water solubility). http://www.pkdb.ifsc.usp.br

OLYMPUS: an automated hybrid clustering method in time series gene expression. Case study: host response after Influenza A (H1N1) infection.

Science.gov (United States)

Dimitrakopoulou, Konstantina; Vrahatis, Aristidis G; Wilk, Esther; Tsakalidis, Athanasios K; Bezerianos, Anastasios

2013-09-01

The increasing flow of short time series microarray experiments for the study of dynamic cellular processes poses the need for efficient clustering tools. These tools must deal with three primary issues: first, to consider the multi-functionality of genes; second, to evaluate the similarity of the relative change of amplitude in the time domain rather than the absolute values; third, to cope with the constraints of conventional clustering algorithms such as the assignment of the appropriate cluster number. To address these, we propose OLYMPUS, a novel unsupervised clustering algorithm that integrates Differential Evolution (DE) method into Fuzzy Short Time Series (FSTS) algorithm with the scope to utilize efficiently the information of population of the first and enhance the performance of the latter. Our hybrid approach provides sets of genes that enable the deciphering of distinct phases in dynamic cellular processes. We proved the efficiency of OLYMPUS on synthetic as well as on experimental data. The discriminative power of OLYMPUS provided clusters, which refined the so far perspective of the dynamics of host response mechanisms to Influenza A (H1N1). Our kinetic model sets a timeline for several pathways and cell populations, implicated to participate in host response; yet no timeline was assigned to them (e.g. cell cycle, homeostasis). Regarding the activity of B cells, our approach revealed that some antibody-related mechanisms remain activated until day 60 post infection. The Matlab codes for implementing OLYMPUS, as well as example datasets, are freely accessible via the Web (http://biosignal.med.upatras.gr/wordpress/biosignal/). Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Impact of Shed/Soluble targets on the PK/PD of approved therapeutic monoclonal antibodies.

Science.gov (United States)

Samineni, Divya; Girish, Sandhya; Li, Chunze

2016-12-01

Suboptimal treatment for monoclonal antibodies (mAbs) directed against endogenous circulating soluble targets and the shed extracellular domains (ECD) of the membrane-bound targets is an important clinical concern due to the potential impact of mAbs on the in vivo efficacy and safety. Consequently, there are considerable challenges in the determination of an optimal dose and/or dosing regimen. Areas covered: This review outlines the impact of shed antigen targets from membrane-bound proteins and soluble targets on the PK and/or PD of therapeutic mAbs that have been approved in the last decade. We discuss various bioanalytical techniques that have facilitated the interpretation of the PK/PD properties of therapeutic mAbs and also considered the factors that may impact such measurements. Quantitative approaches include target-mediated PK models and bi- or tri-molecular interaction PK/PD models that describe the relationships between the antibody PK and the ensuing effects on PD biomarkers, to facilitate the mAb PK/PD characterization. Expert commentary: The proper interpretation of PK/PD relationships through the integrated PK/PD modeling and bioanalytical strategy facilitates a mechanistic understanding of the disease processes and dosing regimen optimization, thereby offering insights into developing effective therapeutic regimens. This review provides an overview of the impact of soluble targets or shed ECD on mAb PK/PD properties. We provide examples of quantitative approaches that facilitate the characterization of mAb PK/PD characteristics and their corresponding bioanalytical strategies.

Cytotoxic effects of 125I-labeled PBZr ligand PK 11195 in prostatic tumor cells: therapeutic implications

International Nuclear Information System (INIS)

Alenfall, J.; Kant, R.; Batra, S.

1998-01-01

The effect of [ 125 I]PK 11195 was examined in human prostatic tumor cells (DU 145) in culture and compared with Na[ 125 I] and non-radioactive PK 11195. [ 125 I]PK 11195 was clearly cytocidal. The data for dose-related cell survival with [ 125 I]PK 11195 showed a linear relationship. Na[ 125 I] or non-labeled PK 11195 at similar concentrations did not lead to any cell killing. The uptake of [ 125 I]PK 11195 and [ 3 H]PK 11195 in cells was very similar. Fragmentation of DNA measured by agarose gel electrophoresis showed that exposure of DU 145 cells to [ 125 I]PK 11195 for 1, 4 or 24 h caused no fragmentation. These results indicate that nuclear DNA is not the prime binding site for [ 125 I]PK 11195, which is consistent with the presence of specific peripheral benzodiazepine receptors (PBZr) in the mitochondria. The cell killing effect of [ 125 I]PK 11195 suggests the use of PBZr ligand for radiotherapy

Pemahaman Guru BK Tentang Pelaksanaan Layanan Peminatan pada Kurikulum 2013

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Finda Marsetyana

2015-04-01

Full Text Available Penelitian ini dilakukan berdasar fenomena yaitu belum adanya kesiapan tentang program peminatan di SMK Negeri se-Kota Semarang. Tujuan penelitian secara umum untuk mengetahui pemahaman guru BK tentang pelaksanaan layanan peminatan pada kurikulum 2013 di SMK Negeri se-Kota Semarang. Medote pengumpulan data yaitu angket tertutup yang diberikan kepada 44 orang guru BK SMK Negeri se Kota Semarang. Analisis data menggunakan analisis deskriptif persentase. Hasil penelitian dari Pemahaman Guru BK Tentang Pelaksanaan Layanan Peminatan Pada Kurikulum 2013 Di SMK Negeri Se-Kota Semarang termasuk dalam kategori tinggi (71.59% dengan perincian indikator variabel yaitu pemahaman guru BK tentang kurikulum 2013 persentase sebesar 75.04% (tinggi, konsep dan strategi pelayanan bimbingan dan konseling pada kurikulum 2013 sebesar 69.31% (sedang, lingkup layanan peminatan sebesar 70.57% (tinggi, dan pelaksanaan layanan peminatan 72.22% (tinggi. Simpulan penelitian ini yakni guru BK SMK Negeri se-Kota Semarang telah mempunyai pemahaman tentang pelaksanaan layanan peminatan pada kurikulum 2013 dengan kriteria tinggi. This research was conducted based on the phenomenon that is there was no readiness about the students’ interest program vocational high schools in around Semarang.The general objective of this research was to know the counseling’s teachers deals with the implementation of students’ interest service towards the 2013 curriculum vocational high schools in around Semarang. Method of data collection is used closed questionnaire and it was given to 44 students vocational high schools in around Semarang in which the data obtained was analysed trough descriptive percentages. The research finding from counseling’s teachers about the implementation of students’ interest in the 2013 curriculum vocational high schools in around Semarang are in a high category (71.59%, with the details of the indicator variable are as follows; the understanding of

Coincident In Vitro Analysis of DNA-PK-Dependent and -Independent Nonhomologous End Joining

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Cynthia L. Hendrickson

2010-01-01

Full Text Available In mammalian cells, DNA double-strand breaks (DSBs are primarily repaired by nonhomologous end joining (NHEJ. The current model suggests that the Ku 70/80 heterodimer binds to DSB ends and recruits DNA-PKcs to form the active DNA-dependent protein kinase, DNA-PK. Subsequently, XRCC4, DNA ligase IV, XLF and most likely, other unidentified components participate in the final DSB ligation step. Therefore, DNA-PK plays a key role in NHEJ due to its structural and regulatory functions that mediate DSB end joining. However, recent studies show that additional DNA-PK-independent NHEJ pathways also exist. Unfortunately, the presence of DNA-PKcs appears to inhibit DNA-PK-independent NHEJ, and in vitro analysis of DNA-PK-independent NHEJ in the presence of the DNA-PKcs protein remains problematic. We have developed an in vitro assay that is preferentially active for DNA-PK-independent DSB repair based solely on its reaction conditions, facilitating coincident differential biochemical analysis of the two pathways. The results indicate the biochemically distinct nature of the end-joining mechanisms represented by the DNA-PK-dependent and -independent NHEJ assays as well as functional differences between the two pathways.

Imipenem in burn patients: pharmacokinetic profile and PK/PD target attainment.

Science.gov (United States)

Gomez, David S; Sanches-Giraud, Cristina; Silva, Carlindo V; Oliveira, Amanda M Ribas Rosa; da Silva, Joao Manoel; Gemperli, Rolf; Santos, Silvia R C J

2015-03-01

Unpredictable pharmacokinetics (PK) in burn patients may result in plasma concentrations below concentrations that are effective against common pathogens. The present study evaluated the imipenem PK profile and pharmacokinetic/pharmacodynamics (PK/PD) correlation in burn patients. Fifty-one burn patients, 38.7 years of age (mean), 68.0 kg, 36.3% total burn surface area (TBSA), of whom 84% (43/51) exhibited thermal injury, 63% inhalation injury and 16% electrical injury (8/51), all of whom were receiving imipenem treatment were investigated. Drug plasma monitoring, PK study (120 sets of plasma levels) and PK/PD correlation were performed in a series of blood samples. Only 250 μl of plasma samples were required for drug plasma measurements using the ultra filtration technique for the purification of biological matrix and quantification using liquid chromatography. Probability of target attainment (PTA) was calculated using a PD target of 40% free drug concentrations above the minimum inhibitory concentration (40%fT>MIC). Significant differences in PK parameters (medians), such as biological half-life (2.2 vs 5.5 h), plasma clearance (16.2 vs 1.4 l h(-1)) and volume of distribution (0.86 vs 0.19 l kg(-1)), were registered in burn patients via comparisons of set periods with normal renal function against periods of renal failure. Correlations between creatinine clearance and total body plasma clearance were also obtained. In addition, the PK profile did not change according to TBSA during sets when renal function was preserved. PTA was >89% for MIC values up to 4 mg l(-1). In conclusion, imipenem efficacy for the control of hospital infection on the basis of PK/PD correlation was guaranteed for burn in patients at the recommended dose regimens for normal renal function (31.1±9.7 mg kg(-1) daily), but the daily dose must be reduced to 17.2±9.7 mg kg(-1) during renal failure to avoid neurotoxicity.

OLYMPUS DISS - A Readily Implemented Geographic Data and Information Sharing System

Science.gov (United States)

Necsoiu, D. M.; Winfrey, B.; Murphy, K.; McKague, H. L.

2002-12-01

Electronic information technology has become a crucial component of business, government, and scientific organizations. In this technology era, many enterprises are moving away from the perception that information repositories are only a tool for decision-making. Instead, many organizations are learning that information systems, which are capable of organizing and following the interrelations between information and both the short-term and strategic organizational goals, are assets themselves, with inherent value. Olympus Data and Information Sharing System (DISS) is a system developed at the Center for Nuclear Waste Regulatory Analyses (CNWRA) to solve several difficult tasks associated with the management of geographical, geological and geophysical data. Three of the tasks were to (1) gather the large amount of heterogeneous information that has accumulated over the operational lifespan of CNWRA, (2) store the data in a central, knowledge-based, searchable database and (3) create quick, easy, convenient, and reliable access to that information. Faced with these difficult tasks CNWRA identified the requirements for designing such a system. Key design criteria were: (a) ability to ingest different data formats (i.e., raster, vector, and tabular data); (b) minimal expense using open-source and commercial off-the-shelf software; (c) seamless management of geospatial data, freeing up time for researchers to focus on analyses or algorithm development, rather than on time consuming format conversions; (d) controlled access; and (e) scalable architecture to meet new and continuing demands. Olympus DISS is a solution that can be easily adapted to small and mid-size enterprises dealing with heterogeneous geographic data. It uses established data standards, provides a flexible mechanism to build applications upon and output geographic data in multiple and clear ways. This abstract is an independent product of the CNWRA and does not necessarily reflect the views or

Hard two-photon contribution to elastic lepton-proton scattering determined by the OLYMPUS experiment

Energy Technology Data Exchange (ETDEWEB)

Henderson, B.S. [Massachusetts Institute of Technology, Cambridge, MA (United States); Ice, L.D. [Arizona State Univ., Tempe, AZ (United States); Khaneft, D. [Mainz Univ. (Germany); Collaboration: OLYMPUS Collaboration; and others

2016-12-15

The OLYMPUS collaboration reports on a precision measurement of the positron-proton to electron-proton elastic cross section ratio, R{sub 2γ}, a direct measure of the contribution of hard two- photon exchange to the elastic cross section. In the OLYMPUS measurement, 2.01 GeV electron and positron beams were directed through a hydrogen gas target internal to the DORIS storage ring at DESY. A toroidal magnetic spectrometer instrumented with drift chambers and time-of-flight scintillators detected elastically scattered leptons in coincidence with recoiling protons over a scattering angle range of ∼20 to 80 . The relative luminosity between the two beam species was monitored using tracking telescopes of interleaved GEM and MWPC detectors at 12 , as well as symmetric Moeller/Bhabha calorimeters at 1.29 . A total integrated luminosity of 4.5 fb{sup -1} was collected. In the extraction of R{sub 2γ}, radiative effects were taken into account using a Monte Carlo generator to simulate the convolutions of internal bremsstrahlung with experiment-specific conditions such as detector acceptance and reconstruction efficiency. The resulting values of R{sub 2γ}, presented here for a wide range of virtual photon polarization 0.456<ε<0.978, are smaller than some hadronic two-photon exchange calculations predict, but are in reasonable agreement with a subtracted dispersion model and a phenomenological fit to the form factor data.

Faktor-Faktor Hambatan Profesionalisasi Guru BK di SMA Negeri se- Kota Purwokerto

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Cahya Dewi Rizkiwati

2014-10-01

Full Text Available Tujuan penelitian ini yaitu untuk mendeskripsikan tentang faktor-faktor hambatan yang terjadi dalam profesionalisasi guru BK. Jenis penelitian ini merupakan penelitian survey. Penelitian ini dilaksanakan di SMA Negeri se-Kota Purwokerto. Penelitian ini adalah penelitian populasi atau sensus karena populasi guru BK berjumlah 25 orang. Metode yang digunakan dalam penelitian ini adalah  inventori dalam bentuk daftar cek masalah. Instrumen tersebut telah diuji validitasnya menggunakan rumus point biserial, sedangkan reliabilitas instrumen digunakan rumus KR-20. Data yang telah diperoleh dianalisis dengan menggunakan teknik deskriptif prosentase. Hasil dari penelitian ini menunjukkan hambatan yang berasal dari faktor internal mendapat prosentase lebih tinggi daripada faktor eksternal. Faktor internal yang paling mempengaruhi profesionalisasi guru BK antara lain latar belakang pendidikan, pengalaman kerja, motivasi kerja, kompetensi guru BK. Sedangkan faktor eksternal yang paling mempengaruhi profesionalisasi guru BK adalah sarana dan prasarana. The purpose of this research is to describe problems  occur in the professionalization of guidance and counseling teachers. The type of the research is survey research . This research was conducted in all of Senior High School in Purwokerto. Population research or census were used as sampling method, since  the population of guidance and counseling teachers were 25 people. Data collection technique was  using inventory with list of issues. The instrument validity has been tested using point biserial formula, whilst its reliability was tested using KR-20 formula. The data was analyzed using descriptive percentage techniques. The results of this research indicate that internal factors get higher percentage than external factors. Internal factors that have the most influence in the professionalization of guidance and counseling teachers include educational background, working experience , motivation, teacher�

Molecular investigations of BK(Ca) channels and the modulatory beta-subunits in porcine basilar and middle cerebral arteries

DEFF Research Database (Denmark)

Johansson, Helle Wulf; Hay-Schmidt, Anders; Poulsen, Asser Nyander

2009-01-01

arteries using reverse transcription polymerase chain reaction (RT-PCR) and quantitative real-time PCR. Western blotting was used to detect immunoreactivity for the porcine BK(Ca) channel alpha-subunit and beta-subunit proteins. The BK(Ca) channel alpha-subunit RNA and protein distribution patterns were......Large conductance calcium-activated potassium (BK(Ca)) channels are fundamental in the regulation of cerebral vascular basal tone. We investigated the expression of the mRNA transcripts for the BK(Ca) channel and its modulatory beta-subunits (beta1-beta4) in porcine basilar and middle cerebral...... visualized using in situ hybridization and immunofluorescence studies, respectively. The study verified that the BK(Ca) channel alpha-subunit is located to smooth muscle cells of porcine basilar and middle cerebral arteries. The mRNA transcript for beta1-, beta2- and beta4-subunit were shown by RT...

Synthesis and characterization of [11C]PK11195 as a PET radiopharmaceutical

International Nuclear Information System (INIS)

Almeida, Fernanda A. F.; Silveira, Marina B.; Oliveira, Amanda P.; Nascimento, Leonardo T.C.; Silva, Juliana B.; Mamede, Marcelo

2017-01-01

The radiopharmaceutical [ 11 C]PK11195 has been used for Positron Emission Tomography (PET) imaging of neuroinflammatory diseases. PK11195 is a tracer that binds to the benzodiazepine peripheral receptor (PBR) currently known as membrane translocator protein (TSPO). [ 11 C]PK11195 is differentially accumulated in tissues which have high TSPO expression, typically microglia activation in brain tissue, which has normally low TSPO expression. The aim of this work was to synthesize and characterize [ 11 C]PK11195 at the Radiopharmaceutical Production Unit of CDTN to make it available for future studies and applications in major brain inflammatory diseases. The [ 11 C]PK11195 syntheses were performed using Tracerlab™ FXC PRO (GE) by [ 11 C]methylation of the precursor (R)-[N-desmethyl] PK11195. Optimizations of the reaction conditions for the synthesis of [ 11 C]PK11195 were: Anhydrous dimethylsulfoxide (DMSO) volume, mass of precursor, and potassium hydroxide (KOH), labelling reaction temperature and time. After comparison of the results obtained for each condition evaluated, the standard best reaction parameters were defined as: 1mg of the precursor dissolved in 300 μL of DMSO (anhydrous); 10-15mg of KOH; and labeling reaction temperature of 40°C during 2 minutes. The total synthesis time was 40 minutes and the mean non-decay-corrected radiochemical yield was 10.93 ± 3.44%. All quality control criteria were met according to previous specifications. (author)

Small molecules, inhibitors of DNA-PK, targeting DNA repair and beyond

Directory of Open Access Journals (Sweden)

David eDavidson

2013-01-01

Full Text Available Many current chemotherapies function by damaging genomic DNA in rapidly dividing cells ultimately leading to cell death. This therapeutic approach differentially targets cancer cells that generally display rapid cell division compared to normal tissue cells. However, although these treatments are initially effective in arresting tumor growth and reducing tumor burden, resistance and disease progression eventually occur. A major mechanism underlying this resistance is increased levels of cellular DNA repair. Most cells have complex mechanisms in place to repair DNA damage that occurs due to environmental exposures or normal metabolic processes. These systems, initially overwhelmed when faced with chemotherapy induced DNA damage, become more efficient under constant selective pressure and as a result chemotherapies become less effective. Thus, inhibiting DNA repair pathways using target specific small molecule inhibitors may overcome cellular resistance to DNA damaging chemotherapies. Non-homologous end joining (NHEJ a major mechanism for the repair of double strand breaks (DSB in DNA is regulated in part by the serine/threonine kinase, DNA dependent protein kinase (DNA-PK. The DNA-PK holoenzyme acts as a scaffold protein tethering broken DNA ends and recruiting other repair molecules. It also has enzymatic activity that may be involved in DNA damage signaling. Because of its’ central role in repair of DSBs, DNA-PK has been the focus of a number of small molecule studies. In these studies specific DNA-PK inhibitors have shown efficacy in synergizing chemotherapies in vitro. However, compounds currently known to specifically inhibit DNA-PK are limited by poor pharmacokinetics: these compounds have poor solubility and have high metabolic lability in vivo leading to short serum half-lives. Future improvement in DNA-PK inhibition will likely be achieved by designing new molecules based on the recently reported crystallographic structure of DNA-PK

Characterization of CoPK02, a Ca2+/calmodulin-dependent protein kinase in mushroom Coprinopsis cinerea.

Science.gov (United States)

Yamashita, Masashi; Sueyoshi, Noriyuki; Yamada, Hiroki; Katayama, Syouichi; Senga, Yukako; Takenaka, Yasuhiro; Ishida, Atsuhiko; Kameshita, Isamu; Shigeri, Yasushi

2018-04-20

We surveyed genome sequences from the basidiomycetous mushroom Coprinopsis cinerea and isolated a cDNA homologous to CMKA, a calmodulin-dependent protein kinase (CaMK) in Aspergillus nidulans. We designated this sequence, encoding 580 amino acids with a molecular weight of 63,987, as CoPK02. CoPK02 possessed twelve subdomains specific to protein kinases and exhibited 43, 35, 40% identity with rat CaMKI, CaMKII, CaMKIV, respectively, and 40% identity with CoPK12, one of the CaMK orthologs in C. cinerea. CoPK02 showed significant autophosphorylation activity and phosphorylated exogenous proteins in the presence of Ca 2+ /CaM. By the CaM-overlay assay we confirmed that the C-terminal sequence (Trp346-Arg358) was the calmodulin-binding site, and that the binding of Ca 2+ /CaM to CoPK02 was reduced by the autophosphorylation of CoPK02. Since CoPK02 evolved in a different clade from CoPK12, and showed different gene expression compared to that of CoPK32, which is homologous to mitogen-activated protein kinase-activated protein kinase, CoPK02 and CoPK12 might cooperatively regulate Ca 2+ -signaling in C. cinerea.

MIDAS/PK code development using point kinetics model

International Nuclear Information System (INIS)

Song, Y. M.; Park, S. H.

1999-01-01

In this study, a MIDAS/PK code has been developed for analyzing the ATWS (Anticipated Transients Without Scram) which can be one of severe accident initiating events. The MIDAS is an integrated computer code based on the MELCOR code to develop a severe accident risk reduction strategy by Korea Atomic Energy Research Institute. In the mean time, the Chexal-Layman correlation in the current MELCOR, which was developed under a BWR condition, is appeared to be inappropriate for a PWR. So as to provide ATWS analysis capability to the MIDAS code, a point kinetics module, PKINETIC, has first been developed as a stand-alone code whose reference model was selected from the current accident analysis codes. In the next step, the MIDAS/PK code has been developed via coupling PKINETIC with the MIDAS code by inter-connecting several thermal hydraulic parameters between the two codes. Since the major concern in the ATWS analysis is the primary peak pressure during the early few minutes into the accident, the peak pressure from the PKINETIC module and the MIDAS/PK are compared with the RETRAN calculations showing a good agreement between them. The MIDAS/PK code is considered to be valuable for analyzing the plant response during ATWS deterministically, especially for the early domestic Westinghouse plants which rely on the operator procedure instead of an AMSAC (ATWS Mitigating System Actuation Circuitry) against ATWS. This capability of ATWS analysis is also important from the view point of accident management and mitigation

Diagnóstico y clasificación molecular del virus BK en receptores de trasplante renal

OpenAIRE

Riva, Omar; Cobos, Marisa; Raimondi, J. Clemente

2010-01-01

La infección primaria por virus BK ocurre durante la infancia permaneciendo latente en el tracto urogenital. En individuos que presentan alteraciones en la inmunidad celular, el virus se reactiva haciendo posible su detección en orina y sangre. En receptores de trasplante renal, la nefropatía producida por el virus BK puede llevar a la pérdida de la función del injerto. El virus BK es miembro de la familia Polyomaviridae, presenta un genoma de ADN circular doble cadena unido en forma covalent...

The RCK1 high-affinity Ca2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels.

Science.gov (United States)

Hou, Shangwei; Xu, Rong; Heinemann, Stefan H; Hoshi, Toshinori

2008-03-11

Carbon monoxide (CO) is a lethal gas, but it is also increasingly recognized as a physiological signaling molecule capable of regulating a variety of proteins. Among them, large-conductance Ca(2+)- and voltage-gated K(+) (Slo1 BK) channels, important in vasodilation and neuronal firing, have been suggested to be directly stimulated by CO. However, the molecular mechanism of the stimulatory action of CO on the Slo1 BK channel has not been clearly elucidated. We report here that CO reliably and repeatedly activates Slo1 BK channels in excised membrane patches in the absence of Ca(2+) in a voltage-sensor-independent manner. The stimulatory action of CO on the Slo1 BK channel requires an aspartic acid and two histidine residues located in the cytoplasmic RCK1 domain, and the effect persists under the conditions known to inhibit the conventional interaction between CO and heme in other proteins. We propose that CO acts as a partial agonist for the high-affinity divalent cation sensor in the RCK1 domain of the Slo1 BK channel.

Uptake of inflammatory cell marker [{sup 11}C]PK11195 into mouse atherosclerotic plaques

Energy Technology Data Exchange (ETDEWEB)

Laitinen, Iina; Marjamaeki, Paeivi; Naagren, Kjell; Roivainen, Anne; Knuuti, Juhani [University of Turku, Turku PET Centre, Turku (Finland); Laine, V.J.O. [Turku University Hospital, Department of Pathology, Turku (Finland); Wilson, Ian [GE Healthcare Biosciences, Medical Diagnostics, London (United Kingdom); Leppaenen, Pia; Ylae-Herttuala, Seppo [University of Kuopio, A.I. Virtanen Institute, Kuopio (Finland)

2009-01-15

The ligand [{sup 11}C]PK11195 binds with high affinity and selectivity to peripheral benzodiazepine receptor, expressed in high amounts in macrophages. In humans, [{sup 11}C]PK11195 has been used successfully for the in vivo imaging of inflammatory processes of brain tissue. The purpose of this study was to explore the feasibility of [{sup 11}C]PK11195 in imaging inflammation in the atherosclerotic plaques. The presence of PK11195 binding sites in the atherosclerotic plaques was verified by examining the in vitro binding of [{sup 3}H]PK11195 onto mouse aortic sections. Uptake of intravenously administered [{sup 11}C]PK11195 was studied ex vivo in excised tissue samples and aortic sections of a LDLR/ApoB48 atherosclerotic mice. Accumulation of the tracer was compared between the atherosclerotic plaques and non-atherosclerotic arterial sites by autoradiography and histological analyses. The [{sup 3}H]PK11195 was found to bind to both the atherosclerotic plaques and the healthy wall. The autoradiography analysis revealed that the uptake of [{sup 11}C]PK11195 to inflamed regions in plaques was more prominent (p = 0.011) than to non-inflamed plaque regions, but overall it was not higher than the uptake to the healthy vessel wall. Also, the accumulation of {sup 11}C radioactivity into the aorta of the atherosclerotic mice was not increased compared to the healthy control mice. Our results indicate that the uptake of [{sup 11}C]PK11195 is higher in inflamed atherosclerotic plaques containing a large number of inflammatory cells than in the non-inflamed plaques. However, the tracer uptake to other structures of the artery wall was also prominent and may limit the use of [{sup 11}C]PK11195 in clinical imaging of atherosclerotic plaques. (orig.)

Translational PK/PD of anti-infective therapeutics.

Science.gov (United States)

Rathi, Chetan; Lee, Richard E; Meibohm, Bernd

Translational PK/PD modeling has emerged as a critical technique for quantitative analysis of the relationship between dose, exposure and response of antibiotics. By combining model components for pharmacokinetics, bacterial growth kinetics and concentration-dependent drug effects, these models are able to quantitatively capture and simulate the complex interplay between antibiotic, bacterium and host organism. Fine-tuning of these basic model structures allows to further account for complicating factors such as resistance development, combination therapy, or host responses. With this tool set at hand, mechanism-based PK/PD modeling and simulation allows to develop optimal dosing regimens for novel and established antibiotics for maximum efficacy and minimal resistance development. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pharmacological considerations for predicting PK/PD at the site of action for therapeutic proteins.

Science.gov (United States)

Wang, Weirong; Zhou, Honghui

For therapeutic proteins whose sites of action are distal to the systemic circulation, both drug and target concentrations at the tissue sites are not necessarily proportional to those in systemic circulation, highlighting the importance of understanding pharmacokinetic/pharmacodynamic (PK/PD) relationship at the sites of action. This review summarizes the pharmacological considerations for predicting local PK/PD and the importance of measuring PK and PD at site of action. Three case examples are presented to show how mechanistic and physiologically based PK/PD (PBPK/PD) models which incorporated the PK and PD at the tissue site can be used to facilitate understanding the exposure-response relationship for therapeutic proteins. Copyright © 2016. Published by Elsevier Ltd.

In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195

Directory of Open Access Journals (Sweden)

Carlos Eduardo Sampaio Guedes

2018-02-01

Full Text Available BACKGROUND Leishmaniasis, one of the most neglected diseases, is a serious public health problem in many countries, including Brazil. Currently available treatments require long-term use and have serious side effects, necessitating the development of new therapeutic interventions. Because translocator protein (TSPO levels are reduced in Leishmania amazonensis-infected cells and because this protein participates in apoptosis and immunomodulation, TSPO represents a potential target for Leishmania chemotherapy. The present study evaluated PK11195, a ligand of this protein, as an anti-leishmanial agent. OBJECTIVE To evaluate the leishmanicidal activity of PK11195 against L. amazonensis in infected CBA mouse macrophages in vitro. METHODS The viability of axenic L. amazonensis, Leishmania major, and Leishmania braziliensis promastigotes was assessed after 48 h treatment with PK11195 (0.2-400 µM. Additionally, intracellular parasite viability was evaluated to determine IC50 values and the number of viable parasites in infected macrophages treated with PK11195 (50-100 µM. Infected macrophages were then treated with PK11195 (25-100 µM to determine the percentage of L. amazonensis-infected cells and the number of parasites per infected cell. Electron microscopy was used to investigate morphological changes caused by PK11195. The production of free oxygen radicals, nitric oxide, and pro-inflammatory cytokines was also evaluated in infected macrophages treated with PK11195 and primed or not primed with IFN-γ. FINDINGS Median IC50 values for PK11195 were 14.2 µM for L. amazonensis, 8.2 µM for L. major, and 3.5 µM for L. braziliensis. The selective index value for L. amazonensis was 13.7, indicating the safety of PK11195 for future testing in mammals. Time- and dose-dependent reductions in the percentage of infected macrophages, the number of parasites per infected macrophage, and the number of viable intracellular parasites were observed. Electron

Hard Two-Photon Contribution to Elastic Lepton-Proton Scattering Determined by the OLYMPUS Experiment

Science.gov (United States)

Henderson, B. S.; Ice, L. D.; Khaneft, D.; O'Connor, C.; Russell, R.; Schmidt, A.; Bernauer, J. C.; Kohl, M.; Akopov, N.; Alarcon, R.; Ates, O.; Avetisyan, A.; Beck, R.; Belostotski, S.; Bessuille, J.; Brinker, F.; Calarco, J. R.; Carassiti, V.; Cisbani, E.; Ciullo, G.; Contalbrigo, M.; de Leo, R.; Diefenbach, J.; Donnelly, T. W.; Dow, K.; Elbakian, G.; Eversheim, P. D.; Frullani, S.; Funke, Ch.; Gavrilov, G.; Gläser, B.; Görrissen, N.; Hasell, D. K.; Hauschildt, J.; Hoffmeister, Ph.; Holler, Y.; Ihloff, E.; Izotov, A.; Kaiser, R.; Karyan, G.; Kelsey, J.; Kiselev, A.; Klassen, P.; Krivshich, A.; Lehmann, I.; Lenisa, P.; Lenz, D.; Lumsden, S.; Ma, Y.; Maas, F.; Marukyan, H.; Miklukho, O.; Milner, R. G.; Movsisyan, A.; Murray, M.; Naryshkin, Y.; Perez Benito, R.; Perrino, R.; Redwine, R. P.; Rodríguez Piñeiro, D.; Rosner, G.; Schneekloth, U.; Seitz, B.; Statera, M.; Thiel, A.; Vardanyan, H.; Veretennikov, D.; Vidal, C.; Winnebeck, A.; Yeganov, V.; Olympus Collaboration

2017-03-01

The OLYMPUS Collaboration reports on a precision measurement of the positron-proton to electron-proton elastic cross section ratio, R2 γ , a direct measure of the contribution of hard two-photon exchange to the elastic cross section. In the OLYMPUS measurement, 2.01 GeV electron and positron beams were directed through a hydrogen gas target internal to the DORIS storage ring at DESY. A toroidal magnetic spectrometer instrumented with drift chambers and time-of-flight scintillators detected elastically scattered leptons in coincidence with recoiling protons over a scattering angle range of ≈20 ° to 80°. The relative luminosity between the two beam species was monitored using tracking telescopes of interleaved gas electron multiplier and multiwire proportional chamber detectors at 12°, as well as symmetric Møller or Bhabha calorimeters at 1.29°. A total integrated luminosity of 4.5 fb-1 was collected. In the extraction of R2 γ, radiative effects were taken into account using a Monte Carlo generator to simulate the convolutions of internal bremsstrahlung with experiment-specific conditions such as detector acceptance and reconstruction efficiency. The resulting values of R2 γ, presented here for a wide range of virtual photon polarization 0.456 <ɛ <0.978 , are smaller than some hadronic two-photon exchange calculations predict, but are in reasonable agreement with a subtracted dispersion model and a phenomenological fit to the form factor data.

Levels of 250Cf populated in the decay of 250Bk

International Nuclear Information System (INIS)

Uecke, J.W.

1975-06-01

The nuclide 250 Bk undergoes β-decay with a half-life of 3.2 h to 13.1 y 250 Cf. A study is undertaken of the excited states in 250 Cf populated by 250 Bk decay which results from the α-decay of 276d 254 Es. The general features of published level schemes for these nuclei are consistent with predictions of the Nilsson and collective models; however, there remain many undiscovered transitions and ambiguous or uncertain level assignments. In an attempt to confirm predictions of current theoretical models which account for nuclear level assignments in this nucleus, these gamma transitions and their levels have been studied. Twenty-eight new γ-rays were determined. The decay of 250 Bk is investigated primarily by high resolution gamma-ray singles spectrometry and supported in part by two-parameter gamma-gamma coincidence spectrometry. The equipment, comprised of a Ge(HP) and a large volume Ge(Li) detector, a 4096-channel two-parameter analyzer, and a PDP-8/e computer system, permitted significant improvement in sensitivity and accuracy over previous investigations on this nucleus. (11 figures, 2 tables) (U.S.)

Characterization of self-assembled virus-like particles of human polyomavirus BK generated by recombinant baculoviruses

International Nuclear Information System (INIS)

Li, T.-C.; Takeda, Naokazu; Kato, Kenzo; Nilsson, Josefina; Xing Li; Haag, Lars; Cheng, R. Holland; Miyamura, Tatsuo

2003-01-01

The major structural protein of the human polyomavirus BK (BKV), VP1, was expressed by using recombinant baculoviruses. A large amount of protein with a molecular mass of about 42 kDa was synthesized and identified by Western blotting. The protein was detected exclusively in the nuclei by immunofluorescent analysis and it was released into culture medium. The expressed BKV VP1 protein was self-assembled into virus-like particles (BK-VLPs) with two different sizes (50 and 26 nm in diameter), which migrated into four different bands in CsCl gradient with buoyant densities of 1.29, 1.30, 1.33, and 1.35 g/cm 3 . The immunological studies on the BK-VLPs suggested that they have similar antigenicity with those of authentic BKV particles. Cryoelectron microscopy and 3D image analysis further revealed that the larger BK-VLPs were composed of 72 capsomers which all were pentamers arranged in a T = 7 surface lattice. This system provides useful information for detailed studies of viral morphogenesis and the structural basis for the antigenicity of BKV

Synthesis and characterization of [{sup 11}C]PK11195 as a PET radiopharmaceutical

Energy Technology Data Exchange (ETDEWEB)

Almeida, Fernanda A. F.; Silveira, Marina B.; Oliveira, Amanda P.; Nascimento, Leonardo T.C.; Silva, Juliana B.; Mamede, Marcelo, E-mail: nanda10a@gmail.com, E-mail: mamede.mm@gmail.com [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizontge, MG (Brazil). Unidade de Pesquisa e Produção de Radiofármacos

2017-07-01

The radiopharmaceutical [{sup 11}C]PK11195 has been used for Positron Emission Tomography (PET) imaging of neuroinflammatory diseases. PK11195 is a tracer that binds to the benzodiazepine peripheral receptor (PBR) currently known as membrane translocator protein (TSPO). [{sup 11}C]PK11195 is differentially accumulated in tissues which have high TSPO expression, typically microglia activation in brain tissue, which has normally low TSPO expression. The aim of this work was to synthesize and characterize [{sup 11}C]PK11195 at the Radiopharmaceutical Production Unit of CDTN to make it available for future studies and applications in major brain inflammatory diseases. The [{sup 11}C]PK11195 syntheses were performed using Tracerlab™ FXC PRO (GE) by [{sup 11}C]methylation of the precursor (R)-[N-desmethyl] PK11195. Optimizations of the reaction conditions for the synthesis of [{sup 11}C]PK11195 were: Anhydrous dimethylsulfoxide (DMSO) volume, mass of precursor, and potassium hydroxide (KOH), labelling reaction temperature and time. After comparison of the results obtained for each condition evaluated, the standard best reaction parameters were defined as: 1mg of the precursor dissolved in 300 μL of DMSO (anhydrous); 10-15mg of KOH; and labeling reaction temperature of 40°C during 2 minutes. The total synthesis time was 40 minutes and the mean non-decay-corrected radiochemical yield was 10.93 ± 3.44%. All quality control criteria were met according to previous specifications. (author)

Applications of the pharmacokinetic/pharmacodynamic (PK/PD) analysis of antimicrobial agents.

Science.gov (United States)

Asín-Prieto, Eduardo; Rodríguez-Gascón, Alicia; Isla, Arantxazu

2015-05-01

The alarming increase of resistance against multiple currently available antibiotics is leading to a rapid lose of treatment options against infectious diseases. Since the antibiotic resistance is partially due to a misuse or abuse of the antibiotics, this situation can be reverted when improving their use. One strategy is the optimization of the antimicrobial dosing regimens. In fact, inappropriate drug choice and suboptimal dosing are two major factors that should be considered because they lead to the emergence of drug resistance and consequently, poorer clinical outcomes. Pharmacokinetic/pharmacodynamic (PK/PD) analysis in combination with Monte Carlo simulation allows to optimize dosing regimens of the antibiotic agents in order to conserve their therapeutic value. Therefore, the aim of this review is to explain the basis of the PK/PD analysis and associated techniques, and provide a brief revision of the applications of PK/PD analysis from a therapeutic point-of-view. The establishment and reevaluation of clinical breakpoints is the sticking point in antibiotic therapy as the clinical use of the antibiotics depends on them. Two methodologies are described to establish the PK/PD breakpoints, which are a big part of the clinical breakpoint setting machine. Furthermore, the main subpopulations of patients with altered characteristics that can condition the PK/PD behavior (such as critically ill, elderly, pediatric or obese patients) and therefore, the outcome of the antibiotic therapy, are reviewed. Finally, some recommendations are provided from a PK/PD point of view to enhance the efficacy of prophylaxis protocols used in surgery. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

PK-ISIS: a new superconducting ECR ion source at Pantechnik

International Nuclear Information System (INIS)

Villari, A.C.; Bieth, C.; Bougy, W.; Brionne, N.; Donzel, X.; Gaubert, G.; Leroy, R.; Sineau, A.; Tasset, O.; Vallerand, C.; Thuillier, T.

2012-01-01

The new ECR ion source PK-ISIS was recently commissioned at Pantechnik. Three superconducting coils generate the axial magnetic field configuration while the radial magnetic field is done with multi-layer permanent magnets. Special care was devoted in the design of the hexapolar structure, allowing a maximum magnetic field of 1.32 T at the wall of the 82 mm diameter plasma chamber. The three superconducting coils using Low Temperature Superconducting wires are cooled by a single double stage cryo-cooler (4.2 K). Cryogen-free technology is used, providing reliability, easy maintenance at low cost. The maximum installed RF power (18.0 GHz) is of 2 kW. Metallic beams can be produced with an oven (T max = 1400 C) installed with an angle of 5 degrees with respect to the source axis or a sputtering system, mounted in the axis of the source. The beam extraction system is constituted of three electrodes in accel-decel configuration. The new source of Pantechnik is conceived for reaching optimum performances at 18 GHz RF frequencies. PK-ISIS delivers 5 to 10 times more beam intensity than the original PK-DELIS and/or shifting the charge state distribution to higher values. PK-ISIS is built with Low Temperature Superconducting wire technology (LTS), but keeps the He-free concept, extremely important for a reliable and easy operation. The radial field circuit is permanent magnet made. Finally, PK-ISIS is also conceived for using in a High-Voltage platform with minor power consumption. The paper is followed by the slides of the presentation. (A.C.)

Search for a narrow baryonic state decaying to pK0S and anti pK0S in deep inelastic scattering at HERA

International Nuclear Information System (INIS)

Abramowicz, H.; Abt, I.; Adamczyk, L.

2016-06-01

A search for a narrow baryonic state in the pK 0 S and anti pK 0 S system has been performed in ep collisions at HERA with the ZEUS detector using an integrated luminosity of 358 pb -1 taken in 2003-2007. The search was performed with deep inelastic scattering events at an ep centre-of-mass energy of 318 GeV for exchanged photon virtuality, Q 2 , between 20 and 100 GeV 2 . Contrary to evidence presented for such a state around 1.52 GeV in a previous ZEUS analysis using a sample of 121 pb -1 taken in 1996-2000, no resonance peak was found in the p(anti p)K 0 S invariant-mass distribution in the range 1.45-1.7 GeV. Upper limits on the production cross section are set.

Role of BK channels in the apoptotic volume decrease in native eel intestinal cells

DEFF Research Database (Denmark)

Lionetto, Maria Giulia; Giordano, Maria Elena; Calisi, Antonio

2010-01-01

High conductance Ca(+)-activated K(+) channels (BK channels) have previously been demonstrated in the eel intestine. They are specifically activated following a hypotonic stress and sustain Regulatory Volume Decrease (RVD). The aim of the present work was to address the possible role...... enterocytes that BK channels, which are involved in RVD in these cells, plays also a crucial role in the AVD process and in the progression of apoptosis....

Ground based measurements of particulate emissions from supersonic transports. Concorde olympus engine

Energy Technology Data Exchange (ETDEWEB)

Whitefield, Ph D; Hagen, D E [Missouri Univ., Rolla, MO (United States). Cloud and Aerosol Sciences Lab.; Lilenfeld, H V [McDonnell Douglas Corp., St. Louis, MO (United States)

1998-12-31

The application of a mobile aerosol monitoring facility, the Mobile Aerosol Sampling System (MASS) is described to characterize engine aerosol emissions from the Rolls Royce Olympus Engine. The multi-configurational MASS has been employed in both ground and airborne field operations. It has been successfully flown on research aircrafts. In ground tests the MASS has participated in numerous jet engine related ground tests, and has been deployed to resolve aerosol generation problems in a high power chemical laser system. In all cases the measurements were made on samples taken from a harsh physical and chemical environment, with both high and low temperature and pressure, and in the presence of highly reactive gases. (R.P.) 9 refs.

Ground based measurements of particulate emissions from supersonic transports. Concorde olympus engine

Energy Technology Data Exchange (ETDEWEB)

Whitefield, Ph.D.; Hagen, D.E. [Missouri Univ., Rolla, MO (United States). Cloud and Aerosol Sciences Lab.; Lilenfeld, H.V. [McDonnell Douglas Corp., St. Louis, MO (United States)

1997-12-31

The application of a mobile aerosol monitoring facility, the Mobile Aerosol Sampling System (MASS) is described to characterize engine aerosol emissions from the Rolls Royce Olympus Engine. The multi-configurational MASS has been employed in both ground and airborne field operations. It has been successfully flown on research aircrafts. In ground tests the MASS has participated in numerous jet engine related ground tests, and has been deployed to resolve aerosol generation problems in a high power chemical laser system. In all cases the measurements were made on samples taken from a harsh physical and chemical environment, with both high and low temperature and pressure, and in the presence of highly reactive gases. (R.P.) 9 refs.

Cellular response to DNA damage. Link between p53 and DNA-PK

International Nuclear Information System (INIS)

Salles-Passador, I.; Fotedar, R.; Fotedar, A.

1999-01-01

Cells which lack DNA-activated protein kinase (DNA-PK) are very susceptible to ionizing radiation and display an inability to repair double-strand DNA breaks. DNA-PK is a member of a protein kinase family that includes ATR and ATM which have strong homology in their carboxy-terminal kinase domain with Pl-3 kinase. ATM has been proposed to act upstream of p53 in cellular response to ionizing radiation. DNA-PK may similarly interact with p53 in cellular growth control and in mediation of the response to ionizing radiation. (author)

The BK(Ca) channels deficiency as a possible reason for radiation-induced vascular hypercontractility.

Science.gov (United States)

Kyrychenko, Sergii; Tishkin, Sergey; Dosenko, Victor; Ivanova, Irina; Novokhatska, Tatiana; Soloviev, Anatoly

2012-01-01

It is likely that large-conductance Ca²⁺-activated K⁺ (BK(Ca)) channels channelopathy tightly involved in vascular malfunctions and arterial hypertension development. In the present study, we compared the results of siRNAs-induced α-BK(Ca) gene silencing and vascular abnormalities produced by whole-body ionized irradiation in rats. The experimental design comprised RT-PCR and patch clamp technique, thoracic aorta smooth muscle (SM) contractile recordings and arterial blood pressure (BP) measurements on the 30th day after whole body irradiation (6Gy) and following siRNAs KCNMA1 gene silencing in vivo. The expression profile of BK(Ca) mRNA transcripts in SM was significantly decreased in siRNAs-treated rats in a manner similar to irradiated SM. In contrast, the mRNA levels of K(v) and K(ATP) were significantly increased while L-type calcium channels mRNA transcripts demonstrated tendency to increment. The SMCs obtained from irradiated animals and after KCNMA1 gene silencing showed a significant decrease in total K⁺ current density amplitude. Paxilline (500 nM)-sensitive components of outward current were significantly decreased in both irradiated and gene silencing SMCs. KCNMA1 gene silencing increased SM sensitivity to norepinephrine while Ach-induced relaxation had decreased. The silencing of KCNMA1 had no significant effect on BP while radiation produced sustained arterial hypertension. Therefore, radiation alters the form and function of the BK(Ca) channel and this type of channelopathy may contribute to related vascular abnormalities. Nevertheless, it is unlikely that BK(Ca) can operate as a crucial factor for radiation-induced arterial hypertension. Copyright © 2012 Elsevier Inc. All rights reserved.

BK channels regulate spontaneous action potential rhythmicity in the suprachiasmatic nucleus.

Directory of Open Access Journals (Sweden)

Jack Kent

Full Text Available BACKGROUND: Circadian ( approximately 24 hr rhythms are generated by the central pacemaker localized to the suprachiasmatic nucleus (SCN of the hypothalamus. Although the basis for intrinsic rhythmicity is generally understood to rely on transcription factors encoded by "clock genes", less is known about the daily regulation of SCN neuronal activity patterns that communicate a circadian time signal to downstream behaviors and physiological systems. Action potentials in the SCN are necessary for the circadian timing of behavior, and individual SCN neurons modulate their spontaneous firing rate (SFR over the daily cycle, suggesting that the circadian patterning of neuronal activity is necessary for normal behavioral rhythm expression. The BK K(+ channel plays an important role in suppressing spontaneous firing at night in SCN neurons. Deletion of the Kcnma1 gene, encoding the BK channel, causes degradation of circadian behavioral and physiological rhythms. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis that loss of robust behavioral rhythmicity in Kcnma1(-/- mice is due to the disruption of SFR rhythms in the SCN, we used multi-electrode arrays to record extracellular action potentials from acute wild-type (WT and Kcnma1(-/- slices. Patterns of activity in the SCN were tracked simultaneously for up to 3 days, and the phase, period, and synchronization of SFR rhythms were examined. Loss of BK channels increased arrhythmicity but also altered the amplitude and period of rhythmic activity. Unexpectedly, Kcnma1(-/- SCNs showed increased variability in the timing of the daily SFR peak. CONCLUSIONS/SIGNIFICANCE: These results suggest that BK channels regulate multiple aspects of the circadian patterning of neuronal activity in the SCN. In addition, these data illustrate the characteristics of a disrupted SCN rhythm downstream of clock gene-mediated timekeeping and its relationship to behavioral rhythms.

Effect of temperature on surface error and laser damage threshold for self-healing BK7 glass.

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Wang, Chu; Wang, Hongxiang; Shen, Lu; Hou, Jing; Xu, Qiao; Wang, Jian; Chen, Xianhua; Liu, Zhichao

2018-03-20

Cracks caused during the lapping and polishing process can decrease the laser-induced damage threshold (LIDT) of the BK7 glass optical elements, which would shorten the lifetime and limit the output power of the high-energy laser system. When BK7 glass is heated under appropriate conditions, the surface cracks can exhibit a self-healing phenomenon. In this paper, based on thermodynamics and viscous fluid mechanics theory, the mechanisms of crack self-healing are explained. The heat-healing experiment was carried out, and the effect of water was analyzed. The multi-spatial-frequency analysis was used to investigate the effect of temperature on surface error for self-healing BK7 glass, and the lapped BK7 glass specimens before and after heat healing were detected by an interferometer and atomic force microscopy. The low-spatial-frequency error was analyzed by peak to valley and root mean square, the mid-spatial-frequency error was analyzed by power spectral density, and the high-spatial-frequency error was analyzed by surface roughness. The results showed that the optimal heating temperature for BK7 was 450°C, and when the heating temperature was higher than the glass transition temperature (555°C), the surface quality decreased a lot. The laser damage test was performed, and the specimen heated at 450°C showed an improvement in LIDT.

Universal features of JIMWLK and BK evolution at small x

CERN Document Server

Rummukainen, K; Rummukainen, Kari; Weigert, Heribert

2004-01-01

In this paper we present the results of numerical studies of the JIMWLK and BK equations with a particular emphasis on the universal scaling properties and phase space structure involved. The results are valid for near zero impact parameter in DIS. We demonstrate IR safety due to the occurrence of a rapidity dependent saturation scale Q_s(\\tau). Within the set of initial conditions chosen both JIMWLK and BK equations show remarkable agreement. We point out the crucial importance of running coupling corrections to obtain consistency in the UV. Despite the scale breaking induced by the running coupling we find that evolution drives correlators towards an asymptotic form with near scaling properties. We discuss asymptotic features of the evolution, such as the \\tau- and A-dependence of Q_s away from the initial condition.

Analýza marketingové komunikace sportovního klubu BK Lokomotiva Karlovy Vary

OpenAIRE

Houdková, Jana

2012-01-01

ANALYSIS OF MARKETING COMMUNICATIONS BK LOKOMOTIVA KARLOVY VARY SPORTS CLUB Objectives: The aim of this work is to analyze the current state of marketing communication with the audience and sponsors for women's basketball club BK Lokomotiva Karlovy Vary and propose a strategy for improving marketing communications. Methods: In this thesis were performed using the methods of observation and personal interviews examined subjects Results: An analysis of marketing communication club, thanks to wh...

Hydronephrosis Resulting from Bilateral Ureteral Stenosis: A Late Complication of Polyoma BK Virus Cystitis?

OpenAIRE

Basara, N.; Rasche, F.-M.; Schwalenberg, T.; Wickenhauser, C.; Maier, M.; Ivovic, J.; Niederwieser, D.; Lindner, T. H.

2010-01-01

We report here a case of acute lymphoblastic leukemia in remission presenting a late-onset bilateral hydronephrosis probably due to polyoma BK virus-induced proliferation of bladder endothelium on both ostii. The diagnosis was made virologically by BK virus Polymerase Chain Reaction (PCR) detection in the absence of any other bladder disease. Awareness of this late complication is necessary not only in patients after renal transplantation but also in patients after hematopoietic stem cell tra...

BK/TD models for analyzing in vitro impedance data on cytotoxicity.

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Teng, S; Barcellini-Couget, S; Beaudouin, R; Brochot, C; Desousa, G; Rahmani, R; Pery, A R R

2015-06-01

The ban of animal testing has enhanced the development of new in vitro technologies for cosmetics safety assessment. Impedance metrics is one such technology which enables monitoring of cell viability in real time. However, analyzing real time data requires moving from static to dynamic toxicity assessment. In the present study, we built mechanistic biokinetic/toxicodynamic (BK/TD) models to analyze the time course of cell viability in cytotoxicity assay using impedance. These models account for the fate of the tested compounds during the assay. BK/TD models were applied to analyze HepaRG cell viability, after single (48 h) and repeated (4 weeks) exposures to three hepatotoxic compounds (coumarin, isoeugenol and benzophenone-2). The BK/TD models properly fit the data used for their calibration that was obtained for single or repeated exposure. Only for one out of the three compounds, the models calibrated with a single exposure were able to predict repeated exposure data. We therefore recommend the use of long-term exposure in vitro data in order to adequately account for chronic hepatotoxic effects. The models we propose here are capable of being coupled with human biokinetic models in order to relate dose exposure and human hepatotoxicity. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

The oncogenic potential of BK-polyomavirus is linked to viral integration into the human genome.

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Kenan, Daniel J; Mieczkowski, Piotr A; Burger-Calderon, Raquel; Singh, Harsharan K; Nickeleit, Volker

2015-11-01

It has been suggested that BK-polyomavirus is linked to oncogenesis via high expression levels of large T-antigen in some urothelial neoplasms arising following kidney transplantation. However, a causal association between BK-polyomavirus, large T-antigen expression and oncogenesis has never been demonstrated in humans. Here we describe an investigation using high-throughput sequencing of tumour DNA obtained from an urothelial carcinoma arising in a renal allograft. We show that a novel BK-polyomavirus strain, named CH-1, is integrated into exon 26 of the myosin-binding protein C1 gene (MYBPC1) on chromosome 12 in tumour cells but not in normal renal cells. Integration of the BK-polyomavirus results in a number of discrete alterations in viral gene expression, including: (a) disruption of VP1 protein expression and robust expression of large T-antigen; (b) preclusion of viral replication; and (c) deletions in the non-coding control region (NCCR), with presumed alterations in promoter feedback loops. Viral integration disrupts one MYBPC1 gene copy and likely alters its expression. Circular episomal BK-polyomavirus gene sequences are not found, and the renal allograft shows no productive polyomavirus infection or polyomavirus nephropathy. These findings support the hypothesis that integration of polyomaviruses is essential to tumourigenesis. It is likely that dysregulation of large T-antigen, with persistent over-expression in non-lytic cells, promotes cell growth, genetic instability and neoplastic transformation. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Algebra task sheets : grades pk-2

CERN Document Server

Reed, Nat

2009-01-01

For grades PK-2, our Common Core State Standards-based resource meets the algebraic concepts addressed by the NCTM standards and encourages the students to learn and review the concepts in unique ways. Each task sheet is organized around a central problem taken from real-life experiences of the students.

Geometry task sheets : grades pk-2

CERN Document Server

Rosenberg, Mary

2009-01-01

For grades PK-2, our Common Core State Standards-based resource meets the geometry concepts addressed by the NCTM standards and encourages the students to learn and review the concepts in unique ways. Each task sheet is organized around a central problem taken from real-life experiences of the students.

A Precise determination of B(K) in quenched QCD

CERN Document Server

Dimopoulos, P.; Palombi, F.; Pena, C.; Sint, S.; Vladikas, A.

2006-01-01

The $B_K$ parameter is computed in quenched lattice QCD with Wilson twisted mass fermions. Two variants of tmQCD are used; in both of them the relevant $\\Delta S = 2$ four-fermion operator is renormalised multiplicatively. The renormalisation adopted is non-perturbative, with a Schroedinger functional renormalisation condition. Renormalisation group running is also non-perturbative, up to very high energy scales. In one of the two tmQCD frameworks the computations have been performed at the physical $K$-meson mass, thus eliminating the need of mass extrapolations. Simulations have been performed at several lattice spacings and the continuum limit was reached by combining results from both tmQCD regularisations. Finite volume effects have been partially checked and turned out to be small. Exploratory studies have also been performed with non-degenerate valence flavours. The final result for the RGI bag parameter, with all sources of uncertainty (except quenching) under control, is $\\hat B_K =0.789 \\pm 0.046$.

Hydronephrosis Resulting from Bilateral Ureteral Stenosis: A Late Complication of Polyoma BK Virus Cystitis?

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Basara, N; Rasche, F-M; Schwalenberg, T; Wickenhauser, C; Maier, M; Ivovic, J; Niederwieser, D; Lindner, T H

2010-01-01

We report here a case of acute lymphoblastic leukemia in remission presenting a late-onset bilateral hydronephrosis probably due to polyoma BK virus-induced proliferation of bladder endothelium on both ostii. The diagnosis was made virologically by BK virus Polymerase Chain Reaction (PCR) detection in the absence of any other bladder disease. Awareness of this late complication is necessary not only in patients after renal transplantation but also in patients after hematopoietic stem cell transplantation from matched unrelated donor.

Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons.

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Kimm, Tilia; Khaliq, Zayd M; Bean, Bruce P

2015-12-16

Little is known about the voltage-dependent potassium currents underlying spike repolarization in midbrain dopaminergic neurons. Studying mouse substantia nigra pars compacta dopaminergic neurons both in brain slice and after acute dissociation, we found that BK calcium-activated potassium channels and Kv2 channels both make major contributions to the depolarization-activated potassium current. Inhibiting Kv2 or BK channels had very different effects on spike shape and evoked firing. Inhibiting Kv2 channels increased spike width and decreased the afterhyperpolarization, as expected for loss of an action potential-activated potassium conductance. BK inhibition also increased spike width but paradoxically increased the afterhyperpolarization. Kv2 channel inhibition steeply increased the slope of the frequency-current (f-I) relationship, whereas BK channel inhibition had little effect on the f-I slope or decreased it, sometimes resulting in slowed firing. Action potential clamp experiments showed that both BK and Kv2 current flow during spike repolarization but with very different kinetics, with Kv2 current activating later and deactivating more slowly. Further experiments revealed that inhibiting either BK or Kv2 alone leads to recruitment of additional current through the other channel type during the action potential as a consequence of changes in spike shape. Enhancement of slowly deactivating Kv2 current can account for the increased afterhyperpolarization produced by BK inhibition and likely underlies the very different effects on the f-I relationship. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell. This work shows that BK calcium-activated potassium channels and Kv2 voltage-activated potassium channels both regulate action potentials in dopamine neurons of the substantia nigra pars compacta. Although both

Hydronephrosis Resulting from Bilateral Ureteral Stenosis: A Late Complication of Polyoma BK Virus Cystitis?

Science.gov (United States)

Basara, N.; Rasche, F.-M.; Schwalenberg, T.; Wickenhauser, C.; Maier, M.; Ivovic, J.; Niederwieser, D.; Lindner, T. H.

2010-01-01

We report here a case of acute lymphoblastic leukemia in remission presenting a late-onset bilateral hydronephrosis probably due to polyoma BK virus-induced proliferation of bladder endothelium on both ostii. The diagnosis was made virologically by BK virus Polymerase Chain Reaction (PCR) detection in the absence of any other bladder disease. Awareness of this late complication is necessary not only in patients after renal transplantation but also in patients after hematopoietic stem cell transplantation from matched unrelated donor. PMID:20936157

Hydronephrosis Resulting from Bilateral Ureteral Stenosis: A Late Complication of Polyoma BK Virus Cystitis?

Directory of Open Access Journals (Sweden)

N. Basara

2010-01-01

Full Text Available We report here a case of acute lymphoblastic leukemia in remission presenting a late-onset bilateral hydronephrosis probably due to polyoma BK virus-induced proliferation of bladder endothelium on both ostii. The diagnosis was made virologically by BK virus Polymerase Chain Reaction (PCR detection in the absence of any other bladder disease. Awareness of this late complication is necessary not only in patients after renal transplantation but also in patients after hematopoietic stem cell transplantation from matched unrelated donor.

A non-cardiomyocyte autonomous mechanism of cardioprotection involving the SLO1 BK channel

Directory of Open Access Journals (Sweden)

Andrew P. Wojtovich

2013-03-01

Full Text Available Opening of BK-type Ca2+ activated K+ channels protects the heart against ischemia-reperfusion (IR injury. However, the location of BK channels responsible for cardioprotection is debated. Herein we confirmed that openers of the SLO1 BK channel, NS1619 and NS11021, were protective in a mouse perfused heart model of IR injury. As anticipated, deletion of the Slo1 gene blocked this protection. However, in an isolated cardiomyocyte model of IR injury, protection by NS1619 and NS11021 was insensitive to Slo1 deletion. These data suggest that protection in intact hearts occurs by a non-cardiomyocyte autonomous, SLO1-dependent, mechanism. In this regard, an in-situ assay of intrinsic cardiac neuronal function (tachycardic response to nicotine revealed that NS1619 preserved cardiac neurons following IR injury. Furthermore, blockade of synaptic transmission by hexamethonium suppressed cardioprotection by NS1619 in intact hearts. These results suggest that opening SLO1 protects the heart during IR injury, via a mechanism that involves intrinsic cardiac neurons. Cardiac neuronal ion channels may be useful therapeutic targets for eliciting cardioprotection.

Quantification of (R)-[11C]PK11195 binding in rheumatoid arthritis

International Nuclear Information System (INIS)

Kropholler, M.A.; Boellaard, R.; Kloet, R.W.; Lammertsma, A.A.; Elzinga, E.H.; Voskuyl, A.E.; Laken, C.J. van der; Dijkmans, B.A.C.; Maruyama, K.

2009-01-01

Rheumatoid arthritis (RA) involves migration of macrophages into inflamed areas. (R)-[ 11 C]PK11195 binds to peripheral benzodiazepine receptors, expressed on macrophages, and may be used to quantify inflammation using positron emission tomography (PET). This study evaluated methods for the quantification of (R)-[ 11 C]PK11195 binding in the knee joints of RA patients. Data from six patients with RA were analysed. Dynamic PET scans were acquired in 3-D mode following (R)-[ 11 C]PK11195 injection. During scanning arterial radioactivity concentrations were measured to determine the plasma (R)-[ 11 C]PK11195 concentrations. Data were analysed using irreversible and reversible one-tissue and two-tissue compartment models and input functions with various types of metabolite correction. Model preferences according to the Akaike information criterion (AIC) and correlations between measures were evaluated. Correlations between distribution volume (V d ) and standardized uptake values (SUV) were evaluated. AIC indicated optimal performance for a one-tissue reversible compartment model including blood volume. High correlations were observed between V d obtained using different input functions (R 2 =0.80-1.00) and between V d obtained with one- and two-tissue reversible compartment models (R 2 =0.75-0.94). A high correlation was observed between optimal V d and SUV after injection (R 2 =0.73). (R)-[ 11 C]PK11195 kinetics in the knee were best described by a reversible single-tissue compartment model including blood volume. Applying metabolite corrections did not increase sensitivity. Due to the high correlation with V d , SUV is a practical alternative for clinical use. (orig.)

Relative transmembrane segment rearrangements during BK channel activation resolved by structurally assigned fluorophore–quencher pairing

Science.gov (United States)

Pantazis, Antonios

2012-01-01

Voltage-activated proteins can sense, and respond to, changes in the electric field pervading the cell membrane by virtue of a transmembrane helix bundle, the voltage-sensing domain (VSD). Canonical VSDs consist of four transmembrane helices (S1–S4) of which S4 is considered a principal component because it possesses charged residues immersed in the electric field. Membrane depolarization compels the charges, and by extension S4, to rearrange with respect to the field. The VSD of large-conductance voltage- and Ca-activated K+ (BK) channels exhibits two salient inconsistencies from the canonical VSD model: (1) the BK channel VSD possesses an additional nonconserved transmembrane helix (S0); and (2) it exhibits a “decentralized” distribution of voltage-sensing charges, in helices S2 and S3, in addition to S4. Considering these unique features, the voltage-dependent rearrangements of the BK VSD could differ significantly from the standard model of VSD operation. To understand the mode of operation of this unique VSD, we have optically tracked the relative motions of the BK VSD transmembrane helices during activation, by manipulating the quenching environment of site-directed fluorescent labels with native and introduced Trp residues. Having previously reported that S0 and S4 diverge during activation, in this work we demonstrate that S4 also diverges from S1 and S2, whereas S2, compelled by its voltage-sensing charged residues, moves closer to S1. This information contributes spatial constraints for understanding the BK channel voltage-sensing process, revealing the structural rearrangements in a non-canonical VSD. PMID:22802360

Porcine circovirus-2 capsid protein induces cell death in PK15 cells

Energy Technology Data Exchange (ETDEWEB)

Walia, Rupali; Dardari, Rkia, E-mail: rdardari@ucalgary.ca; Chaiyakul, Mark; Czub, Markus

2014-11-15

Studies have shown that Porcine circovirus (PCV)-2 induces apoptosis in PK15 cells. Here we report that cell death is induced in PCV2b-infected PK15 cells that express Capsid (Cap) protein and this effect is enhanced in interferon gamma (IFN-γ)-treated cells. We further show that transient PCV2a and 2b-Cap protein expression induces cell death in PK15 cells at rate similar to PCV2 infection, regardless of Cap protein localization. These data suggest that Cap protein may have the capacity to trigger different signaling pathways involved in cell death. Although further investigation is needed to gain deeper insights into the nature of the pathways involved in Cap-induced cell death, this study provides evidence that PCV2-induced cell death in kidney epithelial PK15 cells can be mapped to the Cap protein and establishes the need for future research regarding the role of Cap-induced cell death in PCV2 pathogenesis. - Highlights: • IFN-γ enhances PCV2 replication that leads to cell death in PK15 cells. • IFN-γ enhances nuclear localization of the PCV2 Capsid protein. • Transient PCV2a and 2b-Capsid protein expression induces cell death. • Cell death is not dictated by specific Capsid protein sub-localization.

[Advenella kashmirensis subsp. methylica PK1, a facultative methylotroph from carex rhizosphere].

Science.gov (United States)

Poroshina, M N; Doronina, N V; Kaparullina, E N; Trotsenko, Iu A

2015-01-01

A strain (PK1) of facultative methylobacteria growing on methanol as a carbon and energy source was isolated from carex rhizosphere (Pamukkale National Park, Turkey). The cells were nonmotile gram-negative rods propagating by binary fission. The organism was a strict anaerobe, oxidase- and catalase-positive. Optimal growth occurred at 29°C, pH 8.0-8.5, and 0.5% NaCl; no growth occurred at 2% NaCl. The organism used the ribulose bisphosphate pathway of C1 assimilation. Predominant fatty acids were 11-octodecenoic (18:1ω7) and cis-hexadecenoic (16:1ω7c). Phosphatidylethanolamine and diphosphatidylglycerol were the dominant phospholipids. Q8 was the main ubiquinone. DNA G+C content was 55.4 mol % (mp). Sequencing of the 16S rRNA gene revealed that strain PK1 belonged to the genus Advenella with 98.8 and 99.2% similarity to the type strains A. incenata CCUG 45225T and A. kashmirensis WT001T, respectively. DNA-DNA homology of strain PK1 and A. kashmirensis WT001T was 70%. While MALDI analysis confirmed their close clusterization, RAPD analysis revealed the differences between strain PKI and other Advenella strains. Based on its geno- and phenotypic properties, the isolate PK1 was classified as A. kashmirensis subsp. methylica PK1 (VKM-B 2850 = DSM 27514), the first known methylotroph of the genus Advenella.

BK virus has tropism for human salivary gland cells in vitro: Implications for transmission

International Nuclear Information System (INIS)

Jeffers, Liesl K.; Madden, Vicki; Webster-Cyriaque, Jennifer

2009-01-01

Background: In this study, it was determined that BKV is shed in saliva and an in vitro model system was developed whereby BKV can productively infect both submandibular (HSG) and parotid (HSY) salivary gland cell lines. Results: BKV was detected in oral fluids using quantitative real-time PCR (QRTPCR). BKV infection was determined using quantitative RT-PCR, immunofluorescence and immunoblotting assays. The infectivity of BKV was inhibited by pre-incubation of the virus with gangliosides that saturated the major capsid protein, VP1, halting receptor mediated BKV entry into salivary gland cells. Examination of infected cultures by transmission electron microscopy revealed 45-50 nm BK virions clearly visible within the cells. Subsequent to infection, encapsidated BK virus was detected in the supernatant. Conclusion: We thus demonstrated that BKV was detected in oral fluids and that BK infection and replication occur in vitro in salivary gland cells. These data collectively suggest the potential for BKV oral route of transmission and oral pathogenesis.

BK Virus-Associated Nephropathy: Current Situation in a Resource-Limited Country.

Science.gov (United States)

Yooprasert, P; Rotjanapan, P

Data on BK virus-associated nephropathy (BKVAN) and treatment strategy in a resource-limited country are scarce. This study aimed to evaluate epidemiology of BKVAN and its situation in Thailand. A retrospective analysis was conducted among adult kidney transplant recipients at Ramathibodi Hospital from October 2011 to September 2016. Patients' demographic data, information on kidney transplantation, immunosuppressive therapy, cytomegalovirus and BK virus infections, and allograft outcomes were retrieved and analyzed. This study included 623 kidney transplant recipients. Only 327 patients (52.49%) received BK virus infection screening, and 176 of 327 patients had allograft dysfunction as a trigger for screening. BKVAN was identified in 39 of 327 patients (11.93%). Deceased donor transplantation and cytomegalovirus infection were associated with a higher risk of BKVAN (odds ratio = 2.2, P = .024, 95% confidence intervals [1.1, 4.43], and odds ratio = 2.6, P = .006, 95% confidence intervals [1.29, 5.26], respectively). BKVAN patients were at significantly higher risk for allograft rejection (P < .001) and allograft failure (P = .036). At the end of the study, 4 graft losses were documented (12.12%). BKVAN was associated with high rate of allograft rejection and failure. However, surveillance of its complications has been underperformed at our facility. Implementing a formal practice guideline may improve allograft outcome in resource-limited countries. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Decay properties of ${}_{97}{}^{243}\mathrm{<span\; class="hlt">Bk</span>}$ and ${}_{97}{}^{244}\mathrm{<span\; class="hlt">Bk</span>}$

Energy Technology Data Exchange (ETDEWEB)

Ahmad, I.; Kondev, F. G.; Greene, J. P.; Zhu, S.

2018-01-01

Electron capture decays of Bk-243 and Bk-244 have been studied by measuring the gamma-ray spectra of mass-separated sources and level structures of Cm-243 and Cm-244 have been deduced. In Cm-243, the electron capture population to the ground state, 1/2(+)[631], and 1/2(+)[620] Nilsson states have been observed. The octupole K-pi = 2(-) band was identified in Cm-244 at 933.6 keV. In addition, spins and parities were deduced for several other states and two-quasiparticle configurations have been tentatively assigned to them

Chronic Prenatal Hypoxia Down-Regulated BK Channel Β1 Subunits in Mesenteric Artery Smooth Muscle Cells of the Offspring

Directory of Open Access Journals (Sweden)

Bailin Liu

2018-02-01

Full Text Available Background/Aims: Chronic hypoxia in utero could impair vascular functions in the offspring, underlying mechanisms are unclear. This study investigated functional alteration in large-conductance Ca2+-activated K+ (BK channels in offspring mesenteric arteries following prenatal hypoxia. Methods: Pregnant rats were exposed to normoxic control (21% O2, Con or hypoxic (10.5% O2, Hy conditions from gestational day 5 to 21, their 7-month-old adult male offspring were tested for blood pressure, vascular BK channel functions and expression using patch clamp and wire myograh technique, western blotting, and qRT-PCR. Results: Prenatal hypoxia increased pressor responses and vasoconstrictions to phenylephrine in the offspring. Whole-cell currents density of BK channels and amplitude of spontaneous transient outward currents (STOCs, not the frequency, were significantly reduced in Hy vascular myocytes. The sensitivity of BK channels to voltage, Ca2+, and tamoxifen were reduced in Hy myocytes, whereas the number of channels per patch and the single-channel conductance were unchanged. Prenatal hypoxia impaired NS1102- and tamoxifen-mediated relaxation in mesenteric arteries precontracted with phenylephrine in the presence of Nω-nitro-L-arginine methyl ester. The mRNA and protein expression of BK channel β1, not the α-subunit, was decreased in Hy mesenteric arteries. Conclusions: Impaired BK channel β1-subunits in vascular smooth muscle cells contributed to vascular dysfunction in the offspring exposed to prenatal hypoxia.

Single-channel kinetics of BK (Slo1 channels

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Yanyan eGeng

2015-01-01

Full Text Available Single-channel kinetics has proven a powerful tool to reveal information about the gating mechanisms that control the opening and closing of ion channels. This introductory review focuses on the gating of large conductance Ca2+- and voltage-activated K+ (BK or Slo1 channels at the single-channel level. It starts with single-channel current records and progresses to presentation and analysis of single-channel data and the development of gating mechanisms in terms of discrete state Markov (DSM models. The DSM models are formulated in terms of the tetrameric modular structure of BK channels, consisting of a central transmembrane pore-gate domain (PGD attached to four surrounding transmembrane voltage sensing domains (VSD and a large intracellular cytosolic domain (CTD, also referred to as the gating ring. The modular structure and data analysis shows that the Ca2+ and voltage dependent gating considered separately can each be approximated by 10-state two-tiered models with 5 closed states on the upper tier and 5 open states on the lower tier. The modular structure and joint Ca2+ and voltage dependent gating are consistent with a 50 state two-tiered model with 25 closed states on the upper tier and 25 open states on the lower tier. Adding an additional tier of brief closed (flicker states to the 10-state or 50-state models improved the description of the gating. For fixed experimental conditions a channel would gate in only a subset of the potential number of states. The detected number of states and the correlations between adjacent interval durations are consistent with the tiered models. The examined models can account for the single-channel kinetics and the bursting behavior of gating. Ca2+ and voltage activate BK channels by predominantly increasing the effective opening rate of the channel with a smaller decrease in the effective closing rate. Ca2+ and depolarization thus activate by mainly destabilizing the closed states.

Sandia reactor kinetics codes: SAK and PK1D

International Nuclear Information System (INIS)

Pickard, P.S.; Odom, J.P.

1978-01-01

The Sandia Kinetics code (SAK) is a one-dimensional coupled thermal-neutronics transient analysis code for use in simulation of reactor transients. The time-dependent cross section routines allow arbitrary time-dependent changes in material properties. The one-dimensional heat transfer routines are for cylindrical geometry and allow arbitrary mesh structure, temperature-dependent thermal properties, radiation treatment, and coolant flow and heat-transfer properties at the surface of a fuel element. The Point Kinetics 1 Dimensional Heat Transfer Code (PK1D) solves the point kinetics equations and has essentially the same heat-transfer treatment as SAK. PK1D can address extended reactor transients with minimal computer execution time

BK virus infection in a renal transplant Saudi child

International Nuclear Information System (INIS)

Maghrabi, M.; Marwan, D.; Osoba, Abimbola O.

2007-01-01

BK human polyomavirus (BKV) causes an asymptomatic primary infection in children, but later, establishes latency mainly in the urinary tract. Virus-host interactions influencing persistence and pathogenicity are not well-understood. We present here a 12-year-old Saudi boy, who had renal transplant in Egypt. Seven months later, he was admitted to our Pediatric Nephrology Unit as a case of renal impairment. He developed BKV infection, diagnosed and successfully managed in our hospital. This case demonstrates the expanding clinical importance of BKV in a post renal transplant patient. This virus can be detected in transitional cells in the urine (decoy cells) using cytology. Testing for BKV deoxyribonucleic acid in urine and blood is an early detection assay, and can be used as a screening test in the early stages. The early reduction of immunosuppression can improve the prognosis. No specific antiviral treatment has been established yet. This is the first report of detecting BK virus in a Saudi post-transplant child in urine and blood specimens by using polymerase chain reaction. (author)

Evaluation of the Olympus AU-510 analyser.

Science.gov (United States)

Farré, C; Velasco, J; Ramón, F

1991-01-01

The selective multitest Olympus AU-510 analyser was evaluated according to the recommendations of the Comision de Instrumentacion de la Sociedad Española de Quimica Clinica and the European Committee for Clinical Laboratory Standards. The evaluation was carried out in two stages: an examination of the analytical units and then an evaluation in routine work conditions. The operational characteristics of the system were also studied.THE FIRST STAGE INCLUDED A PHOTOMETRIC STUDY: dependent on the absorbance, the inaccuracy varies between +0.5% to -0.6% at 405 nm and from -5.6% to 10.6% at 340 nm; the imprecision ranges between -0.22% and 0.56% at 405 nm and between 0.09% and 2.74% at 340 nm. Linearity was acceptable, apart from a very low absorbance for NADH at 340 nm; and the imprecision of the serum sample pipetter was satisfactory.TWELVE SERUM ANALYTES WERE STUDIED UNDER ROUTINE CONDITIONS: glucose, urea urate, cholesterol, triglycerides, total bilirubin, creatinine, phosphate, iron, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase.The within-run imprecision (CV%) ranged from 0.67% for phosphate to 2.89% for iron and the between-run imprecision from 0.97% for total bilirubin to 7.06% for iron. There was no carryover in a study of the serum sample pipetter. Carry-over studies with the reagent and sample pipetters shows some cross contamination in the iron assay.

Mārketinga komunikācijas pielietojums atjaunotā BK "VEF Rīga" zīmola virzīšanā

OpenAIRE

Līcis, Mārtiņš

2014-01-01

Darba tēma ir „Mārketinga komunikācijas pielietojums atjaunotā BK „VEF Rīga” zīmola virzīšanā”. Darba mērķis ir noskaidrot mārketinga komunikācijas pielietojumu atjaunotā BK „VEF Rīga” zīmola virzīšanā. Uzdevumi ir izstudēt nepieciešamo teoriju, izanalizēt mārketinga komunikācijas instrumentu pielietojumu, noskaidrot BK „VEF Rīga”, sporta mārketinga speciālista un sabiedrības viedokli par BK „VEF Rīga” zīmolu. Teoriju veido: zīmols, zīmolvedība, mārketinga komunikācija, sociālo mediju mārketi...

Dwarf Elliptical Galaxies in the M81 Group: The Structure and Stellar Populations of BK5N and F8D1

OpenAIRE

Caldwell, Nelson; Armandroff, Taft E.; Da Costa, G. S.; Seitzer, Patrick

1997-01-01

We have obtained HST WFPC2 images through the F555W and F814W filters of two M81 group dE's: BK5N and a new system, designated F8D1. The resulting color-magnitude diagrams show the upper two magnitudes of the red giant branch. Surface brightness and total magnitude measurements indicate that BK5N and F8D1 have similar central surface brightness (24.5 and 25.4 mag/arcsec^2 in V, respectively), but F8D1's larger length scale results in it being 3 magnitudes more luminous than BK5N. BK5N lies on...

Semi-physiological pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation of 5-fluorouracil for thrombocytopenia in rats.

Science.gov (United States)

Kobuchi, Shinji; Ito, Yukako; Hayakawa, Taro; Nishimura, Asako; Shibata, Nobuhito; Takada, Kanji; Sakaeda, Toshiyuki

2015-01-01

1. The aim of this study was to develop a simple pharmacokinetic-pharmacodynamic (PK-PD) model that could characterize the complete time-course of alterations in platelet counts to predict the onset and degree of thrombocytopenia, which severely limits the use of the anticancer agent 5-fluorouracil (5-FU), in rats. 2. Platelet counts were measured in rats following the intravenous administration of various doses of 5-FU for 4 days to obtain data for an analysis of the PK-PD model. Our PK-PD model consisted of a two-compartment PK model, with three compartments for the PD model and 10 structural PK-PD model parameters. 3. After the 5-FU treatment, platelet counts transiently decreased to a nadir level, showed a rebound to above the baseline level before recovering to baseline levels. Nadir platelet counts and rebounds varied with the AUC0-∞ level. The final PK-PD model effectively characterized platelet count data and final PD parameters were estimated with high certainty. 4. This PK-PD model and simulation may represent a valuable tool for quantifying and predicting the complete time-course of alterations in blood cell counts, and could contribute to the development of therapeutic strategies with 5-FU and assessments of various novel anticancer agents that are difficult to examine in humans.

Neuronal fast activating and meningeal silent modulatory BK channel splice variants cloned from rat

DEFF Research Database (Denmark)

Poulsen, Asser Nyander; Jansen-Olesen, Inger; Olesen, Jes

2011-01-01

The big conductance calcium-activated K(+) channel (BK) is involved in regulating neuron and smooth muscle cell excitability. Functional diversity of BK is generated by alpha-subunit splice variation and co-expression with beta subunits. Here, we present six different splice combinations cloned...... and RCK2 (4 aa at SS1) and upstream of the calcium "bowl" (27 aa at SS4). Two other truncated variants, X2(92) and X2(188), lacking the intracellular C-terminal (stop downstream of S6), were cloned from cerebral vascular/meningeal tissue. They appear non-functional as no current expression was observed...

Latin, the Key to English Vocabulary. A Gamebook on English Derivatives and Cognates to Accompany "Voces de Olympo" (Echoes from Mt. Olympus).

Science.gov (United States)

Masciantonio, Rudolph

This gamebook is intended to assist the grade school (FLES) Latin teacher to introduce the reading and writing of English derivatives and cognates after these have been mastered audiolingually in Philadelphia's Latin course "Voces de Olympo (Echoes from Mt. Olympus): A Humanistic Approach to Latin for Children in the Sixth Grade." Games are…

Intermittent losartan administration triggers cardiac post-conditioning in isolated rat hearts: role of BK2 receptors.

