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Sample records for target tissue selectivity

  1. Burglar Target Selection

    Science.gov (United States)

    Townsley, Michael; Bernasco, Wim; Ruiter, Stijn; Johnson, Shane D.; White, Gentry; Baum, Scott

    2015-01-01

    Objectives: This study builds on research undertaken by Bernasco and Nieuwbeerta and explores the generalizability of a theoretically derived offender target selection model in three cross-national study regions. Methods: Taking a discrete spatial choice approach, we estimate the impact of both environment- and offender-level factors on residential burglary placement in the Netherlands, the United Kingdom, and Australia. Combining cleared burglary data from all study regions in a single statistical model, we make statistical comparisons between environments. Results: In all three study regions, the likelihood an offender selects an area for burglary is positively influenced by proximity to their home, the proportion of easily accessible targets, and the total number of targets available. Furthermore, in two of the three study regions, juvenile offenders under the legal driving age are significantly more influenced by target proximity than adult offenders. Post hoc tests indicate the magnitudes of these impacts vary significantly between study regions. Conclusions: While burglary target selection strategies are consistent with opportunity-based explanations of offending, the impact of environmental context is significant. As such, the approach undertaken in combining observations from multiple study regions may aid criminology scholars in assessing the generalizability of observed findings across multiple environments. PMID:25866418

  2. CDTI target selection criteria

    Science.gov (United States)

    Britt, C. L.; Davis, C. M.; Jackson, C. B.; Mcclellan, V. A.

    1984-01-01

    A Cockpit Display of Traffic Information (CDTI) is a cockpit instrument which provides information to the aircrew on the relative location of aircraft traffic in the vicinity of their aircraft (township). In addition, the CDTI may provide information to assist in navigation and in aircraft control. It is usually anticipated that the CDTI will be integrated with a horizontal situation indicator used for navigational purposes and/or with a weather radar display. In this study, several sets of aircraft traffic data are analyzed to determine statistics on the number of targets that will be displayed on a CDTI using various target selection criteria. Traffic data were obtained from an Atlanta Terminal Area Simulation and from radar tapes recorded at the Atlanta and Miami terminal areas. Results are given in the form of plots showing the average percentage of time (or probability) that an aircraft equipped with a CDTI would observe from 0 to 10 other aircraft on the display for range settings on the CDTI up to 30 n. mi. and using various target discrimination techniques.

  3. New Therapeutic Targets in Soft Tissue Sarcoma

    Science.gov (United States)

    Demicco, Elizabeth G; Maki, Robert G; Lev, Dina C.; Lazar, Alexander J

    2012-01-01

    Soft tissue sarcomas are an uncommon and diverse group of more than 50 mesenchymal malignancies. The pathogenesis of many of these is poorly understood, but others have begun to reveal the secrets of their inner workings. With considerable effort over recent years, soft tissue sarcomas have increasingly been classified on the basis of underlying molecular alterations. In turn, this has allowed the development and application of targeted agents in several specific, molecularly defined, sarcoma subtypes. This review will focus the rationale for targeted therapy in sarcoma, with emphasis on the relevance of specific molecular factors and pathways in both translocation-associated sarcomas and in genetically complex tumors. In addition, we will address some of the early successes in sarcoma targeted therapy as well as a few challenges and disappointments in this field. Finally we will discuss several possible opportunities represented by poorly understood, but potentially promising new therapeutic targets, as well as several novel biologic agents currently in preclinical and early phase I/II trials. This will provide the reader with context for understanding the current state this field and a sense of where it may be headed in the coming years. PMID:22498582

  4. Target selection for direct marketing.

    NARCIS (Netherlands)

    Bult, Jan Roelf

    1993-01-01

    In this thesis we concentrated on the use ol direct mail for targeting potential buyers. The major characteristics that influences the success of a plomotional direct mail campaign are the of-fbr,the communication elements, the timing or sequence of these communication elements, and the list of

  5. PPAR agonists, - Could tissue targeting pave the way?

    Science.gov (United States)

    Bugge, Anne; Holst, Dorte

    2017-05-01

    Over the last couple of decades, the PPAR family of transcription factors has received much attention from the pharmaceutical industry due to their profound ability to improve glucose and lipid metabolism upon agonist activation. However, more recently the interest in these nuclear receptors has faded because several clinical trials have shown that it is difficult to develop a ligand that significantly ameliorates glucose and lipid metabolism disorders without concomitantly inducing unacceptable side-effects. Nevertheless, the data also suggests that tissue specific targeting could pave the way to renewed interest and clinical use of PPAR ligands. In this review we summarize the results and learnings from the clinical trials on PPAR agonism and discuss the possibilities for tissue targeting of PPAR ligands by using state of the art technology to fuse them to peptides homing selectively to tissues expressing the cognate surface receptor. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  6. Selection and Identification of Skeletal-Muscle-Targeted RNA Aptamers

    Directory of Open Access Journals (Sweden)

    Styliana Philippou

    2018-03-01

    Full Text Available Oligonucleotide gene therapy has shown great promise for the treatment of muscular dystrophies. Nevertheless, the selective delivery to affected muscles has shown to be challenging because of their high representation in the body and the high complexity of their cell membranes. Current trials show loss of therapeutic molecules to non-target tissues leading to lower target efficacy. Therefore, strategies that increase uptake efficiency would be particularly compelling. To address this need, we applied a cell-internalization SELEX (Systematic Evolution of Ligands by Exponential Enrichment approach and identified a skeletal muscle-specific RNA aptamer. A01B RNA aptamer preferentially internalizes in skeletal muscle cells and exhibits decreased affinity for off-target cells. Moreover, this in vitro selected aptamer retained its functionality in vivo, suggesting a potential new approach for targeting skeletal muscles. Ultimately, this will aid in the development of targeted oligonucleotide therapies against muscular dystrophies.

  7. Selective Nanoparticle Targeting of the Renal Tubules.

    Science.gov (United States)

    Williams, Ryan M; Shah, Janki; Tian, Helen S; Chen, Xi; Geissmann, Frederic; Jaimes, Edgar A; Heller, Daniel A

    2018-01-01

    Direct targeting to the kidneys is a promising strategy to improve drug therapeutic index for the treatment of kidney diseases. We sought to investigate the renal selectivity and safety of kidney-targeted mesoscale nanoparticle technology. We found that direct intravenous administration of these particles resulted in 26-fold renal selectivity and localized negligibly in the liver or other organs. The nanoparticles targeted the renal proximal tubular epithelial cells, as evidenced by intravital microscopy and ex vivo imaging. Mice treated with the nanoparticles exhibited no negative systemic consequences, immune reaction, liver impairment, or renal impairment. The localization of material selectively to the renal tubules is uncommon, and this work portends the development of renal-targeted drugs for the treatment of kidney diseases. © 2017 American Heart Association, Inc.

  8. Electrolytes in Selected Tissues of Heterobranchus bidorsalis ...

    African Journals Online (AJOL)

    Electrolytes in Selected Tissues of Heterobranchus bidorsalis Treated With Sub lethal Levels of Cypermethrin. UU Gabriel, IR Jack, OS Edori, E Egobueze. Abstract. Heterobranchus bidorsalis (mean length 31.50±2.32cm SD; mean weight 241.25± 30.39g SD) was exposed to cypermethrin (0.0005, 0.0075, 0.010, 0.125 and ...

  9. Selective targeting of epigenetic reader domains.

    Science.gov (United States)

    Greschik, Holger; Schüle, Roland; Günther, Thomas

    2017-05-01

    Epigenetic regulators including writers, erasers, and readers of chromatin marks have been implicated in numerous diseases and are therefore subject of intense academic and pharmaceutical research. While several small-molecule inhibitors targeting writers or erasers are either approved drugs or are currently being evaluated in clinical trials, the targeting of epigenetic readers has lagged behind. Proof-of-principle that epigenetic readers are also relevant drug targets was provided by landmark discoveries of selective inhibitors targeting the BET family of acetyl-lysine readers. More recently, high affinity chemical probes for non-BET acetyl- and methyl-lysine reader domains have also been developed. Areas covered: This article covers recent advances with the identification and validation of inhibitors and chemical probes targeting epigenetic reader domains. Issues related to epigenetic reader druggability, quality requirements for chemical probes, interpretation of cellular action, unexpected cross-talk, and future challenges are also discussed. Expert opinion: Chemical probes provide a powerful means to unravel biological functions of epigenetic readers and evaluate their potential as drug targets. To yield meaningful results, potency, selectivity, and cellular target engagement of chemical probes need to be stringently validated. Future chemical probes will probably need to fulfil additional criteria such as strict target specificity or the targeting of readers within protein complexes.

  10. Selective Targeting to Glioma with Nucleic Acid Aptamers.

    Directory of Open Access Journals (Sweden)

    Shraddha Aptekar

    Full Text Available Malignant glioma is characterised by a rapid growth rate and high capacity for invasive infiltration to surrounding brain tissue; hence, diagnosis and treatment is difficult and patient survival is poor. Aptamers contribute a promising and unique technology for the in vitro imaging of live cells and tissues, with a potentially bright future in clinical diagnostics and therapeutics for malignant glioma. The binding selectivity, uptake capacity and binding target of two DNA aptamers, SA43 and SA44, were investigated in glioma cells and patient tissues. The binding assay showed that SA43 and SA44 bound with strong affinity (Kd, 21.56 ± 4.60 nM and Kd, 21.11 ± 3.30 nM respectively to the target U87MG cells. Quantitative analysis by flow cytometry showed that the aptamers were able to actively internalise in U87MG and 1321N1 glioma cells compared to the non-cancerous and non-glioma cell types. Confocal microscopy confirmed staining in the cytoplasm, and co-localisation studies with endoplasmic reticulum, Golgi apparatus and lysosomal markers suggested internalisation and compartmentalisation within the endomembrane system. Both aptamers selectively bound to Ku 70 and Ku 80 DNA repair proteins as determined by aptoprecipitation (AP followed by mass spectrometry analysis and confirmation by Western blot. In addition, aptohistochemical (AHC staining on paraffin embedded, formalin fixed patient tissues revealed that the binding selectivity was significantly higher for SA43 aptamer in glioma tissues (grade I, II, III and IV compared to the non-cancerous tissues, whereas SA44 did not show selectivity towards glioma tissues. The results indicate that SA43 aptamer can differentiate between glioma and non-cancerous cells and tissues and therefore, shows promise for histological diagnosis of glioma.

  11. Selective estrogen receptor modulators: tissue specificity and clinical utility

    Directory of Open Access Journals (Sweden)

    Martinkovich S

    2014-08-01

    Full Text Available Stephen Martinkovich,* Darshan Shah,* Sonia Lobo Planey, John A ArnottDepartment of Basic Sciences, The Commonwealth Medical College, Scranton, PA, USA*These authors contributed equally to this workAbstract: Selective estrogen receptor modulators (SERMs are a diverse group of ­nonsteroidal compounds that function as agonists or antagonists for estrogen receptors (ERs in a target gene-specific and tissue-specific fashion. SERM specificity involves tissue-specific expression of ER subtypes, differential expression of co-regulatory proteins in various tissues, and varying ER conformational changes induced by ligand binding. To date, the major clinical applications of SERMs are their use in the prevention and treatment of breast cancer, the prevention of osteoporosis, and the maintenance of beneficial serum lipid profiles in postmenopausal women. However, SERMs have also been found to promote adverse effects, including thromboembolic events and, in some cases, carcinogenesis, that have proven to be obstacles in their clinical utility. In this review, we discuss the mechanisms of SERM tissue specificity and highlight the therapeutic application of well-known and emergent SERMs.Keywords: selective estrogen receptor modulators, SERMs, estrogen receptors

  12. Nanostructured materials for selective recognition and targeted drug delivery

    International Nuclear Information System (INIS)

    Kotrotsiou, O; Kotti, K; Dini, E; Kammona, O; Kiparissides, C

    2005-01-01

    Selective recognition requires the introduction of a molecular memory into a polymer matrix in order to make it capable of rebinding an analyte with a very high specificity. In addition, targeted drug delivery requires drug-loaded vesicles which preferentially localize to the sites of injury and avoid uptake into uninvolved tissues. The rapid evolution of nanotechnology is aiming to fulfill the goal of selective recognition and optimal drug delivery through the development of molecularly imprinted polymeric (MIP) nanoparticles, tailor-made for a diverse range of analytes (e.g., pharmaceuticals, pesticides, amino acids, etc.) and of nanostructured targeted drug carriers (e.g., liposomes and micelles) with increased circulation lifetimes. In the present study, PLGA microparticles containing multilamellar vesicles (MLVs), and MIP nanoparticles were synthesized to be employed as drug carriers and synthetic receptors respectively

  13. Integrative analysis to select cancer candidate biomarkers to targeted validation

    Science.gov (United States)

    Heberle, Henry; Domingues, Romênia R.; Granato, Daniela C.; Yokoo, Sami; Canevarolo, Rafael R.; Winck, Flavia V.; Ribeiro, Ana Carolina P.; Brandão, Thaís Bianca; Filgueiras, Paulo R.; Cruz, Karen S. P.; Barbuto, José Alexandre; Poppi, Ronei J.; Minghim, Rosane; Telles, Guilherme P.; Fonseca, Felipe Paiva; Fox, Jay W.; Santos-Silva, Alan R.; Coletta, Ricardo D.; Sherman, Nicholas E.; Paes Leme, Adriana F.

    2015-01-01

    Targeted proteomics has flourished as the method of choice for prospecting for and validating potential candidate biomarkers in many diseases. However, challenges still remain due to the lack of standardized routines that can prioritize a limited number of proteins to be further validated in human samples. To help researchers identify candidate biomarkers that best characterize their samples under study, a well-designed integrative analysis pipeline, comprising MS-based discovery, feature selection methods, clustering techniques, bioinformatic analyses and targeted approaches was performed using discovery-based proteomic data from the secretomes of three classes of human cell lines (carcinoma, melanoma and non-cancerous). Three feature selection algorithms, namely, Beta-binomial, Nearest Shrunken Centroids (NSC), and Support Vector Machine-Recursive Features Elimination (SVM-RFE), indicated a panel of 137 candidate biomarkers for carcinoma and 271 for melanoma, which were differentially abundant between the tumor classes. We further tested the strength of the pipeline in selecting candidate biomarkers by immunoblotting, human tissue microarrays, label-free targeted MS and functional experiments. In conclusion, the proposed integrative analysis was able to pre-qualify and prioritize candidate biomarkers from discovery-based proteomics to targeted MS. PMID:26540631

  14. Current Molecular Targeted Therapies for Bone and Soft Tissue Sarcomas

    Directory of Open Access Journals (Sweden)

    Kenji Nakano

    2018-03-01

    Full Text Available Systemic treatment options for bone and soft tissue sarcomas remained unchanged until the 2000s. These cancers presented challenges in new drug development partly because of their rarity and heterogeneity. Many new molecular targeting drugs have been tried in the 2010s, and some were approved for bone and soft tissue sarcoma. As one of the first molecular targeted drugs approved for solid malignant tumors, imatinib’s approval as a treatment for gastrointestinal stromal tumors (GISTs has been a great achievement. Following imatinib, other tyrosine kinase inhibitors (TKIs have been approved for GISTs such as sunitinib and regorafenib, and pazopanib was approved for non-GIST soft tissue sarcomas. Olaratumab, the monoclonal antibody that targets platelet-derived growth factor receptor (PDGFR-α, was shown to extend the overall survival of soft tissue sarcoma patients and was approved in 2016 in the U.S. as a breakthrough therapy. For bone tumors, new drugs are limited to denosumab, a receptor activator of nuclear factor κB ligand (RANKL inhibitor, for treating giant cell tumors of bone. In this review, we explain and summarize the current molecular targeting therapies approved and in development for bone and soft tissue sarcomas.

  15. The effect of target strain error on plantar tissue stress.

    Science.gov (United States)

    Pai, Shruti; Ledoux, William R

    2010-07-01

    Accurate quantification of soft tissue properties, specifically the stress relaxation behavior of viscoelastic tissues such as plantar tissue, requires precise testing under physiologically relevant loading. However, limitations of testing equipment often result in target strain errors that can contribute to large stress errors and confound comparative results to an unknown extent. Previous investigations have modeled this artifact, but they have been unable to obtain empirical data to validate their models. Moreover, there are no studies that address this issue for plantar tissue. The purpose of this research was to directly measure the difference in peak force for a series of small target strain errors within the range of our typical stress relaxation experiments for the subcutaneous plantar soft tissue. Five plantar tissue specimens were tested to seven incremental target strain error levels of -0.9%, -0.6%, -0.3%, 0.0%, 0.3%, 0.6%, and 0.9%, so as to undershoot and overshoot the target displacement in 0.3% increments. The imposed strain errors were accurately attained using a special compensation feature of our materials testing software that can drive the actuator to within 0% (1-2 microm) of the target level for cyclic tests. Since stress relaxation tests are not cyclic, we emulated the ramp portion of our stress relaxation tests with 5 Hz triangle waves. The average total stress variation for all specimens was 25+/-5%, with the highest and lowest stresses corresponding to the largest and smallest strain errors of 0.9% and -0.9%, respectively. A strain overshoot of 0.3%, the target strain error observed in our typical stress relaxation experiments, corresponded to an average stress overshoot of 3+/-1%. Plantar tissue in compression is sensitive to small target strain errors that can result in stress errors that are several fold larger. The extent to which the overshoot may affect the peak stress will likely differ in magnitude for other soft tissues and

  16. Pericyte-targeting drug delivery and tissue engineering

    Directory of Open Access Journals (Sweden)

    Kang E

    2016-05-01

    Full Text Available Eunah Kang,1 Jong Wook Shin2 1School of Chemical Engineering and Material Science, 2Division of Allergic and Pulmonary Medicine, Department of Internal Medicine, College of Medicine, Chung-Ang University, Dongjak-Gu, Seoul, South Korea Abstract: Pericytes are contractile mural cells that wrap around the endothelial cells of capillaries and venules. Depending on the triggers by cellular signals, pericytes have specific functionality in tumor microenvironments, properties of potent stem cells, and plasticity in cellular pathology. These features of pericytes can be activated for the promotion or reduction of angiogenesis. Frontier studies have exploited pericyte-targeting drug delivery, using pericyte-specific peptides, small molecules, and DNA in tumor therapy. Moreover, the communication between pericytes and endothelial cells has been applied to the induction of vessel neoformation in tissue engineering. Pericytes may prove to be a novel target for tumor therapy and tissue engineering. The present paper specifically reviews pericyte-specific drug delivery and tissue engineering, allowing insight into the emerging research targeting pericytes. Keywords: pericytes, pericyte-targeting drug delivery, tissue engineering, platelet-derived growth factor, angiogenesis, vascular remodeling

  17. Intestinal mucosa is a target tissue for pancreatic polypeptide

    International Nuclear Information System (INIS)

    Gilbert, W.R.; Kramer, J.L.; Frank, B.H.; Gingerich, R.L.

    1986-01-01

    Studies were carried out to identify mammalian tissues capable of specifically binding mammalian pancreatic polypeptide (PP). Bovine PP (bPP) radiolabeled with 125 I was purified by HPLC to yield [ 125 I]iodo-(Tyr-27) bPP. The label was injected into three pairs of fasted littermate dogs and allowed to circulate for 5 min. One of the dogs was a control which received an excess of unlabeled porcine PP to provide competition for receptor binding. Unbound bPP was removed by perfusion with Krebs-Ringer bicarbonate and the tissue fixed in situ with Karnovsky's fixative. Tissue samples from various organs were removed, weighed, and counted. The entire gastrointestinal tract demonstrated high levels of 125 I after injection of the labeled peptide. The duodenum, jejunum, ileum, and colon were the only tissues to exhibit specific binding of bPP. These tissues (mucosal and muscle layers) from experimental animals exhibited 31-76% higher binding than the corresponding tissues from the control animals. Sections of the gastrointestinal tract were scraped to separate the mucosal layer from the underlying muscle layer. The mucosal layer of the duodenum, jejunum, and ileum exhibited 145-162% increases in binding compared to the control animals. The muscle layer of these tissues demonstrated no significant increase. These findings demonstrate that mucosal layer of the small intestine is a target tissue for mammalian PP

  18. Selective targeting of microglia by quantum dots

    Directory of Open Access Journals (Sweden)

    Minami S Sakura

    2012-01-01

    Full Text Available Abstract Background Microglia, the resident immune cells of the brain, have been implicated in brain injury and various neurological disorders. However, their precise roles in different pathophysiological situations remain enigmatic and may range from detrimental to protective. Targeting the delivery of biologically active compounds to microglia could help elucidate these roles and facilitate the therapeutic modulation of microglial functions in neurological diseases. Methods Here we employ primary cell cultures and stereotaxic injections into mouse brain to investigate the cell type specific localization of semiconductor quantum dots (QDs in vitro and in vivo. Two potential receptors for QDs are identified using pharmacological inhibitors and neutralizing antibodies. Results In mixed primary cortical cultures, QDs were selectively taken up by microglia; this uptake was decreased by inhibitors of clathrin-dependent endocytosis, implicating the endosomal pathway as the major route of entry for QDs into microglia. Furthermore, inhibiting mannose receptors and macrophage scavenger receptors blocked the uptake of QDs by microglia, indicating that QD uptake occurs through microglia-specific receptor endocytosis. When injected into the brain, QDs were taken up primarily by microglia and with high efficiency. In primary cortical cultures, QDs conjugated to the toxin saporin depleted microglia in mixed primary cortical cultures, protecting neurons in these cultures against amyloid beta-induced neurotoxicity. Conclusions These findings demonstrate that QDs can be used to specifically label and modulate microglia in primary cortical cultures and in brain and may allow for the selective delivery of therapeutic agents to these cells.

  19. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature

    NARCIS (Netherlands)

    Huang, XM; Molema, G; King, S; Watkins, L; Edgington, TS; Thorpe, PE

    1997-01-01

    Selective occlusion of tumor vasculature was tested as a therapy for solid tumors in a mouse model. The formation of blood clots (thrombosis) within the tumor Vessels was initiated by targeting the cell surface domain of human tissue factor, by means of a bispecific antibody, to an experimentally

  20. Parthenolide Selectively Sensitizes Prostate Tumor Tissue to Radiotherapy while Protecting Healthy Tissues In Vivo.

    Science.gov (United States)

    Morel, Katherine L; Ormsby, Rebecca J; Bezak, Eva; Sweeney, Christopher J; Sykes, Pamela J

    2017-05-01

    Radiotherapy is widely used in cancer treatment, however the benefits can be limited by radiation-induced damage to neighboring normal tissues. Parthenolide (PTL) exhibits anti-inflammatory and anti-tumor properties and selectively induces radiosensitivity in prostate cancer cell lines, while protecting primary prostate epithelial cell lines from radiation-induced damage. Low doses of radiation have also been shown to protect from subsequent high-dose-radiation-induced apoptosis as well as DNA damage. These properties of PTL and low-dose radiation could be used to improve radiotherapy by killing more tumor cells and less normal cells. Sixteen-week-old male Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) and C57BL/6J mice were treated with PTL (40 mg/kg), dimethylaminoparthenolide (DMAPT, a PTL analogue with increased bioavailability) (100 mg/kg), or vehicle control three times over one week prior to combinations of low (10 mGy) and high (6 Gy) doses of whole-body X-irradiation. Tissues were analyzed for apoptosis at a range of time points up to 72 h postirradiation. Both PTL and DMAPT protected normal tissues, but not prostate tumor tissues, from a significant proportion of high-dose-radiation-induced apoptosis. DMAPT provided superior protection compared to PTL in normal dorsolateral prostate (71.7% reduction, P = 0.026), spleen (48.2% reduction, P = 0.0001) and colorectal tissue (38.0% reduction, P = 0.0002), and doubled radiation-induced apoptosis in TRAMP prostate tumor tissue (101.3% increase, P = 0.039). Both drugs induced the greatest radiosensitivity in TRAMP prostate tissue in areas with higher grade prostatic intraepithelial neoplasia (PIN) lesions. A 10 mGy dose delivered 3 h prior to a 6 Gy dose induced a radioadaptive apoptosis response in normal C57Bl/6J prostate (28.4% reduction, P = 0.045) and normal TRAMP spleen (13.6% reduction, P = 0.047), however the low-dose-adaptive radioprotection did not significantly add to the PTL

  1. Linking Target Selection to Political Objectives

    National Research Council Canada - National Science Library

    Tew, Scott

    2002-01-01

    ... up for effect, Our goal is to find and effect the targets that will ultimately lead to attainment of our political objectives Yet, how do we logically link a target to the desired political objectives...

  2. Radiopharmaceuticals for localization in target tissues exhibiting a regional pH shift relative to surrounding tissues

    International Nuclear Information System (INIS)

    Blau, M.; Kung, H.F.

    1981-01-01

    This patent relates to the preparation and use of radiopharmaceutical chemical compounds comprising a radioactive isotope, other than an isotope of iodine, in chemical combination with at least one primary, secondary or tertiary amino group. The compounds have a lipophilicity sufficiently high at a pH of 7.6 to permit passage of the compound from the blood of a mammal into a target organ or tissue and sufficiently low at a pH of 6.6 to prevent rapid return of the compound from the target organ or tissue to the blood. The compounds have a percent protein binding of less than ninety percent. These compounds may be selectively deposited in at least one target tissue or organ of a mammal, the tissue or organ of which has a significantly different intracellular pH than the blood of the mammal, by introducing the compound of the invention into the bloodstream of the mammal. A plurality of selenide compounds containing Se-75 isotope are claimed in relation to the patent. (U.K.)

  3. Study of the relationship between the target tissue necrosis volume and the target tissue size in liver tumours using two-compartment finite element RFA modelling.

    Science.gov (United States)

    Zhang, Bing; Moser, Michael A J; Zhang, Edwin M; Luo, Yigang; Zhang, Hongbo; Zhang, Wenjun

    2014-12-01

    The aim of this study was to investigate the relationship between the target tissue necrosis volume and the target tissue size during the radiofrequency ablation (RFA) procedure. The target tissues with four different sizes (dxy = 20, 25, 30 and 35 mm) were modelled using a two-compartment radiofrequency ablation model. Different voltages were applied to seek the maximum target tissue necrosis volume for each target tissue size. The first roll-off occurrence or the standard ablation time (12 min) was taken as the sign for the termination of the RFA procedure. Four different maximum voltages without the roll-off occurrence were found for the four different sizes of target tissues (dxy = 20, 25, 30 and 35 mm), and they were 36.6, 35.4, 33.9 and 32.5 V, respectively. The target tissues with diameters of 20, 25 mm can be cleanly ablated at their own maximum voltages applied (MVA) but the same finding was not found for the 35-mm target tissue. For the target tissue with diameter of 30 mm, the 50 °C isothermal contour (IT50) result showed that the target tissue can be cleanly ablated, but the same result did not show in the Arrhenius damage model result. Furthermore, two optimal RFA protocols with a minimal thermal damage to the healthy tissues were found for the target tissues with diameters of 20 and 25 mm, respectively. The study suggests that target tissues of different sizes should be treated with different RFA protocols. The maximum target tissue volume was achieved with the MVA without the roll-off occurrence for each target tissue size when a constant RF power supply was used.

  4. Selection of reference genes in canine uterine tissues.

    Science.gov (United States)

    Du, M; Wang, X; Yue, Y W; Zhou, P Y; Yao, W; Li, X; Ding, X B; Liu, X F; Guo, H; Ma, W Z

    2016-06-17

    Real-time quantitative polymerase chain reaction (RT-qPCR) is usually employed in gene expression studies in veterinary research, including in studies on canine pyometra. Canine pyometra is a common clinical disease in bitches. When using RT-qPCR, internal standards, such as reference genes, are necessary to investigate relative gene expression by quantitative measurements of mRNA levels. The aim of this study was to evaluate the stability of reference genes and select reference genes suitable for canine pyometra studies. We collected 24 bitch uterine tissue samples, including five healthy and 19 pyometra infected samples. These were used to screen the best reference genes of seven candidate genes (18SrRNA, ACTB, B2M, GAPDH, HPRT, RPL13A, and YWHAZ). The method of KH Sadek and the GeNorm, Normfinder, BestKeeper, and RefFinder software were used to evaluate the stability of gene expression in both pyometra and healthy uterine samples. The results showed that the expression stability of the candidate gene in pyometra and healthy tissues differed. We showed that YWHAZ was the best reference gene, which could be used as an accurate internal control gene in canine pyometra studies. To further validate this recommendation, the expression profile of a target gene insulin-like growth factor 1 receptor gene (IGF1R) was investigated. We found that the expression of IGF1R was significantly altered when different reference genes were used. All reference genes identified in the present study will enable more accurate normalization of gene expression data in both pyometra infected and healthy uterine tissues.

  5. Identification and target prediction of miRNAs specifically expressed in rat neural tissue

    Directory of Open Access Journals (Sweden)

    Tu Kang

    2009-05-01

    Full Text Available Abstract Background MicroRNAs (miRNAs are a large group of RNAs that play important roles in regulating gene expression and protein translation. Several studies have indicated that some miRNAs are specifically expressed in human, mouse and zebrafish tissues. For example, miR-1 and miR-133 are specifically expressed in muscles. Tissue-specific miRNAs may have particular functions. Although previous studies have reported the presence of human, mouse and zebrafish tissue-specific miRNAs, there have been no detailed reports of rat tissue-specific miRNAs. In this study, Home-made rat miRNA microarrays which established in our previous study were used to investigate rat neural tissue-specific miRNAs, and mapped their target genes in rat tissues. This study will provide information for the functional analysis of these miRNAs. Results In order to obtain as complete a picture of specific miRNA expression in rat neural tissues as possible, customized miRNA microarrays with 152 selected miRNAs from miRBase were used to detect miRNA expression in 14 rat tissues. After a general clustering analysis, 14 rat tissues could be clearly classified into neural and non-neural tissues based on the obtained expression profiles with p values Conclusion Our work provides a global view of rat neural tissue-specific miRNA profiles and a target map of miRNAs, which is expected to contribute to future investigations of miRNA regulatory mechanisms in neural systems.

  6. Cyp1a reporter zebrafish reveals target tissues for dioxin

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kun-Hee [Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju (Korea, Republic of); Department of Microbiology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Park, Hye-Jeong [Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju (Korea, Republic of); Kim, Jin Hee [Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju (Korea, Republic of); Department of Microbiology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Kim, Suhyun [Graduate School of Medicine, Korea University, Ansan (Korea, Republic of); Williams, Darren R. [New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju (Korea, Republic of); Kim, Myeong-Kyu [Department of Neurology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Jung, Young Do [Department of Biochemistry, Chonnam National University Medical School, Gwangju (Korea, Republic of); Teraoka, Hiroki [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu (Japan); Park, Hae-Chul [Graduate School of Medicine, Korea University, Ansan (Korea, Republic of); Choy, Hyon E., E-mail: hyonchoy@chonnam.ac.kr [Department of Microbiology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Shin, Boo Ahn, E-mail: bashin@chonnam.ac.kr [Department of Microbiology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Choi, Seok-Yong, E-mail: zebrafish@chonnam.ac.kr [Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju (Korea, Republic of); School of Biological Sciences and Technology, Chonnam National University, Gwangju (Korea, Republic of)

    2013-06-15

    Highlights: •2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic anthropogenic substance ever identified. •Transgenic cyp1a reporter zebrafish reveals target tissues for TCDD. •The retinal bipolar cells, otic vesicle, lateral line, pancreas, cloaca and pectoral fin bud are novel targets in zebrafish for TCDD. •Our findings will further understanding of human health risks by TCDD. -- Abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the unintentional byproduct of various industrial processes, is classified as human carcinogen and could disrupt reproductive, developmental and endocrine systems. Induction of cyp1a1 is used as an indicator of TCDD exposure. We sought to determine tissues that are vulnerable to TCDD toxicity using a transgenic zebrafish (Danio rerio) model. We inserted a nuclear enhanced green fluorescent protein gene (EGFP) into the start codon of a zebrafish cyp1a gene in a fosmid clone using DNA recombineering. The resulting recombineered fosmid was then used to generate cyp1a reporter zebrafish, embryos of which were exposed to TCDD. Expression pattern of EGFP in the reporter zebrafish mirrored that of endogenous cyp1a mRNA. In addition, exposure of the embryos to TCDD at as low as 10 pM for 72 h, which does not elicit morphological abnormalities of embryos, markedly increased GFP expression. Furthermore, the reporter embryos responded to other AhR ligands as well. Exposure of the embryos to TCDD revealed previously reported (the cardiovascular system, liver, pancreas, kidney, swim bladder and skin) and unreported target tissues (retinal bipolar cells, otic vesicle, lateral line, cloaca and pectoral fin bud) for TCDD. Transgenic cyp1a reporter zebrafish we have developed can further understanding of ecotoxicological relevance and human health risks by TCDD. In addition, they could be used to identify agonists of AhR and antidotes to TCDD toxicity.

  7. Sexual selection targets cetacean pelvic bones.

    Science.gov (United States)

    Dines, James P; Otárola-Castillo, Erik; Ralph, Peter; Alas, Jesse; Daley, Timothy; Smith, Andrew D; Dean, Matthew D

    2014-11-01

    Male genitalia evolve rapidly, probably as a result of sexual selection. Whether this pattern extends to the internal infrastructure that influences genital movements remains unknown. Cetaceans (whales and dolphins) offer a unique opportunity to test this hypothesis: since evolving from land-dwelling ancestors, they lost external hind limbs and evolved a highly reduced pelvis that seems to serve no other function except to anchor muscles that maneuver the penis. Here, we create a novel morphometric pipeline to analyze the size and shape evolution of pelvic bones from 130 individuals (29 species) in the context of inferred mating system. We present two main findings: (1) males from species with relatively intense sexual selection (inferred by relative testes size) tend to evolve larger penises and pelvic bones compared to their body length, and (2) pelvic bone shape has diverged more in species pairs that have diverged in inferred mating system. Neither pattern was observed in the anterior-most pair of vertebral ribs, which served as a negative control. This study provides evidence that sexual selection can affect internal anatomy that controls male genitalia. These important functions may explain why cetacean pelvic bones have not been lost through evolutionary time. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

  8. Sexual selection targets cetacean pelvic bones

    Science.gov (United States)

    Dines, J. P.; Otárola-Castillo, E.; Ralph, P.; Alas, J.; Daley, T.; Smith, A. D.; Dean, M. D.

    2014-01-01

    Male genitalia evolve rapidly, probably as a result of sexual selection. Whether this pattern extends to the internal infrastructure that influences genital movements remains unknown. Cetaceans (whales and dolphins) offer a unique opportunity to test this hypothesis: since evolving from land-dwelling ancestors, they lost external hind limbs and evolved a highly reduced pelvis which seems to serve no other function except to anchor muscles that maneuver the penis. Here we create a novel morphometric pipeline to analyze the size and shape evolution of pelvic bones from 130 individuals (29 species) in the context of inferred mating system. We present two main findings: 1) males from species with relatively intense sexual selection (inferred by relative testes size) have evolved relatively large penises and pelvic bones compared to their body size, and 2) pelvic bone shape diverges more quickly in species pairs that have diverged in inferred mating system. Neither pattern was observed in the anterior-most pair of vertebral ribs, which served as a negative control. This study provides evidence that sexual selection can affect internal anatomy that controls male genitalia. These important functions may explain why cetacean pelvic bones have not been lost through evolutionary time. PMID:25186496

  9. Hypericin-mediated selective photomodification of connective tissues

    Energy Technology Data Exchange (ETDEWEB)

    Hovhannisyan, V., E-mail: hovv@phys.ntu.edu.tw; Guo, H. W.; Chen, Y. F., E-mail: yfchen@phys.ntu.edu.tw [Department of Physics, National Taiwan University, Taipei 106, Taiwan (China); Hovhannisyan, A. [Multimedia and Programming, European Regional Education Academy, Yerevan 0037 (Armenia); Ghukasyan, V. [Neuroscience Center, University of North Carolina at Chapel Hill, North Carolina 27514 (United States); Dong, C. Y., E-mail: cydong@phys.ntu.edu.tw [Department of Physics, National Taiwan University, Taipei 106, Taiwan (China); Center for Quantum Science and Engineering, National Taiwan University, Taipei 106, Taiwan (China)

    2014-12-29

    Controllable modification of biological molecules and supramolecular components of connective tissue are important for biophysical and biomedical applications. Through the use of second harmonic generation imaging, two-photon fluorescence microscopy, and spectrofluorimetry, we found that hypericin, a natural pigment, induces photosensitized destruction of collagen fibers but does not affect elastic fibers and lipids in chicken tendon, skin, and blood vessels. We demonstrated the dynamics and efficiency of collagen photomodification and investigated mechanisms of this processes. Our results suggest that hypericin–mediated photoprocesses in biological tissues may be useful in biomedical applications that require selective modification of connective tissues.

  10. Combining Targeted Agents With Modern Radiotherapy in Soft Tissue Sarcomas

    Science.gov (United States)

    Wong, Philip; Houghton, Peter; Kirsch, David G.; Finkelstein, Steven E.; Monjazeb, Arta M.; Xu-Welliver, Meng; Dicker, Adam P.; Ahmed, Mansoor; Vikram, Bhadrasain; Teicher, Beverly A.; Coleman, C. Norman; Machtay, Mitchell; Curran, Walter J.

    2014-01-01

    Improved understanding of soft-tissue sarcoma (STS) biology has led to better distinction and subtyping of these diseases with the hope of exploiting the molecular characteristics of each subtype to develop appropriately targeted treatment regimens. In the care of patients with extremity STS, adjunctive radiation therapy (RT) is used to facilitate limb and function, preserving surgeries while maintaining five-year local control above 85%. In contrast, for STS originating from nonextremity anatomical sites, the rate of local recurrence is much higher (five-year local control is approximately 50%) and a major cause of death and morbidity in these patients. Incorporating novel technological advancements to administer accurate RT in combination with novel radiosensitizing agents could potentially improve local control and overall survival. RT efficacy in STS can be increased by modulating biological pathways such as angiogenesis, cell cycle regulation, cell survival signaling, and cancer-host immune interactions. Previous experiences, advancements, ongoing research, and current clinical trials combining RT with agents modulating one or more of the above pathways are reviewed. The standard clinical management of patients with STS with pretreatment biopsy, neoadjuvant treatment, and primary surgery provides an opportune disease model for interrogating translational hypotheses. The purpose of this review is to outline a strategic vision for clinical translation of preclinical findings and to identify appropriate targeted agents to combine with radiotherapy in the treatment of STS from different sites and/or different histology subtypes. PMID:25326640

  11. Bioaccumulation of selected inorganic substances in the tissue of ...

    African Journals Online (AJOL)

    Bioaccumulation of selected inorganic substances in the tissue of Oreochromis shiranus from Bunda Dam, Malawi. ... around the dam and the presence of the sewage pond nearby have no significant effect on the levels of chemicals in the dam water or its fish. Keywords: chemical parameters; pollution; water; fish; Malawi

  12. An algorithm for preferential selection of spectroscopic targets in LEGUE

    International Nuclear Information System (INIS)

    Carlin, Jeffrey L.; Newberg, Heidi Jo; Lépine, Sébastien; Deng Licai; Chen Yuqin; Fu Xiaoting; Gao Shuang; Li Jing; Liu Chao; Beers, Timothy C.; Christlieb, Norbert; Grillmair, Carl J.; Guhathakurta, Puragra; Han Zhanwen; Hou Jinliang; Lee, Hsu-Tai; Liu Xiaowei; Pan Kaike; Sellwood, J. A.; Wang Hongchi

    2012-01-01

    We describe a general target selection algorithm that is applicable to any survey in which the number of available candidates is much larger than the number of objects to be observed. This routine aims to achieve a balance between a smoothly-varying, well-understood selection function and the desire to preferentially select certain types of targets. Some target-selection examples are shown that illustrate different possibilities of emphasis functions. Although it is generally applicable, the algorithm was developed specifically for the LAMOST Experiment for Galactic Understanding and Exploration (LEGUE) survey that will be carried out using the Chinese Guo Shou Jing Telescope. In particular, this algorithm was designed for the portion of LEGUE targeting the Galactic halo, in which we attempt to balance a variety of science goals that require stars at fainter magnitudes than can be completely sampled by LAMOST. This algorithm has been implemented for the halo portion of the LAMOST pilot survey, which began in October 2011.

  13. Target Selection Models with Preference Variation Between Offenders

    NARCIS (Netherlands)

    Townsley, Michael; Birks, Daniel; Ruiter, Stijn; Bernasco, Wim; White, Gentry

    2016-01-01

    Objectives: This study explores preference variation in location choice strategies of residential burglars. Applying a model of offender target selection that is grounded in assertions of the routine activity approach, rational choice perspective, crime pattern and social disorganization theories,

  14. Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator

    Science.gov (United States)

    Xie, Xinni; Chen, Wei; Zhang, Ning; Yuan, Mei; Xu, Cheng; Zheng, Zhibing; Li, Hua; Wang, Lili

    2017-01-01

    The mechanisms underlying the enhancement of insulin sensitivity by selective peroxisome proliferator-activated receptor γ modulators (sPPARγMs) are still not completely known. Here, the representative sPPARγM, INT131, was used as a probe to investigate the insulin-sensitizing mechanisms of sPPARγM in the context of tissue selective compound distribution and PPARγ regulation. First, 30 mg kg−1 INT131 was observed to produce an insulin-sensitizing effect comparable to that of 10 mg kg−1 rosiglitazone (RSG) in both db/db and DIO mice using the oral glucose and insulin tolerance tests. Similar to RSG, INT131 significantly increased brown adipose tissue (BAT) mass and adipocyte size and up-regulated the expression of BAT-specific genes. Compared with RSG, INT131 exhibited greater potency in inducing white adipose tissue (WAT) browning, decreasing adipocyte size, and increasing BAT-specific and function-related gene expression in subcutaneous WAT (sWAT). However, it did not induce hepatomegaly or hepatic steatosis, which is associated with lower levels of lipogenic genes expression. Pharmacokinetic analysis reveals that in contrast with RSG, INT131 shows higher Cmax, and much longer residency time (AUC0−12h), as well relatively lower elimination rate in adipose tissues and skeletal muscle, this demonstrated INT131 distributed predominantly in adipose tissue. Whereas, INT131 was less abundant in the liver. These results thus suggest that the tissue-selective distribution underlies INT131's selective PPARγ modulation. Compounds favoring adipose tissue may aid in development of better, safer sPPARγM to address the insulin resistance of diabetes. PMID:28611668

  15. Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator

    Directory of Open Access Journals (Sweden)

    Xinni Xie

    2017-05-01

    Full Text Available The mechanisms underlying the enhancement of insulin sensitivity by selective peroxisome proliferator-activated receptor γ modulators (sPPARγMs are still not completely known. Here, the representative sPPARγM, INT131, was used as a probe to investigate the insulin-sensitizing mechanisms of sPPARγM in the context of tissue selective compound distribution and PPARγ regulation. First, 30 mg kg−1 INT131 was observed to produce an insulin-sensitizing effect comparable to that of 10 mg kg−1 rosiglitazone (RSG in both db/db and DIO mice using the oral glucose and insulin tolerance tests. Similar to RSG, INT131 significantly increased brown adipose tissue (BAT mass and adipocyte size and up-regulated the expression of BAT-specific genes. Compared with RSG, INT131 exhibited greater potency in inducing white adipose tissue (WAT browning, decreasing adipocyte size, and increasing BAT-specific and function-related gene expression in subcutaneous WAT (sWAT. However, it did not induce hepatomegaly or hepatic steatosis, which is associated with lower levels of lipogenic genes expression. Pharmacokinetic analysis reveals that in contrast with RSG, INT131 shows higher Cmax, and much longer residency time (AUC0−12h, as well relatively lower elimination rate in adipose tissues and skeletal muscle, this demonstrated INT131 distributed predominantly in adipose tissue. Whereas, INT131 was less abundant in the liver. These results thus suggest that the tissue-selective distribution underlies INT131's selective PPARγ modulation. Compounds favoring adipose tissue may aid in development of better, safer sPPARγM to address the insulin resistance of diabetes.

  16. Target selection biases from recent experience transfer across effectors.

    Science.gov (United States)

    Moher, Jeff; Song, Joo-Hyun

    2016-02-01

    Target selection is often biased by an observer's recent experiences. However, not much is known about whether these selection biases influence behavior across different effectors. For example, does looking at a red object make it easier to subsequently reach towards another red object? In the current study, we asked observers to find the uniquely colored target object on each trial. Randomly intermixed pre-trial cues indicated the mode of action: either an eye movement or a visually guided reach movement to the target. In Experiment 1, we found that priming of popout, reflected in faster responses following repetition of the target color on consecutive trials, occurred regardless of whether the effector was repeated from the previous trial or not. In Experiment 2, we examined whether an inhibitory selection bias away from a feature could transfer across effectors. While priming of popout reflects both enhancement of the repeated target features and suppression of the repeated distractor features, the distractor previewing effect isolates a purely inhibitory component of target selection in which a previewed color is presented in a homogenous display and subsequently inhibited. Much like priming of popout, intertrial suppression biases in the distractor previewing effect transferred across effectors. Together, these results suggest that biases for target selection driven by recent trial history transfer across effectors. This indicates that representations in memory that bias attention towards or away from specific features are largely independent from their associated actions.

  17. Novel target configurations for selective ionization state studies in molybdenum

    International Nuclear Information System (INIS)

    Ilcisin, K.J.; Feldman, U.; Schwob, J.L.; Wouters, A.; Suckewer, S.; Princeton Univ., NJ

    1990-03-01

    Details of experiments aimed at achieving low ionization state selectivity in molybdenum are presented. Targets are excited with a 10 J CO 2 laser and the resultant VUV spectrum (300--700 Angstrom) has been studied. Combinations of focal spot size, target depth, and target geometries are compared. Simple attenuation of energy is shown not to vary ionization stage composition significantly. Experiments conducted with grazing incidence targets result only in a hot plasma. Modular targets with cooling cylinders of various radii demonstrated good selectivity of the ionization states, but with low absolute signals. Finally, results from combinations of focal spot adjustment and radiative cooling illustrate increased control over desired plasma temperature and density for spectroscopic studies of molybdenum. 7 refs., 14 figs

  18. Epithelial-mesenchymal transition: An emerging target in tissue fibrosis

    Science.gov (United States)

    Li, Meirong; Luan, Fuxin; Zhao, Yali; Hao, Haojie; Zhou, Yong; Han, Weidong

    2016-01-01

    Epithelial-mesenchymal transition (EMT) is involved in a variety of tissue fibroses. Fibroblasts/myofibroblasts derived from epithelial cells contribute to the excessive accumulation of fibrous connective tissue in damaged tissue, which can lead to permanent scarring or organ malfunction. Therefore, EMT-related fibrosis cannot be neglected. This review highlights the findings that demonstrate the EMT to be a direct contributor to the fibroblast/myofibroblast population in the development of tissue fibrosis and helps to elucidate EMT-related anti-fibrotic strategies, which may enable the development of therapeutic interventions to suppress EMT and potentially reverse organ fibrosis. PMID:26361988

  19. Egr3 dependent sympathetic target tissue innervation in the absence of neuron death.

    Directory of Open Access Journals (Sweden)

    Lin Li

    Full Text Available Nerve Growth Factor (NGF is a target tissue derived neurotrophin required for normal sympathetic neuron survival and target tissue innervation. NGF signaling regulates gene expression in sympathetic neurons, which in turn mediates critical aspects of neuron survival, axon extension and terminal axon branching during sympathetic nervous system (SNS development. Egr3 is a transcription factor regulated by NGF signaling in sympathetic neurons that is essential for normal SNS development. Germline Egr3-deficient mice have physiologic dysautonomia characterized by apoptotic sympathetic neuron death and abnormal innervation to many target tissues. The extent to which sympathetic innervation abnormalities in the absence of Egr3 is caused by altered innervation or by neuron death during development is unknown. Using Bax-deficient mice to abrogate apoptotic sympathetic neuron death in vivo, we show that Egr3 has an essential role in target tissue innervation in the absence of neuron death. Sympathetic target tissue innervation is abnormal in many target tissues in the absence of neuron death, and like NGF, Egr3 also appears to effect target tissue innervation heterogeneously. In some tissues, such as heart, spleen, bowel, kidney, pineal gland and the eye, Egr3 is essential for normal innervation, whereas in other tissues such as lung, stomach, pancreas and liver, Egr3 appears to have little role in innervation. Moreover, in salivary glands and heart, two tissues where Egr3 has an essential role in sympathetic innervation, NGF and NT-3 are expressed normally in the absence of Egr3 indicating that abnormal target tissue innervation is not due to deregulation of these neurotrophins in target tissues. Taken together, these results clearly demonstrate a role for Egr3 in mediating sympathetic target tissue innervation that is independent of neuron survival or neurotrophin deregulation.

  20. In-silico Leishmania Target Selectivity of Antiparasitic Terpenoids

    Directory of Open Access Journals (Sweden)

    Ifedayo Victor Ogungbe

    2013-07-01

    Full Text Available Neglected Tropical Diseases (NTDs, like leishmaniasis, are major causes of mortality in resource-limited countries. The mortality associated with these diseases is largely due to fragile healthcare systems, lack of access to medicines, and resistance by the parasites to the few available drugs. Many antiparasitic plant-derived isoprenoids have been reported, and many of them have good in vitro activity against various forms of Leishmania spp. In this work, potential Leishmania biochemical targets of antiparasitic isoprenoids were studied in silico. Antiparasitic monoterpenoids selectively docked to L. infantum nicotinamidase, L. major uridine diphosphate-glucose pyrophosphorylase and methionyl t-RNA synthetase. The two protein targets selectively targeted by germacranolide sesquiterpenoids were L. major methionyl t-RNA synthetase and dihydroorotate dehydrogenase. Diterpenoids generally favored docking to L. mexicana glycerol-3-phosphate dehydrogenase. Limonoids also showed some selectivity for L. mexicana glycerol-3-phosphate dehydrogenase and L. major dihydroorotate dehydrogenase while withanolides docked more selectively with L. major uridine diphosphate-glucose pyrophosphorylase. The selectivity of the different classes of antiparasitic compounds for the protein targets considered in this work can be explored in fragment- and/or structure-based drug design towards the development of leads for new antileishmanial drugs.

  1. Improved targeted immunization strategies based on two rounds of selection

    Science.gov (United States)

    Xia, Ling-Ling; Song, Yu-Rong; Li, Chan-Chan; Jiang, Guo-Ping

    2018-04-01

    In the case of high degree targeted immunization where the number of vaccine is limited, when more than one node associated with the same degree meets the requirement of high degree centrality, how can we choose a certain number of nodes from those nodes, so that the number of immunized nodes will not exceed the limit? In this paper, we introduce a new idea derived from the selection process of second-round exam to solve this problem and then propose three improved targeted immunization strategies. In these proposed strategies, the immunized nodes are selected through two rounds of selection, where we increase the quotas of first-round selection according the evaluation criterion of degree centrality and then consider another characteristic parameter of node, such as node's clustering coefficient, betweenness and closeness, to help choose targeted nodes in the second-round selection. To validate the effectiveness of the proposed strategies, we compare them with the degree immunizations including the high degree targeted and the high degree adaptive immunizations using two metrics: the size of the largest connected component of immunized network and the number of infected nodes. Simulation results demonstrate that the proposed strategies based on two rounds of sorting are effective for heterogeneous networks and their immunization effects are better than that of the degree immunizations.

  2. Feature Extraction and Selection Strategies for Automated Target Recognition

    Science.gov (United States)

    Greene, W. Nicholas; Zhang, Yuhan; Lu, Thomas T.; Chao, Tien-Hsin

    2010-01-01

    Several feature extraction and selection methods for an existing automatic target recognition (ATR) system using JPLs Grayscale Optical Correlator (GOC) and Optimal Trade-Off Maximum Average Correlation Height (OT-MACH) filter were tested using MATLAB. The ATR system is composed of three stages: a cursory region of-interest (ROI) search using the GOC and OT-MACH filter, a feature extraction and selection stage, and a final classification stage. Feature extraction and selection concerns transforming potential target data into more useful forms as well as selecting important subsets of that data which may aide in detection and classification. The strategies tested were built around two popular extraction methods: Principal Component Analysis (PCA) and Independent Component Analysis (ICA). Performance was measured based on the classification accuracy and free-response receiver operating characteristic (FROC) output of a support vector machine(SVM) and a neural net (NN) classifier.

  3. WFIRST: Exoplanet Target Selection and Scheduling with Greedy Optimization

    Science.gov (United States)

    Keithly, Dean; Garrett, Daniel; Delacroix, Christian; Savransky, Dmitry

    2018-01-01

    We present target selection and scheduling algorithms for missions with direct imaging of exoplanets, and the Wide Field Infrared Survey Telescope (WFIRST) in particular, which will be equipped with a coronagraphic instrument (CGI). Optimal scheduling of CGI targets can maximize the expected value of directly imaged exoplanets (completeness). Using target completeness as a reward metric and integration time plus overhead time as a cost metric, we can maximize the sum completeness for a mission with a fixed duration. We optimize over these metrics to create a list of target stars using a greedy optimization algorithm based off altruistic yield optimization (AYO) under ideal conditions. We simulate full missions using EXOSIMS by observing targets in this list for their predetermined integration times. In this poster, we report the theoretical maximum sum completeness, mean number of detected exoplanets from Monte Carlo simulations, and the ideal expected value of the simulated missions.

  4. Deep Brain Stimulation Target Selection for Parkinson's Disease.

    Science.gov (United States)

    Honey, Christopher R; Hamani, Clement; Kalia, Suneil K; Sankar, Tejas; Picillo, Marina; Munhoz, Renato P; Fasano, Alfonso; Panisset, Michel

    2017-01-01

    During the "DBS Canada Day" symposium held in Toronto July 4-5, 2014, the scientific committee invited experts to discuss three main questions on target selection for deep brain stimulation (DBS) of patients with Parkinson's disease (PD). First, is the subthalamic nucleus (STN) or the globus pallidus internus (GPi) the ideal target? In summary, both targets are equally effective in improving the motor symptoms of PD. STN allows a greater medications reduction, while GPi exerts a direct antidyskinetic effect. Second, are there further potential targets? Ventral intermediate nucleus DBS has significant long-term benefit for tremor control but insufficiently addresses other motor features of PD. DBS in the posterior subthalamic area also reduces tremor. The pedunculopontine nucleus remains an investigational target. Third, should DBS for PD be performed unilaterally, bilaterally or staged? Unilateral STN DBS can be proposed to asymmetric patients. There is no evidence that a staged bilateral approach reduces the incidence of DBS-related adverse events.

  5. Tissue specific metal characterization of selected fish species in Pakistan.

    Science.gov (United States)

    Ahmed, Mukhtiar; Ahmad, Taufiq; Liaquat, Muhammad; Abbasi, Kashif Sarfraz; Farid, Ibrahim Bayoumi Abdel; Jahangir, Muhammad

    2016-04-01

    Concentration of various metals, i.e., zinc (Zn), copper (Cu), lead (Pb), nickel (Ni), iron (Fe), manganese (Mn), chromium (Cr), and silver (Ag), was evaluated in five indigenous fish species (namely, silver carp, common carp, mahseer, thela fish, and rainbow trout), by using atomic absorption spectrophotometer. It is proved from this study that, overall, mahseer and rainbow trout had high amount of zinc, whereas thela fish and silver carp had high concentration of copper, chromium, silver, nickel, and lead, while common carp had highest amount of iron contents. Furthermore, a tissue-specific discrimination among various fish species was observed, where higher metal concentrations were noticed in fish liver, with decreasing concentration in other organs like skin, gills, and finally the least contents in fish muscle. Multivariate data analysis showed not only a variation in heavy metals among the tissues but also discrimination among the selected fish species.

  6. FACILITATING IMAGE-ANALYSIS OF GLYCOLMETHACRYLATE EMBEDDED TISSUES WITH TISSUE-SELECTIVE AND RESIN-SELECTIVE DYES, CHOSEN BY A NUMERICAL STRUCTURE-STAINING RELATIONSHIP MODEL

    NARCIS (Netherlands)

    GERRITS, PO; HOROBIN, RW; STOKROOS, [No Value

    A method facilitating recording of macroscopic images from glycolmethacrylate (GMA) embedded tissues and tissue-free sections is described. This method used dyes that selectively stain only tissue, only resin, or both, but in contrasting colors. The dyes were selected on the basis of simple

  7. Neural Networks for Target Selection in Direct Marketing

    NARCIS (Netherlands)

    R. Potharst (Rob); U. Kaymak (Uzay); W.H.L.M. Pijls (Wim)

    2001-01-01

    textabstractPartly due to a growing interest in direct marketing, it has become an important application field for data mining. Many techniques have been applied to select the targets in commercial applications, such as statistical regression, regression trees, neural computing, fuzzy clustering

  8. Classification and Target Group Selection Based Upon Frequent Patterns

    NARCIS (Netherlands)

    W.H.L.M. Pijls (Wim); R. Potharst (Rob)

    2000-01-01

    textabstractIn this technical report , two new algorithms based upon frequent patterns are proposed. One algorithm is a classification method. The other one is an algorithm for target group selection. In both algorithms, first of all, the collection of frequent patterns in the training set is

  9. Design, construction and performance evaluation of the target tissue thickness measurement system in intraoperative radiotherapy for breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yazdani, Mohammad Reza, E-mail: myazdani@aut.ac.ir [Faculty of Energy Engineering and Physics, Amirkabir University of Technology, Tehran (Iran, Islamic Republic of); Setayeshi, Saeed, E-mail: setayesh@aut.ac.ir [Faculty of Energy Engineering and Physics, Amirkabir University of Technology, Tehran (Iran, Islamic Republic of); Arabalibeik, Hossein, E-mail: arabalibeik@tums.ac.ir [Research Center for Biomedical Technology and Robotics (RCBTR), Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Akbari, Mohammad Esmaeil [Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran (Iran, Islamic Republic of)

    2017-05-21

    Intraoperative electron radiation therapy (IOERT), which uses electron beams for irradiating the target directly during the surgery, has the advantage of delivering a homogeneous dose to a controlled layer of tissue. Since the dose falls off quickly below the target thickness, the underlying normal tissues are spared. In selecting the appropriate electron energy, the accuracy of the target tissue thickness measurement is critical. In contrast to other procedures applied in IOERT, the routine measurement method is considered to be completely traditional and approximate. In this work, a novel mechanism is proposed for measuring the target tissue thickness with an acceptable level of accuracy. An electronic system has been designed and manufactured with the capability of measuring the tissue thickness based on the recorded electron density under the target. The results indicated the possibility of thickness measurement with a maximum error of 2 mm for 91.35% of data. Aside from system limitation in estimating the thickness of 5 mm phantom, for 88.94% of data, maximum error is 1 mm.

  10. Design, construction and performance evaluation of the target tissue thickness measurement system in intraoperative radiotherapy for breast cancer

    Science.gov (United States)

    Yazdani, Mohammad Reza; Setayeshi, Saeed; Arabalibeik, Hossein; Akbari, Mohammad Esmaeil

    2017-05-01

    Intraoperative electron radiation therapy (IOERT), which uses electron beams for irradiating the target directly during the surgery, has the advantage of delivering a homogeneous dose to a controlled layer of tissue. Since the dose falls off quickly below the target thickness, the underlying normal tissues are spared. In selecting the appropriate electron energy, the accuracy of the target tissue thickness measurement is critical. In contrast to other procedures applied in IOERT, the routine measurement method is considered to be completely traditional and approximate. In this work, a novel mechanism is proposed for measuring the target tissue thickness with an acceptable level of accuracy. An electronic system has been designed and manufactured with the capability of measuring the tissue thickness based on the recorded electron density under the target. The results indicated the possibility of thickness measurement with a maximum error of 2 mm for 91.35% of data. Aside from system limitation in estimating the thickness of 5 mm phantom, for 88.94% of data, maximum error is 1 mm.

  11. Targeted Diazotransfer Reagents Enable Selective Modification of Proteins with Azides.

    Science.gov (United States)

    Lohse, Jonas; Swier, Lotteke J Y M; Oudshoorn, Ruben C; Médard, Guillaume; Kuster, Bernhard; Slotboom, Dirk-Jan; Witte, Martin D

    2017-04-19

    In chemical biology, azides are used to chemically manipulate target structures in a bioorthogonal manner for a plethora of applications ranging from target identification to the synthesis of homogeneously modified protein conjugates. While a variety of methods have been established to introduce the azido group into recombinant proteins, a method that directly converts specific amino groups in endogenous proteins is lacking. Here, we report the first biotin-tethered diazotransfer reagent DtBio and demonstrate that it selectively modifies the model proteins streptavidin and avidin and the membrane protein BioY on cell surface. The reagent converts amines in the proximity of the binding pocket to azides and leaves the remaining amino groups in streptavidin untouched. Reagents of this novel class will find use in target identification as well as the selective functionalization and bioorthogonal protection of proteins.

  12. Target Selection for the SDSS-IV APOGEE-2 Survey

    Energy Technology Data Exchange (ETDEWEB)

    Zasowski, G. [Department of Physics and Astronomy, University of Utah, Salt Lake City, UT 84112 (United States); Cohen, R. E.; Carlberg, J. K.; Fleming, Scott W. [Space Telescope Science Institute, Baltimore, MD 21218 (United States); Chojnowski, S. D.; Holtzman, J. [Department of Astronomy, New Mexico State University, Las Cruces, NM 88001 (United States); Santana, F. [Departamento de Astronomía, Universidad de Chile, Santiago (Chile); Oelkers, R. J.; Bird, J. C. [Department of Physics and Astronomy, Vanderbilt University, Nashville, TN 37235 (United States); Andrews, B. [PITT PACC, Department of Physics and Astronomy, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Beaton, R. L. [The Observatories of the Carnegie Institution for Science, Pasadena, CA 91101 (United States); Bender, C.; Cunha, K. [Steward Observatory, The University of Arizona, Tucson, AZ 85719 (United States); Bovy, J. [Department of Astronomy and Astrophysics and Dunlap Institute for Astronomy and Astrophysics, University of Toronto, Toronto, ON M5S 3H4 (Canada); Covey, K. [Department of Physics and Astronomy, Western Washington University, Bellingham, WA 98225 (United States); Dell’Agli, F.; García-Hernández, D. A. [Departamento de Astrofísica, Universidad de La Laguna, and Instituto de Astrofísica de Canarias, La Laguna, Tenerife (Spain); Frinchaboy, P. M. [Department of Physics and Astronomy, Texas Christian University, Fort Worth, TX 76129 (United States); Harding, P. [Department of Astronomy, Case Western Reserve University, Cleveland, OH 44106 (United States); Johnson, J. A., E-mail: gail.zasowski@gmail.com [Department of Astronomy, The Ohio State University, Columbus, OH 43210 (United States); and others

    2017-11-01

    APOGEE-2 is a high-resolution, near-infrared spectroscopic survey observing ∼3 × 10{sup 5} stars across the entire sky. It is the successor to APOGEE and is part of the Sloan Digital Sky Survey IV (SDSS-IV). APOGEE-2 is expanding on APOGEE’s goals of addressing critical questions of stellar astrophysics, stellar populations, and Galactic chemodynamical evolution using (1) an enhanced set of target types and (2) a second spectrograph at Las Campanas Observatory in Chile. APOGEE-2 is targeting red giant branch and red clump stars, RR Lyrae, low-mass dwarf stars, young stellar objects, and numerous other Milky Way and Local Group sources across the entire sky from both hemispheres. In this paper, we describe the APOGEE-2 observational design, target selection catalogs and algorithms, and the targeting-related documentation included in the SDSS data releases.

  13. Predicting selective drug targets in cancer through metabolic networks

    Science.gov (United States)

    Folger, Ori; Jerby, Livnat; Frezza, Christian; Gottlieb, Eyal; Ruppin, Eytan; Shlomi, Tomer

    2011-01-01

    The interest in studying metabolic alterations in cancer and their potential role as novel targets for therapy has been rejuvenated in recent years. Here, we report the development of the first genome-scale network model of cancer metabolism, validated by correctly identifying genes essential for cellular proliferation in cancer cell lines. The model predicts 52 cytostatic drug targets, of which 40% are targeted by known, approved or experimental anticancer drugs, and the rest are new. It further predicts combinations of synthetic lethal drug targets, whose synergy is validated using available drug efficacy and gene expression measurements across the NCI-60 cancer cell line collection. Finally, potential selective treatments for specific cancers that depend on cancer type-specific downregulation of gene expression and somatic mutations are compiled. PMID:21694718

  14. Target Selection for the SDSS-IV APOGEE-2 Survey

    Science.gov (United States)

    Zasowski, G.; Cohen, R. E.; Chojnowski, S. D.; Santana, F.; Oelkers, R. J.; Andrews, B.; Beaton, R. L.; Bender, C.; Bird, J. C.; Bovy, J.; Carlberg, J. K.; Covey, K.; Cunha, K.; Dell'Agli, F.; Fleming, Scott W.; Frinchaboy, P. M.; García-Hernández, D. A.; Harding, P.; Holtzman, J.; Johnson, J. A.; Kollmeier, J. A.; Majewski, S. R.; Mészáros, Sz.; Munn, J.; Muñoz, R. R.; Ness, M. K.; Nidever, D. L.; Poleski, R.; Román-Zúñiga, C.; Shetrone, M.; Simon, J. D.; Smith, V. V.; Sobeck, J. S.; Stringfellow, G. S.; Szigetiáros, L.; Tayar, J.; Troup, N.

    2017-11-01

    APOGEE-2 is a high-resolution, near-infrared spectroscopic survey observing ˜3 × 105 stars across the entire sky. It is the successor to APOGEE and is part of the Sloan Digital Sky Survey IV (SDSS-IV). APOGEE-2 is expanding on APOGEE’s goals of addressing critical questions of stellar astrophysics, stellar populations, and Galactic chemodynamical evolution using (1) an enhanced set of target types and (2) a second spectrograph at Las Campanas Observatory in Chile. APOGEE-2 is targeting red giant branch and red clump stars, RR Lyrae, low-mass dwarf stars, young stellar objects, and numerous other Milky Way and Local Group sources across the entire sky from both hemispheres. In this paper, we describe the APOGEE-2 observational design, target selection catalogs and algorithms, and the targeting-related documentation included in the SDSS data releases.

  15. Target Selection for the SDSS-III MARVELS Survey

    Science.gov (United States)

    Paegert, Martin; Stassun, Keivan G.; De Lee, Nathan; Pepper, Joshua; Fleming, Scott W.; Sivarani, Thirupathi; Mahadevan, Suvrath; Mack, Claude E., III; Dhital, Saurav; Hebb, Leslie; Ge, Jian

    2015-06-01

    We present the target selection process for the Multi-object APO Radial Velocity Exoplanets Large-area Survey (MARVELS), which is part of the Sloan Digital Sky Survey (SDSS) III. MARVELS is a medium-resolution (R ∼ 11,000) multi-fiber spectrograph capable of obtaining radial velocities for 60 objects at a time in order to find brown dwarfs and giant planets. The survey was configured to target dwarf stars with effective temperatures approximately between 4500 and 6250 K. For the first 2 years MARVELS relied on low-resolution spectroscopic pre-observations to estimate the effective temperature and log (g) for candidate stars and then selected suitable dwarf stars from this pool. Ultimately, the pre-observation spectra proved ineffective at filtering out giant stars; many giants were incorrectly classified as dwarfs, resulting in a giant contamination rate of ∼30% for the first phase of the MARVELS survey. Thereafter, the survey instead applied a reduced proper motion cut to eliminate giants and used the Infrared Flux Method to estimate effective temperatures, using only extant photmetric and proper-motion catalog information. The target selection method introduced here may be useful for other surveys that need to rely on extant catalog data for selection of specific stellar populations.

  16. Comparative analysis of housekeeping and tissue-selective genes in human based on network topologies and biological properties.

    Science.gov (United States)

    Yang, Lei; Wang, Shiyuan; Zhou, Meng; Chen, Xiaowen; Zuo, Yongchun; Sun, Dianjun; Lv, Yingli

    2016-06-01

    Housekeeping genes are genes that are turned on most of the time in almost every tissue to maintain cellular functions. Tissue-selective genes are predominantly expressed in one or a few biologically relevant tissue types. Benefitting from the massive gene expression microarray data obtained over the past decades, the properties of housekeeping and tissue-selective genes can now be investigated on a large-scale manner. In this study, we analyzed the topological properties of housekeeping and tissue-selective genes in the protein-protein interaction (PPI) network. Furthermore, we compared the biological properties and amino acid usage between these two gene groups. The results indicated that there were significant differences in topological properties between housekeeping and tissue-selective genes in the PPI network, and housekeeping genes had higher centrality properties and may play important roles in the complex biological network environment. We also found that there were significant differences in multiple biological properties and many amino acid compositions. The functional genes enrichment and subcellular localizations analysis was also performed to investigate the characterization of housekeeping and tissue-selective genes. The results indicated that the two gene groups showed significant different enrichment in drug targets, disease genes and toxin targets, and located in different subcellular localizations. At last, the discriminations between the properties of two gene groups were measured by the F-score, and expression stage had the most discriminative index in all properties. These findings may elucidate the biological mechanisms for understanding housekeeping and tissue-selective genes and may contribute to better annotate housekeeping and tissue-selective genes in other organisms.

  17. Target selection and deselection at the Berkeley Structural Genomics Center.

    Science.gov (United States)

    Chandonia, John-Marc; Kim, Sung-Hou; Brenner, Steven E

    2006-02-01

    At the Berkeley Structural Genomics Center (BSGC), our goal is to obtain a near-complete structural complement of proteins in the minimal organisms Mycoplasma genitalium and M. pneumoniae, two closely related pathogens. Current targets for structure determination have been selected in six major stages, starting with those predicted to be most tractable to high throughput study and likely to yield new structural information. We report on the process used to select these proteins, as well as our target deselection procedure. Target deselection reduces experimental effort by eliminating targets similar to those recently solved by the structural biology community or other centers. We measure the impact of the 69 structures solved at the BSGC as of July 2004 on structure prediction coverage of the M. pneumoniae and M. genitalium proteomes. The number of Mycoplasma proteins for which the fold could first be reliably assigned based on structures solved at the BSGC (24 M. pneumoniae and 21 M. genitalium) is approximately 25% of the total resulting from work at all structural genomics centers and the worldwide structural biology community (94 M. pneumoniae and 86 M. genitalium) during the same period. As the number of structures contributed by the BSGC during that period is less than 1% of the total worldwide output, the benefits of a focused target selection strategy are apparent. If the structures of all current targets were solved, the percentage of M. pneumoniae proteins for which folds could be reliably assigned would increase from approximately 57% (391 of 687) at present to around 80% (550 of 687), and the percentage of the proteome that could be accurately modeled would increase from around 37% (254 of 687) to about 64% (438 of 687). In M. genitalium, the percentage of the proteome that could be structurally annotated based on structures of our remaining targets would rise from 72% (348 of 486) to around 76% (371 of 486), with the percentage of accurately modeled

  18. Diagnostic radiopharmaceuticals for localization in target tissues exhibiting a regional pH shift relative to surrounding tissues

    International Nuclear Information System (INIS)

    Blau, M.; Kung, H.F.