Directory of Open Access Journals (Sweden)

Luca Sgarra

Full Text Available The angiotensin (Ang and bradykinin (BK tissue-system plays a pivotal role in post-conditioning, but the efficacy of angiotensin type 1 receptor (AT1R blockers (ARBs in post-ischemic strategies is still under investigation. We evaluated functional and morphological outcomes, together with activation of cytosolic RISK pathway kinases, in rat hearts subjected to losartan (LOS or irbesartan (IRB post-ischemic administration.Isolated rat hearts underwent 30 min ischemia and 120 min reperfusion. Post-conditioning was obtained by intermittent (10 s/each or continuous drug infusion during the first 3 min of reperfusion. Left ventricular end-diastolic pressure (LVEDP, left ventricular developed pressure (dLVP, coronary flow (CF, and left ventricular infarct mass (IM were measured together with the activation status of RISK kinases Akt, p42/44 MAPK and GSK3β.When compared to hearts subjected to ischemia/reperfusion (iI/R alone, continuous IRB or LOS administration did not significantly reduce total infarct mass (cIRB or cLOS vs. iI/R, p = 0.2. Similarly, intermittent IRB (iIRB was not able to enhance cardioprotection. Conversely, intermittent LOS administration (iLOS significantly ameliorated cardiac recovery (iLOS vs iI/R, p<0.01. Differences between iLOS and iIRB persisted under continuous blockade of AT2R (iLOS+cPD vs. iIRB+cPD, p<0.05. Interestingly, iLOS cardioprotection was lost when BK2R was simultaneously blocked (iLOS+cHOE vs. iI/R, p = 0.6, whereas concurrent administration of iBK and iIRB replicated iLOS effects (iIRB+iBK vs. iLOS, p = 0.7. At the molecular level, iIRB treatment did not significantly activate RISK kinases, whereas both iLOS and iBK treatments were associated with activation of the Akt/GSK3β branch of the RISK pathways (p<0.05 vs. iI/R, for both.Our results suggest that intermittent losartan is effective in mediating post-conditioning cardioprotection, whereas irbesartan is not. The infarct mass reduction by intermittent

Functional validation of Ca2+-binding residues from the crystal structure of the BK ion channel.

Science.gov (United States)

Kshatri, Aravind S; Gonzalez-Hernandez, Alberto J; Giraldez, Teresa

2018-04-01

BK channels are dually regulated by voltage and Ca 2+ , providing a cellular mechanism to couple electrical and chemical signalling. Intracellular Ca 2+ concentration is sensed by a large cytoplasmic region in the channel known as "gating ring", which is formed by four tandems of regulator of conductance for K + (RCK1 and RCK2) domains. The recent crystal structure of the full-length BK channel from Aplysia californica has provided new information about the residues involved in Ca 2+ coordination at the high-affinity binding sites located in the RCK1 and RCK2 domains, as well as their cooperativity. Some of these residues have not been previously studied in the human BK channel. In this work we have investigated, through site directed mutagenesis and electrophysiology, the effects of these residues on channel activation by voltage and Ca 2+ . Our results demonstrate that the side chains of two non-conserved residues proposed to coordinate Ca 2+ in the A. californica structure (G523 and E591) have no apparent functional role in the human BK Ca 2+ sensing mechanism. Consistent with the crystal structure, our data indicate that in the human channel the conserved residue R514 participates in Ca 2+ coordination in the RCK1 binding site. Additionally, this study provides functional evidence indicating that R514 also interacts with residues E902 and Y904 connected to the Ca 2+ binding site in RCK2. Interestingly, it has been proposed that this interaction may constitute a structural correlate underlying the cooperative interactions between the two high-affinity Ca 2+ binding sites regulating the Ca 2+ dependent gating of the BK channel. This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain. Copyright © 2017 Elsevier B.V. All rights reserved.

Structure of Pseudoknot PK26 Shows 3D Domain Swapping in an RNA

Science.gov (United States)

Lietzke, Susan E; Barnes, Cindy L.

1998-01-01

3D domain swapping provides a facile pathway for the evolution of oligomeric proteins and allosteric mechanisms and a means for using monomer-oligomer equilibria to regulate biological activity. The term "3D domain swapping" describes the exchange of identical domains between two protein monomers to create an oligomer. 3D domain swapping has, so far, only been recognized in proteins. In this study, the structure of the pseudoknot PK26 is reported and it is a clear example of 3D domain swapping in RNA. PK26 was chosen for study because RNA pseudoknots are required structures in several biological processes and they arise frequently in in vitro selection experiments directed against protein targets. PK26 specifically inhibits HIV-1 reverse transcriptase with nanomolar affinity. We have now determined the 3.1 A resolution crystal structure of PK26 and find that it forms a 3D domain swapped dimer. PK26 shows extensive base pairing between and within strands. Formation of the dimer requires the linker region between the pseudoknot folds to adopt a unique conformation that allows a base within a helical stem to skip one base in the stacking register. Rearrangement of the linker would permit a monomeric pseudoknot to form. This structure shows how RNA can use 3D domain swapping to build large scale oligomers like the putative hexamer in the packaging RNA of bacteriophage Phi29.

Towards saturation of the electron-capture delayed fission probability: The new isotopes 240Es and 236Bk

Directory of Open Access Journals (Sweden)

J. Konki

2017-01-01

Full Text Available The new neutron-deficient nuclei 240Es and 236Bk were synthesised at the gas-filled recoil separator RITU. They were identified by their radioactive decay chains starting from 240Es produced in the fusion–evaporation reaction 209Bi(34S,3n240Es. Half-lives of 6(2s and 22−6+13s were obtained for 240Es and 236Bk, respectively. Two groups of α particles with energies Eα=8.19(3MeV and 8.09(3MeV were unambiguously assigned to 240Es. Electron-capture delayed fission branches with probabilities of 0.16(6 and 0.04(2 were measured for 240Es and 236Bk, respectively. These new data show a continuation of the exponential increase of ECDF probabilities in more neutron-deficient isotopes.

A physiologically-based pharmacokinetic(PB-PK) model for ethylene dibromide : relevance of extrahepatic metabolism

NARCIS (Netherlands)

Hissink, A M; Wormhoudt, L.W.; Sherratt, P.J.; Hayes, D.J.; Commandeur, J N; Vermeulen, N P; van Bladeren, P.J.

A physiologically-based pharmacokinetic (PB-PK) model was developed for ethylene dibromide (1,2-dibromoethane, EDB) for rats and humans, partly based on previously published in vitro data (Ploemen et al., 1997). In the present study, this PB-PK model has been validated for the rat. In addition, new

A physiologically-based pharmacokinetic (PB-PK) model for ethylene dibromide : relevance of extrahepatic metabolism

NARCIS (Netherlands)

Hissink, A.M.; Wormhoudt, L.W.; Sherratt, P.J.; Hayes, J.D.; Commandeur, J.N.M.; Vermeulen, N.P.E.; Bladeren, P.J. van

2000-01-01

A physiologically-based pharmacokinetic (PB-PK) model was developed for ethylene dibromide (1,2-dibromoethane, EDB) for rats and humans, partly based on previously published in vitro data (Ploemen et al., 1997). In the present study, this PB-PK model has been validated for the rat. In addition, new

On the Operator ⨁Bk Related to Bessel Heat Equation

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Wanchak Satsanit

2010-01-01

Full Text Available We study the equation (∂/∂tu(x,t=c2⊕Bku(x,t with the initial condition u(x,0=f(x for x∈Rn+. The operator ⊕Bk is the operator iterated k-times and is defined by ⊕Bk=((∑i=1pBxi4-(∑j=p+1p+qBxi4k, where p+q=n is the dimension of the Rn+, Bxi=∂2/∂xi2+(2vi/xi(∂/∂xi, 2vi=2αi+1, αi>-1/2, i=1,2,3,…,n, and k is a nonnegative integer, u(x,t is an unknown function for (x,t=(x1,x2,…,xn,t∈Rn+×(0,∞, f(x is a given generalized function, and c is a positive constant. We obtain the solution of such equation, which is related to the spectrum and the kernel, which is so called Bessel heat kernel. Moreover, such Bessel heat kernel has interesting properties and also related to the kernel of an extension of the heat equation.

Native American Women Perceptions in Pk-12 Administrative Positions in North Dakota Public Schools

Science.gov (United States)

DeCoteau, Lanelia Irene

2012-01-01

Historically Native American women have experienced barriers in their rise to Pk-12 educational leadership positions. There is limited research available on Native American women in educational leadership. Therefore, the purpose for this survey study was to discover what inspired current Pk-12 Native American women educational leaders to choose…

BK Virus Load Associated with Serum Levels of sCD30 in Renal Transplant Recipients

Science.gov (United States)

Malik, Salma N.; Al-Saffer, Jinan M.; Jawad, Rana S.

2016-01-01

Background. Rejection is the main drawback facing the renal transplant operations. Complicated and overlapping factors, mainly related to the immune system, are responsible for this rejection. Elevated serum levels of sCD30 were frequently recorded as an indicator for renal allograft rejection, while BV virus is considered as one of the most serious consequences for immunosuppressive treatment of renal transplant recipients (RTRs). Aims. This study aimed to determine the association of BK virus load with serum levels of sCD30 in RTRs suffering from nephropathy. Patients and Methods. A total of 50 RTRs with nephropathy and 30 age-matched apparently healthy individuals were recruited for this study. Serum samples were obtained from each participant. Real-time PCR was used to quantify BK virus load in RTRs serum, while ELISA technique was employed to estimate serum levels of sCD30. Results. Twenty-two percent of RTRs had detectable BKV with mean viral load of 1.094E + 06 ± 2.291E + 06. RTRs showed higher mean serum level of sCD30 (20.669 ± 18.713 U/mL) than that of controls (5.517 ± 5.304 U/mL) with significant difference. BK virus load had significant positive correlation with the serum levels of sCD30 in RTRs group. Conclusion. These results suggest that serum levels of sCD30 could be used as an indicator of BK viremia, and accordingly the immunosuppressive regime should be adjusted. PMID:27051424

Comprehensive benchmarking reveals H2BK20 acetylation as a distinctive signature of cell-state-specific enhancers and promoters.

Science.gov (United States)

Kumar, Vibhor; Rayan, Nirmala Arul; Muratani, Masafumi; Lim, Stefan; Elanggovan, Bavani; Xin, Lixia; Lu, Tess; Makhija, Harshyaa; Poschmann, Jeremie; Lufkin, Thomas; Ng, Huck Hui; Prabhakar, Shyam

2016-05-01

Although over 35 different histone acetylation marks have been described, the overwhelming majority of regulatory genomics studies focus exclusively on H3K27ac and H3K9ac. In order to identify novel epigenomic traits of regulatory elements, we constructed a benchmark set of validated enhancers by performing 140 enhancer assays in human T cells. We tested 40 chromatin signatures on this unbiased enhancer set and identified H2BK20ac, a little-studied histone modification, as the most predictive mark of active enhancers. Notably, we detected a novel class of functionally distinct enhancers enriched in H2BK20ac but lacking H3K27ac, which was present in all examined cell lines and also in embryonic forebrain tissue. H2BK20ac was also unique in highlighting cell-type-specific promoters. In contrast, other acetylation marks were present in all active promoters, regardless of cell-type specificity. In stimulated microglial cells, H2BK20ac was more correlated with cell-state-specific expression changes than H3K27ac, with TGF-beta signaling decoupling the two acetylation marks at a subset of regulatory elements. In summary, our study reveals a previously unknown connection between histone acetylation and cell-type-specific gene regulation and indicates that H2BK20ac profiling can be used to uncover new dimensions of gene regulation. © 2016 Kumar et al.; Published by Cold Spring Harbor Laboratory Press.

Liikelahjat mikro- ja pk-yrityksissä

OpenAIRE

Danhammer, Joni

2014-01-01

Liikelahjat ovat osa yrityksen menekinedistämistä ja kuuluvat tiiviisti yrityksen markkinointiviestintään. Kuitenkin yleinen talouden kiristynyt tilanne ja vuoden 2014 alussa voimaan astunut verouudistus liikelahjojen verovähennyksissä ovat asioita, jotka vaikuttavat liikelahjojen menekkiin ja niiden antamistapojen muuttumiseen mikro- ja pk-yrityksissä. Näin ollen yrityksillä tulisi tässä tilanteessa olla selkeä käsitys siitä, millaisia liikelahjoja yritys haluaa nykyisin henkilökunnalleen ja...

KCNMA1 encoded cardiac BK channels afford protection against ischemia-reperfusion injury

DEFF Research Database (Denmark)

Soltysinska, Ewa; Bentzen, Bo Hjorth; Barthmes, Maria

2014-01-01

Mitochondrial potassium channels have been implicated in myocardial protection mediated through pre-/postconditioning. Compounds that open the Ca2+- and voltage-activated potassium channel of big-conductance (BK) have a pre-conditioning-like effect on survival of cardiomyocytes after ischemia/rep...

DNA-PK inhibition causes a low level of H2AX phosphorylation and homologous recombination repair in Medaka (Oryzias latipes) cells

International Nuclear Information System (INIS)

Urushihara, Yusuke; Kobayashi, Junya; Matsumoto, Yoshihisa; Komatsu, Kenshi; Oda, Shoji; Mitani, Hiroshi

2012-01-01

Highlights: ► We investigated the effect of DNA-PK inhibition on DSB repair using fish cells. ► A radiation sensitive mutant RIC1 strain showed a low level of DNA-PK activity. ► DNA-PK dysfunction leads defects in HR repair and DNA-PKcs autophosphorylation. ► DNA-PK dysfunction leads a slight increase in the number of 53BP1 foci after DSBs. ► DNA-PK dysfunction leads an alternative NHEJ that depends on 53BP1. -- Abstract: Nonhomologous end joining (NHEJ) and homologous recombination (HR) are known as DNA double-strand break (DSB) repair pathways. It has been reported that DNA-PK, a member of PI3 kinase family, promotes NHEJ and aberrant DNA-PK causes NHEJ deficiency. However, in this study, we demonstrate that a wild-type cell line treated with DNA-PK inhibitor and a mutant cell line with dysfunctional DNA-PK showed decreased HR efficiency in fish cells (Medaka, Oryzias latipes). Previously, we reported that the radiation-sensitive mutant RIC1 strain has a defect in the Histone H2AX phosphorylation after γ-irradiation. Here, we showed that a DNA-PK inhibitor, NU7026, treatment resulted in significant reduction in the number of γH2AX foci after γ-irradiation in wild-type cells, but had no significant effect in RIC1 cells. In addition, RIC1 cells showed significantly lower levels of DNA-PK kinase activity compared with wild-type cells. We investigated NHEJ and HR efficiency after induction of DSBs. Wild-type cells treated with NU7026 and RIC1 cells showed decreased HR efficiency. These results indicated that aberrant DNA-PK causes the reduction in the number of γH2AX foci and HR efficiency in RIC1 cells. We performed phosphorylated DNA-PKcs (Thr2609) and 53BP1 focus assay after γ-irradiation. RIC1 cells showed significant reduction in the number of phosphorylated DNA-PKcs foci and no deference in the number of 53BP1 foci compared with wild-type cells. These results suggest that low level of DNA-PK activity causes aberrant DNA-PKcs autophosphorylation

Inhibition of CUG-binding protein 1 and activation of caspases are critically involved in piperazine derivative BK10007S induced apoptosis in hepatocellular carcinoma cells.

Directory of Open Access Journals (Sweden)

Ju-Ha Kim

Full Text Available Though piperazine derivative BK10007S was known to induce apoptosis in pancreatic cancer xenograft model as a T-type CaV3.1 a1G isoform calcium channel blocker, its underlying antitumor mechanism still remains unclear so far. Thus, in the present study, the antitumor mechanism of BK10007S was elucidated in hepatocellular carcinoma cells (HCCs. Herein, BK10007S showed significant cytotoxicity by 3-[4,5-2-yl]-2,5-diphenyltetra-zolium bromide (MTT assay and anti-proliferative effects by colony formation assay in HepG2 and SK-Hep1 cells. Also, apoptotic bodies and terminal deoxynucleotidyl transferase (TdT dUTP Nick End Labeling (TUNEL positive cells were observed in BK10007S treated HepG2 and SK-Hep1 cells by 4',6-diamidino-2-phenylinodole (DAPI staining and TUNEL assay, respectively. Consistently, BK10007S increased sub G1 population in HepG2 and SK-Hep1 cells by cell cycle analysis. Furthermore, Western blotting revealed that BK10007S activated the caspase cascades (caspase 8, 9 and 3, cleaved poly (ADP-ribose polymerase (PARP, and downregulated the expression of cyclin D1, survivin and for CUG-binding protein 1 (CUGBP1 or CELF1 in HepG2 and SK-Hep1 cells. Conversely, overexpression of CUGBP1 reduced cleavages of PARP and caspase 3, cytotoxicity and subG1 population in BK10007S treated HepG2 cells. Overall, these findings provide scientific evidences that BK10007S induces apoptosis via inhibition of CUGBP1 and activation of caspases in hepatocellular carcinomas as a potent anticancer candidate.

Sustained release ophthalmic dexamethasone: In vitro in vivo correlations derived from the PK-Eye.

Science.gov (United States)

Awwad, Sahar; Day, Richard M; Khaw, Peng T; Brocchini, Steve; Fadda, Hala M

2017-04-30

Corticosteroids have long been used to treat intraocular inflammation by intravitreal injection. We describe dexamethasone loaded poly-DL-lactide-co-glycolide (PLGA) microparticles that were fabricated by thermally induced phase separation (TIPS). The dexamethasone loaded microparticles were evaluated using a two-compartment, in vitro aqueous outflow model of the eye (PK-Eye) that estimates drug clearance time from the back of the eye via aqueous outflow by the anterior route. A dexamethasone dose of 0.20±0.02mg in a 50μL volume of TIPS microparticles resulted in a clearance t 1/2 of 9.6±0.3days using simulated vitreous in the PK-Eye. Since corticosteroids can also clear through the retina, it is necessary to account for clearance through the back of the eye. Retinal permeability data, published human ocular pharmacokinetics (PK) and the PK-Eye clearance times were then used to establish in vitro in vivo correlations (IVIVCs) for intraocular clearance times of corticosteroid formulations. A t 1/2 of 48h was estimated for the dexamethasone-TIPS microparticles, which is almost 9 times longer than that reported for dexamethasone suspension in humans. The prediction of human clearance times of permeable molecules from the vitreous compartment can be determined by accounting for drug retinal permeation and determining the experimental clearance via the anterior aqueous outflow pathway using the PK-Eye. Copyright © 2017. Published by Elsevier B.V.

Observation of the Decays Λ_{b}^{0}→χ_{c1}pK^{-} and Λ_{b}^{0}→χ_{c2}pK^{-}.

Science.gov (United States)

Aaij, R; Adeva, B; Adinolfi, M; Ajaltouni, Z; Akar, S; Albrecht, J; Alessio, F; Alexander, M; Ali, S; Alkhazov, G; Alvarez Cartelle, P; Alves, A A; Amato, S; Amerio, S; Amhis, Y; An, L; Anderlini, L; Andreassi, G; Andreotti, M; Andrews, J E; Appleby, R B; Archilli, F; d'Argent, P; Arnau Romeu, J; Artamonov, A; Artuso, M; Aslanides, E; Auriemma, G; Baalouch, M; Babuschkin, I; Bachmann, S; Back, J J; Badalov, A; Baesso, C; Baker, S; Balagura, V; Baldini, W; Baranov, A; Barlow, R J; Barschel, C; Barsuk, S; Barter, W; Baryshnikov, F; Baszczyk, M; Batozskaya, V; Battista, V; Bay, A; Beaucourt, L; Beddow, J; Bedeschi, F; Bediaga, I; Beiter, A; Bel, L J; Bellee, V; Belloli, N; Belous, K; Belyaev, I; Ben-Haim, E; Bencivenni, G; Benson, S; Beranek, S; Berezhnoy, A; Bernet, R; Bertolin, A; Betancourt, C; Betti, F; Bettler, M-O; van Beuzekom, M; Bezshyiko, Ia; Bifani, S; Billoir, P; Birnkraut, A; Bitadze, A; Bizzeti, A; Blake, T; Blanc, F; Blouw, J; Blusk, S; Bocci, V; Boettcher, T; Bondar, A; Bondar, N; Bonivento, W; Bordyuzhin, I; Borgheresi, A; Borghi, S; Borisyak, M; Borsato, M; Bossu, F; Boubdir, M; Bowcock, T J V; Bowen, E; Bozzi, C; Braun, S; Britton, T; Brodzicka, J; Buchanan, E; Burr, C; Bursche, A; Buytaert, J; Cadeddu, S; Calabrese, R; Calvi, M; Calvo Gomez, M; Camboni, A; Campana, P; Campora Perez, D H; Capriotti, L; Carbone, A; Carboni, G; Cardinale, R; Cardini, A; Carniti, P; Carson, L; Carvalho Akiba, K; Casse, G; Cassina, L; Castillo Garcia, L; Cattaneo, M; Cavallero, G; Cenci, R; Chamont, D; Charles, M; Charpentier, Ph; Chatzikonstantinidis, G; Chefdeville, M; Chen, S; Cheung, S F; Chobanova, V; Chrzaszcz, M; Chubykin, A; Cid Vidal, X; Ciezarek, G; Clarke, P E L; Clemencic, M; Cliff, H V; Closier, J; Coco, V; Cogan, J; Cogneras, E; Cogoni, V; Cojocariu, L; Collins, P; Comerma-Montells, A; Contu, A; Cook, A; Coombs, G; Coquereau, S; Corti, G; Corvo, M; Costa Sobral, C M; Couturier, B; Cowan, G A; Craik, D C; Crocombe, A; Cruz Torres, M; Cunliffe, S; Currie, R; D'Ambrosio, C; Da Cunha Marinho, F; Dall'Occo, E; Dalseno, J; Davis, A; De Aguiar Francisco, O; De Bruyn, K; De Capua, S; De Cian, M; De Miranda, J M; De Paula, L; De Serio, M; De Simone, P; Dean, C T; Decamp, D; Deckenhoff, M; Del Buono, L; Dembinski, H-P; Demmer, M; Dendek, A; Derkach, D; Deschamps, O; Dettori, F; Dey, B; Di Canto, A; Di Nezza, P; Dijkstra, H; Dordei, F; Dorigo, M; Dosil Suárez, A; Dovbnya, A; Dreimanis, K; Dufour, L; Dujany, G; Dungs, K; Durante, P; Dzhelyadin, R; Dziewiecki, M; Dziurda, A; Dzyuba, A; Déléage, N; Easo, S; Ebert, M; Egede, U; Egorychev, V; Eidelman, S; Eisenhardt, S; Eitschberger, U; Ekelhof, R; Eklund, L; Ely, S; Esen, S; Evans, H M; Evans, T; Falabella, A; Farley, N; Farry, S; Fay, R; Fazzini, D; Ferguson, D; Fernandez, G; Fernandez Prieto, A; Ferrari, F; Ferreira Rodrigues, F; Ferro-Luzzi, M; Filippov, S; Fini, R A; Fiore, M; Fiorini, M; Firlej, M; Fitzpatrick, C; Fiutowski, T; Fleuret, F; Fohl, K; Fontana, M; Fontanelli, F; Forshaw, D C; Forty, R; Franco Lima, V; Frank, M; Frei, C; Fu, J; Funk, W; Furfaro, E; Färber, C; Gabriel, E; Gallas Torreira, A; Galli, D; Gallorini, S; Gambetta, S; Gandelman, M; Gandini, P; Gao, Y; Garcia Martin, L M; García Pardiñas, J; Garra Tico, J; Garrido, L; Garsed, P J; Gascon, D; Gaspar, C; Gavardi, L; Gazzoni, G; Gerick, D; Gersabeck, E; Gersabeck, M; Gershon, T; Ghez, Ph; Gianì, S; Gibson, V; Girard, O G; Giubega, L; Gizdov, K; Gligorov, V V; Golubkov, D; Golutvin, A; Gomes, A; Gorelov, I V; Gotti, C; Govorkova, E; Graciani Diaz, R; Granado Cardoso, L A; Graugés, E; Graverini, E; Graziani, G; Grecu, A; Greim, R; Griffith, P; Grillo, L; Gruber, L; Gruberg Cazon, B R; Grünberg, O; Gushchin, E; Guz, Yu; Gys, T; Göbel, C; Hadavizadeh, T; Hadjivasiliou, C; Haefeli, G; Haen, C; Haines, S C; Hamilton, B; Han, X; Hansmann-Menzemer, S; Harnew, N; Harnew, S T; Harrison, J; Hatch, M; He, J; Head, T; Heister, A; Hennessy, K; Henrard, P; Henry, L; van Herwijnen, E; Heß, M; Hicheur, A; Hill, D; Hombach, C; Hopchev, P H; Huard, Z-C; Hulsbergen, W; Humair, T; Hushchyn, M; Hutchcroft, D; Idzik, M; Ilten, P; Jacobsson, R; Jalocha, J; Jans, E; Jawahery, A; Jiang, F; John, M; Johnson, D; Jones, C R; Joram, C; Jost, B; Jurik, N; Kandybei, S; Karacson, M; Kariuki, J M; Karodia, S; Kecke, M; Kelsey, M; Kenzie, M; Ketel, T; Khairullin, E; Khanji, B; Khurewathanakul, C; Kirn, T; Klaver, S; Klimaszewski, K; Klimkovich, T; Koliiev, S; Kolpin, M; Komarov, I; Kopecna, R; Koppenburg, P; Kosmyntseva, A; Kotriakhova, S; Kozachuk, A; Kozeiha, M; Kravchuk, L; Kreps, M; Krokovny, P; Kruse, F; Krzemien, W; Kucewicz, W; Kucharczyk, M; Kudryavtsev, V; Kuonen, A K; Kurek, K; Kvaratskheliya, T; Lacarrere, D; Lafferty, G; Lai, A; Lanfranchi, G; Langenbruch, C; Latham, T; Lazzeroni, C; Le Gac, R; van Leerdam, J; Leflat, A; Lefrançois, J; Lefèvre, R; Lemaitre, F; Lemos Cid, E; Leroy, O; Lesiak, T; Leverington, B; Li, T; Li, Y; Li, Z; Likhomanenko, T; Lindner, R; Lionetto, F; Liu, X; Loh, D; Longstaff, I; Lopes, J H; Lucchesi, D; Lucio Martinez, M; Luo, H; Lupato, A; Luppi, E; Lupton, O; Lusiani, A; Lyu, X; Machefert, F; Maciuc, F; Maev, O; Maguire, K; Malde, S; Malinin, A; Maltsev, T; Manca, G; Mancinelli, G; Manning, P; Maratas, J; Marchand, J F; Marconi, U; Marin Benito, C; Marinangeli, M; Marino, P; Marks, J; Martellotti, G; Martin, M; Martinelli, M; Martinez Santos, D; Martinez Vidal, F; Martins Tostes, D; Massacrier, L M; Massafferri, A; Matev, R; Mathad, A; Mathe, Z; Matteuzzi, C; Mauri, A; Maurice, E; Maurin, B; Mazurov, A; McCann, M; McNab, A; McNulty, R; Meadows, B; Meier, F; Melnychuk, D; Merk, M; Merli, A; Michielin, E; Milanes, D A; Minard, M-N; Mitzel, D S; Mogini, A; Molina Rodriguez, J; Monroy, I A; Monteil, S; Morandin, M; Morello, M J; Morgunova, O; Moron, J; Morris, A B; Morris, A P; Mountain, R; Muheim, F; Mulder, M; Mussini, M; Müller, D; Müller, J; Müller, K; Müller, V; Naik, P; Nakada, T; Nandakumar, R; Nandi, A; Nasteva, I; Needham, M; Neri, N; Neubert, S; Neufeld, N; Neuner, M; Nguyen, T D; Nguyen-Mau, C; Nieswand, S; Niet, R; Nikitin, N; Nikodem, T; Nogay, A; O'Hanlon, D P; Oblakowska-Mucha, A; Obraztsov, V; Ogilvy, S; Oldeman, R; Onderwater, C J G; Ossowska, A; Otalora Goicochea, J M; Owen, P; Oyanguren, A; Pais, P R; Palano, A; Palutan, M; Papanestis, A; Pappagallo, M; Pappalardo, L L; Pappenheimer, C; Parker, W; Parkes, C; Passaleva, G; Pastore, A; Patel, M; Patrignani, C; Pearce, A; Pellegrino, A; Penso, G; Pepe Altarelli, M; Perazzini, S; Perret, P; Pescatore, L; Petridis, K; Petrolini, A; Petrov, A; Petruzzo, M; Picatoste Olloqui, E; Pietrzyk, B; Pikies, M; Pinci, D; Pistone, A; Piucci, A; Placinta, V; Playfer, S; Plo Casasus, M; Poikela, T; Polci, F; Poli Lener, M; Poluektov, A; Polyakov, I; Polycarpo, E; Pomery, G J; Ponce, S; Popov, A; Popov, D; Popovici, B; Poslavskii, S; Potterat, C; Price, E; Prisciandaro, J; Prouve, C; Pugatch, V; Puig Navarro, A; Punzi, G; Qian, C; Qian, W; Quagliani, R; Rachwal, B; Rademacker, J H; Rama, M; Ramos Pernas, M; Rangel, M S; Raniuk, I; Ratnikov, F; Raven, G; Ravonel Salzgeber, M; Reboud, M; Redi, F; Reichert, S; Dos Reis, A C; Remon Alepuz, C; Renaudin, V; Ricciardi, S; Richards, S; Rihl, M; Rinnert, K; Rives Molina, V; Robbe, P; Rodrigues, A B; Rodrigues, E; Rodriguez Lopez, J A; Rodriguez Perez, P; Rogozhnikov, A; Roiser, S; Rollings, A; Romanovskiy, V; Romero Vidal, A; Ronayne, J W; Rotondo, M; Rudolph, M S; Ruf, T; Ruiz Valls, P; Saborido Silva, J J; Sadykhov, E; Sagidova, N; Saitta, B; Salustino Guimaraes, V; Sanchez Gonzalo, D; Sanchez Mayordomo, C; Sanmartin Sedes, B; Santacesaria, R; Santamarina Rios, C; Santimaria, M; Santovetti, E; Sarti, A; Satriano, C; Satta, A; Saunders, D M; Savrina, D; Schael, S; Schellenberg, M; Schiller, M; Schindler, H; Schlupp, M; Schmelling, M; Schmelzer, T; Schmidt, B; Schneider, O; Schopper, A; Schreiner, H F; Schubert, K; Schubiger, M; Schune, M-H; Schwemmer, R; Sciascia, B; Sciubba, A; Semennikov, A; Sergi, A; Serra, N; Serrano, J; Sestini, L; Seyfert, P; Shapkin, M; Shapoval, I; Shcheglov, Y; Shears, T; Shekhtman, L; Shevchenko, V; Siddi, B G; Silva Coutinho, R; Silva de Oliveira, L; Simi, G; Simone, S; Sirendi, M; Skidmore, N; Skwarnicki, T; Smith, E; Smith, I T; Smith, J; Smith, M; Soares Lavra, L; Sokoloff, M D; Soler, F J P; Souza De Paula, B; Spaan, B; Spradlin, P; Sridharan, S; Stagni, F; Stahl, M; Stahl, S; Stefko, P; Stefkova, S; Steinkamp, O; Stemmle, S; Stenyakin, O; Stevens, H; Stoica, S; Stone, S; Storaci, B; Stracka, S; Stramaglia, M E; Straticiuc, M; Straumann, U; Sun, L; Sutcliffe, W; Swientek, K; Syropoulos, V; Szczekowski, M; Szumlak, T; T'Jampens, S; Tayduganov, A; Tekampe, T; Tellarini, G; Teubert, F; Thomas, E; van Tilburg, J; Tilley, M J; Tisserand, V; Tobin, M; Tolk, S; Tomassetti, L; Tonelli, D; Topp-Joergensen, S; Toriello, F; Tourinho Jadallah Aoude, R; Tournefier, E; Tourneur, S; Trabelsi, K; Traill, M; Tran, M T; Tresch, M; Trisovic, A; Tsaregorodtsev, A; Tsopelas, P; Tully, A; Tuning, N; Ukleja, A; Ustyuzhanin, A; Uwer, U; Vacca, C; Vagnoni, V; Valassi, A; Valat, S; Valenti, G; Vazquez Gomez, R; Vazquez Regueiro, P; Vecchi, S; van Veghel, M; Velthuis, J J; Veltri, M; Veneziano, G; Venkateswaran, A; Verlage, T A; Vernet, M; Vesterinen, M; Viana Barbosa, J V; Viaud, B; Vieira, D; Vieites Diaz, M; Viemann, H; Vilasis-Cardona, X; Vitti, M; Volkov, V; Vollhardt, A; Voneki, B; Vorobyev, A; Vorobyev, V; Voß, C; de Vries, J A; Vázquez Sierra, C; Waldi, R; Wallace, C; Wallace, R; Walsh, J; Wang, J; Ward, D R; Wark, H M; Watson, N K; Websdale, D; Weiden, A; Whitehead, M; Wicht, J; Wilkinson, G; Wilkinson, M; Williams, M; Williams, M P; Williams, M; Williams, T; Wilson, F F; Wimberley, J; Winn, M A; Wishahi, J; Wislicki, W; Witek, M; Wormser, G; Wotton, S A; Wraight, K; Wyllie, K; Xie, Y; Xu, Z; Yang, Z; Yang, Z; Yao, Y; Yin, H; Yu, J; Yuan, X; Yushchenko, O; Zarebski, K A; Zavertyaev, M; Zhang, L; Zhang, Y; Zhelezov, A; Zheng, Y; Zhu, X; Zhukov, V; Zonneveld, J B; Zucchelli, S

2017-08-11

The first observation of the decays Λ_{b}^{0}→χ_{c1}pK^{-} and Λ_{b}^{0}→χ_{c2}pK^{-} is reported using a data sample corresponding to an integrated luminosity of 3.0  fb^{-1}, collected by the LHCb experiment in pp collisions at center-of-mass energies of 7 and 8 TeV. The following ratios of branching fractions are measured: B(Λ_{b}^{0}→χ_{c1}pK^{-})/B(Λ_{b}^{0}→J/ψpK^{-})=0.242±0.014±0.013±0.009,B(Λ_{b}^{0}→χ_{c2}pK^{-})/B(Λ_{b}^{0}→J/ψpK^{-})=0.248±0.020±0.014±0.009,B(Λ_{b}^{0}→χ_{c2}pK^{-})/B(Λ_{b}^{0}→χ_{c1}pK^{-})=1.02±0.10±0.02±0.05,where the first uncertainty is statistical, the second systematic, and the third due to the uncertainty on the branching fractions of the χ_{c1}→J/ψγ and χ_{c2}→J/ψγ decays. Using both decay modes, the mass of the Λ_{b}^{0} baryon is also measured to be m_{Λ_{b}^{0}}=5619.44±0.28±0.26  MeV/c^{2}, where the first and second uncertainties are statistical and systematic, respectively.

A single-center epidemiological study of BK virus infection and analysis of risk factors in patients with renal transplantation

Directory of Open Access Journals (Sweden)

Ji-gang LI

2014-10-01

Full Text Available Objective　To investigate the epidemiological characteristics of BK virus (BKV infection in living renal transplantation patients, and analyze the risk factors of BKV infection and BKV nephropathy (BKVN. Methods　The BKV DNA load in urine and blood samples of 43 renal transplant recipients, who had received renal transplantation in 309 Hospital from Feb. 2012 to Feb. 2013, was determined at preoperative period and 0.5, 1, 3, 6, 9, 12 and 15 months after transplantation. Meanwhile, the biopsy of grafted kidney was performed in those patients with continuously elevated serum creatinine and those with higher BKV DNA load. Patients were divided into 3 groups as follows according to the test results: BK viruria group, BK viremia group and pathologically diagnosed BKVN group. Data of each group were then recorded, including gender, age, postoperative diabetes (PTDM, acute rejection (AR, delayed recovery of graft function (DGF, postoperative pulmonary infection, preoperative immune induction therapy, postoperative immunosuppressive regimen, and other information. The risk factors for postoperative BKV infection and BKVN were analyzed. Results　After an average of 15-month follow-up, it was found that the incidence of BKV viruria was 46.5%, that of BKV viremia was 14.0%, and that of BKVN was 2.3%. Sixth month after transplantation was found to be the peak time of viruria and viremia. FK506 was significantly associated with viremia in living donor renal transplantation. The immunosuppressive regimen was the immune related independent risk factor for BK viremia developing BKVN after living renal transplantation. Conclusion　The incidence of BK viremia and BKVN is lower in living donor renal transplantation than in cadaver renal transplantation, but that of viruria is similar in both groups. Immunosuppressive scheme based on FK506 is an immune related independent risk factor leading to BK viremia proceeding to BKVN in living donor kidney

Data analysis & probability task sheets : grades pk-2

CERN Document Server

Cook, Tanya

2009-01-01

For grades PK-2, our Common Core State Standards-based resource meets the data analysis & probability concepts addressed by the NCTM standards and encourages your students to learn and review the concepts in unique ways. Each task sheet is organized around a central problem taken from real-life experiences of the students.

Sosiaalisen median kehittäminen pk-yrityksissä Töpseli-verkoston avulla

OpenAIRE

Palander, Laura

2010-01-01

Tämän opinnäytetyön tarkoituksena oli selvittää, minkälaisena mahdollisuutena pk-yrittäjät kokevat sosiaalisen median ja miten he ymmärtävät sen. Läntisellä Uudellamaalla toimivia yrityksiä on osallistunut Laurea-ammattikorkeakoulun Lohjan toimipisteen Töpseli-verkostoon. Verkoston tarkoituksena on vahvistaa länsi Uudellamaalla toimivien pk-yritysten kilpailukykyä, parantamalla yrittäjien ymmärrystä sosiaalisen median tarjoamista mahdollisuuksista. Työtä varten selvitettiin myös ammattikorkea...

Application of PK/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction

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Ijaz Ahmad

2016-01-01

Full Text Available Among veterinary drugs, antibiotics are frequently used. The true mean of antibiotic treatment is to administer dose of drug that will have enough high possibility of attaining the preferred curative effect, with adequately low chance of concentration associated toxicity. Rising of antibacterial resistance and lack of novel antibiotic is a global crisis; therefore there is an urgent need to overcome this problem. Inappropriate antibiotic selection, group treatment, and suboptimal dosing are mostly responsible for the mentioned problem. One approach to minimizing the antibacterial resistance is to optimize the dosage regimen. PK/PD model is important realm to be used for that purpose from several years. PK/PD model describes the relationship between drug potency, microorganism exposed to drug, and the effect observed. Proper use of the most modern PK/PD modeling approaches in veterinary medicine can optimize the dosage for patient, which in turn reduce toxicity and reduce the emergence of resistance. The aim of this review is to look at the existing state and application of PK/PD in veterinary medicine based on in vitro, in vivo, healthy, and disease model.

EARLY ULTRAVIOLET OBSERVATIONS OF A TYPE IIn SUPERNOVA (2007pk)

International Nuclear Information System (INIS)

Pritchard, T. A.; Roming, P. W. A.; Brown, P. J.; Kuin, N. P. M.; Oates, S. R.; Bayless, Amanda J.; Holland, S. T.; Immler, S.; Milne, P.

2012-01-01

We present some of the earliest UV observations of a Type IIn supernova (SN)—SN 2007pk, where UV and optical observations using Swift's Ultra-Violet/Optical Telescope began 3 days after discovery or ∼5 days after shock breakout. The SN observations commence at approximately maximum light in the UV and u-band filters, suggesting that the UV light curve peaks begin very rapidly after the initial explosion, and subsequently exhibit a linear decay of 0.20, 0.21, 0.16 mag day –1 in the UVOT uvw2, uvm2, uvw1 (λ c = 1928, 2246, 2600 Å) filters. Meanwhile the b- and v-band light curves begin approximately seven days before v-band peak and exhibit a shallow rise followed by a subsequent decay. A series of optical/near-IR spectra taken with the Hobby-Eberly Telescope at days 3-26 after discovery show spectra similar to that of the peculiar Type IIn 1998S. The emission from 2007pk falls below detection ∼20 days after discovery in the UV and 50 days in the optical, showing no sign of the long duration emission seen in other Type IIn SNe. We examine the physical and spectral characteristics of 2007pk and compare its UV light curve and decay rate with other Type II SNe.

Changes in the responsiveness of hypothalamic PK2 and PKR1 gene expression to fasting in developing male rats.

Science.gov (United States)

Iwasa, Takeshi; Matsuzaki, Toshiya; Tungalagsuvd, Altankhuu; Munkhzaya, Munkhsaikhan; Kawami, Takako; Yamasaki, Mikio; Murakami, Masahiro; Kato, Takeshi; Kuwahara, Akira; Yasui, Toshiyuki; Irahara, Minoru

2014-11-01

Prokineticin (PK2) and its receptors (PKRs) are expressed in several regions of the central nervous system, including the hypothalamus. It has been reported that PK2 inhibits food intake via PKR1 and that the hypothalamic PK2 mRNA levels of adult rodents were reduced by food deprivation. However, some hypothalamic factors do not exhibit sensitivity to undernutrition in the early neonatal period, but subsequently become sensitive to it during the neonatal to pre-pubertal period. In this study, we investigated the changes in the sensitivity of hypothalamic PK2 and PKR1 mRNA expression to fasting during the developmental period in male rats. Under the fed conditions, the rats' hypothalamic PK2 and/or PKR1 mRNA levels were higher on postnatal day (PND) 10 than on PND20 or PND30. In addition, the hypothalamic PK2 and/or PKR1 mRNA levels of the male rats were higher than those of the females at all examined ages (PND10, 20, and 30). Hypothalamic PK2 mRNA expression was decreased by 24h fasting at PND10 and 30, but not at PND20. In addition, hypothalamic PKR1 mRNA expression was decreased by 24h fasting at PND10, but not at PND20 or 30. These results indicate that both PK2 and PKR1 are sensitive to nutritional status in male rats and that this sensitivity has already been established by the early neonatal period. It can be speculated that the PK2 system might compensate for the immaturity of other appetite regulatory factors in the early neonatal period. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

Geologic Mapping of the Olympus Mons Volcano, Mars

Science.gov (United States)

Bleacher, J. E.; Williams, D. A.; Shean, D.; Greeley, R.

2012-01-01

We are in the third year of a three-year Mars Data Analysis Program project to map the morphology of the Olympus Mons volcano, Mars, using ArcGIS by ESRI. The final product of this project is to be a 1:1,000,000-scale geologic map. The scientific questions upon which this mapping project is based include understanding the volcanic development and modification by structural, aeolian, and possibly glacial processes. The project s scientific objectives are based upon preliminary mapping by Bleacher et al. [1] along a approx.80-km-wide north-south swath of the volcano corresponding to High Resolution Stereo Camera (HRSC) image h0037. The preliminary project, which covered approx.20% of the volcano s surface, resulted in several significant findings, including: 1) channel-fed lava flow surfaces are areally more abundant than tube-fed surfaces by a ratio of 5:1, 2) channel-fed flows consistently embay tube-fed flows, 3) lava fans appear to be linked to tube-fed flows, 4) no volcanic vents were identified within the map region, and 5) a Hummocky unit surrounds the summit and is likely a combination of non-channelized flows, dust, ash, and/or frozen volatiles. These results led to the suggestion that the volcano had experienced a transition from long-lived tube-forming eruptions to more sporadic and shorter-lived, channel-forming eruptions, as seen at Hawaiian volcanoes between the tholeiitic shield building phase (Kilauea to Mauna Loa) and alkalic capping phase (Hualalai and Mauna Kea).

A PK-PD model of ketamine-induced high-frequency oscillations

Science.gov (United States)

Flores, Francisco J.; Ching, ShiNung; Hartnack, Katharine; Fath, Amanda B.; Purdon, Patrick L.; Wilson, Matthew A.; Brown, Emery N.

2015-10-01

Objective. Ketamine is a widely used drug with clinical and research applications, and also known to be used as a recreational drug. Ketamine produces conspicuous changes in the electrocorticographic (ECoG) signals observed both in humans and rodents. In rodents, the intracranial ECoG displays a high-frequency oscillation (HFO) which power is modulated nonlinearly by ketamine dose. Despite the widespread use of ketamine there is no model description of the relationship between the pharmacokinetic-pharmacodynamics (PK-PDs) of ketamine and the observed HFO power. Approach. In the present study, we developed a PK-PD model based on estimated ketamine concentration, its known pharmacological actions, and observed ECoG effects. The main pharmacological action of ketamine is antagonism of the NMDA receptor (NMDAR), which in rodents is accompanied by an HFO observed in the ECoG. At high doses, however, ketamine also acts at non-NMDAR sites, produces loss of consciousness, and the transient disappearance of the HFO. We propose a two-compartment PK model that represents the concentration of ketamine, and a PD model based in opposing effects of the NMDAR and non-NMDAR actions on the HFO power. Main results. We recorded ECoG from the cortex of rats after two doses of ketamine, and extracted the HFO power from the ECoG spectrograms. We fit the PK-PD model to the time course of the HFO power, and showed that the model reproduces the dose-dependent profile of the HFO power. The model provides good fits even in the presence of high variability in HFO power across animals. As expected, the model does not provide good fits to the HFO power after dosing the pure NMDAR antagonist MK-801. Significance. Our study provides a simple model to relate the observed electrophysiological effects of ketamine to its actions at the molecular level at different concentrations. This will improve the study of ketamine and rodent models of schizophrenia to better understand the wide and divergent

The temperature dependence of the BK channel activity - kinetics, thermodynamics, and long-range correlations.

Science.gov (United States)

Wawrzkiewicz-Jałowiecka, Agata; Dworakowska, Beata; Grzywna, Zbigniew J

2017-10-01

Large-conductance, voltage dependent, Ca 2+ -activated potassium channels (BK) are transmembrane proteins that regulate many biological processes by controlling potassium flow across cell membranes. Here, we investigate to what extent temperature (in the range of 17-37°C with ΔT=5°C step) is a regulating parameter of kinetic properties of the channel gating and memory effect in the series of dwell-time series of subsequent channel's states, at membrane depolarization and hyperpolarization. The obtained results indicate that temperature affects strongly the BK channels' gating, but, counterintuitively, it exerts no effect on the long-range correlations, as measured by the Hurst coefficient. Quantitative differences between dependencies of appropriate channel's characteristics on temperature are evident for different regimes of voltage. Examining the characteristics of BK channel activity as a function of temperature allows to estimate the net activation energy (E act ) and changes of thermodynamic parameters (ΔH, ΔS, ΔG) by channel opening. Larger E act corresponds to the channel activity at membrane hyperpolarization. The analysis of entropy and enthalpy changes of closed to open channel's transition suggest the entropy-driven nature of the increase of open state probability during voltage activation and supports the hypothesis about the voltage-dependent geometry of the channel vestibule. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of Growing Media on Yield and Fruitbody Properties of Hericium Isolates

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Funda Atila

2016-03-01

Full Text Available In the present study, it was aimed to determinate the effects of different substrates on mycelial growth, fructification, yield, sizes and colours of fruit bodies of Hericium isolates (HE-Ankara, HE-Denizli, HE, HE-Trabzon, HE-İzmit, HC, HE-Amerika. Experiments were conducted with 7 different substrates prepared with oak sawdust (MT, wheat bran (BK, cotton seed hulls (PK and olive press cake (ZP (80MT:20BK, 90MT:10PK, 80MT:20PK, 70MT:30PK, 90MT:10ZP, 80MT:20ZP, 70MT:30ZP. 1 kg (wet weight of substrates were packed in polypropylene autoclaveable bags of 25x45 cm and sterilized in autoclave at 121oC during 90 minutes. Sterilized substrate was inoculated and then carried to growing room at 25±2ºC. After full colonization, the bags were exposed to 400 lux for a 12 hours photoperiod at 20±2ºC with a humidity of 80-90% in a cropping room. The best yield and BE were detected from oak sawdust medium supplemented with 20 and 30% cotton seed hulls on HE-Ankara, HE-Denizli, HE, HE-İzmit, HC, HE-Amerika isolates while the best yield and BE were detected from 70MT:30ZP on Trabzon isolate. Significant differences were found among substrates regarding yield, BE, average mushroom weigh, fruit body size and colour of Hericium isolates.

Rapid and efficient radiosynthesis of [123I]I-PK11195, a single photon emission computed tomography tracer for peripheral benzodiazepine receptors

International Nuclear Information System (INIS)

Pimlott, Sally L.; Stevenson, Louise; Wyper, David J.; Sutherland, Andrew

2008-01-01

Introduction: [ 123 I]I-PK11195 is a high-affinity single photon emission computed tomography radiotracer for peripheral benzodiazepine receptors that has previously been used to measure activated microglia and to assess neuroinflammation in the living human brain. This study investigates the radiosynthesis of [ 123 I]I-PK11195 in order to develop a rapid and efficient method that obtains [ 123 I]I-PK11195 with a high specific activity for in vivo animal and human imaging studies. Methods: The synthesis of [ 123 I]I-PK11195 was evaluated using a solid-state interhalogen exchange method and an electrophilic iododestannylation method, where bromine and trimethylstannyl derivatives were used as precursors, respectively. In the electrophilic iododestannylation method, the oxidants peracetic acid and chloramine-T were both investigated. Results: Electrophilic iododestannylation produced [ 123 I]I-PK11195 with a higher isolated radiochemical yield and a higher specific activity than achievable using the halogen exchange method investigated. Using chloramine-T as oxidant provided a rapid and efficient method of choice for the synthesis of [ 123 I]I-PK11195. Conclusions: [ 123 I]I-PK11195 has been successfully synthesized via a rapid and efficient electrophilic iododestannylation method, producing [ 123 I]I-PK11195 with a higher isolated radiochemical yield and a higher specific activity than previously achieved

In cellulo phosphorylation of XRCC4 Ser320 by DNA-PK induced by DNA damage

International Nuclear Information System (INIS)

Sharma, Mukesh Kumar; Imamichi, Shoji; Fukuchi, Mikoto; Samarth, Ravindra Mahadeo; Tomita, Masanori; Matsumoto, Yoshihisa

2016-01-01

XRCC4 is a protein associated with DNA Ligase IV, which is thought to join two DNA ends at the final step of DNA double-strand break repair through non-homologous end joining. In response to treatment with ionizing radiation or DNA damaging agents, XRCC4 undergoes DNA-PK-dependent phosphorylation. Furthermore, Ser260 and Ser320 (or Ser318 in alternatively spliced form) of XRCC4 were identified as the major phosphorylation sites by purified DNA-PK in vitro through mass spectrometry. However, it has not been clear whether these sites are phosphorylated in vivo in response to DNA damage. In the present study, we generated an antibody that reacts with XRCC4 phosphorylated at Ser320 and examined in cellulo phosphorylation status of XRCC4 Ser320. The phosphorylation of XRCC4 Ser320 was induced by γ-ray irradiation and treatment with Zeocin. The phosphorylation of XRCC4 Ser320 was detected even after 1 Gy irradiation and increased in a manner dependent on radiation dose. The phosphorylation was observed immediately after irradiation and remained mostly unchanged for up to 4 h. The phosphorylation was inhibited by DNA-PK inhibitor NU7441 and was undetectable in DNA-PKcs-deficient cells, indicating that the phosphorylation was mainly mediated by DNA-PK. These results suggested potential usefulness of the phosphorylation status of XRCC4 Ser320 as an indicator of DNA-PK functionality in living cells

Phase 1b randomized trial and follow-up study in Uganda of the blood-stage malaria vaccine candidate BK-SE36.

Science.gov (United States)

Palacpac, Nirianne Marie Q; Ntege, Edward; Yeka, Adoke; Balikagala, Betty; Suzuki, Nahoko; Shirai, Hiroki; Yagi, Masanori; Ito, Kazuya; Fukushima, Wakaba; Hirota, Yoshio; Nsereko, Christopher; Okada, Takuya; Kanoi, Bernard N; Tetsutani, Kohhei; Arisue, Nobuko; Itagaki, Sawako; Tougan, Takahiro; Ishii, Ken J; Ueda, Shigeharu; Egwang, Thomas G; Horii, Toshihiro

2013-01-01

Up to now a malaria vaccine remains elusive. The Plasmodium falciparum serine repeat antigen-5 formulated with aluminum hydroxyl gel (BK-SE36) is a blood-stage malaria vaccine candidate that has undergone phase 1a trial in malaria-naive Japanese adults. We have now assessed the safety and immunogenicity of BK-SE36 in a malaria endemic area in Northern Uganda. We performed a two-stage, randomized, single-blinded, placebo-controlled phase 1b trial (Current Controlled trials ISRCTN71619711). A computer-generated sequence randomized healthy subjects for 2 subcutaneous injections at 21-day intervals in Stage1 (21-40 year-olds) to 1-mL BK-SE36 (BKSE1.0) (n = 36) or saline (n = 20) and in Stage2 (6-20 year-olds) to BKSE1.0 (n = 33), 0.5-mL BK-SE36 (BKSE0.5) (n = 33), or saline (n = 18). Subjects and laboratory personnel were blinded. Safety and antibody responses 21-days post-second vaccination (Day42) were assessed. Post-trial, to compare the risk of malaria episodes 130-365 days post-second vaccination, Stage2 subjects were age-matched to 50 control individuals. Nearly all subjects who received BK-SE36 had induration (Stage1, n = 33, 92%; Stage2, n = 63, 96%) as a local adverse event. No serious adverse event related to BK-SE36 was reported. Pre-existing anti-SE36 antibody titers negatively correlated with vaccination-induced antibody response. At Day42, change in antibody titers was significant for seronegative adults (1.95-fold higher than baseline [95% CI, 1.56-2.43], p = 0.004) and 6-10 year-olds (5.71-fold [95% CI, 2.38-13.72], p = 0.002) vaccinated with BKSE1.0. Immunogenicity response to BKSE0.5 was low and not significant (1.55-fold [95% CI, 1.24-1.94], p = 0.75). In the ancillary analysis, cumulative incidence of first malaria episodes with ≥5000 parasites/µL was 7 cases/33 subjects in BKSE1.0 and 10 cases/33 subjects in BKSE0.5 vs. 29 cases/66 subjects in the control group. Risk ratio for BKSE1.0 was 0.48 (95% CI, 0

Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model.

Science.gov (United States)

Tanoshima, Reo; Bournissen, Facundo Garcia; Tanigawara, Yusuke; Kristensen, Judith H; Taddio, Anna; Ilett, Kenneth F; Begg, Evan J; Wallach, Izhar; Ito, Shinya

2014-10-01

Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration-time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk. Using a previously published data set of drug concentrations in milk from 25 women treated with FX, a pop PK model predictive of milk concentration-time profiles of FX and NFX was developed. Simulation was performed with the model to generate FX and NFX concentration-time profiles in milk of 1000 mothers. This milk concentration-based pop PK model was compared with the previously validated plasma/milk concentration-based pop PK model of FX. Milk FX and NFX concentration-time profiles were described reasonably well by a one compartment model with a FX-to-NFX conversion coefficient. Median values of the simulated relative infant dose on a weight basis (sRID: weight-adjusted daily doses of FX and NFX through breastmilk to the infant, expressed as a fraction of therapeutic FX daily dose per body weight) were 0.028 for FX and 0.029 for NFX. The FX sRID estimates were consistent with those of the plasma/milk-based pop PK model. A predictive pop PK model based on only milk concentrations can be developed for simultaneous estimation of milk concentration-time profiles of a parent (FX) and an active metabolite (NFX). © 2014 The British Pharmacological Society.

Pk-yrityksen kansainvälistyminen : Taide esineitä liikelahjoina Japaniin ja Etelä-Koreaan

OpenAIRE

Takala, Sanna; Ristikankare, Roosa

2009-01-01

Tämän opinnäytetyön taustalla oli Laurea-ammattikorkeakoulun ESR-rahoitteinen projekti “Teollisen palveluliiketoiminnan koulutustarpeen selvittäminen Lohjan ja Tammisaaren seutukunnissa ja näiden alueiden pk-yritysten osaamisperustan kehittäminen”. Opinnäytetyö sijoittui hankkeen toimenpidekokonaisuuteen ”Teemakoulutus ja kehityshankkeet yritysryppäälle”, pk-yrityksen kansainvälistymiseen liittyvänä tutkimus- ja kehittämishankkeena. Tutkimus- ja kehittämishankkeen tarkoituksena oli tuotta...

Radioligands for PET studies of central benzodiazepine receptors and PK (peripheral benzodiazepine) binding sites -current status

International Nuclear Information System (INIS)

Pike, V.W.; Osman, S.; Shah, F.; Turton, D.R.; Waters, S.L.; Crouzel, C.; Nutt, D.J.

1993-01-01

The status of the radiochemical development and biological evaluation of radioligands for PET studies of central benzodiazepine (BZ) receptors and the so-called peripheral benzodiazepine binding sites, here discriminated and referred to as PK binding sites, is reviewed against current pharmacological knowledge, indicating those agents with present value and those with future potential. Practical recommendations are given for the preparation of two useful radioligands for PET studies, [N-methyl- 11 C]flumazenil for central BZ receptors, and [N-methyl- 11 C]PK 11195 for PK binding sites. Quality assurance and plasma metabolite analysis are also reviewed for these radioligands and practical recommendations are given on methodology for their performance. (Author)

Chemical consequences of radioactive decay. 1. Study of 249Cf ingrowth into crystalline 249BkBr3: a new crystalline phase of CfBr3

International Nuclear Information System (INIS)

Young, J.P.; Haire, R.G.; Peterson, J.R.; Ensor, D.D.; Fellows, R.L.

1980-01-01

Spectrophotometric and x-ray powder diffraction methods have been applied to a study of the ingrowth of californium-249 by β - decay of berkelium-249 in crystalline 249 BkBr 3 . It was found that the Cf daughter grows in with the same oxidation state and crystal structure as the parent. Thus, six-coordinate BkBr 3 (AlCl 3 -type monoclinic structure) generates six-coordinate CfBr 3 , and eight-coordinate BkBr 3 (PuBr 3 -type orthorhombic structure) generates eight-coordinate CfBr 3 , a previously unknown form of CfBr 3 . It was also found that the daughter Cf(III) in the BkBr 3 parent compound can be reduced to Cf(II) by treatment with H 2 , as it can in pure CfBr 3 . 5 figures

Preliminary study on rotary ultrasonic machining of Bk-7 optical glass rod

International Nuclear Information System (INIS)

Hamzah, E.; Izman, S.; Khoo, C.Y.; Zainal Abidin, N.N.

2007-01-01

This paper presents an experimental observation on rotary ultrasonic machining (RUM) of BK7 optical glass rod. BK7 is a common technical optical glass for high quality optical components due to its high linear optical transmission in the visible range and is chemically stable. RUM is a hybrid machining process that combines the material removal mechanisms of diamond grinding and ultrasonic machining (USM) and it is non-thermal, non-chemical, creates no change in the microstructure, chemical or physical properties of the work piece. In the RUM, a controlled static load is applied to the rotating core drill with metal bonded diamond abrasive and is ultrasonically vibrated in the axial direction. A water-soluble coolant was used to cool the tool and sample during machining processes. By using DOE (Design of Experiment) approach, the effect of spindle speed and feed rate to the ultrasonic machinability had been developed. The main effects and two-factor interactions of process parameters (spindle speed) and feed rate) on output variables (MRR, surface roughness, opaqueness, chipping thickness and chipping size) are studied. (author)

High-level viruria as a screening tool for BK virus nephropathy in renal transplant recipients

Directory of Open Access Journals (Sweden)

W. James Chon

2016-09-01

Conclusion: The presence of high-grade viruria is an early marker for developing BK viremia/BKVN. Detection of high-grade viruria should prompt early allograft biopsy and/or preemptive reduction in immunosuppression.

Functional characteristics of a renal H+/lipophilic cation antiport system in porcine LLC-PK1 cells and rats.

Science.gov (United States)

Matsui, Ryutaro; Hattori, Ryutaro; Usami, Youhei; Koyama, Masumi; Hirayama, Yuki; Matsuba, Emi; Hashimoto, Yukiya

2018-02-01

We have recently found an H + /quinidine (a lipophilic cation, QND) antiport system in Madin-Darby canine kidney (MDCK) cells. The primary aim of the present study was to evaluate whether the H + /lipophilic cation antiport system is expressed in porcine LLC-PK 1 cells. That is, we investigated uptake and/or efflux of QND and another cation, bisoprolol, in LLC-PK 1 cells. In addition, we studied the renal clearance of bisoprolol in rats. Uptake of QND into LLC-PK 1 cells was decreased by acidification of the extracellular pH or alkalization of the intracellular pH. Cellular uptake of QND from the apical side was much greater than from the basolateral side. In addition, apical efflux of QND from LLC-PK 1 cells was increased by acidification of the extracellular pH. Furthermore, lipophilic cationic drugs significantly reduced uptake of bisoprolol in LLC-PK 1 cells. Renal clearance of bisoprolol in rats was approximately 7-fold higher than that of creatinine, and was markedly decreased by alkalization of the urine pH. The present study suggests that the H + /lipophilic cation antiport system is expressed in the apical membrane of LLC-PK 1 cells. Moreover, the H + /lipophilic cation antiport system may be responsible for renal tubular secretion of bisoprolol in rats. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Absence of mutations in the coding sequence of the potential tumor suppressor 3pK in metastatic melanoma

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Houben Roland

2005-12-01

Full Text Available Abstract Background Activation of Ras or Raf contributes to tumorigenesis of melanoma. However, constitutive Raf activation is also a characteristic of the majority of benign melanocytic nevi and high intensity signaling of either Ras or Raf was found to induce growth inhibition and senescence rather than transformation. Since the chromosome 3p kinase (3pK is a target of the Ras/Raf/Mek/Erk signaling pathway which antagonizes the function of the oncogene and anti-differentiation factor Bmi-1, 3pK may function as a tumor suppressor in tumors with constitutive Ras/Raf activation. Consequently, we tested whether inactivating 3pK mutations are present in melanoma. Methods 30 metastatic melanoma samples, which were positive for activating mutations of either BRaf or NRas, were analyzed for possible mutations in the 3pk gene. The 10 coding exons and their flanking intron sequences were amplified by PCR and direct sequencing of the PCR products was performed. Results This analysis revealed that besides the presence of some single nucleotide polymorphisms in the 3pk gene, we could not detect any possible loss of function mutation in any of these 30 metastatic melanoma samples selected for the presence of activating mutations within the Ras/Raf/Mek/Erk signaling pathway. Conclusion Hence, in melanoma with constitutively active Ras/Raf inactivating mutations within the 3pk gene do not contribute to the oncogenic phenotype of this highly malignant tumor.

Effects of Nonlinear Absorption in BK7 and Color Glasses at 355 nm

International Nuclear Information System (INIS)

Adams, J J; McCarville, T; Bruere, J; McElroy, J; Peterson, J

2003-01-01

We have demonstrated a simple experimental technique that can be used to measure the nonlinear absorption coefficients in glasses. We determine BK7, UG1, and UG11 glasses to have linear absorption coefficients of 0.0217 ± 10% cm -1 , 1.7 ± 10% cm -1 , and 0.82 ± 10% cm -1 , respectively, two-photon absorption cross-sections of 0.025 ± 20% cm/GW, 0.035 ± 20% cm/GW, and 0.047 ± 20% cm/GW, respectively, excited-state absorption cross-sections of 8.0 x 10 -18 ± 20% cm 2 , 2.8 x 10 -16 ± 20% cm 2 , and 5 x 10 -17 ± 20% cm 2 , respectively, and solarization coefficients of 8.5 x 10 -20 ± 20% cm 2 , 2.5 x 10 -18 ± 20% cm 2 , and 1.3 x 10 -19 ± 20% cm 2 , respectively. For our application, nonlinear effects in 10-cm of BK7 are small ((le) 2%) for 355-nm fluences 2 for flat-top pulses. However, nonlinear effects are noticeable for 355-nm fluences at 0.8 J/cm 2 . In particular, we determine a 20% increase in the instantaneous absorption from linear, a solarization rate of 4% per 100 shots, and a 10% temporal droop introduced in the pulse, for 355-nm flat-top pulses at a fluence of 0.8 J/cm 2 . For 0.5-cm of UG1 absorbing glass the non-linear absorption has a similar effect as that from 10-cm of BK7 on the pulse shape; however, the effects in UG11 are much smaller

Mechanism-based PK/PD modeling of selective serotonin reuptake inhibitors

NARCIS (Netherlands)

Geldof, Marian

2007-01-01

The main objective of the investigations was to explore the PK/PD correlations of fluvoxamine, as a prototype for the Selective Serotonin Reuptake Inhibitors (SSRIs). In the various investigations, a spectrum of different biomarkers was used, each reflecting a specific process on the causal path

Rapid and efficient radiosynthesis of [{sup 123}I]I-PK11195, a single photon emission computed tomography tracer for peripheral benzodiazepine receptors

Energy Technology Data Exchange (ETDEWEB)

Pimlott, Sally L. [Department of Clinical Physics, West of Scotland Radionuclide Dispensary, Western Infirmary, G11 6NT Glasgow (United Kingdom)], E-mail: s.pimlott@clinmed.gla.ac.uk; Stevenson, Louise [Department of Chemistry, WestCHEM, University of Glasgow, G12 8QQ Glasgow (United Kingdom); Wyper, David J. [Institute of Neurological Sciences, Southern General Hospital, G51 4TF Glasgow (United Kingdom); Sutherland, Andrew [Department of Chemistry, WestCHEM, University of Glasgow, G12 8QQ Glasgow (United Kingdom)

2008-07-15

Introduction: [{sup 123}I]I-PK11195 is a high-affinity single photon emission computed tomography radiotracer for peripheral benzodiazepine receptors that has previously been used to measure activated microglia and to assess neuroinflammation in the living human brain. This study investigates the radiosynthesis of [{sup 123}I]I-PK11195 in order to develop a rapid and efficient method that obtains [{sup 123}I]I-PK11195 with a high specific activity for in vivo animal and human imaging studies. Methods: The synthesis of [{sup 123}I]I-PK11195 was evaluated using a solid-state interhalogen exchange method and an electrophilic iododestannylation method, where bromine and trimethylstannyl derivatives were used as precursors, respectively. In the electrophilic iododestannylation method, the oxidants peracetic acid and chloramine-T were both investigated. Results: Electrophilic iododestannylation produced [{sup 123}I]I-PK11195 with a higher isolated radiochemical yield and a higher specific activity than achievable using the halogen exchange method investigated. Using chloramine-T as oxidant provided a rapid and efficient method of choice for the synthesis of [{sup 123}I]I-PK11195. Conclusions: [{sup 123}I]I-PK11195 has been successfully synthesized via a rapid and efficient electrophilic iododestannylation method, producing [{sup 123}I]I-PK11195 with a higher isolated radiochemical yield and a higher specific activity than previously achieved.

Vaccine for BK Polyomavirus-associated Infections in Transplant Recipients | NCI Technology Transfer Center | TTC

Science.gov (United States)

NCI researches identified a BK polyomavirus (BKV) virulent strain that causes chronic urinary tract infections, and the development of vaccine and therapeutic methods that would block BKV pathogenesis. The NCI Laboratory of Cellular Oncology, seek parties to license or co-develop this technology.

The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics.

Science.gov (United States)

Fishburn, C Simone

2008-10-01

Conjugation of macromolecules to polyethylene glycol (PEG) has emerged recently as an effective strategy to alter the pharmacokinetic (PK) profiles of a variety of drugs, and thereby to improve their therapeutic potential. PEG conjugation increases retention of drugs in the circulation by protecting against enzymatic digestion, slowing filtration by the kidneys and reducing the generation of neutralizing antibodies. Often, PEGylation leads to a loss in binding affinity due to steric interference with the drug-target binding interaction. This loss in potency is offset by the longer circulating half-life of the drugs, and the resulting change in PK-PD profile has led in some cases to enabling of drugs that otherwise could not be developed, and in others to improvements in existing drugs. Thus, whereas most approaches to drug development seek to increase the activity of drugs directly, the creation of PEGylated drugs seeks to balance the pharmacodynamic (PD) and pharmacokinetic properties to produce novel therapies that will meet with both increased efficacy and greater compliance in the clinical setting. This review examines some of the PEGylated drugs developed in recent years, and highlights some of the different strategies taken to employ PEG to maximize the overall PK-PD profiles of these compounds. (c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association

Unraveling hominin behavior at another anthropogenic site from Olduvai Gorge (Tanzania): new archaeological and taphonomic research at BK, Upper Bed II.

Science.gov (United States)

Domínguez-Rodrigo, M; Mabulla, A; Bunn, H T; Barba, R; Diez-Martín, F; Egeland, C P; Espílez, E; Egeland, A; Yravedra, J; Sánchez, P

2009-09-01

New archaeological excavations and research at BK, Upper Bed II (Olduvai Gorge, Tanzania) have yielded a rich and unbiased collection of fossil bones. These new excavations show that BK is a stratified deposit formed in a riverine setting close to an alluvial plain. The present taphonomic study reveals the second-largest collection of hominin-modified bones from Olduvai, with abundant cut marks found on most of the anatomical areas preserved. Meat and marrow exploitation is reconstructed using the taphonomic signatures left on the bones by hominins. Highly cut-marked long limb shafts, especially those of upper limb bones, suggest that hominins at BK were actively engaged in acquiring small and middle-sized animals using strategies other than passive scavenging. The exploitation of large-sized game (Pelorovis) by Lower Pleistocene hominins, as suggested by previous researchers, is supported by the present study.

Overexpression of the Large-Conductance, Ca2+-Activated K+ (BK) Channel Shortens Action Potential Duration in HL-1 Cardiomyocytes.

Science.gov (United States)

Stimers, Joseph R; Song, Li; Rusch, Nancy J; Rhee, Sung W

2015-01-01

Long QT syndrome is characterized by a prolongation of the interval between the Q wave and the T wave on the electrocardiogram. This abnormality reflects a prolongation of the ventricular action potential caused by a number of genetic mutations or a variety of drugs. Since effective treatments are unavailable, we explored the possibility of using cardiac expression of the large-conductance, Ca2+-activated K+ (BK) channel to shorten action potential duration (APD). We hypothesized that expression of the pore-forming α subunit of human BK channels (hBKα) in HL-1 cells would shorten action potential duration in this mouse atrial cell line. Expression of hBKα had minimal effects on expression levels of other ion channels with the exception of a small but significant reduction in Kv11.1. Patch-clamped hBKα expressing HL-1 cells exhibited an outward voltage- and Ca2+-sensitive K+ current, which was inhibited by the BK channel blocker iberiotoxin (100 nM). This BK current phenotype was not detected in untransfected HL-1 cells or in HL-1 null cells sham-transfected with an empty vector. Importantly, APD in hBKα-expressing HL-1 cells averaged 14.3 ± 2.8 ms (n = 10), which represented a 53% reduction in APD compared to HL-1 null cells lacking BKα expression. APD in the latter cells averaged 31.0 ± 5.1 ms (n = 13). The shortened APD in hBKα-expressing cells was restored to normal duration by 100 nM iberiotoxin, suggesting that a repolarizing K+ current attributed to BK channels accounted for action potential shortening. These findings provide initial proof-of-concept that the introduction of hBKα channels into a cardiac cell line can shorten APD, and raise the possibility that gene-based interventions to increase hBKα channels in cardiac cells may hold promise as a therapeutic strategy for long QT syndrome.

Distinct genetic difference between the Duffy binding protein (PkDBPαII) of Plasmodium knowlesi clinical isolates from North Borneo and Peninsular Malaysia.

Science.gov (United States)

Fong, Mun-Yik; Rashdi, Sarah A A; Yusof, Ruhani; Lau, Yee-Ling

2015-02-21

Plasmodium knowlesi is one of the monkey malaria parasites that can cause human malaria. The Duffy binding protein of P. knowlesi (PkDBPαII) is essential for the parasite's invasion into human and monkey erythrocytes. A previous study on P. knowlesi clinical isolates from Peninsular Malaysia reported high level of genetic diversity in the PkDBPαII. Furthermore, 36 amino acid haplotypes were identified and these haplotypes could be separated into allele group I and allele group II. In the present study, the PkDBPαII of clinical isolates from the Malaysian states of Sarawak and Sabah in North Borneo was investigated, and compared with the PkDBPαII of Peninsular Malaysia isolates. Blood samples from 28 knowlesi malaria patients were used. These samples were collected between 2011 and 2013 from hospitals in North Borneo. The PkDBPαII region of the isolates was amplified by PCR, cloned into Escherichia coli, and sequenced. The genetic diversity, natural selection and phylogenetics of PkDBPαII haplotypes were analysed using MEGA5 and DnaSP ver. 5.10.00 programmes. Forty-nine PkDBPαII sequences were obtained. Comparison at the nucleotide level against P. knowlesi strain H as reference sequence revealed 58 synonymous and 102 non-synonymous mutations. Analysis on these mutations showed that PkDBPαII was under purifying (negative) selection. At the amino acid level, 38 different PkDBPαII haplotypes were identified. Twelve of the 28 blood samples had mixed haplotype infections. Phylogenetic analysis revealed that all the haplotypes were in allele group I, but they formed a sub-group that was distinct from those of Peninsular Malaysia. Wright's FST fixation index indicated high genetic differentiation between the North Borneo and Peninsular Malaysia haplotypes. This study is the first to report the genetic diversity and natural selection of PkDBPαII of P. knowlesi from Borneo Island. The PkDBPαII haplotypes found in this study were distinct from those from

Study of the properties of the superheavy nuclei Z=117 produced in the 249Bk + 48Ca reaction

International Nuclear Information System (INIS)

Oganessian, Y.T.; Abdullin, F.S.; Dmitriev, S.N.; Itkis, M.G.; Polyakov, A.N.; Sagaidak, R.N.; Shirokovsky, I.V.; Shumeiko, M.V.; Subbotin, V.G.; Sukhov, A.M.; Tsyganov, Y.S.; Utyonkov, V.K.; Voinov, A.A.; Vostokin, G.K.; Alexander, C.; Binder, J.; Boll, R.A.; Ezold, J.; Felker, K.; Miernik, K.; Roberto, J.B.; Rykaczewski, K.P.; Gostic, J.M.; Henderson, R.A.; Moody, K.J.; Shaughnessy, D.H.; Stoyer, M.A.; Stoyer, N.J.; Grzywacz, R.K.; Miller, D.; Hamilton, J.H.; Ramayya, A.V.; Ryabinin, M.A.

2014-01-01

The reaction of 249 Bk with 48 Ca have been reinvestigated to provide new evidence for the discovery of element 117 on a larger number of events. The experiments were performed at five projectile energies and with a total beam dose of 48 Ca of about 4.6*10 19 . Two isotopes 293,294 117 were synthesized in the 249 Bk+ 48 Ca reaction, providing excitation functions and α-decay spectra of the produced isotopes that establishes these nuclei to be the products of the 4n- and 3n-evaporation channels, respectively. Decay properties of 293,294 117 and of all the daughter products agree with the data of the experiment in which these nuclei were synthesized for the first time in 2010. The new 289 115 events, populated by a decay of 293 117, demonstrate the same decay properties as those observed for 289 115 produced in the 243 Am( 48 Ca,2n) reaction thus providing cross-bombardment evidence. In addition, a single decay of 294 118 was observed from the reaction with 249 Cf - a result of the in-growth of 249 Cf in the 249 Bk target. (authors)

Statin therapy exacerbates alcohol-induced constriction of cerebral arteries via modulation of ethanol-induced BK channel inhibition in vascular smooth muscle.

Science.gov (United States)

Simakova, Maria N; Bisen, Shivantika; Dopico, Alex M; Bukiya, Anna N

2017-12-01

Statins constitute the most commonly prescribed drugs to decrease cholesterol (CLR). CLR is an important modulator of alcohol-induced cerebral artery constriction (AICAC). Using rats on a high CLR diet (2% CLR) we set to determine whether atorvastatin administration (10mg/kg daily for 18-23weeks) modified AICAC. Middle cerebral arteries were pressurized in vitro at 60mmHg and AICAC was evoked by 50mM ethanol, that is within the range of blood alcohol detected in humans following moderate-to-heavy drinking. AICAC was evident in high CLR+atorvastatin group but not in high CLR diet+placebo. Statin exacerbation of AICAC persisted in de-endothelialized arteries, and was blunted by CLR enrichment in vitro. Fluorescence imaging of filipin-stained arteries showed that atorvastatin decreased vascular smooth muscle (VSM) CLR when compared to placebo, this difference being reduced by CLR enrichment in vitro. Voltage- and calcium-gated potassium channels of large conductance (BK) are known VSM targets of ethanol, with their beta1 subunit being necessary for ethanol-induced channel inhibition and resulting AICAC. Ethanol-induced BK inhibition in excised membrane patches from freshly isolated myocytes was exacerbated in the high CLR diet+atorvastatin group when compared to high CLR diet+placebo. Unexpectedly, atorvastatin decreased the amount and function of BK beta1 subunit as documented by immunofluorescence imaging and functional patch-clamp studies. Atorvastatin exacerbation of ethanol-induced BK inhibition disappeared upon artery CLR enrichment in vitro. Our study demonstrates for the first time statin's ability to exacerbate the vascular effect of a widely consumed drug of abuse, this exacerbation being driven by statin modulation of ethanol-induced BK channel inhibition in the VSM via CLR-mediated mechanism. Copyright © 2017 Elsevier Inc. All rights reserved.

The expression of one ankyrin pk2 allele of the WO prophage is correlated with the Wolbachia feminizing effect in isopods

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Pichon Samuel

2012-04-01

Full Text Available Abstract Background The maternally inherited α-Proteobacteria Wolbachia pipientis is an obligate endosymbiont of nematodes and arthropods, in which they induce a variety of reproductive alterations, including Cytoplasmic Incompatibility (CI and feminization. The genome of the feminizing wVulC Wolbachia strain harboured by the isopod Armadillidium vulgare has been sequenced and is now at the final assembly step. It contains an unusually high number of ankyrin motif-containing genes, two of which are homologous to the phage-related pk1 and pk2 genes thought to contribute to the CI phenotype in Culex pipiens. These genes encode putative bacterial effectors mediating Wolbachia-host protein-protein interactions via their ankyrin motifs. Results To test whether these Wolbachia homologs are potentially involved in altering terrestrial isopod reproduction, we determined the distribution and expression of both pk1 and pk2 genes in the 3 Wolbachia strains that induce CI and in 5 inducing feminization of their isopod hosts. Aside from the genes being highly conserved, we found a substantial copy number variation among strains, and that is linked to prophage diversity. Transcriptional analyses revealed expression of one pk2 allele (pk2b2 only in the feminizing Wolbachia strains of isopods. Conclusions These results reveal the need to investigate the functions of Wolbachia ankyrin gene products, in particular those of Pk2, and their host targets with respect to host sex manipulation.

HARP preferentially co-purifies with RPA bound to DNA-PK and blocks RPA phosphorylation.

Science.gov (United States)

Quan, Jinhua; Yusufzai, Timur

2014-05-01

The HepA-related protein (HARP/SMARCAL1) is an ATP-dependent annealing helicase that is capable of rewinding DNA structures that are stably unwound due to binding of the single-stranded DNA (ssDNA)-binding protein Replication Protein A (RPA). HARP has been implicated in maintaining genome integrity through its role in DNA replication and repair, two processes that generate RPA-coated ssDNA. In addition, mutations in HARP cause a rare disease known as Schimke immuno-osseous dysplasia. In this study, we purified HARP containing complexes with the goal of identifying the predominant factors that stably associate with HARP. We found that HARP preferentially interacts with RPA molecules that are bound to the DNA-dependent protein kinase (DNA-PK). We also found that RPA is phosphorylated by DNA-PK in vitro, while the RPA-HARP complexes are not. Our results suggest that, in addition to its annealing helicase activity, which eliminates the natural binding substrate for RPA, HARP blocks the phosphorylation of RPA by DNA-PK.

The pkI gene encoding pyruvate kinase I links to the luxZ gene which enhances bioluminescence of the lux operon from Photobacterium leiognathi.

Science.gov (United States)

Lin, J W; Lu, H C; Chen, H Y; Weng, S F

1997-10-09

Partial 3'-end nucleotide sequence of the pkI gene (GenBank accession No. AF019143) from Photobacterium leiognathi ATCC 25521 has been determined, and the encoded pyruvate kinase I is deduced. Pyruvate kinase I is the key enzyme of glycolysis, which converts phosphoenol pyruvate to pyruvate. Alignment and comparison of pyruvate kinase Is from P. leiognathi, E. coli and Salmonella typhimurium show that they are homologous. Nucleotide sequence reveals that the pkI gene is linked to the luxZ gene that enhances bioluminescence of the lux operon from P. leiognathi. The gene order of the pkI and luxZ genes is-pk1-ter-->-R&R"-luxZ-ter"-->, whereas ter is transcriptional terminator for the pkI and related genes, and R&R" is the regulatory region and ter" is transcriptional terminator for the luxZ gene. It clearly elicits that the pkI gene and luxZ gene are divided to two operons. Functional analysis confirms that the potential hairpin loop omega T is the transcriptional terminator for the pkI and related genes. It infers that the pkI and related genes are simply linked to the luxZ gene in P. leiognathi genome.

Probing the Geometry of the Inner Vestibule of BK Channels with Sugars

Science.gov (United States)

Brelidze, Tinatin I.; Magleby, Karl L.

2005-01-01

The geometry of the inner vestibule of BK channels was probed by examining the effects of different sugars in the intracellular solution on single-channel current amplitude (unitary current). Glycerol, glucose, and sucrose decreased unitary current through BK channels in a concentration- and size-dependent manner, in the order sucrose > glucose > glycerol, with outward currents being reduced more than inward currents. The fractional decrease of outward current was more directly related to the fractional hydrodynamic volume occupied by the sugars than to changes in osmolality. For concentrations of sugars ≤1 M, the i/V plots for outward currents in the presence and absence of sugar superimposed after scaling, and increasing K+ i from 150 mM to 2 M increased the magnitudes of the i/V plots with little effect on the shape of the scaled curves. These observations suggest that sugars ≤1 M reduce outward currents mainly by entering the inner vestibule and reducing the movement of K+ through the vestibule, rather than by limiting diffusion-controlled access of K+ to the vestibule. With 2 M sucrose, the movement of K+ into the inner vestibule became diffusion limited for 150 mM K+ i and voltages >+100 mV. Increasing K+ i then relieved the diffusion limitation. An estimate of the capture radius based on the 5 pA diffusion-limited current for channels without the ring of negative charge at the entrance to the inner vestibule was 2.2 Å. Adding the radius of a hydrated K+ (6–8 Å) then gave an effective radius for the entrance to the inner vestibule of 8–10 Å. Such a functionally wide entrance to the inner vestibule together with our observation that even small concentrations of sugar in the inner vestibule reduce unitary current suggest that a wide inner vestibule is required for the large conductance of BK channels. PMID:16043773

Adequate & Equitable U.S. PK-12 Infrastructure: Priority Actions for Systemic Reform. A Report from the Planning for PK-12 School Infrastructure National Initiative

Science.gov (United States)

Filardo, Mary; Vincent, Jeffrey M.

2017-01-01

To formulate a "systems-based" plan to address the PK-12 infrastructure crisis, in 2016, the 21st Century School Fund (21CSF) and the University of California-Berkeley's Center for Cities + Schools (CC+S), in partnership with the National Council on School Facilities and the Center for Green Schools at the U.S. Green Building Council,…

Characterization of an extracellular lipase by Pseudomonas koreensis BK-L07 isolated from soil.

Science.gov (United States)

Anbu, Periasamy

2014-01-01

Screening using spirit blue agar revealed that strain BK-L07 had the highest lipase activity. Furthermore, the isolated strain was identified as Pseudomonas sp. based on morphological, physiological, biochemical, and molecular analyses. The 16S rRNA gene sequence of strain BK-L07 shared a high similarity with that of Pseudomonas koreensis (99%). The nutritional conditions and physicochemical properties were influenced by P. koreensis BK-L07. The maximum lipase production was obtained in tryptic soy broth medium at pH 8.0 and a temperature of 25°C after 36 hr of incubation. In addition, the lipase activity was determined using different carbon sources and lipase inducers. The lipase production was greatest when 1% maltose was used as the carbon source and olive oil was used as the lipase inducer. The lipase production was significantly increased approximately threefold in the optimized medium when compared with the original medium. Further, the lipase was purified by ammonium sulfate precipitation and gel filtration chromatography with a purification yield of 10.8%. The molecular mass of lipase was 45 kDa. The optimum temperature and pH were 40°C and 8.0, respectively. The enzyme was stable up to 50°C and at pH from 7 to 9. In addition, the enzyme activity was stimulated by MgSO4 and completely inhibited by ethylenediamine tetraacetic acid (EDTA), indicating the metalloenzyme type. The lipase activity was toward medium to long chain length of fatty acids (C10 to C18). Supplemental materials are available for this article. Go to the publisher's online edition of Preparative Biochemistry and Biotechnology to view the supplemental file.

DNA-dependent protein kinase (DAN-PK), a key enzyme in the re-ligation of DNA double-strand breaks

International Nuclear Information System (INIS)

Hennequin, C.; Averbeck, D.

1999-01-01

Repair pathways of DNA are now defined and some important findings have been discovered in the last few years. DNA non-homologous end-joining (NEH) is a crucial process in the repair of radiation-induced double-strand breaks (DSBs). NHEj implies at least three steps: the DNA free-ends must get closer, preparation of the free-ends by exonucleases and then a transient hybridization in a region of DNA with weak homology. DNA-dependent protein kinase (DNA-PK) is the key enzyme in this process. DNA-PK is a nuclear serine/threonine kinase that comprises three components: a catalytic subunit (DNA-PK cs ) and two regulatory subunits, DNA-binding proteins, Ku80 and Ku70. The severe combined immuno-deficient (scid) mice are deficient in DNA-PK cs : this protein is involved both in DNA repair and in the V(D)J recombination of immunoglobulin and T-cell receptor genes. It is a protein-kinase of the P13-kinase family and which can phosphorylate Ku proteins, p53 and probably some other proteins still unknown. DNA-PK is an important actor of DSBs repair (induced by ionising radiations or by drugs like etoposide), but obviously it is not the only mechanism existing in the cell for this function. Some others, like homologous recombination, seem also to have a great importance for cell survival. (authors)

Differential expression of BK channel isoforms and beta-subunits in rat neuro-vascular tissues

DEFF Research Database (Denmark)

Poulsen, Asser Nyander; Wulf, Helle; Hay-Schmidt, Anders

2009-01-01

We investigated the expression of splice variants and beta-subunits of the BK channel (big conductance Ca(2+)-activated K(+) channel, Slo1, MaxiK, K(Ca)1.1) in rat cerebral blood vessels, meninges, trigeminal ganglion among other tissues. An alpha-subunit splice variant X1(+24) was found expresse...

A Business Plan for PK Handbags Manufacturing Company

OpenAIRE

Somchatvong, Laddaporn

2009-01-01

PK Co. Limited is a small family-business-owned company located in Thailand. Since established in 1998, the company’s business is manufacturing women’s fashion handbags for wholesale apparel trading company in Thailand. The company also produces and merchandises premium gifts for Kasikorn Bank, one of the largest banks in Thailand. Over the past ten years, the company has generated more than 200 million Baht in revenue or £ 3.6 million . The founders, Likit and Duangporn Somchatvong, have ...

哈维氏弧菌黑鲷分离株BK-1培养条件优化研究%Studies on the Optimal Culture Conditions of Vibrio harveyi BK-1 from Sparus macrocephalus

Institute of Scientific and Technical Information of China (English)

潘晓艺; 沈锦玉; 尹文林; 曹铮; 马海其; 常抗美

2005-01-01

从患病黑鲷Sparus macrocephalus 的肾脏分离到一致病菌株BK-1,经鉴定为哈维氏弧菌.对哈维氏弧菌BK-1株的最佳生长条件及培养基优化进行了测定.结果表明:不同的培养条件和培养基成份均会影响其产量.哈维氏弧菌最适宜生长条件为:盐度为2%、pH8、温度为30℃;最佳培养基成份为:蛋白胨0.5%,牛肉膏0.75%,甘油0.05%,CuSO40.15 mg/L,CaCl2 0.01 g/L.

SPM analysis of parametric (R)-[11C]PK11195 binding images: plasma input versus reference tissue parametric methods.

Science.gov (United States)

Schuitemaker, Alie; van Berckel, Bart N M; Kropholler, Marc A; Veltman, Dick J; Scheltens, Philip; Jonker, Cees; Lammertsma, Adriaan A; Boellaard, Ronald

2007-05-01

(R)-[11C]PK11195 has been used for quantifying cerebral microglial activation in vivo. In previous studies, both plasma input and reference tissue methods have been used, usually in combination with a region of interest (ROI) approach. Definition of ROIs, however, can be labourious and prone to interobserver variation. In addition, results are only obtained for predefined areas and (unexpected) signals in undefined areas may be missed. On the other hand, standard pharmacokinetic models are too sensitive to noise to calculate (R)-[11C]PK11195 binding on a voxel-by-voxel basis. Linearised versions of both plasma input and reference tissue models have been described, and these are more suitable for parametric imaging. The purpose of this study was to compare the performance of these plasma input and reference tissue parametric methods on the outcome of statistical parametric mapping (SPM) analysis of (R)-[11C]PK11195 binding. Dynamic (R)-[11C]PK11195 PET scans with arterial blood sampling were performed in 7 younger and 11 elderly healthy subjects. Parametric images of volume of distribution (Vd) and binding potential (BP) were generated using linearised versions of plasma input (Logan) and reference tissue (Reference Parametric Mapping) models. Images were compared at the group level using SPM with a two-sample t-test per voxel, both with and without proportional scaling. Parametric BP images without scaling provided the most sensitive framework for determining differences in (R)-[11C]PK11195 binding between younger and elderly subjects. Vd images could only demonstrate differences in (R)-[11C]PK11195 binding when analysed with proportional scaling due to intersubject variation in K1/k2 (blood-brain barrier transport and non-specific binding).

Nano Copper Induces Apoptosis in PK-15 Cells via a Mitochondria-Mediated Pathway.

Science.gov (United States)

Zhang, Hui; Chang, Zhenyu; Mehmood, Khalid; Abbas, Rao Zahid; Nabi, Fazul; Rehman, Mujeeb Ur; Wu, Xiaoxing; Tian, Xinxin; Yuan, Xiaodan; Li, Zhaoyang; Zhou, Donghai

2018-01-01

Nano-sized copper particles are widely used in various chemical, physical, and biological fields. However, earlier studies have shown that nano copper particles (40-100 μg/mL) can induce cell toxicity and apoptosis. Therefore, this study was conducted to investigate the role of nano copper in mitochondrion-mediated apoptosis in PK-15 cells. The cells were treated with different doses of nano copper (20, 40, 60, and 80 μg/mL) to determine the effects of apoptosis using acridine orange/ethidium bromide (AO/EB) fluorescence staining and a flow cytometry assay. The levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in the PK-15 cells were examined using commercially available kits. Moreover, the mRNA levels of the Bax, Bid, Caspase-3, and CYCS genes were assessed by real-time PCR. The results revealed that nano copper exposure induced apoptosis and changed the mitochondrial membrane potential. In addition, nano copper significantly altered the levels of the Bax, Bid, Caspase-3, and CYCS genes at a concentration of 40 μg/mL. To summarize, nano copper significantly (P nano copper can play an important role in inducing the apoptotic pathway in PK-15 cells, which may be the mechanism by which nano copper induces nephrotoxicity.

Population PK and IgE pharmacodynamic analysis of a fully human monoclonal antibody against IL4 receptor.

Science.gov (United States)

Kakkar, Tarundeep; Sung, Cynthia; Gibiansky, Leonid; Vu, Thuy; Narayanan, Adimoolam; Lin, Shao-Lee; Vincent, Michael; Banfield, Christopher; Colbert, Alex; Hoofring, Sarah; Starcevic, Marta; Ma, Peiming

2011-10-01

For AMG 317, a fully human monoclonal antibody to interleukin receptor IL-4Rα, we developed a population pharmacokinetic (PK) model by fitting data from four early phase clinical trials of intravenous and subcutaneous (SC) routes simultaneously, investigated important PK covariates, and explored the relationship between exposure and IgE response. Data for 294 subjects and 2183 AMG 317 plasma concentrations from three Phase 1 and 1 Phase 2 studies were analyzed by nonlinear mixed effects modeling using first-order conditional estimation with interaction. The relationship of IgE response with post hoc estimates of exposure generated from the final PK model was explored based on data from asthmatic patients. The best structural model was a two-compartment quasi-steady-state target-mediated drug disposition model with linear and non-linear clearances. For a typical 80-kg, 40-year subject, linear clearance was 35.0 mL/hr, central and peripheral volumes of distribution were 1.78 and 5.03 L, respectively, and SC bioavailability was 24.3%. Body weight was an important covariate on linear clearance and central volume; age influenced absorption rate. A significant treatment effect was observable between the cumulative AUC and IgE response measured. The population PK model adequately described AMG 317 PK from IV and SC routes over a 60-fold range of doses with two dosing strengths across multiple studies covering healthy volunteers and patients with mild to severe asthma. IgE response across a range of doses and over the sampling time points was found to be related to cumulative AMG 317 exposure.

Properties of optical breakdown in BK7 glass induced by an extended-cavity femtosecond laser oscillator.

Science.gov (United States)

Do, Binh T; Phillips, Mark C; Miller, Paul A; Kimmel, Mark W; Britsch, Justin; Cho, Seong-Ho

2009-02-16

Using an extended-cavity femtosecond oscillator, we investigated optical breakdown in BK7 glass caused by the accumulated action of many laser pulses. By using a pump-probe experiment and collecting the transmitted pump along with the reflected pump and the broadband light generated by the optical breakdown, we measured the build-up time to optical breakdown as a function of the pulse energy, and we also observed the instability of the plasma due to the effect of defocusing and shielding created by the electron gas. The spectrum of the broadband light emitted by the optical breakdown and the origin of the material modification in BK7 glass was studied. We developed a simple model of electromagnetic wave propagation in plasma that is consistent with the observed behavior of the reflection, absorption, and transmission of the laser light.

A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim.

Science.gov (United States)

Niederalt, Christoph; Kuepfer, Lars; Solodenko, Juri; Eissing, Thomas; Siegmund, Hans-Ulrich; Block, Michael; Willmann, Stefan; Lippert, Jörg

2018-04-01

Proteins are an increasingly important class of drugs used as therapeutic as well as diagnostic agents. A generic physiologically based pharmacokinetic (PBPK) model was developed in order to represent at whole body level the fundamental mechanisms driving the distribution and clearance of large molecules like therapeutic proteins. The model was built as an extension of the PK-Sim model for small molecules incorporating (i) the two-pore formalism for drug extravasation from blood plasma to interstitial space, (ii) lymph flow, (iii) endosomal clearance and (iv) protection from endosomal clearance by neonatal Fc receptor (FcRn) mediated recycling as especially relevant for antibodies. For model development and evaluation, PK data was used for compounds with a wide range of solute radii. The model supports the integration of knowledge gained during all development phases of therapeutic proteins, enables translation from pre-clinical species to human and allows predictions of tissue concentration profiles which are of relevance for the analysis of on-target pharmacodynamic effects as well as off-target toxicity. The current implementation of the model replaces the generic protein PBPK model available in PK-Sim since version 4.2 and becomes part of the Open Systems Pharmacology Suite.

Pharmacokinetics (PK), pharmacodynamics (PD), and PK-PD integration of ceftiofur after a single intravenous, subcutaneous and subcutaneous-LA administration in lactating goats.

Science.gov (United States)

Fernández-Varón, Emilio; Cárceles-García, Carlos; Serrano-Rodríguez, Juan Manuel; Cárceles-Rodríguez, Carlos M

2016-10-13

Bacterial pneumonia in goats is usually caused by Mannheimia haemolytica and Pasteurella multocida. Another important infection disease in lactating goats is intramammary infection producing mastitis, usually associated with coagulase-negative Staphylococcus spp. However, treatment of bacterial pneumonia in goats not affected by mastitis problems should be restricted to antimicrobials with scant penetration to milk in order to avoid long withdrawal times. Ceftiofur is a third-generation cephalosporin antimicrobial with activity against various gram-positive and gram-negative, aerobic and anaerobic bacteria encountered by domestic animals. The objectives of the present study were to establish the serum concentration-time profile for ceftiofur in lactating goats after intravenous, subcutaneous and a SC-long-acting ceftiofur formulation; to determine ceftiofur penetration into milk; to determine in vitro and ex vivo activity of ceftiofur establishing MIC, MBC, MPC and time-kill profiles against field strains of M. haemolytica and finally to calculate the main surrogate markers of efficacy. The pharmacokinetics studies revealed an optimal PK properties for the SC-LA formulation tested. Ceftiofur was well absorbed following SC and SC-LA administration, with absolute bioavailabilities (F) of 85.16 and 84.43 %, respectively. After ceftiofur analysis from milk samples, no concentrations were found at any sampling time. The MIC, MBC and MPC data of ceftiofur against five M. haemolytica strains isolated from goats affected by pneumonia were tested showing excelent sensitivity of ceftiofur against this pathogen. For PK-PD analysis, ratios were calculated suggesting a high level of bacterial kill against the five strains of M. haemolytica tested. The systemic ceftiofur exposure achieved in lactating goats following IV, SC and especially with the SC-LA administration is consistent with the predicted PK-PD ratios needed for a positive therapeutic outcome for M. haemolytica

Measurement and tricubic interpolation of the magnetic field for the OLYMPUS experiment

Energy Technology Data Exchange (ETDEWEB)

Bernauer, J.C. [Massachusetts Institute of Technology, Laboratory for Nuclear Science, Cambridge, MA (United States); Diefenbach, J. [Hampton University, Hampton, VA (United States); Elbakian, G. [Alikhanyan National Science Laboratory (Yerevan Physics Institute), Yerevan (Armenia); Gavrilov, G. [Petersburg Nuclear Physics Institute, Gatchina (Russian Federation); Goerrissen, N. [Deutsches Elektronen-Synchrotron DESY, Hamburg (Germany); Hasell, D.K.; Henderson, B.S. [Massachusetts Institute of Technology, Laboratory for Nuclear Science, Cambridge, MA (United States); Holler, Y. [Deutsches Elektronen-Synchrotron DESY, Hamburg (Germany); Karyan, G. [Alikhanyan National Science Laboratory (Yerevan Physics Institute), Yerevan (Armenia); Ludwig, J. [Deutsches Elektronen-Synchrotron DESY, Hamburg (Germany); Marukyan, H. [Alikhanyan National Science Laboratory (Yerevan Physics Institute), Yerevan (Armenia); Naryshkin, Y. [Petersburg Nuclear Physics Institute, Gatchina (Russian Federation); O' Connor, C.; Russell, R.L.; Schmidt, A. [Massachusetts Institute of Technology, Laboratory for Nuclear Science, Cambridge, MA (United States); Schneekloth, U. [Deutsches Elektronen-Synchrotron DESY, Hamburg (Germany); Suvorov, K.; Veretennikov, D. [Petersburg Nuclear Physics Institute, Gatchina (Russian Federation)

2016-07-01

The OLYMPUS experiment used a 0.3 T toroidal magnetic spectrometer to measure the momenta of outgoing charged particles. In order to accurately determine particle trajectories, knowledge of the magnetic field was needed throughout the spectrometer volume. For that purpose, the magnetic field was measured at over 36,000 positions using a three-dimensional Hall probe actuated by a system of translation tables. We used these field data to fit a numerical magnetic field model, which could be employed to calculate the magnetic field at any point in the spectrometer volume. Calculations with this model were computationally intensive; for analysis applications where speed was crucial, we pre-computed the magnetic field and its derivatives on an evenly spaced grid so that the field could be interpolated between grid points. We developed a spline-based interpolation scheme suitable for SIMD implementations, with a memory layout chosen to minimize space and optimize the cache behavior to quickly calculate field values. This scheme requires only one-eighth of the memory needed to store necessary coefficients compared with a previous scheme (Lekien and Marsden, 2005 [1]). This method was accurate for the vast majority of the spectrometer volume, though special fits and representations were needed to improve the accuracy close to the magnet coils and along the toroidal axis.

[Occupational Hearing Loss (BK-No. 2301) - A Retrospective Analysis of 100 Consecutive Cases].

Science.gov (United States)

Reiter, R; Brosch, S

2016-10-01

Introduction: In order for a diagnosis of Occupational Hearing Loss (BK-no. 2301) to be made certain criteria must be fulfilled to establish that the hearing loss is occupational in origin. This work compares 2 groups, those who fulfil the criteria (BKE) and those who do not (BKNE). Methods: A 100 consecutive reports ("Lärmgutachten BK-no. 2301") written by the authors were examined retrospectively. These recorded audiometric examination, an analysis of any tinnitus and noise exposure plus use of hearing protection. Pre- and post-noise exposure status together with an expert assessment of work limitations was made to produce a 7 point score. Results: 67% of the group fulfilled the conditions for occupational hearing loss (9% were entitled to compensation). In the BKE group 82% showed typical audiometric signs of noise damage with 75% of them fulfilling at least 6 criteria of occupational disease no. 2301. Tinnitus typical for noise exposure was found in 26%. Discussion: A 7 point score could be useful in the future as a method of helping distinguish hearing loss and tinnitus from occupational as opposed to other causes. © Georg Thieme Verlag KG Stuttgart · New York.

PK20, a new opioid-neurotensin hybrid peptide that exhibits central and peripheral antinociceptive effects

Directory of Open Access Journals (Sweden)

Tsuda Yuko

2010-12-01

Full Text Available Abstract Background The clinical treatment of various types of pain relies upon the use of opioid analgesics. However most of them produce, in addition to the analgesic effect, several side effects such as the development of dependence and addiction as well as sedation, dysphoria, and constipation. One solution to these problems are chimeric compounds in which the opioid pharmacophore is hybridized with another type of compound to incease antinociceptive effects. Neurotensin-induced antinociception is not mediated through the opioid system. Therefore, hybridizing neurotensin with opioid elements may result in a potent synergistic antinociceptor. Results Using the known structure-activity relationships of neurotensin we have synthesized a new chimeric opioid-neurotensin compound PK20 which is characterized by a very strong antinociceptive potency. The observation that the opioid antagonist naltrexone did not completely reverse the antinociceptive effect, indicates the partial involvement of the nonopioid component in PK20 in the produced analgesia. Conclusions The opioid-neurotensin hybrid analogue PK20, in which opioid and neurotensin pharmacophores overlap partially, expresses high antinociceptive tail-flick effects after central as well as peripheral applications.

IMPLEMENTASI PEMERINTAHAN YANG BERSIH DALAM KERANGKA RENCANA AKSI DAERAH PEMBERANTASAN KORUPSI (RAD-PK (Studi Di Kabupaten Pemalang

Directory of Open Access Journals (Sweden)

Muhammad Fauzan

2012-03-01

Full Text Available This research related to the implementation of good governance, free from corruption, collusion and nepotism. The approach used in this research is a descriptive qualitative approach. The Location of research conducted in the District of Pemalang. Based on the research results can presented that the District of Pemalang is committed and fully supports the government policy in eradicating corruption. District of Pemalang support to efforts to more information accelerate the eradication of corruption stated in the the Regional Action Plan to Accelerate the Eradication of Corruption (RAD-PK in 2011 -2016 which refers to the Medium Term Development Plan (RPJM District of Pemalang from 2011 to 2016 and the National Action Plan for Eradication of Corruption (RAN-PK and the President of Republic of Indonesia Instruction No. 5 Year 2004 on Accelerating the eradication of corruption. RAD-PK 2011-2016 District of Pemalang is a document that contains an action program that aims to accelerate the eradication of corruption. RAD-PK as a program of action containing concrete measures that have been agreed by the stakeholders in the area, so it has been a commitment of local governments prevention efforts corruption through the development of programs and activities aimed at improving public services and the application of the principles of good governance.

Electronic structure and spectral properties of heavy actinides Pu, Am, Cm and Bk

International Nuclear Information System (INIS)

Shick, Alexander B; Kolorenc, Jindrich; Lichtenstein, Alexander I; Havela, Ladislav

2010-01-01

Selected electronic properties of Pu, Am, Cm and Bk are calculated with the aid of charge self-consistent LDA + Hubbard I method. Presented all-electron calculations are performed in the full-potential LAPW basis and incorporate spin-orbit interaction. The results are found to be in good agreement with experimental valence photoelectron spectra as well as with core XAS/EELS spectra of heavy actinides.

Cholesterol influences voltage-gated calcium channels and BK-type potassium channels in auditory hair cells.

Directory of Open Access Journals (Sweden)

Erin K Purcell

Full Text Available The influence of membrane cholesterol content on a variety of ion channel conductances in numerous cell models has been shown, but studies exploring its role in auditory hair cell physiology are scarce. Recent evidence shows that cholesterol depletion affects outer hair cell electromotility and the voltage-gated potassium currents underlying tall hair cell development, but the effects of cholesterol on the major ionic currents governing auditory hair cell excitability are unknown. We investigated the effects of a cholesterol-depleting agent (methyl beta cyclodextrin, MβCD on ion channels necessary for the early stages of sound processing. Large-conductance BK-type potassium channels underlie temporal processing and open in a voltage- and calcium-dependent manner. Voltage-gated calcium channels (VGCCs are responsible for calcium-dependent exocytosis and synaptic transmission to the auditory nerve. Our results demonstrate that cholesterol depletion reduced peak steady-state calcium-sensitive (BK-type potassium current by 50% in chick cochlear hair cells. In contrast, MβCD treatment increased peak inward calcium current (~30%, ruling out loss of calcium channel expression or function as a cause of reduced calcium-sensitive outward current. Changes in maximal conductance indicated a direct impact of cholesterol on channel number or unitary conductance. Immunoblotting following sucrose-gradient ultracentrifugation revealed BK expression in cholesterol-enriched microdomains. Both direct impacts of cholesterol on channel biophysics, as well as channel localization in the membrane, may contribute to the influence of cholesterol on hair cell physiology. Our results reveal a new role for cholesterol in the regulation of auditory calcium and calcium-activated potassium channels and add to the growing evidence that cholesterol is a key determinant in auditory physiology.

The Role of Ca2+ and BK Channels of Locus Coeruleus (LC) Neurons as a Brake to the CO2 Chemosensitivity Response of Rats.

Science.gov (United States)

Imber, Ann N; Patrone, Luis G A; Li, Ke-Yong; Gargaglioni, Luciane H; Putnam, Robert W

2018-06-15

The cellular mechanisms by which LC neurons respond to hypercapnia are usually attributed to an "accelerator" whereby hypercapnic acidosis causes an inhibition of K + channels or activation of Na + and Ca +2 channels to depolarize CO 2 -sensitive neurons. Nevertheless, it is still unknown if this "accelerator" mechanism could be controlled by a brake phenomenon. Whole-cell patch clamping, fluorescence imaging microscopy and plethysmography were used to study the chemosensitive response of the LC neurons. Hypercapnic acidosis activates L-type Ca 2+ channels and large conductance Ca-activated K + (BK) channels, which function as a "brake" on the chemosensitive response of LC neurons. Our findings indicate that both Ca 2+ and BK currents develop over the first 2 weeks of postnatal life in rat LC slices and that this brake pathway may cause the developmental decrease in the chemosensitive firing rate response of LC neurons to hypercapnic acidosis. Inhibition of this brake by paxilline (BK channel inhibitor) returns the magnitude of the chemosensitive firing rate response from LC neurons in rats older than P10 to high values similar to those in LC neurons from younger rats. Inhibition of BK channels in LC neurons by bilateral injections of paxilline into the LC results in a significant increase in the hypercapnic ventilatory response of adult rats. Our findings indicate that a BK channel-based braking system helps to determine the chemosensitive respiratory drive of LC neurons and contributes to the hypercapnic ventilatory response. Perhaps, abnormalities of this braking system could result in hypercapnia-induced respiratory disorders and panic responses. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

DNA-activated protein kinase (DNA-PK) and significance in its responses to radiation. The end is the beginning of the story

International Nuclear Information System (INIS)

Matsumoto, Yoshihisa

1996-01-01

This review described findings hitherto and future perspective on the DNA-PK. The enzyme was activated by double-strand DNA, required the end of the DNA and was the major component of p350 protein. Ku-antigen (an autoimmune antigen) was found a subunit. It phosphorylated p53, c-Myc, RPAp34, DNA ligase I, DNA topoisomerase I and II. Therefore DNA-PK can be a trigger factor which recognizes DNA break induced by radiation, and phosphorylates proteins participating in the DNA repair, cell cycle regulation and cell death. Recently p350 was found to be a responsible gene product to SCID syndrome of mice hypersensitive to ionizing radiation. The review included; On the DNA-PK: Discovery, relation to Ku antigen and molecular properties. On the DNA-PK and radiation sensitivity, and V(D)J recombination: Ku80 was the product of X-ray repair cross-complementing (XRCC). p350 was found the gene product whose lack causing SCID syndrome of radiosensitive mice. On the significance of phosphorylation of DNA-PK and the substrate: p53. RPA (replication protein A, alias RF-A or SSB). P1/MCM3, a possible substrate. On the other properties of DNA-PK: DNA-helicase activity. Suppression of transcription by RNA polymerase. DNA-PKp350 and ATM (ataxia-telangiectasia). Family molecules of p53 and ATM (MEI-41, Tel1p and Mec1p, and Rad3). (H.O). 70 refs

Role of DNA-PK in cellular responses to DNA double-strand breaks

International Nuclear Information System (INIS)

Chen, D.J.

2003-01-01

DNA double-strand breaks (DSBs) are probably the most dangerous of the many different types of DNA damage that occur within the cell. DSBs are generated by exogenous agents such as ionizing radiation (IR) or by endogenously generated reactive oxygen species and occur as intermediates during meiotic and V(D)J recombination. The repair of DSBs is of paramount importance to the cell as misrepair of DSBs can lead to cell death or promote tumorigenesis. In eukaryotes there exists two distinct mechanisms for DNA DSB repair: homologous recombination (HR) and non-homologous end joining (NHEJ). In mammalian cells, however, it is clear that nonhomologous repair of DSBs is highly active and plays a major role in conferring radiation resistance to the cell. The NHEJ machinery minimally consists of the DNA-dependent Protein Kinase (DNA-PK) and a complex of XRCC4 and DNA Ligase IV. The DNA-PK complex is composed of a 470 kDa catalytic subunit (DNA-PKcs), and the heterodimeric Ku70 and Ku80 DNA end-binding complex. DNA-PKcs is a PI-3 kinase with homology to ATM and ATR in its C-terminal kinase domain. The DNA-PK complex protects and tethers the ends, and directs assembly and, perhaps, the activation of other NHEJ proteins. We have previously demonstrated that the kinase activity of DNA-PK is essential for DNA DSB repair and V(D)J recombination. It is, therefore, of immense interest to determine the in vivo targets of DNA-PKcs and the mechanisms by which phosphorylation of these targets modulates NHEJ. Recent studies have resulted in the identification of a number of protein targets that are phosphorylated by and/or interact with DNA-PKcs. Our laboratory has recently identified autophosphorylation site(s) on DNA-PKcs. We find that phosphorylation at these sites in vivo is an early and essential response to DSBs and demonstrate, for the first time, the localization of DNA-PKcs to the sites of DNA damage in vivo. Furthermore, mutation of these phosphorylation sites in mammalian

PENGEMBANGAN INSTRUMEN ASESMEN KEBUTUHAN PERKEMBANGAN UNTUK PENYUSUNAN KURIKULUM DAN EVALUASI PROGRAM BK

Directory of Open Access Journals (Sweden)

Gendon Barus

2013-01-01

Full Text Available Penelitian pengembangan ini bertujuan menghasilkan instrumen asesmen kebutuhan peserta didik, disebut Invantori Kebutuhan Perkembangan Murid (IKPM. Penelitian mengikuti model Plomp (1999 dengan lima fase. Reliabilitas instrumen diestimasi dengan teknik Alpha Cronbach, validitas isi diperiksa oleh pakar dan telaah praktisi melalui FGD. Validitas empirik dan kecocokan model pengukuran dibuktikan dengan analisis faktor konfirmatori (CFA dengan program Lisrel 8.30. Telaah praktisi melibatkan 60 orang guru kelas V dan VI SD dalam dua tahap FGD, sedangkan uji coba empirik dan implementasi melibatkan murid kelas V dan VI. Hasil penelitian pengembang-an ini adalah: 1 IKPM dapat digunakan untuk menghimpun data kebutuhan perkembangan sebagai dasar penyusunan kurikulum bimbingan dan melaksanakan evaluasi program, bimbingan dan alat ukur evaluasi program bimbingan klasikal di sekolah dasar dan 2 teridentifikasi butir-butir kebutuhan per-kembangan murid yang intens dan sangat intens untuk dipenuhi melalui layanan bimbingan klasikal. Kata kunci: instrumen asesmen kebutuhan, kurikulum bimbingan, instrument evaluasi program BK ______________________________________________________________ DEVELOPMENT OF DEVELOPMENTAL NEEDS ASSESSMENT INSTRUMENT FOR CURRICULUM ARRANGEMENT AND EVALUATION OF BK PROGRAM Abstract The goal of this research is to produce a developmental needs assessment instrument, called Student’s Developmental Needs Inventory, which can be use to reveal the needs of students in elementary school. The research method follows the model of Research and Development (R & D by Plomp (1999 with five phases. The instrument which is developed in this study guidance and counseling (Bimbingan Konseling, BK in elementary school. Instrument reliability is estimated using by Alpha Cronbach technique, it content validity is checked by experts judgment and practitioner’s assessment with FGD technique. Furthermore, empirical validity and the goodness of fit

Vitamin E protects against the mitochondrial damage caused by cyclosporin A in LLC-PK1 cells

International Nuclear Information System (INIS)

Arriba, G. de; Perez de Hornedo, J.; Ramirez Rubio, S.; Calvino Fernandez, M.; Benito Martinez, S.; Maiques Camarero, M.; Parra Cid, T.

2009-01-01

Cyclosporin A (CsA) has nephrotoxic effects known to involve reactive oxygen species (ROS), since antioxidants prevent the kidney damage induced by this drug. Given that mitochondria are among the main sources of intracellular ROS, the aims of our study were to examine the mitochondrial effects of CsA in the porcine renal endothelial cell line LLC-PK1 and the influence of the antioxidant Vitamin E (Vit E). Following the treatment of LLC-PK1 cells with CsA, we assessed the mitochondrial synthesis of superoxide anion, permeability transition pore opening, mitochondrial membrane potential, cardiolipin peroxidation, cytochrome c release and cellular apoptosis, using flow cytometry and confocal microscopy procedures. Similar experiments were done after Vit E preincubation of cells. CsA treatment increased superoxide anion in a dose-dependent way. CsA opened the permeability transition pores, caused Bax migration to mitochondria, and decreased mitochondrial membrane potential and cardiolipin content. Also CsA released cytochrome c into cytosol and provoked cellular apoptosis. Vit E pretreatment inhibited the effects that CsA induced on mitochondrial structure and function in LLC-PK1 cells and avoided apoptosis. CsA modifies mitochondrial LLC-PK1 cell physiology with loss of negative electrochemical gradient across the inner mitochondrial membrane and increased lipid peroxidation. These features are related to apoptosis and can explain the cellular damage that CsA induces. As Vit E inhibited these effects, our results suggest that they were mediated by an increase in ROS production by mitochondria.

PK Tradesman Tmi Developing marketing in a multicultural environment

OpenAIRE

Juutilainen, Tomi; Kangasperko, Pyry

2010-01-01

Purpose of the thesis was to find ways to improve PK Tradesman Tmi's customer and partner relations and marketing processes as well as research the viability of its product offering. This was accomplished by researching the concepts of guerrilla marketing and customer relationship management, and comparing different aspects of the Finnish and Chinese culture. The thesis consists in part of exploring the theory of aforementioned concepts, and in part of a ques-tionnaire which was implement...

Translational PK-PD modelling of molecular target modulation for the AMPA receptor positive allosteric modulator Org 26576.

Science.gov (United States)

Bursi, Roberta; Erdemli, Gul; Campbell, Robert; Hutmacher, Matthew M; Kerbusch, Thomas; Spanswick, David; Jeggo, Ross; Nations, Kari R; Dogterom, Peter; Schipper, Jacques; Shahid, Mohammed

2011-12-01

The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor potentiator Org 26576 represents an interesting pharmacological tool to evaluate the utility of glutamatergic enhancement towards the treatment of psychiatric disorders. In this study, a rat-human translational pharmacokinetic-pharmacodynamic (PK-PD) model of AMPA receptor modulation was used to predict human target engagement and inform dose selection in efficacy clinical trials. Modelling and simulation was applied to rat plasma and cerebrospinal fluid (CSF) pharmacokinetic and pharmacodynamic measurements to identify a target concentration (EC(80)) for AMPA receptor modulation. Human plasma pharmacokinetics was determined from 33 healthy volunteers and eight major depressive disorder patients. From four out of these eight patients, CSF PK was also determined. Simulations of human CSF levels were performed for several doses of Org 26576. Org 26576 (0.1-10 mg/kg, i.v.) potentiated rat hippocampal AMPA receptor responses in an exposure-dependant manner. The rat plasma and CSF PK data were fitted by one-compartment model each. The rat CSF PK-PD model yielded an EC(80) value of 593 ng/ml (90% confidence interval 406.8, 1,264.1). The human plasma and CSF PK data were simultaneously well described by a two-compartment model. Simulations showed that in humans at 100 mg QD, CSF levels of Org 26576 would exceed the EC(80) target concentration for about 2 h and that 400 mg BID would engage AMPA receptors for 24 h. The modelling approach provided useful insight on the likely human dose-molecular target engagement relationship for Org 26576. Based on the current analysis, 100 and 400 mg BID would be suitable to provide 'phasic' and 'continuous' AMPA receptor engagement, respectively.

Systemic injection of kainic acid: Gliosis in olfactory and limbic brain regions quantified with [3H]PK 11195 binding autoradiography

International Nuclear Information System (INIS)

Altar, C.A.; Baudry, M.

1990-01-01

Neurodegenerative diseases may result from excessive stimulation of excitatory amino acid receptors by endogenous ligands. Because neuronal degeneration is associated with glial proliferation and hypertrophy, the degenerative changes throughout rat brain following the systemic administration of kainic acid (12 mg/kg) were mapped with quantitative autoradiography of [3H]PK 11195. This radioligand binds to a mitochondrial benzodiazepine binding site (MBBS) on microglia and astrocytes. Analysis of eight horizontal and four coronal brain levels revealed up to 16-fold increases in [3H]PK 11195 binding from 1 to 5 weeks but not 1 day after kainate injection. Increases in [3H]PK 11195 binding were predominantly in ventral limbic brain regions and olfactory projections to neocortical areas, with the olfactory cortex greater than subiculum/CA1 greater than anterior olfactory nucleus, medial thalamic nucleus, and piriform cortex greater than cingulate cortex and rostral hippocampus greater than dentate gyrus, septum, and amygdala greater than entorhinal cortex and temporal cortex. Little or no enhancement of [3H]PK 11195 binding was observed in numerous regions including the caudate-putamen, substantia nigra, nucleus accumbens, olfactory tubercle, cerebellum, thalamic nuclei, choroid plexus, medulla, parietal or occipital cortex, or pons. A 2-fold greater extent of neurodegeneration was obtained in ventral portions of the olfactory bulb, entorhinal cortex, temporal cortex, and dentate gyrus compared with the dorsal portions of these structures. The pattern of increase in [3H]PK 11195 binding closely matched the patterns of neuronal degeneration reported following parenteral kainate injection. These findings strengthen the notion that quantitative autoradiography of [3H]PK 11195 is a valuable tool to quantify the extent of neuronal degeneration

Simulations of the neutron energy-spectra at the Olympus Gate Environmental Monitoring Station due to historical Bevatron operations

International Nuclear Information System (INIS)

Donahue, R.J.; Thomas, R.H.; Zeman, G.H.

2001-01-01

Offsite neutron fluences resulting from Bevatron operations reached a maximum in 1959, prior to the addition of a permanent concrete roof shield, which was constructed in 1962. From the first operation of the Bevatron measurements of neutron fluence were made at locations around the perimeter of the Lawrence Berkeley National Laboratory (LBNL) campus. Since the late 1950's measurements made at several locations, and particularly at the site of what is now called the Olympus Gate Environmental Monitoring Station, have been routinely reported and published. Early measurements were used to establish the shape of the neutron-energy spectrum from which an energy-averaged fluence-to-dose equivalent conversion coefficient could be derived. This conversion coefficient was then applied to a measured total neutron fluence to obtain the appropriate dose equivalent quantity required by regulation. Recent work by Thomas et al. (2000) have compared the early conversion coefficients used in the sixties with those accepted today and suggest suggested that ''the dose equivalents reported in the late fifties and early sixties were conservative by factors between two and four. In any current review of the historical data, therefore it would be prudent to reduce the reported dose equivalents by at least a factor of two.'' However, that analysis was based on the ''state of the art'' neutron energy-spectra of the '60s. This paper provides a detailed knowledge of the neutron energy spectrum at the site boundary paper thus removing any uncertainty in the analysis of Thomas et al., which might be caused by the use of the early neutron energy-spectra. Detailed Monte Carlo analyses of the interactions of 6.2 GeV protons in thick, medium-A targets are described. In the computer simulations, neutrons produced were allowed to scatter in the atmosphere. Detailed neutron energy spectra were calculated at a distance and elevation corresponding to the location of the Olympus Gate EMS. Both older

Generation of static PET images with [{sup 11}C]-(R)-PK11195: Defining time interval; Geração de imagens PET Estáticas com [{sup 11}C]-(R)-PK11195: definição do intervalo temporal

Energy Technology Data Exchange (ETDEWEB)

Schuck, Phelipi Nunes; Dartora, Caroline Machado; Silva, Ana Maria Marques da, E-mail: phelipi.schuck@acad.pucrs.br [Pontificia Universidade catolica do Rio Grande do Sul (PUC-RS), Porto Alegre, RS (Brazil). Núcleo de Pesquisa em Imagens Médicas

2017-07-01

[{sup 11}C]-(R)-PK11195 radiotracer shows microglia affinity in PET images and can be used as neuro inflammatory disease indicator, such as in Multiple Sclerosis (MS). There is no consensus about appropriate time interval to generate static PET images with [{sup 11}C]-(R)-PK11195. The aim of this study is to define the most appropriate time interval to generate static brain PET images with [{sup 11}C]-(R)-PK11195 for quantification. For this study, images from 10 remittent-recurrent MS patients and 5 healthy controls were used. Static images were generated from list-mode dynamic acquisition in the following time intervals: 0-60min, 5-20min, 5-30min, 10-60min, 30-60min e 40-60min. The ratio between SUV mean of juxtacortical and periventricular regions and normal appearing white matter, denominated SUVR{sup WM}, was used for image quantification. Results shown high variation in time intervals that include radiotracer perfusion. SUVRWM higher stability was observed in two time intervals (30-60min and 40-60min), for both control and MS patients groups. In conclusion, the best acquisition time interval to generate static PET images for quantification is from 40 to 60 minutes after administration, meaning an image acquired 40 minutes after [{sup 11}C]-(R)-PK11195 injection, during 20 min. (author)

PK of immunoconjugate anticancer agent CMD-193 in rats: ligand-binding assay approach to determine in vivo immunoconjugate stability.

Science.gov (United States)

Hussain, Azher; Gorovits, Boris; Leal, Mauricio; Fluhler, Eric

2014-01-01

Antibody-drug conjugates (ADCs) are a new generation of anticancer therapeutics. The objective of this manuscript is to propose a methodology that can be used to assess the stability of the ADCs by using the PK data obtained by ligand-binding assays that measure various components of ADCs. The ligand-binding assays format of different components of ADCs provided unique valuable PK information. The mathematical manipulation of the bioanalytical data provided an insight into the in vivo integrity, indicating that the loading of the calicheamicin on the G193 antibody declines in an apparent slow first-order process. This report demonstrates the value of analyzing various components of the ADC and their PK profiles to better understand the disposition and in vivo stability of ADCs.

Biomeasures and mechanistic modeling highlight PK/PD risks for a monoclonal antibody targeting Fn14 in kidney disease.

Science.gov (United States)

Chen, Xiaoying; Farrokhi, Vahid; Singh, Pratap; Ocana, Mireia Fernandez; Patel, Jenil; Lin, Lih-Ling; Neubert, Hendrik; Brodfuehrer, Joanne

2018-01-01

Discovery of the upregulation of fibroblast growth factor-inducible-14 (Fn14) receptor following tissue injury has prompted investigation into biotherapeutic targeting of the Fn14 receptor for the treatment of conditions such as chronic kidney diseases. In the development of monoclonal antibody (mAb) therapeutics, there is an increasing trend to use biomeasures combined with mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling to enable decision making in early discovery. With the aim of guiding preclinical efforts on designing an antibody with optimized properties, we developed a mechanistic site-of-action (SoA) PK/PD model for human application. This model incorporates experimental biomeasures, including concentration of soluble Fn14 (sFn14) in human plasma and membrane Fn14 (mFn14) in human kidney tissue, and turnover rate of human sFn14. Pulse-chase studies using stable isotope-labeled amino acids and mass spectrometry indicated the sFn14 half-life to be approximately 5 hours in healthy volunteers. The biomeasures (concentration, turnover) of sFn14 in plasma reveals a significant hurdle in designing an antibody against Fn14 with desired characteristics. The projected dose (>1 mg/kg/wk for 90% target coverage) derived from the human PK/PD model revealed potential high and frequent dosing requirements under certain conditions. The PK/PD model suggested a unique bell-shaped relationship between target coverage and antibody affinity for anti-Fn14 mAb, which could be applied to direct the antibody engineering towards an optimized affinity. This investigation highlighted potential applications, including assessment of PK/PD risks during early target validation, human dose prediction and drug candidate optimization.

Effect of α1-adrenergic stimulation on phosphoinositide metabolism and protein kinase C (PK-C) in rat cardiomyocytes

International Nuclear Information System (INIS)

Kaku, T.; Lakatta, E.; Filburn, C.R.

1986-01-01

Alpha 1 -adrenergic stimulation is known to enhance membrane phospholipid metabolism resulting in increases in inositol phosphates (IP's) and diacylglycerol (DAG). Cardiomyocytes prelabeled with 3 H-myo-inositol were treated with norepinephrine (NE) for 1-15 min, acid extracted, and IP's separated by ion exchange chromatography. Addition of NE (10 -5 M) in the presence of propranolol (10 -5 M) and LiCl (9 mM) enhanced the accumulation of IP's, linearly with time up to 15 min, and reached 7.3, and 1.5-fold at 15 min for IP 1 , IP 2 , and IP 3 , respectively. KCl at 30 mM had no effect on accumulation of IP's, but augmented the effect of NE. PK-C activity was measured in both cytosol (S) and particulate (P) fractions of treated cells. NE alone had a negligible effect on membrane PK-C, while 30 mM KCl caused a small increase. However, pretreatment with KCl followed by NE produced a significant increase above that seen with KCl alone. Dioctanoylglycerol also stimulated membrane association of PK-C in these cells. These data suggest that α 1 -adrenergic stimulation of membrane association of myocardial PK-C is mediated by DAG but may be dependent on membrane potential and/or the extent of Ca 2+ loading

Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers

International Nuclear Information System (INIS)

Chauveau, Fabien; Camp, Nadja van; Tavitian, Bertrand; Boutin, Herve; Dolle, Frederic

2008-01-01

Neurodegenerative, inflammatory and neoplastic brain disorders involve neuroinflammatory reactions, and a biomarker of neuroinflammation would be useful for diagnostic, drug development and therapy control of these frequent diseases. In vivo imaging can document the expression of the peripheral benzodiazepine receptor (PBR)/translocator protein 18 kDa (TSPO) that is linked to microglial activation and considered a hallmark of neuroinflammation. The prototype positron emission tomography tracer for PBR, [ 11 C]PK11195, has shown limitations that until now have slowed the clinical applications of PBR imaging. In recent years, dozens of new PET and SPECT radioligands for the PBR have been radiolabelled, and several have been evaluated in imaging protocols. Here we review the new PBR ligands proposed as challengers of [ 11 C]PK11195, critically analyze preclinical imaging studies and discuss their potential as neuroinflammation imaging agents. (orig.)

Automated DBS microsampling, microscale automation and microflow LC-MS for therapeutic protein PK.

Science.gov (United States)

Zhang, Qian; Tomazela, Daniela; Vasicek, Lisa A; Spellman, Daniel S; Beaumont, Maribel; Shyong, BaoJen; Kenny, Jacqueline; Fauty, Scott; Fillgrove, Kerry; Harrelson, Jane; Bateman, Kevin P

2016-04-01

Reduce animal usage for discovery-stage PK studies for biologics programs using microsampling-based approaches and microscale LC-MS. We report the development of an automated DBS-based serial microsampling approach for studying the PK of therapeutic proteins in mice. Automated sample preparation and microflow LC-MS were used to enable assay miniaturization and improve overall assay throughput. Serial sampling of mice was possible over the full 21-day study period with the first six time points over 24 h being collected using automated DBS sample collection. Overall, this approach demonstrated comparable data to a previous study using single mice per time point liquid samples while reducing animal and compound requirements by 14-fold. Reduction in animals and drug material is enabled by the use of automated serial DBS microsampling for mice studies in discovery-stage studies of protein therapeutics.

Valores, Creencias Y Objectivos: Base del programa de la Escuela Experimental P.K. Yonge. (Values, Beliefs and Objectives: The Basis of Experimental Schools P.K. Yonge's Program.)

Science.gov (United States)

Florida Univ., Gainesville. Coll. of Education.

The values, beliefs, and objectives that form the core of the program at the Experimental School P.K. Yonge in the University of Florida are presented in this paper which is written in Spanish. This experimental school serves approximately 900 students from grades one through twelve. The function of the school is to conduct research to solve…

Role of XRCC4 phosphorylation by DNA-PK in the regulation of NHEJ repair pathway of DNA double strand break

International Nuclear Information System (INIS)

Sharma, Mukesh Kumar; Imamichi, Shoji; Fukuchi, Mikoto; Kamdar, Radhika P.; Sicheng, Liu; Wanotayan, Rujira; Matsumoto, Yoshihisa

2014-01-01

Non-homologous end-joining (NHEJ) is the predominant pathway of DNA double strand breaks in higher eukaryotes and is active throughout the cell cycle. NHEJ repair includes many factors as Ku70/86, DNA-PKcs, XRCC4-Ligase IV complex and XLF (also known as Cernunnos). In these factors, DNA-PKcs acts as central regulator in NHEJ repair. It recruited at the DNA damages site after DNA damage and after association with Ku its kinase activity is activated. It phosphorylates many of important NHEJ proteins in vitro including XRCC4, Ku 70/86, Artemis, and even DNA-PKcs but till now, very less studies have been done to know the role and significance of phosphorylation in the NHEJ repair. Studies by other researchers identified various phosphorylation sites in XRCC4 by DNA-PK using mass spectrometry but these phosphorylation sites were shown to be dispensable for DSB repair. In the present investigation, we identified 3 serine and one new threonine phosphorylation sites in XRCC4 protein by DNA-PK. In vivo phosphorylation at these sites was verified by generating phosphorylation specific antibodies and the requirement for DNA-PK therein was verified by using DNA-PK inhibitor and DNA-PK proficient and deficient cell lines in response to radiation and zeocin treatment. We have also found that phosphorylation at these sites showed dose dependency in response to radiation treatment. The two serine and one threonine phosphorylation site is also biological important as their mutation into alanine significantly elevated radiosensitivity as measured by colony formation assay. Neutral comet assay showed delayed kinetics in DSB repair of these mutants. Furthermore, we have found a protein, with putative DSB repair function, which interacts with domain including the phosphorylation sites.These results indicate that these phosphorylation sites would mediate functional link between XRCC4 and DNA-PK. (author)

Microglia activation in multiple sclerosis black holes predicts outcome in progressive patients: an in vivo [(11)C](R)-PK11195-PET pilot study.

Science.gov (United States)

Giannetti, Paolo; Politis, Marios; Su, Paul; Turkheimer, Federico; Malik, Omar; Keihaninejad, Shiva; Wu, Kit; Reynolds, Richard; Nicholas, Richard; Piccini, Paola

2014-05-01

The pathophysiological correlates and the contribution to persisting disability of hypointense T1-weighted MRI lesions, black holes (BH), in multiple sclerosis (MS) are still unclear. In order to study the in vivo functional correlates of this MRI finding, we used 11C-PK11195 PET (PK-PET) to investigate changes in microglial activity. Ten relapsing and 9 progressive MS subjects had a PK-PET scan and a MRI scan alongside a full clinical assessment, including the expanded disability status scale (EDSS) for evaluation of disability. We studied the PK binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BPND) in T1 BHs. Out of a total of 1242 BHs identified, 947 were PK enhancing. The PKBPND was correlated with the EDSS (r=0.818; pholes" representing loss of axons and myelin, but display inflammatory activity in the form of activated microglia. The significant association between PKBPND, neurological impairment and outcome in progressive subjects supports a role for activated microglia in disability progression. Copyright © 2014 Elsevier Inc. All rights reserved.

Critical role of bioanalytical strategies in investigation of clinical PK observations, a Phase I case study

Science.gov (United States)

Peng, Kun; Xu, Keyang; Liu, Luna; Hendricks, Robert; Delarosa, Reginald; Erickson, Rich; Budha, Nageshwar; Leabman, Maya; Song, An; Kaur, Surinder; Fischer, Saloumeh K

2014-01-01

RG7652 is a human immunoglobulin 1 (IgG1) monoclonal antibody (mAb) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) and is designed for the treatment of hypercholesterolemia. A target-binding enzyme-linked immunosorbent assay (ELISA) was developed to measure RG7652 levels in human serum in a Phase I study. Although target-binding assay formats are generally used to quantify free therapeutic, the actual therapeutic species being measured are affected by assay conditions, such as sample dilution and incubation time, and levels of soluble target in the samples. Therefore, in the presence of high concentrations of circulating target, the choice of reagents and assay conditions can have a significant effect on the observed pharmacokinetic (PK) profiles. Phase I RG7652 PK analysis using the ELISA data resulted in a nonlinear dose normalized exposure. An investigation was conducted to characterize the ELISA to determine whether the assay format and reagents may have contributed to the PK observation. In addition, to confirm the ELISA results, a second orthogonal method, liquid chromatography tandem mass spectrometry (LC-MS/MS) using a signature peptide as surrogate, was developed and implemented. A subset of PK samples, randomly selected from half of the subjects in the 6 single ascending dose (SAD) cohorts in the Phase I clinical study, was analyzed with the LC-MS/MS assay, and the data were found to be comparable to the ELISA data. This paper illustrates the importance of reagent characterization, as well as the benefits of using an orthogonal approach to eliminate bioanalytical contributions when encountering unexpected observations. PMID:25484037

Mechanism of the modulation of BK potassium channel complexes with different auxiliary subunit compositions by the omega-3 fatty acid DHA.

Science.gov (United States)

Hoshi, Toshinori; Tian, Yutao; Xu, Rong; Heinemann, Stefan H; Hou, Shangwei

2013-03-19

Large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels are well known for their functional versatility, which is bestowed in part by their rich modulatory repertoire. We recently showed that long-chain omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) found in oily fish lower blood pressure by activating vascular BK channels made of Slo1+β1 subunits. Here we examined the action of DHA on BK channels with different auxiliary subunit compositions. Neuronal Slo1+β4 channels were just as well activated by DHA as vascular Slo1+β1 channels. In contrast, the stimulatory effect of DHA was much smaller in Slo1+β2, Slo1+LRRC26 (γ1), and Slo1 channels without auxiliary subunits. Mutagenesis of β1, β2, and β4 showed that the large effect of DHA in Slo1+β1 and Slo1+β4 is conferred by the presence of two residues, one in the N terminus and the other in the first transmembrane segment of the β1 and β4 subunits. Transfer of this amino acid pair from β1 or β4 to β2 introduces a large response to DHA in Slo1+β2. The presence of a pair of oppositely charged residues at the aforementioned positions in β subunits is associated with a large response to DHA. The Slo1 auxiliary subunits are expressed in a highly tissue-dependent fashion. Thus, the subunit composition-dependent stimulation by DHA demonstrates that BK channels are effectors of omega-3 fatty acids with marked tissue specificity.

[18F]DPA-714: Direct comparison with [11C]PK11195 in a model of cerebral ischemia in rats

International Nuclear Information System (INIS)

Boutin, Herve; Prenant, Christian; Smigova, Alison; Cawthorne, Christopher; Brown, Gavin; Herholz, Karl; Maroy, Renaud; Galea, James; Greenhalgh, Andrew D.; Rothwell, Nancy J.; Julyan, Peter; Wilkinson, Shane M.; Banister, Samuel D.; Kassiou, Michael

2013-01-01

Neuro-inflammation is involved in several brain disorders and can be monitored through expression of the translocator protein 18 kDa (TSPO) on activated micro-glia. In recent years, several new PET radioligands for TSPO have been evaluated in disease models. [ 18 F]DPA-714 is a TSPO radiotracer with great promise; however results vary between different experimental models of neuro-inflammation. To further examine the potential of [ 18 F]DPA-714, it was compared directly to [ 11 C]PK11195 in experimental cerebral ischaemia in rats. Under anaesthesia, the middle cerebral artery of adult rats was occluded for 60 min using the filament model. Rats were allowed recovery for 5 to 7 days before one hour dynamic PET scans with [ 11 C]PK11195 and/or [ 18 F]DPA-714 under anaesthesia. Uptake of [ 11 C]PK11195 vs [ 18 F]DPA-714 in the ischemic lesion was similar (core/contralateral ratio: 2.8460.67 vs 2.2860.34 respectively), but severity of the brain ischemia and hence ligand uptake in the lesion appeared to vary greatly between animals scanned with [ 11 C]PK11195 or with [ 18 F]DPA-714. To solve this issue of inter-individual variability, we performed a direct comparison of [ 11 C]PK11195 and [ 18 F]DPA-714 by scanning the same animals sequentially with both tracers within 24 h. In this direct comparison, the core/contralateral ratio (3.3561.21 vs 4.6662.50 for [ 11 C]PK11195 vs [ 18 F]DPA-714 respectively) showed a significantly better signal-to-noise ratio (1.6 (1.3-1.9, 95%CI) fold by linear regression) for [ 18 F]DPA-714. In a clinically relevant model of neuro-inflammation, uptake for both radiotracers appeared to be similar at first, but a high variability was observed in our model. Therefore, to truly compare tracers in such models, we performed scans with both tracers in the same animals. By doing so, our result demonstrated that [ 18 F]DPA-714 displayed a higher signal-to-noise ratio than [ 11 C]PK11195. Our results suggest that, with the longer half-life of [ 18 F

[18F]DPA-714: direct comparison with [11C]PK11195 in a model of cerebral ischemia in rats.

Directory of Open Access Journals (Sweden)

Hervé Boutin

Full Text Available PURPOSE: Neuroinflammation is involved in several brain disorders and can be monitored through expression of the translocator protein 18 kDa (TSPO on activated microglia. In recent years, several new PET radioligands for TSPO have been evaluated in disease models. [(18F]DPA-714 is a TSPO radiotracer with great promise; however results vary between different experimental models of neuroinflammation. To further examine the potential of [(18F]DPA-714, it was compared directly to [(11C]PK11195 in experimental cerebral ischaemia in rats. METHODS: Under anaesthesia, the middle cerebral artery of adult rats was occluded for 60 min using the filament model. Rats were allowed recovery for 5 to 7 days before one hour dynamic PET scans with [(11C]PK11195 and/or [(18F]DPA-714 under anaesthesia. RESULTS: Uptake of [(11C]PK11195 vs [(18F]DPA-714 in the ischemic lesion was similar (core/contralateral ratio: 2.84±0.67 vs 2.28±0.34 respectively, but severity of the brain ischemia and hence ligand uptake in the lesion appeared to vary greatly between animals scanned with [(11C]PK11195 or with [(18F]DPA-714. To solve this issue of inter-individual variability, we performed a direct comparison of [(11C]PK11195 and [(18F]DPA-714 by scanning the same animals sequentially with both tracers within 24 h. In this direct comparison, the core/contralateral ratio (3.35±1.21 vs 4.66±2.50 for [(11C]PK11195 vs [(18F]DPA-714 respectively showed a significantly better signal-to-noise ratio (1.6 (1.3-1.9, 95%CI fold by linear regression for [(18F]DPA-714. CONCLUSIONS: In a clinically relevant model of neuroinflammation, uptake for both radiotracers appeared to be similar at first, but a high variability was observed in our model. Therefore, to truly compare tracers in such models, we performed scans with both tracers in the same animals. By doing so, our result demonstrated that [(18F]DPA-714 displayed a higher signal-to-noise ratio than [(11C]PK11195. Our results suggest

Five strands of math tasks big book : grades pk-2

CERN Document Server

Reed, Nat; Forest, Chris

2009-01-01

For grades PK-2, our Common Core State Standards-based resource meets the five strands of math concepts addressed by the NCTM standards and encourages the students to learn and review the concepts in unique ways. Included are challenging problem-solving tasks which will push the boundaries of critical thought and demonstrate to students the importance of mathematical problems in Number & Operations, Geometry, Measurement, Data Analysis & Probability and Algebra using real world situations.

Five strands of math drills big book : grades PK-2

CERN Document Server

Reed, Nat; Forest, Chris

2011-01-01

For grades PK-2, our Common Core State Standards-based resource meets the five strands of math concepts addressed by the NCTM standards and encourages the students to review the concepts in unique ways. Included are warm-up and timed drill activities which will push the boundaries of critical thought and demonstrate to students the importance of mathematical problems in Number & Operations, Geometry, Measurement, Data Analysis & Probability and Algebra using real world situations.

Draft Genome Sequence of an Invasive Multidrug-Resistant Strain, Pseudomonas aeruginosa BK1, Isolated from a Keratitis Patient

KAUST Repository

Jeganathan, Lakshmi Priya; Prakash, Logambiga; Neelamegam, Sivakumar; Antony, Aju; Alqarawi, Sami; Prajna, Lalitha; Devarajan, Bharanidharan; Mohankumar, Vidyarani

2014-01-01

Pseudomonas aeruginosa infections are difficult to treat due to the presence of a multitude of virulence factors and antibiotic resistance. Here, we report the draft genome sequence of P. aeruginosa BK1, an invasive and multidrug-resistant strain

DNA-PK. The major target for wortmannin-mediated radiosensitization by the inhibition of DSB repair via NHEJ pathway

International Nuclear Information System (INIS)

Hashimoto, Mitsumasa; Rao, S.; Tokuno, Osamu; Utsumi, Hiroshi; Takeda, Shunichi

2003-01-01

The effect of wortmannin posttreatment was studied in cells derived from different species (hamster, mouse, chicken, and human) with normal and defective DNA-dependent protein kinase (DNA-PK) activity, cells with and without the ataxia telangiectasia mutated (ATM) gene, and cells lacking other regulatory proteins involved in the DNA double-strand break (DSB) repair pathways. Clonogenic assays were used to obtain all results. Wortmannin radiosensitization was observed in Chinese hamster cells (V79-B310H, CHO-K1), mouse mammary carcinoma cells (SR-1), transformed human fibroblast (N2KYSV), chicken B lymphocyte wild-type cells (DT40), and chicken Rad54 knockout cells (Rad54 -/- ). However, mouse mammary carcinoma cells (SX9) with defects in the DNA-PK and chicken DNA-PK catalytic subunit (DNA-PKcs) knockout cells (DNA-PKcs -/-/- ) failed to exhibit wortmannin radiosensitization. On the other hand, severe combined immunodeficiency (SCID) mouse cells (SC3VA2) exposed to wortmannin exhibited significant increases in radiosensitivity, possibly because of some residual function of DNA-PKcs. Moreover, the transformed human cells derived from AT patients (AT2KYSV) and chicken ATM knockout cells (ATM -/- ) showed pronounced wortmannin radiosensitization. These studies demonstrate confirm that the mechanism underlying wortmannin radiosensitization is the inhibition of DNA-PK, but not of ATM, thereby resulting in the inhibition of DSB repair via nonhomologous endjoining (NHEJ). (author)

Double-Nanodomain Coupling of Calcium Channels, Ryanodine Receptors, and BK Channels Controls the Generation of Burst Firing.

Science.gov (United States)

Irie, Tomohiko; Trussell, Laurence O

2017-11-15

Action potentials clustered into high-frequency bursts play distinct roles in neural computations. However, little is known about ionic currents that control the duration and probability of these bursts. We found that, in cartwheel inhibitory interneurons of the dorsal cochlear nucleus, the likelihood of bursts and the interval between their spikelets were controlled by Ca 2+ acting across two nanodomains, one between plasma membrane P/Q Ca 2+ channels and endoplasmic reticulum (ER) ryanodine receptors and another between ryanodine receptors and large-conductance, voltage- and Ca 2+ -activated K + (BK) channels. Each spike triggered Ca 2+ -induced Ca 2+ release (CICR) from the ER immediately beneath somatic, but not axonal or dendritic, plasma membrane. Moreover, immunolabeling demonstrated close apposition of ryanodine receptors and BK channels. Double-nanodomain coupling between somatic plasma membrane and hypolemmal ER cisterns provides a unique mechanism for rapid control of action potentials on the millisecond timescale. Copyright © 2017 Elsevier Inc. All rights reserved.

Optimal transfection methods and comparison of PK-15 and Dulac cells for rescue of chimeric porcine circovirus type 1-2.

Science.gov (United States)

Li, Jizong; Yu, Tianqi; Zhou, Jinzhu; Tu, Wei; Gao, Song; Liu, Xiufan

2014-11-01

A chimeric porcine circovirus type 1-2 (PCV1-2) infectious DNA clone has low transfection efficiency and exhibits low levels of proliferation. Electroporation and lipofection parameters were optimized for PK-15 and Dulac cells with the purpose of increasing the efficiency for rescuing infectious PCV1-2. Titers of PCV1-2 in Dulac cells were 100-fold higher than those in PK-15 cells following transfection. The electroporation efficiency into Dulac cells was high when three 400 μs pulses at 250 V with 6 μg of plasmid DNA was used, lipofection efficiency was high when the ratio of DNA to transfection reagent was 1:3. The proportion of infected cells was 55.6% compared with 44.2%, for the electroporation and lipofection techniques respectively. Virus titers were higher in Dulac cells, from 10(4.44) to 10(5.32)TCID50/mL compared with 10(1.90)-10(3.38)TCID(50)/mL for PK-15 cells. Dulac cells were more permissive to PCV1-2 than PK-15 cells regardless of the transfection technique. Copyright © 2014 Elsevier B.V. All rights reserved.

DNA-PK, ATM and ATR collaboratively regulate p53-RPA interaction to facilitate homologous recombination DNA repair.

Science.gov (United States)

Serrano, M A; Li, Z; Dangeti, M; Musich, P R; Patrick, S; Roginskaya, M; Cartwright, B; Zou, Y

2013-05-09

Homologous recombination (HR) and nonhomologous end joining (NHEJ) are two distinct DNA double-stranded break (DSB) repair pathways. Here, we report that DNA-dependent protein kinase (DNA-PK), the core component of NHEJ, partnering with DNA-damage checkpoint kinases ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR), regulates HR repair of DSBs. The regulation was accomplished through modulation of the p53 and replication protein A (RPA) interaction. We show that upon DNA damage, p53 and RPA were freed from a p53-RPA complex by simultaneous phosphorylations of RPA at the N-terminus of RPA32 subunit by DNA-PK and of p53 at Ser37 and Ser46 in a Chk1/Chk2-independent manner by ATR and ATM, respectively. Neither the phosphorylation of RPA nor of p53 alone could dissociate p53 and RPA. Furthermore, disruption of the release significantly compromised HR repair of DSBs. Our results reveal a mechanism for the crosstalk between HR repair and NHEJ through the co-regulation of p53-RPA interaction by DNA-PK, ATM and ATR.

Profil Siswa Agresif dan Peranan Guru BK

Directory of Open Access Journals (Sweden)

Hafiz Hidayat

2013-06-01

Full Text Available Abstract: Teens have a positive and negative behavior. Negative behavior is not characteristic of normal adolescent development, adolescents are developing will exhibit positive behavior. One of the teens indicated negative behavior is aggressive behavior. It can be seen in SMA N 5 Padang is quarrelsome, like teasing, hitting, pinching her, saying rude, insulting. This study aimed to describe the type of aggressive behavior of students and the role of BK teachers to address students' aggressive behavior SMAN 5 Padang. This study used a descriptive approach. The study population was a high school student Padang N 5 340 people with a total sample amounted to 77 people. Questionnaire data collection techniques to use. Data were analyzed using Microsoft Office Excel 2007. The findings showed that students' views of the aggressive actions hurt people physically with a percentage of 35.32%, while the aggressive actions of the student views of hurting people verbally 41.30% and aggression seen from damaging and destroying property by 30 percent, 42%. This means that the presence of aggressive behavior in SMA N 5 Padang.

Concordant and opposite roles of DNA-PK and the "facilitator of chromatin transcription" (FACT in DNA repair, apoptosis and necrosis after cisplatin

Directory of Open Access Journals (Sweden)

Calkins Anne S

2011-06-01

Full Text Available Abstract Background Platinum-containing chemotherapy produces specific DNA damage and is used to treat several human solid tumors. Tumors initially sensitive to platinum-based drugs frequently become resistant. Inhibition of DNA repair is a potential strategy to enhance cisplatin effectiveness. After cisplatin treatment, a balance between repair and apoptosis determines whether cancer cells proliferate or die. DNA-dependent protein kinase (DNA-PK binds to DNA double strand breaks (DSBs through its Ku subunits and initiates non-homologous end joining. Inhibition of DNA-PK sensitizes cancer cells to cisplatin killing. The goal of this study is to elucidate the mechanism underlying the effects of DNA-PK on cisplatin sensitivity. Results Silencing the expression of the catalytic subunit of DNA-PK (DNA-PKcs increased sensitivity to cisplatin and decreased the appearance of γH2AX after cisplatin treatment. We purified DNA-PK by its Ku86 subunit and identified interactors by tandem mass spectrometry before and after cisplatin treatment. The structure specific recognition protein 1 (SSRP1, Spt16 and γH2AX appeared in the Ku86 complex 5 hours after cisplatin treatment. SSRP1 and Spt16 form the facilitator of chromatin transcription (FACT. The cisplatin-induced association of FACT with Ku86 and γH2AX was abrogated by DNase treatment. In living cells, SSRP1 and Ku86 were recruited at sites of DSBs induced by laser beams. Silencing SSRP1 expression increased sensitivity to cisplatin and decreased γH2AX appearance. However, while silencing SSRP1 in cisplatin-treated cells increased both apoptosis and necrosis, DNA-PKcs silencing, in contrast, favored necrosis over apoptosis. Conclusions DNA-PK and FACT both play roles in DNA repair. Therefore both are putative targets for therapeutic inhibition. Since DNA-PK regulates apoptosis, silencing DNA-PKcs redirects cells treated with cisplatin toward necrosis. Silencing FACT however, allows both apoptosis and

Model based population PK-PD analysis of furosemide for BP lowering effect: A comparative study in primary and secondary hypertension.

Science.gov (United States)

Shukla, Mahendra; Ibrahim, Moustafa M A; Jain, Moon; Jaiswal, Swati; Sharma, Abhisheak; Hanif, Kashif; Lal, Jawahar

2017-11-15

Though numerous reports have demonstrated multiple mechanisms by which furosemide can exert its anti-hypertensive response. However, lack of studies describing PK-PD relationship for furosemide featuring its anti-hypertensive property has limited its usage as a blood pressure (BP) lowering agent. Serum concentrations and mean arterial BP were monitored following 40 and 80mgkg -1 multiple oral dose of furosemide in spontaneously hypertensive rats (SHR) and DOCA-salt induced hypertensive (DOCA-salt) rats. A simultaneous population PK-PD relationship using E max model with effect compartment was developed to compare the anti-hypertensive efficacy of furosemide in these rat models. A two-compartment PK model with Weibull-type absorption and first-order elimination best described the serum concentration-time profile of furosemide. In the present study, post dose serum concentrations of furosemide were found to be lower than the EC 50 . The EC 50 predicted in DOCA-salt rats was found to be lower (4.5-fold), whereas the tolerance development was higher than that in SHR model. The PK-PD parameter estimates, particularly lower values of EC 50 , K e and Q in DOCA-salt rats as compared to SHR, pinpointed the higher BP lowering efficacy of furosemide in volume overload induced hypertensive conditions. Insignificantly altered serum creatinine and electrolyte levels indicated a favorable side effect profile of furosemide. In conclusion, the final PK-PD model described the data well and provides detailed insights into the use of furosemide as an anti-hypertensive agent. Copyright © 2017. Published by Elsevier B.V.

Standard PK/PD concepts can be applied to determine a dosage regimen for a macrolide: the case of tulathromycin in the calf.

Science.gov (United States)

Toutain, P-L; Potter, T; Pelligand, L; Lacroix, M; Illambas, J; Lees, P

2017-01-01

The pharmacokinetic (PK) profile of tulathromycin, administered to calves subcutaneously at the dosage of 2.5 mg/kg, was established in serum, inflamed (exudate), and noninflamed (transudate) fluids in a tissue cage model. The PK profile of tulathromycin was also established in pneumonic calves. For Mannheimia haemolytica and Pasteurella multocida, tulathromycin minimum inhibitory concentrations (MIC) were approximately 50 times lower in calf serum than in Mueller-Hinton broth. The breakpoint value of the PK/pharmacodynamic (PD) index (AUC (0-24 h) /MIC) to achieve a bactericidal effect was estimated from in vitro time-kill studies to be approximately 24 h for M. haemolytica and P. multocida. A population model was developed from healthy and pneumonic calves and, using Monte Carlo simulations, PK/PD cutoffs required for the development of antimicrobial susceptibility testing (AST) were determined. The population distributions of tulathromycin doses were established by Monte Carlo computation (MCC). The computation predicted a target attainment rate (TAR) for a tulathromycin dosage of 2.5 mg/kg of 66% for M. haemolytica and 87% for P. multocida. The findings indicate that free tulathromycin concentrations in serum suffice to explain the efficacy of single-dose tulathromycin in clinical use, and that a dosage regimen can be computed for tulathromycin using classical PK/PD concepts. © 2016 John Wiley & Sons Ltd.

Effects on field- and bottom-layer species in an experiment with repeated PK- and NPK-fertilization

International Nuclear Information System (INIS)

Nohrstedt, H.Oe.

1994-01-01

Long-term changes in forest ground vegetation because of repeated PK- and NPK-fertilization were examined in an old field experiment, located in a 85-year-old Pinus sylvestris stand in northern Sweden. Fertilizers were added at 5-(PK, NPK) or 10-(PK) year intervals, beginning 26 years prior to the study. The treatments were tested in two replicates on plots sized 40 x 40 m. The total doses added were N 720 kg/ha, P 222-380 kg/ha and K 318-620 kg/ha. N was given as ammonium nitrate, P as superphosphate and K as potassium chloride. The vegetation on control plots was of the Vaccinium vitis-idaea type. The field layer was dominated by V.vitis-idaea and V.myrtillus, and the bottom layer by Pleurozium schreberi. The effect of fertilization was quantified by examining the areal cover of individual species. This was done in 25 0.25 m 2 frames systematically placed in a grid over each treatment plot. The only pronounced effect in the field layer was on V.myrtillus. The cover was strongly reduced by fertilization with PK. The reduction was 70% for the 5-year interval and 34% for the 10-year interval. The cover more than doubled after NPK-fertilization. Among the cryptogams, a reduction in cover was indicated for Cladina arbuscula and C.rangiferina because of fertilization with NPK. NPK reduced the number of species that were found, totally depending on negative effects on several lichen species. For species absent in the examined frame areas but present somewhere else on the treatment plots, it was seen that Deschampsia flexuosa increased after NPK-fertilization, while Peltigera apthosa and Steroecaulon tomentosum decreased. Hylocomium splendens occurred on both control plots, but only on one fertilized plot. 30 refs, 1 fig, 5 tabs

The Duffy binding protein (PkDBPαII) of Plasmodium knowlesi from Peninsular Malaysia and Malaysian Borneo show different binding activity level to human erythrocytes.

Science.gov (United States)

Lim, Khai Lone; Amir, Amirah; Lau, Yee Ling; Fong, Mun Yik

2017-08-11

The zoonotic Plasmodium knowlesi is a major cause of human malaria in Malaysia. This parasite uses the Duffy binding protein (PkDBPαII) to interact with the Duffy antigen receptor for chemokines (DARC) receptor on human and macaque erythrocytes to initiate invasion. Previous studies on P. knowlesi have reported distinct Peninsular Malaysia and Malaysian Borneo PkDBPαII haplotypes. In the present study, the differential binding activity of these haplotypes with human and macaque (Macaca fascicularis) erythrocytes was investigated. The PkDBPαII of Peninsular Malaysia and Malaysian Borneo were expressed on the surface of COS-7 cells and tested with human and monkey erythrocytes, with and without anti-Fy6 (anti-Duffy) monoclonal antibody treatment. Binding activity level was determined by counting the number of rosettes formed between the transfected COS-7 cells and the erythrocytes. Anti-Fy6 treatment was shown to completely block the binding of human erythrocytes with the transfected COS-7 cells, thus verifying the specific binding of human DARC with PkDBPαII. Interestingly, the PkDBPαII of Peninsular Malaysia displayed a higher binding activity with human erythrocytes when compared with the Malaysian Borneo PkDBPαII haplotype (mean number of rosettes formed = 156.89 ± 6.62 and 46.00 ± 3.57, respectively; P < 0.0001). However, no difference in binding activity level was seen in the binding assay using M. fascicularis erythrocytes. This study is the first report of phenotypic difference between PkDBPαII haplotypes. The biological implication of this finding is yet to be determined. Therefore, further studies need to be carried out to determine whether this differential binding level can be associated with severity of knowlesi malaria in human.

Expression of BK_Ca channels and the modulatory ß-subunits in the rat and porcine trigeminal ganglion

DEFF Research Database (Denmark)

Wulf-Johansson, Helle; Hay-Schmidt, Anders; Poulsen, Asser Nyander

2009-01-01

Large conductance calcium-activated potassium (BK(Ca)) channels contribute to electrical impulses, proper signal transmission of information and regulation of neurotransmitter release. Migraine has been proposed to be a trigeminovascular disease involving the sensory trigeminal pathways and the c...

The role of infection models and PK/PD modelling for optimising care of critically ill patients with severe infections.

Science.gov (United States)

Tängdén, T; Ramos Martín, V; Felton, T W; Nielsen, E I; Marchand, S; Brüggemann, R J; Bulitta, J B; Bassetti, M; Theuretzbacher, U; Tsuji, B T; Wareham, D W; Friberg, L E; De Waele, J J; Tam, V H; Roberts, Jason A

2017-07-01

Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens. Individualised dosing, based on population PK models and patient factors (e.g. renal function and weight) known to influence antimicrobial PK, increases the probability of achieving therapeutic drug exposures while at the same time avoiding toxic concentrations. When therapeutic drug monitoring (TDM) is applied, early dose adaptation to the needs of the individual patient is possible. TDM is likely to be of particular importance for infected critically ill patients, where profound PK changes are present and prompt appropriate antibiotic therapy is crucial. In the light of the continued high mortality rates in critically ill patients with severe infections, a paradigm shift to refined dosing strategies for antimicrobials is warranted to enhance the probability of achieving drug concentrations that increase the likelihood of clinical success.

[11C]-(R)-PK11195 positron emission tomography in patients with complex regional pain syndrome

Science.gov (United States)

Jeon, So Yeon; Seo, Seongho; Lee, Jae Sung; Choi, Soo-Hee; Lee, Do-Hyeong; Jung, Ye-Ha; Song, Man-Kyu; Lee, Kyung-Jun; Kim, Yong Chul; Kwon, Hyun Woo; Im, Hyung-Jun; Lee, Dong Soo; Cheon, Gi Jeong; Kang, Do-Hyung

2017-01-01

Abstract Complex regional pain syndrome (CRPS) is characterized by severe and chronic pain, but the pathophysiology of this disease are not clearly understood. The primary aim of our case–control study was to explore neuroinflammation in patients with CRPS using positron emission tomography (PET), with an 18-kDa translocator protein specific radioligand [11C]-(R)-PK11195. [11C]-(R)-PK11195 PET scans were acquired for 11 patients with CRPS (30–55 years) and 12 control subjects (30–52 years). Parametric image of distribution volume ratio (DVR) for each participant was generated by applying a relative equilibrium-based graphical analysis. The DVR of [11C]-(R)-PK11195 in the caudate nucleus (t(21) = −3.209, P = 0.004), putamen (t(21) = −2.492, P = 0.022), nucleus accumbens (t(21) = −2.218, P = 0.040), and thalamus (t(21) = −2.395, P = 0.026) were significantly higher in CRPS patients than in healthy controls. Those of globus pallidus (t(21) = −2.045, P = 0.054) tended to be higher in CRPS patients than in healthy controls. In patients with CRPS, there was a positive correlation between the DVR of [11C]-(R)-PK11195 in the caudate nucleus and the pain score, the visual analog scale (r = 0.661, P = 0.026, R2 = 0.408) and affective subscales of McGill Pain Questionnaire (r = 0.604, P = 0.049, R2 = 0.364). We demonstrated that neuroinflammation of CRPS patients in basal ganglia. Our results suggest that microglial pathology can be an important pathophysiology of CRPS. Association between the level of caudate nucleus and pain severity indicated that neuroinflammation in this region might play a key role. These results may be essential for developing effective medical treatments. PMID:28072713

Tacrolimus Updated Guidelines through popPK Modeling: How to Benefit More from CYP3A Pre-emptive Genotyping Prior to Kidney Transplantation

Directory of Open Access Journals (Sweden)

Jean-Baptiste Woillard

2017-06-01

Full Text Available Tacrolimus (Tac is a profoundly effective immunosuppressant that reduces the risk of rejection after solid organ transplantation. However, its use is hampered by its narrow therapeutic window along with its highly variable pharmacological (pharmacokinetic [PK] and pharmacodynamic [PD] profile. Part of this variability is explained by genetic polymorphisms affecting the metabolic pathway. The integration of CYP3A4 and CY3A5 genotype in tacrolimus population-based PK (PopPK modeling approaches has been proven to accurately predict the dose requirement to reach the therapeutic window. The objective of the present study was to develop an accurate PopPK model in a cohort of 59 kidney transplant patients to deliver this information to clinicians in a clear and actionable manner. We conducted a non-parametric non-linear effects PopPK modeling analysis in Pmetrics®. Patients were genotyped for the CYP3A4∗22 and CYP3A5∗3 alleles and were classified into 3 different categories [poor-metabolizers (PM, Intermediate-metabolizers (IM or extensive-metabolizers (EM]. A one-compartment model with double gamma absorption route described very accurately the tacrolimus PK. In covariate analysis, only CYP3A genotype was retained in the final model (Δ-2LL = -73. Our model estimated that tacrolimus concentrations were 33% IC95%[20–26%], 41% IC95%[36–45%] lower in CYP3A IM and EM when compared to PM, respectively. Virtually, we proved that defining different starting doses for PM, IM and EM would be beneficial by ensuring better probability of target concentrations attainment allowing us to define new dosage recommendations according to patient CYP3A genetic profile.