    1985-01-01

    Diagnostic radiopharmaceutical compounds are provided which are capable of entering a target tissue or a target organ by passive diffusion through cell walls and which are effectively accumulated and retained within the target tissue or organ due to a regional pH shift. Such compounds are desirably readily accessible synthetically using readily available radionuclides. The compound comprises a radioactive isotope of an element in chemical combination with at least one amine group and preferably with at least two secondary or tertiary amine groups. The radioactive element is an element other than iodine emitting gamma ray, x-ray or positron radiation. When the element is a gamma ray emitting isotope, at least 75 percent of the number of emissions is emitted at energies of between 80 and 400 keV. The half-life of the isotope is usually between two minutes and 15 days. The compound has acid-base characteristics such that the state of ionization of the compound at the pH of the body is significantly different and usually less than its state of ionization at the intracellular pH of the target tissue. The compound has such lipid solubility characteristics that it is capable of ready penetration through cell walls, but within cells its lipid solubility is substantially decreased, whereby the ability of the compound to leave the target tissue is substantially diminished. Specific data relevant to di-beta-(piperidinoethyl)-selenide and di-beta-(morpholinoethyl)-selenide in rat brains are presented

  19. Think Outside The Color Box: Probabilistic Target Selection And The SDSS-XDQSO Quasar Targeting Catalog

    International Nuclear Information System (INIS)

    Bovy, J.; Sheldon, E.; Hennawi, J.F.; Hogg, D.W.; Myers, A.D.

    2011-01-01

    We present the SDSS-XDQSO quasar targeting catalog for efficient flux-based quasar target selection down to the faint limit of the Sloan Digital Sky Survey (SDSS) catalog, even at medium redshifts (2.5 ∼ 3.5) quasar probabilities for all 160,904,060 point sources with dereddened i-band magnitude between 17.75 and 22.45 mag in the 14,555 deg 2 of imaging from SDSS Data Release 8. The catalog can be used to define a uniformly selected and efficient low- or medium-redshift quasar survey, such as that needed for the SDSS-III's Baryon Oscillation Spectroscopic Survey project. We show that the XDQSO technique performs as well as the current best photometric quasar-selection technique at low redshift, and outperforms all other flux-based methods for selecting the medium-redshift quasars of our primary interest. We make code to reproduce the XDQSO quasar target selection publicly available.

  20. Hierarchical Targeting Strategy for Enhanced Tumor Tissue Accumulation/Retention and Cellular Internalization.

    Science.gov (United States)

    Wang, Sheng; Huang, Peng; Chen, Xiaoyuan

    2016-09-01

    Targeted delivery of therapeutic agents is an important way to improve the therapeutic index and reduce side effects. To design nanoparticles for targeted delivery, both enhanced tumor tissue accumulation/retention and enhanced cellular internalization should be considered simultaneously. So far, there have been very few nanoparticles with immutable structures that can achieve this goal efficiently. Hierarchical targeting, a novel targeting strategy based on stimuli responsiveness, shows good potential to enhance both tumor tissue accumulation/retention and cellular internalization. Here, the recent design and development of hierarchical targeting nanoplatforms, based on changeable particle sizes, switchable surface charges and activatable surface ligands, will be introduced. In general, the targeting moieties in these nanoplatforms are not activated during blood circulation for efficient tumor tissue accumulation, but re-activated by certain internal or external stimuli in the tumor microenvironment for enhanced cellular internalization. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Dynamic interactions between visual working memory and saccade target selection

    Science.gov (United States)

    Schneegans, Sebastian; Spencer, John P.; Schöner, Gregor; Hwang, Seongmin; Hollingworth, Andrew

    2014-01-01

    Recent psychophysical experiments have shown that working memory for visual surface features interacts with saccadic motor planning, even in tasks where the saccade target is unambiguously specified by spatial cues. Specifically, a match between a memorized color and the color of either the designated target or a distractor stimulus influences saccade target selection, saccade amplitudes, and latencies in a systematic fashion. To elucidate these effects, we present a dynamic neural field model in combination with new experimental data. The model captures the neural processes underlying visual perception, working memory, and saccade planning relevant to the psychophysical experiment. It consists of a low-level visual sensory representation that interacts with two separate pathways: a spatial pathway implementing spatial attention and saccade generation, and a surface feature pathway implementing color working memory and feature attention. Due to bidirectional coupling between visual working memory and feature attention in the model, the working memory content can indirectly exert an effect on perceptual processing in the low-level sensory representation. This in turn biases saccadic movement planning in the spatial pathway, allowing the model to quantitatively reproduce the observed interaction effects. The continuous coupling between representations in the model also implies that modulation should be bidirectional, and model simulations provide specific predictions for complementary effects of saccade target selection on visual working memory. These predictions were empirically confirmed in a new experiment: Memory for a sample color was biased toward the color of a task-irrelevant saccade target object, demonstrating the bidirectional coupling between visual working memory and perceptual processing. PMID:25228628

  2. Dynamic interactions between visual working memory and saccade target selection.

    Science.gov (United States)

    Schneegans, Sebastian; Spencer, John P; Schöner, Gregor; Hwang, Seongmin; Hollingworth, Andrew

    2014-09-16

    Recent psychophysical experiments have shown that working memory for visual surface features interacts with saccadic motor planning, even in tasks where the saccade target is unambiguously specified by spatial cues. Specifically, a match between a memorized color and the color of either the designated target or a distractor stimulus influences saccade target selection, saccade amplitudes, and latencies in a systematic fashion. To elucidate these effects, we present a dynamic neural field model in combination with new experimental data. The model captures the neural processes underlying visual perception, working memory, and saccade planning relevant to the psychophysical experiment. It consists of a low-level visual sensory representation that interacts with two separate pathways: a spatial pathway implementing spatial attention and saccade generation, and a surface feature pathway implementing color working memory and feature attention. Due to bidirectional coupling between visual working memory and feature attention in the model, the working memory content can indirectly exert an effect on perceptual processing in the low-level sensory representation. This in turn biases saccadic movement planning in the spatial pathway, allowing the model to quantitatively reproduce the observed interaction effects. The continuous coupling between representations in the model also implies that modulation should be bidirectional, and model simulations provide specific predictions for complementary effects of saccade target selection on visual working memory. These predictions were empirically confirmed in a new experiment: Memory for a sample color was biased toward the color of a task-irrelevant saccade target object, demonstrating the bidirectional coupling between visual working memory and perceptual processing. © 2014 ARVO.

  3. Advances in menopausal therapy: the tissue-selective estrogen complex.

    Science.gov (United States)

    Moore, Anne

    2013-03-01

    Most menopausal women experience vasomotor symptoms, vulvar-vaginal atrophy, and/or bone loss. Although available estrogen and progestin therapies are effective in treating menopausal symptoms and preventing bone loss, some women may seek a therapy that provides symptom relief and has an improved tolerability profile. One option is a tissue-selective estrogen complex (TSEC), or the pairing of estrogen(s) with a selective estrogen receptor modulator (SERM) to achieve the benefits of each component with fewer side effects. The first TSEC in clinical development combines the SERM bazedoxifene (BZA) with conjugated estrogens (CEs). The purpose of this article is to review published data for BZA/CE. Data were obtained from phase 3 BZA/CE clinical trial study articles. Daily BZA 20 mg/CE 0.625 mg or 0.45 mg effectively relieved hot flushes, maintained or increased bone mineral density, treated vulvar-vaginal atrophy, and improved quality of life. Further, BZA prevented stimulation of the endometrium by CE, and resulted in rates of amenorrhea and breast pain similar to placebo. These results support the use of a TSEC consisting of BZA/CE as a promising therapy for managing the signs and symptoms from reduced estrogen levels associated with menopause. ©2012 The Author(s) Journal compilation ©2012 American Association of Nurse Practitioners.

  4. SELECTION, PRIORITIZATION, AND CHARACTERISTICS OF KEPLER TARGET STARS

    International Nuclear Information System (INIS)

    Batalha, Natalie M.; Borucki, William J.; Koch, David G.; Bryson, Stephen T.; Haas, Michael R.; Brown, Timothy M.; Caldwell, Douglas A.; Hall, Jennifer R.; Gilliland, Ronald L.; Latham, David W.; Meibom, Soren; Monet, David G.

    2010-01-01

    The Kepler Mission began its 3.5 year photometric monitoring campaign in 2009 May on a select group of approximately 150,000 stars. The stars were chosen from the ∼ half million in the field of view that are brighter than 16th magnitude. The selection criteria are quantitative metrics designed to optimize the scientific yield of the mission with regard to the detection of Earth-size planets in the habitable zone. This yields more than 90,000 G-type stars on or close to the main sequence, >20, 000 of which are brighter than 14th magnitude. At the temperature extremes, the sample includes approximately 3000 M-type dwarfs and a small sample of O- and B-type MS stars (<200). The small numbers of giants are included in the sample: ∼5000 stars with surface gravities log(g) < 3.5. We present a brief summary of the selection process and the stellar populations it yields in terms of surface gravity, effective temperature, and apparent magnitude. In addition to the primary, statistically derived target set, several ancillary target lists were manually generated to enhance the science of the mission, examples being: known eclipsing binaries, open cluster members, and high proper motion stars.

  5. Selective inhibition of retinal angiogenesis by targeting PI3 kinase.

    Directory of Open Access Journals (Sweden)

    Yolanda Alvarez

    Full Text Available Ocular neovascularisation is a pathological hallmark of some forms of debilitating blindness including diabetic retinopathy, age related macular degeneration and retinopathy of prematurity. Current therapies for delaying unwanted ocular angiogenesis include laser surgery or molecular inhibition of the pro-angiogenic factor VEGF. However, targeting of angiogenic pathways other than, or in combination to VEGF, may lead to more effective and safer inhibitors of intraocular angiogenesis. In a small chemical screen using zebrafish, we identify LY294002 as an effective and selective inhibitor of both developmental and ectopic hyaloid angiogenesis in the eye. LY294002, a PI3 kinase inhibitor, exerts its anti-angiogenic effect in a dose-dependent manner, without perturbing existing vessels. Significantly, LY294002 delivered by intraocular injection, significantly inhibits ocular angiogenesis without systemic side-effects and without diminishing visual function. Thus, targeting of PI3 kinase pathways has the potential to effectively and safely treat neovascularisation in eye disease.

  6. Gene Delivery Particle Engineering Strategies for Shape-dependent Targeting of Cells and Tissues.

    Science.gov (United States)

    Kozielski, Kristen L; Sitti, Metin

    2017-01-01

    Successful gene delivery requires overcoming both systemic and intracellular obstacles before the nucleic acid cargo can successfully reach its tissue and subcellular target location. Materials & Methods: Non-viral mechanisms to enable targeting while avoiding off-target delivery have arisen via biological, chemical, and physical engineering strategies. Herein we will discuss the physical parameters in particle design that promote tissue- and cell-targeted delivery of genetic cargo. We will discuss systemic concerns, such as circulation, tissue localization, and clearance, as well as cell-scale obstacles, such as cellular uptake and nucleic acid packaging. In particular, we will focus on engineering particle shape and size in order to enhance delivery and promote precise targeting. We will also address methods to program or change particle shape in situ using environmentally triggered cues. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Expression of protein-tyrosine phosphatases in the major insulin target tissues

    DEFF Research Database (Denmark)

    Norris, K; Norris, F; Kono, D H

    1997-01-01

    Protein-tyrosine phosphatases (PTPs) are key regulators of the insulin receptor signal transduction pathway. We have performed a detailed analysis of PTP expression in the major human insulin target tissues or cells (liver, adipose tissue, skeletal muscle and endothelial cells). To obtain a repre...

  8. Tissue-Specific Posttranslational Modification Allows Functional Targeting of Thyrotropin

    Directory of Open Access Journals (Sweden)

    Keisuke Ikegami

    2014-11-01

    Full Text Available Thyroid-stimulating hormone (TSH; thyrotropin is a glycoprotein secreted from the pituitary gland. Pars distalis-derived TSH (PD-TSH stimulates the thyroid gland to produce thyroid hormones (THs, whereas pars tuberalis-derived TSH (PT-TSH acts on the hypothalamus to regulate seasonal physiology and behavior. However, it had not been clear how these two TSHs avoid functional crosstalk. Here, we show that this regulation is mediated by tissue-specific glycosylation. Although PT-TSH is released into the circulation, it does not stimulate the thyroid gland. PD-TSH is known to have sulfated biantennary N-glycans, and sulfated TSH is rapidly metabolized in the liver. In contrast, PT-TSH has sialylated multibranched N-glycans; in the circulation, it forms the macro-TSH complex with immunoglobulin or albumin, resulting in the loss of its bioactivity. Glycosylation is fundamental to a wide range of biological processes. This report demonstrates its involvement in preventing functional crosstalk of signaling molecules in the body.

  9. An assessment of spacecraft target mode selection methods

    Science.gov (United States)

    Mercer, J. F.; Aglietti, G. S.; Remedia, M.; Kiley, A.

    2017-11-01

    Coupled Loads Analyses (CLAs), using finite element models (FEMs) of the spacecraft and launch vehicle to simulate critical flight events, are performed in order to determine the dynamic loadings that will be experienced by spacecraft during launch. A validation process is carried out on the spacecraft FEM beforehand to ensure that the dynamics of the analytical model sufficiently represent the behavior of the physical hardware. One aspect of concern is the containment of the FEM correlation and update effort to focus on the vibration modes which are most likely to be excited under test and CLA conditions. This study therefore provides new insight into the prioritization of spacecraft FEM modes for correlation to base-shake vibration test data. The work involved example application to large, unique, scientific spacecraft, with modern FEMs comprising over a million degrees of freedom. This comprehensive investigation explores: the modes inherently important to the spacecraft structures, irrespective of excitation; the particular 'critical modes' which produce peak responses to CLA level excitation; an assessment of several traditional target mode selection methods in terms of ability to predict these 'critical modes'; and an indication of the level of correlation these FEM modes achieve compared to corresponding test data. Findings indicate that, although the traditional methods of target mode selection have merit and are able to identify many of the modes of significance to the spacecraft, there are 'critical modes' which may be missed by conventional application of these methods. The use of different thresholds to select potential target modes from these parameters would enable identification of many of these missed modes. Ultimately, some consideration of the expected excitations is required to predict all modes likely to contribute to the response of the spacecraft in operation.

  10. Three-Dimensionally Engineered Normal Human Broncho-epithelial Tissue-Like Assemblies: Target Tissues for Human Respiratory Viral Infections

    Science.gov (United States)

    Goodwin, T. J.; McCarthy, M.; Lin, Y-H

    2006-01-01

    In vitro three-dimensional (3D) human broncho-epithelial (HBE) tissue-like assemblies (3D HBE TLAs) from this point forward referred to as TLAs were engineered in Rotating Wall Vessel (RWV) technology to mimic the characteristics of in vivo tissues thus providing a tool to study human respiratory viruses and host cell interactions. The TLAs were bioengineered onto collagen-coated cyclodextran microcarriers using primary human mesenchymal bronchial-tracheal cells (HBTC) as the foundation matrix and an adult human bronchial epithelial immortalized cell line (BEAS-2B) as the overlying component. The resulting TLAs share significant characteristics with in vivo human respiratory epithelium including polarization, tight junctions, desmosomes, and microvilli. The presence of tissue-like differentiation markers including villin, keratins, and specific lung epithelium markers, as well as the production of tissue mucin, further confirm these TLAs differentiated into tissues functionally similar to in vivo tissues. Increasing virus titers for human respiratory syncytial virus (wtRSVA2) and parainfluenza virus type 3 (wtPIV3 JS) and the detection of membrane bound glycoproteins over time confirm productive infections with both viruses. Therefore, TLAs mimic aspects of the human respiratory epithelium and provide a unique capability to study the interactions of respiratory viruses and their primary target tissue independent of the host's immune system.

  11. Targets of balancing selection in the human genome

    DEFF Research Database (Denmark)

    Andrés, Aida M; Hubisz, Melissa J; Indap, Amit

    2009-01-01

    Balancing selection is potentially an important biological force for maintaining advantageous genetic diversity in populations, including variation that is responsible for long-term adaptation to the environment. By serving as a means to maintain genetic variation, it may be particularly relevant...... to maintaining phenotypic variation in natural populations. Nevertheless, its prevalence and specific targets in the human genome remain largely unknown. We have analyzed the patterns of diversity and divergence of 13,400 genes in two human populations using an unbiased single-nucleotide polymorphism data set......, a genome-wide approach, and a method that incorporates demography in neutrality tests. We identified an unbiased catalog of genes with signatures of long-term balancing selection, which includes immunity genes as well as genes encoding keratins and membrane channels; the catalog also shows enrichment...

  12. Recombinant protein expression by targeting pre-selected chromosomal loci

    Directory of Open Access Journals (Sweden)

    Krömer Wolfgang

    2009-12-01

    Full Text Available Abstract Background Recombinant protein expression in mammalian cells is mostly achieved by stable integration of transgenes into the chromosomal DNA of established cell lines. The chromosomal surroundings have strong influences on the expression of transgenes. The exploitation of defined loci by targeting expression constructs with different regulatory elements is an approach to design high level expression systems. Further, this allows to evaluate the impact of chromosomal surroundings on distinct vector constructs. Results We explored antibody expression upon targeting diverse expression constructs into previously tagged loci in CHO-K1 and HEK293 cells that exhibit high reporter gene expression. These loci were selected by random transfer of reporter cassettes and subsequent screening. Both, retroviral infection and plasmid transfection with eGFP or antibody expression cassettes were employed for tagging. The tagged cell clones were screened for expression and single copy integration. Cell clones producing > 20 pg/cell in 24 hours could be identified. Selected integration sites that had been flanked with heterologous recombinase target sites (FRTs were targeted by Flp recombinase mediated cassette exchange (RMCE. The results give proof of principle for consistent protein expression upon RMCE. Upon targeting antibody expression cassettes 90-100% of all resulting cell clones showed correct integration. Antibody production was found to be highly consistent within the individual cell clones as expected from their isogenic nature. However, the nature and orientation of expression control elements revealed to be critical. The impact of different promoters was examined with the tag-and-targeting approach. For each of the chosen promoters high expression sites were identified. However, each site supported the chosen promoters to a different extent, indicating that the strength of a particular promoter is dominantly defined by its chromosomal context

  13. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

    Science.gov (United States)

    Baar, Marjolein P; Brandt, Renata M C; Putavet, Diana A; Klein, Julian D D; Derks, Kasper W J; Bourgeois, Benjamin R M; Stryeck, Sarah; Rijksen, Yvonne; van Willigenburg, Hester; Feijtel, Danny A; van der Pluijm, Ingrid; Essers, Jeroen; van Cappellen, Wiggert A; van IJcken, Wilfred F; Houtsmuller, Adriaan B; Pothof, Joris; de Bruin, Ron W F; Madl, Tobias; Hoeijmakers, Jan H J; Campisi, Judith; de Keizer, Peter L J

    2017-03-23

    The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging Xpd TTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. How AI localisation in plant tissues determines the targeted pest spectrum of different chemistries

    DEFF Research Database (Denmark)

    Buchholz, Anke; Trapp, Stefan

    Many pests suck on the vascular system and/or cells of different plant tissues. The sucking target in the cell differs between pests such as Hemiptera (e.g. aphids and whiteflies) or Acari (mites). The agronomic control of sucking pests is most effective with pesticides taken up orally. The cuticle...... of the targeted pest....

  15. Positive-negative-selection-mediated gene targeting in rice

    Directory of Open Access Journals (Sweden)

    Zenpei eShimatani

    2015-01-01

    Full Text Available Gene targeting (GT refers to the designed modification of genomic sequence(s through homologous recombination (HR. GT is a powerful tool both for the study of gene function and for molecular breeding. However, in transformation of higher plants, non-homologous end joining (NHEJ occurs overwhelmingly in somatic cells, masking HR-mediated GT. Positive-negative selection (PNS is an approach for finding HR-mediated GT events because it can eliminate NHEJ effectively by expression of a negative-selection marker gene. In rice—a major crop worldwide—reproducible PNS-mediated GT of endogenous genes has now been successfully achieved. The procedure is based on strong PNS using diphtheria toxin A-fragment as a negative marker, and has succeeded in the directed modification of several endogenous rice genes in various ways. In addition to gene knock-outs and knock-ins, a nucleotide substitution in a target gene was also achieved recently. This review presents a summary of the development of the rice PNS system, highlighting its advantages. Different types of gene modification and gene editing aimed at developing new plant breeding technology (NPBT based on PNS are discussed.

  16. Tissue factor is an angiogenic-specific receptor for factor VII-targeted immunotherapy and photodynamic therapy.

    Science.gov (United States)

    Hu, Zhiwei; Cheng, Jijun; Xu, Jie; Ruf, Wolfram; Lockwood, Charles J

    2017-02-01

    Identification of target molecules specific for angiogenic vascular endothelial cells (VEC), the inner layer of pathological neovasculature, is critical for discovery and development of neovascular-targeting therapy for angiogenesis-dependent human diseases, notably cancer, macular degeneration and endometriosis, in which vascular endothelial growth factor (VEGF) plays a central pathophysiological role. Using VEGF-stimulated vascular endothelial cells (VECs) isolated from microvessels, venous and arterial blood vessels as in vitro angiogenic models and unstimulated VECs as a quiescent VEC model, we examined the expression of tissue factor (TF), a membrane-bound receptor on the angiogenic VEC models compared with quiescent VEC controls. We found that TF is specifically expressed on angiogenic VECs in a time-dependent manner in microvessels, venous and arterial vessels. TF-targeted therapeutic agents, including factor VII (fVII)-IgG1 Fc and fVII-conjugated photosensitizer, can selectively bind angiogenic VECs, but not the quiescent VECs. Moreover, fVII-targeted photodynamic therapy can selectively and completely eradicate angiogenic VECs. We conclude that TF is an angiogenic-specific receptor and the target molecule for fVII-targeted therapeutics. This study supports clinical trials of TF-targeted therapeutics for the treatment of angiogenesis-dependent diseases such as cancer, macular degeneration and endometriosis.

  17. Attentional set mixing: Effects on target selection and selective response activation.

    Science.gov (United States)

    Ruge, Hannes; Stoet, Gijsbert; Naumann, Ewald

    2006-07-01

    Performance is impaired under set mixing conditions that require frequent readjustments of attentional focus over an extended time period. We compared set repetitions within pure blocks (constant focus of attention) to physically identical repetitions within mixed blocks (changing focus of attention). The aim was to investigate how set mixing affects target selection, indexed by the N2pc component, and selective response activation, indexed by the lateralized readiness potential (LRP). We found that set mixing prolonged the evolution of the N2pc while leaving its onset unaffected. Impaired target selection indicated by the N2pc mixing effect also delayed the start of response planning indexed by an onset delay of the stimulus-locked LRP, explaining one part of the behavioral mixing cost. A larger part of mixing cost could be attributed to a prolonged response planning phase, indexed by an earlier onset of the response-locked LRP.

  18. Comparative Pharmacokinetics, Tissue Distribution, Excretion of Recombinant Liver-Targeting Interferon with IFN α2b Administered Intramuscular in Rats.

    Science.gov (United States)

    Wang, Jie; Lu, Xuemei; Jin, Xiaobao; Zeng, Wenting; Zhu, Jiayong

    2015-01-01

    Interferon α2b (IFN α2b) is the first cytokine, which has been approved by FDA to treat chronic hepatitis B. However, it has no organ or tissue selectivity effect, and will be rapidly cleared out in the liver after the administration treatment. In our previous study, a novel liver-targeting fusion interferon (IFN-CSP) was constructed by recombining human IFN α2b with a CSP region I-plus peptide. The purpose of this study is to compare pharmacokinetics, tissue distribution, excretion of recombinant liver-targeting interferon IFN-CSP with IFN α2b following intramuscular administration in rats and estimate whether the fusion protein recombinant liver-targeting interferon has liver-targeting effect. Serum, tissue, urinary, fecal, and biliary concentrations of the drug were measured at various time points after administration using ELISA test. The pharmacokinetic character of IFN-CSP and IFNα2b was described using a non-compartmental model after a single intramuscular administration. Our results showed that there were no significant differences between these two drugs in pharmacokinetic and elimination. However, drug concentration of recombinant liver-targeting IFN was higher than IFN α2b in the liver after intramuscular administration in rats at different time points. It was increased in the spleen but not apparently, and decreased in the heart, lung and kidney. In conclusion, compared with traditional IFN α2b, the novel recombinant liver-targeting IFN will be more accumulated in the liver tissue. With this excellent property, IFN-CSP shows a great application prospect in clinical treatment, although further investigation is still needed.

  19. Selecting Tumor-Specific Molecular Targets in Pancreatic Adenocarcinoma: Paving the Way for Image-Guided Pancreatic Surgery.

    Science.gov (United States)

    de Geus, Susanna W L; Boogerd, Leonora S F; Swijnenburg, Rutger-Jan; Mieog, J Sven D; Tummers, Willemieke S F J; Prevoo, Hendrica A J M; Sier, Cornelis F M; Morreau, Hans; Bonsing, Bert A; van de Velde, Cornelis J H; Vahrmeijer, Alexander L; Kuppen, Peter J K

    2016-12-01

    The purpose of this study was to identify suitable molecular targets for tumor-specific imaging of pancreatic adenocarcinoma. The expression of eight potential imaging targets was assessed by the target selection criteria (TASC)-score and immunohistochemical analysis in normal pancreatic tissue (n = 9), pancreatic (n = 137), and periampullary (n = 28) adenocarcinoma. Integrin α v β 6 , carcinoembryonic antigen (CEA), epithelial growth factor receptor (EGFR), and urokinase plasminogen activator receptor (uPAR) showed a significantly higher (all p < 0.001) expression in pancreatic adenocarcinoma compared to normal pancreatic tissue and were confirmed by the TASC score as promising imaging targets. Furthermore, these biomarkers were expressed in respectively 88 %, 71 %, 69 %, and 67 % of the pancreatic adenocarcinoma patients. The results of this study show that integrin α v β 6 , CEA, EGFR, and uPAR are suitable targets for tumor-specific imaging of pancreatic adenocarcinoma.

  20. Deep-Dive Targeted Quantification for Ultrasensitive Analysis of Proteins in Nondepleted Human Blood Plasma/Serum and Tissues

    Energy Technology Data Exchange (ETDEWEB)

    Nie, Song [Biological Sciences Division; Shi, Tujin [Biological Sciences Division; Fillmore, Thomas L. [Biological Sciences Division; Schepmoes, Athena A. [Biological Sciences Division; Brewer, Heather [Biological Sciences Division; Gao, Yuqian [Biological Sciences Division; Song, Ehwang [Biological Sciences Division; Wang, Hui [Biological Sciences Division; Rodland, Karin D. [Biological Sciences Division; Qian, Wei-Jun [Biological Sciences Division; Smith, Richard D. [Biological Sciences Division; Liu, Tao [Biological Sciences Division

    2017-08-11

    Mass spectrometry-based targeted proteomics (e.g., selected reaction monitoring, SRM) is emerging as an attractive alternative to immunoassays for protein quantification. Recently we have made significant progress in SRM sensitivity for enabling quantification of low ng/mL to sub-ng/mL level proteins in nondepleted human blood plasma/serum without affinity enrichment. However, precise quantification of extremely low abundant but biologically important proteins (e.g., ≤100 pg/mL in blood plasma/serum) using targeted proteomics approaches still remains challenging. To address this need, we have developed an antibody-independent Deep-Dive SRM (DD-SRM) approach that capitalizes on multidimensional high-resolution reversed-phase liquid chromatography (LC) separation for target peptide enrichment combined with precise selection of target peptide fractions of interest, significantly improving SRM sensitivity by ~5 orders of magnitude when compared to conventional LC-SRM. Application of DD-SRM to human serum and tissue has been demonstrated to enable precise quantification of endogenous proteins at ~10 pg/mL level in nondepleted serum and at <10 copies per cell level in tissue. Thus, DD-SRM holds great promise for precisely measuring extremely low abundance proteins or protein modifications, especially when high-quality antibody is not available.

  1. Depth-selective fiber-optic probe for characterization of superficial tissue at a constant physical depth.

    Science.gov (United States)

    Fang, Can; Brokl, David; Brand, Randall E; Liu, Yang

    2011-03-14

    The in vivo assessment of superficial tissue has shown great promise in many biomedical applications. Significant efforts have been expended in designing compact fiber-optic probes with short tissue penetration depth targeting the superficial epithelium. In this paper, we present a compact and simple two-channel fiber-optic probe with superior depth selectivity for the superficial tissue. This probe employs a high-index ball-lens with an optimized illumination area and the maximal overlap between light illumination and collection spots, while maintaining sufficient light collection efficiency with minimized specular reflection. Importantly, we show that this probe allows the selection of a constant and shallow physical penetration depth, insensitive to a wide range of tissue-relevant scattering coefficients and anisotropy factors. We demonstrate the capability of this depth-selective fiber-optic probe to accurately quantify the absorber concentration in superficial tissue without the distortion of tissue scattering properties; and characterize the optical properties of superficial skin tissue.

  2. Selected Reaction Monitoring (SRM Analysis of Epidermal Growth Factor Receptor (EGFR in Formalin Fixed Tumor Tissue

    Directory of Open Access Journals (Sweden)

    Hembrough Todd

    2012-05-01

    Full Text Available Abstract Background Analysis of key therapeutic targets such as epidermal growth factor receptor (EGFR in clinical tissue samples is typically done by immunohistochemistry (IHC and is only subjectively quantitative through a narrow dynamic range. The development of a standardized, highly-sensitive, linear, and quantitative assay for EGFR for use in patient tumor tissue carries high potential for identifying those patients most likely to benefit from EGFR-targeted therapies. Methods A mass spectrometry-based Selected Reaction Monitoring (SRM assay for the EGFR protein (EGFR-SRM was developed utilizing the Liquid Tissue®-SRM technology platform. Tissue culture cells (n = 4 were analyzed by enzyme-linked immunosorbent assay (ELISA to establish quantitative EGFR levels. Matching formalin fixed cultures were analyzed by the EGFR-SRM assay and benchmarked against immunoassay of the non-fixed cultured cells. Xenograft human tumor tissue (n = 10 of non-small cell lung cancer (NSCLC origin and NSCLC patient tumor tissue samples (n = 23 were microdissected and the EGFR-SRM assay performed on Liquid Tissue lysates prepared from microdissected tissue. Quantitative curves and linear regression curves for correlation between immunoassay and SRM methodology were developed in Excel. Results The assay was developed for quantitation of a single EGFR tryptic peptide for use in FFPE patient tissue with absolute specificity to uniquely distinguish EGFR from all other proteins including the receptor tyrosine kinases, IGF-1R, cMet, Her2, Her3, and Her4. The assay was analytically validated against a collection of tissue culture cell lines where SRM analysis of the formalin fixed cells accurately reflects EGFR protein levels in matching non-formalin fixed cultures as established by ELISA sandwich immunoassay (R2 = 0.9991. The SRM assay was applied to a collection of FFPE NSCLC xenograft tumors where SRM data range from 305amol/μg to 12,860amol/μg and

  3. CD133, Selectively Targeting the Root of Cancer

    Directory of Open Access Journals (Sweden)

    Jörg U. Schmohl

    2016-05-01

    Full Text Available Cancer stem cells (CSC are capable of promoting tumor initiation and self-renewal, two important hallmarks of carcinoma formation. This population comprises a small percentage of the tumor mass and is highly resistant to chemotherapy, causing the most difficult problem in the field of cancer research, drug refractory relapse. Many CSC markers have been reported. One of the most promising and perhaps least ubiquitous is CD133, a membrane-bound pentaspan glycoprotein that is frequently expressed on CSC. There is evidence that directly targeting CD133 with biological drugs might be the most effective way to eliminate CSC. We have investigated two entirely unrelated, but highly effective approaches for selectively targeting CD133. The first involves using a special anti-CD133 single chain variable fragment (scFv to deliver a catalytic toxin. The second utilizes this same scFv to deliver components of the immune system. In this review, we discuss the development and current status of these CD133 associated biological agents. Together, they show exceptional promise by specific and efficient CSC elimination.

  4. MESSI: metabolic engineering target selection and best strain identification tool.

    Science.gov (United States)

    Kang, Kang; Li, Jun; Lim, Boon Leong; Panagiotou, Gianni

    2015-01-01

    Metabolic engineering and synthetic biology are synergistically related fields for manipulating target pathways and designing microorganisms that can act as chemical factories. Saccharomyces cerevisiae's ideal bioprocessing traits make yeast a very attractive chemical factory for production of fuels, pharmaceuticals, nutraceuticals as well as a wide range of chemicals. However, future attempts of engineering S. cerevisiae's metabolism using synthetic biology need to move towards more integrative models that incorporate the high connectivity of metabolic pathways and regulatory processes and the interactions in genetic elements across those pathways and processes. To contribute in this direction, we have developed Metabolic Engineering target Selection and best Strain Identification tool (MESSI), a web server for predicting efficient chassis and regulatory components for yeast bio-based production. The server provides an integrative platform for users to analyse ready-to-use public high-throughput metabolomic data, which are transformed to metabolic pathway activities for identifying the most efficient S. cerevisiae strain for the production of a compound of interest. As input MESSI accepts metabolite KEGG IDs or pathway names. MESSI outputs a ranked list of S. cerevisiae strains based on aggregation algorithms. Furthermore, through a genome-wide association study of the metabolic pathway activities with the strains' natural variation, MESSI prioritizes genes and small variants as potential regulatory points and promising metabolic engineering targets. Users can choose various parameters in the whole process such as (i) weight and expectation of each metabolic pathway activity in the final ranking of the strains, (ii) Weighted AddScore Fuse or Weighted Borda Fuse aggregation algorithm, (iii) type of variants to be included, (iv) variant sets in different biological levels.Database URL: http://sbb.hku.hk/MESSI/. © The Author(s) 2015. Published by Oxford University

  5. Temperature distribution in target tumor tissue and photothermal tissue destruction during laser immunotherapy

    Science.gov (United States)

    Doughty, Austin; Hasanjee, Aamr; Pettitt, Alex; Silk, Kegan; Liu, Hong; Chen, Wei R.; Zhou, Feifan

    2016-03-01

    Laser Immunotherapy is a novel cancer treatment modality that has seen much success in treating many different types of cancer, both in animal studies and in clinical trials. The treatment consists of the synergistic interaction between photothermal laser irradiation and the local injection of an immunoadjuvant. As a result of the therapy, the host immune system launches a systemic antitumor response. The photothermal effect induced by the laser irradiation has multiple effects at different temperature elevations which are all required for optimal response. Therefore, determining the temperature distribution in the target tumor during the laser irradiation in laser immunotherapy is crucial to facilitate the treatment of cancers. To investigate the temperature distribution in the target tumor, female Wistar Furth rats were injected with metastatic mammary tumor cells and, upon sufficient tumor growth, underwent laser irradiation and were monitored using thermocouples connected to locally-inserted needle probes and infrared thermography. From the study, we determined that the maximum central tumor temperature was higher for tumors of less volume. Additionally, we determined that the temperature near the edge of the tumor as measured with a thermocouple had a strong correlation with the maximum temperature value in the infrared camera measurement.