Cimetidine-induced Leydig cell apoptosis and reduced EG-VEGF (PK-1) immunoexpression in rats: Evidence for the testicular vasculature atrophy.

Science.gov (United States)

Beltrame, Flávia L; Cerri, Paulo S; Sasso-Cerri, Estela

2015-11-01

The antiulcer drug cimetidine has shown to cause changes in the testicular microvasculature of adult rats. Since Leydig cells (LCs) produce the pro-angiogenic factor, EG-VEGF (endocrine gland-derived vascular endothelial growth factor), also known as prokineticin 1 (PK-1), this study examined the effect that cimetidine might have on LCs in testes with damaged vasculature. Rats received intraperitoneal injections of 100mg/kg of cimetidine (cimetidine group) or saline vehicle (control group) for 50 days. Serum testosterone levels were measured by chemiluminescence immunoassay and testicular sections were subjected to TUNEL and immunohistochemical reactions for caspase-3, 17β-HSD6, CD163 (ED2 macrophage), PK-1 and androgen receptor (AR). LCs in the cimetidine group showed TUNEL and caspase-3 positive labeling and apoptotic ultrastructural features. Moreover, the presence of 17β-HSD6-positive inclusions inside macrophages and the reduced number of LCs, AR immunoreactivity and serum testosterone levels correlated with a decrease in either the number of PK-1-immunostained LCs or PK-1 immunoreactivity. Although it is not clear which cell type is the primary target of cimetidine in the testicular interstitial compartment, these findings support a direct link between cimetidine-induced testicular vascular atrophy and LCs damage. Copyright © 2015 Elsevier Inc. All rights reserved.

Conversion from tacrolimus-mycophenolate mofetil to tacrolimus-mTOR immunosuppression after kidney-pancreas transplantation reduces the incidence of both BK and CMV viremia.

Science.gov (United States)

Knight, Richard J; Graviss, Edward A; Nguyen, Duc T; Kuten, Samantha A; Patel, Samir J; Gaber, Lillian; Gaber, A Osama

2018-04-19

We sought to determine whether conversion from tacrolimus/mycophenolate mofetil (TAC-MMF) into tacrolimus/mTOR inhibitor (TAC-mTOR) immunosuppression would reduce the incidences of BK and CMV viremia after kidney/pancreas (KP) transplantation. In this single-center review, the TAC-mTOR cohort (n = 39) was converted at 1 month post-transplant to an mTOR inhibitor and reduced-dose tacrolimus. Outcomes were compared to a cohort of KP recipients (n = 40) maintained on TAC-MMF. At 3 years post-transplant, KP survivals and incidences of kidney/pancreas rejection were equivalent between mTOR and MMF-treated cohorts. (P = ns). BK viremia-free survival was better for the mTOR vs MMF-treated group (P = .004). In multivariate analysis, MMF vs mTOR immunosuppression was an independent risk factor for BK viremia (hazard ratio 12.27, P = .02). Similarly, mTOR-treated recipients displayed better CMV infection-free survival compared to the MMF-treated cohort (P = .01). MMF vs mTOR immunosuppression (hazard ratio 18.77, P = .001) and older recipient age (hazard ratio 1.13 per year, P = .006) were independent risk factors for CMV viremia. Mean estimated GFR and HgbA1c levels were equivalent between groups at 1, 2, and 3 years post-transplantation. Conversion from TAC/MMF into TAC/mTOR immunosuppression after KP transplantation reduced the incidences of BK and CMV viremia with an equivalent risk of acute rejection and similar renal/pancreas function. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Perilaku Bullying dan Peranan Guru BK/Konselor dalam Pengentasannya (Studi Deskriptif terhadap Siswa SMP Negeri 3 Lubuk Basung

Directory of Open Access Journals (Sweden)

Ilfajri Yenes

2016-06-01

Full Text Available Bullying merupakan suatu situasi di mana terjadinya penyalahgunaan kekuatan/kekuasaan yang dilakukan oleh seseorang/kelompok. Perilaku bullying merupakan  salah satu bentuk kekerasan dan agresif siswa di sekolah. Penelitian ini adalah penelitian deskriptif yang bertujuan untuk mendeskripsikan perilaku bullying yang ditampilkan siswa SMPN 3 Lubuk Basung dan peranan guru BK/konselor dalam pengentasannya. Populasi penelitian adalah siswa di SMP Negeri 3 Lubuk Basung berjumlah  564 orang dengan sampel 138 orang diambil dengan menggunakan teknik propotonal stratified random. Teknik pengumpulan data dengan menggunakan angket. Temuan penelitian menunjukkan bahwa jenis perilaku bullying yang dominan terjadi yaitu menyakiti secara verbal dilanjutkan dengan menyakiti secara fisik kemudian menyakiti secara mental dengan faktor keluarga. Faktor teman sebaya merupakan faktor yang lebih dominan sebagai penyebab perilaku bullying siswa. Secara umum guru BK/konselor cukup berperan mengatasi perilaku bullyingdengan memberikan  layanan informasi sebagai layanan yang lebih dominan diberikan dilanjutkan dengan layanan bimbingan kelompok dan konseling kelompok serta pemberian layanan konseling individual.

One hundred cases of laparoscopic subtotal hysterectomy using the PK and Lap Loop systems.

Science.gov (United States)

Erian, John; El-Toukhy, Tarek; Chandakas, Stefanos; Theodoridis, Theo; Hill, Nicholas

2005-01-01

To evaluate the safety and short-term outcomes of laparoscopic subtotal hysterectomy using the PK and Lap Loop systems. Prospective observational study (Canadian Task Force classification II-2). Princess Royal University and Chelsfield Park Hospitals, Kent, UK. One hundred women who underwent laparoscopic subtotal hysterectomy for menorrhagia from February 2003 through July 2004. The procedure was performed using the Plasma Kinetic (PK) system to seal the vascular pedicles and the Lap Loop system to separate the uterus at the level of the internal os. The uterus was removed from the abdominal cavity mainly by morcellation or posterior colpotomy. Of 100 patients, 59 were operated on as outpatients. Mean patient age was 44.6 years, median parity was 2, mean body mass index was 26.8, and mean duration of symptoms was 4 years. Clinically, the uterus was enlarged in 70 patients, and preoperative ultrasound scanning suggested the presence of uterine myomas in 42 patients. In addition to hysterectomy, 47 patients had concomitant pelvic surgery. The mean total operating time was 45.5 minutes, and mean estimated blood loss was 114 mL. The overall major complication rate was 2%; two patients required blood transfusion after surgery. There were no bowel or urinary tract injuries, unintended laparotomy, return to operating room, or anesthetic complications. At follow-up, all patients were satisfied with surgery. Laparoscopic subtotal hysterectomy using the PK and Lap Loop systems for treatment of therapy-resistant menorrhagia is safe, can be performed as an outpatient procedure, and is associated with reduced operating time and high patient satisfaction.

Draft Genome Sequence of an Invasive Multidrug-Resistant Strain, Pseudomonas aeruginosa BK1, Isolated from a Keratitis Patient

KAUST Repository

Jeganathan, Lakshmi Priya

2014-03-27

Pseudomonas aeruginosa infections are difficult to treat due to the presence of a multitude of virulence factors and antibiotic resistance. Here, we report the draft genome sequence of P. aeruginosa BK1, an invasive and multidrug-resistant strain, isolated from a bacterial keratitis patient in southern India.

SUPER-RAMP PK2 cases by START-3. Preliminary Report

International Nuclear Information System (INIS)

Novikov, Vladimir; Kuznetsov, Vladimir; Chulkin, Dmitriy

2013-01-01

The Studsvik SUPER-RAMP Project, an internationally sponsored research project, investigated the failure propensity of typical LWR fuel in the form of test rods when subjected to power ramps, after base irradiation to high burn-up. The following information summarizing the project is abstracted from the Final Report of the SUPER-RAMP project (STSR-32). The Project power ramped 28 individual PWR rods and 16 BWR rods. The PWR rods were all tested using high ramp rates. Due to different objectives for the BWR subprogramme, one set of the BWR rods was tested using a high ramp rate, and another set were tested with a very slow ramp rate. All rods underwent a thorough examination programme, comprising characterisation prior to base irradiation, examination between base and ramp irradiation and examination after ramp irradiation. This consisted of 6 groups of rods with variations in design and material parameters. The rods were base irradiated in a power reactor environment KK Obrigheim or BR-3 at time averaged heat ratings mainly in the range 14-26 kW/m to peak burn-ups in the range 33-45 MWd/kgU and were subsequently ramp tested in the research reactor R2 at Studsvik, Sweden. The result can be summarized as follows: In this document some calculations are made on the PK2 group fuel rods. The rods were standard rods manufactured by Kraftwerk Union AG/Combustion Engineering (KWU/CE). All these rods sustained ramping to power levels in the range 41 to 49 kW/m and power changes 16-24 kW/m without failure, in spite of large deformations, fuel restructuring and fission gas release particularly for the PK2 rods. Though the results of this paper seem to be based on the incomplete dataset (ambiguity in power raise rates, undefined fuel pellet and cladding surface roughness), we think that START-3 Zircalloy-4 model requires further improvements. In order to do them, we kindly ask IAEA to provide us with more detailed irradiation histories (more than 3 axial zones, power increase

Porcine parvovirus infection induces apoptosis in PK-15 cells through activation of p53 and mitochondria-mediated pathway

International Nuclear Information System (INIS)

Zhang, Hongling; Huang, Yong; Du, Qian; Luo, Xiaomao; Zhang, Liang; Zhao, Xiaomin; Tong, Dewen

2015-01-01

Highlights: • PPV reduces PK-15 cells viability by inducing apoptosis. • PPV infection induces apoptosis through mitochondria-mediated pathway. • PPV infection activates p53 to regulate the mitochondria apoptotic signaling. - Abstract: Porcine parvovirus (PPV) infection has been reported to induce the cytopathic effects (CPE) in some special host cells and contribute the occurrence of porcine parvovirus disease, but the molecular mechanisms underlying PPV-induced CPE are not clear. In this study, we investigated the morphological and molecular changes of porcine kidney cell line (PK-15 cells) infected with PPV. The results showed that PPV infection inhibited the viability of PK-15 cells in a time and concentration dependent manner. PPV infection induced typical apoptotic features including chromatin condensation, apoptotic body formation, nuclear fragmentation, and Annexin V-binding activity. Further studies showed that Bax was increased and translocated to mitochondria, whereas Bcl-2 was decreased in PPV-infected cells, which caused mitochondrial outer-membrane permeabilization, resulting in the release of mitochondrial cytochrome c, followed by caspase-9 and caspase-3 activation. However, the expression of Fas and Fas ligand (FasL) did not appear significant changes in the process of PPV-induced apoptosis. Moreover, PPV infection activated p53 signaling, which was involved in the activation of apoptotic signaling induced by PPV infection via regulation of Bax and Bcl-2. Taken together, our results demonstrated that PPV infection induced apoptosis in PK-15 cells through activation of p53 and mitochondria-mediated apoptosis pathway. This study may contribute to shed light on the molecular pathogenesis of PPV infection

Porcine parvovirus infection induces apoptosis in PK-15 cells through activation of p53 and mitochondria-mediated pathway

Energy Technology Data Exchange (ETDEWEB)

Zhang, Hongling; Huang, Yong; Du, Qian; Luo, Xiaomao; Zhang, Liang; Zhao, Xiaomin; Tong, Dewen, E-mail: dwtong@nwsuaf.edu.cn

2015-01-09

Highlights: • PPV reduces PK-15 cells viability by inducing apoptosis. • PPV infection induces apoptosis through mitochondria-mediated pathway. • PPV infection activates p53 to regulate the mitochondria apoptotic signaling. - Abstract: Porcine parvovirus (PPV) infection has been reported to induce the cytopathic effects (CPE) in some special host cells and contribute the occurrence of porcine parvovirus disease, but the molecular mechanisms underlying PPV-induced CPE are not clear. In this study, we investigated the morphological and molecular changes of porcine kidney cell line (PK-15 cells) infected with PPV. The results showed that PPV infection inhibited the viability of PK-15 cells in a time and concentration dependent manner. PPV infection induced typical apoptotic features including chromatin condensation, apoptotic body formation, nuclear fragmentation, and Annexin V-binding activity. Further studies showed that Bax was increased and translocated to mitochondria, whereas Bcl-2 was decreased in PPV-infected cells, which caused mitochondrial outer-membrane permeabilization, resulting in the release of mitochondrial cytochrome c, followed by caspase-9 and caspase-3 activation. However, the expression of Fas and Fas ligand (FasL) did not appear significant changes in the process of PPV-induced apoptosis. Moreover, PPV infection activated p53 signaling, which was involved in the activation of apoptotic signaling induced by PPV infection via regulation of Bax and Bcl-2. Taken together, our results demonstrated that PPV infection induced apoptosis in PK-15 cells through activation of p53 and mitochondria-mediated apoptosis pathway. This study may contribute to shed light on the molecular pathogenesis of PPV infection.

Abnormal differentiation, hyperplasia and embryonic/perinatal lethality in BK5-T/t transgenic mice

Science.gov (United States)

Chen, Xin; Schneider-Broussard, Robin; Hollowell, Debra; McArthur, Mark; Jeter, Collene R.; Benavides, Fernando; DiGiovanni, John; Tang, Dean G.

2009-01-01

The cell-of-origin has a great impact on the types of tumors that develop and the stem/progenitor cells have long been considered main targets of malignant transformation. The SV40 large T and small t antigens (T/t), have been targeted to multiple differentiated cellular compartments in transgenic mice. In most of these studies, transgenic animals develop tumors without apparent defects in animal development. In this study, we used the bovine keratin 5 (BK5) promoter to target the T/t antigens to stem/progenitor cell-containing cytokeratin 5 (CK5) cellular compartment. A transgene construct, BK5-T/t, was made and microinjected into the male pronucleus of FVB/N mouse oocytes. After implanting ∼1700 embryos, only 7 transgenics were obtained, including 4 embryos (E9.5, E13, E15, and E20) and 3 postnatal animals, which died at P1, P2, and P18, respectively. Immunohistological analysis revealed aberrant differentiation and prominent hyperplasia in several transgenic CK5 tissues, especially the upper digestive organs (tongue, oral mucosa, esophagus, and forestomach) and epidermis, the latter of which also showed focal dysplasia. Altogether, these results indicate that constitutive expression of the T/t antigens in CK5 cellular compartment results in abnormal epithelial differentiation and leads to embryonic/perinatal animal lethality. PMID:19272531

Experimental Investigation on Cutting Characteristics in Nanometric Plunge-Cutting of BK7 and Fused Silica Glasses.

Science.gov (United States)

An, Qinglong; Ming, Weiwei; Chen, Ming

2015-03-27

Ductile cutting are most widely used in fabricating high-quality optical glass components to achieve crack-free surfaces. For ultra-precision machining of brittle glass materials, critical undeformed chip thickness (CUCT) commonly plays a pivotal role in determining the transition point from ductile cutting to brittle cutting. In this research, cutting characteristics in nanometric cutting of BK7 and fused silica glasses, including machined surface morphology, surface roughness, cutting force and specific cutting energy, were investigated with nanometric plunge-cutting experiments. The same cutting speed of 300 mm/min was used in the experiments with single-crystal diamond tool. CUCT was determined according to the mentioned cutting characteristics. The results revealed that 320 nm was found as the CUCT in BK7 cutting and 50 nm was determined as the size effect of undeformed chip thickness. A high-quality machined surface could be obtained with the undeformed chip thickness between 50 and 320 nm at ductile cutting stage. Moreover, no CUCT was identified in fused silica cutting with the current cutting conditions, and brittle-fracture mechanism was confirmed as the predominant chip-separation mode throughout the nanometric cutting operation.

Dynamics of Db isotopes formed in reactions induced by 238U, 248Cm, and 249Bk across the Coulomb barrier

Science.gov (United States)

Kaur, Gurjit; Sandhu, Kirandeep; Kaur, Amandeep; Sharma, Manoj K.

2018-05-01

The dynamical cluster decay model is employed to investigate the decay of *265Db and *267Db nuclei, formed in the 27Al+238U , 18O+249Bk , and 19F+248Cm hot fusion reactions at energies around the Coulomb barrier. First, the fission dynamics of the 27Al+238U reaction is explored by investigating the fragmentation and preformation yield of the reaction. The symmetric mass distribution of the fission fragments is observed for *265Db nucleus, when static β2 i deformations are used within hot optimum orientation approach. However, the mass split gets broaden for the use of β2 i-dynamical hot configuration of the fragments and becomes clearly asymmetric for the cold-static-deformed approach. Within the application of cold orientations of fragments, a new fission channel is observed at mass asymmetry η =0.29 . In addition to 238U-induced reaction, the work is carried out to address the fission and neutron evaporation cross sections of *267Db nucleus formed via 19F+248Cm and 18O+249Bk reactions, besides a comprehensive analysis of fusion and capture processes. Higher fusion cross sections and compound nucleus formation probabilities (PCN) are obtained for the 18O+249Bk reaction, as larger mass asymmetry in the entrance channel leads to reduced Coulomb factor. Finally, the role of sticking (IS) and nonsticking (INS) moments of inertia is analyzed for the 4 n and 5 n channels of *267Db nuclear system.

A combination of genistein and magnesium enhances the vasodilatory effect via an eNOS pathway and BK(Ca) current amplification.

Science.gov (United States)

Sun, Lina; Hou, Yunlong; Zhao, Tingting; Zhou, Shanshan; Wang, Xiaoran; Zhang, Liming; Yu, Guichun

2015-04-01

The phytoestrogen genistein (GST) and magnesium have been independently shown to regulate vascular tone; however, their individual vasodilatory effects are limited. The aim of this study was to examine the combined effects of GST plus magnesium on vascular tone in mesenteric arteries. The effects of pretreatment with GST (0-200 μmol/L), MgCl2 (0-4.8 mmol/L) and GST plus MgCl2 on 10 μmol/L phenylephrine (PE) precontracted mesenteric arteries in rats were assessed by measuring isometric force. BK(Ca) currents were detected by the patch clamp method. GST caused concentration- and partial endothelium-dependent relaxation. Magnesium resulted in dual adjustment of vascular tone. Magnesium-free solution eliminated the vasodilatation of GST in both endothelium-intact and denuded rings. GST (50 μmol/L) plus magnesium (4.8 mmol/L) caused stronger relaxation in both endothelium-intact and denuded rings. Pretreatment with the nitric oxide synthase (NOS) inhibitor L-N-nitroarginine methyl ester (L-NAME, 100 μmol/L) significantly inhibited the effects of GST, high magnesium, and the combination of GST and magnesium. BK(Ca) currents were amplified to a greater extent when GST (50 μmol/L) was combined with 4.8 versus 1.2 mmol/L Mg(2+). Our data suggest that GST plus magnesium provides enhanced vasodilatory effects in rat mesenteric arteries compared with that observed when either is used separately, which was related to an eNOS pathway and BK(Ca) current amplification.

Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity

International Nuclear Information System (INIS)

Dittmann, Klaus; Mayer, Claus; Rodemann, Hans-Peter

2005-01-01

Background and purpose: Inhibition of EGFR-function can induce radiosensitization in tumor cells. Purpose of our investigation was to identify the possible molecular mechanism of radiosensitization following treatment with anti-EGFR-antibody C225 (Cetuximab). Materials and methods: The effect of C225 on radiation response was determined in human cell lines of bronchial carcinoma (A549) and breast adenoma cells (MDA MB 231). The molecular effects of C225 on EGFR-function after irradiation were analyzed applying western blotting, immune-precipitation and kinase assays. Effects on DNA-repair were detected by quantification of γ-H2AX positive foci 24 h after irradiation. Results: The EGFR specific antibody C225 induced radiosensitization in A549 and also in MDA MB 231 cells. Radiosensitization in A549 was associated with blockage of radiation-induced EGFR transport into the nucleus, and immobilized the complex of EGFR with DNA-dependent protein kinase (DNA-PK) in the cytoplasm. As a consequence radiation-induced DNA-PK activation was abolished, a process that is essential for DNA-repair after radiation exposure. Likewise C225 treatment increased the residual amount of γ-H2AX-positive foci 24 h after irradiation in A549 and in MDA MB 231 cells. Conclusions: Our results suggest that irradiation induced DNA-PK activation-essential for DNA repair-may be hampered specifically by use of the anti-EGFR-antibody C225. This process is associated with radiosensitization

The influence of ebselen on the toxicity of cisplatin in LLC-PK1 cells

NARCIS (Netherlands)

Baldew, G S; Boymans, A P; Mol, J G; Vermeulen, N P

1992-01-01

LLC-PK1 cells have been used as an in vitro model to study the nephrotoxicity of the antitumor drug cisplatin. A concentration-dependent cytotoxicity of cisplatin, measured as lactate dehydrogenase leakage and amount of protein remaining attached to the culture plate, was observed. At a cisplatin

Neuroinflammation in bipolar disorder : A [C-11]-(R)-PK11195 positron emission tomography study

NARCIS (Netherlands)

Haarman, Bartholomeus C.M.; Riemersma -van der Lek, Rixt; de Groot, Jan Cees; Ruhe, Eric; Klein, Hans C; Zandstra, Tjitske E; Burger, Huibert; Schoevers, Robert A.; de Vries, Erik F.J.; Drexhage, Hemmo A; Nolen, Willem A.; Doorduin, Janine

Background: The "monocyte-T-cell theory of mood disorders" regards neuroinflammation, i.e. marked activation of microglia, as a driving force in bipolar disorder. Microglia activation can be visualized in vivo using [C-11]-(R)-PK11195 PET. Indirect evidence suggests the hippocampus as a potential

Surface binding and uptake of cadmium (Cd2+) by LLC-PK1 cells on permeable membrane supports

International Nuclear Information System (INIS)

Prozialeck, W.C.; Lamar, P.C.

1993-01-01

Recent studies have shown that Cd 2+ has relatively specific damaging effects on cell-cell junctions in the renal epithelial cell line, LLC-PK 1 . The objective of the present studies was to examine the surface binding and uptake of Cd 2+ by LLC-PK 1 cells in relation to the disruption of cell-cell junctions. LLC-PK 1 cells on Falcon Cell Culture Inserts were exposed to CdCl 2 containing trace amounts of 109 Cd 2+ from either the apical or the basolateral compartments, and the accumulation of 109 Cd 2+ was monitored for up to 8 h. The integrity of cell-cell junctions was assessed by monitoring the transepithelial electrical resistance. The results showed that the cells accumulated 3-4 times more Cd 2+ from the basolateral compartment than from the apical compartment. The accumulation of Cd 2+ from the basolateral compartment occurred in two phases: a rapid, exponential phase that occurred in 1-2 h and coincided with a decrease in transepithelial resistance, and a slower, linear phase that continued for 6-8 h. The Cd 2+ that accumulated during the rapid phase was easily removed by washing the cells in EGTA, indicating that most of it was bound to sites on the cell surface. By contrast, most of the Cd 2+ that accumulated during the slower phase could not be removed by EGTA, indicating that it had been taken up by the cells. Additional studies showed that the rapid phase of Cd 2+ accumulation was enhanced when Ca 2+ was present at low concentrations (0.1 mM), and was greatly reduced when Ca 2+ was present at high concentrations (10 mM). These results suggest that ld 2+ damages the junctions between LLC-PK 1 cells by interacting with Ca 2+ -sensitive sites on the basolateral cell surface. (orig.)

Semi quantification study of [{sup 11}C]-(R)-PK11195 PET brain images in multiple sclerosis; Estudo da semiquantificacao de imagens PET cerebrais de [{sup 11}C]-(R)-PK11195 na esclerose multipla

Energy Technology Data Exchange (ETDEWEB)

Narciso, Lucas D.L.; Schuck, Phelipi N.; Dartora, Caroline M.; Matushita, Cristina S.; Becker, Jefferson; Silva, Ana M. Marques da, E-mail: lucas.narciso@acad.pucrs.br [Pontificia Universidade Catolica do Rio Grande do Sul (PUC-RS), Porto Alegre, RS (Brazil)

2016-07-01

PET brain images with [{sup 11}C]-(R)-PK11195 are being widely used to visualize microglial activation in vivo in neuro degenerative diseases, such as multiple sclerosis (MS). The aim of this study is to investigate the uptake behavior in justacortical and periventricular regions of [{sup 11}C]-(R)-PK11195 PET brain images reformatted in different time intervals by applying three methods, seeking method and time interval that significantly differentiate MS patients from healthy controls. Semi-quantitative SUV and uptake relative to a reference region methods were applied to PET images from different time intervals acquired from 10 patients with MS and 5 healthy controls. The results show significant SUV values difference (p = 0.01, 40 to 60 min) in justacortical and periventricular regions between groups and using the normalization method in which the uptake is relative to the mean concentration activity in the white matter (p <0.01, 10 to 60 min). (author)

[Bacteriological evaluation of a procedure for disinfecting the Olympus GIF-D2 panendoscope].

Science.gov (United States)

Ramírez Ramos, A; Domínguez, N; Makino, R; Barrera, C

1980-01-01

We have performed a total of 107 cultures from three critical areas of an Olympus Panendoscope Model GIF-D2 in order to evaluate bacteriologically cur system of desinfection of this endoscope. Samples were taken from the distal end, external surface and biopsy canal before and after an endoscopic examination was performed. The procedure of desinfection employed was as follows: washing of the distal end, external surface and biopsy canal with Hexaclorophel (Phisohex) diluted 50% with water and a second washing with tap water. In the middle of the study, we added a second washing of the biopsy canal with ten ml. of ether alcohol to allow for better drying. As a result of the present study we observed that in the distal end in 50% of the samples we encountered bacteria. Cultures of the external surface were positive in 20% of samples. The biopsy canal should be washed with ether alcohol to allow for complete drying, because when we did not use this method, Pseudomonas Aeruginosa was isolated. After this modification we did not isolate bacteria. The most frequent types of isolated bacteria were from the normal oropharyngeal flora. From the present study we can conclude that desinfection of the Panendespe with Hexaclorophen gives satisfactory results on the external surface of the endoscope. Biopsy canal requires additional washing with ether alcohol. However, both procedures do not assure a satisfactory desinfection of the distal end.

Latest Results on Complex Plasmas with the PK-3 Plus Laboratory on Board the International Space Station

Science.gov (United States)

Schwabe, M.; Du, C.-R.; Huber, P.; Lipaev, A. M.; Molotkov, V. I.; Naumkin, V. N.; Zhdanov, S. K.; Zhukhovitskii, D. I.; Fortov, V. E.; Thomas, H. M.

2018-03-01

Complex plasmas are low temperature plasmas that contain microparticles in addition to ions, electrons, and neutral particles. The microparticles acquire high charges, interact with each other and can be considered as model particles for effects in classical condensed matter systems, such as crystallization and fluid dynamics. In contrast to atoms in ordinary systems, their movement can be traced on the most basic level, that of individual particles. In order to avoid disturbances caused by gravity, experiments on complex plasmas are often performed under microgravity conditions. The PK-3 Plus Laboratory was operated on board the International Space Station from 2006 - 2013. Its heart consisted of a capacitively coupled radio-frequency plasma chamber. Microparticles were inserted into the low-temperature plasma, forming large, homogeneous complex plasma clouds. Here, we review the results obtained with recent analyzes of PK-3 Plus data: We study the formation of crystallization fronts, as well as the microparticle motion in, and structure of crystalline complex plasmas. We investigate fluid effects such as wave transmission across an interface, and the development of the energy spectra during the onset of turbulent microparticle movement. We explore how abnormal particles move through, and how macroscopic spheres interact with the microparticle cloud. These examples demonstrate the versatility of the PK-3 Plus Laboratory.

Inhibition of plasma kallikrein-kinin system to alleviate renal injury and arthritis symptoms in rats with adjuvant-induced arthritis.

Science.gov (United States)

Zhu, Jie; Wang, Hui; Chen, Jingyu; Wei, Wei

2018-04-01

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Impairment of kidney functions in RA was observed. However, the mechanism of kidney injury of RA has not been clear. Plasma kallikrein-kinin system (KKS) was involved in inflammatory processes in kidney disease. This study aimed to explore the role of plasma KKS in immune reactions and kidney injury of RA. The paw of AA rats appeared to be swelling and redness, the arthritis index was significantly increased on the 18, 21 and 24 d after injection and secondary inflammation in multi-sites was observed. Kidney dysfunction accompanied with inflammatory cell infiltration, tubular epithelial cell mitochondrial swelling and vacuolar degeneration, renal glomerular foot process fusions and glomerular basement membrane thickening were observed in AA rats. The expressions of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (Kim-1) in kidney of AA rats were increased. In addition, expressions of BK, PK, B1R and B2R in the renal tissue of AA rats were up-regulated. Pro-inflammatory cytokines IL-2, IFN-γ and TNF-α were increased and anti-inflammatory cytokines IL-4 and IL-10 were low in kidney. Plasma kallikrein (PK) inhibitor PKSI-527 attenuated arthritis signs and renal damage, and inhibited BK, PK, B1R and B2R expressions. The protein expressions of P38, p-P38 and p-JNK and IFN-γ and TNF-α were inhibited by PKSI-527. These findings demonstrate that plasma KKS activation contributed to the renal injury of AA rats through MAPK signaling pathway. Plasma KKS might be a potential target for RA therapy.

Polyomavirus BK replication in renal transplant recipients: combined monitoring of viremia and VP1 mRNA in urine

Directory of Open Access Journals (Sweden)

Sara Astegiano

2010-06-01

Full Text Available Introduction. Human polyomavirus BK (BKV is worldwide distributed, with a seroprevalence rate of 70–90% in the adults. Following primary infection, BK remains latent in the renourinary tract as the epidemiologically most relevant latency site, and in B cell, brain, spleen and probably other tissues. Reactivation may occur in both immunocompetent subjects and immunocompromised patients. In renal transplantation, in the context of intense immunosuppression, viral replication may determine BKV-associated nephropathy (BKVAN with interstitial nephritis and/or ureteral stenosis in 1–10% of the patients and leading to graft failure and return to haemodialysis in 30 to 80% of the cases (5. Screening of BKV replication represents the basic strategy to predict early the onset of BKVAN and may allow for earlier intervention with reduced allograft loss (3, 4. Nowadays, replication of BKV is monitored by quantification of BKV-DNA in serum and urine (2. The aim of this study was to evaluated the role of BKV VP1 mRNA in urine as a marker of viral replication in renal transplant recipients.

The polyomavirus BK agnoprotein co-localizes with lipid droplets

International Nuclear Information System (INIS)

Unterstab, Gunhild; Gosert, Rainer; Leuenberger, David; Lorentz, Pascal; Rinaldo, Christine H.; Hirsch, Hans H.

2010-01-01

Agnoprotein encoded by human polyomavirus BK (BKV) is a late cytoplasmic protein of 66 amino acids (aa) of unknown function. Immunofluorescence microscopy revealed a fine granular and a vesicular distribution in donut-like structures. Using BKV(Dunlop)-infected or agnoprotein-transfected cells, we investigated agnoprotein co-localization with subcellular structures. We found that agnoprotein co-localizes with lipid droplets (LD) in primary human renal tubular epithelial cells as well as in other cells supporting BKV replication in vitro (UTA, Vero cells). Using agnoprotein-enhanced green fluorescent protein (EGFP) fusion constructs, we demonstrate that agnoprotein aa 20-42 are required for targeting LD, whereas aa 1-20 or aa 42-66 were not. Agnoprotein aa 22-40 are predicted to form an amphipathic helix, and mutations A25D and F39E, disrupting its hydrophobic domain, prevented LD targeting. However, changing the phosphorylation site serine-11 to alanine or aspartic acid did not alter LD co-localization. Our findings provide new clues to unravel agnoprotein function.

Mutant prevention concentration and PK-PD relationships of enrofloxacin for Pasteurella multocida in buffalo calves.

Science.gov (United States)

Balaje, R M; Sidhu, P K; Kaur, G; Rampal, S

2013-12-01

This study validated the use of mutant prevention concentration (MPC) and pharmacokinetic and pharmacodynamic (PK-PD) modeling approach for optimization of dose regimen of enrofloxacin to contain the emergence of Pasteurella multocida resistance. The PK and PD characteristics of enrofloxacin were investigated in buffalo calves after intramuscular administration at a dose rate of 12 mg/kg. The concentration of enrofloxacin and ciprofloxacin in serum were determined by high-performance liquid chromatography. The serum peak concentration (Cmax), terminal half-life (t1/2K10), volume of distribution (Vd(area)/F) and mean residence time (MRT) of enrofloxacin were 1.89 ± 0.35 μg/ml, 5.14 ± 0.66 h, 5.59 ± 0.99 l/kg/h and 8.52 ± 1.29 h, respectively. The percent metabolite conversion ratio of ciprofloxacin to enrofloxacin was 79. The binding of enrofloxacin to plasma proteins was 11%. The MIC, MBC and MPC for enrofloxacin against P. multocida were 0.05, 0.06 μg/ml and 1.50 μg/ml.In vitro and ex-vivo bactericidal activity of enrofloxacin was concentration dependent. Modeling of ex-vivo growth inhibition data to the sigmoid Emax equation provided AUC24h/MIC values to produce bacteriostatic (19 h), bactericidal (43 h) and bacterial eradication (64 h). PK-PD data in conjunction with MPC and MIC90 data predicted dosage schedules for enrofloxacin that may achieve optimum efficacy in respect of bacteriological and clinical cure and minimize the risk of emergence of resistance. Copyright © 2013 Elsevier Ltd. All rights reserved.

Survival of Primates in Lethal Septic Shock Following Delayed Treatment with Steroid.

Science.gov (United States)

1981-02-26

TECHNICAL REPORT NO. 142 SURVIVAL OF PRIMATES IN LETHAL SEPTIC SHOCK FOLLOWING DELAYED TREAMENT WIn STEROID L. B. Hinshaw, L. T. Archer, B. K. Belier ...2. Schumer W: Steroids in the treatment of clinical septic shock. Ann Surg 184:333-341, 1976. 3. Hinshaw LB, Belier PK, Archer LT, Flournoy DJ, White...not preventable by antibiotic alone. Infect Immun ZS:538-5)7, 1979. 6. Hinshaw LB, Archer LT, Belier -Todd BK, Coalson .JJ, Flournoy DL, Passey R

Antioxidative effects of fermented sesame sauce against hydrogen peroxide-induced oxidative damage in LLC-PK1 porcine renal tubule cells

Science.gov (United States)

Song, Jia-Le; Choi, Jung-Ho; Seo, Jae-Hoon; Kil, Jeung-Ha

2014-01-01

BACKGROUND/OBJECTIVES This study was performed to investigate the in vitro antioxidant and cytoprotective effects of fermented sesame sauce (FSeS) against hydrogen peroxide (H2O2)-induced oxidative damage in renal proximal tubule LLC-PK1 cells. MATERIALS/METHODS 1,1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl radical (•OH), and H2O2 scavenging assay was used to evaluate the in vitro antioxidant activity of FSeS. To investigate the cytoprotective effect of FSeS against H2O2-induced oxidative damage in LLC-PK1 cells, the cellular levels of reactive oxygen species (ROS), lipid peroxidation, and endogenous antioxidant enzymes including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-px) were measured. RESULTS The ability of FSeS to scavenge DPPH, •OH and H2O2 was greater than that of FSS and AHSS. FSeS also significantly inhibited H2O2-induced (500 µM) oxidative damage in the LLC-PK1 cells compared to FSS and AHSS (P sauces, FSeS also significantly increased cellular CAT, SOD, and GSH-px activities and mRNA expression (P < 0.05). CONCULUSIONS These results from the present study suggest that FSeS is an effective radical scavenger and protects against H2O2-induced oxidative damage in LLC-PK1 cells by reducing ROS levels, inhibiting lipid peroxidation, and stimulating antioxidant enzyme activity. PMID:24741396

Differential effect of detergents on [3H]Ro 5-4864 and [3H]PK 11195 binding to peripheral-type benzodiazepine-binding sites

International Nuclear Information System (INIS)

Awad, M.; Gavish, M.

1988-01-01

The present study demonstrates a differential effect of various detergent treatments on [ 3 H]Ro 5-4864 and [ 3 H]PK 11195 binding to peripheral benzodiazepine binding sites (PBS). Triton X-100 caused a decrease of about 70% in [ 3 H]Ro 5-4864 binding to membranes from various peripheral tissues of rat, but had only a negligible effect on [ 3 H]PK 11195 binding. A similar effect of Triton X-100 was observed on guinea pig and rabbit kidney membranes. The decrease in [ 3 H]Ro 5-4864 binding after treatment with Triton X-100 was apparently due to a decrease in the density of PBS, since the affinity remained unaltered. The detergents 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane sulfonate (CHAPS), Tween 20, deoxycholic acid, or digitonin (0.0125%) caused only a minor change in [ 3 H]Ro 5-4864 and [ 3 H]PK 11195 binding to rat kidney membranes; but when concentrations were substantially increased (0.1%), all detergents caused a decrease of at least 50% in [ 3 H]Ro 5-4864 binding, while [ 3 H]PK 11195 binding to rat kidney membranes remained unaffected by the first three detergents, with only a minor decrease (15%) after treatment with digitonin

Pharmacokinetic-pharmacodynamic (PK-PD) modeling and the rational selection of dosage regimes for the prudent use of antimicrobial drugs.

Science.gov (United States)

Papich, Mark G

2014-07-16

One of the strategies to decrease inappropriate antimicrobial use in veterinary medicine is to apply pharmacokinetic-pharmacodynamic (PK-PD) principles to dosing regimens. If antimicrobials are used appropriately by applying these principles to attain targets for area-under-the-curve to MIC ratio (AUC/MIC), peak concentration to MIC ratio (CMAX/MIC), and time above MIC (T>MIC), more effective antibiotic therapy is possible, thus avoiding ineffective administration. Another mechanism whereby inappropriate antibiotic administration can be avoided is to use accurate Interpretive Criteria established by the Clinical Laboratory Standards Institute (CLSI) for breakpoint selection. Inaccurate breakpoints will encourage antibiotic administration that is likely to be ineffective. For newly approved antimicrobials, three criteria are used for determining breakpoints: PK-PD criteria, MIC distributions, and clinical response. For older (often generic drugs) evaluated by the CLSI, recent clinical data may not be available and breakpoints are derived from PK-PD principles, wild-type distributions, and Monte Carlo simulations. It is the goal of the CLSI subcommittee that these revised breakpoints will encourage more effective antimicrobial use and avoid unnecessary antimicrobial administration. Copyright © 2014 Elsevier B.V. All rights reserved.

Comparison of Plasma Tu-M2-PK and CA19-9 in Pancreatic Cancer

DEFF Research Database (Denmark)

Joergensen, Maiken Thyregod; Heegaard, Niels H H; Schaffalitzky de Muckadell, Ove B

2009-01-01

because of suspicion of pancreatic cancer. Of these, 51 patients had their conditions diagnosed as PDAC, whereas this diagnosis was ruled out in 52 after 12 months of follow-up. The performance of Tu-M2-PK was compared with that of CA19-9 using cutoff values 15 and 37 U/mL, respectively. RESULTS...

Seizing the Opportunity: Building PK3 Systems in New Jersey's School Districts. Policy Brief

Science.gov (United States)

Rice, Cynthia

2008-01-01

This policy brief discusses how the implementation of high quality preschool required by the expansion initiative can set the stage for a more expansive view of the first stage of children's education: the development of a preschool-through third-grade (PK3) system. By adopting a broader view of early childhood education as a period extending from…

DNA-PK/Ku complex binds to latency-associated nuclear antigen and negatively regulates Kaposi's sarcoma-associated herpesvirus latent replication

International Nuclear Information System (INIS)

Cha, Seho; Lim, Chunghun; Lee, Jae Young; Song, Yoon-Jae; Park, Junsoo; Choe, Joonho; Seo, Taegun

2010-01-01

During latent infection, latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) plays important roles in episomal persistence and replication. Several host factors are associated with KSHV latent replication. Here, we show that the catalytic subunit of DNA protein kinase (DNA-PKcs), Ku70, and Ku86 bind the N-terminal region of LANA. LANA was phosphorylated by DNA-PK and overexpression of Ku70, but not Ku86, impaired transient replication. The efficiency of transient replication was significantly increased in the HCT116 (Ku86 +/-) cell line, compared to the HCT116 (Ku86 +/+) cell line, suggesting that the DNA-PK/Ku complex negatively regulates KSHV latent replication.

A phenylalanine ammonia-lyase ortholog (PkPAL1) from Picrorhiza kurrooa Royle ex. Benth: molecular cloning, promoter analysis and response to biotic and abiotic elicitors.

Science.gov (United States)

Bhat, Wajid Waheed; Razdan, Sumeer; Rana, Satiander; Dhar, Niha; Wani, Tariq Ahmad; Qazi, Parvaiz; Vishwakarma, Ram; Lattoo, Surrinder K

2014-09-01

Picrorhiza kurrooa Royle ex Benth. is a highly reputed medicinal herb utilised in the preparation of a number of herbal drug formulations, principally due to the presence of novel monoterpene iridoid glycosides kenned as picrosides. Phenylalanine ammonia-lyase catalyses an important rate-limiting step in phenylpropanoid pathway and supplies precursors like cinnamic acid, vanillic acid, ferulic acid, etc., to a variety of secondary metabolites including picrosides. The imperilled status of P. kurrooa coupled with lack of information regarding biogenesis of picrosides necessitates deciphering the biosynthetic pathway for picrosides. In the present study, a PAL gene, designated PkPAL1 was isolated from P. kurrooa. The cDNA is 2312 bp in length, consisting of an ORF of 2142 bp encoding for a 713 amino acid protein having a predicted molecular weight of 77.66 kDa and an isoelectric point of pH 6.82. qRT-PCR analysis of various tissues of P. kurrooa showed that PkPAL1 transcript levels were highest in the leaves, consistent with picroside accumulation pattern. Using Genome walking, a 718 bp promoter region was also isolated resulting in identification of distinct cis-regulatory elements including TGA-element, TGACG-motif, CGTCA-motif, etc. qRT-PCR indicated up-regulation of PkPAL1 by methyl jasmonate, salicylic acid, 2,4-dicholorophenoxy acetic acid and UV-B elicitations that corroborated positively with the identified cis-elements within the promoter region. Moreover, altitude was found to have a positive effect on the PkPAL1 transcript levels, driving the expression of PkPAL1 abundantly. Based on docking analysis, we identified eight residues as potentially essential for substrate binding in PkPAL1. Copyright © 2014 Elsevier B.V. All rights reserved.

Biomass Yield and N Uptake in Tall Fescue and Reed Canary Grass Depending on N and PK Fertilization on Two Marginal Sites in Denmark

DEFF Research Database (Denmark)

Ugilt Larsen, Søren; Jørgensen, Uffe; Lærke, Poul Erik

2016-01-01

areas with limited suitability for cereal production. Plots with TF and RCG were sown in April 2011, and fertilization trials were established in spring 2012 with three factors: (a) grass species, (b) PK fertilization (either no P and K or 24 and 250 kg ha−1 y−1 of P and K, respectively), and (c) N...... fertilization (0, 150, 300, or 450 kg ha−1 y−1 N). Three cuts were taken annually from 2012 to 2014. Both species responded strongly to N fertilization. In TF, 450 kg ha−1 y−1 N combined with PK fertilization gave DM yields of 19.3, 12.1, and 14.2 t ha−1 y−1 in the 3 years, respectively, and corresponding...... yields for RCG were 17.3, 14.4, and 14.3 t ha−1 y−1. Without PK fertilization yields were significantly lower: 15.2, 7.5, and 7.3 t ha−1 y−1 in TF and 16.3, 8.7, and 4.8 ha−1 y−1 in RCG. When fertilized with PK, N uptake in harvested biomass balanced with N fertilization at rates of 244, 187, and 172 kg...

BK polyomavirus genotypes Ia and Ib1 exhibit different biological properties in renal transplant recipients.

Science.gov (United States)

Varella, Rafael B; Zalona, Ana Carolina J; Diaz, Nuria C; Zalis, Mariano G; Santoro-Lopes, Guilherme

2018-01-02

BK polyomavirus (BKV) is an opportunist agent associated with nephropathy (BKVAN) in 1-10% of kidney transplant recipients. BKV is classified into genotypes or subgroups according to minor nucleotidic variations with unknown biological implications. Studies assessing the possible association between genotypes and the risk of BKVAN in kidney transplant patients have presented conflicting results. In these studies, genotype Ia, which is highly prevalent in Brazil, was less frequently found and, thus, comparative data on the biological properties of this genotype are lacking. In this study, BKV Ia and Ib1 genotypes were compared according to their viral load, genetic evolution (VP1 and NCCR) - in a cohort of renal transplant recipients. The patients infected with Ia (13/23; 56.5%) genotype exhibited higher viral loads in urine [>1.4 log over Ib1 (10/23; 43.5%); p=0.025]. In addition, genotype Ia was associated with diverse mutations at VP1 loops and sites under positive selection outside loops, which were totally absent in Ib1. Although the number of viremic patients was similar, the three patients who had BK nephropathy (BKVAN) were infected with Ia genotype. NCCR architecture (ww or rr) were not distinctive between Ia and Ib1 genotypes. Ia genotype, which is rare in other published BKV cohorts, presented some diverse biological properties in transplanted recipients in comparison to Ib1. Copyright © 2017 Elsevier B.V. All rights reserved.

Study on the PK profiles of magnoflorine and its potential interaction in Cortex phellodendri decoction by LC-MS/MS.

Science.gov (United States)

Tian, Xiaoting; Li, Zhixiong; Lin, Yunfei; Chen, Mingcang; Pan, Guoyu; Huang, Chenggang

2014-01-01

Magnoflorine, an aporphine alkaloid in Cortex phellodendri, is increasingly attracting research attention because of its antidiabetic effects. However, at present, little information on its pharmacokinetics (PK) in vivo is available. In this study, a sensitive, rapid, and selective method was developed to determine the magnoflorine content in rat plasma using liquid chromatography-tandem mass spectrometry. Following liquid-liquid extraction, the calibration curve showed good linearity within the concentration range of 2.93 to 1,500 ng ml(-1). The intra- and inter-day precisions were all below 7.8 %, and the accuracy ranged from 94.9 to 103.4 %. The method was successfully applied in investigating the PK of magnoflorine in rats. The compound had low bioavailability, a high absorption rate, and a high elimination rate. However, area under the curve, T 1/2, and MRT increased approximately twofold when the same dosage of the compound was administered in a C. phellodendri decoction (20.8 g kg(-1)). Moreover, T max was prolonged from 0.3 to 3.33 h. Furthermore, a comparison of coadministration of the mixture group, magnoflorine (40 mg kg(-1)) and berberine (696.4 mg kg(-1)), with the C. phellodendri decoction group, revealed that no statistical difference (P > 0.05) was found in the parameter AUC, and certain similar changes in the PK trend to the herbal medicine group were also observed. These results suggested that oral administration of the herbal medicine decreased the absorption and elimination rates of magnoflorine and increased its bioavailability. Berberine played a significant role in interacting with magnoflorine and in affecting the PK profiles of magnoflorine in the C. phellodendri decoction group.

Role of neurotensin and opioid receptors in the cardiorespiratory effects of [Ile⁹]PK20, a novel antinociceptive chimeric peptide.

Science.gov (United States)

Kaczyńska, Katarzyna; Szereda-Przestaszewska, Małgorzata; Kleczkowska, Patrycja; Lipkowski, Andrzej W

2014-10-15

Ile(9)PK20 is a novel hybrid of opioid-neurotensin peptides synthesized from the C-terminal hexapeptide of neurotensin and endomorphin-2 pharmacophore. This chimeric compound shows potent central and peripheral antinociceptive activity in experimental animals, however nothing is known about its influence on the respiratory and cardiovascular parameters. The present study was designed to determine the cardiorespiratory effects exerted by an intravenous injection (i.v.) of [Ile(9)]PK20. Share of the vagal afferentation and the contribution of NTS1 neurotensin and opioid receptors were tested. Intravenous injection of the hybrid at a dose of 100 μg/kg in the intact, anaesthetized rats provoked an increase in tidal volume preceded by a prompt short-lived decrease. Immediately after the end of injection brief acceleration of the respiratory rhythm appeared, and was ensued by the slowing down of breathing. Changes in respiration were concomitant with a bi-phasic response of the blood pressure: an immediate increase was followed by a sustained hypotension. Midcervical vagotomy eliminated the increase in tidal volume and respiratory rate responses. Antagonist of opioid receptors - naloxone hydrochloride eliminated only [Ile(9)]PK20-evoked decline in tidal volume response. Blockade of NTS1 receptors with an intravenous dose of SR 142,948, lessened the remaining cardiorespiratory effects. This study depicts that [Ile(9)]PK20 acting through neurotensin NTS1 receptors augments the tidal component of the breathing pattern and activates respiratory timing response through the vagal pathway. Blood pressure effects occur outside vagal afferentation and might result from activation of the central and peripheral vascular NTS1 receptors. In summary the respiratory effects of the hybrid appeared not to be profound, but they were accompanied with unfavourable prolonged hypotension. Copyright © 2014 Elsevier B.V. All rights reserved.

BCR/ABL downregulates DNA-PK(CS)-dependent and upregulates backup non-homologous end joining in leukemic cells.

Science.gov (United States)

Poplawski, Tomasz; Blasiak, Janusz

2010-06-01

Non-homologous end joining (NHEJ) and homologous recombination repair (HRR) are the main mechanisms involved in the processing of DNA double strand breaks (DSBs) in humans. We showed previously that the oncogenic tyrosine kinase BCR/ABL stimulated DSBs repair by HRR. To evaluate the role of BCR/ABL in DSBs repair by NHEJ we examined the ability of leukemic BCR/ABL-expressing cell line BV173 to repair DNA damage induced by two DNA topoisomerase II inhibitors: etoposide and sobuzoxane. DNA lesions induced by sobuzoxane are repaired by a NHEJ pathway which is dependent on the catalytic subunit of protein kinase dependent on DNA (DNA-PK(CS); D-NHEJ), whereas damage evoked by etoposide are repaired by two distinct NHEJ pathways, dependent on or independent of DNA-PK(CS) (backup NHEJ, B-NHEJ). Cells incubated with STI571, a highly specific inhibitor of BCR/ABL, displayed resistance to these agents associated with an accelerated kinetics of DSBs repair, as measured by the neutral comet assay and pulsed field gel electrophoresis. However, in a functional NHEJ assay, cells preincubated with STI571 repaired DSBs induced by a restriction enzyme with a lower efficacy than without the preincubation and addition of wortmannin, a specific inhibitor of DNA-PK(CS), did not change efficacy of the NHEJ reaction. We suggest that BCR/ABL switch on B-NHEJ which is more error-prone then D-NHEJ and in such manner contribute to the increase of the genomic instability of leukemic cells.

Lentviral-mediated RNAi to inhibit target gene expression of the porcine integrin αv subunit, the FMDV receptor, and against FMDV infection in PK-15 cells

Directory of Open Access Journals (Sweden)

Lin Tong

2011-09-01

Full Text Available Abstract Background shRNA targeting the integrin αv subunit, which is the foot-and-mouth disease virus (FMDV receptor, plays a key role in virus attachment to susceptible cells. We constructed a RNAi lentiviral vector, iαv pLenti6/BLOCK -iT™, which expressed siRNA targeting the FMDV receptor, the porcine integrin αv subunit, on PK-15 cells. We also produced a lentiviral stock, established an iαv-PK-15 cell line, evaluated the gene silencing efficiency of mRNA using real-time qRT-PCR, integrand αv expression by indirect immunofluorescence assay (IIF and cell enzyme linked immunosorbent assays (cell ELISA, and investigated the in vivo inhibitory effect of shRNA on FMDV replication in PK-15 cells. Results Our results indicated successful establishment of the iαv U6 RNAi entry vector and the iαv pLenti6/BLOCK -iT expression vector. The functional titer of obtained virus was 1.0 × 106 TU/mL. To compare with the control and mock group, the iαv-PK-15 group αv mRNA expression rate in group was reduced by 89.5%, whilst IIF and cell ELISA clearly indicated suppression in the experimental group. Thus, iαv-PK-15 cells could reduce virus growth by more than three-fold and there was a > 99% reduction in virus titer when cells were challenged with 102 TCID50 of FMDV. Conclusions Iαv-PK-15 cells were demonstrated as a cell model for anti-FMDV potency testing, and this study suggests that shRNA could be a viable therapeutic approach for controlling the severity of FMD infection and spread.

A physiologically based pharmacokinetic (PB/PK) model for multiple exposure routes for soman in multiple species

NARCIS (Netherlands)

Sweeney, R.E.; Langenberg, J.P.; Maxwell, D.M.

2006-01-01

A physiologically based pharmacokinetic (PB/PK) model has been developed in advanced computer simulation language (ACSL) to describe blood and tissue concentration-time profiles of the C(±)P(-) stereoisomers of soman after inhalation, subcutaneous and intravenous exposures at low (0.8-1.0 × LD50),

Detection of BK virus in urine from renal transplant subjects by mass spectrometry

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Konietzny Rebecca

2012-04-01

Full Text Available Abstract Background The diagnosis and management of BK virus (BKV reactivation following renal transplantation continues to be a significant clinical problem. Following reactivation of latent virus, impaired cellular immunity enables sustained viral replication to occur in urothelial cells, which potentially leads to the development of BKV-associated nephropathy (BKVAN. Current guidelines recommend regular surveillance for BKV reactivation through the detection of infected urothelial cells in urine (decoy cells or viral nucleic acid in urine or blood. However, these methods have variable sensitivity and cannot routinely distinguish between different viral subtypes. We therefore asked whether mass spectrometry might be able to overcome these limitations and provide an additional non-invasive technique for the surveillance of BKV and identification of recipients at increased risk of BKVAN. Results Here we describe a mass spectrometry (MS-based method for the detection of BKV derived proteins directly isolated from clinical urine samples. Peptides detected by MS derived from Viral Protein 1 (VP1 allowed differentiation between subtypes I and IV. Using this approach, we observed an association between higher decoy cell numbers and the presence of the VP1 subtype Ib-2 in urine samples derived from a cohort of 20 renal transplant recipients, consistent with the hypothesis that certain viral subtypes may be associated with more severe BKVAN. Conclusions This is the first study to identify BK virus proteins in clinical samples by MS and that this approach makes it possible to distinguish between different viral subtypes. Further studies are required to establish whether this information could lead to stratification of patients at risk of BKVAN, facilitate distinction between BKVAN and acute rejection (AR, and ultimately improve patient treatment and outcomes.

Astaxanthin and Docosahexaenoic Acid Reverse the Toxicity of the Maxi-K (BK Channel Antagonist Mycotoxin Penitrem A

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Amira A. Goda

2016-11-01

Full Text Available Penitrem A (PA is a food mycotoxin produced by several terrestrial and few marine Penicillium species. PA is a potent tremorgen through selective antagonism of the calcium-dependent potassium BK (Maxi-K channels. Discovery of natural products that can prevent the toxic effects of PA is important for food safety. Astaxanthin (AST is a marine natural xanthophyll carotenoid with documented antioxidant activity. Unlike other common antioxidants, AST can cross blood brain barriers (BBBs, inducing neuroprotective effects. Docosahexaenoic acid (DHA is polyunsaturated ω-3 fatty acid naturally occurring in fish and algae. DHA is essential for normal neurological and cellular development. This study evaluated the protective activity of AST and DHA against PA-induced toxicity, in vitro on Schwann cells CRL-2765 and in vivo in the worm Caenorhbitidis elegans and Sprague Dawley rat models. PA inhibited the viability of Schwann cells, with an IC50 of 22.6 μM. Dose-dependent treatments with 10–100 μM DHA significantly reversed the PA toxicity at its IC50 dose, and improved the survival of Schwann cells to 70.5%–98.8%. Similarly, dose-dependent treatments with 10–20 μM AST reversed the PA toxicity at its IC50 dose and raised these cells’ survival to 61.7%–70.5%. BK channel inhibition in the nematode C. elegans is associated with abnormal reversal locomotion. DHA and AST counteracted the in vivo PA BK channel antagonistic activity in the C. elegans model. Rats fed a PA-contaminated diet showed high levels of glutamate (GLU, aspartate (ASP, and gamma amino butyric acid (GABA, with observed necrosis or absence of Purkinjie neurons, typical of PA-induced neurotoxicity. Dopamine (DA, serotonin (5-HT, and norepinephrine (NE levels were abnormal, Nitric Oxide (NO and Malondialdehyde (MDA levels were significantly increased, and total antioxidant capacity (TAC level in serum and brain homogenates was significantly decreased in PA-treated rats. DHA and AST

Effects of cyclosporin A on a kidney epithelial cell line (LLC-PK1).

Science.gov (United States)

Becker, G M; Gandolfi, A J; Nagle, R B

1987-05-01

Cyclosporin A (CSA), a potent immunosuppressant with the adverse side effect of nephrotoxicity, inhibited cell growth of pig kidney tubule cells (LLC-PK1) in culture. CSA (10(-5) M) also induced intense cytoplasmic vacuolation and the formation of dense granules. At the same concentration an analogue of CSA, cyclosporin G, had much less effect. This cell line may prove useful for revealing the mechanism of CSA-nephrotoxicity and testing the nephrotoxic potential of new analogues of cyclosporine.

In vivo evaluation in mice and metabolism in blood of human volunteers of [123I]iodo-PK11195: a possible single-photon emission tomography tracer for visualization of inflammation

International Nuclear Information System (INIS)

Dumont, F.; Vos, F. de; Slegers, G.; Versijpt, J.; Jansen, H.M.L.; Dierckx, R.A.; Korf, J.

1999-01-01

We report the in vivo evaluation (biodistribution, displacement and metabolization in blood, brain and heart) in mice and the metabolism in blood of human volunteers of iodine-123 labelled 1-(2-iodophenyl)-N-methyl-N-(1-methyl-propyl)-3-isoquinoline carboxamide ([ 123 I]iodo-PK11195), a potential radioligand for visualization of inflammation in humans by single-photon emission tomography. In three series of 18 white mice (NMRI, 20-25 g), the concentration of radioactivity was measured during 48 h. Blood samples were taken, organs and intestines were excised, excretion was collected and all tissues were weighed and counted for radioactivity. The tissue uptake of radioactivity was measured as % of the injected activity/g of tissue. The excretion was expressed as % of the injected activity. Selective tissue uptake was investigated by pretreatment of another three series of 18 mice with cold PK11195 (1 mg/kg body weight). There was an inflow of [ 123 I]iodo-PK11195 in the brain and among peripheral organs, heart (42.3%), lungs (133.5%) and kidneys (18.4%) had the highest uptake. After pretreatment with cold PK11195, there was a decrease in accumulation in the latter three organs, especially in heart (ca. 55%) and lungs (ca. 80%). Metabolite analysis was performed using high-performance liquid chromatography (HPLC). First, the extraction yield of [ 123 I]iodo-PK11195 from blood and tissue was assessed, and found to be >90%. From blank blood samples and organs spiked with [ 123 I]iodo-PK11195 it was concluded that no metabolization took place during the extraction procedure. Analysis of plasma, brain and heart of mice showed that 10 min p.i. [ 123 I]iodo-PK11195 was the only significant (ca. 95%) radioactive compound in brain and heart where-as in plasma other radioactive products (>60%) appeared. Analysis of plasma samples of the three human volunteers at 7, 20, 37 and 50 min p.i. showed that [ 123 I]iodo-PK11195 rapidly decomposes into two polar metabolites, which at

Dual Identification and Analysis of Differentially Expressed Transcripts of Porcine PK-15 Cells and Toxoplasma gondii during in vitro Infection

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Chun-Xue eZhou

2016-05-01

Full Text Available Toxoplasma gondii is responsible for causing toxoplasmosis, one of the most prevalent zoonotic parasitoses worldwide. The mechanisms that mediate T. gondii infection of pigs (the most common source of human infection and renal tissues are still unknown. To identify the critical alterations that take place in the transcriptome of both porcine kidney (PK-15 cells and T. gondii following infection, infected cell samples were collected at 1, 3, 6, 9, 12, 18, and 24 h post infection and RNA-Seq data were acquired using Illumina Deep Sequencing. Differential Expression of Genes (DEGs analysis was performed to study the concomitant gene-specific temporal patterns of induction of mRNA expression of PK-15 cells and T. gondii. High sequence coverage enabled us to thoroughly characterize T. gondii transcriptome and identify the activated molecular pathways in host cells. More than 6G clean bases/ sample, including > 40 million clean reads were obtained. These were aligned to the reference genome of T. gondii and wild boar (Sus scrofa. DEGs involved in metabolic activities of T. gondii showed time-dependent down-regulation. However, DEGs involved in immune or disease related pathways of PK-15 cells peaked at 6 h PI, and were highly enriched as evidenced by KEGG analysis. Protein-protein interaction analysis revealed that TGME49_120110 (PCNA, TGME49_049180 (DHFR-TS, TGME49_055320 and TGME49_002300 (ITPase are the four hub genes with most interactions with T. gondii at the onset of infection. These results reveal altered profiles of gene expressed by PK-15 cells and T. gondii during infection and provide the groundwork for future virulence studies to uncover the mechanisms of T. gondii interaction with porcine renal tissue by functional analysis of these DEGs.

Toxin-antitoxin loci as stress-response-elements: ChpAK/MazF and ChpBK cleave translated RNAs and are counteracted by tmRNA

DEFF Research Database (Denmark)

Christensen, S.K.; Pedersen, K.; Hansen, Flemming G.

2003-01-01

Prokaryotic chromosomes encode toxin-antitoxin loci, often in multiple copies. In most cases, the function of these genes is not known. The chpA (mazEF) locus of Escherichia coli has been described as a cell killing module that induces bacterial apoptosis during nutritional stress. However, we...... found recently that ChpAK (MazF) does not confer cell killing but rather, induces a bacteriostatic condition from which the cells could be resuscitated. Results presented here yield a mechanistic explanation for the detrimental effect on cell growth exerted by ChpAK and the homologous ChpBK protein of E......AK cleaved tmRNA in its coding region. Thus, ChpAK and ChpBK inhibit translation by a mechanism very similar to that of E. coli RelE. On the basis of these results, we propose a model that integrates TA loci into general prokaryotic stress physiology....

Overexpression of pig selenoprotein S blocks OTA-induced promotion of PCV2 replication by inhibiting oxidative stress and p38 phosphorylation in PK15 cells

Science.gov (United States)

Gan, Fang; Hu, Zhihua; Huang, Yu; Xue, Hongxia; Huang, Da; Qian, Gang; Hu, Junfa; Chen, Xingxiang; Wang, Tian; Huang, Kehe

2016-01-01

Porcine circovirus type 2 (PCV2) is the primary cause of porcine circovirus disease, and ochratoxin A (OTA)-induced oxidative stress promotes PCV2 replication. In humans, selenoprotein S (SelS) has antioxidant ability, but it is unclear whether SelS affects viral infection. Here, we stably transfected PK15 cells with pig pCDNA3.1-SelS to overexpress SelS. Selenium (Se) at 2 or 4 μM and SelS overexpression blocked the OTA-induced increases of PCV2 DNA copy number and infected cell numbers. SelS overexpression also increased glutathione (GSH), NF-E2-related factor 2 (Nrf2) mRNA, and γ-glutamyl-cysteine synthetase mRNA levels; decreased reactive oxygen species (ROS) levels; and inhibited p38 phosphorylation in PCV2-infected PK15 cells, regardless of OTA treatment. Buthionine sulfoximine reversed all of the above SelS-induced changes. siRNA-mediated SelS knockdown decreased Nrf2 mRNA and GSH levels, increased ROS levels, and promoted PCV2 replication in OTA-treated PK15 cells. These data indicate that pig SelS blocks OTA-induced promotion of PCV2 replication by inhibiting the oxidative stress and p38 phosphorylation in PK15 cells. PMID:26943035

TANGGUNGJAWAB REKTOR SEBAGAI KPA DALAM PENGELOLAAN KEUANGAN PERGURUAN TINGGI NEGERI YANG MENYELENGGARAKAN PENGELOLAAN KEUANGAN BADAN LAYANAN UMUM (PTN PK-BLU

Directory of Open Access Journals (Sweden)

Dewi Kania Sugiharti

2013-11-01

Full Text Available Perguruan Tinggi yang menerapkan konsep Badan Layanan Umum (PTN PKBLU dalam menjalankan fungsi sebagai organ yang bergerak dalam bidang pelayanan adalah dukungan sarana dan prasarana melalui barang atau jasa. Sebagai institusi yang berada dalam naungan pemerintah dan menerima anggaran negara maka PTN PK-BLU melaksanakan mekanisme untuk memperoleh barang atau jasa sesuai ketentuan hukum. Namun proses pengadaan dalam memperoleh barang atau jasa terkadang menimbulkan persoalan yang muncul sebagai konsekuensi berjalannya proses pengadaan barang atau jasa yang melibatkan organ-organ di dalamnya seperti PA/KPA, PPK, ULP, dan Panitia/Pejabat Penerima Pengadaan. Rektor sebagai KPA dalam PTN PK-BLU memiliki wewenang dalam melakukan kontrol terhadap organ-organ yang melaksanakan proses pengadaan barang/jasa pada lingkungannya. Kesalahan dalam proses pengadaan barang/jasa yang dilakukan oleh PPK dan ULP/Pejabat Pengadaan menyebabkan kerugian negara akibat kesalahan tersebut, baik akibat kelalaian atau tindakan melanggar hukum. Sebagai KPA dalam proses pengadaan barang/jasa Rektor dapat melakukan kontrol pada organ-organ tersebut sesuai dengan wewenang yang diberikan. Konsekuensi yang diterima jika pada akhirnya pejabat pelaksanaan pengadaan barang/jasa tidak mengindahkan teguran Rektor maka pejabat yang terkait proses pengadaan barang/jasa akan menerima sanksi. Universities that apply the concept of Public Service Agency (BLU - PK PTN in performing functions as an organ which isengaged in the service infrastructure support through goods or services . As an institution under the auspices of the government and the state budget receives PTN PK - BLU implement mechanisms to acquire goods or services in accordance with the law . However, the procurement process in obtaining goods or services sometimes poses problems that arise as a consequence of the passage of the procurement of goods or services involving the organs in it as PA / KPA , KDP , ULP , and

Marketingová situační analýza BK Lions Jindřichův Hradec

OpenAIRE

Hron, Patrik

2014-01-01

The aim of this bachelor thesis is to carry out an analysis of each part of marketing mix and the environment in which the BK Lions Jindřichův Hradec basketball club is situated. Suitable and applicable recommendations are suggested to make the marketing mix more effective based on analysis of marketing situation. The first part is focused on describing the marketing mix and marketing situational analysis at a theoretical level. The practical part describes particular marketing tools which ar...

Lesions inflammatory activity quantification in multiple sclerosis using [{sup 11}C]-(R)-PK11195 PET brain images; Quantificacao da atividade inflamatoria em lesoes na esclerose multipla usando imagens PET cerebrais com [{sup 11}C]-(R)-PK11195

Energy Technology Data Exchange (ETDEWEB)

Schuck, Phelipi N.; Narciso, Lucas D.L.; Dartora, Caroline M.; Silva, Ana M. Marques da, E-mail: phelipi.schuck@acad.pucrs.br [Pontificia Universidade Catolica do Rio Grande do Sul (PUC-RS), Porto Alegre, RS (Brazil). Nucleo de Pesquisa em Imagens Medicas

2016-07-01

The criteria for multiple sclerosis (MS) diagnosis include the presence of lesions in brain regions called black holes (BH), characterized by low signal on magnetic resonance imaging T1-weighted. Studies suggest that lesions in MS, if there is an inflammatory process, can be detected in PET imaging with [{sup 11}C]- (R)-PK11195. The aim of this study is to investigate the uptake of [{sup 11}C]-(R)-PK11195 in BH in PET images, searching for inflammation activity in lesions and neighborhoods. Semiquantitative methods of SUV and uptake normalization were applied to PET images, in different time intervals, acquired from 8 MS patients and 5 healthy controls. Higher uptake was identified in BH and its edges, when compared with health controls white matter, when the SUV method is applied (p < 0,01, 40 to 60 min). When uptake normalization method is applied, smaller uptake in black holes and its your edges is observed, when compared with white matter apparently healthy (p < 0,01, 0 to 60 min). (author)

Comparison of the proteomes of three yeast wild type strains: CEN.PK2, FY1679 and W303

DEFF Research Database (Denmark)

Rogowska-Wrzesinska, A.; Mose Larsen, P.; Blomberg, A.

2001-01-01

Yeast deletion strains created during gene function analysis projects very often show drastic phenotypic differences depending on the genetic background used. These results indicate the existence of important molecular differences between the CEN.PK2, FY1679 and W303 wild type strains...

Assessing the relative potency of (S)- and (R)-warfarin with a new PK-PD model, in relation to VKORC1 genotypes.

Science.gov (United States)

Ferrari, Myriam; Pengo, Vittorio; Barolo, Massimiliano; Bezzo, Fabrizio; Padrini, Roberto

2017-06-01

The purpose of this study is to develop a new pharmacokinetic-pharmacodynamic (PK-PD) model to characterise the contribution of (S)- and (R)-warfarin to the anticoagulant effect on patients in treatment with rac-warfarin. Fifty-seven patients starting warfarin (W) therapy were studied, from the first dose and during chronic treatment at INR stabilization. Plasma concentrations of (S)- and (R)-W and INRs were measured 12, 36 and 60 h after the first dose and at steady state 12-14 h after dosing. Patients were also genotyped for the G>A VKORC1 polymorphism. The PK-PD model assumed a linear relationship between W enantiomer concentration and INR and included a scaling factor k to account for a different potency of (R)-W. Two parallel compartment chains with different transit times (MTT 1 and MTT 2 ) were used to model the delay in the W effect. PD parameters were estimated with the maximum likelihood approach. The model satisfactorily described the mean time-course of INR, both after the initial dose and during long-term treatment. (R)-W contributed to the rac-W anticoagulant effect with a potency of about 27% that of (S)-W. This effect was independent of VKORC1 genotype. As expected, the slope of the PK/PD linear correlation increased stepwise from GG to GA and from GA to AA VKORC1 genotype (0.71, 0.90 and 1.49, respectively). Our PK-PD linear model can quantify the partial pharmacodynamic activity of (R)-W in patients contemporaneously exposed to therapeutic (S)-W plasma levels. This concept may be useful in improving the performance of future algorithms aiming at identifying the most appropriate W maintenance dose.

The first transmembrane domain (TM1) of β2-subunit binds to the transmembrane domain S1 of α-subunit in BK potassium channels

Science.gov (United States)

Morera, Francisco J.; Alioua, Abderrahmane; Kundu, Pallob; Salazar, Marcelo; Gonzalez, Carlos; Martinez, Agustin D.; Stefani, Enrico; Toro, Ligia; Latorre, Ramon

2012-01-01

The BK channel is one of the most broadly expressed ion channels in mammals. In many tissues, the BK channel pore-forming α-subunit is associated to an auxiliary β-subunit that modulates the voltage- and Ca2+-dependent activation of the channel. Structural components present in β-subunits that are important for the physical association with the α-subunit are yet unknown. Here, we show through co-immunoprecipitation that the intracellular C-terminus, the second transmembrane domain (TM2) and the extracellular loop of the β2-subunit are dispensable for association with the α-subunit pointing transmembrane domain 1 (TM1) as responsible for the interaction. Indeed, the TOXCAT assay for transmembrane protein–protein interactions demonstrated for the first time that TM1 of the β2-subunit physically binds to the transmembrane S1 domain of the α-subunit. PMID:22710124

Increased cerebral (R-[11C]PK11195 uptake and glutamate release in a rat model of traumatic brain injury: a longitudinal pilot study

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Lammertsma Adriaan A

2011-06-01

Full Text Available Abstract Background The aim of the present study was to investigate microglia activation over time following traumatic brain injury (TBI and to relate these findings to glutamate release. Procedures Sequential dynamic (R-[11C]PK11195 PET scans were performed in rats 24 hours before (baseline, and one and ten days after TBI using controlled cortical impact, or a sham procedure. Extracellular fluid (ECF glutamate concentrations were measured using cerebral microdialysis. Brains were processed for histopathology and (immuno-histochemistry. Results Ten days after TBI, (R-[11C]PK11195 binding was significantly increased in TBI rats compared with both baseline values and sham controls (p -1 as compared with the sham procedure (6.4 ± 3.6 μmol·L-1. Significant differences were found between TBI and sham for ED-1, OX-6, GFAP, Perl's, and Fluoro-Jade B. Conclusions Increased cerebral uptake of (R-[11C]PK11195 ten days after TBI points to prolonged and ongoing activation of microglia. This activation followed a significant acute posttraumatic increase in ECF glutamate levels.

DNA-PK/Ku complex binds to latency-associated nuclear antigen and negatively regulates Kaposi's sarcoma-associated herpesvirus latent replication

Energy Technology Data Exchange (ETDEWEB)

Cha, Seho [Department of Life Science, Dongguk Univ-Seoul, Seoul 100-715 (Korea, Republic of); Lim, Chunghun [Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701 (Korea, Republic of); Lee, Jae Young [Department of Life Science, Dongguk Univ-Seoul, Seoul 100-715 (Korea, Republic of); Song, Yoon-Jae [Department of Life Science, Kyungwon University, Seongnam-Si, Kyeonggi-Do 461-701 (Korea, Republic of); Park, Junsoo [Division of Biological Science and Technology, Yonsei University, Wonju 220-100 (Korea, Republic of); Choe, Joonho [Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701 (Korea, Republic of); Seo, Taegun, E-mail: tseo@dongguk.edu [Department of Life Science, Dongguk Univ-Seoul, Seoul 100-715 (Korea, Republic of)

2010-04-16

During latent infection, latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) plays important roles in episomal persistence and replication. Several host factors are associated with KSHV latent replication. Here, we show that the catalytic subunit of DNA protein kinase (DNA-PKcs), Ku70, and Ku86 bind the N-terminal region of LANA. LANA was phosphorylated by DNA-PK and overexpression of Ku70, but not Ku86, impaired transient replication. The efficiency of transient replication was significantly increased in the HCT116 (Ku86 +/-) cell line, compared to the HCT116 (Ku86 +/+) cell line, suggesting that the DNA-PK/Ku complex negatively regulates KSHV latent replication.

Incidence and Factors Associated with De Novo DSA After BK Viremia in Renal Transplant Recipients.

Science.gov (United States)

Patel, Samir J; Kuten, Samantha A; Knight, Richard J; Graviss, Edward A; Nguyen, Duc; Gaber, A Osama

2016-01-01

BK polyomavirus infection and de novo donor-human leukocyte antigen (HLA) specific antibodies (dnDSA) are two well-known and distinct complications occurring after kidney transplantation. Recent literature suggests an association between the two events. This study aims to examine the relationship between BK viremia (BKV) and dnDSA and to identify potential risk factors for dnDSA following BKV in kidney transplant recipients. A retrospective review of 1019 recipients from Houston Methodist Hospital was conducted. All patients underwent routine screening for BKV and dnDSA. Median follow-up was 44 months. BKV was detected in 186 (18%) patients at a median of 107 (82-205) days post-transplant. dnDSA occurred in 283 (28%) patients at a median of 272 (62-575) days post-transplant. Of the 69 dnDSA-positive/BKV-positive patients, dnDSA detection occurred after BKV onset in 46 patients. Thus, 46 (28%) previously DSA-negative patients later became dnDSA-positive following BKV, not significantly different from the rate seen in BKV-negative patients (26%; p=0.5). Median time to DSA detection following BKV onset was 232 days (interquartile range, 119-460) post-BKV detection. Multivariate analysis revealed a greater number of HLA mismatches and viral clearance as risk factors for development of dnDSA following BKV, whereas delayed graft function was associated with a lower risk of dnDSA. In conclusion, despite being considered a result of over-immunosuppression, BKV can still be followed by dnDSA in a substantial proportion of patients. Monitoring for dnDSA in patients being managed for BKV may be warranted. Copyright© 2017 by the Terasaki Research Institute.

Measurement of $CP$ asymmetries in $\\Lambda_{b}^{0} \\to pK^{-}$ and $\\Lambda_{b}^{0} \\to p\\pi^-$ decays at LHCb

CERN Document Server

Ferrari, F

2016-01-01

The LHCb experiment has been designed to perform precision measurements in the flavour physics sector at the Large Hadron Collider (LHC). The measurement of the CP-violating observable defined as ΔACP = ACP (Λ0b → pK − ) − ACP (Λ0b → pπ − ), where ACP (Λ0b → pK − ) and ACP (Λ0b → pπ − ) are the direct CP asymmetries in Λ0b → pK − and Λ0b → pπ − decays, is presented for the first time using LHCb data. Using the full 2011 and 2012 data sets of pp collisions collected with the LHCb detector, corresponding to an integrated luminosity of about 3 fb −1, the value ΔACP = (0.8 ± 2.1 ± 0.2)% is obtained. The first uncertainty is statistical and the second corresponds to one of the dominant systematic effects. As the result is compatible with zero, no evidence of CP violation is found. This is the most precise measurement of CP violation in the decays of baryons containing the b quark to date. Once the analysis will be completed with an exhaustive study of systematic uncertainti...

Increasing the reach of the PK-3R continuous Miner; Desarrollo y Ensayo de un Sistema para aumentar el alcance de la Pina de Rozado en un Minador PK-3R

Energy Technology Data Exchange (ETDEWEB)

NONE

1998-12-01

The objective of this project is the development and implementation of a system designed to increase the reach of the cutting head of a PK-3R continuous miner working in our coal operations. Justification for the project stems from our method of coal extraction, whereby once the sub-level gallery has been advanced to it`s limit, extraction of the coal is undertaken by retreat mining, using a room and pillar method. In this method the roof is blasted to allow greater coal recovery. Due to it`s short length, the original position of the cutting arm of the PK-3R miner did not permit the total recovery of the blasted coal piled up on the gallery floor. Therefore an increase in the reach of the arm is very beneficial, facilitating the recovery of coal that previously could not be recovered. The system also permits excavation for support methods to be undertaken more rapidly, and a better adaptation of the miner to the irregularities of the wall, thus permitting it to move up or down more quickly, reducing the movements required. The system has not caused significant breakdowns, and the availability of the miner is good. In addition, the substitution of the turret in the case of a breakdown is an easy task, as during the design stage, the ease of mounting and dismounting the turret was considered as a fundamental parameter. (Author)

Identification of RFLP and NBS/PK profiling markers for disease resistance loci in genetic maps of oats

NARCIS (Netherlands)

Sanz, M.J.; Loarce, Y.; Fominaya, A.; Vossen, J.H.; Ferrer, E.

2013-01-01

Two of the domains most widely shared among R genes are the nucleotide binding site (NBS) and protein kinase (PK) domains. The present study describes and maps a number of new oat resistance gene analogues (RGAs) with two purposes in mind: (1) to identify genetic regions that contain R genes and (2)

The old and the new in prekallikrein deficiency: historical context and a family from Argentina with PK deficiency due to a new mutation (Arg541Gln) in exon 14 associated with a common polymorphysm (Asn124Ser) in exon 5.

Science.gov (United States)

Girolami, Antonio; Vidal, Josè; Sabagh, Marcela; Salagh, Marcela; Gervan, Nora; Parody, Maria; Peroni, Edoardo; Sambado, Luisa; Guglielmone, Hugo

2014-07-01

Prekallikrein (PK) is one of the clotting factors involved in the contact phase of blood. PK has an important historical role as its deficiency state represents the second instance of a clotting defect without bleeding manifestations, the first one being factor XII deficiency. PK deficiency is a rare clotting disorder. Moreover, only 11 patients have been investigated so far by molecular biology techniques. In this article, we briefly review some of the history around PK and also present some recent data on a newly identified family from Argentina suffering from PK deficiency. Two patients are homozygous whereas other family members are heterozygous. PK activity and antigen are 1% of normal in the homozygotes and around 60 to 70% of normal in the heterozygotes. As expected, all patients are asymptomatic of bleeding or thrombosis presentations. However, the two homozygotes showed essential hypertension. The PK deficiency in this family is due to a new mutation (Arg541Gln) in exon 14. The defect segregates together with a known polymorphism, Asn124Ser, in exon 5. The significance of the presence of hypertension in the two homozygotes is discussed in view of the extra coagulation effects of PK on vasodilation, vessel permeability, and the control of blood pressure. Structure function analysis indicates that the substitution of Arg with Gln probably impedes the transmembrane diffusion of the molecule, which therefore cannot be secreted in the homozygotes. The presence of hypertension in patients with PK deficiency has been previously reported in some but not all patients. Future research activities will probably concentrate on the effect of PK and other contact phase factors on the vascular system. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The role of infection models and PK/PD modelling for optimising care of critically ill patients with severe infections

NARCIS (Netherlands)

Tangden, T.; Martin, V.; Felton, T.W.; Nielsen, E.I.; Marchand, S.; Bruggemann, R.J.M.; Bulitta, J.B.; Bassetti, M.; Theuretzbacher, U.; Tsuji, B.T.; Wareham, D.W.; Friberg, L.E.; Waele, J.J. De; Tam, V.H.; Roberts, J.A.

2017-01-01

Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed.

Population PK/PD model of homocysteine concentrations after high-dose methotrexate treatment in patients with acute lymphoblastic leukemia.

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Hauke Rühs

Full Text Available Elevated homocysteine concentrations have been associated with methotrexate-induced neurotoxicity. Based on methotrexate and homocysteine plasma concentrations of 494 children with acute lymphoblastic leukemia treated with high-dose methotrexate in the TOTAL XV study, a pharmacokinetic/pharmacodynamic (PK/PD model was built with NONMEM. Several compartment and indirect response models were investigated. The pharmacokinetic disposition of methotrexate was best described by a two-compartment model. Homocysteine concentrations were included by an indirect response model where methotrexate inhibition of the homocysteine elimination rate was described by an E(max model. The homocysteine baseline level was found to be age-dependent. Simulations revealed that folinate rescue therapy does not affect peak concentrations of homocysteine but leads to a modestly reduced homocysteine exposure. In conclusion, our PK/PD model describes the increase of methotrexate-induced HCY concentrations with satisfactory precision and can be applied to assess the effect of folinate regimens on the HCY concentration-time course.

Lesions inflammatory activity quantification in multiple sclerosis using ["1"1C]-(R)-PK11195 PET brain images

International Nuclear Information System (INIS)

Schuck, Phelipi N.; Narciso, Lucas D.L.; Dartora, Caroline M.; Silva, Ana M. Marques da

2016-01-01

The criteria for multiple sclerosis (MS) diagnosis include the presence of lesions in brain regions called black holes (BH), characterized by low signal on magnetic resonance imaging T1-weighted. Studies suggest that lesions in MS, if there is an inflammatory process, can be detected in PET imaging with ["1"1C]- (R)-PK11195. The aim of this study is to investigate the uptake of ["1"1C]-(R)-PK11195 in BH in PET images, searching for inflammation activity in lesions and neighborhoods. Semiquantitative methods of SUV and uptake normalization were applied to PET images, in different time intervals, acquired from 8 MS patients and 5 healthy controls. Higher uptake was identified in BH and its edges, when compared with health controls white matter, when the SUV method is applied (p < 0,01, 40 to 60 min). When uptake normalization method is applied, smaller uptake in black holes and its your edges is observed, when compared with white matter apparently healthy (p < 0,01, 0 to 60 min). (author)

SPM analysis of parametric (R)-[11C]PK11195 binding images: plasma input versus reference tissue parametric methods

NARCIS (Netherlands)

Schuitemaker, Alie; van Berckel, Bart N. M.; Kropholler, Marc A.; Veltman, Dick J.; Scheltens, Philip; Jonker, Cees; Lammertsma, Adriaan A.; Boellaard, Ronald

2007-01-01

(R)-[11C]PK11195 has been used for quantifying cerebral microglial activation in vivo. In previous studies, both plasma input and reference tissue methods have been used, usually in combination with a region of interest (ROI) approach. Definition of ROIs, however, can be labourious and prone to

Semiparametric mixed-effects analysis of PK/PD models using differential equations.

Science.gov (United States)

Wang, Yi; Eskridge, Kent M; Zhang, Shunpu

2008-08-01

Motivated by the use of semiparametric nonlinear mixed-effects modeling on longitudinal data, we develop a new semiparametric modeling approach to address potential structural model misspecification for population pharmacokinetic/pharmacodynamic (PK/PD) analysis. Specifically, we use a set of ordinary differential equations (ODEs) with form dx/dt = A(t)x + B(t) where B(t) is a nonparametric function that is estimated using penalized splines. The inclusion of a nonparametric function in the ODEs makes identification of structural model misspecification feasible by quantifying the model uncertainty and provides flexibility for accommodating possible structural model deficiencies. The resulting model will be implemented in a nonlinear mixed-effects modeling setup for population analysis. We illustrate the method with an application to cefamandole data and evaluate its performance through simulations.

Gentamicin-induced apoptosis in LLC-PK1 cells: Involvement of lysosomes and mitochondria

International Nuclear Information System (INIS)

Servais, Helene; Van Der Smissen, Patrick; Thirion, Gaetan; Van der Essen, Gauthier; Van Bambeke, Francoise; Tulkens, Paul M.; Mingeot-Leclercq, Marie-Paule

2005-01-01

Gentamicin accumulates in lysosomes and induces apoptosis in kidney proximal tubules and renal cell lines. Using LLC-PK1 cells, we have examined the concentration- and time-dependency of the effects exerted by gentamicin (1-3 mM; 0-3 days) on (i) lysosomal stability; (ii) activation of mitochondrial pathway; (iii) occurrence of apoptosis (concentrations larger than 3 mM caused extensive necrosis as assessed by the measurement of lactate dehydrogenase release). Within 2 h, gentamicin induced a partial relocalization [from lysosomes to cytosol] of the weak organic base acridine orange. We thereafter observed (a) a loss of mitochondrial membrane potential (as from 10 h, based on spectrophotometric and confocal microscopy using JC1 probe) and (b) the release of cytochrome c from granules to cytosol, and the activation of caspase-9 (as from 12 h; evidenced by Western blot analysis). Increase in caspase-3 activity (assayed with Ac-DEVD-AFC in the presence of z-VAD-fmk]) and appearance of fragmented nuclei (DAPI staining) was then detected as from 16 to 24 h together with nuclear fragmentation. Gentamicin produces a fast (within 4 h) release of calcein from negatively-charged liposomes at pH 5.4, which was slowed down by raising the pH to 7.4, or when phosphatidylinositol was replaced by cardiolipin (to mimic the inner mitochondrial membrane). The present data provide temporal evidence that gentamicin causes apoptosis in LLC-PK1 with successive alteration of the permeability of lysosomes, triggering of the mitochondrial pathway, and activation of caspase-3

Efficient uptake of blood-borne BK and JC polyomavirus-like particles in endothelial cells of liver sinusoids and renal vasa recta.

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Jaione Simon-Santamaria

Full Text Available Liver sinusoidal endothelial cells (LSECs are specialized scavenger cells that mediate high-capacity clearance of soluble waste macromolecules and colloid material, including blood-borne adenovirus. To explore if LSECs function as a sink for other viruses in blood, we studied the fate of virus-like particles (VLPs of two ubiquitous human DNA viruses, BK and JC polyomavirus, in mice. Like complete virions, VLPs specifically bind to receptors and enter cells, but unlike complete virions, they cannot replicate. 125I-labeled VLPs were used to assess blood decay, organ-, and hepatocellular distribution of ligand, and non-labeled VLPs to examine cellular uptake by immunohisto- and -cytochemistry. BK- and JC-VLPs rapidly distributed to liver, with lesser uptake in kidney and spleen. Liver uptake was predominantly in LSECs. Blood half-life (∼1 min, and tissue distribution of JC-VLPs and two JC-VLP-mutants (L55F and S269F that lack sialic acid binding affinity, were similar, indicating involvement of non-sialic acid receptors in cellular uptake. Liver uptake was not mediated by scavenger receptors. In spleen, the VLPs localized to the red pulp marginal zone reticuloendothelium, and in kidney to the endothelial lining of vasa recta segments, and the transitional epithelium of renal pelvis. Most VLP-positive vessels in renal medulla did not express PV-1/Meca 32, suggesting location to the non-fenestrated part of vasa recta. The endothelial cells of these vessels also efficiently endocytosed a scavenger receptor ligand, formaldehyde-denatured albumin, suggesting high endocytic activity compared to other renal endothelia. We conclude that LSECs very effectively cleared a large fraction of blood-borne BK- and JC-VLPs, indicating a central role of these cells in early removal of polyomavirus from the circulation. In addition, we report the novel finding that a subpopulation of endothelial cells in kidney, the main organ of polyomavirus persistence, showed

Production and decay of the heaviest odd-Z nuclei in the 249Bk + 48Ca reaction

International Nuclear Information System (INIS)

Oganessian, Yu Ts; Abdullin, F Sh; Dmitriev, S N; Itkis, M G; Polyakov, A N; Alexander, C; Binder, J; Boll, R A; Ezold, J; Felker, K; Grzywacz, R K; Miernik, K; Roberto, J B; Gostic, J M; Henderson, R A; Moody, K J; Hamilton, J H; Ramayya, A V; Miller, D; Ryabinin, M A

2015-01-01

The reaction of 249 Bk with 48 Ca has been investigated with an aim of synthesizing and studying the decay properties of isotopes of the new element 117. The experiments were performed at five projectile energies (in two runs, in 2009-2010 and 2012) and with a total beam dose of 48 Ca ions of about 9x10 19 The experiments yielded data on a-decay characteristics and excitation functions of the produced nuclei that establish these to be 293 117 and 294 117 – the products of the 4n- and 3n-evaporation channels, respectively. In total, we have observed 20 decay chains of Z=117 nuclides. The cross sections were measured to be 1.1 pb for the 3n and 2.4 pb for the 4n-reaction channel. The new 289 115 events, populated by α decay of 117, demonstrate the same decay properties as those observed for 115 produced in the 243 Am( 48 Ca,2n) reaction thus providing cross-bombardment evidence. In addition, a single decay of 294 118 was observed from the reaction with 249 Cf – a result of the in-growth of 249 Cf in the 249 Bk target. The observed decay chain of 294 118 is in good agreement with decay properties obtained in 2002-2005 in the experiments with the reaction 249 Cf( 48 Ca,3n) 294 118. The energies and half-lives of the odd-Z isotopes observed in the 117 decay chains together with the results obtained for lower-Z superheavy nuclei demonstrate enhancement of nuclear stability with increasing neutron number towards the predicted new magic number N=184

Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice.

Science.gov (United States)

Li, Jing-Yun; Ren, Yu-Peng; Yuan, Yin; Ji, Shuang-Min; Zhou, Shu-Pei; Wang, Li-Jie; Mou, Zhen-Zhen; Li, Liang; Lu, Wei; Zhou, Tian-Yan

2016-07-01

Combined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib (ER) with VEGFR TKI sunitinib (SU) did not improve the overall survival in patients with non-small-cell lung cancer (NSCLC). In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling and simulations to optimize the dose regimen. ER (20, 50 mg·kg(-1)·d(-1)) or SU (5, 10, 20 mg·kg(-1)·d(-1)) alone, or their combination were administered to BALB/c nude mice bearing A549 tumors for 22 days. The tumor size and body weight were recorded daily. The experimental data were used to develop PK/PD models describing the quantitative relationship between the plasma concentrations and tumor suppression in different dose regimens. The models were further evaluated and validated, and used to predict the efficacy of different combination regimens and to select the optimal regimen. The in vivo anticancer efficacy of the combination groups was much stronger than that of either drug administered alone. A PK/PD model was developed with a combination index (φ) of 4.4, revealing a strong synergistic effect between ER and SU. The model simulation predicted the tumor growth in different dosage regimens, and showed that the dose of SU played a decisive role in the combination treatment, and suggested that a lower dose of ER (≤5 mg·kg(-1)·d(-1)) and adjusting the dose of SU might yield a better dosage regimen for clinical research. The experimental data and modeling confirm synergistic anticancer effect of ER and SU in the treatment of A549 xenograft mice. The optimal dosage regimen determined by the PK/PD modeling and simulation can be used in future preclinical study and provide a reference for clinical application.

Broadening of white-light continuum by filamentation in BK7 glass at its zero-dispersion point

International Nuclear Information System (INIS)

Jiang, Jiaming; Zhong, Yue; Zheng, Yinghui; Zeng, Zhinan; Ge, Xiaochun; Li, Ruxin

2015-01-01

Broadening of white-light continuum is observed by filamentation of near-infrared femtosecond laser pulses with peak power exceeding the megawatt level in BK7 glass with the presence of the zero-dispersion point. The simulated results show that, due to the low dispersion at the zero-dispersion point, the broadening of white-light continuum can be wider and the filament can persist in propagating stably longer distance. - Highlights: • We observed the white-light continuum by filamentation at the zero-dispersion point. • Peak power significantly exceeding the critical value of self-focusing was used. • Wider spectral broadening was obtained around the zero-dispersion point

Human BK Polyomavirus—The Potential for Head and Neck Malignancy and Disease

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Raquel Burger-Calderon

2015-07-01

Full Text Available Members of the human Polyomaviridae family are ubiquitous and pathogenic among immune-compromised individuals. While only Merkel cell polyomavirus (MCPyV has conclusively been linked to human cancer, all members of the polyomavirus (PyV family encode the oncoprotein T antigen and may be potentially carcinogenic. Studies focusing on PyV pathogenesis in humans have become more abundant as the number of PyV family members and the list of associated diseases has expanded. BK polyomavirus (BKPyV in particular has emerged as a new opportunistic pathogen among HIV positive individuals, carrying harmful implications. Increasing evidence links BKPyV to HIV-associated salivary gland disease (HIVSGD. HIVSGD is associated with elevated risk of lymphoma formation and its prevalence has increased among HIV/AIDS patients. Determining the relationship between BKPyV, disease and tumorigenesis among immunosuppressed individuals is necessary and will allow for expanding effective anti-viral treatment and prevention options in the future.

Hemorrhagic Cystitis due to BK Reactivation in a Young Female Treated for Hodgkin-Disease

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R. Le Calloch

2011-01-01

Full Text Available Hodgkin's lymphoma is a disease with a high rate of curability under classic chemo-radiotherapy regimes. Complications due to chemotherapy could include viral reactivation due to chronic lymphopenia. BK virus (BKV is a polyoma virus belonging to the Papovaviridae family with antibody seroprevalences in healthy populations varying from 60% to 80%. Initial infections are asymptomatic usually occur in early childhood, after which the viruses remain latent in the kidneys or urothelium. Reactivation of BKV occurs in individuals with severe immunosuppression during HIV infections, transplantation or, exceptionally, after classical chemotherapy. BKV incidence is approximately 0% to 5% in immunocompetent individuals. Reactivation is associated with nephropathy and haemorrhagic cystitis. Herein, we present a case of a haemorrhagic cystitis due to BKV reactivation in a patient with Hodgkin's disease treated with chemotherapy.

In Silico Absorption, Distribution, Metabolism, Excretion, and Pharmacokinetics (ADME-PK): Utility and Best Practices. An Industry Perspective from the International Consortium for Innovation through Quality in Pharmaceutical Development.

Science.gov (United States)

Lombardo, Franco; Desai, Prashant V; Arimoto, Rieko; Desino, Kelly E; Fischer, Holger; Keefer, Christopher E; Petersson, Carl; Winiwarter, Susanne; Broccatelli, Fabio

2017-11-22

In silico tools to investigate absorption, distribution, metabolism, excretion, and pharmacokinetics (ADME-PK) properties of new chemical entities are an integral part of the current industrial drug discovery paradigm. While many companies are active in the field, scientists engaged in this area do not necessarily share the same background and have limited resources when seeking guidance on how to initiate and maintain an in silico ADME-PK infrastructure in an industrial setting. This work summarizes the views of a group of industrial in silico and experimental ADME scientists, participating in the In Silico ADME Working Group, a subgroup of the International Consortium for Innovation through Quality in Pharmaceutical Development (IQ) Drug Metabolism Leadership Group. This overview on the benefits, caveats, and impact of in silico ADME-PK should serve as a resource for medicinal chemists, computational chemists, and DMPK scientists working in drug design to increase their knowledge in the area.

Oxidation of Helix-3 methionines precedes the formation of PK resistant PrP.

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Tamar Canello

2010-07-01

Full Text Available While elucidating the peculiar epitope of the alpha-PrP mAb IPC2, we found that PrPSc exhibits the sulfoxidation of residue M213 as a covalent signature. Subsequent computational analysis predicted that the presence of sulfoxide groups at both Met residues 206 and 213 destabilize the alpha-fold, suggesting oxidation may facilitate the conversion of PrPC into PrPSc. To further study the effect of oxidation on prion formation, we generated pAbs to linear PrP peptides encompassing the Helix-3 region, as opposed to the non-linear complexed epitope of IPC2. We now show that pAbs, whose epitopes comprise Met residues, readily detected PrPC, but could not recognize most PrPSc bands unless they were vigorously reduced. Next, we showed that the alpha-Met pAbs did not recognize newly formed PrPSc, as is the case for the PK resistant PrP present in lines of prion infected cells. In addition, these reagents did not detect intermediate forms such as PK sensitive and partially aggregated PrPs present in infected brains. Finally, we show that PrP molecules harboring the pathogenic mutation E200K, which is linked to the most common form of familial CJD, may be spontaneously oxidized. We conclude that the oxidation of methionine residues in Helix-3 represents an early and important event in the conversion of PrPC to PrPSc. We believe that further investigation into the mechanism and role of PrP oxidation will be central in finally elucidating the mechanism by which a normal cell protein converts into a pathogenic entity that causes fatal brain degeneration.

PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis

DEFF Research Database (Denmark)

Vowinckel, E; Reutens, D; Becher, B

1997-01-01

Activated glial cells are implicated in regulating and effecting the immune response that occurs within the CNS as part of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). The peripheral benzodiazepine receptor (PBR) is expressed in glial cells. We...... examined the utility of using in vitro and in vivo ligand binding to the PBR as a measure of lesion activity in autoimmune CNS demyelinating diseases. Applying a combined autoradiography and immunohistochemical approach to spinal cord and brain tissues from mice with EAE, we found a correlation at sites...... of inflammatory lesions between [3H]-PK11195 binding and immunoreactivity for the activated microglial/macrophage marker Mac-1/CD11b. In MS tissues, [3H]-PK11195 binding correlated with sites of immunoreactivity for the microglial/macrophage marker CD68, at the edges of chronic active plaques. Positron emission...

Halogenated benzimidazole inhibitors of phosphorylation, ''in vitro'' and ''in vivo'', of the surface acidic proteins of the yeast ribosomal 60S subunit by endogenous protein kinases CK-II and PK60S

International Nuclear Information System (INIS)

Szyszka, Ryszard; Boguszewska, Aleksandra; Grankowski, Nikodem; Shugar, David

1996-01-01

Several halogeno benzimidazoles and 2-azabenzimidazoles, previously shown to be relatively selective inhibitors of protein kinases CK-I and/or CK-II from various sources, including CK-II from yeast [Szyszka et al. (1995) Biochem. Biophys. Res. Commun. 208, 418-424] inhibit also the yeast ribosomal protein kinase PK60S. The most effective inhibitor of CK-II and PK60S was tetrabromo-2-azabenzimidazole (TetraBr-2-azaBz), which was competitive with respect to ATP (and GTP in the case of CK-II) with K i values of 0.7 μM for CK-II, and 0.1 μM for PK60S. PK60S phosphorylates only three (YP1β, YB1β', YP2α) out of five polypeptides of pp13 kDa acidic proteins of 60S subunit phosphorylated by CK-II [Szyszka et al. (1995) Acta Biochim. Polon. 42, 357-362]. Accordingly, TetraBr-azaBz inhibits phosphorylation only of these polypeptides, catalysed by PK60S. Addition of TetraBr-2Bz to cultures of yeast cells, at concentrations which were without effect on cell growth, led to inhibition of intracellular phosphorylation of ribosomal acidic proteins, paralleling that observed ''in vitro''. TetraBr-2-azaBz is shown to be a useful tool for studies on the intracellular regulation of phosphorylation of the ribosomal 60S acidic proteins, which are involved in formation of active ribosomes. (author). 36 refs, 4 figs, 2 tabs

Predictive performance of two PK-PD models of D2 receptor occupancy of the antipsychotics risperidone and paliperidone in rats

NARCIS (Netherlands)

Kozielska, Magdalena; Johnson, Martin; Pilla Reddy, Venkatesh; Vermeulen, An; de Greef, Rik; Li, Cheryl; Grimwood, Sarah; Liu, Jing; Groothuis, Genoveva; Danhof, Meindert; Proost, Johannes

2010-01-01

Objectives: The level of dopamine D2 receptor occupancy is predictive of efficacy and safety in schizophrenia. Population PK-PD modelling has been used to link observed plasma and brain concentrations to receptor occupancy. The objective of this study was to compare the predictive performance of two

Experimental Study of Tool Wear and Grinding Forces During BK-7 Glass Micro-grinding with Modified PCD Tool

Science.gov (United States)

Pratap, A.; Sahoo, P.; Patra, K.; Dyakonov, A. A.

2017-09-01

This study focuses on the improvement in grinding performance of BK-7 glass using polycrystalline diamond micro-tool. Micro-tools are modified using wire EDM and performance of modified tools is compared with that of as received tool. Tool wear of different types of tools are observed. To quantify the tool wear, a method based on weight loss of tool is introduced in this study. Modified tools significantly reduce tool wear in comparison to the normal tool. Grinding forces increase with machining time due to tool wear. However, modified tools produce lesser forces thus can improve life of the PCD micro-grinding tool.

IPv6:n käyttöönotto PK-yrityksessä

OpenAIRE

Salonen, Arttu Petteri

2011-01-01

Tämän opinnäytetyön tarkoituksena on selvittää, kuinka IPv6-yhteydet otetaan käyt-töön PK-yrityksessä. Työssä selvitetään minkälaiset vaatimukset IPv6 asettaa lait-teistolle ja minkälaisia käytännön asioita yrityksen täytyy huomioida IPv6:n käyt-töönotossa. Lisäksi työssä on laboratoriosimulaation avulla havainnollistettu eri käyt-töjärjestelmien tukea IPv6:lle ja käyttöönottoon liittyviä reititin- ja osoitekonfiguraati-oita. Käyttöönoton lisäksi opinnäytetyössä esitellään IPv6-protokoll...

Pharmacokinetics, bioavailability and PK/PD relationship of cefquinome for Escherichia coli in Beagle dogs.

Science.gov (United States)

Zhou, Y F; Zhao, D H; Yu, Y; Yang, X; Shi, W; Peng, Y B; Liu, Y H

2015-12-01

The pharmacokinetics and bioavailability of cefquinome in Beagle dogs were determined by intravenous (IV), intramuscular (IM) or subcutaneous (SC) injection at a single dose of 2 mg/kg body weight (BW). The minimum inhibitory concentrations (MIC) of cefquinome against 217 Escherichia coli isolated from dogs were also investigated. After IV injection, the plasma concentration-time curve of cefquinome was analyzed using a two-compartmental model, and the mean values of t1/2α (h), t1/2β (h), Vss (L/kg), ClB (L/kg/h) and AUC (μg·h/mL) were 0.12, 0.98, 0.30, 0.24 and 8.51, respectively. After IM and SC administration, the PK data were best described by a one-compartmental model with first-order absorption. The mean values of t1/2Kel , t1/2Ka , tmax (h), Cmax (μg/mL) and AUC (μg·h/mL) were corresponding 0.85, 0.14, 0.43, 4.83 and 8.24 for IM administration, 0.99, 0.29, 0.72, 3.88 and 9.13 for SC injection. The duration of time that drug levels exceed the MIC (%T > MIC) were calculated using the determined MIC90 (0.125 μg/mL) and the PK data obtained in this study. The results indicated that the dosage regimen of cefquinome at 2 mg/kg BW with 12-h intervals could achieve %T > MIC above 50% that generally produced a satisfactory bactericidal effect against E. coli isolated from dogs in this study. © 2015 John Wiley & Sons Ltd.

PERFORMA DOMBA YANG DIBERI COMPLETE FEED KULIT BUAH KAKAO TERFERMENTASI

Directory of Open Access Journals (Sweden)

Kamalidin (Kamalidin

2013-03-01

Full Text Available Penelitian ini bertujuan untuk mengetahui performa domba yang diberi complete feed kulit buah kakao (KBK terfermentasi. Domba ekor tipis umur 1-1,5 tahun sebanyak 15 ekor digunakan dalam penelitian ini dengan pemberian pakan dan air minum secara ad libitum. Perlakuan yang dicobakan adalah K yang merupakan pakan kontrol terdiri dari hijauan (sumber serat + konsentrat, NF merupakan complete feed dari kulit buah kakao (sumber serat + konsentrat tanpa fermentasi dan F merupakan complete feed dari kulit buah kakao (sumber serat + konsentrat yang melalui proses fermentasi (CFF dengan perbandingan antara sumber serat dan konsentrat adalah 40% : 60%. Variabel yang diamati adalah konsumsi pakan, pertambahan bobot badan, konversi pakan, feed cost per gain dan income over feed cost. Hasil penelitian menunjukkan bahwa complete feed berpengaruh nyata terhadap konsumsi bahan kering (BK, bahan organik (BO, protein kasar (PK, serat kasar (SK, lemak kasar (LK dan total digestible nutrients (TDN, sedangkan pertambahan bobot badan harian dan konversi pakan tidak berbeda nyata terhadap formulasi complete feed. Rerata konsumsi BK, BO, PK, SK, LK, dan TDN berturut-turut adalah 87,72; 78,21; 10,12; 12,21; 1,77, dan 59,52 g/kg BW0,75. Rerata pertambahan bobot badan harian adalah 128,67 g/hari atau 0,88 g/kg BW0,75, sedangkan rerata konversi pakan adalah 6,27. Disimpulkan bahwa pemberian ransum complete feed menghasilkan konsumsi nutrien yang tinggi tetapi tidak memberikan efek pertambahan bobot badan harian dan nilai konversi pakan yang lebih tinggi. Pemanfaatan fermentasi KBK menggunakan biofit menghasilkan PBBH 128,57 g/ekor/hari atau 0,88% g/kg BB0,75 efektif untuk digunakan dalam ransum penggemukan ternak domba. (Kata kunci: Domba, Complete feed, Kinerja

Transport of S-cysteine conjugates in LL-PK1 cells and its role in toxicity

International Nuclear Information System (INIS)

Schaeffer, V.; Stevens, J.

1986-01-01

In order to study its role in S-cysteine conjugate toxicity, the transport of the nephrotoxic cysteine conjugate, S-1,2-dichlorovinyl-L-cysteine (L-DCVC), was investigated in the kidney cell line, LLC-PK1. When incubated with [ 35 S]-DCVC, accumulation of radioactivity within the cells was linear for at least 5 min with 92% of the 35 S present as unmetabolized L-DCVC. Kinetic analysis indicated two saturable uptake systems; Km = 6.8 μM and 1.6 mM; V/sub max/ = .048 and 1.4 nmol/min/mg protein. Both systems were Na + -independent and were inhibited by amino acid transport system L substrates but not substrates of systems A, ASC or organic anion transport. L-DCVC uptake at 5 μM and 500 μM was significantly greater in subconfluent cells than in confluent cultures by 5 and 2.8 fold, respectively. The presence of the non-toxic conjugates S-methyl-(SMC), S-ethyl-(SEC), S-benzyl-L- cysteine (SBC) and the D isomer of DCVC blocked the toxicity and inhibited the transport of L-DCVC in LLC-PK1 cells in the rank order of SBC > SEC congruent to D-DCVC > SMC. The metabolism of L-DCVC, previously shown to be required for cytotoxicity, was only slightly inhibited by these conjugates and did not correlate with their relative protection against toxicity. This study suggests that L-DCVC is transported into these cells by the system L transporter and that protection against toxicity by non-toxic S-cysteine conjugates is due to the inhibition of transport

Naxos disease in an Arab family is not caused by the Pk2157del2 mutation; evidance for exclusion of the plakoglobin gene

International Nuclear Information System (INIS)

Stuhmann, M.; El-Harith, A.; Bukhari, Iqbal A.

2004-01-01

Nax os disease is a rare hereditary disorder characterized by palmoplantar keratoderma, woolly hair and cardiomyopathy. This study aims to determine whether Naxos disease in a Saudi Arab family is caused by the Pk2157del2 mutation that was identified in Greek families from Naxos Island where the disease had originally been described. This study was undertaken at King Fahad Hospital of the University, Al-Khobar, and the Medical University of Hannover, in the spring of 2003. Naxos disease has been encountered in a 2-year-old girl and her 30-year-old aunt of a Saudi Arab family. Deoxyribonucleic acid samples of this family were analyzed by polymerase chain-reaction (PCR) amplification of the respective region of the plakoglobin gene, and direct nucleotide sequencing of the PCR-products. Segregation analysis was performed employing the newly detected IVS11+22G/A polymorphism. Molecular genetic analysis of the DNA sample of the child diagnosed with Naxos disease showed absence of the Pk2157del2 mutation. In addition, the segregation analysis revealed heterozygosity for IVS11+22G/A in the affected girl. Absence of the Pk2157del2 frameshift in the affected child proved that Naxos disease in this Saudi Arab family is not caused by the same mutation that was identified in the Greek families. Furthermore, heterozygosity for the IVS11+22G/A polymorphism provided evidence for exclusion of the plakoglobin gene in this consanguineous family. (author)

DNA ligase III is involved in a DNA-PK independent pathway of NHEJ in human cells

International Nuclear Information System (INIS)

Wang, H.; Perrault, A.R.; Qin, W.; Wang, H.; Iliakis, G.

2003-01-01

Full text: Double strand breaks (DSB) induced by ionizing radiation (IR) and other cytotoxic agents in the genome of higher eukaryotes are thought to be repaired either by homologous recombination repair (HRR), or non-homologous endjoining (NHEJ). We previously reported the operation of two components of NHEJ in vivo: a DNA-PK dependent component that operates with fast kinetics (D-NHEJ), and a DNA-PK independent component that acts as a backup (basic or B-NHEJ) and operates with kinetics an order of magnitude slower. To gain further insight into the mechanisms of B-NHEJ, we investigated DNA endjoining in extracts 180BR, a human cell line deficient in DNA ligase IV, using an in vitro plasmid-based DNA endjoining assay. An anti DNA ligase III antibody inhibited almost completely DNA endjoining activity in these extracts. On the other hand, an anti DNA ligase I antibody had no measurable effect in DNA endjoining activity. Immunodepletion of DNA ligase III from 180BR cell extracts abolished the DNA endjoining activity, which could be restored by addition of purified human DNA ligase IIIb. Full-length DNA ligase III bound to double stranded DNA and stimulated DNA endjoining in both intermolecular and intramolecular ligation. Furthermore, fractionation of HeLa cell extracts demonstrated the presence of an activity stimulating the function of DNA ligase III. Based on these observations we propose that DNA ligase III is the ligase operating in B-NHEJ

Development of a loop-mediated isothermal amplification assay for rapid detection of BK virus.

Science.gov (United States)

Bista, Bipin Raj; Ishwad, Chandra; Wadowsky, Robert M; Manna, Pradip; Randhawa, Parmjeet Singh; Gupta, Gaurav; Adhikari, Meena; Tyagi, Rakhi; Gasper, Gina; Vats, Abhay

2007-05-01

Loop-mediated isothermal amplification (LAMP) is a novel method for rapid amplification of DNA. Its advantages include rapidity and minimal equipment requirement. The LAMP assay was developed for BK virus (BKV), which is a leading cause of morbidity in renal transplant recipients. The characteristics of the assay, including its specificity and sensitivity, were evaluated. BKV LAMP was performed using various incubation times with a variety of specimens, including unprocessed urine and plasma samples. A ladder pattern on gel electrophoresis, typical of successful LAMP reactions, was observed specifically only for BKV and not for other viruses. The sensitivity of the assay with 1 h of incubation was 100 copies/tube of a cloned BKV fragment. Additionally, a positive reaction was visually ascertained by a simple color reaction using SYBR green dye. BKV LAMP was also successful for urine and plasma specimens without the need for DNA extraction. Due to its simplicity and specificity, the LAMP assay can potentially be developed for "point of care" screening of BKV.

A comparison of HK-CONWIP and BK-CONWIP control strategies in a multi-product manufacturing system

Directory of Open Access Journals (Sweden)

Chukwunonyelum Emmanuel Onyeocha

2015-12-01

Full Text Available This paper evaluates the performance of the Hybrid Kanban Constant Work-In-Process control strategy and Basestock Kanban Constant Work-In-Process control strategy operating Shared Kanban Allocation Policy (S-KAP and Dedicated Kanban Allocation Policy (D-KAP in a multi-product serial flow line. We explored the effect of an increase of product types on the WIP inventory in the system. A simulation-based optimisation technique was used in determining the optimal settings for the strategies. The strategies were compared via pairwise comparison technique and Nelson’s ranking and selection procedure. S-KAP responds quicker to demand than D-KAP. BK-CONWIP outperforms HK-CONWIP in a serial manufacturing system. It was shown that an increase in the number of product-type increases the number of PAC and WIP inventory.

Rapid detection of urinary polyomavirus BK by heterodyne-based surface plasmon resonance biosensor

Science.gov (United States)

Su, Li-Chen; Tian, Ya-Chung; Chang, Ying-Feng; Chou, Chien; Lai, Chao-Sung

2014-01-01

In renal transplant patients, immunosuppressive therapy may result in the reactivation of polyomavirus BK (BKV), leading to polyomavirus-associated nephropathy (PVAN), which inevitably causes allograft failure. Since the treatment outcomes of PVAN remain unsatisfactory, early identification and continuous monitoring of BKV reactivation and reduction of immunosuppressants are essential to prevent PVAN development. The present study demonstrated that the developed dual-channel heterodyne-based surface plasmon resonance (SPR) biosensor is applicable for the rapid detection of urinary BKV. The use of a symmetrical reference channel integrated with the poly(ethylene glycol)-based low-fouling self-assembled monolayer to reduce the environmental variations and the nonspecific noise was proven to enhance the sensitivity in urinary BKV detection. Experimentally, the detection limit of the biosensor for BKV detection was estimated to be around 8500 copies/mL. In addition, urine samples from five renal transplant patients were tested to rapidly distinguish PVAN-positive and PVAN-negative renal transplant patients. By virtue of its simplicity, rapidity, and applicability, the SPR biosensor is a remarkable potential to be used for continuous clinical monitoring of BKV reactivation.

"Legal highs"--toxicity in the clinical and medico-legal aspect as exemplified by suicide with bk-MBDB administration.

Science.gov (United States)

Rojek, Sebastian; Kłys, Małgorzata; Strona, Marcin; Maciów, Martyna; Kula, Karol

2012-10-10

The easily available "legal highs", which are products containing psychoactive substances, such as cathinones, piperazines and synthetic cannabinoids, are abused by adolescents in Poland and in the world as alternatives to classic drugs, such as amphetamines or marijuana. The majority of these potentially dangerous substances are still legal and they are associated with a risk of severe poisoning or even death, and provide new challenges in clinical and forensic toxicological practice. Investigations in the field of "designer drugs" may be well illustrated by the case of a suicide of a 21-year old male who ingested a specified dose of a preparation called "Amphi-bi-a" that contains bk-MBDB, chemically 2-methylamino-1-(3,4-methylenedioxyphenyl) butan-1-one, which belongs to the cathinone group, as a synthetic euphoric empathogen and psychoactive stimulant that is chemically similar to MDMA. It is one of more common components of "legal highs" examined in Poland and other countries. The documentation of the case includes a clinical assessment of the patient's health status performed during his almost 4-h hospitalization before death, autopsy and histological examinations supported by toxicological findings revealing bk-MBDB at extremely high concentrations (at 20 mg/l in the blood and 33 mg/kg in the liver); hence, this body of evidence contributes to knowledge in the field of "designer drugs". Inventions of designers of new psychoactive xenobiotics, which are much in demand, especially in view of the dynamic Internet marketing, which drums up narcobusiness, must be balanced by a national strategy developed by medical, legal and educational circles in the modern civilized world in order to prevent the spreading of the phenomenon. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Coinfection with Epstein–Barr Virus (EBV), Human Papilloma Virus (HPV) and Polyoma BK Virus (BKPyV) in Laryngeal, Oropharyngeal and Oral Cavity Cancer

OpenAIRE

Drop, Bartłomiej; Strycharz-Dudziak, Małgorzata; Kliszczewska, Ewa; Polz-Dacewicz, Małgorzata

2017-01-01

Most research providing evidence for the role of oncogenic viruses in head and neck squamous cell carcinoma (SCC) development is focused on one type of virus without analyzing possible interactions between two or more types of viruses. The aim of this study was to analyse the prevalence of co-infection with human papillomavirus (HPV), Epstein–Barr virus (EBV) and polyoma BK virus (BKPyV) in oral, oropharyngeal and laryngeal squamous cell carcinomas in Polish patients. The correlations between...

Determining the pk(a) of N,N-dimethylsphingosine and the flip-flop rate of related compounds with deuterium nuclear magnetic resonance

International Nuclear Information System (INIS)

Lau, Bienca

1995-01-01

Deuterium nuclear magnetic resonance ( 2 H-NMR) spectroscopy was applied to determine the pk(a) of the protein kinase C (PKC) inhibitor, N,N-dimethylsphingosine (DMS), when bound to 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers. The quadrupolar splittings from deuterium labels at the α- and the β-positions of the POPC headgroup responded in a manner indicative of a positive surface charge density at pH 7.0. Conversely, at pH 10.0 DMS had virtually no influence on either quadrupolar splitting, an effect attributed to titration of the dimethylamino group of DMS to its neutral form. A DMS titration curve was obtained by quantifying the charge in the quadrupolar splittings as a function of pH. Simulation of this curve yielded a pk(a) of 8.8 of membrane-bound DMS. Using a similar approach, the dynamic process of flip-flop was examined in two DMS analogues. We discuss here the quantitative and the qualitative aspects as well as the limitations of this application. (author)

Cytomegalovirus and BK-Virus co-infection of a clinically non-functioning adrenal adenoma: innocent bystanders or new pathogenetic agents?

Science.gov (United States)

Pomara, G; Cappello, F; Barzon, L; Morelli, G; Rappa, F; Benvegna, L; Giannarini, G; Palù, G; Selli, C

2006-01-01

We report a case of a 64-year-old woman who underwent left adrenalectomy with removal of a 8,5 cm clinically non-functioning adrenocortical adenoma and a 4-cm myelolipoma. Molecular testing for viral infection demonstrated the presence of cytomegalovirus (CMV) DNA sequences in the adrenal adenoma, but not in the myelolipoma (confirmed by immunohistochemistry). Moreover, the adrenal adenoma was also positive for parvovirus B19, and both adrenal tumor samples were positive for polyomavirus BK (BKV) and adenovirus DNA sequences. This is the first report of co-infection of an adrenocortical adenoma by CMV and BKV. The role of these viruses in adrenal tumorigenesis was postulated.

Cytomegalovirus and BK-Virus co-infection of a clinically non-functioning adrenal adenoma: innocent bystanders or new pathogenetic agents?

Directory of Open Access Journals (Sweden)

G Pomara

2009-06-01

Full Text Available We report a case of a 64-year-old woman who underwent left adrenalectomy with removal of a 8,5 cm clinically non-functioning adrenocortical adenoma and a 4-cm myelolipoma. Molecular testing for viral infection demonstrated the presence of cytomegalovirus (CMV DNA sequences in the adrenal adenoma, but not in the myelolipoma (confirmed by immunohistochemistry. Moreover, the adrenal adenoma was also positive for parvovirus B19, and both adrenal tumor samples were positive for polyomavirus BK (BKV and adenovirus DNA sequences. This is the first report of co-infection of an adrenocortical adenoma by CMV and BKV. The role of these viruses in adrenal tumorigenesis was postulated.

ASAI ISOLAT BAKTERI KITINOLITIK BACILLUS SP. BK17 PADA MEDIA PEMBAWA TANAH GAMBUT DAN KOMPOS JANJANG KELAPA SAWIT DALAM MENGHAMBAT PERTUMBUHAN JAMUR PATOGEN SCLEROTIUM ROLFSII DAN FUSARIUM OXYSPORUM PADA KECAMBAH CABAI

Directory of Open Access Journals (Sweden)

Deswidya Hutauruk

2016-10-01

Full Text Available Assay of chitinolytic bacterial isolate of Bacillus sp. Bk17 in peat and palm oil bunch compost as carrier media in inhibiting Sclerotium rolfsii and Fusarium oxysporum of chilli seedlings. Sclerotium rolfsii and Fusarium oxysporum have been known as causal agents of seedling-off of chilli. Biological control has been used as an alternative control to replace chemical control. This study was aimed to determine the viability and ability of chitinolityc bacteria Bacillus sp. BK17 in carrier media of peat and palm oil bunch compost and in growing media to control seedling-off caused by S. rolfsii dan F. oxysporum of chilli. Our previous study showed that Bacillus sp. BK17 could reduce disease severity and intensity. Bacterial viability was measured as colony number grown after 90 days of storage in minimum salt medium with colloidal chitin as sole C source. Reduction of disease infection was measured as seedling number infected by S. rolfsii dan F. oxysporum. Seedling performances were measured as seedling height, leaf number and dry-weight after 30-days of growth. The result showed that bacterial cell viability was still high in both peat and palm oil bunch compost both with and without colloidal chitin addition after 90 days of storage. It was also shown that during application bacterial cell could grow. Seedling performaces i.e. seedling height, leaf number and dry-weight showed to be normal or even increase compared to those of pathogenic fungal inoculation only and (- control.

Effects of the benzodiazepine antagonists RO 15-1788, CGS-8216 and PK-11195 on amygdaloid kindled seizures and the anticonvulsant efficacy of diazepam.

Science.gov (United States)

Albertson, T E; Walby, W F

1986-11-01

The anticonvulsant effectiveness of the benzodiazepine antagonists RO 15-1788, CGS-8216 and PK-11195 were evaluated against threshold and suprathreshold (400 microA) stimulation in fully amygdaloid-kindled rats. Pretreatment with either RO 15-1788 (3, 10 and 30 mg/kg), CGS-8216 (3, 10 and 30 mg/kg) or PK-11195 (10 and 60 mg/kg) failed in this study to modify consistently either the afterdischarge thresholds or elicited suprathreshold seizures or duration of afterdischarge. Using a double injection paradigm, the effectiveness of these three benzodiazepine antagonists to reverse the anti-convulsant and behavioral effects of diazepam were studied. When diazepam (3 mg/kg) was injected 15 min before or after a second injection of the vehicle control DMSO (0.25 ml/kg), a significant reduction in the duration of afterdischarge and seizure rank, elicited by a suprathreshold stimulation in amygdaloid-kindled rats, occurred. When either CGS 8216 (10 mg/kg) or RO 15-1788 (10 mg/kg) were given 15 min before diazepam (3 mg/kg) prior to stimulation, the anticonvulsant properties of diazepam were blocked. When RO 15-1788 (10 mg/kg) was given 15 min after diazepam, antagonism of the anticonvulsant effects on diazepam was shown. However, when either CGS-8216 (10 mg/kg) or PK-11195 (10 and 60 mg/kg) were given 15 min after diazepam (3 mg/kg), the anticonvulsant properties of diazepam were not blocked. The anticonvulsant effects of diazepam were reversed when CGS-8216 (10 mg/kg) was given 5 min after diazepam (3 mg/kg) or when a larger dose (30 mg/kg) was given at the same 15 min interval.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical polyomavirus BK variants with agnogene deletion are non-functional but rescued by trans-complementation

International Nuclear Information System (INIS)

Myhre, Marit Renee; Olsen, Gunn-Hege; Gosert, Rainer; Hirsch, Hans H.; Rinaldo, Christine Hanssen

2010-01-01

High-level replication of polyomavirus BK (BKV) in kidney transplant recipients is associated with the emergence of BKV variants with rearranged (rr) non-coding control region (NCCR) increasing viral early gene expression and cytopathology. Cloning and sequencing revealed the presence of a BKV quasispecies which included non-functional variants when assayed in a recombinant virus assay. Here we report that the rr-NCCR of BKV variants RH-3 and RH-12, both bearing a NCCR deletion including the 5' end of the agnoprotein coding sequence, mediated early and late viral reporter gene expression in kidney cells. However, in a recombinant virus they failed to produce infectious progeny despite large T-antigen and VP1 expression and the formation of nuclear virus-like particles. Infectious progeny was generated when the agnogene was reconstructed in cis or agnoprotein provided in trans from a co-existing BKV rr-NCCR variant. We conclude that complementation can rescue non-functional BKV variants in vitro and possibly in vivo.

No evidence for infection of UK prostate cancer patients with XMRV, BK virus, Trichomonas vaginalis or human papilloma viruses.

Science.gov (United States)

Groom, Harriet C T; Warren, Anne Y; Neal, David E; Bishop, Kate N

2012-01-01

The prevalence of specific infections in UK prostate cancer patients was investigated. Serum from 84 patients and 62 controls was tested for neutralisation of xenotropic murine leukaemia virus-related virus (XMRV) Envelope. No reactivity was found in the patient samples. In addition, a further 100 prostate DNA samples were tested for XMRV, BK virus, Trichomonas vaginalis and human papilloma viruses by nucleic acid detection techniques. Despite demonstrating DNA integrity and assay sensitivity, we failed to detect the presence of any of these agents in DNA samples, bar one sample that was weakly positive for HPV16. Therefore we conclude that these infections are absent in this typical cohort of men with prostate cancer.

No evidence for infection of UK prostate cancer patients with XMRV, BK virus, Trichomonas vaginalis or human papilloma viruses.

Directory of Open Access Journals (Sweden)

Harriet C T Groom

Full Text Available The prevalence of specific infections in UK prostate cancer patients was investigated. Serum from 84 patients and 62 controls was tested for neutralisation of xenotropic murine leukaemia virus-related virus (XMRV Envelope. No reactivity was found in the patient samples. In addition, a further 100 prostate DNA samples were tested for XMRV, BK virus, Trichomonas vaginalis and human papilloma viruses by nucleic acid detection techniques. Despite demonstrating DNA integrity and assay sensitivity, we failed to detect the presence of any of these agents in DNA samples, bar one sample that was weakly positive for HPV16. Therefore we conclude that these infections are absent in this typical cohort of men with prostate cancer.

P-waves imaging of the FRI and BK zones at the Grimsel Rock Laboratory

International Nuclear Information System (INIS)

Majer, E.L.; Peterson, J.E. Jr.; Blueming, P.; Sattel, G.

1990-08-01

This report is one of a series documenting the results of the Nagra-DOE Cooperative (NDC-I) research program in which the cooperating scientists explore the geological, geophysical, hydrological, geochemical, and structural effects anticipated from the use of a rock mass as a geological repository for nuclear waste. Tomographic imaging studies using a high frequency (10 Khz.) piezoelectric source and a three component receiver were carried out in two different regions of the underground Nagra Grimsel test facility in Switzerland. Both sites were in fractured granite, one being in a strongly foliated granite (FRI site), and the other being in a relatively homogeneous granite (BK zone). The object of the work was to determine if the seismic techniques could be useful in imaging the fracture zones and provide information on the hydrologic conditions. Both amplitude and velocity tomograms were obtained from the Data. The results indicate that the fracture zones strongly influenced the seismic wave propagation, thus imaging the fracture zones that were hydrologically important. 11 refs., 24 figs

Development of a Loop-Mediated Isothermal Amplification Assay for Rapid Detection of BK Virus▿

Science.gov (United States)

Bista, Bipin Raj; Ishwad, Chandra; Wadowsky, Robert M.; Manna, Pradip; Randhawa, Parmjeet Singh; Gupta, Gaurav; Adhikari, Meena; Tyagi, Rakhi; Gasper, Gina; Vats, Abhay

2007-01-01

Loop-mediated isothermal amplification (LAMP) is a novel method for rapid amplification of DNA. Its advantages include rapidity and minimal equipment requirement. The LAMP assay was developed for BK virus (BKV), which is a leading cause of morbidity in renal transplant recipients. The characteristics of the assay, including its specificity and sensitivity, were evaluated. BKV LAMP was performed using various incubation times with a variety of specimens, including unprocessed urine and plasma samples. A ladder pattern on gel electrophoresis, typical of successful LAMP reactions, was observed specifically only for BKV and not for other viruses. The sensitivity of the assay with 1 h of incubation was 100 copies/tube of a cloned BKV fragment. Additionally, a positive reaction was visually ascertained by a simple color reaction using SYBR green dye. BKV LAMP was also successful for urine and plasma specimens without the need for DNA extraction. Due to its simplicity and specificity, the LAMP assay can potentially be developed for “point of care” screening of BKV. PMID:17314224

Determination of the pK values of 5-aminosalicylic acid and N-acetylaminosalicylic acid and comparison of the pH dependent lipid-water partition coefficients of sulphasalazine and its metabolites.

Science.gov (United States)

Allgayer, H; Sonnenbichler, J; Kruis, W; Paumgartner, G

1985-01-01

Sulphasalazine (SASP), used in the treatment of inflammatory bowel disease, is split into sulphapyridine (SP) and 5-aminosalicylic acid (5-ASA) in the colon. Lower plasma levels of SASP and 5-ASA as compared to those of SP may be due to different absorption rates from the colon because of different pK values and pH dependent lipid-water partition coefficients. In this study we determined the pK values of 5-ASA and its major metabolite, N-acetyl amino-salicylic acid (AcASA), by 13C-NMR spectroscopy and compared the pH dependent apparent benzene-water partition coefficients (Papp) of SASP, SP and 5-ASA with respect to their different plasma levels. The COOH group of 5-ASA had a pK value of 3.0, the -NH3+ group had 6.0, the -OH group 13.9; the -COOH group of AcASA had 2.7 and the -OH group 12.9; The Papp of SASP (0.042 +/- 0.004) and 5-ASA (0.059 +/- 0.01) were significantly lower than that of SP (0.092 +/- 0.03) (at pH 5.5).

Addition of ash and PK with or without N on a peatland in southern Sweden. Effects on tree growth and needle element concentrate; Tillfoersel av aska och PK med eller utan N paa en torvmark i soedra Sverige. Effekter paa traedtillvaext och aemneshalter i barr

Energy Technology Data Exchange (ETDEWEB)

Sikstroem, Ulf (Forestry Research Inst. of Sweden, Uppsala (Sweden))

2008-04-15

In Sweden, about 1.3 million tonnes of ash are produced annually. Out of that amount, 150 000 - 300 000 tonnes have been estimated to originate from forest fuels, i.e. ashes that potentially can be brought back to the forest. Apart from being a compensatory measure after intensive forest harvest (e.g. including tops and branches), the ash may be used to increase the tree growth on peat soils (ash fertilization). On peat soils, tree growth is generally increased after addition of ash or phosphorous (P) and potassium (K) fertilizers. However, in some cases also nitrogen (N) addition is required. On sparsely stocked mires, fertilization may promote the regeneration as well as increase the growth of the trees. Sufficient drainage and supply of plant-available N are some prerequisites for increasing tree growth by PK-addition. In 1982, Skogforsk established a field experiment (168 Perstorp) located in the province of Scania in a sparsely stocked Pinus Sylvestris (L.) sapling stand on a ditched mire where different nutrient regimes were tested. The experiment had a randomized block design including four blocks and seven treatments. Ash and different dozes of P (raw phosphate) and K (potassium chloride), with or without simultaneous N addition, were included as well as un untreated control. The aim of the present study was to evaluate the effects on tree growth and needle elemental concentrations 26 years after treatment. The addition of similar dozes of P (approx. 40 kg P/ha), as ash (2.5 tonnes/ha) or as PK-fertilizer rendered similar growth responses. The increase in stem-wood growth was in the order of 1,6 - 1,9 m3/ha/yr during the 26-year period. The N-addition had no additional effect. On the control plots, the growth was more or less negligible (approx. 0,04 m3sk/ha/yr). On average, the high dozes of raw-phosphate and potassium chloride (40 kg P/ha and 80 kg K/ha) gave a higher growth increase than the low dozes (20 kg P/ha and 40 kg K/ha), although this effect was

Optimalisasi Pengelolaan dan Pemanfaatan Aset Tanah dan Bangunan Perguruan Tinggi Negeri (PTN yang Melaksanakan Pengelolaan Keuangan Badan Layanan Umum (PK BLU0 dalam Rangka Meningkatkan Pelayanan Pendidikan

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Dewi Kania Sugiharti

2014-08-01

Full Text Available Abstrak Perguruan Tinggi Negeri Pengelolaan Keuangan Badan Layanan Umum (PTN-PK BLU merupakan instansi pemerintah yang diberi kewenangan untuk melakukan pengelolaan keuangan badan layanan umum, dengan tujuan untuk meningkatkan pelayanan bidang pendidikan kepada masyarakat dalam rangka mencerdaskan kehidupan bangsa. Fleksibilitas dalam pengelolaan keuangan PTNPKBLU berdasarkan prinsip ekonomi dan produktivitas, serta penerapan praktik bisnis yang sehat. Berdasarkan PP Nomor 23 Tahun 2005 dan PP Nomor 6 Tahun 2006 sebagaimana telah diubah dengan PP Nomor 38 Tahun 2008, fleksibilitas tersebut hanya berlaku dalam pengelolaan keuangan. Tanah dan bangunan yang berada dalam penguasaan PTNPKBLU, wajib dipergunakan sesuai dengan tugas pokok dan fungsi PTNPKBLU tersebut. Secara normatif, tidak ada ketentuan yang memberikan wewenang kepada kuasa pengguna barang untuk memanfaatkannya untuk tujuan lain. Aturan memberi peluang untuk mendayagunakan barang milik negara yang tidak dipergunakan sesuai dengan tugas pokok dan fungsi, yaitu dalam bentuk sewa, pinjam pakai, kerja sama pemanfaatan, dan bangun serah guna/bangun guna serah dengan tidak mengubah status kepemilikan, namun pemanfaatan tersebut hanya dapat dilakukan oleh pengelola barang, bukan oleh kuasa pengguna barang. Dalam hal ini, kuasa pengguna barang milik negara hanya berwenang dan bertanggung jawab untuk menyerahkan tanah dan/atau bangunan yang tidak dimanfaatkan untuk kepentingan penyelenggaraan tugas pokok dan fungsi kantor yang dipimpinnya tersebut, kepada pengguna barang. Abstract State University implementing PK BLU is a government agency with the right to use Pengelolaan Keuangan Badan Layanan Umum (PK BLU to better increase educational service in order to improve the intellectual life of the people of Indonesia. Flexibility in a State University implementing PK BLU has to be based on economic principles, productivity, and fairness. Based on Government Regulation 23/2005 and Government

Urological management (medical and surgical of BK-virus associated haemorrhagic cystitis in children following haematopoietic stem cell transplantation

Directory of Open Access Journals (Sweden)

Nikhil Vasdev

2013-10-01

Full Text Available Aim: Haemorrhagic cystitis (HC is uncommon and in its severe form potentially life threatening complication of Haematopoietic stem cell transplantation (HSCT in children. We present our single centre experience in the urological management of this clinically challenging condition. Patients and Methods: Fourteen patients were diagnosed with BK-Virus HC in our centre. The mean age at diagnosis was 8.8 years (range, 3.2-18.4 years. The mean number of days post-BMT until onset of HC was 20.8 (range, 1 – 51. While all patients tested urine positive for BKV at the clinical onset of HC, only four patients had viral quantification, with viral loads ranging from 97,000 to >1 billion/ml. 8 patients had clinical HC. Ten patients experienced acute GVHD (grade I: 6 patients, grade II: 3 patients, grade 4: 1 patient.Results: Four patients received medical management for their HC. Treatments included hyperhydration, MESNA, blood and platelet transfusion, premarin and oxybutynin (Table 6.  Two patients received both medical and surgical management which included cystoscopy with clot evacuation, bladder irrigation and supra-pubic catheter insertion. One patient received exclusive surgical management. Seven patients were treated conservatively. Conclusion: There is limited available evidence for other potential therapeutic strategies highlighting the need for more research into the pathophysiology of HSCT-associated HC. Commonly used interventions with possible clinical benefit (e.g. cidofovir, ciprofloxacin still require to be evaluated in multi-centre, high-quality studies. Potential future preventative and therapeutic options, such as modulation of conditioning, immunosuppression and engraftment, new antiviral and anti-inflammatory and less nephrotoxic agents need to be assessed.---------------------------Cite this article as:Vasdev N, Davidson A, Harkensee C, Slatter M, Gennery A, Willetts I, Thorpe A.Urological management (medical and surgical of BK

Study of the production of $\\Lambda_b^0$ and $\\overline{B}^0$ hadrons in $pp$ collisions and first measurement of the $\\Lambda_b^0\\rightarrow J/\\psi pK^-$ branching fraction

CERN Document Server

Aaij, R.; Adinolfi, Marco; Affolder, Anthony; Ajaltouni, Ziad; Akar, Simon; Albrecht, Johannes; Alessio, Federico; Alexander, Michael; Ali, Suvayu; Alkhazov, Georgy; Alvarez Cartelle, Paula; Alves Jr, Antonio Augusto; Amato, Sandra; Amerio, Silvia; Amhis, Yasmine; An, Liupan; Anderlini, Lucio; Anderson, Jonathan; Andreassi, Guido; Andreotti, Mirco; Andrews, Jason; Appleby, Robert; Aquines Gutierrez, Osvaldo; Archilli, Flavio; d'Argent, Philippe; Artamonov, Alexander; Artuso, Marina; Aslanides, Elie; Auriemma, Giulio; Baalouch, Marouen; Bachmann, Sebastian; Back, John; Badalov, Alexey; Baesso, Clarissa; Baldini, Wander; Barlow, Roger; Barschel, Colin; Barsuk, Sergey; Barter, William; Batozskaya, Varvara; Battista, Vincenzo; Bay, Aurelio; Beaucourt, Leo; Beddow, John; Bedeschi, Franco; Bediaga, Ignacio; Bel, Lennaert; Bellee, Violaine; Belloli, Nicoletta; Belyaev, Ivan; Ben-Haim, Eli; Bencivenni, Giovanni; Benson, Sean; Benton, Jack; Berezhnoy, Alexander; Bernet, Roland; Bertolin, Alessandro; Bettler, Marc-Olivier; van Beuzekom, Martinus; Bien, Alexander; Bifani, Simone; Billoir, Pierre; Bird, Thomas; Birnkraut, Alex; Bizzeti, Andrea; Blake, Thomas; Blanc, Frédéric; Blouw, Johan; Blusk, Steven; Bocci, Valerio; Bondar, Alexander; Bondar, Nikolay; Bonivento, Walter; Borghi, Silvia; Borsato, Martino; Bowcock, Themistocles; Bowen, Espen Eie; Bozzi, Concezio; Braun, Svende; Britsch, Markward; Britton, Thomas; Brodzicka, Jolanta; Brook, Nicholas; Buchanan, Emma; Bursche, Albert; Buytaert, Jan; Cadeddu, Sandro; Calabrese, Roberto; Calvi, Marta; Calvo Gomez, Miriam; Campana, Pierluigi; Campora Perez, Daniel; Capriotti, Lorenzo; Carbone, Angelo; Carboni, Giovanni; Cardinale, Roberta; Cardini, Alessandro; Carniti, Paolo; Carson, Laurence; Carvalho Akiba, Kazuyoshi; Casse, Gianluigi; Cassina, Lorenzo; Castillo Garcia, Lucia; Cattaneo, Marco; Cauet, Christophe; Cavallero, Giovanni; Cenci, Riccardo; Charles, Matthew; Charpentier, Philippe; Chefdeville, Maximilien; Chen, Shanzhen; Cheung, Shu-Faye; Chiapolini, Nicola; Chrzaszcz, Marcin; Cid Vidal, Xabier; Ciezarek, Gregory; Clarke, Peter; Clemencic, Marco; Cliff, Harry; Closier, Joel; Coco, Victor; Cogan, Julien; Cogneras, Eric; Cogoni, Violetta; Cojocariu, Lucian; Collazuol, Gianmaria; Collins, Paula; Comerma-Montells, Albert; Contu, Andrea; Cook, Andrew; Coombes, Matthew; Coquereau, Samuel; Corti, Gloria; Corvo, Marco; Couturier, Benjamin; Cowan, Greig; Craik, Daniel Charles; Crocombe, Andrew; Cruz Torres, Melissa Maria; Cunliffe, Samuel; Currie, Robert; D'Ambrosio, Carmelo; Dall'Occo, Elena; Dalseno, Jeremy; David, Pieter; Davis, Adam; De Bruyn, Kristof; De Capua, Stefano; De Cian, Michel; De Miranda, Jussara; De Paula, Leandro; De Simone, Patrizia; Dean, Cameron Thomas; Decamp, Daniel; Deckenhoff, Mirko; Del Buono, Luigi; Déléage, Nicolas; Demmer, Moritz; Derkach, Denis; Deschamps, Olivier; Dettori, Francesco; Dey, Biplab; Di Canto, Angelo; Di Ruscio, Francesco; Dijkstra, Hans; Donleavy, Stephanie; Dordei, Francesca; Dorigo, Mirco; Dosil Suárez, Alvaro; Dossett, David; Dovbnya, Anatoliy; Dreimanis, Karlis; Dufour, Laurent; Dujany, Giulio; Dupertuis, Frederic; Durante, Paolo; Dzhelyadin, Rustem; Dziurda, Agnieszka; Dzyuba, Alexey; Easo, Sajan; Egede, Ulrik; Egorychev, Victor; Eidelman, Semen; Eisenhardt, Stephan; Eitschberger, Ulrich; Ekelhof, Robert; Eklund, Lars; El Rifai, Ibrahim; Elsasser, Christian; Ely, Scott; Esen, Sevda; Evans, Hannah Mary; Evans, Timothy; Falabella, Antonio; Färber, Christian; Farley, Nathanael; Farry, Stephen; Fay, Robert; Ferguson, Dianne; Fernandez Albor, Victor; Ferrari, Fabio; Ferreira Rodrigues, Fernando; Ferro-Luzzi, Massimiliano; Filippov, Sergey; Fiore, Marco; Fiorini, Massimiliano; Firlej, Miroslaw; Fitzpatrick, Conor; Fiutowski, Tomasz; Fohl, Klaus; Fol, Philip; Fontana, Marianna; Fontanelli, Flavio; Forty, Roger; Francisco, Oscar; Frank, Markus; Frei, Christoph; Frosini, Maddalena; Fu, Jinlin; Furfaro, Emiliano; Gallas Torreira, Abraham; Galli, Domenico; Gallorini, Stefano; Gambetta, Silvia; Gandelman, Miriam; Gandini, Paolo; Gao, Yuanning; García Pardiñas, Julián; Garra Tico, Jordi; Garrido, Lluis; Gascon, David; Gaspar, Clara; Gauld, Rhorry; Gavardi, Laura; Gazzoni, Giulio; Gerick, David; Gersabeck, Evelina; Gersabeck, Marco; Gershon, Timothy; Ghez, Philippe; Gianì, Sebastiana; Gibson, Valerie; Girard, Olivier Göran; Giubega, Lavinia-Helena; Gligorov, V.V.; Göbel, Carla; Golubkov, Dmitry; Golutvin, Andrey; Gomes, Alvaro; Gotti, Claudio; Grabalosa Gándara, Marc; Graciani Diaz, Ricardo; Granado Cardoso, Luis Alberto; Graugés, Eugeni; Graverini, Elena; Graziani, Giacomo; Grecu, Alexandru; Greening, Edward; Gregson, Sam; Griffith, Peter; Grillo, Lucia; Grünberg, Oliver; Gui, Bin; Gushchin, Evgeny; Guz, Yury; Gys, Thierry; Hadavizadeh, Thomas; Hadjivasiliou, Christos; Haefeli, Guido; Haen, Christophe; Haines, Susan; Hall, Samuel; Hamilton, Brian; Han, Xiaoxue; Hansmann-Menzemer, Stephanie; Harnew, Neville; Harnew, Samuel; Harrison, Jonathan; He, Jibo; Head, Timothy; Heijne, Veerle; Hennessy, Karol; Henrard, Pierre; Henry, Louis; van Herwijnen, Eric; Heß, Miriam; Hicheur, Adlène; Hill, Donal; Hoballah, Mostafa; Hombach, Christoph; Hulsbergen, Wouter; Humair, Thibaud; Hussain, Nazim; Hutchcroft, David; Hynds, Daniel; Idzik, Marek; Ilten, Philip; Jacobsson, Richard; Jaeger, Andreas; Jalocha, Pawel; Jans, Eddy; Jawahery, Abolhassan; Jing, Fanfan; John, Malcolm; Johnson, Daniel; Jones, Christopher; Joram, Christian; Jost, Beat; Jurik, Nathan; Kandybei, Sergii; Kanso, Walaa; Karacson, Matthias; Karbach, Moritz; Karodia, Sarah; Kecke, Matthieu; Kelsey, Matthew; Kenyon, Ian; Kenzie, Matthew; Ketel, Tjeerd; Khanji, Basem; Khurewathanakul, Chitsanu; Klaver, Suzanne; Klimaszewski, Konrad; Kochebina, Olga; Kolpin, Michael; Komarov, Ilya; Koopman, Rose; Koppenburg, Patrick; Kozeiha, Mohamad; Kravchuk, Leonid; Kreplin, Katharina; Kreps, Michal; Krocker, Georg; Krokovny, Pavel; Kruse, Florian; Krzemien, Wojciech; Kucewicz, Wojciech; Kucharczyk, Marcin; Kudryavtsev, Vasily; Kuonen, Axel Kevin; Kurek, Krzysztof; Kvaratskheliya, Tengiz; Lacarrere, Daniel; Lafferty, George; Lai, Adriano; Lambert, Dean; Lanfranchi, Gaia; Langenbruch, Christoph; Langhans, Benedikt; Latham, Thomas; Lazzeroni, Cristina; Le Gac, Renaud; van Leerdam, Jeroen; Lees, Jean-Pierre; Lefèvre, Regis; Leflat, Alexander; Lefrançois, Jacques; Lemos Cid, Edgar; Leroy, Olivier; Lesiak, Tadeusz; Leverington, Blake; Li, Yiming; Likhomanenko, Tatiana; Liles, Myfanwy; Lindner, Rolf; Linn, Christian; Lionetto, Federica; Liu, Bo; Liu, Xuesong; Loh, David; Longstaff, Iain; Lopes, Jose; Lucchesi, Donatella; Lucio Martinez, Miriam; Luo, Haofei; Lupato, Anna; Luppi, Eleonora; Lupton, Oliver; Lusiani, Alberto; Machefert, Frederic; Maciuc, Florin; Maev, Oleg; Maguire, Kevin; Malde, Sneha; Malinin, Alexander; Manca, Giulia; Mancinelli, Giampiero; Manning, Peter Michael; Mapelli, Alessandro; Maratas, Jan; Marchand, Jean François; Marconi, Umberto; Marin Benito, Carla; Marino, Pietro; Marks, Jörg; Martellotti, Giuseppe; Martin, Morgan; Martinelli, Maurizio; Martinez Santos, Diego; Martinez Vidal, Fernando; Martins Tostes, Danielle; Massafferri, André; Matev, Rosen; Mathad, Abhijit; Mathe, Zoltan; Matteuzzi, Clara; Mauri, Andrea; Maurin, Brice; Mazurov, Alexander; McCann, Michael; McCarthy, James; McNab, Andrew; McNulty, Ronan; Meadows, Brian; Meier, Frank; Meissner, Marco; Melnychuk, Dmytro; Merk, Marcel; Michielin, Emanuele; Milanes, Diego Alejandro; Minard, Marie-Noelle; Mitzel, Dominik Stefan; Molina Rodriguez, Josue; Monroy, Ignacio Alberto; Monteil, Stephane; Morandin, Mauro; Morawski, Piotr; Mordà, Alessandro; Morello, Michael Joseph; Moron, Jakub; Morris, Adam Benjamin; Mountain, Raymond; Muheim, Franz; Müller, Dominik; Müller, Janine; Müller, Katharina; Müller, Vanessa; Mussini, Manuel; Muster, Bastien; Naik, Paras; Nakada, Tatsuya; Nandakumar, Raja; Nandi, Anita; Nasteva, Irina; Needham, Matthew; Neri, Nicola; Neubert, Sebastian; Neufeld, Niko; Neuner, Max; Nguyen, Anh Duc; Nguyen, Thi-Dung; Nguyen-Mau, Chung; Niess, Valentin; Niet, Ramon; Nikitin, Nikolay; Nikodem, Thomas; Ninci, Daniele; Novoselov, Alexey; O'Hanlon, Daniel Patrick; Oblakowska-Mucha, Agnieszka; Obraztsov, Vladimir; Ogilvy, Stephen; Okhrimenko, Oleksandr; Oldeman, Rudolf; Onderwater, Gerco; Osorio Rodrigues, Bruno; Otalora Goicochea, Juan Martin; Otto, Adam; Owen, Patrick; Oyanguren, Maria Aranzazu; Palano, Antimo; Palombo, Fernando; Palutan, Matteo; Panman, Jacob; Papanestis, Antonios; Pappagallo, Marco; Pappalardo, Luciano; Pappenheimer, Cheryl; Parkes, Christopher; Passaleva, Giovanni; Patel, Girish; Patel, Mitesh; Patrignani, Claudia; Pearce, Alex; Pellegrino, Antonio; Penso, Gianni; Pepe Altarelli, Monica; Perazzini, Stefano; Perret, Pascal; Pescatore, Luca; Petridis, Konstantinos; Petrolini, Alessandro; Petruzzo, Marco; Picatoste Olloqui, Eduardo; Pietrzyk, Boleslaw; Pilař, Tomas; Pinci, Davide; Pistone, Alessandro; Piucci, Alessio; Playfer, Stephen; Plo Casasus, Maximo; Poikela, Tuomas; Polci, Francesco; Poluektov, Anton; Polyakov, Ivan; Polycarpo, Erica; Popov, Alexander; Popov, Dmitry; Popovici, Bogdan; Potterat, Cédric; Price, Eugenia; Price, Joseph David; Prisciandaro, Jessica; Pritchard, Adrian; Prouve, Claire; Pugatch, Valery; Puig Navarro, Albert; Punzi, Giovanni; Qian, Wenbin; Quagliani, Renato; Rachwal, Bartolomiej; Rademacker, Jonas; Rama, Matteo; Rangel, Murilo; Raniuk, Iurii; Rauschmayr, Nathalie; Raven, Gerhard; Redi, Federico; Reichert, Stefanie; Reid, Matthew; dos Reis, Alberto; Ricciardi, Stefania; Richards, Sophie; Rihl, Mariana; Rinnert, Kurt; Rives Molina, Vincente; Robbe, Patrick; Rodrigues, Ana Barbara; Rodrigues, Eduardo; Rodriguez Lopez, Jairo Alexis; Rodriguez Perez, Pablo; Roiser, Stefan; Romanovsky, Vladimir; Romero Vidal, Antonio; Ronayne, John William; Rotondo, Marcello; Rouvinet, Julien; Ruf, Thomas; Ruiz Valls, Pablo; Saborido Silva, Juan Jose; Sagidova, Naylya; Sail, Paul; Saitta, Biagio; Salustino Guimaraes, Valdir; Sanchez Mayordomo, Carlos; Sanmartin Sedes, Brais; Santacesaria, Roberta; Santamarina Rios, Cibran; Santimaria, Marco; Santovetti, Emanuele; Sarti, Alessio; Satriano, Celestina; Satta, Alessia; Saunders, Daniel Martin; Savrina, Darya; Schiller, Manuel; Schindler, Heinrich; Schlupp, Maximilian; Schmelling, Michael; Schmelzer, Timon; Schmidt, Burkhard; Schneider, Olivier; Schopper, Andreas; Schubiger, Maxime; Schune, Marie Helene; Schwemmer, Rainer; Sciascia, Barbara; Sciubba, Adalberto; Semennikov, Alexander; Serra, Nicola; Serrano, Justine; Sestini, Lorenzo; Seyfert, Paul; Shapkin, Mikhail; Shapoval, Illya; Shcheglov, Yury; Shears, Tara; Shekhtman, Lev; Shevchenko, Vladimir; Shires, Alexander; Siddi, Benedetto Gianluca; Silva Coutinho, Rafael; Silva de Oliveira, Luiz Gustavo; Simi, Gabriele; Sirendi, Marek; Skidmore, Nicola; Skwarnicki, Tomasz; Smith, Edmund; Smith, Eluned; Smith, Iwan Thomas; Smith, Jackson; Smith, Mark; Snoek, Hella; Sokoloff, Michael; Soler, Paul; Soomro, Fatima; Souza, Daniel; Souza De Paula, Bruno; Spaan, Bernhard; Spradlin, Patrick; Sridharan, Srikanth; Stagni, Federico; Stahl, Marian; Stahl, Sascha; Stefkova, Slavorima; Steinkamp, Olaf; Stenyakin, Oleg; Stevenson, Scott; Stoica, Sabin; Stone, Sheldon; Storaci, Barbara; Stracka, Simone; Straticiuc, Mihai; Straumann, Ulrich; Sun, Liang; Sutcliffe, William; Swientek, Krzysztof; Swientek, Stefan; Syropoulos, Vasileios; Szczekowski, Marek; Szczypka, Paul; Szumlak, Tomasz; T'Jampens, Stephane; Tayduganov, Andrey; Tekampe, Tobias; Teklishyn, Maksym; Tellarini, Giulia; Teubert, Frederic; Thomas, Christopher; Thomas, Eric; van Tilburg, Jeroen; Tisserand, Vincent; Tobin, Mark; Todd, Jacob; Tolk, Siim; Tomassetti, Luca; Tonelli, Diego; Topp-Joergensen, Stig; Torr, Nicholas; Tournefier, Edwige; Tourneur, Stephane; Trabelsi, Karim; Tran, Minh Tâm; Tresch, Marco; Trisovic, Ana; Tsaregorodtsev, Andrei; Tsopelas, Panagiotis; Tuning, Niels; Ukleja, Artur; Ustyuzhanin, Andrey; Uwer, Ulrich; Vacca, Claudia; Vagnoni, Vincenzo; Valenti, Giovanni; Vallier, Alexis; Vazquez Gomez, Ricardo; Vazquez Regueiro, Pablo; Vázquez Sierra, Carlos; Vecchi, Stefania; Velthuis, Jaap; Veltri, Michele; Veneziano, Giovanni; Vesterinen, Mika; Viaud, Benoit; Vieira, Daniel; Vieites Diaz, Maria; Vilasis-Cardona, Xavier; Volkov, Vladimir; Vollhardt, Achim; Volyanskyy, Dmytro; Voong, David; Vorobyev, Alexey; Vorobyev, Vitaly; Voß, Christian; de Vries, Jacco; Waldi, Roland; Wallace, Charlotte; Wallace, Ronan; Walsh, John; Wandernoth, Sebastian; Wang, Jianchun; Ward, David; Watson, Nigel; Websdale, David; Weiden, Andreas; Whitehead, Mark; Wilkinson, Guy; Wilkinson, Michael; Williams, Mark Richard James; Williams, Matthew; Williams, Mike; Williams, Timothy; Wilson, Fergus; Wimberley, Jack; Wishahi, Julian; Wislicki, Wojciech; Witek, Mariusz; Wormser, Guy; Wotton, Stephen; Wright, Simon; Wyllie, Kenneth; Xie, Yuehong; Xu, Zhirui; Yang, Zhenwei; Yu, Jiesheng; Yuan, Xuhao; Yushchenko, Oleg; Zangoli, Maria; Zavertyaev, Mikhail; Zhang, Liming; Zhang, Yanxi; Zhelezov, Alexey; Zhokhov, Anatoly; Zhong, Liang; Zucchelli, Stefano

2016-01-27

The product of the $\\Lambda_b^0$ ($\\overline{B}^0$) differential production cross-section and the branching fraction of the decay $\\Lambda_b^0\\rightarrow J/\\psi pK^-$ ($\\overline{B}^0\\rightarrow J/\\psi\\overline{K}^*(892)^0$) is measured as a function of the beauty hadron transverse momentum, $p_{\\rm T}$, and rapidity, $y$. The kinematic region of the measurements is $p_{\\rm T}<20~{\\rm GeV}/c$ and $2.0 < y < 4.5$. The measurements use a data sample corresponding to an integrated luminosity of $3~{\\rm fb}^{-1}$ collected by the LHCb detector in $pp$ collisions at centre-of-mass energies $\\sqrt{s}=7~{\\rm TeV}$ in 2011 and $\\sqrt{s}=8~{\\rm TeV}$ in 2012. Based on previous LHCb results of the fragmentation fraction ratio, $f_{\\Lambda_B^0}/f_d$, the branching fraction of the decay $\\Lambda_b^0\\rightarrow J/\\psi pK^-$ is measured to be \\begin{equation*} \\mathcal{B}(\\Lambda_b^0\\rightarrow J/\\psi pK^-)= (3.04\\pm0.04\\pm0.06\\pm0.33^{+0.43}_{-0.27})\\times10^{-4}, \\end{equation*} where the first uncertainty is st...

Widespread Dependence of Backup NHEJ on Growth State: Ramifications for the Use of DNA-PK Inhibitors

International Nuclear Information System (INIS)

Singh, Satyendra K.; Wu Wenqi; Zhang Lihua; Klammer, Holger; Wang Minli; Iliakis, George

2011-01-01

Purpose: The backup pathway of nonhomologous end joining (B-NHEJ) enables cells to process DNA double-strand breaks (DSBs) when the DNA-PK-dependent pathway of NHEJ (D-NHEJ) is compromised. Our previous results show marked reduction in the activity of B-NHEJ when LIG4 -/- mouse embryo fibroblasts (MEFs) cease to grow and enter a plateau phase. The dependence of B-NHEJ on growth state is substantially stronger than that of D-NHEJ and points to regulatory mechanisms or processing determinants that require elucidation. Because the different D-NHEJ mutants show phenotypes distinct in their details, it is necessary to characterize the dependence of their DSB repair capacity on growth state and to explore species-specific responses. Methods and Materials: DSB repair was measured in cells of different genetic background from various species using pulsed-field gel electrophoresis, or the formation of γ-H2AX foci, at different stages of growth. Results: Using pulsed-field gel electrophoresis, we report a marked reduction of B-NHEJ during the plateau phase of growth in KU and XRCC4, mouse or Chinese hamster, mutants. Notably, this reduction is only marginal in DNA-PKcs-deficient cells. However, reduced B-NHEJ is also observed in repair proficient, plateau-phase cells after treatment with DNA-PK inhibitors. The reduction of B-NHEJ activity in the plateau phase of growth does not derive from the reduced expression of participating proteins, is detectable by γ-H2AX foci analysis, and leads to enhanced cell killing. Conclusions: These results further document the marked dependence on growth state of an essential DSB repair pathway and show the general nature of the effect. Molecular characterization of the mechanism underlying this response will help to optimize the administration of DNA repair inhibitors as adjuvants in radiation therapy.

Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).

Science.gov (United States)

Joerger, M; von Pawel, J; Kraff, S; Fischer, J R; Eberhardt, W; Gauler, T C; Mueller, L; Reinmuth, N; Reck, M; Kimmich, M; Mayer, F; Kopp, H-G; Behringer, D M; Ko, Y-D; Hilger, R A; Roessler, M; Kloft, C; Henrich, A; Moritz, B; Miller, M C; Salamone, S J; Jaehde, U

2016-10-01

Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767). © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Observation of $S=+1$ Narrow Resonances in the System $pK^0_s$ from $p+\\rm {C_3H_8}$ Collision at 10 GeV/$c$

CERN Document Server

Aslanyan, P Zh; Rikhvitskaya, G G

2004-01-01

Experimental data from a 2 m propane bubble chamber have been analyzed to search for an exotic baryon state, the $\\Theta^+$ baryon, in the $pK^0_s$ decay mode for the reaction $p+{\\rm C_3H_8}$ at 10 GeV/$c$. The $pK^0_s$ invariant mass spectrum shows resonant structures with $M_{p K_s^0}=1540\\pm 8$, $1613\\pm10$, $1821\\pm11$ MeV/$c^2$ and $\\Gamma_{p K_s^0}= 9.2\\pm1.8$, $16.1\\pm4.1$, $28.0\\pm9.4$ MeV/$c^2$. The statistical significance of these peaks has been estimated as $5.5$, $4.8$ and $5.0$ s.d., respectively. There are also small peaks in mass regions of 1487 (3.0 s.d.), 1690 (3.6 s.d.) and 1980 (3.0 s.d.) MeV/$c^2$.

Involvement of DNA-PK and ATM in radiation- and heat-induced DNA damage recognition and apoptotic cell death

International Nuclear Information System (INIS)

Tomita, Masanori

2010-01-01

Exposure to ionizing radiation and hyperthermia results in important biological consequences, e.g. cell death, chromosomal aberrations, mutations, and DNA strand breaks. There is good evidence that the nucleus, specifically cellular DNA, is the principal target for radiation-induced cell lethality. DNA double-strand breaks (DSBs) are considered to be the most serious type of DNA damage induced by ionizing radiation. On the other hand, verifiable mechanisms which can lead to heat-induced cell death are damage to the plasma membrane and/or inactivation of heat-labile proteins caused by protein denaturation and subsequent aggregation. Recently, several reports have suggested that DSBs can be induced after hyperthermia because heat-induced phosphorylated histone H2AX (γ-H2AX) foci formation can be observed in several mammalian cell lines. In mammalian cells, DSBs are repaired primarily through two distinct and complementary mechanisms: non-homologous end joining (NHEJ), and homologous recombination (HR) or homology-directed repair (HDR). DNA-dependent protein kinase (DNA-PK) and ataxia-telangiectasia mutated (ATM) are key players in the initiation of DSB repair and phosphorylate and/or activate many substrates, including themselves. These phosphorylated substrates have important roles in the functioning of cell cycle checkpoints and in cell death, as well as in DSB repair. Apoptotic cell death is a crucial cell suicide mechanism during development and in the defense of homeostasis. If DSBs are unrepaired or misrepaired, apoptosis is a very important system which can protect an organism against carcinogenesis. This paper reviews recently obtained results and current topics concerning the role of DNA-PK and ATM in heat- or radiation-induced apoptotic cell death. (author)

Pharmacokinetics of enrofloxacin HCl-2H2O (ENRO-C) in dogs and PK/PD Monte Carlo simulations against Leptospira sp.