  6. Immunological tumor destruction in a murine melanoma model by targeted LTalpha independent of secondary lymphoid tissue

    DEFF Research Database (Denmark)

    Schrama, D.; Voigt, H.; Eggert, A.O.

    2008-01-01

    BACKGROUND: We previously demonstrated that targeting lymphotoxin alpha (LTalpha) to the tumor evokes its immunological destruction in a syngeneic B16 melanoma model. Since treatment was associated with the induction of peritumoral tertiary lymphoid tissue, we speculated that the induced immune...... of specific T-cell responses even in the absence of secondary lymphoid organs. In addition, this effect is accompanied by the initiation of tertiary lymphoid tissue at the tumor site in which B and T lymphocytes are compartmentalized in defined areas and which harbor expanded numbers of tumor specific T cells...... as demonstrated by in situ TRP-2/K(b) tetramer staining. Mechanistically, targeted LTalpha therapy seems to induce changes at the tumor site which allows a coordinated interaction of immune competent cells triggering the induction of tertiary lymphoid tissue. CONCLUSION: Thus, our data demonstrate that targeted...

  7. Deciphering the code for retroviral integration target site selection.

    Directory of Open Access Journals (Sweden)

    Federico Andrea Santoni

    2010-11-01

    Full Text Available Upon cell invasion, retroviruses generate a DNA copy of their RNA genome and integrate retroviral cDNA within host chromosomal DNA. Integration occurs throughout the host cell genome, but target site selection is not random. Each subgroup of retrovirus is distinguished from the others by attraction to particular features on chromosomes. Despite extensive efforts to identify host factors that interact with retrovirion components or chromosome features predictive of integration, little is known about how integration sites are selected. We attempted to identify markers predictive of retroviral integration by exploiting Precision-Recall methods for extracting information from highly skewed datasets to derive robust and discriminating measures of association. ChIPSeq datasets for more than 60 factors were compared with 14 retroviral integration datasets. When compared with MLV, PERV or XMRV integration sites, strong association was observed with STAT1, acetylation of H3 and H4 at several positions, and methylation of H2AZ, H3K4, and K9. By combining peaks from ChIPSeq datasets, a supermarker was identified that localized within 2 kB of 75% of MLV proviruses and detected differences in integration preferences among different cell types. The supermarker predicted the likelihood of integration within specific chromosomal regions in a cell-type specific manner, yielding probabilities for integration into proto-oncogene LMO2 identical to experimentally determined values. The supermarker thus identifies chromosomal features highly favored for retroviral integration, provides clues to the mechanism by which retrovirus integration sites are selected, and offers a tool for predicting cell-type specific proto-oncogene activation by retroviruses.

  8. Improved axenic hydroponic whole plant propagation for rapid production of roots as transformation target tissue

    OpenAIRE

    Benzle, Kyle; Cornish, Katrina

    2017-01-01

    Background Plant roots are used as an efficient target tissue for plant transformation assays. In root propagable species transformed roots are able to regenerate into whole plants without the addition of exogenous hormones, thus avoiding somaclonal variation associated with many plant transformation protocols. Plants grown in soil or soilless solid medium have roots that tend to be extremely delicate and are difficult to sterilize in advance of plant transformation experiments. Axenic tissue...

  9. An off-on fluorescence probe targeting mitochondria based on oxidation-reduction response for tumor cell and tissue imaging

    Science.gov (United States)

    Yao, Hanchun; Cao, Li; Zhao, Weiwei; Zhang, Suge; Zeng, Man; Du, Bin

    2017-10-01

    In this study, a tumor-targeting poly( d, l-lactic-co-glycolic acid) (PLGA) loaded "off-on" fluorescent probe nanoparticle (PFN) delivery system was developed to evaluate the region of tumor by off-on fluorescence. The biodegradability of the nanosize PFN delivery system readily released the probe under tumor acidic conditions. The probe with good biocompatibility was used to monitor the intracellular glutathione (GSH) of cancer cells and selectively localize to mitochondria for tumor imaging. The incorporated tumor-targeting probe was based on the molecular photoinduced electron transfer (PET) mechanism preventing fluorescence ("off" state) and could be easily released under tumor acidic conditions. However, the released tumor-targeting fluorescence probe molecule was selective towards GSH with high selectivity and an ultra-sensitivity for the mitochondria of cancer cells and tissues significantly increasing the probe molecule fluorescence signal ("on" state). The tumor-targeting fluorescence probe showed sensitivity to GSH avoiding interference from cysteine and homocysteine. The PFNs could enable fluorescence-guided cancer imaging during cancer therapy. This work may expand the biological applications of PFNs as a diagnostic reagent, which will be beneficial for fundamental research in tumor imaging. [Figure not available: see fulltext.

  10. Estimation of lung tissue incompressibility variation throughout respiration for tumor targeting in lung radiotherapy

    Science.gov (United States)

    Shirzadi, Zahra; Samani, Abbas

    2013-03-01

    A novel technique is proposed to characterize lung tissue incompressibility variation during respiration. Lung tissue incompressibility variation stems from significant air content variation in the tissue throughout respiration. Estimating lung tissue incompressibility and its variation is critical for computer assisted tumor motion tracking. Continuous tumor motion during respiration is a major challenge in lung cancer treatment by external beam radiotherapy. If not accounted for, this motion leads to areas of radiation over dosage for the lung normal tissues. Since no effective imaging modality is available for real-time lung tumor tracking, computer based modeling which has the capability for accurate tissue deformation estimation can be a good alternative. Lung tissue deformation estimation can be made using the lung Finite Element (FE) model where its accuracy depends on input tissue biomechanical properties including incompressibility parameter. In this research, an optimization algorithm is proposed to estimate the incompressibility parameter function in terms of respiration cycle time. In this algorithm, the incompressibility parameter and lung pressure values are varied systematically until optimal values, which result in maximum similarity between acquired and simulated 4D CT images of the lung, are achieved for each respiration time point. The simulated images are constructed using a reference image in conjunction with the deformation field obtained from the lung's FE model in each respiration time increment. We demonstrated that utilizing the calculated function along with respiratory system FE modeling leads to accurate tumor targeting, hence potentially improving lung radiotherapy outcome.

  11. Histological assessment of selected tissues in tigerfish ( Hydrocynus ...

    African Journals Online (AJOL)

    Eighteen tigerfish were collected by seine netting along the north-eastern shoreline of the Sanyati Basin in April 2014 and samples of their gill, liver, kidney, muscle and brain tissue were processed for histology and assessed using light microscopy. No detectable levels of DDT and/or its metabolites were found in the water ...

  12. 83 Electrolytes in Selected Tissues of Heterobranchus bidorsalis ...

    African Journals Online (AJOL)

    `123456789jkl''''#

    cations (sodium, Na+, potassium, K+) and anion, Cl- in the gill, kidney, liver and muscle tissue. Hyponatraemia ... insecticides are neurotoxic and act on the .... functional failure. Sodium and potassium is the major cation of the extracellular fluid and K+ chloride being the major anion of the intracellular fluid. (Adegoye, 2007).

  13. Metal concentrations in selected organs and tissues of five Red ...

    African Journals Online (AJOL)

    ... existed between coots of the reference site (Steynsrus farm dams) and those from the other four localities. It is concluded that the impact of metal-containing diets on the tissue concentrations of these metals in birds plays a far more significant role compared to the migratory habits or short-range movements of the coots.

  14. Tissue-restricted expression of Nrf2 and its target genes in zebrafish with gene-specific variations in the induction profiles.

    Directory of Open Access Journals (Sweden)

    Hitomi Nakajima

    Full Text Available The Keap1-Nrf2 system serves as a defense mechanism against oxidative stress and electrophilic toxicants by inducing more than one hundred cytoprotective proteins, including antioxidants and phase 2 detoxifying enzymes. Since induction profiles of Nrf2 target genes have been studied exclusively in cultured cells, and not in animal models, their tissue-specificity has not been well characterized. In this paper, we examined and compared the tissue-specific expression of several Nrf2 target genes in zebrafish larvae by whole-mount in situ hybridization (WISH. Seven zebrafish genes (gstp1, mgst3b, prdx1, frrs1c, fthl, gclc and hmox1a suitable for WISH analysis were selected from candidates for Nrf2 targets identified by microarray analysis. Tissue-restricted induction was observed in the nose, gill, and/or liver for all seven genes in response to Nrf2-activating compounds, diethylmaleate (DEM and sulforaphane. The Nrf2 gene itself was dominantly expressed in these three tissues, implying that tissue-restricted induction of Nrf2 target genes is defined by tissue-specific expression of Nrf2. Interestingly, the induction of frrs1c and gclc in liver and nose, respectively, was quite low and that of hmox1a was restricted in the liver. These results indicate the existence of gene-specific variations in the tissue specificity, which can be controlled by factors other than Nrf2.

  15. Pharmacokinetics and tissue concentrations of tylosin in selected avian species

    Science.gov (United States)

    Locke, D.; Bush, M.; Carpenter, J.W.

    1982-01-01

    Tissue and plasma concentrations and the biological half-life of tylosin in avian species of a variety of body sizes and metabolic rates were studied. The species chosen were eastern bobwhite quail (Colinus virginianus virginianus), pigeons (Columba livia), greater sandhill cranes (Grus canadensis tabida), and emus (Dromaius novaehollandiae). In the 1st phase of this study, tylosin was administered IM to quail, pigeons, and emus at a dosage rate of 25 mg/kg of body weight and to cranes at a dosage rate of 15 mg/kg. The average peak plasma concentrations of tylosin in quail, pigeons, cranes, and emus were 4.31, 5.63, 3.62, and 3.26 microgram/ml, respectively. These peak concentrations occurred at 0.5 to 1.5 hours after administration. The biological half-life of tylosin averaged 1.2 hours in quail, pigeons, and cranes, and was 4.7 hours in emus. In the 2nd phase of this study, tylosin concentrations in the tissues of quail, pigeons, and cranes were markedly higher than were plasma concentrations at corresponding sampling times. Six hours after antibiotic administration, tissue concentrations of tylosin in all species remained within the minimum inhibitory concentration for most pathogenic organisms. Dosage regimens of 25 mg of tylosin/kg 4 times daily for quail and pigeons, 15 mg/kg 3 times daily for cranes, and 25 mg/kg 3 times daily for emus would be needed to establish and maintain therapeutic tissue concentrations.

  16. Target product selection - where can Molecular Pharming make the difference?

    Science.gov (United States)

    Paul, Mathew J; Teh, Audrey Y H; Twyman, Richard M; Ma, Julian K-C

    2013-01-01

    Four major developments have taken place in the world of Molecular Pharming recently. In the USA, the DARPA initiative challenged plant biotechnology companies to develop strategies for the large-scale manufacture of influenza vaccines, resulting in a successful Phase I clinical trial; in Europe the Pharma-Planta academic consortium gained regulatory approval for a plant-derived monoclonal antibody and completed a first-in-human phase I clinical trial; the Dutch pharmaceutical company Synthon acquired the assets of Biolex Therapeutics, an established Molecular Pharming company with several clinical candidates produced in their proprietary LEX system based on aquatic plants; and finally, the Israeli biotechnology company Protalix Biotherapeutics won FDA approval for the commercial release of a recombinant form of the enzyme glucocerebrosidase produced in carrot cells, the first plant biotechnology-derived biopharmaceutical in the world approved for the market. Commercial momentum is gathering pace with additional candidates now undergoing or awaiting approval for phase III clinical trials. Filling the product pipeline is vital to establish commercial sustainability, and the selection of appropriate target products for Molecular Pharming will be a critical factor. An interesting feature of the four stories outlined above is that they span the use of very different platform technologies addressing different types of molecules which aim to satisfy distinct market demands. In each case, Molecular Pharming was an economically and technically suitable approach, but this decisionmaking process is not necessarily straightforward. Although the various technologies available to Molecular Pharming are broad ranging and flexible, competing technologies are better established, so there needs to be a compelling reason to move into plants. It is most unlikely that plant biotechnology will be the answer for the whole biologics field. In this article, we discuss the current plant

  17. EFFECTIVELY SELECTING A TARGET POPULATION FOR A FUTURE COMPARATIVE STUDY.

    Science.gov (United States)

    Zhao, Lihui; Tian, Lu; Cai, Tianxi; Claggett, Brian; Wei, L J

    2013-01-01

    When comparing a new treatment with a control in a randomized clinical study, the treatment effect is generally assessed by evaluating a summary measure over a specific study population. The success of the trial heavily depends on the choice of such a population. In this paper, we show a systematic, effective way to identify a promising population, for which the new treatment is expected to have a desired benefit, utilizing the data from a current study involving similar comparator treatments. Specifically, using the existing data, we first create a parametric scoring system as a function of multiple multiple baseline covariates to estimate subject-specific treatment differences. Based on this scoring system, we specify a desired level of treatment difference and obtain a subgroup of patients, defined as those whose estimated scores exceed this threshold. An empirically calibrated threshold-specific treatment difference curve across a range of score values is constructed. The subpopulation of patients satisfying any given level of treatment benefit can then be identified accordingly. To avoid bias due to overoptimism, we utilize a cross-training-evaluation method for implementing the above two-step procedure. We then show how to select the best scoring system among all competing models. Furthermore, for cases in which only a single pre-specified working model is involved, inference procedures are proposed for the average treatment difference over a range of score values using the entire data set, and are justified theoretically and numerically. Lastly, the proposals are illustrated with the data from two clinical trials in treating HIV and cardiovascular diseases. Note that if we are not interested in designing a new study for comparing similar treatments, the new procedure can also be quite useful for the management of future patients, so that treatment may be targeted towards those who would receive nontrivial benefits to compensate for the risk or cost of the

  18. Localized increase of tissue oxygen tension by magnetic targeted drug delivery

    Science.gov (United States)

    Liong, Celine; Ortiz, Daniel; Ao-ieong, Eilleen; Navati, Mahantesh S.; Friedman, Joel M.; Cabrales, Pedro

    2014-07-01

    Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O2) tension (PO2) of tissue by delivering more O2 have been clinically disappointing, largely due to the way O2 is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O2 transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O2 delivery to a target tissue by decreasing the Hb-O2 affinity of the blood circulating within the targeted tissue. As the Hb-O2 affinity decreases, the tissue PO2 to satisfy tissue O2 metabolic needs increases without increasing O2 delivery or extraction. Paramagnetic nanoparticles (PMNPs), synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector L35 (3,5-trichlorophenylureido-phenoxy-methylpropionic acid). L35 decreases Hb affinity for O2 and favors the release of O2. The L35-coated PMNPs (L35-PMNPs) were intravenously infused (10 mg kg-1) to hamsters instrumented with the dorsal window chamber model. A magnetic field of 3 mT was applied to localize the effects of the L35-PMNPs to the window chamber. Systemic O2 transport characteristics and microvascular tissue oxygenation were measured after administration of L35-PMNPs with and without magnetic field. The tissue PO2 in untreated control animals was 25.2 mmHg. L35-PMNPs without magnetic field decreased tissue PO2 to 23.4 mmHg, increased blood pressure, and reduced blood flow, largely due to systemic modification of Hb-O2 affinity. L35-PMNPs with magnetic field increased tissue PO2 to 27.9 mmHg, without systemic or microhemodynamic changes. These results indicate that localized modification of Hb-O2 affinity can increase PO2 of target tissue without affecting systemic O2 delivery or triggering O2 autoregulation mechanisms. This technology can be used to treat local hypoxia and to

  19. Hypoxia-Inducible Factors: Mediators of Cancer Progression; Prognostic and Therapeutic Targets in Soft Tissue Sarcomas

    International Nuclear Information System (INIS)

    Sadri, Navid; Zhang, Paul J.

    2013-01-01

    Soft-tissue sarcomas remain aggressive tumors that result in death in greater than a third of patients due to either loco-regional recurrence or distant metastasis. Surgical resection remains the main choice of treatment for soft tissue sarcomas with pre- and/or post-operational radiation and neoadjuvant chemotherapy employed in more advanced stage disease. However, in recent decades, there has been little progress in the average five-year survival for the majority of patients with high-grade soft tissue sarcomas, highlighting the need for improved targeted therapeutic agents. Clinical and preclinical studies demonstrate that tumor hypoxia and up-regulation of hypoxia-inducible factors (HIFs) is associated with decreased survival, increased metastasis, and resistance to therapy in soft tissue sarcomas. HIF-mediated gene expression regulates many critical aspects of tumor biology, including cell survival, metabolic programming, angiogenesis, metastasis, and therapy resistance. In this review, we discuss HIFs and HIF-mediated genes as potential prognostic markers and therapeutic targets in sarcomas. Many pharmacological agents targeting hypoxia-related pathways are in development that may hold therapeutic potential for treating both primary and metastatic sarcomas that demonstrate increased HIF expression

  20. Assessment of Mercury in Fish Tissue from Select Lakes of Northeastern Oregon

    Science.gov (United States)

    A fish tissue study was conducted in five northeastern Oregon reservoirs to evaluate mercury concentrations in an area where elevated atmospheric mercury deposition had been predicted by a national EPA model, but where tissue data were sparse. The study targeted resident predator...

  1. Dysregulated homeostasis of target tissues or autoantigens - A novel principle in autoimmunity.

    Science.gov (United States)

    Petersen, Frank; Yue, Xiaoyang; Riemekasten, Gabriela; Yu, Xinhua

    2017-06-01

    Monogenic autoimmune disorders provide a powerful tool for our understanding of the principles of autoimmunity due to the obvious impact of a single gene on the disease. So far, approximately 100 single gene defects causing murine monogenic autoimmune disorders have been reported and the functional characterization of these genes will provide significant progress in understanding the nature of autoimmunity. According to their function, genes leading to monogenic autoimmune disorders can be categorized into two groups. An expectable first group contains genes involved in the homeostasis of the immune system, including homeostasis of immune organs and immune cells. Intriguingly, the second group consists of genes functionally involved in the homeostasis of target tissues or autoantigens. According to our novel hypothesis, we propose that autoimmunity represents a consequence of a dysregulated homeostasis of the immune system and/or its targets including autoantigens and target tissues. In this review we refer to both aspects of homeostasis in autoimmunity with a highlight on the role of the homeostasis of target tissues and autoantigens. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Effects of Mode of Target Task Selection on Learning about Plants in a Mobile Learning Environment: Effortful Manual Selection versus Effortless QR-Code Selection

    Science.gov (United States)

    Gao, Yuan; Liu, Tzu-Chien; Paas, Fred

    2016-01-01

    This study compared the effects of effortless selection of target plants using quick respond (QR) code technology to effortful manual search and selection of target plants on learning about plants in a mobile device supported learning environment. In addition, it was investigated whether the effectiveness of the 2 selection methods was…

  3. Targeted Diazotransfer Reagents Enable Selective Modification of Proteins with Azides

    NARCIS (Netherlands)

    Lohse, Jonas; Swier, Lotteke; Oudshoorn, Ruben; Médard, Guillaume; Kuster, Bernhard; Slotboom, Dirk Jan; Witte, Martin D

    In chemical biology, azides are used to chemically manipulate target structures in a bioorthogonal manner for a plethora of applications ranging from target identification to the synthesis of homogeneously modified protein conjugates. While a variety of methods have been established to introduce the

  4. Quantitative detection of HER2 protein concentration in breast cancer tissue does not increase the number of patients eligible for adjuvant HER2-targeted therapy

    DEFF Research Database (Denmark)

    Bechmann, Troels; Olsen, Dorte Aalund; Jakobsen, Erik Hugger

    2013-01-01

    Human epidermal growth factor receptor-2 (HER2) is overexpressed in 15-20% of breast cancer patients and is associated with an aggressive tumor and a poor prognosis. Currently, patients are selected for adjuvant HER2-targeted therapy based on HER2 status by immunohistochemistry (IHC) and fluoresc......Human epidermal growth factor receptor-2 (HER2) is overexpressed in 15-20% of breast cancer patients and is associated with an aggressive tumor and a poor prognosis. Currently, patients are selected for adjuvant HER2-targeted therapy based on HER2 status by immunohistochemistry (IHC...... by Centaur, but not treated with adjuvant HER2-targeted therapy, compared to patients defined as HER2-positive by IHC/FISH and therefore treated with adjuvant HER2-targeted therapy. Tumor tissue was obtained at primary surgery from 415 breast cancer patients between 2004 and 2010. HER2 status was determined...... by quantitative immunoassay of fresh-frozen tissue and by IHC/FISH of corresponding paraffin-embedded tissue. We compared the clinical outcome in four groups of patients defined by tissue HER2 status and adjuvant HER2-targeted therapy. The final analysis included 379 patients after a median follow-up of 3.9 years...

  5. Advancing the sensitivity of selected reaction monitoring-based targeted quantitative proteomics

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Tujin; Su, Dian; Liu, Tao; Tang, Keqi; Camp, David G.; Qian, Weijun; Smith, Richard D.

    2012-04-01

    Selected reaction monitoring (SRM)—also known as multiple reaction monitoring (MRM)—has emerged as a promising high-throughput targeted protein quantification technology for candidate biomarker verification and systems biology applications. A major bottleneck for current SRM technology, however, is insufficient sensitivity for e.g., detecting low-abundance biomarkers likely present at the pg/mL to low ng/mL range in human blood plasma or serum, or extremely low-abundance signaling proteins in the cells or tissues. Herein we review recent advances in methods and technologies, including front-end immunoaffinity depletion, fractionation, selective enrichment of target proteins/peptides or their posttranslational modifications (PTMs), as well as advances in MS instrumentation, which have significantly enhanced the overall sensitivity of SRM assays and enabled the detection of low-abundance proteins at low to sub- ng/mL level in human blood plasma or serum. General perspectives on the potential of achieving sufficient sensitivity for detection of pg/mL level proteins in plasma are also discussed.

  6. Identification of Human Housekeeping Genes and Tissue-Selective Genes by Microarray Meta-Analysis

    Science.gov (United States)

    Chang, Cheng-Wei; Cheng, Wei-Chung; Chen, Chaang-Ray; Shu, Wun-Yi; Tsai, Min-Lung; Huang, Ching-Lung; Hsu, Ian C.

    2011-01-01

    Background Categorizing protein-encoding transcriptomes of normal tissues into housekeeping genes and tissue-selective genes is a fundamental step toward studies of genetic functions and genetic associations to tissue-specific diseases. Previous studies have been mainly based on a few data sets with limited samples in each tissue, which restrained the representativeness of their identified genes, and resulted in low consensus among them. Results This study compiled 1,431 samples in 43 normal human tissues from 104 microarray data sets. We developed a new method to improve gene expression assessment, and showed that more than ten samples are needed to robustly identify the protein-encoding transcriptome of a tissue. We identified 2,064 housekeeping genes and 2,293 tissue-selective genes, and analyzed gene lists by functional enrichment analysis. The housekeeping genes are mainly involved in fundamental cellular functions, and the tissue-selective genes are strikingly related to functions and diseases corresponding to tissue-origin. We also compared agreements and related functions among our housekeeping genes and those of previous studies, and pointed out some reasons for the low consensuses. Conclusions The results indicate that sufficient samples have improved the identification of protein-encoding transcriptome of a tissue. Comprehensive meta-analysis has proved the high quality of our identified HK and TS genes. These results could offer a useful resource for future research on functional and genomic features of HK and TS genes. PMID:21818400

  7. Thermal infrared images to quantify thermal ablation effects of acid and base on target tissues

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Ran, E-mail: jliubme@tsinghua.edu.cn, E-mail: liuran@tsinghua.edu.cn; Liu, Jing, E-mail: jliubme@tsinghua.edu.cn, E-mail: liuran@tsinghua.edu.cn [Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084 (China); Wang, Jia [Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218 (United States)

    2015-07-15

    Hyperthermia (42-46°C), treatment of tumor tissue through elevated temperature, offers several advantages including high cost-effectiveness, highly targeted ablation and fewer side effects and hence higher safety level over traditional therapies such as chemotherapy and radiotherapy. Recently, hyperthermia using heat release through exothermic acid-base neutralization comes into view owing to its relatively safe products of salt and water and highly confined ablation. However, lack of quantitative understanding of the spatial and temporal temperature profiles that are produced by simultaneous diffusion of liquid chemical and its chemical reaction within tumor tissue impedes the application of this method. This article is dedicated to quantify thermal ablation effects of acid and base both individually and as in neutralization via infrared captured thermal images. A theoretical model is used to approximate specific heat absorption rate (SAR) based on experimental measurements that contrast two types of tissue, normal pork and pig liver. According to the computation, both pork and liver tissue has a higher ability in absorbing hydrochloric acid (HCl) than sodium hydroxide, hence suggesting that a reduced dosage for HCl is appropriate in a surgery. The heating effect depends heavily on the properties of tissue types and amount of chemical reagents administered. Given thermal parameters such as SAR for different tissues, a computational model can be made in predicting temperature transitions which will be helpful in planning and optimizing surgical hyperthermia procedures.

  8. Thermal infrared images to quantify thermal ablation effects of acid and base on target tissues

    Science.gov (United States)

    Liu, Ran; Wang, Jia; Liu, Jing

    2015-07-01

    Hyperthermia (42-46°C), treatment of tumor tissue through elevated temperature, offers several advantages including high cost-effectiveness, highly targeted ablation and fewer side effects and hence higher safety level over traditional therapies such as chemotherapy and radiotherapy. Recently, hyperthermia using heat release through exothermic acid-base neutralization comes into view owing to its relatively safe products of salt and water and highly confined ablation. However, lack of quantitative understanding of the spatial and temporal temperature profiles that are produced by simultaneous diffusion of liquid chemical and its chemical reaction within tumor tissue impedes the application of this method. This article is dedicated to quantify thermal ablation effects of acid and base both individually and as in neutralization via infrared captured thermal images. A theoretical model is used to approximate specific heat absorption rate (SAR) based on experimental measurements that contrast two types of tissue, normal pork and pig liver. According to the computation, both pork and liver tissue has a higher ability in absorbing hydrochloric acid (HCl) than sodium hydroxide, hence suggesting that a reduced dosage for HCl is appropriate in a surgery. The heating effect depends heavily on the properties of tissue types and amount of chemical reagents administered. Given thermal parameters such as SAR for different tissues, a computational model can be made in predicting temperature transitions which will be helpful in planning and optimizing surgical hyperthermia procedures.

  9. Thermal infrared images to quantify thermal ablation effects of acid and base on target tissues

    International Nuclear Information System (INIS)

    Liu, Ran; Liu, Jing; Wang, Jia

    2015-01-01

    Hyperthermia (42-46°C), treatment of tumor tissue through elevated temperature, offers several advantages including high cost-effectiveness, highly targeted ablation and fewer side effects and hence higher safety level over traditional therapies such as chemotherapy and radiotherapy. Recently, hyperthermia using heat release through exothermic acid-base neutralization comes into view owing to its relatively safe products of salt and water and highly confined ablation. However, lack of quantitative understanding of the spatial and temporal temperature profiles that are produced by simultaneous diffusion of liquid chemical and its chemical reaction within tumor tissue impedes the application of this method. This article is dedicated to quantify thermal ablation effects of acid and base both individually and as in neutralization via infrared captured thermal images. A theoretical model is used to approximate specific heat absorption rate (SAR) based on experimental measurements that contrast two types of tissue, normal pork and pig liver. According to the computation, both pork and liver tissue has a higher ability in absorbing hydrochloric acid (HCl) than sodium hydroxide, hence suggesting that a reduced dosage for HCl is appropriate in a surgery. The heating effect depends heavily on the properties of tissue types and amount of chemical reagents administered. Given thermal parameters such as SAR for different tissues, a computational model can be made in predicting temperature transitions which will be helpful in planning and optimizing surgical hyperthermia procedures

  10. Magnetic nanoparticle-based approaches to locally target therapy and enhance tissue regeneration in vivo

    Science.gov (United States)

    Sensenig, Richard; Sapir, Yulia; MacDonald, Cristin; Cohen, Smadar; Polyak, Boris

    2013-01-01

    Magnetic-based systems utilizing superparamagnetic nanoparticles and a magnetic field gradient to exert a force on these particles have been used in a wide range of biomedical applications. This review is focused on drug targeting applications that require penetration of a cellular barrier as well as strategies to improve the efficacy of targeting in these biomedical applications. Another focus of this review is regenerative applications utilizing tissue engineered scaffolds prepared with the aid of magnetic particles, the use of remote actuation for release of bioactive molecules and magneto–mechanical cell stimulation, cell seeding and cell patterning. PMID:22994959

  11. Modulation of Rhamm (CD168) for selective adipose tissue development

    Science.gov (United States)

    Turley, Eva A; Bissell, Mina J

    2014-05-06

    Herein is described the methods and compositions for modulation of Rhamm, also known as CD 186, and its effects on wound repair, muscle differentiation, bone density and adipogeneisis through its ability to regulate mesenchymal stem cell differentiation. Compositions and methods are provided for blocking Rhamm function for selectively increasing subcutaneous, but not, visceral fat. Compositions and methods for modulating Rhamm in wound repair are also described.

  12. Bioengineered yeast-derived vacuoles with enhanced tissue-penetrating ability for targeted cancer therapy.

    Science.gov (United States)

    Gujrati, Vipul; Lee, Miriam; Ko, Young-Joon; Lee, Sangeun; Kim, Daejin; Kim, Hyungjun; Kang, Sukmo; Lee, Soyoung; Kim, Jinjoo; Jeon, Hyungsu; Kim, Sun Chang; Jun, Youngsoo; Jon, Sangyong

    2016-01-19

    Despite the appreciable success of synthetic nanomaterials for targeted cancer therapy in preclinical studies, technical challenges involving their large-scale, cost-effective production and intrinsic toxicity associated with the materials, as well as their inability to penetrate tumor tissues deeply, limit their clinical translation. Here, we describe biologically derived nanocarriers developed from a bioengineered yeast strain that may overcome such impediments. The budding yeast Saccharomyces cerevisiae was genetically engineered to produce nanosized vacuoles displaying human epidermal growth factor receptor 2 (HER2)-specific affibody for active targeting. These nanosized vacuoles efficiently loaded the anticancer drug doxorubicin (Dox) and were effectively endocytosed by cultured cancer cells. Their cancer-targeting ability, along with their unique endomembrane compositions, significantly enhanced drug penetration in multicellular cultures and improved drug distribution in a tumor xenograft. Furthermore, Dox-loaded vacuoles successfully prevented tumor growth without eliciting any prolonged immune responses. The current study provides a platform technology for generating cancer-specific, tissue-penetrating, safe, and scalable biological nanoparticles for targeted cancer therapy.

  13. Clinical pharmacokinetics and pharmacodynamic target attainment of pazufloxacin in prostate tissue: Dosing considerations for prostatitis.

    Science.gov (United States)

    Nakamura, Kogenta; Ikawa, Kazuro; Nishikawa, Genya; Kobayashi, Ikuo; Narushima, Masahiro; Muramatsu, Hiroyuki; Morinaga, Shingo; Kajikawa, Keishi; Kato, Yoshiharu; Watanabe, Masahito; Zennami, Kenji; Kanao, Kent; Morikawa, Norifumi; Sumitomo, Makoto

    2017-12-01

    The present study examined the clinical pharmacokinetics of pazufloxacin in prostate tissue and estimated the probability of target attainment for tissue-specific pharmacodynamic goals related to treating prostatitis using various intravenous dosing regimens. Patients with prostatic hypertrophy received prophylactic infusions of pazufloxacin (500 mg, n = 23; 1000 mg, n = 25) for 0.5 h prior to transurethral prostate resection. Drug concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were measured by high-performance liquid chromatography and used for subsequent noncompartmental and three-compartmental analysis. Monte Carlo simulation was performed to evaluate the probability of target attainment of a specific minimum inhibitory concentration (MIC) in prostate tissue: the proportion that achieved both area under the drug concentration over time curve (AUC)/MIC = 100 and maximum concentration (C max )/MIC = 8. Prostatic penetration of pazufloxacin was good with mean C max ratios (prostate tissue/plasma) of 0.82-0.99 and for AUC, 0.80-0.98. The probability of reaching target MIC concentrations in prostate tissue was more than 90% for dosing schedules of 0.25 mg/L for 500 mg every 24 h (500 mg daily), 0.5 mg/L for 500 mg every 12 h (1000 mg daily), 1 mg/L for 1000 mg every 24 h (1000 mg daily), and 2 mg/L for 1000 mg every 12 h (2000 mg daily). Importantly, the 2000 mg daily regimen of pazufloxacin produced a profile sufficient to have an antibacterial effect in prostate tissue against clinical isolates of Escherichia coli and Klebsiella pneumonia with MIC values less than 2 mg/L. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  14. The importance of surrounding tissues and window settings for contouring of moving targets

    Energy Technology Data Exchange (ETDEWEB)

    Borm, Kai Joachim [Technische Universitaet Muenchen, Medical School, Munich (Germany); Klinikum rechts der Isar, Technische Universitaet Muenchen, Department of Radiation Oncology, Munich (Germany); Oechsner, Markus; Berndt, Johannes; Combs, Stephanie Elisabeth; Molls, Michael; Duma, Marciana Nona [Klinikum rechts der Isar, Technische Universitaet Muenchen, Department of Radiation Oncology, Munich (Germany)

    2015-09-15

    The aim of the study was to assess the importance of surrounding tissues for the delineation of moving targets in tissue-specific phantoms and to find optimal settings for lung, soft tissue, and liver tumors. Tumor movement was simulated by a water-filled table tennis ball (target volume, TV). Three phantoms were created: corkboards to simulate lung tissue (lung phantom, LunPh), animal fat as fatty soft tissue (fatty tissue phantom, FatPh), and water enhanced with contrast medium as the liver tissue (liver phantom, LivPh). Slow planning three-dimensional compute tomography images (3D-CTs) were acquired with and without phantom movements. One-dimensional tumor movement (1D), three-dimensional tumor movement (3D), as well as a real patient's tumor trajectories were simulated. The TV was contoured using two lung window settings, two soft-tissue window settings, and one liver window setting. The volumes were compared to mathematical calculated values. TVs were underestimated in all phantoms due to movement. The use of soft-tissue windows in the LivPh led to a significantunderestimation of the TV (70.8 % of calculated TV). When common window settings [LunPh + 200 HU/-1,000 HU (upper window/lower window threshold); FatPh: + 240 HU/-120 HU; LivPh: + 175 HU/+ 50 HU] were used, the contoured TVs were: LivPh, 84.0 %; LunPh, 93.2 %, and FatPh, 92.8 %. The lower window threshold had a significant impact on the size of the delineated TV, whereas changes of the upper threshold led only to small differences. The decisive factor for window settings is the lower window threshold (for adequate TV delineation in the lung and fatty-soft tissue it should be lower than density values of surrounding tissue). The use of a liver window should be considered. (orig.) [German] Das Ziel dieser Arbeit war es, den Einfluss des umgebenden Gewebes auf die Konturierung bewegter Objekte zu untersuchen. Um die optimalen CT-Fensterungen fuer Lungen-, Weichteil- und Lebertumoren zu bestimmen

  15. Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders.