Science.gov (United States)

Sumano, Hector; Ocampo, Luis; Tapia, Graciela; Mendoza, C de Jesus; Gutierrez, Lilia

2018-04-12

Pharmacokinetics/pharmacodynamics (PK/PD) ratios of reference enrofloxacin (Enro-R) and enrofloxacin as HCl-2H 2 O (Enro-C), as well as Monte Carlo simulations based on composite MIC 50 and MIC 90 vs. Leptospira sp., were carried out in dogs after their IM and oral administration (10 mg/kg). Plasma determination of enrofloxacin was achieved by means of high performance liquid chromatography (HPLC). Maximum plasma concentration values after oral administration were 1.47 ± 0.19 µg/mL and 5.3 ± 0.84 µg/mL for Enro-R and Enro-C, respectively, and 1.6 ± 0.12 µg/mL and 7.6 ± 0.93 µg/mL after IM administration. Area under the plasma vs. time concentrations in 24 h (AUC 0-24 ) were 8.02 µg/mL/h and 36.2 µg/mL/h for Enro-R oral and Enro-C oral , respectively, and 8.55 ± 0.85 µg/mL/h and 56.4 ± 6.21 µg/mL/h after IM administration of these drugs. Only PK/PD ratios and Monte Carlo simulations obtained with Enro-C, anticipate that its IM administration to dogs will result in therapeutic concentrations to treat leptospirosis. This is the first time enrofloxacin has been recommended to treat this disease in dogs.

The proteasome inhibitor MG-132 sensitizes PC-3 prostate cancer cells to ionizing radiation by a DNA-PK-independent mechanism

International Nuclear Information System (INIS)

Pajonk, Frank; Ophoven, Arndt van; Weissenberger, Christian; McBride, William H

2005-01-01

By modulating the expression levels of specific signal transduction molecules, the 26S proteasome plays a central role in determining cell cycle progression or arrest and cell survival or death in response to stress stimuli, including ionizing radiation. Inhibition of proteasome function by specific drugs results in cell cycle arrest, apoptosis and radiosensitization of many cancer cell lines. This study investigates whether there is also a concomitant increase in cellular radiosensitivity if proteasome inhibition occurs only transiently before radiation. Further, since proteasome inhibition has been shown to activate caspase-3, which is involved in apoptosis, and caspase-3 can cleave DNA-PKcs, which is involved in DNA-double strand repair, the hypothesis was tested that caspase-3 activation was essential for both apoptosis and radiosensitization following proteasome inhibition. Prostate carcinoma PC-3 cells were treated with the reversible proteasome inhibitor MG-132. Cell cycle distribution, apoptosis, caspase-3 activity, DNA-PKcs protein levels and DNA-PK activity were monitored. Radiosensitivity was assessed using a clonogenic assay. Inhibition of proteasome function caused cell cycle arrest and apoptosis but this did not involve early activation of caspase-3. Short-time inhibition of proteasome function also caused radiosensitization but this did not involve a decrease in DNA-PKcs protein levels or DNA-PK activity. We conclude that caspase-dependent cleavage of DNA-PKcs during apoptosis does not contribute to the radiosensitizing effects of MG-132

Eleven new heaviest isotopes of elements Z=105 to Z=117 identified among the products of 249Bk+48Ca reactions

International Nuclear Information System (INIS)

Oganessian, Yu. Ts.; Abdullin, F. Sh.; Dmitriev, S. N.; Itkis, M. G.; Lobanov, Yu. V.; Mezentsev, A. N.; Polyakov, A. N.; Sagaidak, R. N.; Shirokovsky, I. V.; Subbotin, V. G.; Sukhov, A. M.; Tsyganov, Yu. S.; Utyonkov, V. K.; Voinov, A. A.; Vostokin, G. K.; Bailey, P. D.; Benker, D. E.; Ezold, J. G.; Porter, C. E.; Riley, F. D.

2011-01-01

The heaviest isotopes of elements Z=117 to Z=105, 294 117, 293 117, 290 115, 289 115, 286 113, 285 113, 282 Rg, 281 Rg, 278 Mt, 274 Bh, and 270 Db, were identified by means of the Dubna gas-filled recoil separator among the products of the 249 Bk + 48 Ca reaction. The details of the observed six decay chains, indicating the production and decay of isotopes 293 117 and 294 117, are presented and discussed. The decay energies and resulting half-lives of these new nuclei show a strong rise of stability with increasing neutron number, validating the concept of the island of enhanced stability for superheavy nuclei [Oganessian et al., Phys. Rev. Lett. 104, 142502 (2010)].

De Novo collapsing glomerulopathy in renal allograft in association with BK virus nephropathy in a child and stabilization of renal function by elimination of viremia

Directory of Open Access Journals (Sweden)

D N Gera

2017-01-01

Full Text Available Well-recognized association between HIV 1 infection and collapsing glomerulopathy (CG raises the possibility that intrarenal infection by other viruses may also contribute to the development of this lesion in native or post-transplant kidneys. There is evidence in literature about association of these lesions with cytomegalovirus, Epstein–Barr virus, hepatitis C virus, and parvovirus B19 infections. Here, we present a case report of post-transplant BK virus nephropathy in a male child who was found to have CG in subsequent biopsy 2 months later. His renal function and proteinuria were stabilized on elimination of viremia.

DNA-PK dependent targeting of DNA-ends to a protein complex assembled on matrix attachment region DNA sequences

International Nuclear Information System (INIS)

Mauldin, S.K.; Getts, R.C.; Perez, M.L.; DiRienzo, S.; Stamato, T.D.

2003-01-01

Full text: We find that nuclear protein extracts from mammalian cells contain an activity that allows DNA ends to associate with circular pUC18 plasmid DNA. This activity requires the catalytic subunit of DNA-PK (DNA-PKcs) and Ku since it was not observed in mutants lacking Ku or DNA-PKcs but was observed when purified Ku/DNA-PKcs was added to these mutant extracts. Competition experiments between pUC18 and pUC18 plasmids containing various nuclear matrix attachment region (MAR) sequences suggest that DNA ends preferentially associate with plasmids containing MAR DNA sequences. At a 1:5 mass ratio of MAR to pUC18, approximately equal amounts of DNA end binding to the two plasmids were observed, while at a 1:1 ratio no pUC18 end-binding was observed. Calculation of relative binding activities indicates that DNA-end binding activities to MAR sequences was 7 to 21 fold higher than pUC18. Western analysis of proteins bound to pUC18 and MAR plasmids indicates that XRCC4, DNA ligase IV, scaffold attachment factor A, topoisomerase II, and poly(ADP-ribose) polymerase preferentially associate with the MAR plasmid in the absence or presence of DNA ends. In contrast, Ku and DNA-PKcs were found on the MAR plasmid only in the presence of DNA ends. After electroporation of a 32P-labeled DNA probe into human cells and cell fractionation, 87% of the total intercellular radioactivity remained in nuclei after a 0.5M NaCl extraction suggesting the probe was strongly bound in the nucleus. The above observations raise the possibility that DNA-PK targets DNA-ends to a repair and/or DNA damage signaling complex which is assembled on MAR sites in the nucleus

Rescue of DNA-PK Signaling and T-Cell Differentiation by Targeted Genome Editing in a prkdc Deficient iPSC Disease Model.

Directory of Open Access Journals (Sweden)

Shamim H Rahman

2015-05-01

Full Text Available In vitro disease modeling based on induced pluripotent stem cells (iPSCs provides a powerful system to study cellular pathophysiology, especially in combination with targeted genome editing and protocols to differentiate iPSCs into affected cell types. In this study, we established zinc-finger nuclease-mediated genome editing in primary fibroblasts and iPSCs generated from a mouse model for radiosensitive severe combined immunodeficiency (RS-SCID, a rare disorder characterized by cellular sensitivity to radiation and the absence of lymphocytes due to impaired DNA-dependent protein kinase (DNA-PK activity. Our results demonstrate that gene editing in RS-SCID fibroblasts rescued DNA-PK dependent signaling to overcome radiosensitivity. Furthermore, in vitro T-cell differentiation from iPSCs was employed to model the stage-specific T-cell maturation block induced by the disease causing mutation. Genetic correction of the RS-SCID iPSCs restored T-lymphocyte maturation, polyclonal V(DJ recombination of the T-cell receptor followed by successful beta-selection. In conclusion, we provide proof that iPSC-based in vitro T-cell differentiation is a valuable paradigm for SCID disease modeling, which can be utilized to investigate disorders of T-cell development and to validate gene therapy strategies for T-cell deficiencies. Moreover, this study emphasizes the significance of designer nucleases as a tool for generating isogenic disease models and their future role in producing autologous, genetically corrected transplants for various clinical applications.

Calcidiol and vitamin D binding protein uptake by LLC-PK1 cells

International Nuclear Information System (INIS)

Keenan, M.J.; Holmes, R.P.

1986-01-01

The process by which target cells take up vitamin D and its metabolites is not known. The authors studied the uptake of both 3 H-calcidiol and 125 I-Vitamin D Binding Protein (DBP) by LLC-PK 1 cells. Uptake was directly related to their extracellular concentrations. In the presence of 55 serum in the growth media cells previously incubated with 10 nM calcitriol for 4 hr had a greater uptake of calcidiol than those cells not incubated with calcitriol. This effect of calcitriol on calcidiol uptake was absent when cells were grown in hormone-supplemented, serum-free media, despite these cells having a cytosolic calcitriol receptor. Equal uptake of calcidiol occurred when DBP was absent and when DBP was present in a one to one molar ratio to calcidiol. With a 1:1 ratio of DBP to calcidiol and a measured K/sub D/ of 2 x 10 -8 M, the uptake of calcidiol could not be accounted for by uptake of the free ligand alone. A large excess of DBP (100:1) in relation to calcidiol suppressed uptake of calcidiol by approx. 90%. The authors have not been able to identify a saturable, specific uptake of either calcidiol or DBP despite DBP appearing to facilitate calcidiol uptake

Prediction of brain target site concentrations on the basis of CSF PK : impact of mechanisms of blood-to-brain transport and within brain distribution

OpenAIRE

Westerhout, J.

2014-01-01

In the development of drugs for the treatment of central nervous system (CNS) disorders, the prediction of human CNS drug action is a big challenge. Direct measurement of brain extracellular fluid (brainECF) concentrations is highly restricted in human. Therefore, unbound drug concentrations in human cerebrospinal fluid (CSF) are used as a surrogate for human brainECF concentrations. Due to qualitative and quantitative differences in processes that govern the pharmacokinetics (PK) of drugs in...

Endothelial cell permeability during hantavirus infection involves factor XII-dependent increased activation of the kallikrein-kinin system.

Directory of Open Access Journals (Sweden)

Shannon L Taylor

Full Text Available Hemorrhagic fever with renal syndrome (HFRS and hantavirus pulmonary syndrome (HPS are diseases caused by hantavirus infections and are characterized by vascular leakage due to alterations of the endothelial barrier. Hantavirus-infected endothelial cells (EC display no overt cytopathology; consequently, pathogenesis models have focused either on the influx of immune cells and release of cytokines or on increased degradation of the adherens junction protein, vascular endothelial (VE-cadherin, due to hantavirus-mediated hypersensitization of EC to vascular endothelial growth factor (VEGF. To examine endothelial leakage in a relevant in vitro system, we co-cultured endothelial and vascular smooth muscle cells (vSMC to generate capillary blood vessel-like structures. In contrast to results obtained in monolayers of cultured EC, we found that despite viral replication in both cell types as well as the presence of VEGF, infected in vitro vessels neither lost integrity nor displayed evidence of VE-cadherin degradation. Here, we present evidence for a novel mechanism of hantavirus-induced vascular leakage involving activation of the plasma kallikrein-kinin system (KKS. We show that incubation of factor XII (FXII, prekallikrein (PK, and high molecular weight kininogen (HK plasma proteins with hantavirus-infected EC results in increased cleavage of HK, higher enzymatic activities of FXIIa/kallikrein (KAL and increased liberation of bradykinin (BK. Measuring cell permeability in real-time using electric cell-substrate impedance sensing (ECIS, we identified dramatic increases in endothelial cell permeability after KKS activation and liberation of BK. Furthermore, the alterations in permeability could be prevented using inhibitors that directly block BK binding, the activity of FXIIa, or the activity of KAL. Lastly, FXII binding and autoactivation is increased on the surface of hantavirus-infected EC. These data are the first to demonstrate KKS activation

[Study of Image Quality Comparison Based on the MTF Method Between Different Medical Rigid Endoscopes in an In Vitro Model].

Science.gov (United States)

Wang, Yunlong; Ji, Jun; Jiang, Changsong; Huang, Zengyue

2015-04-01

This study was aimed to use the method of modulation transfer function (MTF) to compare image quality among three different Olympus medical rigid cystoscopes in an in vitro model. During the experimental processes, we firstly used three different types of cystoscopes (i. e. OLYMPUS cystourethroscopy with FOV of 12 degrees, OLYMPUS Germany A22003A and OLYMPUS A2013A) to collect raster images at different brightness with industrial camera and computer from the resolution target which is with different spatial frequency, and then we processed the collected images using MALAB software with the optical transfer function MTF to obtain the values of MTF at different brightness and different spatial frequency. We then did data mathematical statistics and compared imaging quality. The statistical data showed that all three MTF values were smaller than 1. MTF values with the spatial frequency gradually increasing would decrease approaching 0 at the same brightness. When the brightness enhanced in the same process at the same spatial frequency, MTF values showed a slowly increasing trend. The three endoscopes' MTF values were completely different. In some cases the MTF values had a large difference, and the maximum difference could reach 0.7. Conclusion can be derived from analysis of experimental data that three Olympus medical rigid cystoscopes have completely different imaging quality abilities. The No. 3 endoscope OLYMPUS A2013A has low resolution but high contrast. The No. 1 endoscope OLYMPUS cystourethroscopy with FOV of 12 degrees, on the contrary, had high resolution and lower contrast. The No. 2 endoscope OLYMPUS Germany A22003A had high contrast and high resolution, and its image quality was the best.

Optimizing an online SPE-HPLC method for analysis of (R)-[11C]1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)- 3-isoquinolinecarboxamide [(R)-[11C]PK11195] and its metabolites in humans

International Nuclear Information System (INIS)

Greuter, Henri N.J.M.; van Ophemert, Patricia L.B.; Luurtsema, Gert; van Berckel, Bart N.M.; Franssen, Eric J.F.; Windhorst, Bert D.; Lammertsma, Adriaan A.

2005-01-01

(R)-[ 11 C]PK11195 is used as a positron emission tomography tracer for activated microglia in several neurological disorders. Quantification of specific binding requires a metabolite-corrected plasma input function. In this study, a high-performance liquid chromatography (HPLC) procedure with online solid phase extraction was modified for analyzing (R)-[ 11 C]PK11195 plasma samples, yielding total sample recoveries of more than 98%. When applied to human studies, the use of two HPLC systems enabled analysis of up to seven plasma samples under regular conditions. Online radioactivity detection was compared with offline sample measurements of HPLC profiles. Offline measurements provided the most reliable results especially for late plasma samples. In 10 patients, an average decrease of parent compound from 94.6% at 2.5 min to 45.2% at 1 h after administration was observed

Hsp27, Hsp70, and metallothionein in MDCK and LLC-PK1 renal epithelial cells: effects of prolonged exposure to cadmium

International Nuclear Information System (INIS)

Bonham, Rita T.; Fine, Michael R.; Pollock, Fiona M.; Shelden, Eric A.

2003-01-01

Cadmium is a widely distributed industrial and environmental toxin. The principal target organ of chronic sublethal cadmium exposure is the kidney. In renal epithelial cells, acute high-dose cadmium exposure induces differential expression of proteins, including heat shock proteins. However, few studies have examined heat shock protein expression in cells after prolonged exposure to cadmium at sublethal concentrations. Here, we assayed total cell protein, neutral red uptake, cell death, and levels of metallothionein and heat shock proteins Hsp27 and inducible Hsp70 in cultures of MDCK and LLC-PK1 renal epithelial cells treated with cadmium for 3 days. Treatment with cadmium at concentrations equal to or greater than 10 μM (LLC-PK1) or 25 μM (MDCK) reduced measures of cell vitality and induced cell death. However, a concentration-dependent increase in Hsp27 was detected in both cell types treated with as little as 5 μM cadmium. Accumulation of Hsp70 was correlated only with cadmium treatment at concentrations also causing cell death. Metallothionein was maximally detected in cells treated with cadmium at concentrations that did not reduce cell vitality, and further increases were not detected at greater concentrations. These results reveal that heat shock proteins accumulate in renal epithelial cells during prolonged cadmium exposure, that cadmium induces differential expression of heat shock protein in epithelial cells, and that protein expression patterns in epithelial cells are specific to the cadmium concentration and degree of cellular injury. A potential role for Hsp27 in the cellular response to sublethal cadmium-induced injury is also implicated by our results

Aliphatic semisynthetic amino terminal variants of myoglobin: enrichment with carbon-13, determination and interpretation of terminal pK values and motions

International Nuclear Information System (INIS)

Busch, M.R.

1985-01-01

The synthesis of a series of myoglobins substituted in the amino terminal residue to provide variation in the aliphatic nature of the side chain and enrichment in 13 C was accomplished by semisynthetic methods. The replacements of valine, the native first residue, included 13 C enriched glycine, alanine, valine, leucine, and isoleucine. The products were extensively characterized and found to be virtually indistinguishable by most physical methods. 13 C NMR spectroscopy showed significant differences in the amino terminal pK value, ranging from 7.72 for myoglobin to 7.15 for myoglobin. Consideration of the electrostatic effects of the charge array indicated a balance of interactions at this site not significantly altered by variations in the side chain. By examination of the crystal structure, consideration of earlier work regarding the interactions of the side chain of Leu-2, and data regarding the motions of the terminal residue, it was concluded that the interaction of the side chain of the first residue with the hydrophobic cluster formed primarily by close contact of invariant residues Leu-2 and Leu-137 was the primary cause for the reduction in the terminal pK values seen for the larger aliphatics. By restricting the freedom of the residue, this interaction limits the available hydration volume, and consequently favors the unprotonated form of the amine. The concurrent observation of both functional elements in the series of α amino terminal residues brings out the interrelated consequences for the two categories of solvent interactions controlling structural and functional properties in a graded way

Modelling redshift space distortion in the post-reionization H I 21-cm power spectrum

Science.gov (United States)

Sarkar, Debanjan; Bharadwaj, Somnath

2018-05-01

The post-reionization H I 21-cm signal is an excellent candidate for precision cosmology, this however requires accurate modelling of the expected signal. Sarkar et al. have simulated the real space H I 21-cm signal and have modelled the H I power spectrum as P_{{H I}}(k)=b^2 P(k), where P(k) is the dark matter power spectrum and b(k) is a (possibly complex) scale-dependent bias for which fitting formulas have been provided. This paper extends these simulations to incorporate redshift space distortion and predicts the expected redshift space H I 21-cm power spectrum P^s_{{H I}}(k_{\\perp },k_{allel }) using two different prescriptions for the H I distributions and peculiar velocities. We model P^s_{{H I}}(k_{\\perp },k_{allel }), assuming that it is the product of P_{{H I}}(k)=b^2 P(k) with a Kaiser enhancement term and a Finger of God (FoG) damping which has σp the pair velocity dispersion as a free parameter. Considering several possibilities for the bias and the damping profile, we find that the models with a scale-dependent bias and a Lorentzian damping profile best fit the simulated P^s_{{H I}}(k_{\\perp },k_{allel }) over the entire range 1 ≤ z ≤ 6. The best-fitting value of σp falls approximately as (1 + z)-m with m = 2 and 1.2, respectively, for the two different prescriptions. The model predictions are consistent with the simulations for k models underpredict P^s_2(k) at large k, and the fit is restricted to k < 0.15 Mpc-1.

[Pharmacokinetics/pharmacodinamic (PK/PD) evaluation of a short course of oral administration of metronidazole for the management of infections caused by Bacteroides fragilis].

Science.gov (United States)

Morales-León, Felipe; von Plessing-Rossel, Carlos; Villa-Zapata, Lorenzo; Fernández-Rocca, Pola; Sanhueza-Sanhueza, Cindy; Bello-Toledo, Helia; Mella-Montecinos, Sergio

2015-04-01

Metronidazole is the antibiotic of choice for the management of infections caused by anaerobes. Its administration requires multiple daily doses causing increased medication errors. Due to its high post-antibiotic effect and rapid concentration-dependent bactericidal activity, administration of this antibiotic in an extended dosing interval would achieve PK/PD parameters effectively. To assess the probability of achieving effective PK/PD relationship with the administration of 1,000 mg every 24 hours of metronidazole for Bacteroides fragilis infections. A clinical trial was conducted in a group of volunteers who received a single oral dose of 500 or 1,000 mg of metronidazole. Determinations of values of Cmax, t max, and AUCC0-24 h. determined using the trapezoidal method, were obtained for a Markov simulation that would allow for determining the likelihood of achieving a AUC0-24 h/MIC ratio above 70 for infections caused by susceptible B. fragilis. Cmax (24,03 ± 6,89 mg/L) and t max (1,20 ± 0.80 hrs) and the value of AUC0-24 h (241.91 ± 48.14 mg * h/L) were determined. The probability of obtaining a AUC0-24 h/MIC ratio greater than 70 was greater than 99%. From a pharmacokinetic perspective, with the administration of a daily dose of 1,000 mg of metronidazole, it is possible to achieve a therapeutic goal of AUC0-24 h/MIC ratio above 70 for the treatment of anaerobic infections.

BK virus encephalopathy and sclerosing vasculopathy in a patient with hypohidrotic ectodermal dysplasia and immunodeficiency.

Science.gov (United States)

Darbinyan, Armine; Major, Eugene O; Morgello, Susan; Holland, Steven; Ryschkewitsch, Caroline; Monaco, Maria Chiara; Naidich, Thomas P; Bederson, Joshua; Malaczynska, Joanna; Ye, Fei; Gordon, Ronald; Cunningham-Rundles, Charlotte; Fowkes, Mary; Tsankova, Nadejda M

2016-07-13

Human BK polyomavirus (BKV) is reactivated under conditions of immunosuppression leading most commonly to nephropathy or cystitis; its tropism for the brain is rare and poorly understood. We present a unique case of BKV-associated encephalopathy in a man with hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID) due to IKK-gamma (NEMO) mutation, who developed progressive neurological symptoms. Brain biopsy demonstrated polyomavirus infection of gray and white matter, with predominant involvement of cortex and distinct neuronal tropism, in addition to limited demyelination and oligodendroglial inclusions. Immunohistochemistry demonstrated polyoma T-antigen in neurons and glia, but expression of VP1 capsid protein only in glia. PCR analysis on both brain biopsy tissue and cerebrospinal fluid detected high levels of BKV DNA. Sequencing studies further identified novel BKV variant and disclosed unique rearrangements in the noncoding control region of the viral DNA (BKVN NCCR). Neuropathological analysis also demonstrated an unusual form of obliterative fibrosing vasculopathy in the subcortical white matter with abnormal lysosomal accumulations, possibly related to the patient's underlying ectodermal dysplasia. Our report provides the first neuropathological description of HED-ID due to NEMO mutation, and expands the diversity of neurological presentations of BKV infection in brain, underscoring the importance of its consideration in immunodeficient patients with unexplained encephalopathy. We also document novel BKVN NCCR rearrangements that may be associated with the unique neuronal tropism in this patient.

UV protection filters by dielectric multilayer thin films on Glass BK-7 and Infrasil 301

International Nuclear Information System (INIS)

Abdel-Aziz, M.M.; Azim, Osama A.; Abdel-Wahab, L.A.; Seddik, Mohamed M.

2006-01-01

The increasing use of Ultraviolet (UV) light in medicine, industrial environments, for cosmetic use, and even in consumer products necessitates that greater attention be paid to the potential hazards of this type of electromagnetic radiation. To avoid any adverse effects of exposure to this type of radiation, four suitable protection filters were produced to block three UV bands (UVA, UVB, and UVC). The design structure of the required dielectric multilayer filters was done by optical thin film technology using the absorbing property of UV radiation for the substrates and dielectric materials. The computer analyses of the multilayer filter formulas were prepared using Macleod Software for the production processes. The deposition technique was achieved on optical substrates (Glass BK-7 and Infrasil 301) by dielectric material combinations including Titanium dioxide (Ti 2 O 3 ), Hafnium dioxide (HfO 2 ), and Lima (mixture of oxides SiO 2 /Al 2 O 3 ); deposition being achieved using an electron beam gun. The output results of the theoretical and experimental transmittance values for spectral band from 200 nm to 800 nm were discussed in four processes. To analyze the suitability for use in 'real world' applications, the test pieces were subjected to the durability tests (adhesion, abrasion resistance, and humidity) according to Military Standard MIL-C-675C and MIL-C-48497A

UV protection filters by dielectric multilayer thin films on Glass BK-7 and Infrasil 301

Science.gov (United States)

Abdel-Aziz, M. M.; Azim, Osama A.; Abdel-Wahab, L. A.; Seddik, Mohamed M.

2006-10-01

The increasing use of Ultraviolet (UV) light in medicine, industrial environments, for cosmetic use, and even in consumer products necessitates that greater attention be paid to the potential hazards of this type of electromagnetic radiation. To avoid any adverse effects of exposure to this type of radiation, four suitable protection filters were produced to block three UV bands (UVA, UVB, and UVC). The design structure of the required dielectric multilayer filters was done by optical thin film technology using the absorbing property of UV radiation for the substrates and dielectric materials. The computer analyses of the multilayer filter formulas were prepared using Macleod Software for the production processes. The deposition technique was achieved on optical substrates (Glass BK-7 and Infrasil 301) by dielectric material combinations including Titanium dioxide (Ti 2O 3), Hafnium dioxide (HfO 2), and Lima (mixture of oxides SiO 2/Al 2O 3); deposition being achieved using an electron beam gun. The output results of the theoretical and experimental transmittance values for spectral band from 200 nm to 800 nm were discussed in four processes. To analyze the suitability for use in 'real world' applications, the test pieces were subjected to the durability tests (adhesion, abrasion resistance, and humidity) according to Military Standard MIL-C-675C and MIL-C-48497A.

Perpendicular diffusion of a dilute beam of charged particles in the PK-4 dusty plasma

Science.gov (United States)

Liu, Bin; Goree, John

2015-09-01

We study the random walk of a dilute beam of projectile dust particles that drift through a target dusty plasma. This random walk is a diffusion that occurs mainly due to Coulomb collisions with target particles that have a different size. In the direction parallel to the drift, projectiles exhibit mobility-limited motion with a constant average velocity. We use a 3D molecular dynamics (MD) simulation of the dust particle motion to determine the diffusion and mobility coefficients for the dilute beam. The dust particles are assumed to interact with a shielded Coulomb repulsion. They also experience gas drag. The beam particles are driven by a prescribed net force that is not applied to the target particles; in the experiments this net force is due to an imbalance of the electric and ion drag forces. This simulation is motivated by microgravity experiments, with the expectation that the scattering of projectiles studied here will be observed in upcoming PK-4 experiments on the International Space Station. Supported by NASA and DOE.

Nitrofuranyl Methyl Piperazines as New Anti-TB Agents: Identification, Validation, Medicinal Chemistry, and PK Studies

Science.gov (United States)

2015-01-01

Whole-cell screening of 20,000 drug-like small molecules led to the identification of nitrofuranyl methylpiperazines as potent anti-TB agents. In the present study, validation followed by medicinal chemistry has been used to explore the structure–activity relationship. Ten compounds demonstrated potent MIC in the range of 0.17–0.0072 μM against H37Rv Mycobacterium tuberculosis (MTB) and were further investigated against nonreplicating and resistant (RifR and MDR) strains of MTB. These compounds were also tested for cytotoxicity. Among the 10 tested compounds, five showed submicromolar to nanomolar potency against nonreplicating and resistant (RifR and MDR) strains of MTB along with a good safety index. Based on their overall in vitro profiles, the solubility and pharmacokinetic properties of five potent compounds were studied, and two analogues, 14f and 16g, were found to have comparatively better solubility than others tested and acceptable pharmacokinetic properties. This study presents the rediscovery of a nitrofuranyl class of compounds with improved aqueous solubility and acceptable oral PK properties, opening a new direction for further development. PMID:26487909

Proyecto del paso superior sobre la carretera M-503 y accesos. Enlace con Villanueva del Pardillo en el P.K. 3+290 (Madrid)

OpenAIRE

Alonso Placín, Alba

2009-01-01

El presente Proyecto tiene por objeto definir y valorar las obras necesarias para la construcción del paso superior sobre la carretera M-503 en el PK 3+290, entre el tramo comprendido entre la M-50 y la M-600, así como los accesos correspondientes desde las glorietas colindantes. La carretera sobre la que discurre el paso superior objeto de proyecto tiene previsto un desdoblamiento para soportar más capacidad, con lo cual se harán referencias en ciertos casos, a esta nueva c...

Prevalence of Polyoma BK Virus (BKPyV), Epstein-Barr Virus (EBV) and Human Papilloma Virus (HPV) in Oropharyngeal Cancer.

Science.gov (United States)

Polz-Gruszka, Dorota; Morshed, Kamal; Jarzyński, Adrian; Polz-Dacewicz, Małgorzata

2015-01-01

The aim of this study was to analyze the prevalence of BK virus, Human Papillomavirus and Epstein-Barr virus in oropharyngeal cancer, and to test our hypothesis that BKV/HPV/EBV co-infection plays a role in oropharyngeal squamous cell carcinoma. The correlation between viral infection, OSCC, anatomic location, pre-treatment staging, evidence of metastases to lymph nodes, and grading was also investigated. The examination samples were collected from 62 patients from paraffin tissue blocks. Males (90.3%) with, smoking (83.9%) and alcohol abuse (67.7%) problems prevailed in the studied group. G2 histological type was recognized in 80.6% cases. T4 (77.4%) and N2 (56.5%) traits occurred in the majority of patients. No cases of metastasis were observed (M0 100%). HPV - 24.2%, EBV - 27.4% and BKV 17.7% were detected in the studied samples. We observed co-infection EBV/BKV in 8% of cases, HPV/BKV in 4.8%, and HPV/EBV in 9% cases. Only in two cases co-infection of all three viruses was found.

Comparative Evaluation of the Translocator Protein Radioligands 11C-DPA-713, 18F-DPA- 714, and 11C-PK11195 in a Rat Model of Acute Neuro-inflammation

International Nuclear Information System (INIS)

Chauveau, F.; Van Camp, N.; Dolle, F.; Kuhnast, B.; Hinnen, F.; Damont, A.; Boutin, H.; Tavitian, B.; Chauveau, F.; Van Camp, N.; Boutin, H; Tavitian, B.; Chauveau, F.; Boutin, H.; James, M.; Kassiou, M.; Kassiou, M.

2009-01-01

Overexpression of the translocator protein, TSPO (18 kDa), formerly known as the peripheral benzodiazepine receptor, is a hallmark of activation of cells of monocytic lineage (micro-glia and macrophages) during neuro-inflammation. Radiolabeling of TSPO ligands enables the detection of neuro-inflammatory lesions by PET. Two new radioligands, 11 C-labeled N, N-diethyl-2-[2-(4- methoxy-phenyl)-5, 7-dimethylpyrazolo[1, 5-a]pyrimidin-3-yl] acetamide (DPA-713) and 18 F-labeled N, N-diethyl-2-(2-(4-(2- fluoroethoxy)phenyl)-5, 7-dimethylpyrazolo[1, 5-a]pyrimidin-3-yl) acetamide (DPA-714), both belonging to the pyrazolopyrimidine class, were compared in vivo and in vitro using a rodent model of neuro-inflammation. Methods: 11 C-DPA-713 and 18 F-DPA-714, as well as the classic radioligand 11 C-labeled (R)-N-methyl- N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide (PK11195), were used in the same rat model, in which intra-striatal injection of (R, S)-a-amino-3-hydroxy-5-methyl-4-isoxazolopropionique gave rise to a strong neuro-inflammatory response. Comparative endpoints included in vitro autoradiography and in vivo imaging on a dedicated small-animal PET scanner under identical conditions. Results: 11 C-DPA-713 and 18 F-DPA-714 could specifically localize the neuro-inflammatory site with a similar signal-to-noise ratio in vitro. In vivo, 18 F-DPA-714 performed better than 11 C-DPA-713 and 11 C-PK11195, with the highest ratio of ipsilateral to contralateral uptake and the highest binding potential. Conclusion: 18 F-DPA-714 appears to be an attractive alternative to 11 C-PK11195 because of its increased bioavailability in brain tissue and its reduced nonspecific binding. Moreover, its labeling with 18 F, the preferred PET isotope for radiopharmaceutical chemistry, favors its dissemination and wide clinical use. 18 F-DPA-714 will be further evaluated in longitudinal studies of neuro-inflammatory conditions such as are encountered in stroke or neuro

Population pharmacokinetic (PK) analysis of laromustine, an emerging alkylating agent, in cancer patients.

Science.gov (United States)

Nassar, Ala F; Wisnewski, Adam V; King, Ivan

2017-05-01

1. Alkylating agents are capable of introducing an alkyl group into nucleophilic sites on DNA or RNA through covalent bond. Laromustine is an active member of a relatively new class of sulfonylhydrazine prodrugs under development as antineoplastic alkylating agents, and displays significant single-agent activity. 2. This is the first report of the population pharmacokinetic analysis of laromustine, 106 patients, 66 with hematologic malignancies and 40 with solid tumors, participated in five clinical trials worldwide. Of these, 104 patients were included in the final NONMEM analysis. 3. The population estimates for total clearance (CL) and volume of distribution of the central compartment (V 1 ) were 96.3 L/h and 45.9 L, associated with high inter-patient variability of 52.9% and 79.8% and inter-occasion variability of 26.7% and 49.3%, respectively. The population estimates for Q and V 2 were 73.2 L/h and 29.9 L, and inter-patient variability in V 2 was 63.1%, respectively. 4. The estimate of V ss (75.8 L) exceeds total body water, indicating that laromustine is distributed to tissues. The half-life is short, less than 1 h, reflecting rapid clearance. Population PK analysis showed laromustine pharmacokinetics to be independent of dose and organ function with no effect on subsequent dosing cycles.

Analysis of real-time mixture cytotoxicity data following repeated exposure using BK/TD models.

Science.gov (United States)

Teng, S; Tebby, C; Barcellini-Couget, S; De Sousa, G; Brochot, C; Rahmani, R; Pery, A R R

2016-08-15

Cosmetic products generally consist of multiple ingredients. Thus, cosmetic risk assessment has to deal with mixture toxicity on a long-term scale which means it has to be assessed in the context of repeated exposure. Given that animal testing has been banned for cosmetics risk assessment, in vitro assays allowing long-term repeated exposure and adapted for in vitro - in vivo extrapolation need to be developed. However, most in vitro tests only assess short-term effects and consider static endpoints which hinder extrapolation to realistic human exposure scenarios where concentration in target organs is varies over time. Thanks to impedance metrics, real-time cell viability monitoring for repeated exposure has become possible. We recently constructed biokinetic/toxicodynamic models (BK/TD) to analyze such data (Teng et al., 2015) for three hepatotoxic cosmetic ingredients: coumarin, isoeugenol and benzophenone-2. In the present study, we aim to apply these models to analyze the dynamics of mixture impedance data using the concepts of concentration addition and independent action. Metabolic interactions between the mixture components were investigated, characterized and implemented in the models, as they impacted the actual cellular exposure. Indeed, cellular metabolism following mixture exposure induced a quick disappearance of the compounds from the exposure system. We showed that isoeugenol substantially decreased the metabolism of benzophenone-2, reducing the disappearance of this compound and enhancing its in vitro toxicity. Apart from this metabolic interaction, no mixtures showed any interaction, and all binary mixtures were successfully modeled by at least one model based on exposure to the individual compounds. Copyright © 2016 Elsevier Inc. All rights reserved.

Analytical characterization of three cathinone derivatives, 4-MPD, 4F-PHP and bk-EPDP, purchased as bulk powder from online vendors.

Science.gov (United States)

Apirakkan, Orapan; Frinculescu, Anca; Shine, Trevor; Parkin, Mark C; Cilibrizzi, Agostino; Frascione, Nunzianda; Abbate, Vincenzo

2018-02-01

Novel emerging drugs of abuse, also referred as new psychoactive substances, constitute an ever-changing mixture of chemical compounds designed to circumvent legislative controls by means of chemical modifications of previously banned recreational drugs. One such class, synthetic cathinones, namely β-keto derivatives of amphetamines, has been largely abused over the past decade. A number of new synthetic cathinones are detected each year, either in bulk powders/crystals or in biological matrices. It is therefore important to continuously monitor the supply of new synthetic derivatives and promptly report them. By using complementary analytical techniques (i.e. one- and two-dimensional NMR, FT-IR, GC-MS, HRMS and HPLC-UV), this study investigates the detection, identification and full characterization of 1-(4-methylphenyl)-2-(methylamino)pentanone (4-methylpentedrone, 4-MPD), 1-(4-fluorophenyl)-2-(pyrrolidin-1-yl)hexanone (4F-PHP) and 1-(1,3-benzodioxol-5-yl)-2-(ethylamino)-1-pentanone (bk-EPDP), three emerging cathinone derivatives. Copyright © 2017 John Wiley & Sons, Ltd.

Study of the production of A0 b and B0 hadrons in pp collisions and first measurement of the ∧ o b !J= pK.. branching fraction

NARCIS (Netherlands)

Aaij, R.; Adeva, B.; Adinolfi, M.; Affolder, A.; Ajaltouni, Z.; Akar, S.; Albrecht, J.; Alessio, F.; Alexander, M.; Ali, S.; Alkhazov, G.; Alvarez Cartelle, P.; Alves, A. A.; Amato, S.; Amerio, S.; Amhis, Y.; Everse, LA; Anderlini, L.; Anderson, J.; Andreassi, G.; Andreotti, M.; Andrews, J.E.; Appleby, R. B.; Aquines Gutierrez, O.; Archilli, F.; d'Argent, P.; Artamonov, A.; Artuso, M.; Aslanides, E.; Auriemma, G.; Baalouch, M.; Bachmann, S.; Back, J. J.; Badalov, A.; Baesso, C.; Baldini, W.; Barlow, R. J.; Barschel, C.; Barsuk, S.; Barter, W.; Batozskaya, V.; Battista, V.; Bay, A.; Beaucourt, L.; Beddow, J.; Bedeschi, F.; Bediaga, I.; Bel, L. J.; Bellee, V.; Belloli, N.; Belyaev, I.; Ben-Haim, E.; Bencivenni, G.; Benson, S.; Benton, J.; Berezhnoy, A.; Bernet, R.; Bertolin, A.; Bettler, M-O.; Van Beuzekom, Martin; Bien, A.; Bifani, S.; Billoir, P.; Bird, T.D.; Birnkraut, A.; Bizzeti, A.; Blake, T.; Blanc, F.; Blouw, J.; Blusk, S.; Bocci, V.; Bondar, A.; Bondar, N.; Bonivento, W.; Borghi, S.; Borsato, M.; Bowcock, T. J. V.; Bowen, E.; Bozzi, C.; Braun, S.; Britsch, M.; Britton, T.; Brodzicka, J.; Brook, N. H.; Buchanan, E.; Bursche, A.; Buytaert, J.; Cadeddu, S.; Calabrese, R.; Calvi, M.; Calvo Gomez, M.; Campana, P.; Campora Perez, D.; Capriotti, L.; Carbone, A.; Carboni, G.; Cardinale, R.; Cardini, A.; Carniti, P.; Carson, L.; Carvalho Akiba, K.; Casse, G.; Cassina, L.; Castillo Garcia, L.; Cattaneo, M.; Cauet, Ch; Cavallero, G.; Cenci, R.; Charles, M.; Charpentier, Ph; Chefdeville, M.; Chen, S.; Cheung, S-F.; Chiapolini, N.; Chrzaszcz, M.; Cid Vidal, X.; Ciezarek, G.; Clarke, P. E. L.; Clemencic, M.; Cliff, H. V.; Closier, J.; Coco, V.; Cogan, J.; Cogneras, E.; Cogoni, V.; Cojocariu, L.; Collazuol, G.; Collins, P.; Comerma-Montells, A.; Contu, A.; Cook, A.; Coombes, M.; Coquereau, S.; Corti, G.; Corvo, M.; Couturier, B.; Cowan, G. A.; Craik, D. C.; Crocombe, A.; Cruz Torres, M.; Cunliffe, S.; Currie, C.R.; D'Ambrosio, C.; Dall'Occo, E.; Dalseno, J.; David, P. N.Y.; Davis, A.; De Bruyn, K.; De Capua, S.; De Cian, M.; de Miranda, J. M.; Paula, L.E.; De Simone, P.; Dean, C-T.; Decamp, D.; Deckenhoff, M.; Del Buono, L.; Déleáge, N.; Demmer, M.; Derkach, D.; Deschamps, O.; Dettori, F.; Dey, B.; Di Canto, A.; Di Ruscio, F.; Dijkstra, H.; Donleavy, S.; Dordei, F.; Dorigo, M.; Dosil Suárez, A.; Dossett, D.; Dovbnya, A.; Dreimanis, K.; Dufour, L.; Dujany, G.; Dupertuis, F.; Durante, P.; Dzhelyadin, R.; Dziurda, A.; Dzyuba, A.; Easo, S.; Egede, U.; Egorychev, V.; Eidelman, S.; Eisenhardt, S.; Eitschberger, U.; Ekelhof, R.; Eklund, L.; El Rifai, I.; Elsasser, Ch.; Ely, S.; Esen, S.; Evans, H. M.; Evans, T. M.; Falabella, A.; Färber, C.; Farley, N.; Farry, S.; Fay, R.; Ferguson, D.; Fernandez Albor, V.; Ferrari, F.; Ferreira Rodrigues, F.; Ferro-Luzzi, M.; Filippov, S.; Fiore, M.; Fiorini, M.; Firlej, M.; Fitzpatrick, C.; Fiutowski, T.; Fohl, K.; Fol, P.; Fontana, Mark; Fontanelli, F.; Forty, R.; De Aguiar Francisco, O.; Frank, M.; Frei, C.; Frosini, M.; Fu, J.; Furfaro, E.; Gallas Torreira, A.; Galli, D.; Gallorini, S.; Gambetta, S.; Gandelman, M.; Gandini, P.; Gao, Y.; Garciá Pardinãs, J.; Garra Tico, J.; Garrido, L.; Gascon, D.; Carvalho-Gaspar, M.; Gauld, Rhorry; Gavardi, L.; Gazzoni, G.; Gerick, D.; Gersabeck, E.; Gersabeck, M.; Gershon, T. J.; Ghez, Ph; Gianì, S.; Gibson, V.; Girard, O. G.; Giubega, L.; Gligorov, V. V.; Göbel, C.; Golubkov, D.; Golutvin, A.; Gomes, A.Q.; Gotti, C.; Grabalosa Gándara, M.; Graciani Diaz, R.; Granado Cardoso, L. A.; Graugés, E.; Graverini, E.; Graziani, G.; Grecu, A.; Greening, E.; Gregson, S.; Griffith, P.; Grillo, L.; Grünberg, O.; Gui, B.; Gushchin, E.; Guz, Yu; Gys, T.; Hadavizadeh, T.; Hadjivasiliou, C.; Haefeli, G.; Haen, C.; Haines, S. C.; Hall, S.; Hamilton, B.; Han, X.; Hansmann-Menzemer, S.; Harnew, N.; Harnew, S. T.; Harrison, J.; He, J.; Head, T.; Heijne, V.; Hennessy, K.; Henrard, P.; Henry, L.; van Herwijnen, E.; Heß, M.; Hicheur, A.; Hill, D.; Hoballah, M.; Hombach, C.; Hulsbergen, W.; Humair, T.; Hussain, N.; Hutchcroft, D. E.; Hynds, D.; Idzik, M.; Ilten, P.; Jacobsson, R.; Jaeger, A.; Jalocha, J.; Jans, E.; Jawahery, A.; Jing, F.; John, M.; Johnson, D.; Jones, C. R.; Joram, C.; Jost, B.; Jurik, N.; Kandybei, S.; Kanso, W.; Karacson, M.; Karbach, T. M.; Karodia, S.; Kecke, M.; Kelsey, M. H.; Kenyon, I. R.; Kenzie, M.; Ketel, T.; Khanji, B.; Khurewathanakul, C.; Klaver, S.M.; Klimaszewski, K.; Kochebina, O.; Kolpin, M.; Komarov, I.; Koopman, R. F.; Koppenburg, P.; Kozeiha, M.; Kravchuk, L.; Kreplin, K.; Kreps, M.; Krocker, G.; Krokovny, P.; Kruse, F.; Krzemien, W.; Kucewicz, W.; Kucharczyk, M.; Kudryavtsev, V.; Kuonen, A. K.; Kurek, K.; Kvaratskheliya, T.; Lacarrere, D.; Lafferty, G. D.; Lai, A.; Lambert, D.M.; Lanfranchi, G.; Langenbruch, C.; Langhans, B.; Latham, T. E.; Lazzeroni, C.; Le Gac, R.; Van Leerdam, J.; Lees, J. P.; Lefèvre, R.; Leflat, A.; Lefrançois, J.; Lemos Cid, E.; Leroy, O.; Lesiak, T.; Leverington, B.; Li, Y.; Likhomanenko, T.; Liles, M.; Lindner, R.; Linn, S.C.; Lionetto, F.; Liu, B.; Liu, X.; Loh, D.; Longstaff, I.; Lopes, J. H.; Lucchesi, D.; Lucio Martinez, M.; Luo, H.; Lupato, A.; Luppi, E.; Lupton, O.; Lusiani, A.; Machefert, F.; Maciuc, F.; Maev, O.; Maguire, K.; Malde, S.; Malinin, A.; Manca, G.; Mancinelli, G.; Manning, P.; Mapelli, A.; Maratas, J.; Marchand, J. F.; Marconi, U.; Marin Benito, C.; Marino, P.; Marks, J.; Martellotti, G.; Martin, M.; Martinelli-Boneschi, F.; Martinez-Santos, D.; Martinez-Vidal, F.; Martins Tostes, D.; Massafferri, A.; Matev, R.; Mathad, A.; Mathe, Z.; Matteuzzi, C.; Mauri, A.; Maurin, B.; Mazurov, A.; McCann, M.; McCarthy, J.; Mcnab, A.; McNulty, R.; Meadows, B. T.; Meier, F.; Meissner, M.; Melnychuk, D.; Merk, M.; Michielin, E.; Milanes, D. A.; Minard, M. N.; Mitzel, D. S.; Molina Rodriguez, J.; Monroy, I. A.; Monteil, S.; Morandin, M.; Morawski, P.; Mordà, A.; Morello, M. J.; Moron, J.; Morris, A. B.; Mountain, R.; Muheim, F.; Müller, D.; Müller, J.; Müller, Karl; von Müller, L.; Mussini, M.; Muster, B.; Naik, P.; Nakada, T.; Nandakumar, R.; Nandi, A.; Nasteva, I.; Needham, M.; Neri, N.; Neubert, S.; Neufeld, N.; Neuner, M.; Nguyen, A. D.; Nguyen, T. D.; Nguyen-Mau, C.; Niess, V.; Niet, R.; Nikitin, N.; Nikodem, T.; Ninci, D.; Novoselov, A.; O'Hanlon, D. P.; Oblakowska-Mucha, A.; Obraztsov, V.; Ogilvy, S.; Okhrimenko, O.; Oldeman, R.; Onderwater, C. J.G.; Osorio Rodrigues, B.; Otalora Goicochea, J. M.; Otto, E.A.; Owen, R.P.; Oyanguren, A.; Palano, A.; Palombo, F.; Palutan, M.; Panman, J.; Papanestis, A.; Pappagallo, M.; Pappalardo, L.L.; Pappenheimer, C.; Parkes, C.; Passaleva, G.; Patel, G. D.; Patel, M.; Patrignani, C.; Pearce, D.A.; Pellegrino, A.; Penso, G.; Pepe Altarelli, M.; Perazzini, S.; Perret, P.; Pescatore, L.; Petridis, K.; Petrolini, A.; Petruzzo, M.; Picatoste Olloqui, E.; Pietrzyk, B.; Pilar, T.; Pinci, D.; Pistone, A.; Piucci, A.; Playfer, S.; Plo Casasus, M.; Poikela, T.; Polci, F.; Poluektov, A.; Polyakov, I.; Polycarpo, E.; Popov, A.; Popov, D.; Popovici, B.; Potterat, C.; Price, M. E.; Price, J.D.; Prisciandaro, J.; Pritchard, C.A.; Prouve, C.; Pugatch, V.; Puig Navarro, A.; Punzi, G.; Qian, Y.W.; Quagliani, R.; Rachwal, B.; Rademacker, J. H.; Rama, M.; Rangel, M. S.; Raniuk, I.; Rauschmayr, N.; Raven, G.; Redi, F.; Reichert, S.; Reid, M.; dos Reis, A. C.; Ricciardi, S.; Richards, Jennifer S; Rihl, M.; Rinnert, K.; Rives Molina, V.; Robbe, P.; Rodrigues, A. B.; Rodrigues, L.E.T.; Rodriguez Lopez, J. A.; Rodriguez Perez, P.; Roiser, S.; Romanovsky, V.; Romero Vidal, A.; Ronayne, J. W.; Rotondo, M.; Rouvinet, J.; Ruf, T.; Ruiz Valls, P.; Saborido Silva, J. J.; Sagidova, N.; Sail, P.; Saitta, B.; Salustino Guimaraes, V.; Sanchez Mayordomo, C.; Sanmartin Sedes, B.; Santacesaria, R.; Santamarina Rios, C.; Santimaria, M.; Santovetti, E.; Sarti, A.; Satriano, C.; Satta, A.; Saunders, D. M.; Savrina, D.; Schiller, M.; Schindler, R. H.; Schlupp, M.; Schmelling, M.; Schmelzer, T.; Schmidt, B.; Schneider, O.; Schopper, A.; Schubiger, M.; Schune, M. H.; Schwemmer, R.; Sciascia, B.; Sciubba, A.; Semennikov, A.; Serra, N.; Serrano, J.; Sestini, L.; Seyfert, P.; Shapkin, M.; Shapoval, I.; Shcheglov, Y.; Shears, T.; Shekhtman, L.; Shevchenko, V.; Shires, A.; Siddi, B. G.; Silva Coutinho, R.; Silva de Oliveira, L.; Simi, G.; Sirendi, M.; Skidmore, N.; Skwarnicki, T.; Smith, E.; Smith, E.; Smith, I. T.; Smith, J; Smith, M.; Snoek, H.; Sokoloff, M. D.; Soler, F. J. P.; Soomro, F.; de Souza, D.K.; Souza De Paula, B.; Spaan, B.; Spradlin, P.; Sridharan, S.; Stagni, F.; Stahl, M.; Stahl, S.; Stefkova, S.; Steinkamp, O.; Stenyakin, O.; Stevenson-Moore, P.; Stoica, S.; Stone, S.; Storaci, B.; Stracka, S.; Straticiuc, M.; Straumann, U.; Sun, L.; Sutcliffe, W.; Swientek, K.; Swientek, S.; Syropoulos, V.; Szczekowski, M.; Szczypka, P.; Szumlak, T.; T'Jampens, S.; Tayduganov, A.; Tekampe, T.; Teklishyn, M.; Tellarini, G.; Teubert, F.; Thomas, C.; Thomas, E.; Van Tilburg, J.; Tisserand, V.; Tobin, M. N.; Todd, Jim; Tolk, S.; Tomassetti, L.; Tonelli, D.; Topp-Joergensen, S.; Torr, N.; Tournefier, E.; Tourneur, S.; Trabelsi, K.; Tran, N.T.M.T.; Tresch, M.; Trisovic, A.; Tsaregorodtsev, A.; Tsopelas, P.; Tuning, N.; Ukleja, A.; Ustyuzhanin, A.; Uwer, U.; Vacca, C.; Vagnoni, V.; Valenti, G.; Vallier, A.; Vazquez Gomez, R.; Vazquez Regueiro, P.; Vázquez Sierra, C.; Vecchi, S.; Velthuis, M.J.; Veltri, M.; Veneziano, G.; Vesterinen, M.; Viaud, B.; Vieira, D.; Vieites Diaz, M.; Vilasis-Cardona, X.; Volkov, V.; Vollhardt, A.; Volyanskyy, D.; Voong, D.; Vorobyev, A.; Vorobyev, V.; Voß, C.; De Vries, J. A.; Waldi, R.; Wallace, C.; Wallace, R.; Walsh, John; Wandernoth, S.; Wang, J.; Ward, D. R.; Watson, N. K.; Websdale, D.; Weiden, A.; Whitehead, M.; Wilkinson, G.; Wilkinson, M.; Williams, M.; Williams, M.P.; Williams, M.; Williams, T.; Wilson, James F; Wimberley, J.; Wishahi, J.; Wislicki, W.; Witek, M.; Wormser, G.; Wotton, S. A.; Wright, S.J.; Wyllie, K.; Xie, Y.; Xu, Z.; Yang, Z.; Yu, J.; Yuan, X.; Yushchenko, O.; Zangoli, M.; Zavertyaev, M.; Zhang, L.; Zhang, Y.; Zhelezov, A.; Zhokhov, A.; Zhong, L.; Zucchelli, S.

2016-01-01

The product of the Λ0 b (B0) differential production cross-section and the branching fraction of the decay Λ0 bJ= pK.. (B0!J= K Λ (892)0) is measured as a function of the beauty hadron transverse momentum, pT, and rapidity, y. The kinematic region of the measurements is pT >20 GeV=c and 2:0>y>4:5.

Farklı Yetiştirme Ortamlarının Pleurotus eryngii Mantarının Gelişimi ve Verimi Üzerine Etkileri

Directory of Open Access Journals (Sweden)

Beyhan Kibar

2016-05-01

Full Text Available Bu çalışma farklı yetiştirme ortamlarının Pleurotus eryngii mantarının misel gelişim süresi, ilk hasat süresi, verim ve biyolojik etkinliği üzerine etkilerini belirlemek amacıyla yapılmıştır. Çalışmada buğday sapı (BS, mısır sapı (MS, kavak talaşı (KT ve çaşır bitki artığı (ÇBA ortamları tek başlarına ve bu ortamlara %20 oranında buğday kepeği (BK ve çeltik kepeği (ÇK ilave edilerek hazırlanan toplam 12 farklı yetiştirme ortamı kullanılmıştır. Buğday sapından (%100 buğday sapı hazırlanan yetiştirme ortamı kontrol olarak ele alınmıştır. Yetiştirme ortamların özelliklerinin belirlenmesi amacıyla sterilizasyon sonrasında değişik yetiştirme ortamlarından alınan örneklerde pH, nem, kül, C, N ve C:N oranı tespit edilmiştir. Farklı yetiştirme ortamlarında misel gelişim süresi, ilk hasat süresi, verim ve biyolojik etkinlik oranı belirlenmiştir. Misel gelişim süresi (gün, ilk hasat süresi (gün, verim (g/100 g ortam ve biyolojik etkinlik (% bakımından yetiştirme ortamları arasındaki farklılık istatistiki olarak çok önemli (P<0.01 bulunmuştur. Çalışmanın sonucunda en kısa misel gelişim süresi ve ilk hasat süresi MS ortamında belirlenirken, en uzun misel gelişim süresi ve ilk hasat süresi BS+PK ortamında gözlenmiştir. En yüksek verim ve biyolojik etkinlik MS ortamından (sırasıyla 24.4 g/100 g ortam ve %81.33 elde edilmiştir. Onu istatistiksel olarak MS ortamı ile aralarında fark bulunmayan ÇBA, MS+PK, BS+BK ve ÇBA+PK ortamları izlemiştir. Buna karşılık, en düşük verim ve biyolojik etkinlik değerleri ise sırasıyla BS+PK, KT ve BS ortamlarında bulunmuştur. Doğu Anadolu Bölgesi’nde bol bulunan ve kolayca temin edilebilen çaşır bitki artıklarının tek başına ya da buğday veya çeltik kepeği ile karıştırılarak P. eryngii yetiştiriciliğinde kullanılabileceği sonucuna varılmıştır.

KANDUNGAN ASAM AMINO, TAURIN, MINERAL MAKRO-MIKRO, DAN VITAMIN B12 UBUR-UBUR (Aurelia aurita SEGAR DAN KERING

Directory of Open Access Journals (Sweden)

- - Nurjanah

2014-06-01

Full Text Available Tujuan penelitian adalah menentukan komposisi gizi, asam amino, taurin, mineral makro dan mikro,dan vitamin B12 pada ubur-ubur (Aurelia aurita segar dan kering. Asam amino esensial pada ubur-uburyaitu arginina, leusina, valina, treonina, lisina, isoleusina, fenilalanina, metionina, dan histidina, sedangkanasam amino non esensial yaitu asam glutamat, glisina, asam aspartat, serina, alanina, dan tirosina. Asamamino esensial tertinggi segar dan kering adalah arginina sebesar 1,72% (bk dan 1,44% (bk dan terendahhistidina yaitu sebesar 0,19% (bk dan 0,13% (bk. Asam amino non esensial segar dan kering tertinggiadalah asam glutamat dan glisina yaitu sebesar 3,26% (bk dan 2,62% (bk dan terkecil tirosina sebesar0,38% (bk dan 0,41% (bk. Taurin segar sebesar 2,68% (bk dan kering sebesar 0,67% (bk. Mineral makrotertinggi segar dan kering adalah natrium yaitu 180.092,1 ppm (bk dan 111.209,4 ppm (bk, terkecil adalahkalsium yaitu 5.750,2 ppm (bk dan 11,1 ppm (bk. Mineral mikro tertinggi segar dan kering adalah iodium yaitu8.291,5 ppm (bk dan 1.800 ppm (bk dan yang terkecil adalah tembaga yaitu 1,1 ppm (bk dan 0,6 ppm (bk.Vitamin B12 segar adalah 396,6 μm/100 g (bk dan kering 63,5 μm/100 g (bk.Kata kunci: asam amino, mineral, taurin, ubur-ubur (Aurelia aurita, vitamin B12

[PK/PD breakpoints and clinical/bacteriological effects of cefcapene pivoxil fine granules for children at free drug concentrations in pediatric patients with respiratory infection].

Science.gov (United States)

Toyonaga, Yoshikiyo; Iwai, Naoichi; Motohiro, Takashi; Sunakawa, Keisuke; Fujii, Ryochi

2008-06-01

A post-marketing clinical study was previously conducted in pediatric patients with respiratory infection to evaluate the pharmacokinetics, efficacy and safety of cefcapene pivoxil (CFPN-PI) fine granules for children. Based on the results from this study, we evaluated PK/PD breakpoints and clinical/bacteriological effects of CFPN-PI at free drug concentrations in pediatric patients with respiratory infection to determine an effective and safe dosage regimen of CFPN-PI. The following results were obtained from 61 pediatric patients evaluated in our research. 1) The response rate of pediatric respiratory infection to CFPN-PI was 100% for laryngopharyngitis, 84.6% for acute bronchitis, 100% for tonsillitis, 100% for pneumonia and 95.8% for all. 2) The bacteriological response (eradication rate of Haemophilus influenzae, Streptococcus pyogenes, Moraxella catarrhalis, Streptococcus pneumoniae, etc.) of pediatric respiratory infection to CFPN-PI was 87.5% for laryngopharyngitis, 66.7% for acute bronchitis, 75.0% for tonsillitis, 63.6% for pneumonia and 73.8% for all. 3) The blood concentration simulation demonstrated that the PK/PD breakpoint exceeding the time above MIC (TAM) of 40% after administration of CFPN-PI 3 mg/kg three times daily was 0.27 microg/mL. 4) The pediatric patients with respiratory infection were stratified by the TAM (%) of CFPN-PI into 40% to 100% (TAM > or = 40% group) and 0% to 40% (TAM or = 40% group, and 88.9% and 62.5% in the TAM or = 40% group than in the TAM < 40% group, although the between-group difference was not statistically significant.

Omega 3 (peripheral type benzodiazepine binding) site distribution in the rat immune system: an autoradiographic study with the photoaffinity ligand [3H]PK 14105

International Nuclear Information System (INIS)

Benavides, J.; Dubois, A.; Dennis, T.; Hamel, E.; Scatton, B.

1989-01-01

The anatomical distribution of omega 3 (peripheral type benzodiazepine binding) sites in the immune system organs of the rat has been studied autoradiographically at both macroscopic and microscopic levels of resolution using either reversible or irreversible (UV irradiation) labeling with [ 3 H]PK 14105. In thymus sections, [ 3 H]PK 14105 labeled with high affinity (Kd, derived from saturation experiments = 10.8 nM) a single population of sites which possessed the pharmacological characteristics of omega 3 sites. In the thymus gland, higher omega 3 site densities were detected in the cortex than in the medulla; in these subregions, silver grains were associated to small (10-18 microns diameter) cells. In the spleen, omega 3 sites were more abundant in the white than in the red pulp. In the white pulp, silver grains were denser in the marginal zone than in the vicinity of the central artery and labeling was, as in the thymus, associated to small cytoplasm-poor cells. In the red pulp, omega 3 site associated silver grains were observed mainly in the Bilroth cords. In the lymph nodes, the medullary region showed a higher labeling than the surrounding follicles and paracortex. A significant accumulation of silver grains was observed in the lymph node medullary cords. In the intestine, Peyer patches were particularly enriched in omega 3 sites (especially in the periphery of the follicles). The distribution of omega 3 sites in the immune system organs suggests a preferential labeling of cells of T and monocytic lineages. This is consistent with the proposed immunoregulatory properties of some omega 3 site ligands

Medium pressure boiler water chemistry optimization using neutralizing amines mixture reagent AMINAT™ PK-2 at CEPP “Borovichi Refractories Plant” of JSC “BKO”

Science.gov (United States)

Guseva, O. V.; Butakova, M. V.; Orlov, K. A.; Vinogradov, S. V.; Pavlenko, L. S.

2017-11-01

An overview of the neutralizing amine based reagent AMINAT PK-2 usage for water chemistry of steam boilers for medium pressure boiler was given. Long term experiment showed that new reagent allows to decrease corrosion rate comparing with old water chemistry based on ammonia only. Two dosage schemes in different cycle places discussed. Scheme with two points on injection showed better results. Results of corrosion rates experiments and photos of tubes inner surfaces are presented. Based on fuel savings due to reducing scale formation the total annual economy for last year was 5.1 million Russian roubles.

48Ca+249Bk fusion reaction leading to element Z = 117: long-lived α-decaying 270Db and discovery of 266Lr.

Science.gov (United States)

Khuyagbaatar, J; Yakushev, A; Düllmann, Ch E; Ackermann, D; Andersson, L-L; Asai, M; Block, M; Boll, R A; Brand, H; Cox, D M; Dasgupta, M; Derkx, X; Di Nitto, A; Eberhardt, K; Even, J; Evers, M; Fahlander, C; Forsberg, U; Gates, J M; Gharibyan, N; Golubev, P; Gregorich, K E; Hamilton, J H; Hartmann, W; Herzberg, R-D; Heßberger, F P; Hinde, D J; Hoffmann, J; Hollinger, R; Hübner, A; Jäger, E; Kindler, B; Kratz, J V; Krier, J; Kurz, N; Laatiaoui, M; Lahiri, S; Lang, R; Lommel, B; Maiti, M; Miernik, K; Minami, S; Mistry, A; Mokry, C; Nitsche, H; Omtvedt, J P; Pang, G K; Papadakis, P; Renisch, D; Roberto, J; Rudolph, D; Runke, J; Rykaczewski, K P; Sarmiento, L G; Schädel, M; Schausten, B; Semchenkov, A; Shaughnessy, D A; Steinegger, P; Steiner, J; Tereshatov, E E; Thörle-Pospiech, P; Tinschert, K; Torres De Heidenreich, T; Trautmann, N; Türler, A; Uusitalo, J; Ward, D E; Wegrzecki, M; Wiehl, N; Van Cleve, S M; Yakusheva, V

2014-05-02

The superheavy element with atomic number Z=117 was produced as an evaporation residue in the (48)Ca+(249)Bk fusion reaction at the gas-filled recoil separator TASCA at GSI Darmstadt, Germany. The radioactive decay of evaporation residues and their α-decay products was studied using a detection setup that allowed measuring decays of single atomic nuclei with half-lives between sub-μs and a few days. Two decay chains comprising seven α decays and a spontaneous fission each were identified and are assigned to the isotope (294)117 and its decay products. A hitherto unknown α-decay branch in (270)Db (Z = 105) was observed, which populated the new isotope (266)Lr (Z = 103). The identification of the long-lived (T(1/2) = 1.0(-0.4)(+1.9) h) α-emitter (270)Db marks an important step towards the observation of even more long-lived nuclei of superheavy elements located on an "island of stability."

Identification and analysis of differential miRNAs in PK-15 cells after foot-and-mouth disease virus infection.

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Ke-Shan Zhang

Full Text Available The alterations of MicroRNAs(miRNAs in host cell after foot-and-mouth disease virus (FMDV infection is still obscure. To increase our understanding of the pathogenesis of FMDV at the post-transcriptional regulation level, Solexa high-throu MicroRNAs (miRNAs play an important role both in the post-transcriptional regulation of gene expression and host-virus interactions. Despite investigations of miRNA expression ghput sequencing and bioinformatic tools were used to identify differentially expressed miRNAs and analyze their functions during FMDV infection of PK-15 cells. Results indicated that 9,165,674 and 9,230,378 clean reads were obtained, with 172 known and 72 novel miRNAs differently expressed in infected and uninfected groups respectively. Some of differently expressed miRNAs were validated using stem-loop real-time quantitative RT-PCR. The GO annotation and KEGG pathway analysis for target genes revealed that differently expressed miRNAs were involved in immune response and cell death pathways.

Comparison of autologous 111In-leukocytes, 18F-FDG, 11C-methionine, 11C-PK11195 and 68Ga-citrate for diagnostic nuclear imaging in a juvenile porcine haematogenous Staphylococcus aureus osteomyelitis model

DEFF Research Database (Denmark)

Nielsen, Ole L.; Afzelius, Pia; Bender, Dirk

characterized as abscesses/cellulitis, arthritis in three joints and five enlarged lymph nodes. None of the tracers accumulated in joints with arthritis. By comparing the 10 infectious lesions, 18F-FDG accumulated in nine, 111In-leukocytes in eight, 11C-methionine in six, 68Ga-citrate in four and 11C-PK11195...

Phylogenetic reconstruction and polymorphism analysis of BK virus VP2 gene isolated from renal transplant recipients in China.

Science.gov (United States)

Wang, Zhang-Yang; Hong, Wei-Long; Zhu, Zhe-Hui; Chen, Yun-Hao; Ye, Wen-LE; Chu, Guang-Yu; Li, Jia-Lin; Chen, Bi-Cheng; Xia, Peng

2015-11-01

BK polyomavirus (BKV) is important pathogen for kidney transplant recipients, as it is frequently re-activated, leading to nephropathy. The aim of this study was to investigate the phylogenetic reconstruction and polymorphism of the VP2 gene in BKV isolated from Chinese kidney transplant recipients. Phylogenetic analysis was carried out in the VP2 region from 135 BKV-positive samples and 28 reference strains retrieved from GenBank. The unweighted pair-group method with arithmetic mean (UPGMA) grouped all strains into subtypes, but failed to subdivide strains into subgroups. Among the plasma and urine samples, all plasma (23/23) and 82 urine samples (82/95) were identified to contain subtype I; the other 10 urine samples contained subtype IV. A 86-bp fragment was identified as a highly conserved sequence. Following alignment with 36 published BKV sequences from China, 92 sites of polymorphism were identified, including 11 single nucleotide polymorphisms (SNPs) prevalent in Chinese individuals and 30 SNPs that were specific to the two predominant subtypes I and IV. The limitations of the VP2 gene segment in subgrouping were confirmed by phylogenetic analysis. The conserved sequence and polymorphism identified in this study may be helpful in the detection and genotyping of BKV.

Surface deformation and friction characteristic of nano scratch at ductile-removal regime for optical glass BK7.

Science.gov (United States)

Li, Chen; Zhang, Feihu; Ding, Ye; Liu, Lifei

2016-08-20

Nano scratch for optical glass BK7 based on the ductile-removal regime was carried out, and the influence rule of scratch parameters on surface deformation and friction characteristic was analyzed. Experimental results showed that, with increase of normal force, the deformation of burrs in the edge of the scratch was more obvious, and with increase of the scratch velocity, the deformation of micro-fracture and burrs in the edge of the scratch was more obvious similarly. The residual depth of the scratch was measured by atomic force microscope. The experimental results also showed that, with increase of normal force, the residual depth of the scratch increased linearly while the elastic recovery rate decreased. Furthermore, with increase of scratch velocity, the residual depth of the scratch decreased while the elastic recovery rate increased. The scratch process of the Berkovich indenter was divided into the cutting process of many large negative rake faces based on the improved cutting model, and the friction characteristic of the Berkovich indenter and the workpiece was analyzed. The analysis showed that the coefficient of friction increased and then tended to be stable with the increase of normal force. Meanwhile, the coefficient of friction decreased with the increase of scratch velocity, and the coefficients, k ln(v) and μ0, were introduced to improve the original formula of friction coefficient.

De novo inv(17)(p11.2q21.3) in an intellectually disabled girl ...

Indian Academy of Sciences (India)

2012-08-09

Aug 9, 2012 ... LUIS E. FIGUERA1 and HORACIO RIVERA1,2∗. 1División de ... an uneven number of meiotic crossovers within the inversion results in a recom- ... cence Olympus AX70 microscope (Olympus Optical, Tokyo,. Japan) fitted with ...

Mafic inclusions in Yosemite granites and Lassen Pk lavas: records of complex crust-mantle interactions

Energy Technology Data Exchange (ETDEWEB)

Reid, J.B. Jr.; Flinn, J.E.

1985-01-01

This study compares three small-scale magmatic systems dominated by mafic/felsic interaction that appear to be analogs to the evolution of their larger host systems: mafic inclusions from modern Lassen Pk lavas along with inclusions and related synplutonic dike materials from granitoids in the Tuolumne Intrusive Series. Each system represents quickly chilled mafic melt previously contaminated by digestion of rewarmed, super-solidus felsic hosts. Contaminants occur in part as megacrysts of reworked oligoclase with lesser hb and biot. Within each group MgO-variation diagrams for Fe, Ca, Ti, Si are strikingly linear (r>.96); alkalis are decidedly less regular, and many hybrid rocks show a curious, pronounced Na enrichment. Field data, petrography, and best fit modeling suggests this may result from flow concentration of oligoclase xenocrysts within contaminated synplutonic dikes, and is preserved in the inclusions when dike cores chill as pillows in their felsic host. Dissolution of mafic inclusions erases these anomalies and creates a more regular series of two-component mafic-felsic mixtures in the large host system. The inclusions and dikes thus appear to record a variety of late-stage mafic-felsic interactive processes that earlier and on a larger scale created much of the compositional variety of their intermediate host rocks.

Erythropoietin suppresses epithelial to mesenchymal transition and intercepts Smad signal transduction through a MEK-dependent mechanism in pig kidney (LLC-PK1) cell lines

International Nuclear Information System (INIS)

Chen, Chien-Liang; Chou, Kang-Ju; Lee, Po-Tsang; Chen, Ying-Shou; Chang, Tsu-Yuan; Hsu, Chih-Yang; Huang, Wei-Chieh; Chung, Hsiao-Min; Fang, Hua-Chang

2010-01-01

Purpose: Tumor growth factor-β1 (TGF-β1) plays a pivotal role in processes like kidney epithelial-mesenchymal transition (EMT) and interstitial fibrosis, which correlate well with progression of renal disease. Little is known about underlying mechanisms that regulate EMT. Based on the anatomical relationship between erythropoietin (EPO)-producing interstitial fibroblasts and adjacent tubular cells, we investigated the role of EPO in TGF-β1-mediated EMT and fibrosis in kidney injury. Methods: We examined apoptosis and EMT in TGF-β1-treated LLC-PK1 cells in the presence or absence of EPO. We examined the effect of EPO on TGF-β1-mediated Smad signaling. Apoptosis and cell proliferation were assessed with flow cytometry and hemocytometry. We used Western blotting and indirect immunofluorescence to evaluate expression levels of TGF-β1 signal pathway proteins and EMT markers. Results: We demonstrated that ZVAD-FMK (a caspase inhibitor) inhibited TGF-β1-induced apoptosis but did not inhibit EMT. In contrast, EPO reversed TGF-β1-mediated apoptosis and also partially inhibited TGF-β1-mediated EMT. We showed that EPO treatment suppressed TGF-β1-mediated signaling by inhibiting the phosphorylation and nuclear translocation of Smad 3. Inhibition of mitogen-activated protein kinase kinase 1 (MEK 1) either directly with PD98059 or with MEK 1 siRNA resulted in inhibition of EPO-mediated suppression of EMT and Smad signal transduction in TGF-β1-treated cells. Conclusions: EPO inhibited apoptosis and EMT in TGF-β1-treated LLC-PK1 cells. This effect of EPO was partially mediated by a mitogen-activated protein kinase-dependent inhibition of Smad signal transduction.

Utility of a Novel Three-Dimensional and Dynamic (3DD Cell Culture System for PK/PD Studies: Evaluation of a Triple Combination Therapy at Overcoming Anti-HER2 Treatment Resistance in Breast Cancer

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Anusha Ande

2018-05-01

Full Text Available Background: Emergence of Human epidermal growth factor receptor 2 (HER2 therapy resistance in HER2-positive (HER2+ breast cancer (BC poses a major clinical challenge. Mechanisms of resistance include the over-activation of the PI3K/mTOR and Src pathways. This work aims to investigate a novel combination therapy that employs paclitaxel (PAC, a mitotic inhibitor, with everolimus (EVE, an mTOR inhibitor, and dasatinib (DAS, an Src kinase inhibitor, as a modality to overcome resistance.Methods: Static (two dimensional, 2D and three-dimensional dynamic (3DD cell culture studies were conducted using JIMT-1 cells, a HER2+ BC cell line refractory to HER2 therapies. Cell viability and caspase-3 expression were examined after JIMT-1 cell exposure to agents as monotherapy or in combination using a 2D setting. A pharmacokinetic/pharmacodynamic (PK/PD combination study with PAC+DAS+EVE was conducted over 3 weeks in a 3DD setting. PAC was administered into the system via a 3 h infusion followed by the addition of a continuous infusion of EVE+DAS 24 h post-PAC dosing. Cell counts and caspase-3 expression were quantified every 2 days. A semi-mechanistic PK/PD model was developed using the 2D data and scaled up to capture the 3DD data. The final model integrated active caspase-3 as a biomarker to bridge between drug exposures and cancer cell dynamics. Model fittings were performed using Monolix software.Results: The triple combination significantly induced caspase-3 activity in the 2D cell culture setting. In the 3DD cell culture setting, sequential dosing of PAC then EVE+DAS showed a 5-fold increase in caspase-3 activity and 8.5-fold decrease in the total cell number compared to the control. The semi-mechanistic PK/PD models fit the data well, capturing the time-course profiles of drug concentrations, caspase-3 expression, and cell counts in the 2D and 3DD settings.Conclusion: A novel, sequential triple combination therapeutic regimen was successfully evaluated

$\\pi \\pi $ phase-shifts in the reaction $\\pi p\\rightarrow p \\pi ^{+} \\pi ^{+} \\pi ^{-} $ at 8 GeV/c and $K \\pi $ Chew-Low anlysis in the reaction $\\K ^{-}p \\rightarrow pK ^{-} \\pi ^{+} \\pi ^{-}$ at 10 GeV

CERN Document Server

CERN. Geneva

1971-01-01

$\\pi \\pi $ phase-shifts in the reaction $\\pi p\\rightarrow p \\pi ^{+} \\pi ^{+} \\pi ^{-} $ at 8 GeV/c and $K \\pi $ Chew-Low anlysis in the reaction $\\K ^{-}p \\rightarrow pK ^{-} \\pi ^{+} \\pi ^{-}$ at 10 GeV

Analysis of real-time mixture cytotoxicity data following repeated exposure using BK/TD models

International Nuclear Information System (INIS)

Teng, S.; Tebby, C.; Barcellini-Couget, S.; De Sousa, G.; Brochot, C.; Rahmani, R.; Pery, A.R.R.

2016-01-01

Cosmetic products generally consist of multiple ingredients. Thus, cosmetic risk assessment has to deal with mixture toxicity on a long-term scale which means it has to be assessed in the context of repeated exposure. Given that animal testing has been banned for cosmetics risk assessment, in vitro assays allowing long-term repeated exposure and adapted for in vitro – in vivo extrapolation need to be developed. However, most in vitro tests only assess short-term effects and consider static endpoints which hinder extrapolation to realistic human exposure scenarios where concentration in target organs is varies over time. Thanks to impedance metrics, real-time cell viability monitoring for repeated exposure has become possible. We recently constructed biokinetic/toxicodynamic models (BK/TD) to analyze such data (Teng et al., 2015) for three hepatotoxic cosmetic ingredients: coumarin, isoeugenol and benzophenone-2. In the present study, we aim to apply these models to analyze the dynamics of mixture impedance data using the concepts of concentration addition and independent action. Metabolic interactions between the mixture components were investigated, characterized and implemented in the models, as they impacted the actual cellular exposure. Indeed, cellular metabolism following mixture exposure induced a quick disappearance of the compounds from the exposure system. We showed that isoeugenol substantially decreased the metabolism of benzophenone-2, reducing the disappearance of this compound and enhancing its in vitro toxicity. Apart from this metabolic interaction, no mixtures showed any interaction, and all binary mixtures were successfully modeled by at least one model based on exposure to the individual compounds. - Highlights: • We could predict cell response over repeated exposure to mixtures of cosmetics. • Compounds acted independently on the cells. • Metabolic interactions impacted exposure concentrations to the compounds.

Analysis of real-time mixture cytotoxicity data following repeated exposure using BK/TD models

Energy Technology Data Exchange (ETDEWEB)

Teng, S.; Tebby, C. [Models for Toxicology and Ecotoxicology Unit, INERIS, Parc Technologique Alata, BP 2, 60550 Verneuil-en-Halatte (France); Barcellini-Couget, S. [ODESIA Neosciences, Sophia Antipolis, 400 route des chappes, 06903 Sophia Antipolis (France); De Sousa, G. [INRA, ToxAlim, 400 route des Chappes, BP, 167 06903 Sophia Antipolis, Cedex (France); Brochot, C. [Models for Toxicology and Ecotoxicology Unit, INERIS, Parc Technologique Alata, BP 2, 60550 Verneuil-en-Halatte (France); Rahmani, R. [INRA, ToxAlim, 400 route des Chappes, BP, 167 06903 Sophia Antipolis, Cedex (France); Pery, A.R.R., E-mail: alexandre.pery@agroparistech.fr [AgroParisTech, UMR 1402 INRA-AgroParisTech Ecosys, 78850 Thiverval Grignon (France); INRA, UMR 1402 INRA-AgroParisTech Ecosys, 78850 Thiverval Grignon (France)

2016-08-15

Cosmetic products generally consist of multiple ingredients. Thus, cosmetic risk assessment has to deal with mixture toxicity on a long-term scale which means it has to be assessed in the context of repeated exposure. Given that animal testing has been banned for cosmetics risk assessment, in vitro assays allowing long-term repeated exposure and adapted for in vitro – in vivo extrapolation need to be developed. However, most in vitro tests only assess short-term effects and consider static endpoints which hinder extrapolation to realistic human exposure scenarios where concentration in target organs is varies over time. Thanks to impedance metrics, real-time cell viability monitoring for repeated exposure has become possible. We recently constructed biokinetic/toxicodynamic models (BK/TD) to analyze such data (Teng et al., 2015) for three hepatotoxic cosmetic ingredients: coumarin, isoeugenol and benzophenone-2. In the present study, we aim to apply these models to analyze the dynamics of mixture impedance data using the concepts of concentration addition and independent action. Metabolic interactions between the mixture components were investigated, characterized and implemented in the models, as they impacted the actual cellular exposure. Indeed, cellular metabolism following mixture exposure induced a quick disappearance of the compounds from the exposure system. We showed that isoeugenol substantially decreased the metabolism of benzophenone-2, reducing the disappearance of this compound and enhancing its in vitro toxicity. Apart from this metabolic interaction, no mixtures showed any interaction, and all binary mixtures were successfully modeled by at least one model based on exposure to the individual compounds. - Highlights: • We could predict cell response over repeated exposure to mixtures of cosmetics. • Compounds acted independently on the cells. • Metabolic interactions impacted exposure concentrations to the compounds.

Performance comparison of two Olympus InnovX handheld x-ray analyzers for feasibility of measuring arsenic in skin in vivo – Alpha and Delta models

International Nuclear Information System (INIS)

Desouza, E.D.; Gherase, M.R.; Fleming, D.E.B.; Chettle, D.R.; O’Meara, J.M.; McNeill, F.E.