    Science.gov (United States)

    Calo, Eliezer; Gu, Bo; Bowen, Margot E; Aryan, Fardin; Zalc, Antoine; Liang, Jialiang; Flynn, Ryan A; Swigut, Tomek; Chang, Howard Y; Attardi, Laura D; Wysocka, Joanna

    2018-02-01

    Many craniofacial disorders are caused by heterozygous mutations in general regulators of housekeeping cellular functions such as transcription or ribosome biogenesis. Although it is understood that many of these malformations are a consequence of defects in cranial neural crest cells, a cell type that gives rise to most of the facial structures during embryogenesis, the mechanism underlying cell-type selectivity of these defects remains largely unknown. By exploring molecular functions of DDX21, a DEAD-box RNA helicase involved in control of both RNA polymerase (Pol) I- and II-dependent transcriptional arms of ribosome biogenesis, we uncovered a previously unappreciated mechanism linking nucleolar dysfunction, ribosomal DNA (rDNA) damage, and craniofacial malformations. Here we demonstrate that genetic perturbations associated with Treacher Collins syndrome, a craniofacial disorder caused by heterozygous mutations in components of the Pol I transcriptional machinery or its cofactor TCOF1 (ref. 1), lead to relocalization of DDX21 from the nucleolus to the nucleoplasm, its loss from the chromatin targets, as well as inhibition of rRNA processing and downregulation of ribosomal protein gene transcription. These effects are cell-type-selective, cell-autonomous, and involve activation of p53 tumour-suppressor protein. We further show that cranial neural crest cells are sensitized to p53-mediated apoptosis, but blocking DDX21 loss from the nucleolus and chromatin rescues both the susceptibility to apoptosis and the craniofacial phenotypes associated with Treacher Collins syndrome. This mechanism is not restricted to cranial neural crest cells, as blood formation is also hypersensitive to loss of DDX21 functions. Accordingly, ribosomal gene perturbations associated with Diamond-Blackfan anaemia disrupt DDX21 localization. At the molecular level, we demonstrate that impaired rRNA synthesis elicits a DNA damage response, and that rDNA damage results in tissue-selective and

  16. Determination of the most efficient target tissue and helium pressure for biolistic transformation of oil palm (Elaeis guineensis Jacq.

    Directory of Open Access Journals (Sweden)

    Amornrat Phongdara

    2008-03-01

    Full Text Available An efficient genetic transformation system for oil palm using particle bombardment was established. The transformation was performed using the pCAMBIA 1302 DNA which contains the green fluorescent protein (mgfp5 reporter gene and the selectable marker hygromycin phosphotransferase (hph gene. Oil palm explants were bombarded under the following conditions: rupture disk to macrocarrier distance, 11 mm; macrocarrier to target tissue, 90 mm and using 1 μm gold particles as microcarrier. Four different pressures of helium were tested with three types of target tissues (mature embryo, embryogenic callus and young seedlings. From the transformation efficiency, calli were much more efficiently transformed in the biolistic process compared with mature embryos and seedlings. A 100% transformation efficiency for DNA delivery into callus oil palm explants was obtained at 850 psi helium pressures, for embryos a maximum 81.8% efficiency required 850 psi and for seedlings a maximum 75.9% efficiency required 1,550 psi. Using a confocal laser scanning microscope, and appropriate filters to block out the red fluorescence of chlorophyll, expression of the GFP gene was observed in all three bombarded explant types by a bright-green fluorescence. The mgfp5 gene was still present more than 8 months after bombardment, hence it indicated the stability of transgene in those transformants.

  17. Hard tissue formation of STRO-1-selected rat dental pulp stem cells in vivo.

    NARCIS (Netherlands)

    Yang, X.; Walboomers, X.F.; Beucken, J.J.J.P van den; Bian, Z.; Fan, M.; Jansen, J.A.

    2009-01-01

    The objective of this study was to examine hard tissue formation of STRO-1-selected rat dental pulp-derived stem cells, seeded into a calcium phosphate ceramic scaffold, and implanted subcutaneously in mice. Previously, STRO-1 selection was used to obtain a mesenchymal stem cell progenitor

  18. Rational design of chemical ligands for selective mitochondrial targeting

    Czech Academy of Sciences Publication Activity Database

    Rimpelová, S.; Bříza, T.; Králová, Jarmila; Záruba, K.; Kejík, Z.; Císařová, I.; Martásek, P.; Ruml, T.; Král, V.

    2013-01-01

    Roč. 24, č. 9 (2013), s. 1445-1454 ISSN 1520-4812 R&D Projects: GA ČR(CZ) GAP303/11/1291; GA ČR GA203/09/1311 Grant - others:GA AV ČR(CZ) KAN200100801; GA MŠk(CZ) ED0030/01/01 Program:KA Institutional support: RVO:68378050 Keywords : intracellular targeting * mitochondria * cardiolipin * pentamethine * fluorescent dyes Subject RIV: EB - Genetics ; Molecular Biology

  19. Development of Antibacterials Targeting the MEP Pathway of Select Agents

    Science.gov (United States)

    2015-03-01

    Yersinia pestis will serve as effective antibiotics by blocking isoprene biosynthesis . In strong support of this hypothesis, we have demonstrated the dose... antibiotic resistant strains and the ease by which antibiotic resistance can be engineered into bacteria further highlights the need for continued...development of novel antibiotics against new bacterial targets. This research project directly addresses this need through the development of a broad spectrum

  20. Relative binding affinity of carboxylate-, phosphonate-, and bisphosphonate-functionalized gold nanoparticles targeted to damaged bone tissue

    Energy Technology Data Exchange (ETDEWEB)

    Ross, Ryan D. [Rush University Medical Center, Department of Anatomy and Cell Biology (United States); Cole, Lisa E.; Roeder, Ryan K., E-mail: rroeder@nd.edu [University of Notre Dame, Department of Aerospace and Mechanical Engineering Bioengineering Graduate Program (United States)

    2012-10-15

    Functionalized Au NPs have received considerable recent interest for targeting and labeling cells and tissues. Damaged bone tissue can be targeted by functionalizing Au NPs with molecules exhibiting affinity for calcium. Therefore, the relative binding affinity of Au NPs surface functionalized with either carboxylate (l-glutamic acid), phosphonate (2-aminoethylphosphonic acid), or bisphosphonate (alendronate) was investigated for targeted labeling of damaged bone tissue in vitro. Targeted labeling of damaged bone tissue was qualitatively verified by visual observation and backscattered electron microscopy, and quantitatively measured by the surface density of Au NPs using field-emission scanning electron microscopy. The surface density of functionalized Au NPs was significantly greater within damaged tissue compared to undamaged tissue for each functional group. Bisphosphonate-functionalized Au NPs exhibited a greater surface density labeling damaged tissue compared to glutamic acid- and phosphonic acid-functionalized Au NPs, which was consistent with the results of previous work comparing the binding affinity of the same functionalized Au NPs to synthetic hydroxyapatite crystals. Targeted labeling was enabled not only by the functional groups but also by the colloidal stability in solution. Functionalized Au NPs were stabilized by the presence of the functional groups, and were shown to remain well dispersed in ionic (phosphate buffered saline) and serum (fetal bovine serum) solutions for up to 1 week. Therefore, the results of this study suggest that bisphosphonate-functionalized Au NPs have potential for targeted delivery to damaged bone tissue in vitro and provide motivation for in vivo investigation.

  1. Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets.

    Science.gov (United States)

    Akoumianakis, Ioannis; Tarun, Akansha; Antoniades, Charalambos

    2017-10-01

    Adipose tissue (AT) is an active endocrine organ with the ability to dynamically secrete a wide range of adipocytokines. Importantly, its secretory profile is altered in various cardiovascular disease states. AT surrounding vessels, or perivascular AT (PVAT), is recognized in particular as an important local regulator of vascular function and dysfunction. Specifically, PVAT has the ability to sense vascular paracrine signals and respond by secreting a variety of vasoactive adipocytokines. Due to the crucial role of PVAT in regulating many aspects of vascular biology, it may constitute a novel therapeutic target for the prevention and treatment of vascular disease pathogenesis. Signalling pathways in PVAT, such as those using adiponectin, H 2 S, glucagon-like peptide 1 or pro-inflammatory cytokines, are among the potential novel pharmacological therapeutic targets of PVAT. This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc. © 2016 The British Pharmacological Society.

  2. Targeting tissue-specific metabolic signaling pathways in aging: the promise and limitations.

    Science.gov (United States)

    Hu, Fang; Liu, Feng

    2014-01-01

    It has been well established that most of the age-related diseases such as insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, osteoporosis, and atherosclerosis are all closely related to metabolic dysfunction. On the other hand, interventions on metabolism such as calorie restriction or genetic manipulations of key metabolic signaling pathways such as the insulin and mTOR signaling pathways slow down the aging process and improve healthy aging. These findings raise an important question as to whether improving energy homeostasis by targeting certain metabolic signaling pathways in specific tissues could be an effective anti-aging strategy. With a more comprehensive understanding of the tissue-specific roles of distinct metabolic signaling pathways controlling energy homeostasis and the cross-talks between these pathways during aging may lead to the development of more effective therapeutic interventions not only for metabolic dysfunction but also for aging.

  3. Epigenetic Editing: targeted rewriting of epigenetic marks to modulate expression of selected target genes.

    NARCIS (Netherlands)

    de Groote, M.L.; Verschure, P.J.; Rots, M.G.

    2012-01-01

    Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined

  4. Epigenetic Editing : targeted rewriting of epigenetic marks to modulate expression of selected target genes

    NARCIS (Netherlands)

    de Groote, Marloes L.; Verschure, Pernette J.; Rots, Marianne G.

    2012-01-01

    Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined

  5. Signal Transduction and Molecular Targets of Selected Flavonoids

    Science.gov (United States)

    Bode, Ann M.

    2013-01-01

    Abstract Significance: Diet exerts a major influence on the risk for developing cancer and heart disease. Food factors such as flavonoids are alleged to protect cells from premature aging and disease by shielding DNA, proteins, and lipids from oxidative damage. Recent Advances: Our work has focused on clarifying the effects of dietary components on cancer cell proliferation and tumor growth, discovering mechanisms to explain the effects, and identifying the specific molecular targets of these compounds. Our strategy for identifying specific molecular targets of phytochemicals involves the use of supercomputer technology combined with protein crystallography, molecular biology, and experimental laboratory verification. Critical Issues: One of the greatest challenges for scientists is to reduce the accumulation of distortion and half truths reported in the popular media regarding the health benefits of certain foods or food supplements. The use of these is not new, but interest has increased dramatically because of perceived health benefits that are presumably acquired without unpleasant side effects. Flavonoids are touted to exert many beneficial effects in vitro. However, whether they can produce these effects in vivo is disputed. Future Directions: The World Health Organization indicates that one third of all cancer deaths are preventable and that diet is closely linked to prevention. Based on this idea and epidemiological findings, attention has centered on dietary phytochemicals as an effective intervention in cancer development. However, an unequivocal link between diet and cancer has not been established. Thus, identifying cancer preventive dietary agents with specific molecular targets is essential to move forward toward successful cancer prevention. Antioxid. Redox Signal. 19, 163–180. PMID:23458437

  6. Crustacean hyperglycemic hormone (CHH) neuropeptidesfamily: Functions, titer, and binding to target tissues.

    Science.gov (United States)

    Chung, J Sook; Zmora, N; Katayama, H; Tsutsui, N

    2010-05-01

    The removal of the eyestalk (s) induces molting and reproduction promoted the presence of regulatory substances in the eyestalk (ES), particularly medulla terminalis X-organ and the sinus gland (MTXO-SG). The PCR-based cloning strategies have allowed for isolating a great number of cDNAs sequences of crustacean hyperglycemic hormone (CHH) neuropeptides family from the eyestalk and non-eyestalk tissues, e.g., pericardial organs and fore- and hindguts. However, the translated corresponding neuropeptides in these tissues, their circulating concentrations, the mode of actions, and specific physiological functions have not been well described. The profiles of CHH neuropeptides present in the MTXO-SG may differ among decapod crustacean species, but they can be largely divided into two sub-groups on the basis of structural homology: (1) CHH and (2) molt-inhibiting hormone (MIH)/mandibular organ-inhibiting hormone (MOIH)/vitellogenesis/gonad-inhibiting hormone (V/GIH). CHH typically elevating the level of circulating glucose from animals under stressful conditions (hyper- and hypothermia, hypoxia, and low salinity) has multiple target tissues and functions such as ecdysteroidogenesis, osmoregulation, and vitellogenesis. Recently, MIH, known for exclusively suppressing ecdysteroidogenesis in Y-organs, is also reported to have an additional role in vitellogenesis of adult female crustacean species, suggesting that some CHH neuropeptides may acquire an extra regulatory role in reproduction at adult stage. This paper reviews the regulatory roles of CHH and MIH at the levels of specific functions, temporal and spatial expression, titers, their binding sites on the target tissues, and second messengers from two crab species: the blue crab, Callinectes sapidus, and the European green crab, Carcinus maenas. It further discusses the diverse regulatory roles of these neuropeptides and the functional plasticity of these neuropeptides in regard to life stage and species

  7. Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man.

    Directory of Open Access Journals (Sweden)

    Evangelia Charmandari

    Full Text Available Circulating cortisol fluctuates diurnally under the control of the "master" circadian CLOCK, while the peripheral "slave" counterpart of the latter regulates the transcriptional activity of the glucocorticoid receptor (GR at local glucocorticoid target tissues through acetylation. In this manuscript, we studied the effect of CLOCK-mediated GR acetylation on the sensitivity of peripheral tissues to glucocorticoids in humans.We examined GR acetylation and mRNA expression of GR, CLOCK-related and glucocorticoid-responsive genes in peripheral blood mononuclear cells (PBMCs obtained at 8 am and 8 pm from 10 healthy subjects, as well as in PBMCs obtained in the morning and cultured for 24 hours with exposure to 3-hour hydrocortisone pulses every 6 hours. We used EBV-transformed lymphocytes (EBVLs as non-synchronized controls.GR acetylation was higher in the morning than in the evening in PBMCs, mirroring the fluctuations of circulating cortisol in reverse phase. All known glucocorticoid-responsive genes tested responded as expected to hydrocortisone in non-synchronized EBVLs, however, some of these genes did not show the expected diurnal mRNA fluctuations in PBMCs in vivo. Instead, their mRNA oscillated in a Clock- and a GR acetylation-dependent fashion in naturally synchronized PBMCs cultured ex vivo in the absence of the endogenous glucocorticoid, suggesting that circulating cortisol might prevent circadian GR acetylation-dependent effects in some glucocorticoid-responsive genes in vivo.Peripheral CLOCK-mediated circadian acetylation of the human GR may function as a target-tissue, gene-specific counter regulatory mechanism to the actions of diurnally fluctuating cortisol, effectively decreasing tissue sensitivity to glucocorticoids in the morning and increasing it at night.

  8. Peripheral CLOCK Regulates Target-Tissue Glucocorticoid Receptor Transcriptional Activity in a Circadian Fashion in Man

    Science.gov (United States)

    Charmandari, Evangelia; Chrousos, George P.; Lambrou, George I.; Pavlaki, Aikaterini; Koide, Hisashi; Ng, Sinnie Sin Man; Kino, Tomoshige

    2011-01-01

    Context and Objective Circulating cortisol fluctuates diurnally under the control of the “master” circadian CLOCK, while the peripheral “slave” counterpart of the latter regulates the transcriptional activity of the glucocorticoid receptor (GR) at local glucocorticoid target tissues through acetylation. In this manuscript, we studied the effect of CLOCK-mediated GR acetylation on the sensitivity of peripheral tissues to glucocorticoids in humans. Design and Participants We examined GR acetylation and mRNA expression of GR, CLOCK-related and glucocorticoid-responsive genes in peripheral blood mononuclear cells (PBMCs) obtained at 8 am and 8 pm from 10 healthy subjects, as well as in PBMCs obtained in the morning and cultured for 24 hours with exposure to 3-hour hydrocortisone pulses every 6 hours. We used EBV-transformed lymphocytes (EBVLs) as non-synchronized controls. Results GR acetylation was higher in the morning than in the evening in PBMCs, mirroring the fluctuations of circulating cortisol in reverse phase. All known glucocorticoid-responsive genes tested responded as expected to hydrocortisone in non-synchronized EBVLs, however, some of these genes did not show the expected diurnal mRNA fluctuations in PBMCs in vivo. Instead, their mRNA oscillated in a Clock- and a GR acetylation-dependent fashion in naturally synchronized PBMCs cultured ex vivo in the absence of the endogenous glucocorticoid, suggesting that circulating cortisol might prevent circadian GR acetylation-dependent effects in some glucocorticoid-responsive genes in vivo. Conclusions Peripheral CLOCK-mediated circadian acetylation of the human GR may function as a target-tissue, gene-specific counter regulatory mechanism to the actions of diurnally fluctuating cortisol, effectively decreasing tissue sensitivity to glucocorticoids in the morning and increasing it at night. PMID:21980503

  9. Quantitative modeling of selective lysosomal targeting for drug design

    DEFF Research Database (Denmark)

    Trapp, Stefan; Rosania, G.; Horobin, R.W.

    2008-01-01

    Lysosomes are acidic organelles and are involved in various diseases, the most prominent is malaria. Accumulation of molecules in the cell by diffusion from the external solution into cytosol, lysosome and mitochondrium was calculated with the Fick–Nernst–Planck equation. The cell model considers...... the diffusion of neutral and ionic molecules across biomembranes, protonation to mono- or bivalent ions, adsorption to lipids, and electrical attraction or repulsion. Based on simulation results, high and selective accumulation in lysosomes was found for weak mono- and bivalent bases with intermediate to high...... predicted by the model and three were close. Five of the antimalarial drugs were lipophilic weak dibasic compounds. The predicted optimum properties for a selective accumulation of weak bivalent bases in lysosomes are consistent with experimental values and are more accurate than any prior calculation...

  10. Target detect system in 3D using vision apply on plant reproduction by tissue culture

    Science.gov (United States)

    Vazquez Rueda, Martin G.; Hahn, Federico

    2001-03-01

    This paper presents the preliminary results for a system in tree dimension that use a system vision to manipulate plants in a tissue culture process. The system is able to estimate the position of the plant in the work area, first calculate the position and send information to the mechanical system, and recalculate the position again, and if it is necessary, repositioning the mechanical system, using an neural system to improve the location of the plant. The system use only the system vision to sense the position and control loop using a neural system to detect the target and positioning the mechanical system, the results are compared with an open loop system.

  11. Targeted Curing of All Lysogenic Bacteriophage from Streptococcus pyogenes Using a Novel Counter-selection Technique

    Science.gov (United States)

    Euler, Chad W.; Juncosa, Barbara; Ryan, Patricia A.; Deutsch, Douglas R.; McShan, W. Michael; Fischetti, Vincent A.

    2016-01-01

    Streptococcus pyogenes is a human commensal and a bacterial pathogen responsible for a wide variety of human diseases differing in symptoms, severity, and tissue tropism. The completed genome sequences of >37 strains of S. pyogenes, representing diverse disease-causing serotypes, have been published. The greatest genetic variation among these strains is attributed to numerous integrated prophage and prophage-like elements, encoding several virulence factors. A comparison of isogenic strains, differing in prophage content, would reveal the effects of these elements on streptococcal pathogenesis. However, curing strains of prophage is often difficult and sometimes unattainable. We have applied a novel counter-selection approach to identify rare S. pyogenes mutants spontaneously cured of select prophage. To accomplish this, we first inserted a two-gene cassette containing a gene for kanamycin resistance (KanR) and the rpsL wild-type gene, responsible for dominant streptomycin sensitivity (SmS), into a targeted prophage on the chromosome of a streptomycin resistant (SmR) mutant of S. pyogenes strain SF370. We then applied antibiotic counter-selection for the re-establishment of the KanS/SmR phenotype to select for isolates cured of targeted prophage. This methodology allowed for the precise selection of spontaneous phage loss and restoration of the natural phage attB attachment sites for all four prophage-like elements in this S. pyogenes chromosome. Overall, 15 mutants were constructed that encompassed every permutation of phage knockout as well as a mutant strain, named CEM1ΔΦ, completely cured of all bacteriophage elements (a ~10% loss of the genome); the only reported S. pyogenes strain free of prophage-like elements. We compared CEM1ΔΦ to the WT strain by analyzing differences in secreted DNase activity, as well as lytic and lysogenic potential. These mutant strains should allow for the direct examination of bacteriophage relationships within S. pyogenes and

  12. Optimizing target selection and development strategy in cancer treatment: the next wave.

    Science.gov (United States)

    Sausville, Edward A

    2004-09-01

    Successful cancer treatments of the future are being developed with a focus on the molecular targets underlying the pathophysiology of neoplasia. Prominent targets which have emerged are those which are mutated in the course of a cancer's development, and mediate activation or release from suppression of pathways mediating proliferation or apoptosis. These arguably are "pathogenic" targets. However, equally important are targets which can be defined on the basis of "large scale" analysis techniques of gene or protein expression in tumors which define targets expressed as a result of a tumor's differentiation state or tissue of origin ("ontogenic" targets); targets mediating drug uptake or metabolism ("pharmacologic" targets), and "microenvironmental" targets mediating the alteration of tumor stromal elements. Irrespective of the nature of the molecular target which is the focus of new therapeutic efforts, target definition in susceptible tumors or patients ideally would be part of the development plan. In addition, an understanding of the therapeutic index which might be achieved in host vs tumor tissues using a surrogate or actual marker of drug effect ideally would be available from animal models and inform the development strategy in humans.

  13. Leveraging big data to transform target selection and drug discovery.

    Science.gov (United States)

    Chen, B; Butte, A J

    2016-03-01

    The advances of genomics, sequencing, and high throughput technologies have led to the creation of large volumes of diverse datasets for drug discovery. Analyzing these datasets to better understand disease and discover new drugs is becoming more common. Recent open data initiatives in basic and clinical research have dramatically increased the types of data available to the public. The past few years have witnessed successful use of big data in many sectors across the whole drug discovery pipeline. In this review, we will highlight the state of the art in leveraging big data to identify new targets, drug indications, and drug response biomarkers in this era of precision medicine. © 2015 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  14. Mechanisms involved in the transport of mercuric ions in target tissues

    Science.gov (United States)

    Bridges, Christy C.; Zalups, Rudolfs K.

    2016-01-01

    Mercury exists in the environment in various forms, all of which pose a risk to human health. Despite guidelines regulating the industrial release of mercury into the environment, humans continue to be exposed regularly to various forms of this metal via inhalation or ingestion. Following exposure, mercuric ions are taken up by and accumulate in numerous organs, including brain, intestine, kidney, liver, and placenta. In order to understand the toxicological effects of exposure to mercury, a thorough understanding of the mechanisms that facilitate entry of mercuric ions into target cells must first be obtained. A number of mechanisms for the transport of mercuric ions into target cells and organs have been proposed in recent years. However, the ability of these mechanisms to transport mercuric ions and the regulatory features of these carriers have not been characterized completely. The purpose of this review is to summarize the current findings related to the mechanisms that may be involved in the transport of inorganic and organic forms of mercury in target tissues and organs. This review will describe mechanisms known to be involved in the transport of mercury and will also propose additional mechanisms that may potentially be involved in the transport of mercuric ions into target cells. PMID:27422290

  15. Diannexin protects against renal ischemia reperfusion injury and targets phosphatidylserines in ischemic tissue.

    Directory of Open Access Journals (Sweden)

    Kimberley E Wever

    Full Text Available Renal ischemia/reperfusion injury (IRI frequently complicates shock, renal transplantation and cardiac and aortic surgery, and has prognostic significance. The translocation of phosphatidylserines to cell surfaces is an important pro-inflammatory signal for cell-stress after IRI. We hypothesized that shielding of exposed phosphatidylserines by the annexin A5 (ANXA5 homodimer Diannexin protects against renal IRI. Protective effects of Diannexin on the kidney were studied in a mouse model of mild renal IRI. Diannexin treatment before renal IRI decreased proximal tubule damage and leukocyte influx, decreased transcription and expression of renal injury markers Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule-1 and improved renal function. A mouse model of ischemic hind limb exercise was used to assess Diannexin biodistribution and targeting. When comparing its biodistribution and elimination to ANXA5, Diannexin was found to have a distinct distribution pattern and longer blood half-life. Diannexin targeted specifically to the ischemic muscle and its affinity exceeded that of ANXA5. Targeting of both proteins was inhibited by pre-treatment with unlabeled ANXA5, suggesting that Diannexin targets specifically to ischemic tissues via phosphatidylserine-binding. This study emphasizes the importance of phosphatidylserine translocation in the pathophysiology of IRI. We show for the first time that Diannexin protects against renal IRI, making it a promising therapeutic tool to prevent IRI in a clinical setting. Our results indicate that Diannexin is a potential new imaging agent for the study of phosphatidylserine-exposing organs in vivo.

  16. Bombesin peptide antagonist for target-selective delivery of liposomal doxorubicin on cancer cells.

    Science.gov (United States)

    Accardo, Antonella; Mansi, Rosalba; Salzano, Giuseppina; Morisco, Anna; Aurilio, Michela; Parisi, Antonio; Maione, Francesco; Cicala, Carla; Ziaco, Barbara; Tesauro, Diego; Aloj, Luigi; De Rosa, Giuseppe; Morelli, Giancarlo

    2012-11-21

    Purpose: This study addresses novel peptide modified liposomal doxorubicin to specifically target tissues overexpressing bombesin (BN) receptors. Methods: DOTA-(AEEA)(2)-peptides containing the [7-14]bombesin and the new BN-AA1 sequence have been synthesized to compare their binding properties and in serum stabilities. The amphiphilic peptide derivative (MonY-BN-AA1) containing BN-AA1, a hydrophobic moiety, polyethylenglycole (PEG), and diethylenetriaminepentaacetate (DTPA), has been synthesized. Liposomes have been obtained by mixing of MonY-BN-AA1 with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). Results: Both (111)In labeled peptide derivatives present nanomolar Kd to PC-3 cells. (177)Lu labeled peptide DOTA-(AEEA)(2)-BN-AA1 is very stable (half-life 414.1 h), while DOTA-(AEEA)(2)-BN, shows a half-life of 15.5 h. In vivo studies on the therapeutic efficacy of DSPC/MonY-BN-AA1/Dox in comparison to DSPC/MonY-BN/Dox, were performed in PC-3 xenograft bearing mice. Both formulations showed similar tumor growth inhibition (TGI) compared to control animals treated with non-targeted DSPC/Dox liposomes or saline solution. For DSPC/MonY-BN-AA1/Dox the maximum effect was observed 19 days after treatment. Conclusions: DSPC/MonY-BN-AA1/Dox nanovectors confirm the ability to selectively target and provide therapeutic efficacy in mice. The lack of receptor activation and possible acute biological side effects provided by using the AA1 antagonist bombesin sequence should provide safe working conditions for further development of this class of drug delivery vehicles.

  17. Metformin selectively targets redox control of complex I energy transduction

    Directory of Open Access Journals (Sweden)

    Amy R. Cameron

    2018-04-01

    Full Text Available Many guanide-containing drugs are antihyperglycaemic but most exhibit toxicity, to the extent that only the biguanide metformin has enjoyed sustained clinical use. Here, we have isolated unique mitochondrial redox control properties of metformin that are likely to account for this difference. In primary hepatocytes and H4IIE hepatoma cells we found that antihyperglycaemic diguanides DG5-DG10 and the biguanide phenformin were up to 1000-fold more potent than metformin on cell signalling responses, gluconeogenic promoter expression and hepatocyte glucose production. Each drug inhibited cellular oxygen consumption similarly but there were marked differences in other respects. All diguanides and phenformin but not metformin inhibited NADH oxidation in submitochondrial particles, indicative of complex I inhibition, which also corresponded closely with dehydrogenase activity in living cells measured by WST-1. Consistent with these findings, in isolated mitochondria, DG8 but not metformin caused the NADH/NAD+ couple to become more reduced over time and mitochondrial deterioration ensued, suggesting direct inhibition of complex I and mitochondrial toxicity of DG8. In contrast, metformin exerted a selective oxidation of the mitochondrial NADH/NAD+ couple, without triggering mitochondrial deterioration. Together, our results suggest that metformin suppresses energy transduction by selectively inducing a state in complex I where redox and proton transfer domains are no longer efficiently coupled. Keywords: Diabetes, Metformin, Mitochondria, NADH, NAD+

  18. PEG-functionalized microparticles selectively target inflamed mucosa in inflammatory bowel disease.

    Science.gov (United States)

    Lautenschläger, Christian; Schmidt, Carsten; Lehr, Claus-Michael; Fischer, Dagmar; Stallmach, Andreas

    2013-11-01

    The systemic therapy of inflammatory bowel diseases (IBD) by oral administration of anti-inflammatory and immunosuppressive agents is characterized by an increased probability of adverse drug reactions. A successful treatment with a simultaneous reduction in adverse events may be achieved by the administration of micro- and nanosized targeted drug delivery systems, which accumulate selectively in inflamed mucosal areas without systemic absorption. We described in a first in vivo study in IBD patients a significantly enhanced, but minor accumulation of non-functionalized poly(lactic-co-glycolic acid) (PLGA) microparticles in ulcerous lesions very recently. The aim of this study was therefore the assessment of an increased targeting potential of different non-, chitosan- and polyethylene glycol (PEG)-functionalized PLGA micro- and nanoparticles to inflamed intestinal mucosa compared to healthy mucosa. For the quantification of nano- and microparticles, fluoresceinamine-labeled-PLGA was synthesized by carbodiimide reaction. Fluorescent chitosan-, PEG-, and non-functionalized PLGA micro- and nanoparticles with mean hydrodynamic diameters of 3000 nm and 300 nm were prepared by solvent evaporation technique. The targeting efficiencies in terms of particle translocation and deposition were investigated in Ussing chamber experiments. Healthy and inflamed macrobiopsies were received from routine endoscopic examinations of patients with IBD as well as control patients. One-hundred and one Ussing chamber experiments of patients with IBD (Crohn's disease: n=7 and ulcerative colitis: n=9) as well as healthy control patients (n=5) were performed. Histomorphological and electrophysiological investigations of inflamed mucosal tissues confirmed a significant alteration of mucosal barrier integrity in IBD patients (TER: healthy: 34.1 Ω cm(2); inflamed: 21.6 Ωc m(2); p=0.034). In summary, nanoparticles showed an increased translocation and deposition compared to microparticles in

  19. Rhodacyanine derivative selectively targets cancer cells and overcomes tamoxifen resistance.

    Directory of Open Access Journals (Sweden)

    John Koren

    Full Text Available MKT-077, a rhodacyanine dye, was shown to produce cancer specific cell death. However, complications prevented the use of this compound beyond clinical trials. Here we describe YM-1, a derivative of MKT-077. We found that YM-1 was more cytotoxic and localized differently than MKT-077. YM-1 demonstrated this cytotoxicity across multiple cancer cell lines. This toxicity was limited to cancer cell lines; immortalized cell models were unaffected. Brief applications of YM-1 were found to be non-toxic. Brief treatment with YM-1 restored tamoxifen sensitivity to a refractory tamoxifen-resistant MCF7 cell model. This effect is potentially due to altered estrogen receptor alpha phosphorylation, an outcome precipitated by selective reductions in Akt levels (Akt/PKB. Thus, modifications to the rhodocyanine scaffold could potentially be made to improve efficacy and pharmacokinetic properties. Moreover, the impact on tamoxifen sensitivity could be a new utility for this compound family.

  20. Characterization of alendronic- and undecylenic acid coated magnetic nanoparticles for the targeted delivery of rosiglitazone to subcutaneous adipose tissue.

    Science.gov (United States)

    Saatchi, Katayoun; Tod, Sarah E; Leung, Donna; Nicholson, Kenton E; Andreu, Irene; Buchwalder, Christian; Schmitt, Veronika; Häfeli, Urs O; Gray, Sarah L

    2017-02-01

    Obesity is a state of positive energy balance where excess white adipose tissue accumulates to the detriment of metabolic health. Improving adipocyte function with systemic administration of thiazolidinediones (TZDs) improves metabolic outcomes in obesity, however TZD use is limited clinically due to undesirable side effects. Here we evaluate magnetic nanoparticles (MNPs) as a tool to target rosiglitazone (Rosi) specifically to adipose tissue. Results show Rosi can be adsorbed to MNPs (Rosi-MNPs) with hydrophobic coatings for which we present binding and release kinetics. Rosi adsorbed to MNPs retained the ability to induce PPARγ target gene expression in cells. Biodistribution analysis of radiolabeled Rosi-MNPs revealed a fat-implanted magnet significantly enhanced localization of Rosi to the targeted adipose tissue when administered by subcutaneous injection to obese mice. We propose MNPs for targeted delivery of anti-diabetic agents to superficially located subcutaneous adipose tissue. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Visual cells remember earlier applied target: plasticity of orientation selectivity.

    Directory of Open Access Journals (Sweden)

    Narcis Ghisovan

    Full Text Available BACKGROUND: A canonical proposition states that, in mature brain, neurons responsive to sensory stimuli are tuned to specific properties installed shortly after birth. It is amply demonstrated that that neurons in adult visual cortex of cats are orientation-selective that is they respond with the highest firing rates to preferred oriented stimuli. METHODOLOGY/PRINCIPAL FINDINGS: In anesthetized cats, prepared in a conventional fashion for single cell recordings, the present investigation shows that presenting a stimulus uninterruptedly at a non-preferred orientation for twelve minutes induces changes in orientation preference. Across all conditions orientation tuning curves were investigated using a trial by trial method. Contrary to what has been previously reported with shorter adaptation duration, twelve minutes of adaptation induces mostly attractive shifts, i.e. toward the adapter. After a recovery period allowing neurons to restore their original orientation tuning curves, we carried out a second adaptation which produced three major results: (1 more frequent attractive shifts, (2 an increase of their magnitude, and (3 an additional enhancement of responses at the new or acquired preferred orientation. Additionally, we also show that the direction of shifts depends on the duration of the adaptation: shorter adaptation in most cases produces repulsive shifts, whereas adaptation exceeding nine minutes results in attractive shifts, in the same unit. Consequently, shifts in preferred orientation depend on the duration of adaptation. CONCLUSION/SIGNIFICANCE: The supplementary response improvements indicate that neurons in area 17 keep a memory trace of the previous stimulus properties, thereby upgrading cellular performance. It also highlights the dynamic nature of basic neuronal properties in adult cortex since repeated adaptations modified both the orientation tuning selectivity and the response strength to the preferred orientation. These

  2. In vitro effects of toxaphene on mitochondrial calcium ATPase and calcium uptake in selected rat tissues

    International Nuclear Information System (INIS)

    Trottman, C.H.; Rao, K.S.P.; Morrow, W.; Uzodinma, J.E.; Desaiah, D.