2017-01-01

The Figure-Of-Merit (FOM) performance, a combination of detection limit and dose, is compared between two generations of handheld X-Ray Fluorescence (XRF) spectrometers for the feasibility of in vivo XRF measurement of arsenic (As) in skin. The Olympus InnovX Delta model analyzer (40 kVp using either 37 or 17 μA) was found to show improvements in Minimum Detection Limit (MDL) using arsenic As-doped skin calibration phantoms with bulk tissue backing, when compared to the first generation InnovX Alpha model (40 kVp, 20 μA) in 120 s measurements. Differences between two different definitions of MDL are discussed. On the Delta system, an MDL of (0.462±0.002) μg/g As was found in phantoms, with a nylon backing behind to mimic bulk tissue behind skin. The equivalent and effective doses were found to be (10±2) mSv and ~7×10 −3 μSv respectively for the Alpha and (15±4) mSv and ~8×10 −3 μSv respectively for the Delta system in 120 s exposures. Combining MDL and effective dose, a lower (better) FOM was found for the Delta, (1.7±0.4) ppm mSv 1/2 , compared to (4.4±0.5) ppm mSv 1/2 for the Alpha model system. The Delta analyzer demonstrates improved overall system performance for a rapid 2-min measurement in As skin phantoms, such that it can be considered for use in populations exposed to arsenic. - Highlights: • Second generation portable XRF system reports lower Arsenic detection limit. • When excluded from calibration, <1 ppm error in predicted 5, 20 ppm As concentration. • Effective dose of both generations of systems in stand mode is within ICRP limit.

Transcellular transport of radioiodinated 3-iodo-α-methyl-L-tyrosine across monolayers of kidney epithelial cell line LLC-PK1

International Nuclear Information System (INIS)

Shikano, Naoto; Nakajima, Syuichi; Kubota, Nobuo; Ishikawa, Nobuyoshi; Kawai, Keiichi; Kubodera, Akiko; Saji, Hideo

2004-01-01

3-[ 123 I]iodo-α-methyl-L-tyrosine ([ 123 I]IMT) is an imaging agent for amino acid transport. In order to obtain fundamental data related to tumor imaging with [ 123 I]IMT and renal physiological accumulation of [ 123 I]IMT, we investigated the transport characteristics of [ 125 I]IMT in porcine kidney epithelial cell line LLC-PK 1 using cell monolayers grown on microporous membrane filters. LLC-PK 1 monolayers were created on a collagen-coated microporous (3 μm) membrane (4.7 cm 2 ). To examine transcellular transport (secretion and reabsorption) and accumulation, the monolayers were incubated for up to 90 min at 37 deg C with 18.5 kBq [ 125 I]IMT in Dulbecco's phosphate-buffered saline (pH 7.4) as an uptake solution. After incubation, transcellular transport was assessed by quantifying the radioactivity of the solutions on each side of the monolayer. For the accumulation experiment, the cells were solubilized in NaOH solution, and the radioactivity was quantified. For the inhibition experiment, the inhibitor was added at a final concentration of 1 mM. For the pH dependence experiment, the pH of the apical-side uptake solution was varied from pH 5 to pH 8. Transport of [ 14 C]Tyr was examined for comparison. Bi-directional transcellular transport of [ 125 I]IMT was observed, corresponding to secretion and reabsorption in proximal tubule. Accumulation of [ 125 I]IMT from the basolateral side (1.62±0.15%) and the apical side (2.62±0.35%) was observed at 90 min. 2-Amino-bicyclo[2,2,1]heptane-2-carboxylic acid (a specific inhibitor of system L), L -Tyr (mother compound of [ 125 I]IMT) and 2-aminoisobutyric acid (an inhibitor of system L and A) inhibited both directional transport (p 125 I]IMT from both sides (p 125 I]IMT transport is system L, rather than Na + -dependent transport, in both apical and basolateral membrane. [ 125 I]IMT was transported by the system that transported L-Tyr, but the observed pH dependence of transport suggests that different

Angiotensin I-converting enzyme inhibitors potentiate bradykinin's inotropic effects independently of blocking its inactivation.

Science.gov (United States)

Minshall, R D; Erdös, E G; Vogel, S M

1997-08-04

The positive inotropic effects of bradykinin (BK) and 2 analogs resistant to angiotensin I-converting enzyme (ACE) were potentiated on isolated guinea pig atrial preparations by enalaprilat. The stable BK analogs, dextran-BK and [Hyp3-Tyr(Me)8]-BK, were as active as BK. Pretreatment for 5 min with enalaprilat augmented the maximal positive inotropic effect of [Hyp3-Tyr(Me)8]-BK 2.8-fold, from 19% to 53% and that of BK from 28% to 42% over baseline; inotropic responses to dextran-BK (1 microM) were similarly increased. The activity of atrial ACE, a zinc-requiring enzyme, was completely inhibited by 8-hydroxyquinoline-5-sulfonic acid (QSA, 10 mM), which raised the maximal inotropic effect of BK to 39% above baseline. This value rose to 67% when in addition to QSA, 1 microM enalaprilat was added; enalaprilat thus, potentiated the effects of BK independently of enzyme inhibition. The positive inotropic effects to BK and its analogs decline with time in the presence of these agonists. After 10 min of exposure, the response to 1 microM [Hyp3-Tyr(Me)8]-BK decreased to about half, and after 20 min, to 0. Enalaprilat, when present in the tissue bath, prevented the decline in inotropy; even after tachyphylaxis occurred, it reversed this decrease in activity when added. The effects of 1 microM [Hyp3-Tyr(Me)8]-BK, in the absence or presence of enalaprilat, were abolished by the BK B2 receptor antagonist icatibant (0.75 microM). The results indicate that ACE inhibitors, by potentiating the BK effects and blocking BK B2-receptor desensitization, may contribute to the beneficial cardiac effects of BK independently of blocking its inactivation.

Biodistribution of the radionuclides 18F-FDG, 11C-methionine, 11C-PK11195, and 68Ga-citrate in domestic juvenile female pigs and morphological and molecular imaging of the tracers in hematogenously disseminated Staphylococcus aureus lesions

DEFF Research Database (Denmark)

Afzelius, Pia; Nielsen, Ole Lerberg; Alstrup, Aage K. O.

2016-01-01

with experimental bacterial infection. Four juvenile 14-15 weeks old female domestic pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of S. aureus using a sequential scanning protocol with 18F-FDG, 11C-methionine, 11C-PK11195 and 68Ga...

Regulation of intracellular pH in LLC-PK1 cells by Na+/H+ exchange.

Science.gov (United States)

Montrose, M H; Murer, H

1986-01-01

Suspensions of LLC-PK1 cells (a continuous epitheliod cell line with renal characteristics) are examined for mechanisms of intracellular pH regulation using the fluorescent probe BCECF. Initial experiments determine suitable calibration procedures for use of the BCECF fluorescent signal. They also determine that the cell suspension contains cells which (after 4 hr in suspension) have Na+ and K+ gradients comparable to those of cells in monolayer culture. The steady-state intracellular pH (7.05 +/- 0.01, n = 5) of cells which have recovered in (pH 7.4) Na+-containing medium is not affected over several minutes by addition of 100 microM amiloride or removal of extracellular Na+ (Na+o less than 1 mM). In contrast, when the cells recover from an acid load (caused by NH4 preincubation and removal), the recovery is largely Na+ dependent and is sensitive to 100 microM amiloride. These results suggest that with resting pH near neutrality, both Na+o/H+i and Na+i/H+o exchange reactions are functionally inactive (compared to cellular buffering capacity). In contrast, Na+o/H+i exchange is activated by an increased cellular acid load. This activation may be observed directly either as a stimulation of net H+ efflux or net Na+ influx with decreasing intracellular pH. The extrapolation of this latter data suggests a "set point" of Na+/H+ exchange of approximately pH 7.0, consistent with the observed resting intracellular pH of approximately 7.05.

Up-Regulatory Effects of Curcumin on Large Conductance Ca2+-Activated K+ Channels

Science.gov (United States)

Hei, Hongya; Li, Fangping; Wang, Yunman; Peng, Wen; Zhang, Xuemei

2015-01-01

Large conductance Ca2+-activated potassium channels (BK) are targets for research that explores therapeutic means to various diseases, owing to the roles of the channels in mediating multiple physiological processes in various cells and tissues. We investigated the pharmacological effects of curcumin, a compound isolated from the herb Curcuma longa, on BK channels. As recorded by whole-cell patch-clamp, curcumin increased BK (α) and BK (α+β1) currents in transfected HEK293 cells as well as the current density of BK in A7r5 smooth muscle cells in a dose-dependent manner. By incubating with curcumin for 24 hours, the current density of exogenous BK (α) in HEK293 cells and the endogenous BK in A7r5 cells were both enhanced notably, though the steady-state activation of the channels did not shift significantly, except for BK (α+β1). Curcumin up-regulated the BK protein expression without changing its mRNA level in A7r5 cells. The surface expression and the half-life of BK channels were also increased by curcumin in HEK293 cells. These effects of curcumin were abolished by MG-132, a proteasome inhibitor. Curcumin also increased ERK 1/2 phosphorylation, while inhibiting ERK by U0126 attenuated the curcumin-induced up-regulation of BK protein expression. We also observed that the curcumin-induced relaxation in the isolated rat aortic rings was significantly attenuated by paxilline, a BK channel specific blocker. These results show that curcumin enhances the activity of the BK channels by interacting with BK directly as well as enhancing BK protein expression through inhibiting proteasomal degradation and activating ERK signaling pathway. The findings suggest that curcumin is a potential BK channel activator and provide novel insight into its complicated pharmacological effects and the underlying mechanisms. PMID:26672753

Up-Regulatory Effects of Curcumin on Large Conductance Ca2+-Activated K+ Channels.

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Qijing Chen

Full Text Available Large conductance Ca2+-activated potassium channels (BK are targets for research that explores therapeutic means to various diseases, owing to the roles of the channels in mediating multiple physiological processes in various cells and tissues. We investigated the pharmacological effects of curcumin, a compound isolated from the herb Curcuma longa, on BK channels. As recorded by whole-cell patch-clamp, curcumin increased BK (α and BK (α+β1 currents in transfected HEK293 cells as well as the current density of BK in A7r5 smooth muscle cells in a dose-dependent manner. By incubating with curcumin for 24 hours, the current density of exogenous BK (α in HEK293 cells and the endogenous BK in A7r5 cells were both enhanced notably, though the steady-state activation of the channels did not shift significantly, except for BK (α+β1. Curcumin up-regulated the BK protein expression without changing its mRNA level in A7r5 cells. The surface expression and the half-life of BK channels were also increased by curcumin in HEK293 cells. These effects of curcumin were abolished by MG-132, a proteasome inhibitor. Curcumin also increased ERK 1/2 phosphorylation, while inhibiting ERK by U0126 attenuated the curcumin-induced up-regulation of BK protein expression. We also observed that the curcumin-induced relaxation in the isolated rat aortic rings was significantly attenuated by paxilline, a BK channel specific blocker. These results show that curcumin enhances the activity of the BK channels by interacting with BK directly as well as enhancing BK protein expression through inhibiting proteasomal degradation and activating ERK signaling pathway. The findings suggest that curcumin is a potential BK channel activator and provide novel insight into its complicated pharmacological effects and the underlying mechanisms.

Large-conductance Ca2+-activated K+ channel β1-subunit knockout mice are not hypertensive

Science.gov (United States)

Garver, Hannah; Galligan, James J.; Fink, Gregory D.

2011-01-01

Large-conductance Ca2+-activated K+ (BK) channels are composed of pore-forming α-subunits and accessory β1-subunits that modulate Ca2+ sensitivity. BK channels regulate arterial myogenic tone and renal Na+ clearance/K+ reabsorption. Previous studies using indirect or short-term blood pressure measurements found that BK channel β1-subunit knockout (BK β1-KO) mice were hypertensive. We evaluated 24-h mean arterial pressure (MAP) and heart rate in BK β1-KO mice using radiotelemetry. BK β1-KO mice did not have a higher 24-h average MAP when compared with wild-type (WT) mice, although MAP was ∼10 mmHg higher at night. The dose-dependent peak declines in MAP by nifedipine were only slightly larger in BK β1-KO mice. In BK β1-KO mice, giving 1% NaCl to mice to drink for 7 days caused a transient (5 days) elevation of MAP (∼5 mmHg); MAP returned to pre-saline levels by day 6. BK β1-KO mesenteric arteries in vitro demonstrated diminished contractile responses to paxilline, increased reactivity to Bay K 8644 and norepinephrine (NE), and maintained relaxation to isoproterenol. Paxilline and Bay K 8644 did not constrict WT or BK β1-KO mesenteric veins (MV). BK β1-subunits are not expressed in MV. The results indicate that BK β1-KO mice are not hypertensive on normal or high-salt intake. BK channel deficiency increases arterial reactivity to NE and L-type Ca2+ channel function in vitro, but the L-type Ca2+ channel modulation of MAP is not altered in BK β1-KO mice. BK and L-type Ca2+ channels do not modulate murine venous tone. It appears that selective loss of BK channel function in arteries only is not sufficient to cause sustained hypertension. PMID:21131476

Complete genomic and transcriptional landscape analysis using third-generation sequencing: a case study of Saccharomyces cerevisiae CEN.PK113-7D

DEFF Research Database (Denmark)

Jenjaroenpun, Piroon; Wongsurawat, Thidathip; Pereira, Rui

2018-01-01

Completion of eukaryal genomes can be difficult task with the highly repetitive sequences along the chromosomes and short read lengths of secondgeneration sequencing. Saccharomyces cerevisiae strain CEN. PK113-7D, widely used as a model organism and a cell factory, was selected for this study...... to demonstrate the superior capability of very long sequence reads for de novo genome assembly. We generated long reads using two common third-generation sequencing technologies (Oxford Nanopore Technology (ONT) and Pacific Biosciences (PacBio)) and used short reads obtained using Illumina sequencing for error...... correction. Assembly of the reads derived from all three technologies resulted in complete sequences for all 16 yeast chromosomes, as well as themitochondrial chromosome, in one step. Further, we identified three types of DNA methylation (5mC, 4mC and 6mA). Comparison between the reference strain S288C...

Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach.

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Arturo Blazquez-Navarro

2018-05-01

Full Text Available BK virus (BKV associated nephropathy affects 1-10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.

Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach.

Science.gov (United States)

Blazquez-Navarro, Arturo; Schachtner, Thomas; Stervbo, Ulrik; Sefrin, Anett; Stein, Maik; Westhoff, Timm H; Reinke, Petra; Klipp, Edda; Babel, Nina; Neumann, Avidan U; Or-Guil, Michal

2018-05-01

BK virus (BKV) associated nephropathy affects 1-10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot) in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.

The determination and arrangement of a combination of enzyme lactate dehydrogenase of bacteria Acinetobacter sp. as a device the identity important bacteria agent composts

Science.gov (United States)

Sukmawati, D.; Puspitaningrum, R.; Muzajjanah

2017-07-01

The number of garbage generated by the industry or society is a usual problem encountered by almost all urban centers, especially large cities such as Jakarta. Waste prevention strategy required quickly and accurately. One strategy for tackling the Junk was getting lactic acid-producing bacteria. It has been shown that lactic acid can increase the acceleration of organic matter such as an overhaul of lignin and cellulose as well as out causing toxic compounds arising from decay. This research will be conducted on the determination and characterization of the enzyme-producing compost bacteria LDH lactate dehydrogenase LDH - which in isolation from the garbage Landfill Rawasari. Methodology: Research carried out consists: isolation of lactic acid-producing bacteria; identification of microscopic, macroscopic and staining Gram; cellulose assay, and optimization of PCR conditions LDH enzymes producing bacteria. Isolation is performed by dilution method and the direct method. As many as 5-point sampling. Each stage is conducted from 10 grams of soil from the top surface of the compost. Isolation results obtained 100 isolate the bacteria. Base on the characteristic of macroscopic and microscopic observations retrieved 14 isolates of bacteria have shaped rods and brought forth a negative kind of Gram positive staining. Bacterial isolates with codes (BK1; BK3; BK4; BK5; BK6; BK7; BK8; BK9; BK10; BK11: BK12; BK 13). The potential bacteria with ability produce lactate dehydrogenase was BK1 and BK3. Base for analysis phylogenetic there was identification bacteria bak1 and bak3 where Acinetobacter sp.

D-Arg0-Bradykinin-Arg-Arg, a Latent Vasoactive Bradykinin B2 Receptor Agonist Metabolically Activated by Carboxypeptidases

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Hélène Bachelard

2018-03-01

Full Text Available We previously reported hypotensive and vasodilator effects from C-terminally extended bradykinin (BK sequences that behave as B2 receptor (B2R agonists activated by vascular or plasma peptidases. D-Arg0-BK-Arg-Arg (r-BK-RR is a novel prodrug peptide hypothetically activated by two catalytic cycles of Arg-carboxypeptidases (CPs to release the direct agonist D-Arg0-BK. N-terminally extending the BK sequence with D-Arg0 in the latter peptide was meant to block the second kinin inactivation pathway in importance, aminopeptidase P. The affinity of r-BK and r-BK-RR for recombinant B2R was assessed using a [3H]BK binding displacement assay. Their pharmacology was evaluated in human isolated umbilical vein, a contractile bioassay for the B2R, in a morphological assay involving the endocytosis of B2R-green fusion protein (GFP and in anesthetized rats instrumented to record hemodynamic responses to bolus intravenous injection of both peptides. r-BK exhibited an affinity equal to that of BK for the rat B2R, while r-BK-RR was 61-fold less potent. In the vein and the B2R-GFP internalization assay, r-BK was a direct agonist unaffected by the blockade of angiotensin converting enzyme (ACE with enalaprilat, or Arg-CPs with Plummer’s inhibitor. However, the in vitro effects of r-BK-RR were reduced by these inhibitors, more so by enalaprilat. In anesthetized rats, r-BK and r-BK-RR were equipotent hypotensive agents and their effects were inhibited by icatibant (a B2R antagonist. The hypotensive effects of r-BK were potentiated by enalaprilat, but not influenced by the Arg-CPs inhibitor, which is consistent with a minor role of Arg-CPs in the metabolism of r-BK. However, in rats pretreated with both enalaprilat and Plummer’s inhibitor, the hypotensive responses and the duration of the hypotensive episode to r-BK were significantly potentiated. The hypotensive responses to r-BK-RR were not affected by enalaprilat, but were reduced by pre-treatment with the Arg

Impact of low-level BK polyomavirus viremia on intermediate-term renal allograft function.

Science.gov (United States)

Korth, Johannes; Widera, Marek; Dolff, Sebastian; Guberina, Hana; Bienholz, Anja; Brinkhoff, Alexandra; Anastasiou, Olympia Evdoxia; Kribben, Andreas; Dittmer, Ulf; Verheyen, Jens; Wilde, Benjamin; Witzke, Oliver

2018-02-01

BK polyomavirus (BKPyV)-associated nephropathy (PyVAN) is a significant cause of premature renal transplant failure. High-level BKPyV viremia is predictive for PyVAN; however, low-level BKPyV viremia does not necessarily exclude the presence of PyVAN. As data are limited regarding whether or not low-level BKPyV viremia has an effect on intermediate-term graft outcome, this study analyzes the impact of low-level BKPyV viremia on intermediate-term graft function and outcome compared with high-level viremia and non-viremic patients. All renal transplant patients received follow-up examinations at the Department of Nephrology, University Hospital Essen. Patients were screened for BKPyV viremia and stratified into three groups according to their maximum BKPyV load in serum (low-level viremia, high-level viremia, and no viremia). In 142 of 213 (67%) patients, BKPyV was never detected in serum; 42 of 213 (20%) patients were found positive for low-level viremia (≤10 4 copies/mL); and 29 of 213 (13%) patients showed high-level viremia (>10 4 copies/mL). No significant differences regarding transplant function and graft failure were observed between patients without BKPyV viremia (delta estimated glomerular filtration rate [eGFR] +0.1 mL/min [month 1 vs last visit at month 44]) and patients with low-level BKPyV viremia (delta eGFR -1.7 mL/min). In patients with high-level viremia, transplant function was significantly restricted (delta eGFR -6.5 mL/min) compared with low-level viremia until the last visit at 44 ± 9.7 months after transplantation. Although the graft function and graft loss were worse in the high-level viremia group compared with no viremia (eGFR 37 vs 45 mL/min), the difference was not significant. High-level viremia was associated with impaired graft function. In contrast, low-level BKPyV viremia had no significant impact on intermediate-term graft function. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Educación en la promoción de estilos de vida saludables para la prevención de recaídas en pacientes con tuberculosis pulmonar bk (+), en el hospital Carlos Monge Medrano Juliaca 2010.

OpenAIRE

Maldonado Zanabria, Dionicia

2011-01-01

El presente estudio se realizó con el objetivo de evaluar la efectividad de la Educación en la Promoción de estilos de vida saludable para la prevención de recaídas en pacientes con Tuberculosis Pulmonar BK (+) en el Hospital Carlos Monge Medran o Juliaca 2010. El estudio es de carácter Cuasi-Experimental, con diseño de pre y post test; la muestra estuvo constituida por 18 pacientes. Para recolección de datos se utilizó como instrumentos un cuestionario. La prueba de hipótesis se realizó con ...

Urinary Excretion of Tetrodotoxin Modeled in a Porcine Renal Proximal Tubule Epithelial Cell Line, LLC-PK1

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Takuya Matsumoto

2017-07-01

Full Text Available This study examined the urinary excretion of tetrodotoxin (TTX modeled in a porcine renal proximal tubule epithelial cell line, LLC-PK1. Time course profiles of TTX excretion and reabsorption across the cell monolayers at 37 °C showed that the amount of TTX transported increased linearly for 60 min. However, at 4 °C, the amount of TTX transported was approximately 20% of the value at 37 °C. These results indicate that TTX transport is both a transcellular and carrier-mediated process. Using a transport inhibition assay in which cell monolayers were incubated with 50 µM TTX and 5 mM of a transport inhibitor at 37 °C for 30 min, urinary excretion was significantly reduced by probenecid, tetraethylammonium (TEA, l-carnitine, and cimetidine, slightly reduced by p-aminohippuric acid (PAH, and unaffected by 1-methyl-4-phenylpyridinium (MPP+, oxaliplatin, and cefalexin. Renal reabsorption was significantly reduced by PAH, but was unaffected by probenecid, TEA and l-carnitine. These findings indicate that TTX is primarily excreted by organic cation transporters (OCTs and organic cation/carnitine transporters (OCTNs, partially transported by organic anion transporters (OATs and multidrug resistance-associated proteins (MRPs, and negligibly transported by multidrug and toxic compound extrusion transporters (MATEs.

Bowman-Birk Protease Inhibitor from Vigna unguiculata Seeds Enhances the Action of Bradykinin-Related Peptides

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Alice da Cunha M. Álvares

2014-10-01

Full Text Available The hydrolysis of bradykinin (Bk by different classes of proteases in plasma and tissues leads to a decrease in its half-life. Here, Bk actions on smooth muscle and in vivo cardiovascular assays in association with a protease inhibitor, Black eyed-pea trypsin and chymotrypsin inhibitor (BTCI and also under the effect of trypsin and chymotrypsin were evaluated. Two synthetic Bk-related peptides, Bk1 and Bk2, were used to investigate the importance of additional C-terminal amino acid residues on serine protease activity. BTCI forms complexes with Bk and analogues at pH 5.0, 7.4 and 9.0, presenting binding constants ranging from 103 to 104 M−1. Formation of BTCI-Bk complexes is probably driven by hydrophobic forces, coupled with slight conformational changes in BTCI. In vitro assays using guinea pig (Cavia porcellus ileum showed that Bk retains the ability to induce smooth muscle contraction in the presence of BTCI. Moreover, no alteration in the inhibitory activity of BTCI in complex with Bk and analogous was observed. When the BTCI and BTCI-Bk complexes were tested in vivo, a decrease of vascular resistance and consequent hypotension and potentiating renal and aortic vasodilatation induced by Bk and Bk2 infusions was observed. These results indicate that BTCI-Bk complexes may be a reliable strategy to act as a carrier and protective approach for Bk-related peptides against plasma serine proteases cleavage, leading to an increase in their half-life. These findings also indicate that BTCI could remain stable in some tissues to inhibit chymotrypsin or trypsin-like enzymes that cleave and inactivate bradykinin in situ.

ECIL guidelines for the prevention, diagnosis and treatment of BK polyomavirus-associated haemorrhagic cystitis in haematopoietic stem cell transplant recipients.

Science.gov (United States)

Cesaro, Simone; Dalianis, Tina; Hanssen Rinaldo, Christine; Koskenvuo, Minna; Pegoraro, Anna; Einsele, Hermann; Cordonnier, Catherine; Hirsch, Hans H

2018-01-01

To define guidelines for BK polyomavirus (BKPyV)-associated haemorrhagic cystitis (BKPyV-HC) after paediatric and adult HSCT. Review of English literature and evidence-based recommendations by expert consensus. BKPyV-HC occurs in 8%-25% of paediatric and 7%-54% of adult recipients undergoing allogeneic HSCT. Diagnosis requires the triad of cystitis, macro-haematuria and high urine BKPyV loads >7 log10 copies/mL, and exclusion of other relevant aetiologies. BKPyV viraemia is frequent and may serve as a more specific semiquantitative follow-up marker. No randomized controlled trials are available to inform antiviral prophylaxis or treatment. However, hyper-hydration and/or bladder irrigation showed limited prophylactic value. Fluoroquinolones are not effective for prophylaxis or treatment, but rather increase antibiotic resistance. Hyperbaric oxygen or fibrin glue is marginally effective based on small case series from correspondingly equipped centres. Although cidofovir has been reported to improve and/or reduce BKPyV viraemia or viruria, the current data do not support its regular use. BKPyV-HC remains a disabling unmet clinical need in HSCT that requires novel approaches supported by proper clinical trials. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Vectorial transport of unconjugated and conjugated bile salts by monolayers of LLC-PK1 cells doubly transfected with human NTCP and BSEP or with rat Ntcp and Bsep.

Science.gov (United States)

Mita, Sachiko; Suzuki, Hiroshi; Akita, Hidetaka; Hayashi, Hisamitsu; Onuki, Reiko; Hofmann, Alan F; Sugiyama, Yuichi

2006-03-01

Na(+)-taurocholate-cotransporting peptide (NTCP)/SLC10A1 and bile salt export pump (BSEP)/ABCB11 synergistically play an important role in the transport of bile salts by the hepatocyte. In this study, we transfected human NTCP and BSEP or rat Ntcp and Bsep into LLC-PK1 cells, a cell line devoid of bile salts transporters. Transport by these cells was characterized with a focus on substrate specificity between rats and humans. The basal to apical flux of taurocholate across NTCP- and BSEP-expressing LLC-PK1 monolayers was 10 times higher than that in the opposite direction, whereas the flux across the monolayer of control and NTCP or BSEP single-expressing cells did not show any vectorial transport. The basal to apical flux of taurocholate was saturated with a K(m) value of 20 microM. Vectorial transcellular transport was also observed for cholate, chenodeoxycholate, ursodeoxycholate, their taurine and glycine conjugates, and taurodeoxycholate and glycodeoxycholate, whereas no transport of lithocholate was detected. To evaluate the respective functions of NTCP and BSEP and to compare them with those of rat Ntcp and Bsep, we calculated the clearance by each transporter in this system. A good correlation in the clearance of the examined bile salts (cholate, chenodeoxycholate, ursodeoxycholate, and their taurine or glycine conjugates) was observed between transport by human and that of rat transporters in terms of their rank order: for NTCP, taurine conjugates > glycine conjugates > unconjugated bile salts, and for BSEP, unconjugated bile salts and glycine conjugates > taurine conjugates. In conclusion, the substrate specificity of human and rat NTCP and BSEP appear to be very similar at least for monovalent bile salts under physiological conditions.

Microsystems Research in Japan

Science.gov (United States)

2003-09-01

diagram of MEMS devices mounted on catheters and pipe repair instruments ...................34 5.5 Olympus microfine active bending catheter equipped...heating ‡B Bending portion bends to avoid further contact Figure 5.5. Olympus microfine active bending catheter equipped with contact sensors...communication in a harsh environment was also difficult. The inspection for the outer surface of the tubes , small machines follow the outside of the

A measurement of the CP asymmetry difference between Λ c + → pK - K + and pπ-π+ decays

Science.gov (United States)

Aaij, R.; Adeva, B.; Adinolfi, M.; Ajaltouni, Z.; Akar, S.; Albrecht, J.; Alessio, F.; Alexander, M.; Alfonso Albero, A.; Ali, S.; Alkhazov, G.; Alvarez Cartelle, P.; Alves, A. A.; Amato, S.; Amerio, S.; Amhis, Y.; An, L.; Anderlini, L.; Andreassi, G.; Andreotti, M.; Andrews, J. E.; Appleby, R. B.; Archilli, F.; d'Argent, P.; Arnau Romeu, J.; Artamonov, A.; Artuso, M.; Aslanides, E.; Atzeni, M.; Auriemma, G.; Baalouch, M.; Babuschkin, I.; Bachmann, S.; Back, J. J.; Badalov, A.; Baesso, C.; Baker, S.; Balagura, V.; Baldini, W.; Baranov, A.; Barlow, R. J.; Barschel, C.; Barsuk, S.; Barter, W.; Baryshnikov, F.; Batozskaya, V.; Battista, V.; Bay, A.; Beaucourt, L.; Beddow, J.; Bedeschi, F.; Bediaga, I.; Beiter, A.; Bel, L. J.; Beliy, N.; Bellee, V.; Belloli, N.; Belous, K.; Belyaev, I.; Ben-Haim, E.; Bencivenni, G.; Benson, S.; Beranek, S.; Berezhnoy, A.; Bernet, R.; Berninghoff, D.; Bertholet, E.; Bertolin, A.; Betancourt, C.; Betti, F.; Bettler, M. O.; van Beuzekom, M.; Bezshyiko, Ia.; Bifani, S.; Billoir, P.; Birnkraut, A.; Bizzeti, A.; Bjørn, M.; Blake, T.; Blanc, F.; Blusk, S.; Bocci, V.; Boettcher, T.; Bondar, A.; Bondar, N.; Bordyuzhin, I.; Borghi, S.; Borisyak, M.; Borsato, M.; Bossu, F.; Boubdir, M.; Bowcock, T. J. V.; Bowen, E.; Bozzi, C.; Braun, S.; Brodzicka, J.; Brundu, D.; Buchanan, E.; Burr, C.; Bursche, A.; Buytaert, J.; Byczynski, W.; Cadeddu, S.; Cai, H.; Calabrese, R.; Calladine, R.; Calvi, M.; Calvo Gomez, M.; Camboni, A.; Campana, P.; Campora Perez, D. H.; Capriotti, L.; Carbone, A.; Carboni, G.; Cardinale, R.; Cardini, A.; Carniti, P.; Carson, L.; Carvalho Akiba, K.; Casse, G.; Cassina, L.; Cattaneo, M.; Cavallero, G.; Cenci, R.; Chamont, D.; Chapman, M. G.; Charles, M.; Charpentier, Ph.; Chatzikonstantinidis, G.; Chefdeville, M.; Chen, S.; Cheung, S. F.; Chitic, S.-G.; Chobanova, V.; Chrzaszcz, M.; Chubykin, A.; Ciambrone, P.; Cid Vidal, X.; Ciezarek, G.; Clarke, P. E. L.; Clemencic, M.; Cliff, H. V.; Closier, J.; Coco, V.; Cogan, J.; Cogneras, E.; Cogoni, V.; Cojocariu, L.; Collins, P.; Colombo, T.; Comerma-Montells, A.; Contu, A.; Coombs, G.; Coquereau, S.; Corti, G.; Corvo, M.; Costa Sobral, C. M.; Couturier, B.; Cowan, G. A.; Craik, D. C.; Crocombe, A.; Cruz Torres, M.; Currie, R.; D'Ambrosio, C.; Da Cunha Marinho, F.; Da Silva, C. L.; Dall'Occo, E.; Dalseno, J.; Davis, A.; De Aguiar Francisco, O.; De Bruyn, K.; De Capua, S.; De Cian, M.; De Miranda, J. M.; De Paula, L.; De Serio, M.; De Simone, P.; Dean, C. T.; Decamp, D.; Del Buono, L.; Dembinski, H.-P.; Demmer, M.; Dendek, A.; Derkach, D.; Deschamps, O.; Dettori, F.; Dey, B.; Di Canto, A.; Di Nezza, P.; Dijkstra, H.; Dordei, F.; Dorigo, M.; Dosil Suárez, A.; Douglas, L.; Dovbnya, A.; Dreimanis, K.; Dufour, L.; Dujany, G.; Durante, P.; Durham, J. M.; Dutta, D.; Dzhelyadin, R.; Dziewiecki, M.; Dziurda, A.; Dzyuba, A.; Easo, S.; Ebert, M.; Egede, U.; Egorychev, V.; Eidelman, S.; Eisenhardt, S.; Eitschberger, U.; Ekelhof, R.; Eklund, L.; Ely, S.; Esen, S.; Evans, H. M.; Evans, T.; Falabella, A.; Farley, N.; Farry, S.; Fazzini, D.; Federici, L.; Ferguson, D.; Fernandez, G.; Fernandez Declara, P.; Fernandez Prieto, A.; Ferrari, F.; Ferreira Lopes, L.; Ferreira Rodrigues, F.; Ferro-Luzzi, M.; Filippov, S.; Fini, R. A.; Fiorini, M.; Firlej, M.; Fitzpatrick, C.; Fiutowski, T.; Fleuret, F.; Fontana, M.; Fontanelli, F.; Forty, R.; Franco Lima, V.; Frank, M.; Frei, C.; Fu, J.; Funk, W.; Furfaro, E.; Färber, C.; Gabriel, E.; Gallas Torreira, A.; Galli, D.; Gallorini, S.; Gambetta, S.; Gandelman, M.; Gandini, P.; Gao, Y.; Garcia Martin, L. M.; García Pardiñas, J.; Garra Tico, J.; Garrido, L.; Gascon, D.; Gaspar, C.; Gavardi, L.; Gazzoni, G.; Gerick, D.; Gersabeck, E.; Gersabeck, M.; Gershon, T.; Ghez, Ph.; Gianì, S.; Gibson, V.; Girard, O. G.; Giubega, L.; Gizdov, K.; Gligorov, V. V.; Golubkov, D.; Golutvin, A.; Gomes, A.; Gorelov, I. V.; Gotti, C.; Govorkova, E.; Grabowski, J. P.; Graciani Diaz, R.; Granado Cardoso, L. A.; Graugés, E.; Graverini, E.; Graziani, G.; Grecu, A.; Greim, R.; Griffith, P.; Grillo, L.; Gruber, L.; Gruberg Cazon, B. R.; Grünberg, O.; Gushchin, E.; Guz, Yu.; Gys, T.; Göbel, C.; Hadavizadeh, T.; Hadjivasiliou, C.; Haefeli, G.; Haen, C.; Haines, S. C.; Hamilton, B.; Han, X.; Hancock, T. H.; Hansmann-Menzemer, S.; Harnew, N.; Harnew, S. T.; Hasse, C.; Hatch, M.; He, J.; Hecker, M.; Heinicke, K.; Heister, A.; Hennessy, K.; Henrard, P.; Henry, L.; van Herwijnen, E.; Heß, M.; Hicheur, A.; Hill, D.; Hopchev, P. H.; Hu, W.; Huang, W.; Huard, Z. C.; Hulsbergen, W.; Humair, T.; Hushchyn, M.; Hutchcroft, D.; Ibis, P.; Idzik, M.; Ilten, P.; Jacobsson, R.; Jalocha, J.; Jans, E.; Jawahery, A.; Jiang, F.; John, M.; Johnson, D.; Jones, C. R.; Joram, C.; Jost, B.; Jurik, N.; Kandybei, S.; Karacson, M.; Kariuki, J. M.; Karodia, S.; Kazeev, N.; Kecke, M.; Keizer, F.; Kelsey, M.; Kenzie, M.; Ketel, T.; Khairullin, E.; Khanji, B.; Khurewathanakul, C.; Kirn, T.; Klaver, S.; Klimaszewski, K.; Klimkovich, T.; Koliiev, S.; Kolpin, M.; Kopecna, R.; Koppenburg, P.; Kosmyntseva, A.; Kotriakhova, S.; Kozeiha, M.; Kravchuk, L.; Kreps, M.; Kress, F.; Krokovny, P.; Krzemien, W.; Kucewicz, W.; Kucharczyk, M.; Kudryavtsev, V.; Kuonen, A. K.; Kvaratskheliya, T.; Lacarrere, D.; Lafferty, G.; Lai, A.; Lanfranchi, G.; Langenbruch, C.; Latham, T.; Lazzeroni, C.; Le Gac, R.; Leflat, A.; Lefrançois, J.; Lefèvre, R.; Lemaitre, F.; Lemos Cid, E.; Leroy, O.; Lesiak, T.; Leverington, B.; Li, P.-R.; Li, T.; Li, Y.; Li, Z.; Liang, X.; Likhomanenko, T.; Lindner, R.; Lionetto, F.; Lisovskyi, V.; Liu, X.; Loh, D.; Loi, A.; Longstaff, I.; Lopes, J. H.; Lucchesi, D.; Lucio Martinez, M.; Luo, H.; Lupato, A.; Luppi, E.; Lupton, O.; Lusiani, A.; Lyu, X.; Machefert, F.; Maciuc, F.; Macko, V.; Mackowiak, P.; Maddrell-Mander, S.; Maev, O.; Maguire, K.; Maisuzenko, D.; Majewski, M. W.; Malde, S.; Malecki, B.; Malinin, A.; Maltsev, T.; Manca, G.; Mancinelli, G.; Marangotto, D.; Maratas, J.; Marchand, J. F.; Marconi, U.; Marin Benito, C.; Marinangeli, M.; Marino, P.; Marks, J.; Martellotti, G.; Martin, M.; Martinelli, M.; Martinez Santos, D.; Martinez Vidal, F.; Massafferri, A.; Matev, R.; Mathad, A.; Mathe, Z.; Matteuzzi, C.; Mauri, A.; Maurice, E.; Maurin, B.; Mazurov, A.; McCann, M.; McNab, A.; McNulty, R.; Mead, J. V.; Meadows, B.; Meaux, C.; Meier, F.; Meinert, N.; Melnychuk, D.; Merk, M.; Merli, A.; Michielin, E.; Milanes, D. A.; Millard, E.; Minard, M.-N.; Minzoni, L.; Mitzel, D. S.; Mogini, A.; Molina Rodriguez, J.; Mombächer, T.; Monroy, I. A.; Monteil, S.; Morandin, M.; Morello, M. J.; Morgunova, O.; Moron, J.; Morris, A. B.; Mountain, R.; Muheim, F.; Mulder, M.; Müller, D.; Müller, J.; Müller, K.; Müller, V.; Naik, P.; Nakada, T.; Nandakumar, R.; Nandi, A.; Nasteva, I.; Needham, M.; Neri, N.; Neubert, S.; Neufeld, N.; Neuner, M.; Nguyen, T. D.; Nguyen-Mau, C.; Nieswand, S.; Niet, R.; Nikitin, N.; Nikodem, T.; Nogay, A.; O'Hanlon, D. P.; Oblakowska-Mucha, A.; Obraztsov, V.; Ogilvy, S.; Oldeman, R.; Onderwater, C. J. G.; Ossowska, A.; Otalora Goicochea, J. M.; Owen, P.; Oyanguren, A.; Pais, P. R.; Palano, A.; Palutan, M.; Papanestis, A.; Pappagallo, M.; Pappalardo, L. L.; Parker, W.; Parkes, C.; Passaleva, G.; Pastore, A.; Patel, M.; Patrignani, C.; Pearce, A.; Pellegrino, A.; Penso, G.; Pepe Altarelli, M.; Perazzini, S.; Pereima, D.; Perret, P.; Pescatore, L.; Petridis, K.; Petrolini, A.; Petrov, A.; Petruzzo, M.; Picatoste Olloqui, E.; Pietrzyk, B.; Pietrzyk, G.; Pikies, M.; Pinci, D.; Pisani, F.; Pistone, A.; Piucci, A.; Placinta, V.; Playfer, S.; Plo Casasus, M.; Polci, F.; Poli Lener, M.; Poluektov, A.; Polyakov, I.; Polycarpo, E.; Pomery, G. J.; Ponce, S.; Popov, A.; Popov, D.; Poslavskii, S.; Potterat, C.; Price, E.; Prisciandaro, J.; Prouve, C.; Pugatch, V.; Puig Navarro, A.; Pullen, H.; Punzi, G.; Qian, W.; Qin, J.; Quagliani, R.; Quintana, B.; Rachwal, B.; Rademacker, J. H.; Rama, M.; Ramos Pernas, M.; Rangel, M. S.; Raniuk, I.; Ratnikov, F.; Raven, G.; Ravonel Salzgeber, M.; Reboud, M.; Redi, F.; Reichert, S.; dos Reis, A. C.; Remon Alepuz, C.; Renaudin, V.; Ricciardi, S.; Richards, S.; Rihl, M.; Rinnert, K.; Robbe, P.; Robert, A.; Rodrigues, A. B.; Rodrigues, E.; Rodriguez Lopez, J. A.; Rogozhnikov, A.; Roiser, S.; Rollings, A.; Romanovskiy, V.; Romero Vidal, A.; Rotondo, M.; Rudolph, M. S.; Ruf, T.; Ruiz Valls, P.; Ruiz Vidal, J.; Saborido Silva, J. J.; Sadykhov, E.; Sagidova, N.; Saitta, B.; Salustino Guimaraes, V.; Sanchez Mayordomo, C.; Sanmartin Sedes, B.; Santacesaria, R.; Santamarina Rios, C.; Santimaria, M.; Santovetti, E.; Sarpis, G.; Sarti, A.; Satriano, C.; Satta, A.; Saunders, D. M.; Savrina, D.; Schael, S.; Schellenberg, M.; Schiller, M.; Schindler, H.; Schmelling, M.; Schmelzer, T.; Schmidt, B.; Schneider, O.; Schopper, A.; Schreiner, H. F.; Schubiger, M.; Schune, M. H.; Schwemmer, R.; Sciascia, B.; Sciubba, A.; Semennikov, A.; Sepulveda, E. S.; Sergi, A.; Serra, N.; Serrano, J.; Sestini, L.; Seyfert, P.; Shapkin, M.; Shapoval, I.; Shcheglov, Y.; Shears, T.; Shekhtman, L.; Shevchenko, V.; Siddi, B. G.; Silva Coutinho, R.; Silva de Oliveira, L.; Simi, G.; Simone, S.; Sirendi, M.; Skidmore, N.; Skwarnicki, T.; Smith, I. T.; Smith, J.; Smith, M.; Soares Lavra, l.; Sokoloff, M. D.; Soler, F. J. P.; Souza De Paula, B.; Spaan, B.; Spradlin, P.; Sridharan, S.; Stagni, F.; Stahl, M.; Stahl, S.; Stefko, P.; Stefkova, S.; Steinkamp, O.; Stemmle, S.; Stenyakin, O.; Stepanova, M.; Stevens, H.; Stone, S.; Storaci, B.; Stracka, S.; Stramaglia, M. E.; Straticiuc, M.; Straumann, U.; Sun, J.; Sun, L.; Swientek, K.; Syropoulos, V.; Szumlak, T.; Szymanski, M.; T'Jampens, S.; Tayduganov, A.; Tekampe, T.; Tellarini, G.; Teubert, F.; Thomas, E.; van Tilburg, J.; Tilley, M. J.; Tisserand, V.; Tobin, M.; Tolk, S.; Tomassetti, L.; Tonelli, D.; Tourinho Jadallah Aoude, R.; Tournefier, E.; Traill, M.; Tran, M. T.; Tresch, M.; Trisovic, A.; Tsaregorodtsev, A.; Tsopelas, P.; Tully, A.; Tuning, N.; Ukleja, A.; Usachov, A.; Ustyuzhanin, A.; Uwer, U.; Vacca, C.; Vagner, A.; Vagnoni, V.; Valassi, A.; Valat, S.; Valenti, G.; Vazquez Gomez, R.; Vazquez Regueiro, P.; Vecchi, S.; van Veghel, M.; Velthuis, J. J.; Veltri, M.; Veneziano, G.; Venkateswaran, A.; Verlage, T. A.; Vernet, M.; Vesterinen, M.; Viana Barbosa, J. V.; Vieira, D.; Vieites Diaz, M.; Viemann, H.; Vilasis-Cardona, X.; Vitti, M.; Volkov, V.; Vollhardt, A.; Voneki, B.; Vorobyev, A.; Vorobyev, V.; Voß, C.; de Vries, J. A.; Vázquez Sierra, C.; Waldi, R.; Walsh, J.; Wang, J.; Wang, Y.; Ward, D. R.; Wark, H. M.; Watson, N. K.; Websdale, D.; Weiden, A.; Weisser, C.; Whitehead, M.; Wicht, J.; Wilkinson, G.; Wilkinson, M.; Williams, M.; Williams, M.; Williams, T.; Wilson, F. F.; Wimberley, J.; Winn, M.; Wishahi, J.; Wislicki, W.; Witek, M.; Wormser, G.; Wotton, S. A.; Wyllie, K.; Xie, Y.; Xu, M.; Xu, Q.; Xu, Z.; Xu, Z.; Yang, Z.; Yang, Z.; Yao, Y.; Yin, H.; Yu, J.; Yuan, X.; Yushchenko, O.; Zarebski, K. A.; Zavertyaev, M.; Zhang, L.; Zhang, Y.; Zhelezov, A.; Zheng, Y.; Zhu, X.; Zhukov, V.; Zonneveld, J. B.; Zucchelli, S.

2018-03-01

The difference between the CP asymmetries in the decays Λ c + → pK - K + and Λ c + → pπ - π + is presented. Proton-proton collision data taken at centre-of-mass energies of 7 and 8 TeV collected by the LHCb detector in 2011 and 2012 are used, corresponding to an integrated luminosity of 3 fb-1. The Λ c + candidates are reconstructed as part of the Λ b 0 → Λ c + μ - X decay chain. In order to maximize the cancellation of production and detection asymmetries in the difference, the final-state kinematic distributions of the two samples are aligned by applying phase-space-dependent weights to the Λ c + → pπ - π + sample. This alters the definition of the integrated CP asymmetry to A CP wgt ( pπ - π +). Both samples are corrected for reconstruction and selection efficiencies across the five-dimensional Λ c + decay phase space. The difference in CP asymmetries is found to be Δ {A}_{CP}^{wgt}={A}_{CP}(p{K}-{K}+) - {A}_{CP}^{wgt}(p{π}-{π}+) = (0.30 ± 0.91 ± 0.61) %, where the first uncertainty is statistical and the second is systematic.

Kur’an-ı Kerim’e Göre Ehl-i Kitap

OpenAIRE

Kaya, Remzi

2005-01-01

İbn Manzûr, I/698; Râgıb, Müfredât, s. 423. Bakara, 2/183; 216; Nisâ, 4/77; Mâide, 5/45. Bk. İbn Manzûr, Lisânü’l-Arab, I/698-699; Zebidî, I/444; Râgıb, s. 423. Türk Dil Kurumu, Türkçe Sözlük, Ank. 1983, s. 718-719. Bk. Bakara, 2/2; Hûd, 11/1; Sâd, 38/29. Bk. Furkân, 25/1; Bakara, 2/53; İbn Manzûr, X/302. Bk. Bakara, 2/97. Bk. Burûc, 85/21. Geniş bilgi için bk, Râzî, Tefsir, II/14-17. Farklı anlamlar için bk. Bakara, 2/177; Âl-i İmrân, 3/3, 7, 119; Zebîdî, II/331-332. Bk. ...

Search for a narrow baryonic state decaying to ${pK^0_S}$ and ${\\overline{p}K^0_S}$ in deep inelastic scattering at HERA

CERN Document Server

Abramowicz, H.; Adamczyk, L.; Adamus, M.; Antonelli, S.; Aushev, V.; Behnke, O.; Behrens, U.; Bertolin, A.; Bhadra, S.; Bloch, I.; Boos, E.G.; Brock, I.; Brook, N.H.; Brugnera, R.; Bruni, A.; Bussey, P.J.; Caldwell, A.; Capua, M.; Catterall, C.D.; Chwastowski, J.; Ciborowski, J.; Ciesielski, R.; Cooper-Sarkar, A.M.; Corradi, M.; Dementiev, R.K.; Devenish, RCE; Dusini, S.; Foster, B.; Gach, G; Gallo, E.; Garfagnini, A.; Geiser, A.; Gizhko, A.; Gladilin, L.K.; Golubkov, Yu.A.; Grzelak, G.; Guzik, M.; Gwenlan, C.; Hain, W.; Hlushchenko, O.; Hochman, D.; Hori, R.; Ibrahim, Z.A.; Iga, Y.; Ishitsuka, M.; Januschek, F.; Jomhari, N.Z.; Kadenko, I.; Kananov, S.; Karshon, U.; Kaur, P.; Kisielewska, D.; Klanner, R.; Klein, U.; Korzhavina, I.A.; Kotański, A.; Kötz, U.; Kovalchuk, N.; Kowalski, H.; Krupa, B.; Kuprash, O.; Kuze, M; Levchenko, B.B.; Levy, A.; Limentani, S.; Lisovyi, M.; Lobodzinska, E.; Löhr, B.; Lohrmann, E.; Longhin, A.; Lontkovskyi, D.; Lukina, O.Yu.; Makarenko, I.; Malka, J.; Mastroberardino, A.; Mohamad Idris, F.; Mohammad Nasir, N; Myronenko, V.; Nagano, K.; Nobe, T.; Nowak, R.J.; Onishchuk, Yu.; Paul, E.; Perlański, W.; Pokrovskiy, N.S.; Polini, A.; Przybycien, M.; Roloff, P.; Ruspa, M.; Saxon, D.H.; Schioppa, M.; Schneekloth, U.; Schörner-Sadenius, T.; Shcheglova, L.M.; Shevchenko, R.; Shkola, O.; Shyrma, Yu.; Singh, I.; Skillicorn, I.O.; Słomiński, W.; Solano, A.; Stanco, L.; Stefaniuk, N.; Stern, A.; Stopa, P.; Sztuk-Dambietz, J.; Tassi, E.; Tokushuku, K.; Tomaszewska, J.; Tsurugai, T.; Turcato, M.; Turkot, O.; Tymieniecka, T.; Verbytskyi, A.; Wan Abdullah, W.A.T.; Wichmann, K.; Wing, M.; Yamada, S.; Yamazaki, Y.; Zakharchuk, N.; Żarnecki, A.F.; Zawiejski, L.; Zenaiev, O.; Zhautykov, B.O.; Zotkin, D.S.; Mastroberardino, A

2016-08-10

A search for a narrow baryonic state in the $pK^0_S$ and $\\overline{p}K^0_S$ system has been performed in $ep$ collisions at HERA with the ZEUS detector using an integrated luminosity of 358 pb$^{-1}$ taken in 2003-2007. The search was performed with deep inelastic scattering events at an $ep$ centre-of-mass energy of 318 GeV for exchanged photon virtuality, $Q^2$, between 20 and 100 $\\rm{} GeV^{2}$. Contrary to evidence presented for such a state around 1.52 GeV in a previous ZEUS analysis using a sample of 121 pb$^{-1}$ taken in 1996-2000, no resonance peak was found in the $p(\\overline{p})K^0_S$ invariant-mass distribution in the range 1.45-1.7 GeV. Upper limits on the production cross section are set.

227-IJBCS-Article-Pauline Bationo-Kando

African Journals Online (AJOL)

RHUMSIKI

BK2 BK4 BK5 BK9 RA3 RA4 RA5 RA6 RA7 RA9 TA2 TA5 TA6. TA7 GA1 GA2 GA4 GA6 GA7 GA8 GA10 GA12 BR1. 4. 28. KA6 SP1 SP3 SP4 SP10 SP12 SK8 SK9 SK20 SK23 BA4 BA5 BA6. BA9 BA11 BA12 NP1 NP4 NP6 NP9 NP14 NP17 BK1 BK11 RA8. GA3 GA5 BR2. Tableau 10: Performances moyennes des groupes ...

Rhodiolae Kirliowii Radix et Rhizoma and Crataegus pinnatifida Fructus Extracts Effectively Inhibit BK Virus and JC Virus Infection of Host Cells

Directory of Open Access Journals (Sweden)

San-Yuan Chen

2017-01-01

Full Text Available The human polyomaviruses BK (BKPyV and JC (JCPyV are ubiquitous pathogens long associated with severe disease in immunocompromised individuals. BKPyV causes polyomavirus-associated nephropathy and hemorrhagic cystitis, whereas JCPyV is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy. No effective therapies targeting these viruses are currently available. The goal of this study was to identify Chinese medicinal herbs with antiviral activity against BKPyV and JCPyV. We screened extracts of Chinese medicinal herbs for the ability to inhibit hemagglutination by BKPyV and JCPyV virus-like particles (VLPs and the ability to inhibit BKPyV and JCPyV binding and infection of host cells. Two of the 40 herbal extracts screened, Rhodiolae Kirliowii Radix et Rhizoma and Crataegus pinnatifida Fructus, had hemagglutination inhibition activity on BKPyV and JCPyV VLPs and further inhibited infection of the cells by BKPyV and JCPyV, as evidenced by reduced expression of viral proteins in BKPyV-infected and JCPyV-infected cells after treatment with Rhodiolae Kirliowii Radix et Rhizoma or Crataegus pinnatifida Fructus extract. The results in this work show that both Rhodiolae Kirliowii Radix et Rhizoma and Crataegus pinnatifida Fructus may be sources of potential antiviral compounds for treating BKPyV and JCPyV infections.

Purification, structural characterization, and myotropic activity of a peptide related to des-Arg(9)-bradykinin from an elasmobranch fish, the little skate, Leucoraja erinacea.

Science.gov (United States)

Anderson, W Gary; Leprince, Jérôme; Conlon, J Michael

2008-08-01

A bradykinin (BK)-related peptide was isolated from heat-denaturated plasma from an elasmobranch fish, the little skate, Leucoraja erinacea after incubation with porcine pancreatic kallikrein. The primary structure of the peptide (H-Gly-Ile-Thr-Ser-Trp-Leu-Pro-Phe-OH; skate BK) shows limited structural similarity to the mammalian B1 receptor agonist, des-Arg(9)-BK. The myotropic activities of synthetic skate BK, and the analog skate [Arg(9)]BK, were examined in isolated skate vascular and intestinal smooth muscle preparations. Skate BK produced a concentration-dependent constriction of the mesenteric artery (EC(50)=4.37x10(-8)M; maximum response=103.4+/-10.23% of the response to 60mM KCl) but the response to skate [Arg(9)]BK was appreciably weaker (response to 10(-6)M=73.0+/-23.4% of the response to 60mM KCl). Neither the first branchial gill arch nor the ventral aorta responded to either purified peptide. Skate BK also produced a concentration-dependent constriction of intestinal smooth muscle preparations (EC(50)=2.74x10(-7)M; maximum response 31.0+/-12.2% of the response to 10(-5)M acetylcholine). Skate [Arg(9)]BK was without effect on the intestinal preparation. The data provide evidence for the existence of the kallikrein-kinin system in a phylogenetically ancient vertebrate group and the greater potency of skate BK compared with the analog skate [Arg(9)]BK suggests that the receptor mediating vascular responses resembles the mammalian B1 receptor more closely than the B2 receptor.

Neurophysiological mechanisms of bradykinin-evoked mucosal chloride secretion in guinea pig small intestine.

Science.gov (United States)

Qu, Mei-Hua; Ji, Wan-Sheng; Zhao, Ting-Kun; Fang, Chun-Yan; Mao, Shu-Mei; Gao, Zhi-Qin

2016-02-15

To investigate the mechanism for bradykinin (BK) to stimulate intestinal secretomotor neurons and intestinal chloride secretion. Muscle-stripped guinea pig ileal preparations were mounted in Ussing flux chambers for the recording of short-circuit current (Isc). Basal Isc and Isc stimulated by BK when preincubated with the BK receptors antagonist and other chemicals were recorded using the Ussing chamber system. Prostaglandin E2 (PGE2) production in the intestine was determined by enzyme immunologic assay (EIA). Application of BK or B2 receptor (B2R) agonist significantly increased the baseline Isc compared to the control. B2R antagonist, tetrodotoxin and scopolamine (blockade of muscarinic receptors) significantly suppressed the increase in Isc evoked by BK. The BK-evoked Isc was suppressed by cyclooxygenase (COX)-1 or COX-2 specific inhibitor as well as nonselective COX inhibitors. Preincubation of submucosa/mucosa preparations with BK for 10 min significantly increased PGE2 production and this was abolished by the COX-1 and COX-2 inhibitors. The BK-evoked Isc was suppressed by nonselective EP receptors and EP4 receptor antagonists, but selective EP1 receptor antagonist did not have a significant effect on the BK-evoked Isc. Inhibitors of PLC, PKC, calmodulin or CaMKII failed to suppress BK-induced PGE2 production. The results suggest that BK stimulates neurogenic chloride secretion in the guinea pig ileum by activating B2R, through COX increasing PGE2 production. The post-receptor transduction cascade includes activation of PLC, PKC, CaMK, IP3 and MAPK.

Neutral endopeptidase up-regulation in isolated human umbilical artery: involvement in desensitization of bradykinin-induced vasoconstrictor effects.

Science.gov (United States)

Pelorosso, Facundo Germán; Halperin, Ana Verónica; Palma, Alejandro Martín; Nowak, Wanda; Errasti, Andrea Emilse; Rothlin, Rodolfo Pedro

2007-02-01

Previous reports show that bradykinin B(2) receptors mediate contractile responses induced by bradykinin (BK) in human umbilical artery (HUA). However, although it has been reported that BK-induced responses can desensitize in several inflammatory models, the effects of prolonged in vitro incubation on BK-induced vasoconstriction in HUA have not been studied. In isolated HUA rings, BK-induced responses after a 5-h in vitro incubation showed a marked desensitization compared with responses at 2 h. Inhibition of either angiotensin-converting enzyme (ACE) or neutral endopeptidase (NEP), both BK-inactivating enzymes, failed to modify responses to BK at 2 h. After 5 h, ACE inhibition produced only a slight potentiation of BK-induced responses. In contrast, BK-induced vasoconstriction at 5 h was markedly potentiated by NEP inhibition. Moreover, NEP activity, measured by hydrolysis of its synthetic substrate (Z-Ala-Ala-Leu-p-nitroanilide), showed a 2.4-fold increase in 5-h incubated versus 2-h incubated tissues, which was completely reversed by cycloheximide (CHX) treatment. Furthermore, CHX significantly potentiated BK-induced responses, suggesting that NEP-mediated kininase activity increase at 5 h depends on de novo protein synthesis. In addition, under NEP inhibition, CHX treatment failed to produce an additional potentiation of BK-induced vasoconstriction. Still, NEP up-regulation was confirmed by Western blot, showing a 2.1-fold increase in immunoreactive NEP in 5-h incubated versus 2-h incubated HUA. In summary, the present study provides strong pharmacological evidence that NEP is up-regulated and plays a key role in desensitization of BK-induced vasoconstriction after prolonged in vitro incubation in HUA. Our results provide new insights into the possible mechanisms involved in BK-induced response desensitization during sustained inflammatory conditions.

Comparing Effects of BK Virus Agnoprotein and Herpes Simplex-1 ICP47 on MHC-I and MHC-II Expression

Directory of Open Access Journals (Sweden)

Michela Cioni

2013-01-01

Full Text Available Background. Among human polyomaviruses, only BK virus (BKV and JC virus (JCV encode an agnoprotein upstream of VP1 on the viral late transcript. BKV agnoprotein is abundantly expressed late in the viral life cycle, but specific cellular and humoral immune responses are low or absent. We hypothesized that agnoprotein might contribute to BKV immune evasion by downregulating HLA expression, similar to Herpes simplex virus-1 ICP47. Methods UTA-6 or primary human renal proximal tubular epithelial cells (RPTEC were co-transfected with plasmids constitutively expressing agnoprotein, or ICP47, and enhanced green-fluorescent protein (EGFP. EGFP-gated cells were analyzed for HLA-ABC and HLA-DR expression by flow cytometry. HLA-ABC and HLA-DR expression was also analyzed on UTA-6 bearing tetracycline-regulated agnoprotein or ICP47. Effects of agnoprotein on viral peptide-dependent T-cell killing were investigated using 51Cr release. Results. ICP47 downregulated HLA-ABC without affecting HLA-DR, whereas agnoprotein did not affect HLA-ABC or HLA-DR expression. Interferon-γ treatment increased HLA-ABC in a dose-dependent manner, which was antagonized by ICP47, but not by agnoprotein. In UTA-6 cells, agnoprotein expression did neither impair HLA-ABC or -DR expression nor peptide-specific killing impaired by HLA-matched T-cells. Conclusion. Unlike the HSV-1 ICP47, BKV agnoprotein does not contribute to viral immune evasion by down-regulating HLA-ABC, or interfere with HLA-DR expression or peptide-dependent T-cell cytotoxicity.

Importance of the terminal α-amino group of bradykinin and some kynins on capillary permeability increase

International Nuclear Information System (INIS)

Sugavara, S.

1979-01-01

A simple and reliable method is described for the quantitative evaluation of vascular permeability increase induced by vasoactive drugs with Evans blue labelled with iodine-125 or 131. By using this method the importance of α-amino group of bradykinin (Bk), kallidin (Kd) and methionyl-kallidin (Met-Kd) on the biological activity were studied after reacting the kinins with pyridoxal 5'-phosphate followed by reduction with sodium borohydride. Phosphopyridoxyl-kinins were formed leaving free the guanidino groups. Aminoacid analysis of phosphopyridoxyl-kinin showed that the efficiency of the reaction was extremely good in the blockage of α-amino groups [phosphopyridoxyl-bradikinin (PP-Bk) = 98,8%, phosphopyridoxyl-kallidin (PP-Kd) = 95,2%, phosphopyridoxyl-methionyl-kallidin (PP-Met-Kd) = 98,0%. Log dose-response curves were obtained for Bk, Kd, Met-Kd, acetyl-bradykinin (Ac-Bk), PP-Bk, PP-Kd and PP-Met-Kd and the relative potencies calculated through the Lineweaver-Burk plots. The relative potencies were: PP-Bk about 16% the activity of Bk, Ac-Bk about 31% the activity of Bk, PP-Kd about 17% the activity of Kd, PP-Met-Kd about 12% the activity of Met-Kd. The results show that the terminal α-amino group of kinins is important in the mechanisms of biological activity. (Author) [pt

KEBIJAKAN KEPALA SEKOLAH TERHADAP PELAYANAN BIMBINGAN KONSELING DI SMA NEGERI SE-KABUPATEN PURBALINGGA

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Dinka Rizki Apriliana Mahanggi

2014-06-01

Full Text Available Tujuan penelitian ini untuk mengetahui bagaimana pelaksanaan kebijakan kepala sekolah terhadap pelayanan BK di SMA Negeri se-Kabupaten Purbalingga. Penelitian ini adalah penelitian kualitatifdengan pendekatan penelitian kebijakan, sumber dataprimer dan sekunder. Subyek penelitian yaitu seluruh kepala SMA Negeri se-Kabupaten Purbalingga. Instrumen yang digunakan adalah observasi, wawancara dan dokumentasi.Hasil penelitian menunjukkan bahwa kebijakan sarpras untuk BK sudah cukup lengkap walaupun belum maksimal karena minimnya anggaran dana. Kebijakan alokasi jam BK, prosentasenya 20% sama sekali tidak ada jam BK, 40% semua kelas ada jam BK, sedangkan 40% lainnya hanya sebagian kelas yang ada. Kebijakan mengenai kualifikasi akademik konselor, 50% dari jumlah seluruh guru BK yang berlatarbelakang pendidikan BK, dan 50% lainnya non BK. Hampir semua guru BK sudah memenuhi kriteria beban kerja guru BK yaitu minimal mengampu 150 siswa.Supervisi BK oleh kepala sekolah masih belum optimal. Anggapan BK sebagai polisi sekolah sudah mulai hilang karena kebijakan kepala sekolah yang menetapkan guru BK tidak boleh menghukum siswa. Simpulan penelitiannya yaitu secara umum kepala sekolah sudah mengetahui peran serta tanggungjawab kepala sekolah terhadap pelayanan BK, tetapi dalam pelaksanaannya kepala sekolah kurang menerapkan pemahamannya serta kurang melihat kebutuhan dari guru BK dan siswa. The purpose of this study is to find out how the application of headmaster’ policytowards guidance and counseling service in state high schools. It used qualitative research with policy research analysis approach, primary and secondary data sources. The subjects of this research are all headmasters of state high schools throughout Purbalingga district. Observation, interview, documentation are the instruments used in this research. Result of this study shows that in providing the infrastructureis generally appropriate. There are 20% of which haven’t any time allocation

Kebijakan Kepala Sekolah Terhadap Pelayanan Bimbingan Konseling di SMA Negeri Se-Kabupaten Purbalingga

Directory of Open Access Journals (Sweden)

Dinka Rizki Apriliana Mahanggi

2014-06-01

Full Text Available Tujuan penelitian ini untuk mengetahui bagaimana pelaksanaan kebijakan kepala sekolah terhadap pelayanan BK di SMA Negeri se-Kabupaten Purbalingga. Penelitian ini adalah penelitian kualitatifdengan pendekatan penelitian kebijakan, sumber dataprimer dan sekunder. Subyek penelitian yaitu seluruh kepala SMA Negeri se-Kabupaten Purbalingga. Instrumen yang digunakan adalah observasi, wawancara dan dokumentasi.Hasil penelitian menunjukkan bahwa kebijakan sarpras untuk BK sudah cukup lengkap walaupun belum maksimal karena minimnya anggaran dana. Kebijakan alokasi jam BK, prosentasenya 20% sama sekali tidak ada jam BK, 40% semua kelas ada jam BK, sedangkan 40% lainnya hanya sebagian kelas yang ada. Kebijakan mengenai kualifikasi akademik konselor, 50% dari jumlah seluruh guru BK yang berlatarbelakang pendidikan BK, dan 50% lainnya non BK. Hampir semua guru BK sudah memenuhi kriteria beban kerja guru BK yaitu minimal mengampu 150 siswa.Supervisi BK oleh kepala sekolah masih belum optimal. Anggapan BK sebagai polisi sekolah sudah mulai hilang karena kebijakan kepala sekolah yang menetapkan guru BK tidak boleh menghukum siswa. Simpulan penelitiannya yaitu secara umum kepala sekolah sudah mengetahui peran serta tanggungjawab kepala sekolah terhadap pelayanan BK, tetapi dalam pelaksanaannya kepala sekolah kurang menerapkan pemahamannya serta kurang melihat kebutuhan dari guru BK dan siswa. The purpose of this study is to find out how the application of headmaster’ policytowards guidance and counseling service in state high schools. It used qualitative research with policy research analysis approach, primary and secondary data sources. The subjects of this research are all headmasters of state high schools throughout Purbalingga district. Observation, interview, documentation are the instruments used in this research. Result of this study shows that in providing the infrastructureis generally appropriate. There are 20% of which haven’t any time allocation

H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations.

Science.gov (United States)

Anandakrishnan, Ramu; Aguilar, Boris; Onufriev, Alexey V

2012-07-01

The accuracy of atomistic biomolecular modeling and simulation studies depend on the accuracy of the input structures. Preparing these structures for an atomistic modeling task, such as molecular dynamics (MD) simulation, can involve the use of a variety of different tools for: correcting errors, adding missing atoms, filling valences with hydrogens, predicting pK values for titratable amino acids, assigning predefined partial charges and radii to all atoms, and generating force field parameter/topology files for MD. Identifying, installing and effectively using the appropriate tools for each of these tasks can be difficult for novice and time-consuming for experienced users. H++ (http://biophysics.cs.vt.edu/) is a free open-source web server that automates the above key steps in the preparation of biomolecular structures for molecular modeling and simulations. H++ also performs extensive error and consistency checking, providing error/warning messages together with the suggested corrections. In addition to numerous minor improvements, the latest version of H++ includes several new capabilities and options: fix erroneous (flipped) side chain conformations for HIS, GLN and ASN, include a ligand in the input structure, process nucleic acid structures and generate a solvent box with specified number of common ions for explicit solvent MD.

Immunochemical characterization of the O antigens of two Proteus strains, O8-related antigen of Proteus mirabilis 12 B-r and O2-related antigen of Proteus genomospecies 5/6 12 B-k, infecting a hospitalized patient in Poland.

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Drzewiecka, Dominika; Shashkov, Alexander S; Arbatsky, Nikolay P; Knirel, Yuriy A

2016-05-01

A hospitalized 73-year-old woman was infected with a Proteus mirabilis strain, 12 B-r, isolated from the place of injection of a blood catheter. Another strain, 12 B-k, recognized as Proteus genomospecies 5 or 6, was isolated from the patient's faeces, which was an example of a nosocomial infection rather than an auto-infection. Serological investigation using ELISA and Western blotting showed that strain 12 B-k from faeces belonged to the Proteus O2 serogroup. Strain 12 B-r from the wound displayed cross-reactions with several Proteus O serogroups due to common epitopes on the core or O-specific parts of the lipopolysaccharide. Studies of the isolated 12 B-r O-specific polysaccharide by NMR spectroscopy revealed its close structural similarity to that of Proteus O8. The only difference in 12 B-r was the presence of an additional GlcNAc-linked phosphoethanolamine residue, which creates a putative epitope responsible for the cross-reactivity with Pt. mirabilis O16. The new O-antigen form could appear as a result of adaptation of the bacterium to a changing environment. On the basis of the data obtained, we suggest division of the O8 serogroup into two subgroups: O8a for strains of various Proteus species that have been previously classified into the O8 serogroup, and O8a,b for Pt. mirabilis 12 B-r, where 'a' is a common epitope and 'b' is a phosphoethanolamine-associated epitope. These findings further confirm serological and structural heterogeneity of O antigens of Proteus strains isolated lately from patients in Poland.

Advanced Guidance Algorithms for Homing Missiles with Bearings-Only Measurements.

Science.gov (United States)

1987-11-01

poles are no longer determined by A - BK, and A - KfC . However, the following theorem shows that the coupling H,(s) :=I+PLN(sI -A +BK,) between the...jw) given in Section H-C deter- = N(sI -A + BK,(sI- A + BK, + KC) - ’ KfC )- IM mines the robustness of the FSRO control system. However, N(sl - A + BK...by (si-A+ KfC )-’M constructing a TITO system for the state-feedback regulator.) Therefore, Theorem 3 implies that a regulator with an asymptotic =N(sl-A

Estimation of radiating conditions in the reservoirs located close uranium mining of regions of Kazakhstan

International Nuclear Information System (INIS)

Bakhtin, M.; Kazymbet, P.; Akhmetova, Z.

2010-01-01

For the first time by the analysis of capacity of an equivalent doze of scales - radiations, the maintenance radionuclide and heavy metals in water, ground adjournment and hydrobionts the objective estimation of a radioecological condition of reservoirs in places of extraction, processing and warehousing of uranium ores Akmolinsk of area is given. It is shown, that the investigated reservoirs differ among themselves with a weak, average and high mineralization of water. These circumstances can influence essentially behaviour radionuclides at their hit in a reservoir, and consequently, and on radiating conditions arising at it. Capacity of an equivalent doze of scales - radiations in a coastal part of the majority of the investigated reservoirs corresponds to background values ( 2 ) and beta particles (4,75-4,93 part./mines x sm 2 ) also is marked. The analysis of a radioecological situation in river system Aksu has shown, that its basic components - river water, ground adjournment, water plants and fishes test radiating loading: concentration 238 U in water, ground deposits, a cane and fabrics of the perch makes accordingly 0,66±0,21 Bk/l, 210±2,8 Bk/kg, 0,64±0,19 Bk/kg and 2,50±0,11 Bk/kg. Specific activity 226 Ra in water, ground adjournment, plants and fishes made accordingly 0,02±0,005 Bk/l, 32,20±0,45 Bk/kg, 0,78±0,05 Bk/kg and 2,41±0,31 Bk/kg. Complex radioecological conditions in river system 'Kutunguz' is caused by dump in the river of miner waters with mine 1. In river water concentration 238 U, 226 Ra, 210 Po, 230 Th and 210 Pb makes accordingly on the average - 4,54 Bk/l, 0,11 Bk/l, 2,50 Bk/l, 0,1 Bk/l and 0,37 Bk/l. If the maintenance specified radionuclides in a ground before dump of miner waters varied in limits from 33,1 Bk/kg up to 56,5 Bk/kg in places of dump of miner waters it makes in limits from 62,0 Bk/kg up to 122 Bk/kg, and is lower on a watercourse, in area of settlement B eseloe , in 27 km from a place of dumps - from 92,0 Bk/kg up

Cardiovascular and vasoconstrictive actions of skate bradykinin in the little skate, Leucoraja erinacea (Elasmobranchii).

Science.gov (United States)

Dasiewicz, Patricia J; Conlon, J Michael; Anderson, W Gary

2011-11-01

The vasoconstrictive and cardiovascular actions of a recently identified bradykinin (BK)-related peptide (Gly-Ile-Thr-Ser-Trp-Leu-Pro-Phe) from the little skate, Leucoraja erinacea were examined in the unanesthetised little skate. Intra-arterial administration of a skate BK (0.1-1 nmolkg(-1)) produced a hypertensive response with a rise in blood pressure reaching a maximum elevation of 28.7±4.8% over baseline (Pskate BK. Further, in vivo administration of 1 nmolkg(-1) skate BK induced a significant delayed increase in stroke volume (reaching a maximum of 54.4±14.7% above baseline) without significant effect on either cardiac output or heart rate. In vitro, skate BK constricted the 1st branchial, mesenteric (EC(50) 2.7×10(-9)M) and coeliac (EC(50) 3.1×10(-9)M) arterial preparations of the skate. In contrast, skate [Arg(9)]BK, the mammalian B(1) receptor agonist des-[Arg(9)]BK, and the mammalian B(2) receptor antagonist HOE-140 failed to induce vasoconstriction in these isolated arterial preparations. The vasoconstrictor actions of skate BK in the isolated mesenteric, coeliac and branchial arterial preparations were significantly inhibited when co-administrated with esculetin and phentolamine. Indomethacin also inhibited the vasoconstrictor actions of skate BK in the isolated branchial artery. We conclude that, as in mammals and teleost fish, multiple pathways involving at least the alpha adrenergic and leukotriene synthesis pathway are involved in mediating the vasoconstrictive actions of BK in vascular smooth muscle of the little skate. Copyright © 2011 Elsevier Inc. All rights reserved.

Human umbilical vein: involvement of cyclooxygenase-2 pathway in bradykinin B1 receptor-sensitized responses.

Science.gov (United States)

Errasti, A E; Rey-Ares, V; Daray, F M; Rogines-Velo, M P; Sardi, S P; Paz, C; Podestá, E J; Rothlin, R P

2001-08-01

In isolated human umbilical vein (HUV), the contractile response to des-Arg9-bradykinin (des-Arg9-BK), selective BK B1 receptor agonist, increases as a function of the incubation time. Here, we evaluated whether cyclooxygenase (COX) pathway is involved in BK B1-sensitized response obtained in 5-h incubated HUV rings. The effect of different concentrations of indomethacin, sodium salicylate, ibuprofen, meloxicam, lysine clonixinate or NS-398 administrated 30 min before concentration-response curves (CRC) was studied. All treatments produced a significant rightward shift of the CRC to des-Arg9-BK in a concentration-dependent manner, which provides pharmacological evidence that COX pathway is involved in the BK B1 responses. Moreover, in this tissue, the NS-398 pKb (5.2) observed suggests that COX-2 pathway is the most relevant. The strong correlation between published pIC50 for COX-2 and the NSAIDs' pKbs estimated further supports the hypothesis that COX-2 metabolites are involved in BK B1 receptor-mediated responses. In other rings, indomethacin (30, 100 micromol/l) or NS-398 (10, 30 micromol/l) produced a significant rightward shift of the CRC to BK, selective BK B2 agonist, and its pKbs were similar to the values to inhibit BK B1 receptor responses, suggesting that COX-2 pathway also is involved in BK B2 receptor responses. Western blot analysis shows that COX-1 and COX-2 isoenzymes are present before and after 5-h in vitro incubation and apparently COX-2 does not suffer additional induction.

Vasoinhibins Prevent Bradykinin-Stimulated Endothelial Cell Proliferation by Inactivating eNOS via Reduction of both Intracellular Ca2+ Levels and eNOS Phosphorylation at Ser1179

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Carmen Clapp

2011-07-01

Full Text Available Vasoinhibins, a family of antiangiogenic peptides derived from prolactin proteolysis, inhibit the vascular effects of several proangiogenic factors, including bradykinin (BK. Here, we report that vasoinhibins block the BK-induced proliferation of bovine umbilical vein endothelial cells. This effect is mediated by the inactivation of endothelial nitric oxide synthase (eNOS, as the NO donor DETA-NONOate reverted vasoinhibin action. It is an experimentally proven fact that the elevation of intracellular Ca2+ levels ([Ca2+]i upon BK stimulation activates eNOS, and vasoinhibins blocked the BK-mediated activation of phospholipase C and the formation of inositol 1,4,5-triphosphate leading to a reduced release of Ca2+ from intracellular stores. The [Ca2+]i rise evoked by BK also involves the influx of extracellular Ca2+ via canonical transient receptor potential (TRPC channels. Vasoinhibins likely interfere with TRPC-mediated Ca2+ entry since La3+, which is an enhancer of TRPC4 and TRPC5 channel activity, prevented vasoinhibins from blocking the stimulation by BK of endothelial cell NO production and proliferation, and vasoinhibins reduced the BK-induced increase of TRPC5 mRNA expression. Finally, vasoinhibins prevented the BK-induced phosphorylation of eNOS at Ser1179, a post-translational modification that facilitates Ca2+-calmodulin activation of eNOS. Together, our data show that vasoinhibins, by lowering NO production through the inhibition of both [Ca2+]i mobilization and eNOS phosphorylation, prevent the BK-induced stimulation of endothelial cell proliferation. Thus, vasoinhibins help to regulate BK effects on angiogenesis and vascular homeostasis.

Adubação mineral para a batatinha - Solanum tuberosum L: influência dos elementos N, P e K em solos ricos em matéria orgânica do Vale do Paraíba

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O. J. Boock

1951-01-01

Full Text Available Besults are presented of mineral fertilizer trials witht Irish potato crop in the State of São Paulo. The experiments were conducted in the flat lands of the Paraíba River banks. In this region, potato plantings are usually made from May to October, a period with little rain, :nul practically free from flood. From October to April, when good weather conditions prevail, rice is almost the only crop grown. Iu other regions of the State, potato is planted in February or in August. Chemical analyses of an average sample of the soil revealed a high organic matter content, about seven fold higher total nitrogen content and a twelve fold higher total carbon content, as compared with those found in a soil sample taken from Capão Bonito, an important potato area in the State, where phosphoric acid has been found to be responsible for increases in tuber productions. The experimental design was arranged so that conclusions could be drawn from the influence of increasing amounts of each nutrient element N, P and K, in the presence of a constant amount of the other two. In spite of the high total nitrogen content of the soil, results have shown this element not to he in available form for plants. In these experiments, application of nitrogen has been found to be effective and even decisive in increasing tuber yield. Lack of this element results in a lower production, in some cases, even inferior to check plots. In experiment n.° 38, for instance, PK yielded two tons of tubers per hectar, whereas NK and NP yielded, respectively, 1.1.9 and 12.4 tons. In another trial, n.° 40 BK yielded 10.5 tons per hectar (less than check, while NPK yielded 16.2 tons. From the economical point of view, an amount of 80 kg of N to the hectar in the presence of PK, brougth better profits, application of PK alone, resulted in losses. Determinations of starch content in tubers of every treatment have shown no appreciable differences between them.

Robust Finite-Dimensional LQG (Linear Quadric Gaussian)-Based Controllers for a Class of Distributed Parameter Systems.

Science.gov (United States)

1988-06-01

loop equations can be written in terms of the extended space XE = h ., where . C 7, to get SA = + G 0w(54 ) X K C A- BK - KfC j [0 K] 7] or in terms...C where in LQG notation C, = l,(sJ - (A - BK, - AfC))-’kj C = K (sl - (A - BK, - KfC ))-1K ! 44 Uy Recall that only Kf has to be approximated in...the oper- ators A-BK, and A- KfC both generate stable semigroups [24]. If (A+AA-BK) and (A + AA - 1’fC) also generale stable semigroups, then the

Porcine proximal tubular cells (LLC-PK1) are able to tolerate high levels of lithium chloride in vitro: assessment of the influence of 1-20 mM LiCl on cell death and alterations in cell biology and biochemistry.