    1985-01-01

    In vitro effects of toxaphene on Ca 2+ -ATPase activity and 45 Ca 2+ -uptake were studied in mitochondrial fractions of heart, kidney and liver tissues of rat. Mitochondrial fractions were prepared by the conventional centrifugation method. Ca 2+ -ATPase activity was determined by measuring the inorganic phosphate liberated during ATP hydrolysis. Toxaphene inhibited Ca 2+ -ATPase in a concentration dependent manner in all the three tissues. Substrate activation kinetics, with heart, kidney and liver tissue fractions, revealed that toxaphene inhibited Ca 2+ -ATPase activity non-competetively by decreasing the maximum velocity of the enzyme without affecting the enzyme-substrate affinity. Toxaphene also inhibited mitochondrial 45 Ca 2+ -uptake in the three selected tissues in a concentration dependent manner. These results indicate that toxaphene is an inhibitor of mitochondrial Ca 2+ -ATPase and calcium transport in heart, kidney and liver tissues of rat. 19 references, 5 figures

  3. Aldoxorubicin: a tumor-targeted doxorubicin conjugate for relapsed or refractory soft tissue sarcomas

    Directory of Open Access Journals (Sweden)

    Gong J

    2018-04-01

    Full Text Available Jun Gong,1,* Jessica Yan,2,* Charles Forscher,3 Andrew Hendifar4 1Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA; 2Department of Hematology and Oncology, Harbor-UCLA Medical Center, Torrance, CA, USA; 3Sarcoma Program, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 4Gastrointestinal and Neuroendocrine Malignancies, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA *These authors contributed equally to this work Abstract: Despite available therapies after initial systemic therapy, prognosis remains poor in relapsed or refractory soft tissue sarcomas (STS. The rational and clinical development of novel agents to improve outcomes in this area of high unmet need is desperately warranted. Aldoxorubicin is a prodrug of doxorubicin that binds to serum albumin immediately after administration through an acid-sensitive hydrazone linker and is subsequently transported to tumor tissues where the acidic environment cleaves the linker and facilitates delivery of a tumor-targeted drug payload. In clinical studies to date, there has been evidence of efficacy and mitigated cardiac toxicity. In this review, we comprehensively detail the clinical development of aldoxorubicin in STS to date. Specifically, we highlight available data on the pharmacokinetics and efficacy from Phase I, Phase II, and Phase III trials in advanced or metastatic STS. We conclude with considerations for future directions of investigation for this promising antitumor agent.Keywords: aldoxorubicin, albumin conjugate, soft tissue sarcomas, clinical trials, pharmacokinetics, cardiotoxicity 

  4. Differentiating Immune Cell Targets in Gut-Associated Lymphoid Tissue for HIV Cure.

    Science.gov (United States)

    Khan, Shahzada; Telwatte, Sushama; Trapecar, Martin; Yukl, Steven; Sanjabi, Shomyseh

    2017-11-01

    The single greatest challenge to an HIV cure is the persistence of latently infected cells containing inducible, replication-competent proviral genomes, which constitute only a small fraction of total or infected cells in the body. Although resting CD4 + T cells in the blood are a well-known source of viral rebound, more than 90% of the body's lymphocytes reside elsewhere. Many are in gut tissue, where HIV DNA levels per million CD4 + T cells are considerably higher than in the blood. Despite the significant contribution of gut tissue to viral replication and persistence, little is known about the cell types that support persistence of HIV in the gut; importantly, T cells in the gut have phenotypic, functional, and survival properties that are distinct from T cells in other tissues. The mechanisms by which latency is established and maintained will likely depend on the location and cytokine milieu surrounding the latently infected cells in each compartment. Therefore, successful HIV cure strategies require identification and characterization of the exact cell types that support viral persistence, particularly in the gut. In this review, we describe the seeding of the latent HIV reservoir in the gut mucosa; highlight the evidence for compartmentalization and depletion of T cells; summarize the immunologic consequences of HIV infection within the gut milieu; propose how the damaged gut environment may promote the latent HIV reservoir; and explore several immune cell targets in the gut and their place on the path toward HIV cure.

  5. Unraveling Chagas disease transmission through the oral route: Gateways to Trypanosoma cruzi infection and target tissues

    Science.gov (United States)

    Silva-dos-Santos, Danielle; Barreto-de-Albuquerque, Juliana; Guerra, Bárbara; Moreira, Otacilio C.; Berbert, Luiz Ricardo; Ramos, Mariana Tavares; Mascarenhas, Barbara Angelica S.; Britto, Constança; Morrot, Alexandre; Serra Villa-Verde, Déa M.; Garzoni, Luciana Ribeiro; Savino, Wilson; Cotta-de-Almeida, Vinícius; de Meis, Juliana

    2017-01-01

    Oral transmission of Trypanosoma cruzi, the causative agent of Chagas disease, is the most important route of infection in Brazilian Amazon and Venezuela. Other South American countries have also reported outbreaks associated with food consumption. A recent study showed the importance of parasite contact with oral cavity to induce a highly severe acute disease in mice. However, it remains uncertain the primary site of parasite entry and multiplication due to an oral infection. Here, we evaluated the presence of T. cruzi Dm28c luciferase (Dm28c-luc) parasites in orally infected mice, by bioluminescence and quantitative real-time PCR. In vivo bioluminescent images indicated the nasomaxillary region as the site of parasite invasion in the host, becoming consistently infected throughout the acute phase. At later moments, 7 and 21 days post-infection (dpi), luminescent signal is denser in the thorax, abdomen and genital region, because of parasite dissemination in different tissues. Ex vivo analysis demonstrated that the nasomaxillary region, heart, mandibular lymph nodes, liver, spleen, brain, epididymal fat associated to male sex organs, salivary glands, cheek muscle, mesenteric fat and lymph nodes, stomach, esophagus, small and large intestine are target tissues at latter moments of infection. In the same line, amastigote nests of Dm28c GFP T. cruzi were detected in the nasal cavity of 6 dpi mice. Parasite quantification by real-time qPCR at 7 and 21 dpi showed predominant T. cruzi detection and expansion in mouse nasal cavity. Moreover, T. cruzi DNA was also observed in the mandibular lymph nodes, pituitary gland, heart, liver, small intestine and spleen at 7 dpi, and further, disseminated to other tissues, such as the brain, stomach, esophagus and large intestine at 21 dpi. Our results clearly demonstrated that oral cavity and adjacent compartments is the main target region in oral T. cruzi infection leading to parasite multiplication at the nasal cavity. PMID

  6. Unraveling Chagas disease transmission through the oral route: Gateways to Trypanosoma cruzi infection and target tissues.

    Science.gov (United States)

    Silva-Dos-Santos, Danielle; Barreto-de-Albuquerque, Juliana; Guerra, Bárbara; Moreira, Otacilio C; Berbert, Luiz Ricardo; Ramos, Mariana Tavares; Mascarenhas, Barbara Angelica S; Britto, Constança; Morrot, Alexandre; Serra Villa-Verde, Déa M; Garzoni, Luciana Ribeiro; Savino, Wilson; Cotta-de-Almeida, Vinícius; Meis, Juliana de

    2017-04-01

    Oral transmission of Trypanosoma cruzi, the causative agent of Chagas disease, is the most important route of infection in Brazilian Amazon and Venezuela. Other South American countries have also reported outbreaks associated with food consumption. A recent study showed the importance of parasite contact with oral cavity to induce a highly severe acute disease in mice. However, it remains uncertain the primary site of parasite entry and multiplication due to an oral infection. Here, we evaluated the presence of T. cruzi Dm28c luciferase (Dm28c-luc) parasites in orally infected mice, by bioluminescence and quantitative real-time PCR. In vivo bioluminescent images indicated the nasomaxillary region as the site of parasite invasion in the host, becoming consistently infected throughout the acute phase. At later moments, 7 and 21 days post-infection (dpi), luminescent signal is denser in the thorax, abdomen and genital region, because of parasite dissemination in different tissues. Ex vivo analysis demonstrated that the nasomaxillary region, heart, mandibular lymph nodes, liver, spleen, brain, epididymal fat associated to male sex organs, salivary glands, cheek muscle, mesenteric fat and lymph nodes, stomach, esophagus, small and large intestine are target tissues at latter moments of infection. In the same line, amastigote nests of Dm28c GFP T. cruzi were detected in the nasal cavity of 6 dpi mice. Parasite quantification by real-time qPCR at 7 and 21 dpi showed predominant T. cruzi detection and expansion in mouse nasal cavity. Moreover, T. cruzi DNA was also observed in the mandibular lymph nodes, pituitary gland, heart, liver, small intestine and spleen at 7 dpi, and further, disseminated to other tissues, such as the brain, stomach, esophagus and large intestine at 21 dpi. Our results clearly demonstrated that oral cavity and adjacent compartments is the main target region in oral T. cruzi infection leading to parasite multiplication at the nasal cavity.

  7. Unraveling Chagas disease transmission through the oral route: Gateways to Trypanosoma cruzi infection and target tissues.

    Directory of Open Access Journals (Sweden)

    Danielle Silva-Dos-Santos

    2017-04-01

    Full Text Available Oral transmission of Trypanosoma cruzi, the causative agent of Chagas disease, is the most important route of infection in Brazilian Amazon and Venezuela. Other South American countries have also reported outbreaks associated with food consumption. A recent study showed the importance of parasite contact with oral cavity to induce a highly severe acute disease in mice. However, it remains uncertain the primary site of parasite entry and multiplication due to an oral infection. Here, we evaluated the presence of T. cruzi Dm28c luciferase (Dm28c-luc parasites in orally infected mice, by bioluminescence and quantitative real-time PCR. In vivo bioluminescent images indicated the nasomaxillary region as the site of parasite invasion in the host, becoming consistently infected throughout the acute phase. At later moments, 7 and 21 days post-infection (dpi, luminescent signal is denser in the thorax, abdomen and genital region, because of parasite dissemination in different tissues. Ex vivo analysis demonstrated that the nasomaxillary region, heart, mandibular lymph nodes, liver, spleen, brain, epididymal fat associated to male sex organs, salivary glands, cheek muscle, mesenteric fat and lymph nodes, stomach, esophagus, small and large intestine are target tissues at latter moments of infection. In the same line, amastigote nests of Dm28c GFP T. cruzi were detected in the nasal cavity of 6 dpi mice. Parasite quantification by real-time qPCR at 7 and 21 dpi showed predominant T. cruzi detection and expansion in mouse nasal cavity. Moreover, T. cruzi DNA was also observed in the mandibular lymph nodes, pituitary gland, heart, liver, small intestine and spleen at 7 dpi, and further, disseminated to other tissues, such as the brain, stomach, esophagus and large intestine at 21 dpi. Our results clearly demonstrated that oral cavity and adjacent compartments is the main target region in oral T. cruzi infection leading to parasite multiplication at the nasal

  8. In Vitro Selection and Characterization of DNA Aptamers to a Small Molecule Target.

    Science.gov (United States)

    Ruscito, Annamaria; McConnell, Erin M; Koudrina, Anna; Velu, Ranganathan; Mattice, Christopher; Hunt, Vernon; McKeague, Maureen; DeRosa, Maria C

    2017-12-14

    Aptamers, synthetic oligonucleotide-based molecular recognition probes, have found use in a wide array of biosensing technologies based on their tight and highly selective binding to a variety of molecular targets. However, the inherent challenges associated with the selection and characterization of aptamers for small molecule targets have resulted in their underrepresentation, despite the need for small molecule detection in fields such as medicine, the environment, and agriculture. This protocol describes the steps in the selection, sequencing, affinity characterization, and truncation of DNA aptamers that are specific for small molecule targets. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

  9. Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates

    Energy Technology Data Exchange (ETDEWEB)

    Green, Damian J.; Pagel, John M.; Nemecek, Eneida R.; Lin, Yukang; Kenoyer, Aimee L.; Pantelias, Anastasia; Hamlin, Donald K.; Wilbur, D. S.; Fisher, Darrell R.; Rajendran, Joseph G.; Gopal, Ajay K.; Park, Steven I.; Press, Oliver W.

    2009-08-06

    Pretargeted radioimmunotherapy (PRIT) is designed to enhance the directed delivery of radionuclides to malignant cells. Through a series of studies in nineteen nonhuman primates (M. fascicularis) the potential therapeutic advantage of anti-CD45 PRIT was evaluated. Anti-CD45 PRIT demonstrated a significant improvement in target-to-normal organ ratios of absorbed radiation when compared to directly radiolabeled bivalent antibody (conventional radioimmunotherapy [RIT]). Radio-DOTA-biotin administered 48 hours after anti-CD45 streptavidin fusion protein (FP) [BC8 (scFv)4SA] produced markedly lower concentrations of radiation in non-target tissues when compared to conventional RIT. PRIT generated superior target:normal organ ratios in the blood, lung and liver (10.3:1, 18.9:1 and 9.9:1 respectively) when compared to the conventional RIT controls (2.6:1, 6.4:1 and 2.9:1 respectively). The FP demonstrated superior retention in target tissues relative to comparable directly radiolabeled bivalent anti-CD45 RIT. The time-point of administration of the second step radiolabeled ligand (radio-DOTA-biotin) significantly impacted the biodistribution of radioactivity in target tissues. Rapid clearance of the FP from the circulation rendered unnecessary the addition of a synthetic clearing agent in this model. These results support proceeding to anti-CD45 PRIT clinical trials for patients with both leukemia and lymphoma.

  10. Liver-targeting of interferon-alpha with tissue-specific domain antibodies.

    Directory of Open Access Journals (Sweden)

    Edward Coulstock

    Full Text Available Interferon alpha (IFNα is used for the treatment of hepatitis C infection and whilst efficacious it is associated with multiple adverse events including reduced leukocyte, erythrocyte, and platelet counts, fatigue, and depression. These events are most likely caused by systemic exposure to interferon. We therefore hypothesise that targeting the therapeutic directly to the intended site of action in the liver would reduce exposure in blood and peripheral tissue and hence improve the safety and tolerability of IFNα therapy. We genetically fused IFN to a domain antibody (dAb specific to a hepatocyte restricted antigen, asialoglycoprotein receptor (ASGPR. Our results show that the murine IFNα2 homolog (mIFNα2 fused to an ASGPR specific dAb, termed DOM26h-196-61, could be expressed in mammalian tissue culture systems and retains the desirable biophysical properties and activity of both fusion partners when measured in vitro. Furthermore a clear increase in in vivo targeting of the liver by mIFNα2-ASGPR dAb fusion protein, compared to that observed with either unfused mIFNα2 or mIFNα2 fused to an isotype control dAb VHD2 (which does not bind ASGPR was demonstrated using microSPECT imaging. We suggest that these findings may be applicable in the development of a liver-targeted human IFN molecule with improved safety and patient compliance in comparison to the current standard of care, which could ultimately be used as a treatment for human hepatitis virus infections.

  11. Chemopreventive glucosinolate accumulation in various broccoli and collard tissues: Microfluidic-based targeted transcriptomics for by-product valorization.

    Science.gov (United States)

    Lee, Young-Sang; Ku, Kang-Mo; Becker, Talon M; Juvik, John A

    2017-01-01

    Floret, leaf, and root tissues were harvested from broccoli and collard cultivars and extracted to determine their glucosinolate and hydrolysis product profiles using high performance liquid chromatography and gas chromotography. Quinone reductase inducing bioactivity, an estimate of anti-cancer chemopreventive potential, of the extracts was measured using a hepa1c1c7 murine cell line. Extracts from root tissues were significantly different from other tissues and contained high levels of gluconasturtiin and glucoerucin. Targeted gene expression analysis on glucosinolate biosynthesis revealed that broccoli root tissue has elevated gene expression of AOP2 and low expression of FMOGS-OX homologs, essentially the opposite of what was observed in broccoli florets, which accumulated high levels of glucoraphanin. Broccoli floret tissue has significantly higher nitrile formation (%) and epithionitrile specifier protein gene expression than other tissues. This study provides basic information of the glucosinolate metabolome and transcriptome for various tissues of Brassica oleracea that maybe utilized as potential byproducts for the nutraceutical market.

  12. Ken & barbie selectively regulates the expression of a subset of Jak/STAT pathway target genes.

    Science.gov (United States)

    Arbouzova, Natalia I; Bach, Erika A; Zeidler, Martin P

    2006-01-10

    A limited number of evolutionarily conserved signal transduction pathways are repeatedly reused during development to regulate a wide range of processes. Here we describe a new negative regulator of JAK/STAT signaling and identify a potential mechanism by which the pleiotropy of responses resulting from pathway activation is generated in vivo. As part of a genetic interaction screen, we have identified Ken & Barbie (Ken) , which is an ortholog of the mammalian proto-oncogene BCL6 , as a negative regulator of the JAK/STAT pathway. Ken genetically interacts with the pathway in vivo and recognizes a DNA consensus sequence overlapping that of STAT92E in vitro. Tissue culture-based assays demonstrate the existence of Ken-sensitive and Ken-insensitive STAT92E binding sites, while ectopically expressed Ken is sufficient to downregulate a subset of JAK/STAT pathway target genes in vivo. Finally, we show that endogenous Ken specifically represses JAK/STAT-dependent expression of ventral veins lacking (vvl) in the posterior spiracles. Ken therefore represents a novel regulator of JAK/STAT signaling whose dynamic spatial and temporal expression is capable of selectively modulating the transcriptional repertoire elicited by activated STAT92E in vivo.

  13. HDR monotherapy for prostate cancer: A simulation study to determine the effect of catheter displacement on target coverage and normal tissue irradiation

    International Nuclear Information System (INIS)

    Kolkman-Deurloo, Inger-Karine K.; Roos, Martin A.; Aluwini, Shafak

    2011-01-01

    Purpose: The aim of this study was to systematically analyse the effect of catheter displacements both on target coverage and normal tissue irradiation in fractionated high dose rate (HDR) prostate brachytherapy, using a simulation study, and to define tolerances for catheter displacement ensuring that both target coverage and normal tissue doses remain clinically acceptable. Besides the effect of total implant displacement, also displacements of catheters belonging to selected template rows only were evaluated in terms of target coverage and normal tissue dose, in order to analyse the change in dose distribution as a function of catheter dwell weight and catheter location. Material and methods: Five representative implant geometries, with 17 catheters each, were selected. The clinical treatment plan was compared to treatment plans in which an entire implant displacement in caudal direction over 3, 5, 7 and 10 mm was simulated. Besides, treatment plans were simulated considering a displacement of either the central, most ventral or most dorsal catheter rows only, over 5 mm caudally. Results: Due to displacement of the entire implant the target coverage drops below the tolerance of 93% for all displacements studied. The effect of displacement of the entire implant on organs at risk strongly depended on the patient anatomy; e.g., for 80% of the implant geometries the V 80 of the rectum exceeded its tolerance for all displacements. The effect of displacement of catheters belonging to selected template rows depended strongly on the relative weight of each catheter row when considering the target coverage and on its location when considering the dose in the organs at risk. Conclusion: This study supports the need for a check of the catheter locations before each fraction and correction of deviations of the catheter position exceeding 3 mm.

  14. Evaluating gaze-based interface tools to facilitate point-and-select tasks with small targets

    DEFF Research Database (Denmark)

    Skovsgaard, Henrik; Mateo, Julio C.; Hansen, John Paulin

    2011-01-01

    Gaze interaction affords hands-free control of computers. Pointing to and selecting small targets using gaze alone is difficult because of the limited accuracy of gaze pointing. This is the first experimental comparison of gaze-based interface tools for small-target (e.g. <12 × 12 pixels) point-a...

  15. Goal-driven modulations as a function of time in saccadic target selection

    NARCIS (Netherlands)

    van Zoest, L.J.F.M.; Donk, M.

    2008-01-01

    Four experiments were performed to investigate the contribution of goal-driven modulation in saccadic target selection as a function of time. Observers were required to make an eye movement to a prespecified target that was concurrently presented with multiple nontargets and possibly one distractor.

  16. Selective sensitivity of Mueller imaging for tissue scattering over absorption changes in cancer mimicking phantoms

    Science.gov (United States)

    Fathima, Adeeba; Sharma B. S., Mahima; N., Sujatha

    2018-03-01

    Tissue characterization using optical polarimetry, especially Mueller imaging is receiving sustained interest due to its potential in achieving optical contrast between normal and malignant variations. This is particularly important in identifying the margin of malignant growth in suspected tissue regions for accurate surgical removal, or in aiding the sampling procedure during biopsy. The sensitivity of Mueller matrix derived depolarization index to the combined effects of changes in scattering and absorption occurring in a cancerous growth is illustrated in this study. Depolarization imaging is shown to be useful in demarcating the boundary of two regions of differing optical properties using a tissue phantom, modeled according to the changes expected during cancerous growth in tissue. Tissue scattering and absorption are expected to generally increase with the nuclear size change and crowding as well as angiogenesis associated with malignancy. We have observed that there is selective sensitivity for the Mueller elements and derived depolarization index to tissue scattering over absorption in the object field. Although the scattering and absorption are expected to increase and decrease depolarization respectively, the optical contrast of Mueller images and the derived depolarization index between normal and cancerous tissue is found appreciable in this region.

  17. Evaluating the forensic application of 19 target microRNAs as biomarkers in body fluid and tissue identification.

    Science.gov (United States)

    Sirker, M; Fimmers, R; Schneider, P M; Gomes, I

    2017-03-01

    RNA-based body fluid and tissue identification has evolved as a promising and reliable new technique to classify type and source of biological evidence in crime cases. In particular, mRNA-based approaches are currently on the rise to replace conventional protein-based methods and are increasingly implemented into forensic casework. However, degradation of these nucleic acid molecules can cause issues on laboratory scale and need to be considered for a credible investigation. For this reason, the analysis of miRNAs using qPCR has been proposed to be a sensitive and specific approach to identify the origin of a biological trace taking advantage of their small size and resistance to degradation. Despite the straightforward workflow of this method, suitable endogenous controls are inevitable when performing real-time PCR to ensure accurate normalization of gene expression data in order to allow a meaningful interpretation. In this regard, we have validated reference genes for a set of forensically relevant body fluids and tissues (blood, saliva, semen, vaginal secretions, menstrual blood and skin) and tested 15 target genes aiming to identify abovementioned sample types. Our data showed that preselected endogenous controls (miR26b, miR92 and miR484) and miR144, initially selected as potential marker for the detection of menstrual blood, were the most stable expressed genes among our set of samples. Normalizing qPCR data with these four validated references revealed that only five miRNA markers are necessary to differentiate between the six different cell types selected in this study. Nevertheless, our observations in the present study indicate that miRNA analysis methods may not provide straightforward data interpretation strategies required for an implementation in forensic casework. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Targeting Adipose Tissue Lipid Metabolism to Improve Glucose Metabolism in Cardiometabolic Disease

    Directory of Open Access Journals (Sweden)

    Johan W.E. Jocken

    2014-10-01

    Full Text Available With Type 2 diabetes mellitus and cardiovascular disease prevalence on the rise, there is a growing need for improved strategies to prevent or treat obesity and insulin resistance, both of which are major risk factors for these chronic diseases. Impairments in adipose tissue lipid metabolism seem to play a critical role in these disorders. In the classical picture of intracellular lipid breakdown, cytosolic lipolysis was proposed as the sole mechanism for triacylglycerol hydrolysis in adipocytes. Recent evidence suggests involvement of several hormones, membrane receptors, and intracellular signalling cascades, which has added complexity to the regulation of cytosolic lipolysis. Interestingly, a specific form of autophagy, called lipophagy, has been implicated as alternative lipolytic pathway. Defective regulation of cytosolic lipolysis and lipophagy might have substantial effects on lipid metabolism, thereby contributing to adipose tissue dysfunction, insulin resistance, and related cardiometabolic (cMet diseases. This review will discuss recent advances in our understanding of classical lipolysis and lipophagy in adipocyte lipid metabolism under normal and pathological conditions. Furthermore, the question of whether modulation of adipocyte lipolysis and lipophagy might be a potential therapeutic target to combat cMet disorders will be addressed.

  19. Modelling PET radionuclide production in tissue and external targets using Geant4

    Science.gov (United States)

    Amin, T.; Infantino, A.; Lindsay, C.; Barlow, R.; Hoehr, C.

    2017-07-01

    The Proton Therapy Facility in TRIUMF provides 74 MeV protons extracted from a 500 MeV H- cyclotron for ocular melanoma treatments. During treatment, positron emitting radionuclides such as 1C, 15O and 13N are produced in patient tissue. Using PET scanners, the isotopic activity distribution can be measured for in-vivo range verification. A second cyclotron, the TR13, provides 13 MeV protons onto liquid targets for the production of PET radionuclides such as 18F, 13N or 68Ga, for medical applications. The aim of this work was to validate Geant4 against FLUKA and experimental measurements for production of the above-mentioned isotopes using the two cyclotrons. The results show variable degrees of agreement. For proton therapy, the proton-range agreement was within 2 mm for 11C activity, whereas 13N disagreed. For liquid targets at the TR13 the average absolute deviation ratio between FLUKA and experiment was 1.9±2.7, whereas the average absolute deviation ratio between Geant4 and experiment was 0. 6±0.4. This is due to the uncertainties present in experimentally determined reaction cross sections.

  20. Quantifying the Tendency of Therapeutic Target Proteins to Bind Promiscuous or Selective Compounds

    Science.gov (United States)

    Hu, Ye; Bajorath, Jürgen

    2015-01-01

    The ability of target proteins to bind structurally diverse compounds and compounds with different degrees of promiscuity (multi-target activity) was systematically assessed on the basis of currently available activity data and target annotations. Intuitive first- and second-order target promiscuity indices were introduced to quantify these binding characteristics and relate them to each other. For compounds and targets, opposite promiscuity trends were observed. Furthermore, the analysis detected many targets that interacted with compounds representing a similar degree of structural diversity but displayed strong tendencies to recognize either promiscuous or selective compounds. Moreover, target families were identified that preferentially interacted with promiscuous compounds. Taken together, these findings further extend our understanding of the molecular basis of polypharmacology. PMID:26000736

  1. Prior Knowledge of Target Direction and Intended Movement Selection Improves Indirect Reaching Movement Decoding.

    Science.gov (United States)

    Li, Hongbao; Hao, Yaoyao; Zhang, Shaomin; Wang, Yiwen; Chen, Weidong; Zheng, Xiaoxiang

    2017-01-01

    Objective. Previous studies have demonstrated that target direction information presented by the dorsal premotor cortex (PMd) during movement planning could be incorporated into neural decoder for achieving better decoding performance. It is still unknown whether the neural decoder combined with only target direction could work in more complex tasks where obstacles impeded direct reaching paths. Methods. In this study, spike activities were collected from the PMd of two monkeys when performing a delayed obstacle-avoidance task. We examined how target direction and intended movement selection were encoded in neuron population activities of the PMd during movement planning. The decoding performances of movement trajectory were compared for three neural decoders with no prior knowledge, or only target direction, or both target direction and intended movement selection integrated into a mixture of trajectory model (MTM). Results. We found that not only target direction but also intended movement selection was presented in neural activities of the PMd during movement planning. It was further confirmed by quantitative analysis. Combined with prior knowledge, the trajectory decoder achieved the best performance among three decoders. Conclusion. Recruiting prior knowledge about target direction and intended movement selection extracted from the PMd could enhance the decoding performance of hand trajectory in indirect reaching movement.

  2. Targeted delivery using peptide-functionalised gold nanoparticles to white adipose tissues of obese rats

    International Nuclear Information System (INIS)

    Thovhogi, Ntevheleni; Sibuyi, Nicole; Meyer, Mervin; Onani, Martin; Madiehe, Abram

    2015-01-01

    Obesity is a complex metabolic disease of excessive fat accumulation. It is a worldwide epidemic affecting billions of people. Current pharmacological treatment of obesity remains limited and ineffective due to systemic drug toxicity and undesirable side effects. The current epidemic raises a serious need for development of safer drugs to treat obesity. Nanotechnology-based drug delivery system for administering pharmaceutical compound to achieve therapeutic effects is currently an exciting field in cancer treatment. Drug delivery involves either modification of drug release profile, absorption, distribution and/or elimination, for the benefit of improving drug efficacy and safety. Therefore, nanotechnology holds promise in the treatment of diseases including obesity. Gold nanoparticles (GNPs) functionalised with different biomolecules have been successfully used as drug delivery, labelling and imaging tools in biomedical research. In this study, the binding-specificity and targeting ability of adipose homing peptide (AHP)-functionalised GNPs (AHP-GNPs) were evaluated using flow cytometry and inductively coupled plasma-optical emission spectroscopy. Caco-2 cells and rats fed either chow or a high-fat diet were treated with either unfunctionalised GNPs or AHP-GNPs. Cellular uptake of GNPs was detected in cells treated with AHP-GNPs and not those treated with GNPs alone. Binding of AHP to cells was both temperature- and concentration-dependent. Compared to rats treated with GNPs alone, treatment of obese rats with AHP-GNPs resulted in the targeted delivery of the GNPs to the white adipose tissue (WAT). This paper reports the successful targeting of AHP-functionalised GNPs to WAT of obese rats

  3. Targeted delivery using peptide-functionalised gold nanoparticles to white adipose tissues of obese rats

    Energy Technology Data Exchange (ETDEWEB)

    Thovhogi, Ntevheleni; Sibuyi, Nicole [Medical Research Council, Diabetes Research Group (South Africa); Meyer, Mervin [University of the Western Cape, Biotechnology Department, DST/Mintek Nanotechnology Innovation Centre (South Africa); Onani, Martin [University of the Western Cape, Chemistry Department (South Africa); Madiehe, Abram, E-mail: amadiehe@csir.co.za [Medical Research Council, Diabetes Research Group (South Africa)

    2015-02-15

    Obesity is a complex metabolic disease of excessive fat accumulation. It is a worldwide epidemic affecting billions of people. Current pharmacological treatment of obesity remains limited and ineffective due to systemic drug toxicity and undesirable side effects. The current epidemic raises a serious need for development of safer drugs to treat obesity. Nanotechnology-based drug delivery system for administering pharmaceutical compound to achieve therapeutic effects is currently an exciting field in cancer treatment. Drug delivery involves either modification of drug release profile, absorption, distribution and/or elimination, for the benefit of improving drug efficacy and safety. Therefore, nanotechnology holds promise in the treatment of diseases including obesity. Gold nanoparticles (GNPs) functionalised with different biomolecules have been successfully used as drug delivery, labelling and imaging tools in biomedical research. In this study, the binding-specificity and targeting ability of adipose homing peptide (AHP)-functionalised GNPs (AHP-GNPs) were evaluated using flow cytometry and inductively coupled plasma-optical emission spectroscopy. Caco-2 cells and rats fed either chow or a high-fat diet were treated with either unfunctionalised GNPs or AHP-GNPs. Cellular uptake of GNPs was detected in cells treated with AHP-GNPs and not those treated with GNPs alone. Binding of AHP to cells was both temperature- and concentration-dependent. Compared to rats treated with GNPs alone, treatment of obese rats with AHP-GNPs resulted in the targeted delivery of the GNPs to the white adipose tissue (WAT). This paper reports the successful targeting of AHP-functionalised GNPs to WAT of obese rats.

  4. Targeted delivery using peptide-functionalised gold nanoparticles to white adipose tissues of obese rats

    Science.gov (United States)

    Thovhogi, Ntevheleni; Sibuyi, Nicole; Meyer, Mervin; Onani, Martin; Madiehe, Abram

    2015-02-01

    Obesity is a complex metabolic disease of excessive fat accumulation. It is a worldwide epidemic affecting billions of people. Current pharmacological treatment of obesity remains limited and ineffective due to systemic drug toxicity and undesirable side effects. The current epidemic raises a serious need for development of safer drugs to treat obesity. Nanotechnology-based drug delivery system for administering pharmaceutical compound to achieve therapeutic effects is currently an exciting field in cancer treatment. Drug delivery involves either modification of drug release profile, absorption, distribution and/or elimination, for the benefit of improving drug efficacy and safety. Therefore, nanotechnology holds promise in the treatment of diseases including obesity. Gold nanoparticles (GNPs) functionalised with different biomolecules have been successfully used as drug delivery, labelling and imaging tools in biomedical research. In this study, the binding-specificity and targeting ability of adipose homing peptide (AHP)-functionalised GNPs (AHP-GNPs) were evaluated using flow cytometry and inductively coupled plasma-optical emission spectroscopy. Caco-2 cells and rats fed either chow or a high-fat diet were treated with either unfunctionalised GNPs or AHP-GNPs. Cellular uptake of GNPs was detected in cells treated with AHP-GNPs and not those treated with GNPs alone. Binding of AHP to cells was both temperature- and concentration-dependent. Compared to rats treated with GNPs alone, treatment of obese rats with AHP-GNPs resulted in the targeted delivery of the GNPs to the white adipose tissue (WAT). This paper reports the successful targeting of AHP-functionalised GNPs to WAT of obese rats.

  5. Directional enhancement of selected high-order-harmonics from intense laser irradiated blazed grating targets.

    Science.gov (United States)

    Zhang, Guobo; Chen, Min; Liu, Feng; Yuan, Xiaohui; Weng, Suming; Zheng, Jun; Ma, Yanyun; Shao, Fuqiu; Sheng, Zhengming; Zhang, Jie

    2017-10-02

    Relativistically intense laser solid target interaction has been proved to be a promising way to generate high-order harmonics, which can be used to diagnose ultrafast phenomena. However, their emission direction and spectra still lack tunability. Based upon two-dimensional particle-in-cell simulations, we show that directional enhancement of selected high-order-harmonics can be realized using blazed grating targets. Such targets can select harmonics with frequencies being integer times of the grating frequency. Meanwhile, the radiation intensity and emission area of the harmonics are increased. The emission direction is controlled by tailoring the local blazed structure. Theoretical and electron dynamics analysis for harmonics generation, selection and directional enhancement from the interaction between multi-cycle laser and grating target are carried out. These studies will benefit the generation and application of laser plasma-based high order harmonics.

  6. Detecting signatures of balancing selection to identify targets of anti-parasite immunity.

    Science.gov (United States)

    Weedall, Gareth D; Conway, David J

    2010-07-01

    Parasite antigen genes might evolve under frequency-dependent immune selection. The distinctive patterns of polymorphism that result can be detected using population genetic methods that test for signatures of balancing selection, allowing genes encoding important targets of immunity to be identified. Analyses can be complicated by population structures, histories and features of a parasite's genome. However, new sequencing technologies facilitate scans of polymorphism throughout parasite genomes to identify the most exceptional gene specific signatures. We focus on malaria parasites to illustrate challenges and opportunities for detecting targets of frequency-dependent immune selection to discover new potential vaccine candidates. Copyright 2010 Elsevier Ltd. All rights reserved.

  7. Pro and cons of targeted selective treatment against digestive-tract strongyles of ruminants

    Directory of Open Access Journals (Sweden)

    Cabaret J.

    2008-09-01

    Full Text Available The increasing prevalence of resistance to anthelmintics among gastrointestinal nematodes and the desire for lower input agriculture have promoted the idea that targeted selective treatment (treating the animals in need of such a treatment and only them could be a sustainable solution for controlling internal parasites of ruminants. The pros are the slowing of resistance prevalence, lower residues of anthelmintics in meat and milk, and lower cost; the cons are the difficulty and time spent on selecting animals in need of treatment and the possibility of lower production. Using actual experiments and modelling we show that targeted selective treatment can be used to sustainably control gastrointestinal nematode infections in flock.

  8. Efficacious and safe tissue-selective controlled gene therapy approaches for the cornea.

    Directory of Open Access Journals (Sweden)

    Rajiv R Mohan

    2011-04-01

    Full Text Available Untargeted and uncontrolled gene delivery is a major cause of gene therapy failure. This study aimed to define efficient and safe tissue-selective targeted gene therapy approaches for delivering genes into keratocytes of the cornea in vivo using a normal or diseased rabbit model. New Zealand White rabbits, adeno-associated virus serotype 5 (AAV5, and a minimally invasive hair-dryer based vector-delivery technique were used. Fifty microliters of AAV5 titer (6.5×10(12 vg/ml expressing green fluorescent protein gene (GFP was topically applied onto normal or diseased (fibrotic or neovascularized rabbit corneas for 2-minutes with a custom vector-delivery technique. Corneal fibrosis and neovascularization in rabbit eyes were induced with photorefractive keratectomy using excimer laser and VEGF (630 ng using micropocket assay, respectively. Slit-lamp biomicroscopy and immunocytochemistry were used to confirm fibrosis and neovascularization in rabbit corneas. The levels, location and duration of delivered-GFP gene expression in the rabbit stroma were measured with immunocytochemistry and/or western blotting. Slot-blot measured delivered-GFP gene copy number. Confocal microscopy performed in whole-mounts of cornea and thick corneal sections determined geometric and spatial localization of delivered-GFP in three-dimensional arrangement. AAV5 toxicity and safety were evaluated with clinical eye exam, stereomicroscopy, slit-lamp biomicroscopy, and H&E staining. A single 2-minute AAV5 topical application via custom delivery-technique efficiently and selectively transduced keratocytes in the anterior stroma of normal and diseased rabbit corneas as evident from immunocytochemistry and confocal microscopy. Transgene expression was first detected at day 3, peaked at day 7, and was maintained up to 16 weeks (longest tested time point. Clinical and slit-lamp eye examination in live rabbits and H&E staining did not reveal any significant changes between AAV5

  9. A porous tissue engineering scaffold selectively degraded by cell-generated reactive oxygen species.

    Science.gov (United States)

    Martin, John R; Gupta, Mukesh K; Page, Jonathan M; Yu, Fang; Davidson, Jeffrey M; Guelcher, Scott A; Duvall, Craig L

    2014-04-01

    Biodegradable tissue engineering scaffolds are commonly fabricated from poly(lactide-co-glycolide) (PLGA) or similar polyesters that degrade by hydrolysis. PLGA hydrolysis generates acidic breakdown products that trigger an accelerated, autocatalytic degradation mechanism that can create mismatched rates of biomaterial breakdown and tissue formation. Reactive oxygen species (ROS) are key mediators of cell function in both health and disease, especially at sites of inflammation and tissue healing, and induction of inflammation and ROS are natural components of the in vivo response to biomaterial implantation. Thus, polymeric biomaterials that are selectively degraded by cell-generated ROS may have potential for creating tissue engineering scaffolds with better matched rates of tissue in-growth and cell-mediated scaffold biodegradation. To explore this approach, a series of poly(thioketal) (PTK) urethane (PTK-UR) biomaterial scaffolds were synthesized that degrade specifically by an ROS-dependent mechanism. PTK-UR scaffolds had significantly higher compressive moduli than analogous poly(ester urethane) (PEUR) scaffolds formed from hydrolytically-degradable ester-based diols (p PEUR scaffolds, the PTK-UR scaffolds were stable under aqueous conditions out to 25 weeks but were selectively degraded by ROS, indicating that their biodegradation would be exclusively cell-mediated. The in vitro oxidative degradation rates of the PTK-URs followed first-order degradation kinetics, were significantly dependent on PTK composition (p PEUR scaffolds. These combined results indicate that ROS-degradable PTK-UR tissue engineering scaffolds have significant advantages over analogous polyester-based biomaterials and provide a robust, cell-degradable substrate for guiding new tissue formation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Abnormal Base Excision Repair at Trinucleotide Repeats Associated with Diseases: A Tissue-Selective Mechanism

    Directory of Open Access Journals (Sweden)

    Agathi-Vasiliki Goula

    2013-07-01

    Full Text Available More than fifteen genetic diseases, including Huntington’s disease, myotonic dystrophy 1, fragile X syndrome and Friedreich ataxia, are caused by the aberrant expansion of a trinucleotide repeat. The mutation is unstable and further expands in specific cells or tissues with time, which can accelerate disease progression. DNA damage and base excision repair (BER are involved in repeat instability and might contribute to the tissue selectivity of the process. In this review, we will discuss the mechanisms of trinucleotide repeat instability, focusing more specifically on the role of BER.

  11. Molecular Connectivity Predefines Polypharmacology: Aliphatic Rings, Chirality, and sp3 Centers Enhance Target Selectivity

    Directory of Open Access Journals (Sweden)

    Stefania Monteleone

    2017-08-01

    Full Text Available Dark chemical matter compounds are small molecules that have been recently identified as highly potent and selective hits. For this reason, they constitute a promising class of possible candidates in the process of drug discovery and raise the interest of the scientific community. To this purpose, Wassermann et al. (2015 have described the application of 2D descriptors to characterize dark chemical matter. However, their definition was based on the number of reported positive assays rather than the number of known targets. As there might be multiple assays for one single target, the number of assays does not fully describe target selectivity. Here, we propose an alternative classification of active molecules that is based on the number of known targets. We cluster molecules in four classes: black, gray, and white compounds are active on one, two to four, and more than four targets respectively, whilst inactive compounds are found to be inactive in the considered assays. In this study, black and inactive compounds are found to have not only higher solubility, but also a higher number of chiral centers, sp3 carbon atoms and aliphatic rings. On the contrary, white compounds contain a higher number of double bonds and fused aromatic rings. Therefore, the design of a screening compound library should consider these molecular properties in order to achieve target selectivity or polypharmacology. Furthermore, analysis of four main target classes (GPCRs, kinases, proteases, and ion channels shows that GPCR ligands are more selective than the other classes, as the number of black compounds is higher in this target superfamily. On the other side, ligands that hit kinases, proteases, and ion channels bind to GPCRs more likely than to other target classes. Consequently, depending on the target protein family, appropriate screening libraries can be designed in order to minimize the likelihood of unwanted side effects early in the drug discovery process

  12. Determination of target detection limits in hyperspectral data using band selection and dimensionality reduction

    Science.gov (United States)

    Gross, W.; Boehler, J.; Twizer, K.; Kedem, B.; Lenz, A.; Kneubuehler, M.; Wellig, P.; Oechslin, R.; Schilling, H.; Rotman, S.; Middelmann, W.

    2016-10-01

    Hyperspectral remote sensing data can be used for civil and military applications to robustly detect and classify target objects. High spectral resolution of hyperspectral data can compensate for the comparatively low spatial resolution, which allows for detection and classification of small targets, even below image resolution. Hyperspectral data sets are prone to considerable spectral redundancy, affecting and limiting data processing and algorithm performance. As a consequence, data reduction strategies become increasingly important, especially in view of near-real-time data analysis. The goal of this paper is to analyze different strategies for hyperspectral band selection algorithms and their effect on subpixel classification for different target and background materials. Airborne hyperspectral data is used in combination with linear target simulation procedures to create a representative amount of target-to-background ratios for evaluation of detection limits. Data from two different airborne hyperspectral sensors, AISA Eagle and Hawk, are used to evaluate transferability of band selection when using different sensors. The same target objects were recorded to compare the calculated detection limits. To determine subpixel classification results, pure pixels from the target materials are extracted and used to simulate mixed pixels with selected background materials. Target signatures are linearly combined with different background materials in varying ratios. The commonly used classification algorithms Adaptive Coherence Estimator (ACE) is used to compare the detection limit for the original data with several band selection and data reduction strategies. The evaluation of the classification results is done by assuming a fixed false alarm ratio and calculating the mean target-to-background ratio of correctly detected pixels. The results allow drawing conclusions about specific band combinations for certain target and background combinations. Additionally

  13. A method for mapping tissue volume model onto target volume using volumetric self-organizing deformable model

    Science.gov (United States)

    Miyauchi, Shoko; Morooka, Ken'ichi; Tsuji, Tokuo; Miyagi, Yasushi; Fukuda, Takaichi; Kurazume, Ryo

    2016-03-01

    This paper proposes a new method for mapping volume models of human tissues onto a target volume with simple shapes. The proposed method is based on our modified self-organizing deformable model (mSDM)1, 2 which finds the one-to-one mapping with no foldovers between arbitrary surface model and a target surface. By extending mSDM to apply to volume models, the proposed method, called volumetric SDM (vSDM), establishes the one-to-one correspondence between the tissue volume model and its target volume. At the same time, vSDM can preserve geometrical properties of the original model before and after mapping. This characteristic of vSDM makes it easy to find the correspondence between tissue models.

  14. Improved axenic hydroponic whole plant propagation for rapid production of roots as transformation target tissue.

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    Benzle, Kyle; Cornish, Katrina

    2017-01-01

    Plant roots are used as an efficient target tissue for plant transformation assays. In root propagable species transformed roots are able to regenerate into whole plants without the addition of exogenous hormones, thus avoiding somaclonal variation associated with many plant transformation protocols. Plants grown in soil or soilless solid medium have roots that tend to be extremely delicate and are difficult to sterilize in advance of plant transformation experiments. Axenic tissue culture plants grown on semi-solid media are slow to produce large amounts of biomass compared to plants grown in solution-based media. Seeds were germinated and grown for 14 days on half-strength semi-solid Murashige and Skoog medium containing 1% sucrose. Seedlings were then transferred to Magenta™ GA7 vessels containing either liquid or semi-solid ½ MS medium with 0.25, 0.5, 1, 2 or 3% sucrose. In the hydroponics (liquid medium) treatments, expanded clay balls were used to anchor seedlings. Hydroponic vessels were fitted with a sterile air aeration hose and filled ¾ full (100 mL) with liquid ½ MS media. Liquid media were replaced after 7 days. All plants were grown under fluorescent lights for 14 days. We have developed an improved axenic hydroponic propagation system for producing large quantities of plant roots for use in transformation assays using Taraxacum kok - saghyz as a model for root propagable species. Plants grew significantly faster in liquid media than on solid media. Addition of sucrose from 0.25 to 2% was correlated with an increase in biomass accumulation in plants grown in liquid media. Our improved axenic hydroponic method yields sufficient quantities of roots for extensive plant transformation/molecular studies.

  15. Endothelial and Perivascular Adipose Tissue Abnormalities in Obesity-Related Vascular Dysfunction: Novel Targets for Treatment.

    Science.gov (United States)

    Schinzari, Francesca; Tesauro, Manfredi; Cardillo, Carmine

    2017-06-01

    The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. In addition to its well-established role in maintaining vascular homeostasis, the endothelium has been increasingly recognized as a key player in modulating healthy adipose tissue expansion in response to excess calories by providing adipocyte precursors and driving angiogenesis. When this increased storage need is unmet, excessive deposition of fat occurs at ectopic locations, including perivascular adipose tissue (PVAT). PVAT is in intimate contact with the vessel wall, hence affecting vascular function and structure. In lean individuals, PVAT exerts anticontractile and anti-inflammatory activities to protect the vasculature. In obesity, instead, these beneficial properties are lost and PVAT releases inflammatory mediators, promotes oxidative stress, and contributes to vascular dysfunction. The underlying mechanisms elicited by these outside-in signals include resistance to the vasodilator actions of insulin and activation of endothelin (ET)-1-mediated vasoconstriction. A number of adipokines and gut hormones, which are important modulators of food intake, energy balance, glucose and lipid metabolism, insulin sensitivity, and inflammation, have also positive vascular actions. This feature makes them promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant benefits. There is, therefore, real hope that unleashing the power of fat- and gut-derived substances might provide effective dual-action therapies for obesity and its complications.

  16. Ubiquitin fusion expression and tissue-dependent targeting of hG-CSF in transgenic tobacco

    Science.gov (United States)

    2011-01-01

    Background Human granulocyte colony-stimulating factor (hG-CSF) is an important human cytokine which has been widely used in oncology and infection protection. To satisfy clinical needs, expression of recombinant hG-CSF has been studied in several organisms, including rice cell suspension culture and transient expression in tobacco leaves, but there was no published report on its expression in stably transformed plants which can serve as a more economical expression platform with potential industrial application. Results In this study, hG-CSF expression was investigated in transgenic tobacco leaves and seeds in which the accumulation of hG-CSF could be enhanced through fusion with ubiquitin by up to 7 fold in leaves and 2 fold in seeds, leading to an accumulation level of 2.5 mg/g total soluble protein (TSP) in leaves and 1.3 mg/g TSP in seeds, relative to hG-CSF expressed without a fusion partner. Immunoblot analysis showed that ubiquitin was processed from the final protein product, and ubiquitination was up-regulated in all transgenic plants analyzed. Driven by CaMV 35S promoter and phaseolin signal peptide, hG-CSF was observed to be secreted into apoplast in leaves but deposited in protein storage vacuole (PSV) in seeds, indicating that targeting of the hG-CSF was tissue-dependent in transgenic tobacco. Bioactivity assay showed that hG-CSF expressed in both seeds and leaves was bioactive to support the proliferation of NFS-60 cells. Conclusions In this study, the expression of bioactive hG-CSF in transgenic plants was improved through ubiquitin fusion strategy, demonstrating that protein expression can be enhanced in both plant leaves and seeds through fusion with ubiquitin and providing a typical case of tissue-dependent expression of recombinant protein in transgenic plants. PMID:21985646

  17. Preparation of thermosensitive magnetic liposome encapsulated recombinant tissue plasminogen activator for targeted thrombolysis

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Hao-Lung [Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan, ROC (China); Chen, Jyh-Ping, E-mail: jpchen@mail.cgu.edu.tw [Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan, ROC (China); Department of Plastic and Reconstructive Surgery and Craniofacial Research Center, Chang Gung Memorial Hospital, Kwei-San, Taoyuan 33305, Taiwan, ROC (China); Graduate Institute of Health Industry and Technology, Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kwei-San, Taoyuan 33302, Taiwan, ROC (China); Department of Materials Engineering, Ming Chi University of Technology, Tai-Shan, New Taipei City 24301, Taiwan, ROC (China)

    2017-04-01

    Recombinant tissue plasminogen activator (rtPA) was encapsulated in thermosensitive magnetic liposome (TML) prepared from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, distearolyphosphatidyl ethanolamine-N-poly(ethylene glycol) 2000, cholesterol and Fe{sub 3}O{sub 4} magnetic nanoparticles by solvent evaporation/sonication and freeze-thaw cycles method. Response surface methodology was proved to be a powerful tool to predict the drug encapsulation efficiency and temperature-sensitive drug release. Validation experiments verified the accuracy of the model that provides a simple and effective method for fabricating TML with controllable encapsulation efficiency and predictable temperature-sensitive drug release behavior. The prepared samples were characterized for physico-chemical properties by dynamic light scattering, transmission electron microscopy, X-ray diffraction and differential scanning calorimetry. Temperature-sensitive release of rtPA could be confirmed from in vitro thrombolysis experiments. A thrombolytic drug delivery system using TML could be proposed for magnetic targeted delivery of rtPA to the site of thrombus followed by temperature-triggered controlled drug release in an alternating magnetic field. - Highlights: • rtPA and Fe{sub 3}O{sub 4} MNP were encapsulated in thermosensitive magnetic liposome (TML). • RSM could predict the drug encapsulation efficiency and temperature-sensitive drug release from TML. • Temperature-sensitive release of rtPA was confirmed from in vitro thrombolysis experiments. • TML-rtPA will be useful as a magnetic targeted nanodrug to improve clinical thrombolytic therapy.

  18. Small interference RNA targeting tissue factor inhibits human lung adenocarcinoma growth in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Wang Jianing

    2011-05-01

    Full Text Available Abstract Background The human coagulation trigger tissue factor (TF is overexpressed in several types of cancer and involved in tumor growth, vascularization, and metastasis. To explore the role of TF in biological processes of lung adenocarcinoma, we used RNA interference (RNAi technology to silence TF in a lung adenocarcinoma cell line A549 with high-level expression of TF and evaluate its antitumor effects in vitro and in vivo. Methods The specific small interfering RNA (siRNA designed for targeting human TF was transfected into A549 cells. The expression of TF was detected by reverse transcription-PCR and Western blot. Cell proliferation was measured by MTT and clonogenic assays. Cell apoptosis was assessed by flow cytometry. The metastatic potential of A549 cells was determined by wound healing, the mobility and Matrigel invasion assays. Expressions of PI3K/Akt, Erk1/2, VEGF and MMP-2/-9 in transfected cells were detected by Western blot. In vivo, the effect of TF-siRNA on the growth of A549 lung adenocarcinoma xenografts in nude mice was investigated. Results TF -siRNA significantly reduced the expression of TF in the mRNA and protein levels. The down-regulation of TF in A549 cells resulted in the suppression of cell proliferation, invasion and metastasis and induced cell apoptosis in dose-dependent manner. Erk MAPK, PI3K/Akt pathways as well as VEGF and MMP-2/-9 expressions were inhibited in TF-siRNA transfected cells. Moreover, intratumoral injection of siRNA targeting TF suppressed the tumor growth of A549 cells in vivo model of lung adenocarcinoma. Conclusions Down-regulation of TF using siRNA could provide a potential approach for gene therapy against lung adenocarcinoma, and the antitumor effects may be associated with inhibition of Erk MAPK, PI3K/Akt pathways.

  19. Autotransplant tissue selection criteria with or without stereomicroscopy in parathyroidectomy for treatment of renal hyperparathyroidism

    Directory of Open Access Journals (Sweden)

    Monique Nakayama Ohe

    2014-07-01

    Full Text Available INTRODUCTION: Several methods have been proposed to improve operative success in renal hyperparathyroidism. OBJECTIVE: To evaluate stereomicroscopy in parathyroid tissue selection for total parathyroidectomy with autotransplantation in secondary (SHPT/tertiary (THPT hyperparathyroidism. METHODS: 118 renal patients underwent surgery from April of 2000 to October 2009. They were divided into two groups: G1, 66 patients operated from April of 2000 to May of 2005, with tissue selection based on macroscopic observation; G2, 52 patients operated from March of 2008 to October 2009 with stereomicroscopy for tissue selection searching for the presence of adipose cells. All surgeries were performed by the same surgeon. Patients presented SHPT (dialysis treatment or THPT (renal-grafted. Follow-up was 12-36 months. Intra-operative parathyroid hormone (PTH was measured in 100/118 (84.7% patients. RESULTS: Data are presented as means. G1 included 66 patients (38 SHPT, 24 females/14 males; 40.0 years of age; 28 THPT, 14 females/14 males; 44 years of age. G2 included 52 patients (29 SHPT, 11 females/18 males; 50.7 years of age; 23 THPT, 13 females/10 males, 44.4 years of age. SHPT patients from G2 presented preoperative serum calcium higher than those of SHPT patients in G1 (p < 0.05, suggesting a more severe disease. Definitive hypoparathyroidism was found in seven of 118 patients (5.9%. Graft-dependent recurrence occurred in four patients, two in each group. All occurred in dialysis patients. CONCLUSION: Stereomicroscopy in SHPT/THPT surgical treatment may be a useful tool to standardize parathyroid tissue selection.

  20. Occurrence Prospect of HDR and Target Site Selection Study in Southeastern of China

    Science.gov (United States)

    Lin, W.; Gan, H.

    2017-12-01

    Hot dry rock (HDR) geothermal resource is one of the most important clean energy in future. Site selection a HDR resource is a fundamental work to explore the HDR resources. This paper compiled all the HDR development projects domestic and abroad, and summarized the location of HDR geothermal geological index. After comparing the geological background of HDR in the southeast coastal area of China, Yangjiang Xinzhou in Guangdong province, Leizhou Peninsula area, Lingshui in Hainan province and Huangshadong in Guangzhou were selected from some key potential target area along the southeast coast of China. Deep geothermal field model of the study area is established based on the comprehensive analysis of the target area of deep geothermal geological background and deep thermal anomalies. This paper also compared the hot dry rock resources target locations, and proposed suggestions for the priority exploration target area and exploration scheme.

  1. Stress-Related and Circadian Secretion and Target Tissue Actions of Glucocorticoids: Impact on Health

    Directory of Open Access Journals (Sweden)

    Nicolas C. Nicolaides

    2017-04-01

    Full Text Available Living organisms are highly complex systems that must maintain a dynamic equilibrium or homeostasis that requires energy to be sustained. Stress is a state in which several extrinsic or intrinsic disturbing stimuli, the stressors, threaten, or are perceived as threatening, homeostasis. To achieve homeostasis against the stressors, organisms have developed a highly sophisticated system, the stress system, which provides neuroendocrine adaptive responses, to restore homeostasis. These responses must be appropriate in terms of size and/or duration; otherwise, they may sustain life but be associated with detrimental effects on numerous physiologic functions of the organism, leading to a state of disease-causing disturbed homeostasis or cacostasis. In addition to facing a broad spectrum of external and/or internal stressors, organisms are subject to recurring environmental changes associated with the rotation of the planet around itself and its revolution around the sun. To adjust their homeostasis and to synchronize their activities to day/night cycles, organisms have developed an evolutionarily conserved biologic system, the “clock” system, which influences several physiologic functions in a circadian fashion. Accumulating evidence suggests that the stress system is intimately related to the circadian clock system, with dysfunction of the former resulting in dysregulation of the latter and vice versa. In this review, we describe the functional components of the two systems, we discuss their multilevel interactions, and we present how excessive or prolonged activity of the stress system affects the circadian rhythm of glucocorticoid secretion and target tissue effects.

  2. The potentials of human adipose tissue derived mesenchymal stem cells in targeted therapy of experimental glioma

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    FAN Cun-gang

    2012-12-01

    Full Text Available Glioblastoma is the most common primary malignant brain tumor in adults. With current standard therapy which includes extensive microsurgical resection along with concurrent chemoradiotherapy and adjuvant temozolomide (TMZ, the median survival of glioblastoma patients is only 14.60 months nowadays. Recent studies demonstrated that human adipose tissue derived mesenchymal stem cells (hAT-MSCs possessed the glioma-trophic migratory capacity. The engineered hAT-MSCs expressing herpes simplex virus-thymidine kinase (HSV-tk, yeast cytosine deaminase::uracil phosphoribosyltransferase (CDy:: UPRT, and rabbit carboxylesterase (rCE could exert inhibitory effects on glioma when combined with prodrugs, such as ganciclovir (GCV, 5-fluorocytosine (5-FC and irinotecan (CPT-11, respectively. hAT-MSCs carrying the oncolytic virus or expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL also could inhibit the growth of glioma. This paper summarizes the recent progress in this field to pave the way for hAT-MSCs based targeted therapy of glioma in future.

  3. Human brown adipose tissue as a target for obesity management; beyond cold-induced thermogenesis.

    Science.gov (United States)

    Loh, R K C; Kingwell, B A; Carey, A L

    2017-11-01

    Elevating energy expenditure via adaptive thermogenesis in brown adipose tissue (BAT) is a potential strategy to reverse obesity. Much early enthusiasm for this approach, based on rodent studies, was tempered by the belief that BAT was relatively inconsequential in healthy adult humans. Interest was reinvigorated a decade ago when a series of studies re-identified BAT, primarily in upper thoracic regions, in adults. Despite the ensuing explosion of pre-clinical investigations and identification of an extensive list of potential target molecules for BAT recruitment, our understanding of human BAT physiology remains limited, particularly regarding interventions which might hold therapeutic promise. Cold-induced BAT thermogenesis (CIT) has been well studied, although is not readily translatable as an anti-obesity approach, whereas little is known regarding the role of BAT in human diet-induced thermogenesis (DIT). Furthermore, human studies dedicated to translating known pharmacological mechanisms of adipose browning from animal models are sparse. Several lines of recent evidence suggest that molecular regulation and physiology of human BAT differ to that of laboratory rodents, which form the majority of our knowledge base. This review will summarize knowledge on CIT and expand upon the current understanding and evidence gaps related to human adaptive thermogenesis via mechanisms other than cold. © 2017 World Obesity Federation.

  4. Contextual control over selective attention: evidence from a two-target method.

    Science.gov (United States)

    MacLellan, Ellen; Shore, David I; Milliken, Bruce

    2015-07-01

    Selective attention is generally studied with conflict tasks, using response time as the dependent measure. Here, we study the impact of selective attention to a first target, T1, presented simultaneously with a distractor, on the accuracy of subsequent encoding of a second target item, T2. This procedure produces an "attentional blink" (AB) effect much like that reported in other studies, and allowed us to study the influence of context on cognitive control with a novel method. In particular, we examined whether preparation to attend selectively to T1 had an impact on the selective encoding of T1 that would translate to report of T2. Preparation to attend selectively was manipulated by varying whether difficult selective attention T1 trials were presented in the context of other difficult selective attention T1 trials. The results revealed strong context effects of this nature, with smaller AB effects when difficult selective attention T1 trials were embedded in a context with many, rather than few, other difficult selective attention T1 trials. Further, the results suggest that both the trial-to-trial local context and the block-wide global context modulate performance in this task.

  5. Social exclusion impairs distractor suppression but not target enhancement in selective attention.

    Science.gov (United States)

    Xu, Mengsi; Li, Zhiai; Diao, Liuting; Fan, Lingxia; Zhang, Lijie; Yuan, Shuge; Yang, Dong

    2017-11-01

    Social exclusion has been thought to weaken one's ability to exert inhibitory control. Existing studies have primarily focused on the relationship between exclusion and behavioral inhibition, and have reported that exclusion impairs behavioral inhibition. However, whether exclusion also affects selective attention, another important aspect of inhibitory control, remains unknown. Therefore, the current study aimed to explore whether social exclusion impairs selective attention, and to specifically examine its effect on two hypothesized mechanisms of selective attention: target enhancement and distractor suppression. The Cyberball game was used to manipulate social exclusion. Participants then performed a visual search task while event-related potentials were recorded. In the visual search task, target and salient distractor were either both presented laterally or one was presented on the vertical midline and the other laterally. Results showed that social exclusion differentially affected target and distractor processing. While exclusion impaired distractor suppression, reflected as smaller distractor-positivity (Pd) amplitudes for the exclusion group compared to the inclusion group, it did not affect target enhancement, reflected as similar target-negativity (Nt) amplitudes for both the exclusion and inclusion groups. Together, these results extend our understanding of the relationship between exclusion and inhibitory control, and suggest that social exclusion affects selective attention in a more complex manner than previously thought. Copyright © 2017. Published by Elsevier B.V.

  6. Testosterone differentially regulates targets of lipid and glucose metabolism in liver, muscle and adipose tissues of the testicular feminised mouse.

    Science.gov (United States)

    Kelly, Daniel M; Akhtar, Samia; Sellers, Donna J; Muraleedharan, Vakkat; Channer, Kevin S; Jones, T Hugh

    2016-11-01

    Testosterone deficiency is commonly associated with obesity, metabolic syndrome, type 2 diabetes and their clinical consequences-hepatic steatosis and atherosclerosis. The testicular feminised mouse (non-functional androgen receptor and low testosterone) develops fatty liver and aortic lipid streaks on a high-fat diet, whereas androgen-replete XY littermate controls do not. Testosterone treatment ameliorates these effects, although the underlying mechanisms remain unknown. We compared the influence of testosterone on the expression of regulatory targets of glucose, cholesterol and lipid metabolism in muscle, liver, abdominal subcutaneous and visceral adipose tissue. Testicular feminised mice displayed significantly reduced GLUT4 in muscle and glycolytic enzymes in muscle, liver and abdominal subcutaneous but not visceral adipose tissue. Lipoprotein lipase required for fatty acid uptake was only reduced in subcutaneous adipose tissue; enzymes of fatty acid synthesis were increased in liver and subcutaneous tissue. Stearoyl-CoA desaturase-1 that catalyses oleic acid synthesis and is associated with insulin resistance was increased in visceral adipose tissue and cholesterol efflux components (ABCA1, apoE) were decreased in subcutaneous and liver tissue. Master regulator nuclear receptors involved in metabolism-Liver X receptor expression was suppressed in all tissues except visceral adipose tissue, whereas PPARγ was lower in abdominal subcutaneous and visceral adipose tissue and PPARα only in abdominal subcutaneous. Testosterone treatment improved the expression (androgen receptor independent) of some targets but not all. These exploratory data suggest that androgen deficiency may reduce the buffering capability for glucose uptake and utilisation in abdominal subcutaneous and muscle and fatty acids in abdominal subcutaneous. This would lead to an overspill and uptake of excess glucose and triglycerides into visceral adipose tissue, liver and arterial walls.

  7. Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses.

    Science.gov (United States)

    Sironi, Manuela; Forni, Diego; Clerici, Mario; Cagliani, Rachele

    2016-09-01

    The Flavivirus genus comprises several human pathogens such as dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). Although ZIKV usually causes mild symptoms, growing evidence is linking it to congenital birth defects and to increased risk of Guillain-Barré syndrome. ZIKV encodes a polyprotein that is processed to produce three structural and seven nonstructural (NS) proteins. We investigated the evolution of the viral polyprotein in ZIKV and in related flaviviruses (DENV, Spondweni virus, and Kedougou virus). After accounting for saturation issues, alignment uncertainties, and recombination, we found evidence of episodic positive selection on the branch that separates DENV from the other flaviviruses. NS1 emerged as the major selection target, and selected sites were located in immune epitopes or in functionally important protein regions. Three of these sites are located in an NS1 region that interacts with structural proteins and is essential for virion biogenesis. Analysis of the more recent evolutionary history of ZIKV lineages indicated that positive selection acted on NS5 and NS4B, this latter representing the preferential target. All selected sites were located in the N-terminal portion of NS4B, which inhibits interferon response. One of the positively selected sites (26M/I/T/V) in ZIKV also represents a selection target in sylvatic DENV2 isolates, and a nearby residue evolves adaptively in JEV. Two additional positively selected sites are within a protein region that interacts with host (e.g. STING) and viral (i.e. NS1, NS4A) proteins. Notably, mutations in the NS4B region of other flaviviruses modulate neurovirulence and/or neuroinvasiveness. These results suggest that the positively selected sites we identified modulate viral replication and contribute to immune evasion. These sites should be prioritized in future experimental studies. However, analyses herein detected no selective events associated to the spread of the Asian

  8. Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses.

    Directory of Open Access Journals (Sweden)

    Manuela Sironi

    2016-09-01

    Full Text Available The Flavivirus genus comprises several human pathogens such as dengue virus (DENV, Japanese encephalitis virus (JEV, and Zika virus (ZIKV. Although ZIKV usually causes mild symptoms, growing evidence is linking it to congenital birth defects and to increased risk of Guillain-Barré syndrome. ZIKV encodes a polyprotein that is processed to produce three structural and seven nonstructural (NS proteins. We investigated the evolution of the viral polyprotein in ZIKV and in related flaviviruses (DENV, Spondweni virus, and Kedougou virus. After accounting for saturation issues, alignment uncertainties, and recombination, we found evidence of episodic positive selection on the branch that separates DENV from the other flaviviruses. NS1 emerged as the major selection target, and selected sites were located in immune epitopes or in functionally important protein regions. Three of these sites are located in an NS1 region that interacts with structural proteins and is essential for virion biogenesis. Analysis of the more recent evolutionary history of ZIKV lineages indicated that positive selection acted on NS5 and NS4B, this latter representing the preferential target. All selected sites were located in the N-terminal portion of NS4B, which inhibits interferon response. One of the positively selected sites (26M/I/T/V in ZIKV also represents a selection target in sylvatic DENV2 isolates, and a nearby residue evolves adaptively in JEV. Two additional positively selected sites are within a protein region that interacts with host (e.g. STING and viral (i.e. NS1, NS4A proteins. Notably, mutations in the NS4B region of other flaviviruses modulate neurovirulence and/or neuroinvasiveness. These results suggest that the positively selected sites we identified modulate viral replication and contribute to immune evasion. These sites should be prioritized in future experimental studies. However, analyses herein detected no selective events associated to the spread of

  9. Improved Selectivity From a Wavelength Addressable Device for Wireless Stimulation of Neural Tissue

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    Elif Ç. Seymour

    2014-02-01

    Full Text Available Electrical neural stimulation with micro electrodes is a promising technique for restoring lost functions in the central nervous system as a result of injury or disease. One of the problems related to current neural stimulators is the tissue response due to the connecting wires and the presence of a rigid electrode inside soft neural tissue. We have developed a novel, optically activated, microscale photovoltaic neurostimulator based on a custom layered compound semiconductor heterostructure that is both wireless and has a comparatively small volume. Optical activation provides a wireless means of energy transfer to the neurostimulator, eliminating wires and the associated complications. This neurostimulator was shown to evoke action potentials and a functional motor response in the rat spinal cord. In this work, we extend our design to include wavelength selectivity and thus allowing independent activation of devices. As a proof of concept, we fabricated two different microscale devices with different spectral responsivities in the near-infrared region. We assessed the improved addressability of individual devices via wavelength selectivity as compared to spatial selectivity alone through on-bench optical measurements of the devices in combination with an in vivo light intensity profile in the rat cortex obtained in a previous study. We show that wavelength selectivity improves the individual addressability of the floating stimulators, thus increasing the number of devices that can be implanted in close proximity to each other.

  10. Mechanism of the tissue-specific action of the selective androgen receptor modulator S-101479.

    Science.gov (United States)

    Furuya, Kazuyuki; Yamamoto, Noriko; Ohyabu, Yuki; Morikyu, Teruyuki; Ishige, Hirohide; Albers, Michael; Endo, Yasuhisa

    2013-01-01

    Selective androgen receptor modulators (SARMs) comprise a new class of molecules that induce anabolic effects with fewer side effects than those of other anabolic agents. We previously reported that the novel SARM S-101479 had a tissue-selective bone anabolic effect with diminished side effects in female animals. However, the mechanism of its tissue selectivity is not well known. In this report, we show that S-101479 increased alkaline phosphatase activity and androgen receptor (AR) transcriptional activity in osteoblastic cell lines in the same manner as the natural androgen ligand dihydrotestosterone (DHT); conversely, stimulation of AR dimerization was very low compared with that of DHT (34.4%). S-101479 increased bone mineral content in ovariectomized rats without promoting endometrial proliferation. Yeast two-hybrid interaction assays revealed that DHT promoted recruitment of numerous cofactors to AR such as TIF2, SRC1, β-catenin, NCoA3, gelsolin and PROX1 in a dose-dependent manner. SARMs induced recruitment of fewer cofactors than DHT; in particular, S-101479 failed to induce recruitment of canonical p160 coactivators such as SRC1, TIF2 and notably NCoA3 but only stimulated binding of AR to gelsolin and PROX1. The results suggest that a full capability of the AR to dimerize and to effectively and unselectively recruit all canonical cofactors is not a prerequisite for transcriptional activity in osteoblastic cells and resulting anabolic effects in bone tissues. Instead, few relevant cofactors might be sufficient to promote AR activity in these tissues.