Science.gov (United States)

Lucas, Kirsten C; Hart, David A; Becker, Rolf W

2010-01-25

Lithium, a prophylactic drug for the treatment of bipolar disorder, is prescribed with caution due to its side effects, including renal damage. In this study porcine LLC-PK1 renal tubular cells were used to establish the direct toxicity of lithium on proximal cells and gain insights into the molecular mechanisms involved. In the presence of LiCl, cell proliferation exhibited insignificant decreases in a concentration-dependent manner, but once confluent, constant cell numbers were observed. Cell cycle studies indicated a small dose-dependent accumulation of cells in the G2/M stage after 24 h, as well as an increase in cells in the G0/G1 phase after treatment with 1-10 mM LiCl, but not at 20 mM LiCl. No evidence of apoptosis was observed based on cell morphology or DNA fragmentation studies, or evidence of protein expression changes for Bax, Bcl-2, and p53 proteins using immunocytochemistry. In addition caspases 3, 8 and 9 activity remained unaltered between control and lithium-treated cultures. To conclude, exposure to high concentrations of lithium did not result in overt toxic effects to LLC-PK1 renal cells, although LiCl did alter some aspects of cell behaviour, which could potentially influence function over time.

Hydrophobic interaction between contiguous residues in the S6 transmembrane segment acts as a stimuli integration node in the BK channel

Science.gov (United States)

Carrasquel-Ursulaez, Willy; Contreras, Gustavo F.; Sepúlveda, Romina V.; Aguayo, Daniel; González-Nilo, Fernando

2015-01-01

Large-conductance Ca2+- and voltage-activated K+ channel (BK) open probability is enhanced by depolarization, increasing Ca2+ concentration, or both. These stimuli activate modular voltage and Ca2+ sensors that are allosterically coupled to channel gating. Here, we report a point mutation of a phenylalanine (F380A) in the S6 transmembrane helix that, in the absence of internal Ca2+, profoundly hinders channel opening while showing only minor effects on the voltage sensor active–resting equilibrium. Interpretation of these results using an allosteric model suggests that the F380A mutation greatly increases the free energy difference between open and closed states and uncouples Ca2+ binding from voltage sensor activation and voltage sensor activation from channel opening. However, the presence of a bulky and more hydrophobic amino acid in the F380 position (F380W) increases the intrinsic open–closed equilibrium, weakening the coupling between both sensors with the pore domain. Based on these functional experiments and molecular dynamics simulations, we propose that F380 interacts with another S6 hydrophobic residue (L377) in contiguous subunits. This pair forms a hydrophobic ring important in determining the open–closed equilibrium and, like an integration node, participates in the communication between sensors and between the sensors and pore. Moreover, because of its effects on open probabilities, the F380A mutant can be used for detailed voltage sensor experiments in the presence of permeant cations. PMID:25548136

Flank tectonics of Martian volcanoes

International Nuclear Information System (INIS)

Thomas, P.J.; Squyres, S.W.; Carr, M.H.

1990-01-01

On the flanks of Olympus Mons is a series of terraces, concentrically distributed around the caldera. Their morphology and location suggest that they could be thrust faults caused by compressional failure of the cone. In an attempt to understand the mechanism of faulting and the possible influences of the interior structure of Olympus Mons, the authors have constructed a numerical model for elastic stresses within a Martian volcano. In the absence of internal pressurization, the middle slopes of the cone are subjected to compressional stress, appropriate to the formation of thrust faults. These stresses for Olympus Mons are ∼250 MPa. If a vacant magma chamber is contained within the cone, the region of maximum compressional stress is extended toward the base of the cone. If the magma chamber is pressurized, extensional stresses occur at the summit and on the upper slopes of the cone. For a filled but unpressurized magma chamber, the observed positions of the faults agree well with the calculated region of high compressional stress. Three other volcanoes on Mars, Ascraeus Mons, Arsia Mons, and Pavonis Mons, possess similar terraces. Extending the analysis to other Martian volcanoes, they find that only these three and Olympus Mons have flank stresses that exceed the compressional failure strength of basalt, lending support to the view that the terraces on all four are thrust faults

Synovial and systemic pharmacokinetics (PK) of triamcinolone acetonide (TA) following intra-articular (IA) injection of an extended-release microsphere-based formulation (FX006) or standard crystalline suspension in patients with knee osteoarthritis (OA).

Science.gov (United States)

Kraus, V B; Conaghan, P G; Aazami, H A; Mehra, P; Kivitz, A J; Lufkin, J; Hauben, J; Johnson, J R; Bodick, N

2018-01-01

Intra-articular (IA) corticosteroids relieve osteoarthritis (OA) pain, but rapid absorption into systemic circulation may limit efficacy and produce untoward effects. We compared the pharmacokinetics (PK) of IA triamcinolone acetonide (TA) delivered as an extended-release, microsphere-based formulation (FX006) vs a crystalline suspension (TAcs) in knee OA patients. This Phase 2 open-label study sequentially enrolled 81 patients who received a single IA injection of FX006 (5 mL, 32 mg delivered dose, N = 63) or TAcs (1 mL, 40 mg, N = 18). Synovial fluid (SF) aspiration was attempted in each patient at baseline and one post-IA-injection visit (FX006: Week 1, Week 6, Week 12, Week 16 or Week 20; TAcs: Week 6). Blood was collected at baseline and multiple post-injection times. TA concentrations (validated LC-MS/MS, geometric means (GMs)), PK (non-compartmental analysis models), and adverse events (AEs) were assessed. SF TA concentrations following FX006 were quantifiable through Week 12 (pg/mL: 231,328.9 at Week 1; 3590.0 at Week 6; 290.6 at Week 12); post-TAcs, only two of eight patients had quantifiable SF TA at Week 6 (7.7 pg/mL). Following FX006, plasma TA gradually increased to peak (836.4 pg/mL) over 24 h and slowly declined to IA injection prolonged SF joint residency, diminished peak plasma levels, and thus reduced systemic TA exposure relative to TAcs. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

The research of radioimmunoassay using double abs for bradykinin

International Nuclear Information System (INIS)

Cheng Jinxuan; Wang Li; Duan Jinhong; Han Fengyun; Liu Jinsheng; Wang Zhengang; Ren Minfeng

1996-01-01

Bradykinin (BK) is a potent vasodilative substance, and plays great physiological and pathological roles in animals and human beings. To measure the quantity of BK, the radioimmunoassay (RIA) has been devised, but the traditional RIA method has certain defects, such as presence of numerous interfering factors and errors and time consuming. Now, we produce anti-BK serum in rabbits by using BK-ovalbumin conjugate as an immunogen, and the 125 I labeled Tyr 8 -BK by using a modified chloramine-T method. High specific activity has been obtained after purification with DEAE-Sephadex A-25 column chromatography. We use the donkey anti-rabbit Ab and PEG 6000 to separate the bound from the free 125 I-tyr 8 -BK. The limitation range of standard curve is from 25 to 1600 pg, NSB is 3.1%, affinity constant (K) is 0.8 x 10 10 L/mol, and there is no significant interference with other biological BK analogues. The blood samples are treated by adding Polybrene (inhibitor) and PEG 6000 to deposit the big serum proteins in order to reduce the disturbing substances. This method has been shown to be a sensitive, specific, reliable, simple and convenient measure of the serum BK level. By this method, the serum BK quantities in men, women and rats are respectively 1584 +- 347 pg/ml, 1642 +- 302 pg/ml and 1805 +- 225 pg/ml, and recycling rate is 95%, the inter-group CV is 5.0% and outer-group CV = 9.2%

Potentiation of the actions of bradykinin by angiotensin I-converting enzyme inhibitors. The role of expressed human bradykinin B2 receptors and angiotensin I-converting enzyme in CHO cells.

Science.gov (United States)

Minshall, R D; Tan, F; Nakamura, F; Rabito, S F; Becker, R P; Marcic, B; Erdös, E G

1997-11-01

Part of the beneficial effects of angiotensin I-converting enzyme (ACE) inhibitors are due to augmenting the actions of bradykinin (BK). We studied this effect of enalaprilat on the binding of [3H]BK to Chinese hamster ovary (CHO) cells stably transfected to express the human BK B2 receptor alone (CHO-3B) or in combination with ACE (CHO-15AB). In CHO-15AB cells, enalaprilat (1 mumol/L) increased the total number of low-affinity [3H]BK binding sites on the cells at 37 degrees C, but not at 4 degrees C, from 18.4 +/- 4.3 to 40.3 +/- 11.9 fmol/10(6) cells (P potentiated the release of [3H]arachidonic acid and the liberation of inositol 1,4,5-trisphosphate (IP3) induced by BK and [Hyp3-Tyr(Me)8]BK. Moreover, enalaprilat (1 mumol/L) completely and immediately restored the response of the B2 receptor, desensitized by the agonist (1 mumol/L [Hyp3-Tyr(Me)8]BK); this effect was blocked by the antagonist, HOE 140. Finally, enalaprilat, but not the prodrug enalapril, decreased internalization of the receptor from 70 +/- 9% to 45 +/- 9% (P desensitization, and decrease internalization, thereby potentiating BK beyond blocking its hydrolysis.

Upaya Guru Bimbingan dan Konseling dalam Mencegah Perilaku Bullying di SMA Negeri Se Kota Padang

Directory of Open Access Journals (Sweden)

Riri Yunika

2013-09-01

Full Text Available Bullying is a behavior consciously done by someone to abuse and hurt others. Ideally, the guidance and counseling teachers (BK teachersare demanded to give attentions in preventing bullying behavior. However, in fact, the BK teachers have not plan special programs yet to prevent the bullying behavior among students in school. This research aims to describe the understanding of BK teachers about the concept of bullying behavior. Then, it aims to describe the treatment of the BK given by the teachers to the students. Finally, it aims to describe the cooperation among the BK teachers within the school. This research is kind of descriptive research. The population of this research is all of the BK teachers of SMA Negeri (State school for secondary education in Padang. Sample is taken by using area sampling and simple random sampling techniques. Generally, the result implicates that the BK teachers have done preventing efforts toward bullying behavior among students in the school. Thus, the teachers should increase the understanding in reference to bullying behavior among students to prevent the behavior in school.

Molecular and functional expression of high conductance Ca 2+ activated K+ channels in the eel intestinal epithelium

DEFF Research Database (Denmark)

Lionetto, Maria G; Rizzello, Antonia; Giordano, Maria E

2008-01-01

Several types of K(+) channels have been identified in epithelial cells. Among them high conductance Ca(2+)-activated K(+) channels (BK channels) are of relevant importance for their involvement in regulatory volume decrease (RVD) response following hypotonic stress. The aim of the present work...... was to investigate the functional and molecular expression of BK in the eel intestine, which is a useful experimental model for cell volume regulation research. In the present paper using rat BK channel-specific primer, a RT-PCR signal of 696 pb cDNA was detected in eel intestine, whole nucleotide sequence showed...... high similarity (83%) to the alpha subunit of BK channel family. BK channel protein expression was verified by immunoblotting and confocal microscopy, while the functional role of BK channels in epithelial ion transport mechanisms and cell volume regulation was examined by electrophysiological...

Computer simulation of lower-hybrid heating and current drive in tokamaks. Progress report, September 1, 1982-July 1, 1983

International Nuclear Information System (INIS)

Ogden, J.M.

1983-07-01

A lower hybrid ray tracing package has been adapted for use in the PPPL 1-D tokamak transport code TRANSP. The code LHRAY has been written in OLYMPUS format and is suitable for use as a separate simulation program or in conjunction with TRANSP. The generality of the OLYMPUS conventions was chosen in order to make LHRAY easily transferable to other OLYMPUS style transport codes such as BALDUR. The details of LHRAY are described in this report. The physical model documented in our first progress report has been used with one major modification. Instead of solving the 1-D Fokker-Planck equations numerically to give the electron distribution function F/sub e/ in the presence of a background electric field, we have approximated F/sub e/ analytically using the theory of Liu et al for runaway electron distributions. The organization of LHRAY is given and the naming conventions are noted. Finally, preliminary results are presented. Program documentation and a listing of the code are included as appendices

Computed Tomography Findings of Human Polyomavirus BK (BKV)-Associated Cystitis in Allogeneic Hematopoietic Stem Cell Transplant Recipients

International Nuclear Information System (INIS)

Schulze, M.; Beck, R.; Igney, A.; Vogel, M.; Maksimovic, O.; Claussen, C.D.; Faul, C.; Horger, M.

2008-01-01

Background: Over 70% of the general population worldwide is positive for antibodies against polyomavirus hominis type 1 (BKV). Polyomavirus can be reactivated in immunocompromised patients and thereby induce urogenital tract infection, including cystitis. Purpose: To describe the computed tomography (CT) findings of human polyomavirus-induced cystitis in adult patients after allogeneic hematopoietic stem cell transplantation (allogeneic HCT). Material and Methods: The study population was a retrospective cohort of 11 consecutive adult patients (eight men, three women; age range 22-59 years, mean 42.9 years) who received allogeneic HCT between December 2003 and December 2007 and were tested positive for urinary BKV infection. All CT scans were evaluated with regard to bladder wall thickness, mucosal enhancement, distinct layering of thickened bladder wall, and presence of intravesical clots, perivesical stranding as well as attenuation values of intravesical urine. Clinical data concerning transplant and conditioning regimen variables and laboratory parameters were correlated with degree and extent of imaging findings. Results: All patients had clinical signs of cystitis with different degrees of thickening of the urinary bladder wall. Well-delineated urinary bladder layers were present in six patients. Thickening of the urinary bladder wall was continuous in nine of 11 patients. Increased attenuation of intravesical urine was found in seven patients with hemorrhagic cystitis. Four patients had intraluminal clots. Perivesical stranding was not a major CT finding, occurring in a mild fashion in three of 11 patients. The clinical classification of hemorrhagic cystitis did not correlate with the analyzed imaging parameters. Patient outcome was not influenced by this infectious complication. Conclusion: CT findings in patients with polyomavirus BK cystitis consist of different degrees of bladder wall thickening usually with good delineation of all mural layers and

Computed Tomography Findings of Human Polyomavirus BK (BKV)-Associated Cystitis in Allogeneic Hematopoietic Stem Cell Transplant Recipients

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Schulze, M.; Beck, R.; Igney, A.; Vogel, M.; Maksimovic, O.; Claussen, C.D.; Faul, C.; Horger, M. [Dept. of Diagnostic Radiology, Dept. of Internal Medicine-Oncology, and Inst. of Medical Virology, Eberhard-Karls Univ., Tbingen (Germany)

2008-12-15

Background: Over 70% of the general population worldwide is positive for antibodies against polyomavirus hominis type 1 (BKV). Polyomavirus can be reactivated in immunocompromised patients and thereby induce urogenital tract infection, including cystitis. Purpose: To describe the computed tomography (CT) findings of human polyomavirus-induced cystitis in adult patients after allogeneic hematopoietic stem cell transplantation (allogeneic HCT). Material and Methods: The study population was a retrospective cohort of 11 consecutive adult patients (eight men, three women; age range 22-59 years, mean 42.9 years) who received allogeneic HCT between December 2003 and December 2007 and were tested positive for urinary BKV infection. All CT scans were evaluated with regard to bladder wall thickness, mucosal enhancement, distinct layering of thickened bladder wall, and presence of intravesical clots, perivesical stranding as well as attenuation values of intravesical urine. Clinical data concerning transplant and conditioning regimen variables and laboratory parameters were correlated with degree and extent of imaging findings. Results: All patients had clinical signs of cystitis with different degrees of thickening of the urinary bladder wall. Well-delineated urinary bladder layers were present in six patients. Thickening of the urinary bladder wall was continuous in nine of 11 patients. Increased attenuation of intravesical urine was found in seven patients with hemorrhagic cystitis. Four patients had intraluminal clots. Perivesical stranding was not a major CT finding, occurring in a mild fashion in three of 11 patients. The clinical classification of hemorrhagic cystitis did not correlate with the analyzed imaging parameters. Patient outcome was not influenced by this infectious complication. Conclusion: CT findings in patients with polyomavirus BK cystitis consist of different degrees of bladder wall thickening usually with good delineation of all mural layers and

Computed Tomography Findings of Human Polyomavirus BK (BKV)-Associated Cystitis in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Energy Technology Data Exchange (ETDEWEB)

Schulze, M.; Beck, R.; Igney, A.; Vogel, M.; Maksimovic, O.; Claussen, C.D.; Faul, C.; Horger, M. (Dept. of Diagnostic Radiology, Dept. of Internal Medicine-Oncology, and Inst. of Medical Virology, Eberhard-Karls Univ., Tbingen (Germany))

2008-12-15

Background: Over 70% of the general population worldwide is positive for antibodies against polyomavirus hominis type 1 (BKV). Polyomavirus can be reactivated in immunocompromised patients and thereby induce urogenital tract infection, including cystitis. Purpose: To describe the computed tomography (CT) findings of human polyomavirus-induced cystitis in adult patients after allogeneic hematopoietic stem cell transplantation (allogeneic HCT). Material and Methods: The study population was a retrospective cohort of 11 consecutive adult patients (eight men, three women; age range 22-59 years, mean 42.9 years) who received allogeneic HCT between December 2003 and December 2007 and were tested positive for urinary BKV infection. All CT scans were evaluated with regard to bladder wall thickness, mucosal enhancement, distinct layering of thickened bladder wall, and presence of intravesical clots, perivesical stranding as well as attenuation values of intravesical urine. Clinical data concerning transplant and conditioning regimen variables and laboratory parameters were correlated with degree and extent of imaging findings. Results: All patients had clinical signs of cystitis with different degrees of thickening of the urinary bladder wall. Well-delineated urinary bladder layers were present in six patients. Thickening of the urinary bladder wall was continuous in nine of 11 patients. Increased attenuation of intravesical urine was found in seven patients with hemorrhagic cystitis. Four patients had intraluminal clots. Perivesical stranding was not a major CT finding, occurring in a mild fashion in three of 11 patients. The clinical classification of hemorrhagic cystitis did not correlate with the analyzed imaging parameters. Patient outcome was not influenced by this infectious complication. Conclusion: CT findings in patients with polyomavirus BK cystitis consist of different degrees of bladder wall thickening usually with good delineation of all mural layers and

Potentiation of the vascular response to kinins by inhibition of myocardial kininases.

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Dendorfer, A; Wolfrum, S; Schäfer, U; Stewart, J M; Inamura, N; Dominiak, P

2000-01-01

Inhibitors of angiotensin I-converting enzyme (ACE) are very efficacious in the potentiation of the actions of bradykinin (BK) and are able to provoke a B(2) receptor-mediated vasodilation even after desensitization of this receptor. Because this activity cannot be easily explained only by an inhibition of kinin degradation, direct interactions of ACE inhibitors with the B(2) receptor or its signal transduction have been hypothesized. To clarify the significance of degradation-independent potentiation, we studied the vasodilatory effects of BK and 2 degradation-resistant B(2) receptor agonists in the isolated rat heart, a model in which ACE and aminopeptidase P (APP) contribute equally to the degradation of BK. Coronary vasodilation to BK and to a peptidic (B6014) and a nonpeptidic (FR190997) degradation-resistant B(2) agonist was assessed in the presence or absence of the ACE inhibitor ramiprilat, the APP inhibitor mercaptoethanol, or both. Ramiprilat or mercaptoethanol induced leftward shifts in the BK dose-response curve (EC(50)=3.4 nmol/L) by a factor of 4.6 or 4.9, respectively. Combined inhibition of ACE and APP reduced the EC(50) of BK to 0.18 nmol/L (ie, by a factor of 19) but potentiated the activity of B6014 (EC(50)=1.9 nmol/L) only weakly without altering that of FR190997 (EC(50)=0.34 nmol/L). Desensitization of B(2) receptors was induced by the administration of BK (0.2 micromol/L) or FR190997 (0.1 micromol/L) for 30 minutes; the vascular reactivity to ramiprilat or increasing doses of BK was tested thereafter. After desensitization with BK, but not FR190997, an additional application of ramiprilat provoked a B(2) receptor-mediated vasodilation. High BK concentrations were still effective at the desensitized receptor. The process of desensitization was not altered by ramiprilat. These results show that in this model, all potentiating actions of ACE inhibitors on kinin-induced vasodilation are exclusively related to the reduction in BK breakdown and are

Open Circuit Potential Changes upon Protonation/Deprotonation of ω-Functionalized Alkanethiols on Au: Determination of Surface pK {sub 1/2} in Aqueous and Non-Aqueous System

Energy Technology Data Exchange (ETDEWEB)

Yoo, Seung Ryul; Park, Kyung Soon; Jang, Jae Won; Hwang, Seong Pil [Korea Univ., Sejong (Korea, Republic of)

2016-09-15

The controlled assembly of functional nanomaterials has been drawing significant interest for making devices by integration of nanomaterials. The building blocks of functional nanomaterials might be confined spatially on the chemically patterned surface through both covalent and non-covalent bonds. Potentiometric measurement is affordable technique for various researchers because it requires only voltmeter and reference electrode. Moreover, it can be applied to various polar solvent such as methanol and ethanol. The open circuit potential (OCP) is measured indicating the potential difference between reference electrode and working electrode. The potential of working electrode might be affected by redox chemical reaction and charge state/separation. Our results provide the simple and affordable method to investigate pK {sub 1/2} of thin film both in aqueous phase and in non-aqueous phase, which has significant role in colloidal chemistry, nanochemistry, surface chemistry, electrochemistry, and others.

Quantification and distribution of big conductance Ca2+-activated K+ channels in kidney epithelia

DEFF Research Database (Denmark)

Grunnet, Morten; Hay-Schmidt, Anders; Klaerke, Dan A

2005-01-01

and immunohistochemical studies. In cortical collecting ducts, BK channels were exclusively located in principal cells while no channels could be found in intercalated cells. The abundant and distinct distribution in kidney epithelia talks in favor for BK channels being important contributors in maintaining salt......Big conductance Ca2+ activated K+ channels (BK channels) is an abundant channel present in almost all kind of tissue. The accurate quantity and especially the precise distribution of this channel in kidney epithelia are, however, still debated. The aim of the present study has therefore been...... to examine the presence of BK channels in kidney epithelia and determine the actual number and distribution of these channels. For this purpose, a selective peptidyl ligand for BK channels called iberiotoxin or the radiolabeled double mutant analog 125I-IbTX-D19Y/Y36F has been employed. The presence of BK...

Antigen-Specificity of T Cell Infiltrates in Biopsies With T Cell-Mediated Rejection and BK Polyomavirus Viremia: Analysis by Next Generation Sequencing.

Science.gov (United States)

Zeng, G; Huang, Y; Huang, Y; Lyu, Z; Lesniak, D; Randhawa, P

2016-11-01

This study interrogates the antigen-specificity of inflammatory infiltrates in renal biopsies with BK polyomavirus (BKPyV) viremia (BKPyVM) with or without allograft nephropathy (BKPyVN). Peripheral blood mononuclear cells (PBMC) from five healthy HLA-A0101 subjects were stimulated by peptides derived from the BKPYV proteome or polymorphic regions of HLA. Next generation sequencing of the T cell-receptor complementary DNA was performed on peptide-stimulated PBMC and 23 biopsies with T cell-mediated rejection (TCMR) or BKPyVN. Biopsies from patients with BKPyVM or BKVPyVN contained 7.7732 times more alloreactive than virus-reactive clones. Biopsies with TCMR also contained BKPyV-specific clones, presumably a manifestation of heterologous immunity. The mean cumulative T cell clonal frequency was 0.1378 for alloreactive clones and 0.0375 for BKPyV-reactive clones. Samples with BKPyVN and TCMR clustered separately in dendrograms of V-family and J-gene utilization patterns. Dendrograms also revealed that V-gene, J-gene, and D-gene usage patterns were a function of HLA type. In conclusion, biopsies with BKPyVN contain abundant allospecific clones that exceed the number of virus-reactive clones. The T cell component of tissue injury in viral nephropathy appears to be mediated primarily by an "innocent bystander" mechanism in which the principal element is secondary T cell influx triggered by both antiviral and anti-HLA immunity. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Homogeneous distribution of large-conductance calcium-dependent potassium channels on soma and apical dendrite of rat neocortical layer 5 pyramidal neurons.

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Benhassine, Narimane; Berger, Thomas

2005-02-01

Voltage-gated conductances on dendrites of layer 5 pyramidal neurons participate in synaptic integration and output generation. We investigated the properties and the distribution of large-conductance calcium-activated potassium channels (BK channels) in this cell type using excised patches in acute slice preparations of rat somatosensory cortex. BK channels were characterized by their large conductance and sensitivity to the specific blockers paxilline and iberiotoxin. BK channels showed a pronounced calcium-dependence with a maximal opening probability of 0.69 at 10 microm and 0.42 at 3 microm free calcium. Their opening probability and transition time constants between open and closed states are voltage-dependent. At depolarized potentials, BK channel gating is described by two open and one closed states. Depolarization increases the opening probability due to a prolongation of the open time constant and a shortening of the closed time constant. Calcium-dependence and biophysical properties of somatic and dendritic BK channels were identical. The presence of BK channels on the apical dendrite of layer 5 pyramidal neurons was shown by immunofluorescence. Patch-clamp recordings revealed a homogeneous density of BK channels on the soma and along the apical dendrite up to 850 microm with a mean density of 1.9 channels per microm(2). BK channels are expressed either isolated or in clusters containing up to four channels. This study shows the presence of BK channels on dendrites. Their activation might modulate the shape of sodium and calcium action potentials, their propagation along the dendrite, and thereby the electrotonic distance between the somatic and dendritic action potential initiation zones.

A new method for the measurement of anteversion of the acetabular cup after total hip arthroplasty.

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Aydogan, Mehmet; Burç, Halil; Saka, Gursel

2014-08-01

Many methods of determining the anteversion of the acetabular cup have been described in the literature. The advantages and disadvantages of each of these methods are discussed in this paper. We present a new method of measuring the acetabular anteversion at the anteroposterior hip. The formula designed by the authors was anteversion angle (α) = arc sin |PK|/√ |AK| × |BK|. The formula was tested using the AutoCAD software, and an experimental study was conducted to evaluate the accuracy. Three groups were created, and 16 X-ray images were taken and coded. Ten orthopaedic surgeons measured the acetabular anteversion from these X-rays using our formula. The results in Group 1 were closer to the actual value; in contrast, the results in Group 2 differed from the actual values. The results in Group 3 were as close to the actual anteversion values as were those in Group 1. Developments in technology often bring an increase in complications. Despite newly developed surgical methods and technology, the position of the acetabular cup is still used to determine the results of a total hip arthroplasty. Our method is simple, cost-effective and achieves almost 100 % accuracy.

Biochemical Properties and Potential Applications of Recombinant Leucine Aminopeptidase from Bacillus kaustophilus CCRC 11223

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Yonghua Wang

2011-11-01

Full Text Available Experiments were carried out to investigate the effects of various factors on the activity and conformation of recombinant leucine aminopeptidase of Bacillus kaustophilus CCRC 11223 (BkLAP and potential utilization of BkLAP in the hydrolysis of anchovy protein. Optimal temperature and pH of BkLAP were 70 °C and 8.0 in potassium-phosphate buffer, respectively, and the activity was strongly stimulated by Ni2+, followed by Mn2+ and Co2+. Conformational studies via circular dichroism spectroscopy indicated that various factors could influence the secondary structure of BkLAP to different extents and further induce the changes in enzymatic activity. The secondary structure of BkLAP was slightly modified by Ni2+ at the concentration of 1×10−4 M, however, significant changes on the secondary structures of the enzyme were observed when Hg2+ was added to the concentration of 1×10−4 M. The potential application of BkLAP was evaluated through combination with the commercial or endogenous enzyme to hydrolysis the anchovy protein. Results showed that combining the BkLAP with other enzymes could significantly increase the degree of hydrolysis and amino acid component of hydrolysate. In this regard, BkLAP is a potential enzyme that can be used in the protein hydrolysate industry.

Nitric oxide inhibits the bradykinin B2 receptor-mediated adrenomedullary catecholamine release but has no effect on adrenal blood flow response in vivo.

Science.gov (United States)

Bouallegue, Ali; Yamaguchi, Nobuharu

2005-06-01

The role of nitric oxide (NO) in bradykinin (BK)-induced adrenal catecholamine secretion still remains obscure. The present study was to investigate whether an inhibition of NO synthase with N(omega)-nitro-L-arginine methyl ester (L-NAME) would modulate BK-induced adrenal catecholamine secretion (ACS) and adrenal vasodilating response (AVR) in anesthetized dogs. Plasma catecholamine concentrations were determined with an HPLC coupled with an electrochemical detector. All drugs were locally administered to the left adrenal gland via intra-arterial infusion. BK dose-dependently increased both ACS and AVR. Hoe-140, a selective B(2) antagonist, significantly blocked the BK-induced increases in both ACS and AVR. In the presence of L-NAME, the BK-induced ACS was significantly enhanced, while the simultaneous AVR remained unaffected. These results suggest that the both BK-induced ACS and AVR are primarily mediated by B(2) receptors in the canine adrenal gland. Our results also suggest that the enhanced ACS in response to BK in the presence of L-NAME may have resulted from a specific inhibition of NO formation in the adrenal gland. It is concluded that the BK-induced NO may play an inhibitory role in the B(2)-receptor-mediated mechanisms regulating ACS, while it may not be implicated in the B(2)-receptor-mediated AVR under in vivo conditions.

Pro-apoptotic effect of a Mycoplasma hyopneumoniae putative type I signal peptidase on PK(15) swine cells.

Science.gov (United States)

Paes, Jéssica A; Virginio, Veridiana G; Cancela, Martín; Leal, Fernanda M A; Borges, Thiago J; Jaeger, Natália; Bonorino, Cristina; Schrank, Irene S; Ferreira, Henrique B

2017-03-01

Mycoplasma hyopneumoniae is an economically significant swine pathogen that causes porcine enzootic pneumonia (PEP). Important processes for swine infection by M. hyopneumoniae depend on cell surface proteins, many of which are secreted by secretion pathways not completely elucidated so far. A putative type I signal peptidase (SPase I), a possible component of a putative Sec-dependent pathway, was annotated as a product of the sipS gene in the pathogenic M. hyopneumoniae 7448 genome. This M. hyopneumoniae putative SPase I (MhSPase I) displays only 14% and 23% of sequence identity/similarity to Escherichia coli bona fide SPase I, and, in complementation assays performed with a conditional E. coli SPase I mutant, only a partial restoration of growth was achieved with the heterologous expression of a recombinant MhSPase I (rMhSPase I). Considering the putative surface location of MhSPase I and its previously demonstrated capacity to induce a strong humoral response, we then assessed its potential to elicit a cellular and possible immunomodulatory response. In assays for immunogenicity assessment, rMhSPase I unexpectedly showed a cytotoxic effect on murine splenocytes. This cytotoxic effect was further confirmed using the swine epithelial PK(15) cell line in MTT and annexin V-flow cytometry assays, which showed that rMhSPase I induces apoptosis in a dose dependent-way. It was also demonstrated that this pro-apoptotic effect of rMhSPase I involves activation of a caspase-3 cascade. The potential relevance of the rMhSPase I pro-apoptotic effect for M. hyopneumoniae-host interactions in the context of PEP is discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

Surgeons' vision rewarded.

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Baillie, Jonathan

2010-08-01

Surgeons and clinical staff, theatre circulation and scrub personnel, and anaesthetists, as well as the estates and facilities team at Kent's Maidstone Hospital, have worked with specialist supplier of integrated audio, video, and instrumentation systems for the operating room, Olympus Medical, to develop what is claimed is among the UK's most advanced operating theatres yet built for laparoscopic and endoscopic surgery. HEJ editor Jonathan Baillie discussed the project with Amir Nisar, the surgeon who championed efforts to get the facility built, and Olympus Medical national sales manager, systems integration, James Watts.

Non-invasive measurement of pressure gradients using ultrasound

DEFF Research Database (Denmark)

Olesen, Jacob Bjerring; Traberg, Marie Sand; Pihl, Michael Johannes

2013-01-01

for isotropic fluids to the estimated velocity fields. The velocity fields were measured for a steady flow on a carotid bifurcation phantom (Shelley Medical, Canada) with a 70% constriction on the internal branch. Scanning was performed with a BK8670 linear transducer (BK Medical, Denmark) connected to a BK...

Possible stabilization of the tetravalent oxidation state of berkelium and californium in acetonitrile with triphenylarsine oxide

International Nuclear Information System (INIS)

Payne, G.F.; Peterson, J.R.

1987-01-01

It appears that we may have prepared Bk(IV) nitrate.nTPAs0 and Bk(IV) perchlorate.nTPAs0 complexes which formed the corresponding Cf(IV) complexes through the beta decay of Bk-249. Definitive proof should come from similar experiments with quantities of Bk-249 large enough to allow spectrophotometric detection of the characteristic f→f transitions in these berkelium and californium species. It is clear, however, that TPAs0 and acetonitrile can play a pivotal role in the stabilization of lanact(IV) species

Identification of Receptor Ligands and Receptor Subtypes Using Antagonists in a Capillary Electrophoresis Single-Cell Biosensor Separation System

Science.gov (United States)

Fishman, Harvey A.; Orwar, Owe; Scheller, Richard H.; Zare, Richard N.

1995-08-01

A capillary electrophoresis system with single-cell biosensors as a detector has been used to separate and identify ligands in complex biological samples. The power of this procedure was significantly increased by introducing antagonists that inhibited the cellular response from selected ligand-receptor interactions. The single-cell biosensor was based on the ligand-receptor binding and G-protein-mediated signal transduction pathways in PC12 and NG108-15 cell lines. Receptor activation was measured as increases in cytosolic free calcium ion concentration by using fluorescence microscopy with the intracellular calcium ion indicator fluo-3 acetoxymethyl ester. Specifically, a mixture of bradykinin (BK) and acetylcholine (ACh) was fractionated and the components were identified by inhibiting the cellular response with icatibant (HOE 140), a selective antagonist to the BK B_2 receptor subtype (B_2BK), and atropine, an antagonist to muscarinic ACh receptor subtypes. Structurally related forms of BK were also identified based on inhibiting B_2BK receptors. Applications of this technique include identification of endogenous BK in a lysate of human hepatocellular carcinoma cells (Hep G2) and screening for bioactivity of BK degradation products in human blood plasma. The data demonstrate that the use of antagonists with a single-cell biosensor separation system aids identification of separated components and receptor subtypes.

A new Agraecina spider species from the Balkan Peninsula (FYR Macedonia) (Araneae: Liocranidae).

Science.gov (United States)

Deltshev, Christo; Wang, Chunxia

2016-05-30

        Specimens were collected using pitfall traps. Coloration is described from alcohol-preserved specimens. Specimens were examined and measured using a Wild M5A stereomicroscope. Further details were studied and measured under an Olympus BX41 compound microscope. All drawings were made using a drawing apparatus attached to a Leica stereomicroscope. Male palps and female genitalia were examined and illustrated after they were dissected from the spiders' bodies. Photos were taken with an Olympus C7070 wide zoom digital camera mounted on an Olympus SZX12 stereomicroscope. The images were montaged using Helicon Focus image stacking software. Measurements of the legs are taken from the dorsal side. Total length of the body includes the chelicerae. All measurements were taken in mm. Abbreviations used in text include: AME, anterior median eyes; ALE, anterior lateral eyes; EM, embolus; MA, median apophysis; CD, copulatory duct; ST, spermatheca; fe, femur; pa, patella; ti, tibia; mt, metatarsus; p, prolateral; d, dorsal; r, retrolateral; v, ventral. Type specimens are deposited in the National Museum of Natural History (NMNHS), Sofia, Bulgaria.

Bradykinin Contributes to Sympathetic and Pressor Responses Evoked by Activation of Skeletal Muscle Afferents P2X in Heart Failure

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Jihong Xing

2016-11-01

Full Text Available Background/Aims: Published data suggest that purinergic P2X receptors of muscle afferent nerves contribute to the enhanced sympathetic nervous activity (SNA and blood pressure (BP responses during static exercise in heart failure (HF. In this study, we examined engagement of bradykinin (BK in regulating responses of SNA and BP evoked by P2X stimulation in rats with HF. We further examined cellular mechanisms responsible for BK. We hypothesized that BK potentiates P2X currents of muscle dorsal root ganglion (DRG neurons, and this effect is greater in HF due to upregulation of BK kinin B2 and P2X3 receptor. As a result, BK amplifies muscle afferents P2X-mediated SNA and BP responses. Methods: Renal SNA and BP responses were recorded in control rats and rats with HF. Western Blot analysis and patch-clamp methods were employed to examine the receptor expression and function of DRG neurons involved in the effects of BK. Results: BK injected into the arterial blood supply of the hindlimb muscles heightened the reflex SNA and BP responses induced by P2X activation with α,β-methylene ATP to a greater degree in HF rats. In addition, HF upregulated the protein expression of kinin B2 and P2X3 in DRG and the prior application of BK increased the magnitude of α,β-methylene ATP-induced currents in muscle DRG neurons from HF rats. Conclusion: BK plays a facilitating role in modulating muscle afferent P2X-engaged reflex sympathetic and pressor responses. In HF, P2X responsivness is augmented due to increases in expression of kinin B2 and P2X3 receptors and P2X current activity.

Bradykinin induced a positive chronotropic effect via stimulation of T- and L-type calcium currents in heart cells.

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El-Bizri, Nesrine; Bkaily, Ghassan; Wang, Shimin; Jacques, Danielle; Regoli, Domenico; D'Orléans-Juste, Pedro; Sukarieh, Rami

2003-03-01

Using Fluo-3 calcium dye confocal microscopy and spontaneously contracting embryonic chick heart cells, bradykinin (10(-10) M) was found to induce positive chronotropic effects by increasing the frequency of the transient increase of cytosolic and nuclear free Ca2+. Pretreatment of the cells with either B1 or B2 receptor antagonists (R126 and R817, respectively) completely prevented bradykinin (BK) induced positive chronotropic effects on spontaneously contracting single heart cells. Using the whole-cell voltage clamp technique and ionic substitution to separate the different ionic current species, our results showed that BK (10(-6) M) had no effect on fast Na+ inward current and delayed outward potassium current. However, both L- and T-type Ca2+ currents were found to be increased by BK in a dose-dependent manner (10(-10)-10(-7) M). The effects of BK on T- and L-type Ca2+ currents were partially blocked by the B1 receptor antagonist [Leu8]des-Arg9-BK (R592) (10(-7) M) and completely reversed by the B2 receptor antagonist D-Arg[Hyp3,D-Phe7,Leu8]BK (R-588) (10(-7) M) or pretreatment with pertussis toxin (PTX). These results demonstrate that BK induced a positive chronotropic effect via stimulation of T- and L-type Ca2+ currents in heart cells mainly via stimulation of B2 receptor coupled to PTX-sensitive G-proteins. The increase of both types of Ca2+ current by BK in heart cells may explain the positive inotropic and chronotropic effects of this hormone.

Protective effect and mechanism of action of saponins isolated from the seeds of gac (Momordica cochinchinensis Spreng.) against cisplatin-induced damage in LLC-PK1 kidney cells.

Science.gov (United States)

Jung, Kiwon; Lee, Dahae; Yu, Jae Sik; Namgung, Hojin; Kang, Ki Sung; Kim, Ki Hyun

2016-03-01

This study was performed to investigate the renoprotective effect and mechanism of Momordicae Semen, gac seeds, against the cisplatin-induced damage in LLC-PK1 kidney cells. In order to identify the active components, three major saponins were isolated from extract of the gac seed, gypsogenin 3-O-β-d-galactopyranosyl(1→2)-[α-L-rhamnopyranosyl(1→3)]-β-d-glucuronopyranoside (1), quillaic acid 3-O-β-D-galactopyranosyl(1→2)-[α-L-rhamnopyranosyl(1→3)]-β-D-glucuronopyranoside (2), and momordica saponin I (3). Compounds 1 and 2 ameliorated cisplatin-induced nephrotoxicity up to 80% of the control value at both 5 and 25μM. Phosphorylation of MAPKs was decreased along cisplatin treatment after treatment with compounds 1 and 2. These results show that blocking the MAPKs signaling cascade plays a critical role in mediating the renoprotective effect of Momordicae Semen extract and compounds 1 and 2. Copyright © 2016 Elsevier Ltd. All rights reserved.

PK-PD Integration Modeling and Cutoff Value of Florfenicol against Streptococcus suis in Pigs

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Zhixin Lei

2018-01-01

Full Text Available The aims of the present study were to establish optimal doses and provide an alternate COPD for florfenicol against Streptococcus suis based on pharmacokinetic-pharmacodynamic integration modeling. The recommended dose (30 mg/kg b.w. were administered in healthy pigs through intramuscular and intravenous routes for pharmacokinetic studies. The main pharmacokinetic parameters of Cmax, AUC0-24h, AUC, Ke, t1/2ke, MRT, Tmax, and Clb, were estimated as 4.44 μg/ml, 88.85 μg⋅h/ml, 158.56 μg⋅h/ml, 0.048 h-1, 14.46 h, 26.11 h, 4 h and 0.185 L/h⋅kg, respectively. The bioavailability of florfenicol was calculated to be 99.14% after I.M administration. A total of 124 Streptococcus suis from most cities of China were isolated to determine the minimum inhibitory concentration (MIC of florfenicol. The MIC50 and MIC90 were calculated as 1 and 2 μg/ml. A serotype 2 Streptococcus suis (WH-2, with MIC value similar to MIC90, was selected as a representative for an in vitro and ex vivo pharmacodynamics study. The MIC values of WH-2 in TSB and plasma were 2 μg/ml, and the MBC/MIC ratios were 2 in TSB and plasma. The MPC was detected to be 3.2 μg/ml. According to inhibitory sigmoid Emax model, plasma AUC0-24h/MIC values of florfenicol versus Streptococcus suis were 37.89, 44.02, and 46.42 h for the bactericidal, bacteriostatic, and elimination activity, respectively. Monte Carlo simulations the optimal doses for bactericidal, bacteriostatic, and elimination effects were calculated as 16.5, 19.17, and 20.14 mg/kg b.w. for 50% target attainment rates (TAR, and 21.55, 25.02, and 26.85 mg/kg b.w. for 90% TAR, respectively. The PK-PD cutoff value (COPD analyzed from MCS for florfenicol against Streptococcus suis was 1 μg/ml which could provide a sensitivity cutoff value. These results contributed an optimized alternative to clinical veterinary medicine and showed that the dose of 25.02 mg/kg florfenicol for 24 h could have a bactericidal action against

Corrección del deslizamiento de una ladera en la autovia A-4. PK. 340 en el término municipal de Marmolejo, Jaén mediante pantalla de pilotes y sistemas de drenaje

OpenAIRE

Sastre Alonso, Julio

2013-01-01

En este proyecto se describe el cálculo y diseño de una serie de medidas correctoras propuestas a raíz de un deslizamiento de ladera que tuvo lugar en noviembre de 2010 y afectó a parte de la calzada de la autovía A-4 en el P.K. 340 entre Córdoba y Jaén; principalmente en la ejecución de una pantalla de pilotes como elemento estructural de estabilización y contención del terreno, por medio del método de equilibrio límite y cálculo del módulo de reacción o coeficiente de balasto horizontal, a ...

Biotechnological Fluorescent Ligands of the Bradykinin B1 Receptor: Protein Ligands for a Peptide Receptor.

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Xavier Charest-Morin

Full Text Available The bradykinin (BK B1 receptor (B1R is a peculiar G protein coupled receptor that is strongly regulated to the point of being inducible in immunopathology. Limited clinical evidence suggests that its expression in peripheral blood mononuclear cells is a biomarker of active inflammatory states. In an effort to develop a novel imaging/diagnostic tool, we report the rational design and testing of a fusion protein that is a ligand of the human B1R but not likely to label peptidases. This ligand is composed of a fluorescent protein (FP (enhanced green FP [EGFP] or mCherry prolonged at its N-terminus by a spacer peptide and a classical peptide agonist or antagonist (des-Arg9-BK, [Leu8]des-Arg9-BK, respectively. The design of the spacer-ligand joint peptide was validated by a competition assay for [3H]Lys-des-Arg9-BK binding to the human B1R applied to 4 synthetic peptides of 18 or 19 residues. The labeling of B1R-expressing cells with EGFP or mCherry fused with 7 of such peptides was performed in parallel (microscopy. Both assays indicated that the best design was FP-(Asn-Glyn-Lys-des-Arg9-BK; n = 15 was superior to n = 5, suggesting benefits from minimizing steric hindrance between the FP and the receptor. Cell labeling concerned mostly plasma membranes and was inhibited by a B1R antagonist. EGFP-(Asn-Gly15-Lys-des-Arg9-BK competed for the binding of [3H]Lys-des-Arg9-BK to human recombinant B1R, being only 10-fold less potent than the unlabeled form of Lys-des-Arg9-BK to do so. The fusion protein did not label HEK 293a cells expressing recombinant human BK B2 receptors or angiotensin converting enzyme. This study identifies a modular C-terminal sequence that can be adapted to protein cargoes, conferring high affinity for the BK B1R, with possible applications in diagnostic cytofluorometry, histology and drug delivery (e.g., in oncology.

Neurogenic detrusor overactivity is associated with decreased expression and function of the large conductance voltage- and Ca(2+-activated K(+ channels.

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Kiril L Hristov

Full Text Available Patients suffering from a variety of neurological diseases such as spinal cord injury, Parkinson's disease, and multiple sclerosis often develop neurogenic detrusor overactivity (NDO, which currently lacks a universally effective therapy. Here, we tested the hypothesis that NDO is associated with changes in detrusor smooth muscle (DSM large conductance Ca(2+-activated K(+ (BK channel expression and function. DSM tissue samples from 33 patients were obtained during open bladder surgeries. NDO patients were clinically characterized preoperatively with pressure-flow urodynamics demonstrating detrusor overactivity, in the setting of a clinically relevant neurological condition. Control patients did not have overactive bladder and did not have a clinically relevant neurological disease. We conducted quantitative polymerase chain reactions (qPCR, perforated patch-clamp electrophysiology on freshly-isolated DSM cells, and functional studies on DSM contractility. qPCR experiments revealed that DSM samples from NDO patients showed decreased BK channel mRNA expression in comparison to controls. Patch-clamp experiments demonstrated reduced whole cell and transient BK currents (TBKCs in freshly-isolated DSM cells from NDO patients. Functional studies on DSM contractility showed that spontaneous phasic contractions had a decreased sensitivity to iberiotoxin, a selective BK channel inhibitor, in DSM strips isolated from NDO patients. These results reveal the novel finding that NDO is associated with decreased DSM BK channel expression and function leading to increased DSM excitability and contractility. BK channel openers or BK channel gene transfer could be an alternative strategy to control NDO. Future clinical trials are needed to evaluate the value of BK channel opening drugs or gene therapies for NDO treatment and to identify any possible adverse effects.

Cell volume and membrane stretch independently control K+ channel activity

DEFF Research Database (Denmark)

Bomholtz, Sofia Hammami; Willumsen, Niels J; Olsen, Hervør L

2009-01-01

A number of potassium channels including members of the KCNQ family and the Ca(2+) activated IK and SK, but not BK, are strongly and reversibly regulated by small changes in cell volume. It has been argued that this general regulation is mediated through sensitivity to changes in membrane stretch...... was not affected by membrane stretch. The results indicate that (1) activation of BK channels by local membrane stretch is not mimicked by membrane stress induced by cell swelling, and (2) activation of KCNQ1 channels by cell volume increase is not mediated by local tension in the cell membrane. We conclude....... To test this hypothesis we have studied the regulation of KCNQ1 and BK channels after expression in Xenopus oocytes. Results from cell-attached patch clamp studies (approximately 50 microm(2) macropatches) in oocytes expressing BK channels demonstrate that the macroscopic volume-insensitive BK current...

Chelation and stabilization of berkelium in oxidation state +IV

Science.gov (United States)

Deblonde, Gauthier J.-P.; Sturzbecher-Hoehne, Manuel; Rupert, Peter B.; An, Dahlia D.; Illy, Marie-Claire; Ralston, Corie Y.; Brabec, Jiri; de Jong, Wibe A.; Strong, Roland K.; Abergel, Rebecca J.

2017-09-01

Berkelium (Bk) has been predicted to be the only transplutonium element able to exhibit both +III and +IV oxidation states in solution, but evidence of a stable oxidized Bk chelate has so far remained elusive. Here we describe the stabilization of the heaviest 4+ ion of the periodic table, under mild aqueous conditions, using a siderophore derivative. The resulting Bk(IV) complex exhibits luminescence via sensitization through an intramolecular antenna effect. This neutral Bk(IV) coordination compound is not sequestered by the protein siderocalin—a mammalian metal transporter—in contrast to the negatively charged species obtained with neighbouring trivalent actinides americium, curium and californium (Cf). The corresponding Cf(III)-ligand-protein ternary adduct was characterized by X-ray diffraction analysis. Combined with theoretical predictions, these data add significant insight to the field of transplutonium chemistry, and may lead to innovative Bk separation and purification processes.

NS19504

DEFF Research Database (Denmark)

Nausch, Bernhard; Rode, Frederik; Jørgensen, Susanne

2014-01-01

channel activators and identified a small-molecule positive modulator, NS19504 (5-[(4-bromophenyl)methyl]-1,3-thiazol-2-amine), which activated the BK channel with an EC50 value of 11.0 ± 1.4 µM. Hit validation was performed using high-throughput electrophysiology (QPatch), and further characterization......19504 activated BK channels in native smooth muscle cells from guinea pig urinary bladder. In guinea pig urinary bladder strips, NS19504 (1 µM) reduced spontaneous phasic contractions, an effect that was significantly inhibited by the specific BK channel blocker iberiotoxin. In contrast, NS19504 (1 µ......M) only modestly inhibited nerve-evoked contractions and had no effect on contractions induced by a high K(+) concentration consistent with a K(+) channel-mediated action. Collectively, these results show that NS19504 is a positive modulator of BK channels and provide support for the role of BK channels...

MENARIK MINAT SISWA PADA LAYANAN BIMBINGAN DAN KONSELING ISLAMI DI SEKOLAH MENGGUNAKAN LAYANAN INFORMASI DENGAN TEKNIK MODELLING

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Ismah -

2016-08-01

Full Text Available Rendahnya minat siswa pada layanan bimbingan dan konseling terlihat dari minimnya siswa yang datang keruang BK untuk memanfaatkan layanan bimbingan dan konseling di sekolah. Permasalahan yang dikaji dalam penulisan ini adalah, Bagaiman layanan informasi dengan teknik modelling dapat menarik terhadap minat siswa pada layanan bimbingan dan konseling di sekolah khususnya bimbingan dan konseling islami. Tujuan yang hendak dicapai dalam penulisan ini adalah untuk memberi masukan kepada guru BK di sekolah supaya siswa-siswinya tertarik atau berminat berkunjung di ruang BK, menggunakan cara ”layanan informasi dengan teknik modelling terhadap minat siswa pada layanan bimbingan dan konseling siswa di sekolah khususnya bimbingan dan konseling islami”. Pada kajian ini dapat dianalisis bahwa: layanan informasi dengan teknik modelling, diharapkan dapat berdampak positif terhadap minat siswa berkunjung ke ruang BK, sehingga guru BK dapat memberi layanan bimbingan konseling khusunya bimbingan dan konseling islami dengan kesadaran siswa tanpa pemaksaan.

Simple synthesis of carbon-11-labeled chromen-4-one derivatives as new potential PET agents for imaging of DNA-dependent protein kinase (DNA-PK) in cancer

International Nuclear Information System (INIS)

Gao, Mingzhang; Wang, Min; Miller, Kathy D.; Zheng, Qi-Huang

2012-01-01

Carbon-11-labeled chromen-4-one derivatives were synthesized as new potential PET agents for imaging of DNA repair enzyme DNA-dependent protein kinase (DNA-PK) in cancer. The target tracers, X-[ 11 C]methoxy-2-morpholino-4H-chromen-4-ones (X=8, 7, 6, 5; [ 11 C]4a–d), were prepared from their corresponding precursors, X-hydroxy-2-morpholino-4H-chromen-4-ones (X=8, 7, 6, 5; 5a–d), with [ 11 C]CH 3 OTf through O-[ 11 C]methylation and isolated by a simplified solid-phase extraction (SPE) method using a C-18 Sep-Pak Plus cartridge. The radiochemical yields decay corrected to end of bombardment (EOB), from [ 11 C]CO 2 , were 40–60%. The specific activity at end of synthesis (EOS) was 185–370 GBq/μmol. - Highlights: ► New chromen-4-one derivatives were synthesized. ► New carbon-11-labeled chromen-4-one derivatives were synthesized. ► Simple solid-phase extraction (SPE) method was employed in radiosynthesis.

Hierarchies of hyper-AFLs

NARCIS (Netherlands)

Engelfriet, Joost

1985-01-01

For a full semi-AFL K, B(K) is defined as the family of languages generated by all K-extended basic macro grammars, while H(K) B(K) is the smallest full hyper-AFL containing K; a full basic-AFL is a full AFL K such that B(K) = K (hence every full basic-AFL is a full hyper-AFL). For any full semi-AFL

Differential Patterns of Large Tumor Antigen-Specific Immune Responsiveness in Patients with BK Polyomavirus-Positive Prostate Cancer or Benign Prostatic Hyperplasia

Science.gov (United States)

Sais, Giovanni; Wyler, Stephen; Hudolin, Tvrtko; Banzola, Irina; Mengus, Chantal; Bubendorf, Lukas; Wild, Peter J.; Hirsch, Hans H.; Sulser, Tullio; Spagnoli, Giulio C.

2012-01-01

The role of the polyomavirus BK (BKV) large tumor antigen (L-Tag) as a target of immune response in patients with prostate cancer (PCa) has not been investigated thus far. In this study, we comparatively analyzed humoral and cellular L-Tag-specific responsiveness in age-matched patients bearing PCa or benign prostatic hyperplasia, expressing or not expressing BKV L-Tag-specific sequences in their tissue specimens, and in non-age-matched healthy individuals. Furthermore, results from patients with PCa were correlated to 5-year follow-up clinical data focusing on evidence of biochemical recurrence (BR) after surgery (prostate specific antigen level of ≥0.2 ng/ml). In peripheral blood mononuclear cells (PBMC) from patients with PCa with evidence of BR and BKV L-Tag-positive tumors, stimulation with peptides derived from the BKV L-Tag but not those derived from Epstein-Barr virus, influenza virus, or cytomegalovirus induced a peculiar cytokine gene expression profile, characterized by high expression of interleukin-10 (IL-10) and transforming growth factor β1 and low expression of gamma interferon genes. This pattern was confirmed by protein secretion data and correlated with high levels of anti-BKV L-Tag IgG. Furthermore, in PBMC from these PCa-bearing patients, L-Tag-derived peptides significantly expanded an IL-10-secreting CD4+ CD25+(high) CD127− FoxP3+ T cell population with an effector memory phenotype (CD103+) capable of inhibiting proliferation of autologous anti-CD3/CD28-triggered CD4+ CD25− T cells. Collectively, our findings indicate that potentially tolerogenic features of L-Tag-specific immune response are significantly associated with tumor progression in patients with BKV+ PCa. PMID:22647697

Large-conductance calcium-dependent potassium channels prevent dendritic excitability in neocortical pyramidal neurons.

Science.gov (United States)

Benhassine, Narimane; Berger, Thomas

2009-03-01

Large-conductance calcium-dependent potassium channels (BK channels) are homogeneously distributed along the somatodendritic axis of layer 5 pyramidal neurons of the rat somatosensory cortex. The relevance of this conductance for dendritic calcium electrogenesis was studied in acute brain slices using somatodendritic patch clamp recordings and calcium imaging. BK channel activation reduces the occurrence of dendritic calcium spikes. This is reflected in an increased critical frequency of somatic spikes necessary to activate the distal initiation zone. Whilst BK channels repolarise the somatic spike, they dampen it only in the distal dendrite. Their activation reduces dendritic calcium influx via glutamate receptors. Furthermore, they prevent dendritic calcium electrogenesis and subsequent somatic burst discharges. However, the time window for coincident somatic action potential and dendritic input to elicit dendritic calcium events is not influenced by BK channels. Thus, BK channel activation in layer 5 pyramidal neurons affects cellular excitability primarily by establishing a high threshold at the distal action potential initiation zone.

Local calcium signalling is mediated by mechanosensitive ion channels in mesenchymal stem cells

International Nuclear Information System (INIS)

Chubinskiy-Nadezhdin, Vladislav I.; Vasileva, Valeria Y.; Pugovkina, Natalia A.; Vassilieva, Irina O.; Morachevskaya, Elena A.; Nikolsky, Nikolay N.; Negulyaev, Yuri A.

2017-01-01

Mechanical forces are implicated in key physiological processes in stem cells, including proliferation, differentiation and lineage switching. To date, there is an evident lack of understanding of how external mechanical cues are coupled with calcium signalling in stem cells. Mechanical reactions are of particular interest in adult mesenchymal stem cells because of their promising potential for use in tissue remodelling and clinical therapy. Here, single channel patch-clamp technique was employed to search for cation channels involved in mechanosensitivity in mesenchymal endometrial-derived stem cells (hMESCs). Functional expression of native mechanosensitive stretch-activated channels (SACs) and calcium-sensitive potassium channels of different conductances in hMESCs was shown. Single current analysis of stretch-induced channel activity revealed functional coupling of SACs and BK channels in plasma membrane. The combination of cell-attached and inside-out experiments have indicated that highly localized Ca 2+ entry via SACs triggers BK channel activity. At the same time, SK channels are not coupled with SACs despite of high calcium sensitivity as compared to BK. Our data demonstrate novel mechanism controlling BK channel activity in native cells. We conclude that SACs and BK channels are clusterized in functional mechanosensitive domains in the plasma membrane of hMESCs. Co-clustering of ion channels may significantly contribute to mechano-dependent calcium signalling in stem cells. - Highlights: • Stretch-induced channel activity in human mesenchymal stem cells was analyzed. • Functional expression of SACs and Ca 2+ -sensitive BK and SK channels was shown. • Local Ca 2+ influx via stretch-activated channels triggers BK channel activity. • SK channels are not coupled with SACs despite higher sensitivity to [Ca 2+ ] i . • Functional clustering of SACs and BK channels in stem cell membrane is proposed.

Brittle stalk 2 encodes a putative glycosylphosphatidylinositol-anchored protein that affects mechanical strength of maize tissues by altering the composition and structure of secondary cell walls.

Science.gov (United States)

Ching, Ada; Dhugga, Kanwarpal S; Appenzeller, Laura; Meeley, Robert; Bourett, Timothy M; Howard, Richard J; Rafalski, Antoni

2006-10-01

A spontaneous maize mutant, brittle stalk-2 (bk2-ref), exhibits dramatically reduced tissue mechanical strength. Reduction in mechanical strength in the stalk tissue was highly correlated with a reduction in the amount of cellulose and an uneven deposition of secondary cell wall material in the subepidermal and perivascular sclerenchyma fibers. Cell wall accounted for two-thirds of the observed reduction in dry matter content per unit length of the mutant stalk in comparison to the wildtype stalk. Although the cell wall composition was significantly altered in the mutant in comparison to the wildtype stalks, no compensation by lignin and cell wall matrix for reduced cellulose amount was observed. We demonstrate that Bk2 encodes a Cobra-like protein that is homologous to the rice Bc1 protein. In the bk2-ref gene, a 1 kb transposon-like element is inserted in the beginning of the second exon, disrupting the open reading frame. The Bk2 gene was expressed in the stalk, husk, root, and leaf tissues, but not in the embryo, endosperm, pollen, silk, or other tissues with comparatively few or no secondary cell wall containing cells. The highest expression was in the isolated vascular bundles. In agreement with its role in secondary wall formation, the expression pattern of the Bk2 gene was very similar to that of the ZmCesA10, ZmCesA11, and ZmCesA12 genes, which are known to be involved in secondary wall formation. We have isolated an independent Mutator-tagged allele of bk2, referred to as bk2-Mu7, the phenotype of which is similar to that of the spontaneous mutant. Our results demonstrate that mutations in the Bk2 gene affect stalk strength in maize by interfering with the deposition of cellulose in the secondary cell wall in fiber cells.

Prokineticin 2 Plays a Pivotal Role in Psoriasis

Directory of Open Access Journals (Sweden)

Xiaoqin He

2016-11-01

Full Text Available Psoriasis is histologically characterized by keratinocytes (KC hyperproliferation, inflammation, and increased angiogenesis, but the pathological factor responsible for these symptoms is unknown. Here, a neuroendocrine peptide (prokineticin 2, PK2, is highly expressed in human and mouse psoriatic skins but no significant change in other autoimmune diseases, suggesting that PK2 is a psoriasis-specific factor. Bacterial products significantly up-regulated PK2, implying that infection induces PK2 over-expression. PK2 promoted KC and macrophage to produce interleukin-1 (IL-1, the central player of inflammation and psoriasis, which acts on adjacent fibroblast to induce inflammatory cascades and KC hyperproliferation. IL-1 feeds back on macrophages to induce PK2 production to perpetuate PK2-IL-1 positive feedback loop. PK2 also promoted angiogenesis, another psoriatic symptom. In mouse models, PK2 over-expression aggravated psoriasis while its knock-down inhibited pathological development. The results indicate that PK2 over-production perpetuates psoriatic symptoms by creating PK-2-IL-1 vicious loop. PK2 is a central player in psoriasis and a promising psoriasis-specific target.

Quantification and diversity in the black seeds (nigella sativa L.) gene stock of pakistan for their composition of mineral nutrients

International Nuclear Information System (INIS)

Iqbal, M.S.; Qureshi, A.S.; Ghafoor, A.

2009-01-01

Nigella saliva (L.) a member of family Ranunculaceae is an annual herbaceous plant indigenous to the Mediterranean region that contains more than 100 nutrients and had been used for edible and medicinal purposes in major parts of the world since long. Present study is on the analysis of thirty four accessions with two check genotypes for genetic diversity based on thirteen mineral nutrients. High variation for Fe, Ca, Cu, Mg, Pb, Zn, Co, Mn, Na, P, B, K and N indicated the scope of sample selection for these characters. Coefficient of correlation studies revealed that Cu had significantly positive correlation with Ca, whereas Mg was significantly correlated with Ca and Cu. Linkages of desirable traits are suggested to be broken through novel techniques for maximum exploitation of genomic diversity for valuable phyto-chemicals. Based on principal component analysis, first four factors contributed 62 percent of the variability amongst genotypes for mineral nutrients. Eigen value> I exhibited 23.57 % of variation for component I, 17.28 % for component 2 and 12.43 % of variation for component 3, respectively. Moreover, it also reflects the potential of improvement, through building broad based gene pool by acquiring more samples from diverse geographical areas. These principal components could be selected individually for the improvement of specific mineral nutrients for multipurpose use and applications. Six clusters were observed for 36 genotypes based on mineral nutrients. The genotypes Pk-020877, Pk-020749, Pk-020876, Pk-020545, Pk-020561, Pk-020781 and Pk-020729, Pk-020620, Pk-020561, Pk-020631, Pk-020879, Pk-020868 produced the highest N (5.56), Fe (0.74), Ca (10.83), Mg (11.56), Pb (0.09), Zn (0.09), Na (0.68), P (0.66), B (39.58), and K (0.99), whereas Pk-020873 produced lowest N (1.67), Pk-020766 Fe (0.10), Pk-020576 Ca (7.38), Pk-020585 Mg (9.40), check-2 Pb (0.02), Pk-020872 Zn (0.01), Pk-020781 and Pk-020877 Na (0.17), check-2 P (0.50), Pk-020585 B (13

Fagopyrum esculentum Alters Its Root Exudation after Amaranthus retroflexus Recognition and Suppresses Weed Growth.

Science.gov (United States)

Gfeller, Aurélie; Glauser, Gaétan; Etter, Clément; Signarbieux, Constant; Wirth, Judith

2018-01-01

Weed control by crops through growth suppressive root exudates is a promising alternative to herbicides. Buckwheat ( Fagopyrum esculentum ) is known for its weed suppression and redroot pigweed ( Amaranthus retroflexus ) control is probably partly due to allelopathic root exudates. This work studies whether other weeds are also suppressed by buckwheat and if the presence of weeds is necessary to induce growth repression. Buckwheat and different weeds were co-cultivated in soil, separating roots by a mesh allowing to study effects due to diffusion. Buckwheat suppressed growth of pigweed, goosefoot and barnyard grass by 53, 42, and 77% respectively without physical root interactions, probably through allelopathic compounds. Root exudates were obtained from sand cultures of buckwheat (BK), pigweed (P), and a buckwheat/pigweed mixed culture (BK-P). BK-P root exudates inhibited pigweed root growth by 49%. Characterization of root exudates by UHPLC-HRMS and principal component analysis revealed that BK and BK-P had a different metabolic profile suggesting that buckwheat changes its root exudation in the presence of pigweed indicating heterospecific recognition. Among the 15 different markers, which were more abundant in BK-P, tryptophan was identified and four others were tentatively identified. Our findings might contribute to the selection of crops with weed suppressive effects.

An in-house assay for BK polyomavirus quantification using the Abbott m2000 RealTime system.

Science.gov (United States)

Muldrew, Kenneth L; Lovett, Jennie L

2013-11-01

BK polyomavirus (BKPyV) quantification is useful for monitoring renal transplant patient response to therapy. The Abbott m2000 RealTime System employed by some clinical laboratories to perform US Food and Drug Administration-approved assays can also be used to develop in-house assays such as the one presented here. This study aimed to validate an in-house quantitative real-time PCR assay targeting the BKPyV major capsid VP1 gene for assessment of viral load using the Abbott m2000 RealTime System. BKPyV load was measured in 95 urine and plasma samples previously tested for BKPyV by one of three laboratories (46 BKPyV-positive samples consisting of 35 plasma and 11 urine samples; 49 samples negative for BKPyV consisting of 47 plasma and two urine samples). Two additional plasma specimens from the College of American Pathologists proficiency testing survey were also analysed. Precision studies were performed by diluting a high-viral-titre patient sample into BKPyV-negative pooled plasma to create high-positive (6.16 log10 copies ml(-1)) and low-positive (3.16 log10 copies ml(-1)) samples. For precision studies of inter-assay variability, a high-positive (7.0 log10 copies ml(-1)) and a low-positive (3.0 log10 copies ml(-1)) sample were measured in 20 separate runs. The assay's limit of quantification and limit of detection were 2.70 and 2.25 log10 copies ml(-1), respectively. The assay was linear from 2.70 to 9.26 log10 copies ml(-1). Of the 48 known positives, 43 were detected as positive, with three reported by the reference laboratory as values lower than the limit of detection. Two known positives at 3.27 and 3.80 log10 copies ml(-1) tested negative by the m2000 BKPyV assay. Of the 49 known negative samples, 48 were negative by the m2000 BKPyV load assay, with one sample confirmed positive by a reference laboratory. Qualitative analysis prior to discrepancy testing demonstrated a sensitivity of 89.58 % and a specificity of 97.96 %. Precision studies

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach.

Science.gov (United States)

Betts, Alison; Keunecke, Anne; van Steeg, Tamara J; van der Graaf, Piet H; Avery, Lindsay B; Jones, Hannah; Berkhout, Jan

2018-04-10

The linear pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs) can be considered a class property with values that are similar to endogenous IgG. Knowledge of these parameters across species could be used to avoid unnecessary in vivo PK studies and to enable early PK predictions and pharmacokinetic/pharmacodynamic (PK/PD) simulations. In this work, population-pharmacokinetic (popPK) modeling was used to determine a single set of 'typical' popPK parameters describing the linear PK of mAbs in human, cynomolgus monkey and transgenic mice expressing the human neonatal Fc receptor (hFcRn Tg32), using a rich dataset of 27 mAbs. Non-linear PK was excluded from the datasets and a 2-compartment model was applied to describe mAb disposition. Typical human popPK estimates compared well with data from comparator mAbs with linear PK in the clinic. Outliers with higher than typical clearance were found to have non-specific interactions in an affinity-capture self-interaction nanoparticle spectroscopy assay, offering a potential tool to screen out these mAbs at an early stage. Translational strategies were investigated for prediction of human linear PK of mAbs, including use of typical human popPK parameters and allometric exponents from cynomolgus monkey and Tg32 mouse. Each method gave good prediction of human PK with parameters predicted within 2-fold. These strategies offer alternative options to the use of cynomolgus monkeys for human PK predictions of linear mAbs, based on in silico methods (typical human popPK parameters) or using a rodent species (Tg32 mouse), and call into question the value of completing extensive in vivo preclinical PK to inform linear mAb PK.

Calcium activated K⁺ channels in the electroreceptor of the skate confirmed by cloning. Details of subunits and splicing.

Science.gov (United States)

King, Benjamin L; Shi, Ling Fang; Kao, Peter; Clusin, William T

2016-03-01

Elasmobranchs detect small potentials using excitable cells of the ampulla of Lorenzini which have calcium-activated K(+) channels, first described in 1974. A distinctive feature of the outward current in voltage clamped ampullae is its apparent insensitivity to voltage. The sequence of a BK channel α isoform expressed in the ampulla of the skate was characterized. A signal peptide is present at the beginning of the gene. When compared to human isoform 1 (the canonical sequence), the largest difference was absence of a 59 amino acid region from the S8-S9 intra-cellular linker that contains the strex regulatory domain. The ampulla isoform was also compared with the isoform predicted in late skate embryos where strex was also absent. The BK voltage sensors were conserved in both skate isoforms. Differences between the skate and human BK channel included alternative splicing. Alternative splicing occurs at seven previously defined sites that are characteristic for BK channels in general and hair cells in particular. Skate BK sequences were highly similar to the Australian ghost shark and several other vertebrate species. Based on alignment of known BK sequences with the skate genome and transcriptome, there are at least two isoforms of Kcnma1α expressed in the skate. One of the β subunits (β4), which is known to decrease voltage sensitivity, was also identified in the skate genome and transcriptome and in the ampulla. These studies advance our knowledge of BK channels and suggest further studies in the ampulla and other excitable tissues. Copyright © 2015 Elsevier B.V. All rights reserved.

Calcium Activated K+ Channels in The Electroreceptor of the Skate Confirmed by Cloning. Details of Subunits and Splicing

Science.gov (United States)

King, Benjamin L.; Shi, Ling Fang; Kao, Peter; Clusin, William T.

2015-01-01

Elasmobranchs detect small potentials using excitable cells of the ampulla of Lorenzini which have calcium-activated K+ channels, first described in l974. A distinctive feature of the outward current in voltage clamped ampullae is its apparent insensitivity to voltage. The sequence of a BK channel α isoform expressed in the ampulla of the skate was characterized. A signal peptide is present at the beginning of the gene. When compared to human isoform 1 (the canonical sequence), the largest difference was absence of a 59 amino acid region from the S8-S9 intracellular linker that contains the strex regulatory domain. The ampulla isoform was also compared with the isoform predicted˜ in late skate embryos where strex was also absent. The BK voltage sensors were conserved in both skate isoforms. Differences between the skate and human BK channel included alternative splicing. Alternative splicing occurs at seven previously defined sites that are characteristic for BK channels in general and hair cells in particular. Skate BK sequences were highly similar to the Australian ghost shark and several other vertebrate species. Based on alignment of known BK sequences with the skate genome and transcriptome, there are at least two isoforms of Kcnma1α expressed in the skate. One of the β subunits (β4), which is known to decrease voltage sensitivity, was also identified in the skate genome and transcriptome and in the ampulla. These studies advance our knowledge of BK channels and suggest further studies in the ampulla and other excitable tissues. PMID:26687710

Evaluating the impact of pre-transplant desensitization utilizing a plasmapheresis and low-dose intravenous immunoglobulin protocol on BK viremia in renal transplant recipients.

Science.gov (United States)

Gabardi, S; Townsend, K; Martin, S T; Chandraker, A

2013-08-01

A correlation exists between polyomavirus BK (BKV) viremia in renal transplant recipients (RTR) and the degree of immunosuppression. However, the impact of pre-transplant desensitization on the incidence of BKV viremia is unknown. This retrospective study evaluated living-donor RTR between January 2004 and December 2008 receiving routine BKV viral load monitoring. Patients were divided into those who underwent pre-transplant desensitization (n = 20) and those who did not (n = 71). The primary endpoint was the incidence of BKV viremia at 1 year post transplant. All demographic data were similar, except for more female patients (65% vs. 36.6%; P = 0.0392) in the desensitized group. More desensitized patients had a previous transplant (75% vs. 12.7%; P < 0.0001) and were more likely to be induced with basiliximab (75% vs. 35.2%; P = 0.0021). Following transplantation, antibody-mediated rejection (AMR) rates were highest in the desensitized group (55% vs. 1.4%; P < 0.0001). The incidence of BKV viremia at 1 year post transplant was significantly higher in desensitized patients (45% vs. 19.7%; P = 0.0385). Desensitization was also associated with a higher prevalence of BKV viremia at any time post transplant (50% vs. 22.5%; P = 0.0245), polyomavirus-associated nephropathy (20% vs. 2.8%; P = 0.0198) and BKV-related allograft loss (10% vs. 0%; P = 0.0464). Also of note, in a subgroup analysis of only our desensitized patients, it did not appear that development of AMR significantly impacted the incidence of BKV viremia in these individuals. This analysis reveals that pre-transplant desensitization significantly increases the risk for BKV viremia and nephropathy. © 2013 John Wiley & Sons A/S.

Recurrent rates and risk factors associated with recurrent painful bullous keratopathy after primary phototherapeutic keratectomy

Directory of Open Access Journals (Sweden)

Kasetsuwan N

2015-09-01

Full Text Available Ngamjit Kasetsuwan, Kanokorn Sakpisuttivanit, Usanee Reinprayoon, Vilavun Puangsricharern Department of Ophthalmology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand Objective: To assess the recurrent rate, mean survival time, and risk factors associated with recurrent painful bullous keratopathy (BK after primary treatment with phototherapeutic keratectomy.Methods: Medical records from 72 patients (72 eyes who had phototherapeutic keratectomy for painful BK were evaluated. Data for sex, age, duration of BK, associated ocular and systemic diseases (hypertension, diabetes mellitus, ischemic heart disease, asthma, dyslipidemia, and rheumatoid arthritis, frequency and degree of pain (grade 1–3, visual acuity, corneal thickness, intraocular pressure, and laser setting were extracted and analyzed.Results: The mean age of the patients was 64.2±11.4 years. The mean preoperative duration of BK was 15.0±11.0 months. Most patients had pseudophakic BK (69.40%. Majority of the cases had grade 3 degree of pain (48.60%. Glaucoma and hypertension were markedly found among these patients (51.40% and 19.40%, respectively. Preoperative mean intraocular pressure and corneal thickness were 13.70±4.95 mmHg and 734.1±83.80 µm, respectively. The mean laser diameter and depth were 8.36±1.22 mm and 38.89±8.81 µm, respectively. Systemic disease was significantly associated with the risk for developing recurrent painful BK (P=0.022, hazard ratio [HR] 1.673, 95% confidence interval [CI] 1.08–2.58. The overall recurrent rate was 51%. The average duration time of recurrent painful BK was 17.3±12.9 months (range 1–50 months. The median survival time before recurrence was 29.0±6.6 months.Conclusion: Systemic disease was found to be the only risk factor significantly associated with the development of recurrent painful BK. Low recurrent rate and long mean survival time showed that phototherapeutic

Improved upper limits on B(KL0 → μe) and B(KL0 → ee) and a new value for B(KL0 → μμ)

International Nuclear Information System (INIS)

Molzon, W.R.

1998-01-01

The author gives recent results from E791 at BNL with improved upper limits on the branching fractions B(K L 0 → μe) and B(K L 0 → ee) of 8.5 x 10 -11 and 11.6 x 10 -11 at 90% C.L. He also gives a preliminary result of a new measurement B(K L 0 → μμ) = 7.6 ± 0.5(stat) ± 0.4(syst) x 10 -9

Discrete Element Simulations of Density-Driven Volcanic Deformation: Applications to Martian and Terrestrial Volcanoes

Science.gov (United States)

Farrell, L. L.; McGovern, P. J.; Morgan, J. K.

2008-12-01

We have carried out 2-D numerical simulations using the discrete element method (DEM) to investigate density-driven deformation in volcanic edifices on Earth (e.g., Hawaii) and Mars (e.g., Olympus Mons and Arsia Mons). Located within volcanoes are series of magma chambers, reservoirs, and conduits where magma travels and collects. As magma differentiates, dense minerals settle out, building thick accumulations referred to as cumulates that can flow ductilely due to stresses imparted by gravity. To simulate this process, we construct granular piles subject to Coulomb frictional rheology, incrementally capture internal rectangular regions to which higher densities and lower interparticle friction values are assigned (analogs for denser, weaker cumulates), and then bond the granular edifice. Thus, following each growth increment, the edifice is allowed to relax gravitationally with a reconfigured weak cumulate core. The presence and outward spreading of the cumulate causes the development of distinctive structural and stratigraphic patterns. We obtained a range of volcanic shapes that vary from broad, shallowly dipping flanks reminiscent of those of Olympus Mons, to short, steep surface slopes more similar to Arsia Mons. Edifices lacking internal cumulate exhibit relatively horizontal strata compared to the high-angle, inward dipping strata that develops within the cumulate-bearing edifices. Our simulated volcanoes also illustrate a variety of gravity driven deformation features, including regions of thrust faulting within the flanks and large-scale flank collapses, as observed in Hawaii and inferred on Olympus Mons. We also see significant summit subsidence, and of particular interest, distinct summit calderas. The broad, flat caldera and convex upward profile of Arsia Mons appears to be well-simulated by cumulate-driven volcanic spreading. In contrast, the concave upward slopes of Olympus Mons are more challenging to reproduce, and instead are attributed to volcanic

The MLH1 c.1852_1853delinsGC (p.K618A variant in colorectal cancer: genetic association study in 18,723 individuals.

Directory of Open Access Journals (Sweden)

Anna Abulí

Full Text Available Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world. Mendelian syndromes account for about 5% of the total burden of CRC, being Lynch syndrome and familial adenomatous polyposis the most common forms. Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2. A significant proportion of variants identified by screening these genes correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as "variants of uncertain significance", being the c.1852_1853delinsGC (p.K618A variant in the MLH1 gene a clear example. The implication of this variant as a low-penetrance risk variant for CRC was assessed in the present study by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206 including 18,723 individuals (8,055 colorectal cancer cases and 10,668 controls and a case-only genotype-phenotype correlation with several clinical and pathological characteristics restricted to the Epicolon cohort. Our results showed no involvement of this variant as a low-penetrance variant for colorectal cancer genetic susceptibility and no association with any clinical and pathological characteristics including family history for this neoplasm or Lynch syndrome.

[Radiobiological effects on plants and animals within Semipalatinsk Test Site (Kazakhstan)].

Science.gov (United States)

Mozolin, E M; Geras'kin, S A; Minkenova, K S

2008-01-01

The Semipalatinsk Test Site (STS) was the main place of nuclear devices tests in the former Soviet Union. From 1949 to 1989 about 460 nuclear explosions have been carried out at STS. Radioactive contamination of STS territory has the extremely non-uniform character. The main dose-forming radionuclides are 137Cs, 90Sr, 152Eu, as well as 154Eu, 60CO, 239,240Pu and 241Am. The greatest specific activity of 137Cs and 239,240Pu in ground are n x 10(3) kBk/kg, 152Eu - 96 kBk/kg, 154Eu - 10.4 kBk/kg, 60Co - 20.5 kBk/kg, 241Am - 15 kBk/kg. However, up to now, within STS sites exists where gamma-dose rate comes to 60 microGy/h, that is enough for induction reliable biological effects in animals and plants. Inhabiting territory of STS plants and animals are characterized by increased level of mutagenesis, changes of morpho-anatomic indices and parameters of peripheral blood, by the increase of asymmetry bilateral indices, change of composition and structure of communities.

Level selection in leg amputation for arterial occlusive disease

DEFF Research Database (Denmark)

Holstein, P

1982-01-01

In 102 leg amputations for arterial occlusion including 84 below-knee (BK), 16 above-knee (AD) and 2 through-knee (TK) amputations, the amputation level was determined by means of clinical criteria. The healing results and the selection of levels were then compared with sealed preoperative...... measurements of the skin perfusion pressure (SPP). Out of 62 BK amputations with an SPP above 30 mmHg wound healing failed in only 2 cases (3 per cent). Out of 13 BK amputations with an SPP between 20 and 30 mmHg 7 cases (54 per cent) failed and out of 9 BK amputations with an SPP below 20 mmHg no less than 8...... cases (89 per cent) failed to heal. The difference in failure rate is significant (P less than 0.0001). Out of the 15 failed BK amputations at low pressures (below 30 mmHg) only one case had local signs of ischaemia, which might have warned the surgeons. On the other hand, in 13 out of the 18 cases...

Unearthing Bacillus endophytes from desert plants that enhance growth of Arabidopsis thaliana under abiotic stress conditions

KAUST Repository

Bokhari, Ameerah

2018-01-01

that these bacteria can confer resilience to plants under salt stress conditions. B. circulans (PK3-15 and PK3-109), B. cereus (PK6-15) B. subtilis (PK3-9) and B. licheniformis (PK5-26) displayed the ability to increased the fresh weight of A. thaliana under salt

Pharmacokinetic modeling of therapies for systemic lupus erythematosus

OpenAIRE

Yang, Xiaoyan; Sherwin, Catherine MT; Yu, Tian; Yellepeddi, Venkata K; Brunner, Hermine I; Vinks, Alexander A

2015-01-01

With the increasing use of different types of therapies in treating autoimmune diseases such as systemic lupus erythematosus (SLE), there is a need to utilize pharmacokinetic (PK) strategies to optimize the clinical outcome of these treatments. Various PK analysis approaches, including population PK modeling and physiologically based PK modeling, have been used to evaluate drug PK characteristics and population variability or to predict drug PK profiles in a mechanistic manner. This review ou...