  11. Inter- and intra-observer variation in soft-tissue sarcoma target definition.

    Science.gov (United States)

    Roberge, D; Skamene, T; Turcotte, R E; Powell, T; Saran, N; Freeman, C

    2011-08-01

    To evaluate inter- and intra-observer variability in gross tumor volume definition for adult limb/trunk soft tissue sarcomas. Imaging studies of 15 patients previously treated with preoperative radiation were used in this study. Five physicians (radiation oncologists, orthopedic surgeons and a musculoskeletal radiologist) were asked to contour each of the 15 tumors on T1-weighted, gadolinium-enhanced magnetic resonance images. These contours were drawn twice by each physician. The volume and center of mass coordinates for each gross tumor volume were extracted and a Boolean analysis was performed to measure the degree of volume overlap. The median standard deviation in gross tumor volumes across observers was 6.1% of the average volume (range: 1.8%-24.9%). There was remarkably little variation in the 3D position of the gross tumor volume center of mass. For the 15 patients, the standard deviation of the 3D distance between centers of mass ranged from 0.06 mm to 1.7 mm (median 0.1mm). Boolean analysis demonstrated that 53% to 90% of the gross tumor volume was common to all observers (median overlap: 79%). The standard deviation in gross tumor volumes on repeat contouring was 4.8% (range: 0.1-14.4%) with a standard deviation change in the position of the center of mass of 0.4mm (range: 0mm-2.6mm) and a median overlap of 93% (range: 73%-98%). Although significant inter-observer differences were seen in gross tumor volume definition of adult soft-tissue sarcoma, the center of mass of these volumes was remarkably consistent. Variations in volume definition did not correlate with tumor size. Radiation oncologists should not hesitate to review their contours with a colleague (surgeon, radiologist or fellow radiation oncologist) to ensure that they are not outliers in sarcoma gross tumor volume definition. Protocols should take into account variations in volume definition when considering tighter clinical target volumes. Copyright © 2011 Société française de radioth

  12. Sparing Healthy Tissue and Increasing Tumor Dose Using Bayesian Modeling of Geometric Uncertainties for Planning Target Volume Personalization

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    Herschtal, Alan, E-mail: Alan.Herschtal@petermac.org [Department of Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne (Australia); Faculty of Health, Arts and Design, Swinburne University of Technology, Melbourne (Australia); Te Marvelde, Luc [Department of Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne (Australia); Mengersen, Kerrie [School of Mathematical Sciences, Science and Engineering Faculty, Queensland University of Technology, Brisbane (Australia); Foroudi, Farshad [Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne (Australia); The Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne (Australia); Eade, Thomas [Northern Sydney Cancer Centre, Radiation Oncology Department, Royal North Shore Hospital, St. Leonards, Sydney (Australia); Northern Clinical School, University of Sydney (Australia); Pham, Daniel [Department of Radiation Therapy, Peter MacCallum Cancer Centre, Melbourne (Australia); Caine, Hannah [Northern Sydney Cancer Centre, Radiation Oncology Department, Royal North Shore Hospital, St. Leonards, Sydney (Australia); Kron, Tomas [The Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne (Australia); Department of Physical Sciences, Peter MacCallum Cancer Centre, Melbourne (Australia)

    2015-06-01

    Objective: To develop a mathematical tool that can update a patient's planning target volume (PTV) partway through a course of radiation therapy to more precisely target the tumor for the remainder of treatment and reduce dose to surrounding healthy tissue. Methods and Materials: Daily on-board imaging was used to collect large datasets of displacements for patients undergoing external beam radiation therapy for solid tumors. Bayesian statistical modeling of these geometric uncertainties was used to optimally trade off between displacement data collected from previously treated patients and the progressively accumulating data from a patient currently partway through treatment, to optimally predict future displacements for that patient. These predictions were used to update the PTV position and margin width for the remainder of treatment, such that the clinical target volume (CTV) was more precisely targeted. Results: Software simulation of dose to CTV and normal tissue for 2 real prostate displacement datasets consisting of 146 and 290 patients treated with a minimum of 30 fractions each showed that re-evaluating the PTV position and margin width after 8 treatment fractions reduced healthy tissue dose by 19% and 17%, respectively, while maintaining CTV dose. Conclusion: Incorporating patient-specific displacement patterns from early in a course of treatment allows PTV adaptation for the remainder of treatment. This substantially reduces the dose to healthy tissues and thus can reduce radiation therapy–induced toxicities, improving patient outcomes.

  13. Kinetics of naphthalene metabolism in target and non-target tissues of rodents and in nasal and airway microsomes from the Rhesus monkey

    Energy Technology Data Exchange (ETDEWEB)

    Buckpitt, Alan, E-mail: arbuckpitt@ucdavis.edu [Department of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, CA 95616 (United States); Morin, Dexter [Department of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, CA 95616 (United States); Murphy, Shannon; Edwards, Patricia; Van Winkle, Laura [Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, UC Davis, Davis, CA 95616 (United States); Center for Health and the Environment, UC Davis, Davis, CA 95616 United States (United States)

    2013-07-15

    Naphthalene produces species and cell selective injury to respiratory tract epithelial cells of rodents. In these studies we determined the apparent K{sub m}, V{sub max}, and catalytic efficiency (V{sub max}/K{sub m}) for naphthalene metabolism in microsomal preparations from subcompartments of the respiratory tract of rodents and non-human primates. In tissues with high substrate turnover, major metabolites were derived directly from naphthalene oxide with smaller amounts from conjugates of diol epoxide, diepoxide, and 1,2- and 1,4-naphthoquinones. In some tissues, different enzymes with dissimilar K{sub m} and V{sub max} appeared to metabolize naphthalene. The rank order of V{sub max} (rat olfactory epithelium > mouse olfactory epithelium > murine airways ≫ rat airways) correlated well with tissue susceptibility to naphthalene. The V{sub max} in monkey alveolar subcompartment was 2% that in rat nasal olfactory epithelium. Rates of metabolism in nasal compartments of the monkey were low. The catalytic efficiencies of microsomes from known susceptible tissues/subcompartments are 10 and 250 fold higher than in rat airway and monkey alveolar subcompartments, respectively. Although the strong correlations between catalytic efficiencies and tissue susceptibility suggest that non-human primate tissues are unlikely to generate metabolites at a rate sufficient to produce cellular injury, other studies showing high levels of formation of protein adducts support the need for additional studies. - Highlights: • Naphthalene is metabolized with high catalytic efficiency in susceptible tissue. • Naphthalene is metabolized at low catalytic efficiency in non-susceptible tissue. • Respiratory tissues of the non human primate metabolize naphthalene slowly.

  14. W::Neo: a novel dual-selection marker for high efficiency gene targeting in Drosophila.

    Science.gov (United States)

    Zhou, Wenke; Huang, Juan; Watson, Annie M; Hong, Yang

    2012-01-01

    We have recently developed a so-called genomic engineering approach that allows for directed, efficient and versatile modifications of Drosophila genome by combining the homologous recombination (HR)-based gene targeting with site-specific DNA integration. In genomic engineering and several similar approaches, a "founder" knock-out line must be generated first through HR-based gene targeting, which can still be a potentially time and resource intensive process. To significantly improve the efficiency and success rate of HR-based gene targeting in Drosophila, we have generated a new dual-selection marker termed W::Neo, which is a direct fusion between proteins of eye color marker White (W) and neomycin resistance (Neo). In HR-based gene targeting experiments, mutants carrying W::Neo as the selection marker can be enriched as much as fifty times by taking advantage of the antibiotic selection in Drosophila larvae. We have successfully carried out three independent gene targeting experiments using the W::Neo to generate genomic engineering founder knock-out lines in Drosophila.

  15. In silico tools used for compound selection during target-based drug discovery and development.

    Science.gov (United States)

    Caldwell, Gary W

    2015-01-01

    The target-based drug discovery process, including target selection, screening, hit-to-lead (H2L) and lead optimization stage gates, is the most common approach used in drug development. The full integration of in vitro and/or in vivo data with in silico tools across the entire process would be beneficial to R&D productivity by developing effective selection criteria and drug-design optimization strategies. This review focuses on understanding the impact and extent in the past 5 years of in silico tools on the various stage gates of the target-based drug discovery approach. There are a large number of in silico tools available for establishing selection criteria and drug-design optimization strategies in the target-based approach. However, the inconsistent use of in vitro and/or in vivo data integrated with predictive in silico multiparameter models throughout the process is contributing to R&D productivity issues. In particular, the lack of reliable in silico tools at the H2L stage gate is contributing to the suboptimal selection of viable lead compounds. It is suggested that further development of in silico multiparameter models and organizing biologists, medicinal and computational chemists into one team with a single accountable objective to expand the utilization of in silico tools in all phases of drug discovery would improve R&D productivity.

  16. THE SDSS-IV EXTENDED BARYON OSCILLATION SPECTROSCOPIC SURVEY: LUMINOUS RED GALAXY TARGET SELECTION

    Energy Technology Data Exchange (ETDEWEB)

    Prakash, Abhishek; Licquia, Timothy C.; Newman, Jeffrey A.; Rao, Sandhya M. [PITT PACC, Department of Physics and Astronomy, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Ross, Ashley J. [Center for Cosmology and Astro-Particle Physics, Ohio State University, Columbus, OH 43210 (United States); Myers, Adam D. [Department of Physics and Astronomy, University of Wyoming, Laramie, WY 82071 (United States); Dawson, Kyle S.; Bautista, Julian E.; Brownstein, Joel R. [Department of Physics and Astronomy, University of Utah, Salt Lake City, UT 84112 (United States); Kneib, Jean-Paul [Laboratoire d’Astrophysique, Ecole Polytechnique Fédérale de Lausanne Observatoire de Sauverny, 1290 Versoix (Switzerland); Percival, Will J. [Institute of Cosmology and Gravitation, Dennis Sciama Building, University of Portsmouth, Portsmouth, PO1 3FX (United Kingdom); Comparat, Johan [Instituto de Física Teórica, (UAM/CSIC), Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid (Spain); Tinker, Jeremy L. [Center for Cosmology and Particle Physics, Department of Physics, New York University, 4 Washington Place, New York, NY 10003 (United States); Schlegel, David J. [Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, CA 94720 (United States); Tojeiro, Rita [School of Physics and Astronomy, St Andrews, KY16 9SS (United Kingdom); Ho, Shirley; Lang, Dustin [Bruce and Astrid McWilliams Center for Cosmology, Department of Physics, Carnegie Mellon University, 5000 Forbes Avenue, Pittsburgh, PA 15213 (United States); McBride, Cameron K. [Harvard-Smithsonian Center for Astrophysics, Harvard University, 60 Garden Street, Cambridge, MA 02138 (United States); Zhu, Guangtun Ben, E-mail: abp15@pitt.edu [Department of Physics and Astronomy, Johns Hopkins University, Baltimore, MD 21218 (United States); and others

    2016-06-01

    We describe the algorithm used to select the luminous red galaxy (LRG) sample for the extended Baryon Oscillation Spectroscopic Survey (eBOSS) of the Sloan Digital Sky Survey IV (SDSS-IV) using photometric data from both the SDSS and the Wide-field Infrared Survey Explorer . LRG targets are required to meet a set of color selection criteria and have z -band and i -band MODEL magnitudes z < 19.95 and 19.9 < i < 21.8, respectively. Our algorithm selects roughly 50 LRG targets per square degree, the great majority of which lie in the redshift range 0.6 < z < 1.0 (median redshift 0.71). We demonstrate that our methods are highly effective at eliminating stellar contamination and lower-redshift galaxies. We perform a number of tests using spectroscopic data from SDSS-III/BOSS ancillary programs to determine the redshift reliability of our target selection and its ability to meet the science requirements of eBOSS. The SDSS spectra are of high enough signal-to-noise ratio that at least ∼89% of the target sample yields secure redshift measurements. We also present tests of the uniformity and homogeneity of the sample, demonstrating that it should be clean enough for studies of the large-scale structure of the universe at higher redshifts than SDSS-III/BOSS LRGs reached.

  17. Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells

    DEFF Research Database (Denmark)

    Spiess, Katja; Jeppesen, Mads G.; Malmgaard-Clausen, Mikkel

    2017-01-01

    Immunotoxins as antiviral therapeutics are largely unexplored but have promising prospective due to their high selectivity potential and their unparalleled efficiency. One recent example targeted the virus-encoded G protein-coupled receptor US28 as a strategy for specific and efficient treatment ...

  18. Mature Epitope Density - A strategy for target selection based on immunoinformatics and exported prokaryotic proteins

    DEFF Research Database (Denmark)

    Santos, Anderson R; Pereira, Vanessa Bastos; Barbosa, Eudes

    2013-01-01

    . However, currently available tools do not account for the concentration of epitope products in the mature protein product and its relation to the reliability of target selection. RESULTS: We developed a computational strategy based on measuring the epitope's concentration in the mature protein, called...

  19. Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets.

    Directory of Open Access Journals (Sweden)

    Pooja Ghatalia

    Full Text Available Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR and mammalian target of rapamycin (mTOR improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC, but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T, matched normal kidney (N and metastatic tumor tissue (M may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79 compared to those that did not develop metastasis for at least 2 years (n = 187. Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001. The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation.

  20. Receptor binding peptides for target-selective delivery of nanoparticles encapsulated drugs.

    Science.gov (United States)

    Accardo, Antonella; Aloj, Luigi; Aurilio, Michela; Morelli, Giancarlo; Tesauro, Diego

    2014-01-01

    Active targeting by means of drug encapsulated nanoparticles decorated with targeting bioactive moieties represents the next frontier in drug delivery; it reduces drug side effects and increases the therapeutic index. Peptides, based on their chemical and biological properties, could have a prevalent role to direct drug encapsulated nanoparticles, such as liposomes, micelles, or hard nanoparticles, toward the tumor tissues. A considerable number of molecular targets for peptides are either exclusively expressed or overexpressed on both cancer vasculature and cancer cells. They can be classified into three wide categories: integrins; growth factor receptors (GFRs); and G-protein coupled receptors (GPCRs). Therapeutic agents based on nanovectors decorated with peptides targeting membrane receptors belonging to the GPCR family overexpressed by cancer cells are reviewed in this article. The most studied targeting membrane receptors are considered: somatostatin receptors; cholecystokinin receptors; receptors associated with the Bombesin like peptides family; luteinizing hormone-releasing hormone receptors; and neurotensin receptors. Nanovectors of different sizes and shapes (micelles, liposomes, or hard nanoparticles) loaded with doxorubicin or other cytotoxic drugs and externally functionalized with natural or synthetic peptides are able to target the overexpressed receptors and are described based on their formulation and in vitro and in vivo behaviors.

  1. Development of colloids for cell and tissue targeting: bisphosphonate-functionalized gold nanoparticles for the investigation of bone targeting

    OpenAIRE

    Zayed, Gamal

    2010-01-01

    Gold nanoparticles (GNPs) possess a great potential as model systems for the investigation of nanoparticulate drug delivery due to their ease of production, low toxicity and also the high stability of the noble metal in biological fluids. Due to their unique surface chemistry, they can be used as building platform for stable self assembled monolayers of thioalkylated poly(ethylene glycol)s with different surface functionalities, allowing the investigation of different drug targeting principle...

  2. Comparative NEXAFS study of the selected icefish hard tissues and hydroxyapatite

    Science.gov (United States)

    Petrova, O. V.; Nekipelov, S. V.; Sivkov, D. V.; Mingaleva, A. E.; Nikolaev, A.; Frank-Kamenetskaya, O. V.; Bazhenov, V. V.; Vyalikh, D. V.; Molodtsov, S. L.; Sivkov, V. N.; Ehrlich, H.

    2017-11-01

    The structure of native Champsocephalus gunnari icefish otoliths, scales, teeth, bones and pristine hydroxyapatite (HA) were examined using Near Edge X-ray Absorption Fine Structure (NEXAFS) spectroscopy. NEXAFS Cls-absorption spectra of the selected icefish hard tissues indicate that otoliths contain anion [CO3]2-. NEXAFS P2p-spectra clearly indicate the absence of phosphorus atoms only within otoliths and scales samples. However, the icefish teeth and bones P2p-spectra demonstrate identical spectral feature typical for the HA. NEXAFS Ca2p-spectra of the icefish hard tissues studied also shows features, which are in good correspondence with HA spectra. Interestingly, there is a red shift ≈ 0.1 eV of the 2p1/2,3/2 → 3d transition energies in NEXAFS Ca2p-spectra of teethes and bones of the C. gunnari in comparison to HA.

  3. Nuclear microprobe analysis of the selective boron uptake obtained with BPA in brain tumour tissue

    International Nuclear Information System (INIS)

    Wegden, M.; Kristiansson, P.; Ceberg, C.; Munck af Rosenschoeld, P.; Auzelyte, V.; Elfman, M.; Malmqvist, K.G.; Nilsson, C.; Pallon, J.; Shariff, A.

    2004-01-01

    The tumour selective ability of the boron compound boronophenylalanine (BPA), today used in Boron Neutron Capture Therapy in Sweden, has been investigated with the Lund Nuclear Microprobe. The tumour to tissue ratio of the boron concentration, as well as the location of boron within the cells, is critical for the efficiency of the therapy. It is desirable that the boron is accumulated as close as possible to the cell nucleus, since the alpha particles produced in the 10 B(n,α) 7 Li reaction only have a range of about 10 microns, i.e. a cell diameter. The nuclear reaction 11 B(p,α)2α, which has an especially high cross-section (300 mb) for 660 keV protons, has been used to analyse brain tissue from BPA-injected rats. Previous studies on other boron compounds have shown significant background problems when the alpha particles are detected in the backward direction. By a specially designed set-up, alpha particles in the forward and backward direction are detected simultaneously, and only the coincidences between the two directions are considered to be true boron events. In this way we could achieve excellent background suppression. The analysis shows that BPA indeed is tumour selective. Quantifications show a boron abundance of 150 ± 20 ng/cm 2 in normal tissue and 567 ± 70 ng/cm 2 in tumour tissue. If the rat is fed with L-dopa before the injection of BPA the uptake increases 3-4 times. The boron is homogeneously distributed in the cellular structure and no specific intracellular accumulation has been shown

  4. Comparative transcriptome analysis reveals significant differences in MicroRNA expression and their target genes between adipose and muscular tissues in cattle.

    Science.gov (United States)

    Sun, Jiajie; Zhang, Bowen; Lan, Xianyong; Zhang, Chunlei; Lei, Chuzhao; Chen, Hong

    2014-01-01

    The posttranscriptional gene regulation mediated by microRNAs (miRNAs) plays an important role in various species. However, to date limited miRNAs have been reported between fat and muscle tissues in beef cattle. In this paper, 412 known and 22 novel miRNAs in backfat as well as 334 known and 10 novel miRNAs in longissimus thoracis were identified in the Chinese Qinchuan beef cattle. Bta-miR-199a-3p, -154c, -320a and -432 were expressed at higher levels in backfat tissue, while bta-miR-1, -133a, -206, and -378 were also significantly enriched in muscle tissue. Functional analysis revealed that fat-enriched miRNAs targeted PRKAA1/2, PPARA and PPARG genes to modulate lipid and fatty acid metabolism, and muscle-enriched miRNAs targeted CSRP3 gene to present function involved in skeletal and muscular system development. The results obtained may help in the design of new selection strategies to improve beef quality.

  5. Treatment Strategies that Enhance the Efficacy and Selectivity of Mitochondria-Targeted Anticancer Agents

    Directory of Open Access Journals (Sweden)

    Josephine S. Modica-Napolitano

    2015-07-01

    Full Text Available Nearly a century has passed since Otto Warburg first observed high rates of aerobic glycolysis in a variety of tumor cell types and suggested that this phenomenon might be due to an impaired mitochondrial respiratory capacity in these cells. Subsequently, much has been written about the role of mitochondria in the initiation and/or progression of various forms of cancer, and the possibility of exploiting differences in mitochondrial structure and function between normal and malignant cells as targets for cancer chemotherapy. A number of mitochondria-targeted compounds have shown efficacy in selective cancer cell killing in pre-clinical and early clinical testing, including those that induce mitochondria permeability transition and apoptosis, metabolic inhibitors, and ROS regulators. To date, however, none has exhibited the standards for high selectivity and efficacy and low toxicity necessary to progress beyond phase III clinical trials and be used as a viable, single modality treatment option for human cancers. This review explores alternative treatment strategies that have been shown to enhance the efficacy and selectivity of mitochondria-targeted anticancer agents in vitro and in vivo, and may yet fulfill the clinical promise of exploiting the mitochondrion as a target for cancer chemotherapy.

  6. Target-selective phototherapy using a ligand-based photosensitizer for type 2 cannabinoid receptor.

    Science.gov (United States)

    Zhang, Shaojuan; Jia, Ningyang; Shao, Pin; Tong, Qin; Xie, Xiang-Qun; Bai, Mingfeng

    2014-03-20

    Phototherapy is a powerful, noninvasive approach for cancer treatment, with several agents currently in clinical use. Despite the progress and promise, most current phototherapy agents have serious side effects as they can lead to damage to healthy tissue, even when the photosensitizers are fused to targeting molecules due to nonspecific light activation of the unbound photosensitizer. To overcome these limitations, we developed a phototherapy agent that combines a functional ligand and a near infrared phthalocyanine dye. Our target is type 2 cannabinoid receptor (CB2R), considered an attractive therapeutic target for phototherapy given it is overexpressed by many types of cancers that are located at a surface or can be reached by an endoscope. We show that our CB2R-targeted phototherapy agent, IR700DX-mbc94, is specific for CB2R and effective only when bound to the target receptor. Overall, this opens up the opportunity for development of an alternative treatment option for CB2R-positive cancers. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Design, construction, and characterization of high-performance membrane fusion devices with target-selectivity.

    Science.gov (United States)

    Kashiwada, Ayumi; Yamane, Iori; Tsuboi, Mana; Ando, Shun; Matsuda, Kiyomi

    2012-01-31

    Membrane fusion proteins such as the hemagglutinin glycoprotein have target recognition and fusion accelerative domains, where some synergistically working elements are essential for target-selective and highly effective native membrane fusion systems. In this work, novel membrane fusion devices bearing such domains were designed and constructed. We selected a phenylboronic acid derivative as a recognition domain for a sugar-like target and a transmembrane-peptide (Leu-Ala sequence) domain interacting with the target membrane, forming a stable hydrophobic α-helix and accelerating the fusion process. Artificial membrane fusion behavior between the synthetic devices in which pilot and target liposomes were incorporated was characterized by lipid-mixing and inner-leaflet lipid-mixing assays. Consequently, the devices bearing both the recognition and transmembrane domains brought about a remarkable increase in the initial rate for the membrane fusion compared with the devices containing the recognition domain alone. In addition, a weakly acidic pH-responsive device was also constructed by replacing three Leu residues in the transmembrane-peptide domain by Glu residues. The presence of Glu residues made the acidic pH-dependent hydrophobic α-helix formation possible as expected. The target-selective liposome-liposome fusion was accelerated in a weakly acidic pH range when the Glu-substituted device was incorporated in pilot liposomes. The use of this pH-responsive device seems to be a potential strategy for novel applications in a liposome-based delivery system. © 2011 American Chemical Society

  8. Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells

    Directory of Open Access Journals (Sweden)

    Katja Spiess

    2017-01-01

    Full Text Available Immunotoxins as antiviral therapeutics are largely unexplored but have promising prospective due to their high selectivity potential and their unparalleled efficiency. One recent example targeted the virus-encoded G protein-coupled receptor US28 as a strategy for specific and efficient treatment of human cytomegalovirus (HCMV infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP consisted of a variant (F49A of CX3CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin A (PE. Here, we systematically seek to improve F49A-FTP by modifications in its three structural domains; we generated variants with (1 altered chemokine sequence (K14A, F49L, and F49E, (2 shortened and elongated linker region, and (3 modified toxin domain. Only F49L-FTP displayed higher selectivity in its binding to US28 versus CX3CR1, the endogenous receptor for CX3CL1, but this was not matched by a more selective killing of US28-expressing cells. A longer linker and different toxin variants decreased US28 affinity and selective killing. Thereby, F49A-FTP represents the best candidate for HCMV treatment. Many viruses encode internalizing receptors suggesting that not only HCMV but also, for instance, Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus may be targeted by FTPs.

  9. Out with the old? The role of selective attention in retaining targets in partial report.

    Science.gov (United States)

    Lindsey, Dakota R B; Bundesen, Claus; Kyllingsbæk, Søren; Petersen, Anders; Logan, Gordon D

    2017-01-01

    In the partial-report task, subjects are asked to report only a portion of the items presented. Selective attention chooses which objects to represent in short-term memory (STM) on the basis of their relevance. Because STM is limited in capacity, one must sometimes choose which objects are removed from memory in light of new relevant information. We tested the hypothesis that the choices among newly presented information and old information in STM involve the same process-that both are acts of selective attention. We tested this hypothesis using a two-display partial-report procedure. In this procedure, subjects had to select and retain relevant letters (targets) from two sequentially presented displays. If selection in perception and retention in STM are the same process, then irrelevant letters (distractors) in the second display, which demanded attention because of their similarity to the targets, should have decreased target report from the first display. This effect was not obtained in any of four experiments. Thus, choosing objects to keep in STM is not the same process as choosing new objects to bring into STM.

  10. Selection, processing and clinical application of muscle-skeletal tissue; Seleccion, Procesamiento y Aplicacion Clinica de Tejido Musculo-Esqueletico

    Energy Technology Data Exchange (ETDEWEB)

    Luna Z, D.; Reyes F, M.L.; Lavalley E, C.; Castaneda J, G. [ININ, Carretera Mexico-Toluca s/n, 52750 La Marquesa, Ocoyoacac, Estado de Mexico (Mexico)]. e-mail: dlz@nuclear.inin. mx

    2007-07-01

    Due to the increase in the average of the world population's life, people die each time to more age, this makes that the tissues of support of the human body, as those muscle-skeletal tissues, when increasing the individual's age go weakening, this in turn leads to the increment of the illnesses like the osteoporosis and the arthritis, that undoubtedly gives as a result more injure of the muscle-skeletal tissues joined a greater number of traffic accidents where particularly these tissues are affected, for that the demand of tissues muscle-skeletal for transplant every day will be bigger. The production of these tissues in the Bank of Radio sterilized Tissues, besides helping people to improve its quality of life saved foreign currencies because most of the muscle-skeletal tissues transplanted in Mexico are of import. The use of the irradiation to sterilize tissues for transplant has shown to be one of the best techniques with that purpose for what the International Atomic Energy Agency believes a Technical cooperation program to establish banks of tissues using the nuclear energy, helping mainly to countries in development. In this work the stages that follows the bank of radio sterilized tissues of the National Institute of Nuclear Research for the cadaverous donor's of muscle-skeletal tissue selection are described, as well as the processing and the clinical application of these tissues. (Author)

  11. Gene expression levels are a target of recent natural selection in the human genome.

    Science.gov (United States)

    Kudaravalli, Sridhar; Veyrieras, Jean-Baptiste; Stranger, Barbara E; Dermitzakis, Emmanouil T; Pritchard, Jonathan K

    2009-03-01

    Changes in gene expression may represent an important mode of human adaptation. However, to date, there are relatively few known examples in which selection has been shown to act directly on levels or patterns of gene expression. In order to test whether single nucleotide polymorphisms (SNPs) that affect gene expression in cis are frequently targets of positive natural selection in humans, we analyzed genome-wide SNP and expression data from cell lines associated with the International HapMap Project. Using a haplotype-based test for selection that was designed to detect incomplete selective sweeps, we found that SNPs showing signals of selection are more likely than random SNPs to be associated with gene expression levels in cis. This signal is significant in the Yoruba (which is the population that shows the strongest signals of selection overall) and shows a trend in the same direction in the other HapMap populations. Our results argue that selection on gene expression levels is an important type of human adaptation. Finally, our work provides an analytical framework for tackling a more general problem that will become increasingly important: namely, testing whether selection signals overlap significantly with SNPs that are associated with phenotypes of interest.

  12. Selection of seed lots of Pinus taeda L. for tissue culture

    Directory of Open Access Journals (Sweden)

    Diego Pascoal Golle

    2014-06-01

    Full Text Available The aim of this work was to identify the fungi genera associated with three Pinus taeda L. seed lots and to assess the sanitary and physiological quality of these lots for use as selection criteria for tissue culture and evaluate the in vitro establishment of explants from seminal origin in different nutritive media. It was possible to discriminate the lots on the sanitary and physiological quality, as well as to establish in vitro plants of Pinus taeda from cotyledonary nodes obtained from aseptic seed germination of a selected lot by the sanitary and physiological quality higher. The nutritive media MS, ½ MS and WPM were equally suitable for this purpose. For the sanitary analysis the fungal genera Fusarium, Penicillium and Trichoderma were those of the highest sensitivity. For the physiological evaluation were important the variables: abnormal seedlings, strong normal seedlings; length, fresh and dry weight of strong normal seedlings. The analyzes were favorable to choose lots of seeds for in vitro culture and all culture media were adequate for the establishment of this species in tissue culture.

  13. Monte Carlo model to describe depth selective fluorescence spectra of epithelial tissue

    Science.gov (United States)

    Pavlova, Ina; Weber, Crystal Redden; Schwarz, Richard A.; Williams, Michelle; El-Naggar, Adel; Gillenwater, Ann; Richards-Kortum, Rebecca

    2008-01-01

    We present a Monte Carlo model to predict fluorescence spectra of the oral mucosa obtained with a depth-selective fiber optic probe as a function of tissue optical properties. A model sensitivity analysis determines how variations in optical parameters associated with neoplastic development influence the intensity and shape of spectra, and elucidates the biological basis for differences in spectra from normal and premalignant oral sites. Predictions indicate that spectra of oral mucosa collected with a depth-selective probe are affected by variations in epithelial optical properties, and to a lesser extent, by changes in superficial stromal parameters, but not by changes in the optical properties of deeper stroma. The depth selective probe offers enhanced detection of epithelial fluorescence, with 90% of the detected signal originating from the epithelium and superficial stroma. Predicted depth-selective spectra are in good agreement with measured average spectra from normal and dysplastic oral sites. Changes in parameters associated with dysplastic progression lead to a decreased fluorescence intensity and a shift of the spectra to longer emission wavelengths. Decreased fluorescence is due to a drop in detected stromal photons, whereas the shift of spectral shape is attributed to an increased fraction of detected photons arising in the epithelium. PMID:19123659

  14. Normal tissue sparing in a phase II trial on daily adaptive plan selection in radiotherapy for urinary bladder cancer.

    Science.gov (United States)

    Vestergaard, Anne; Muren, Ludvig P; Lindberg, Henriette; Jakobsen, Kirsten L; Petersen, Jørgen B B; Elstrøm, Ulrik V; Agerbæk, Mads; Høyer, Morten

    2014-08-01

    Background: Patients with urinary bladder cancer often display large changes in the shape and size of their bladder target during a course of radiotherapy (RT), making adaptive RT (ART) appealing for this tumour site. We are conducting a clinical phase II trial of daily plan selection-based ART for bladder cancer and here report dose-volume data from the first 20 patients treated in the trial. All patients received 60 Gy in 30 fractions to the bladder; in 13 of the patients the pelvic lymph nodes were simultaneously treated to 48 Gy. Daily patient set-up was by use of cone beam computed tomography (CBCT) guidance. The first 5 fractions were delivered with large, population-based (non-adaptive) margins. The bladder contours from the CBCTs acquired in the first 4 fractions were used to create a patient-specific library of three plans, corresponding to a small, medium and large size bladder. From fraction 6, daily online plan selection was performed, where the smallest plan covering the bladder was selected prior to each treatment delivery. A total of 600 treatment fractions in the 20 patients were evaluated. Small, medium and large size plans were used almost equally often, with an average of 10, 9 and 11 fractions, respectively. The median volume ratio of the course-averaged PTV (PTV-ART) relative to the non-adaptive PTV was 0.70 (range: 0.46-0.89). A linear regression analysis showed a 183 cm(3) (CI 143-223 cm(3)) reduction in PTV-ART compared to the non-adaptive PTV (R(2) = 0.94). Daily adaptive plan selection in RT of bladder cancer results in a considerable normal tissue sparing, of a magnitude that we expect will translate into a clinically significant reduction of the treatment-related morbidity.

  15. [Origins and selection of epidermal progenitors and stem cells: a challenge for tissue engineering].

    Science.gov (United States)

    Deshayes, Nathalie; Rathman-Josserand, Michelle

    2008-01-01

    The use of epidermal stem cells and their progeny for tissue engineering and cell therapy represents a source of hope and major interest in view of applications such as replacing the loss of functionality in failing tissues or obtaining physiologic skin equivalents for skin grafting. The use of such cells necessitates the isolation and purification of rare populations of keratinocytes and then increasing their numbers by mass culture. This is not currently possible since part of the specific phenotype of these cells is lost once the cells are placed in culture. Furthermore, few techniques are available to unequivocally detect the presence of skin stem cells and/or their progeny in culture and thus quantify them. Two different sources of stem cells are currently being studied for skin research and clinical applications: skin progenitors either obtained from embryonic stem cells (ESC) or from selection from adult skin tissue. It has been shown that "keratinocyte-like" cells can be derived from ESC; however, the culturing processes must still be optimized to allow for the mass culture of homogeneous populations at a controlled stage of differentiation. The functional characterization of such populations must also be more thoroughly achieved. In order to use stem cells from adult tissues, improvements must be made in order to obtain a satisfactory degree of purification and characterization of this rare population. Distinguishing stem cells from progenitor cells at the molecular level also remains a challenge. Furthermore, stem cell research inevitably requires cultivating these cells outside their physiological environment or niche. It will thus be necessary to better understand the impact of this specific environmental niche on the preservation of the cellular phenotypes of interest.

  16. Design, synthesis, and biological evaluation of 16-substituted 4-azasteroids as tissue-selective androgen receptor modulators (SARMs).

    Science.gov (United States)

    Mitchell, Helen J; Dankulich, William P; Hartman, George D; Prueksaritanont, Thomayant; Schmidt, Azriel; Vogel, Robert L; Bai, Chang; McElwee-Witmer, Sheila; Zhang, Hai Z; Chen, Fang; Leu, Chih-Tai; Kimmel, Donald B; Ray, William J; Nantermet, Pascale; Gentile, Michael A; Duggan, Mark E; Meissner, Robert S

    2009-08-13

    A novel series of 16-substituted-4-azasteroids has been identified as potential tissue-selective androgen receptor modulators. These ligands display potent hAR binding and agonist activity, low virilizing potential, and good pharmacokinetic profiles in dogs. On the basis of its in vitro profile, 21 was evaluated in the OVX and ORX rat models and exhibited an osteoanabolic, tissue-selective profile.

  17. Specific and selective target detection of supra-genome 21 Mers Salmonella via silicon nanowires biosensor

    Science.gov (United States)

    Mustafa, Mohammad Razif Bin; Dhahi, Th S.; Ehfaed, Nuri. A. K. H.; Adam, Tijjani; Hashim, U.; Azizah, N.; Mohammed, Mohammed; Noriman, N. Z.

    2017-09-01

    The nano structure based on silicon can be surface modified to be used as label-free biosensors that allow real-time measurements. The silicon nanowire surface was functionalized using 3-aminopropyltrimethoxysilane (APTES), which functions as a facilitator to immobilize biomolecules on the silicon nanowire surface. The process is simple, economical; this will pave the way for point-of-care applications. However, the surface modification and subsequent detection mechanism still not clear. Thus, study proposed step by step process of silicon nano surface modification and its possible in specific and selective target detection of Supra-genome 21 Mers Salmonella. The device captured the molecule with precisely; the approach took the advantages of strong binding chemistry created between APTES and biomolecule. The results indicated how modifications of the nanowires provide sensing capability with strong surface chemistries that can lead to specific and selective target detection.

  18. Diverse Actions and Target-Site Selectivity of Neonicotinoids: Structural Insights

    Science.gov (United States)

    Matsuda, Kazuhiko; Kanaoka, Satoshi; Akamatsu, Miki; Sattelle, David B.

    2009-01-01

    The nicotinic acetylcholine receptors (nAChRs) are targets for human and veterinary medicines as well as insecticides. Subtype-selectivity among the diverse nAChR family members is important for medicines targeting particular disorders, and pest-insect selectivity is essential for the development of safer, environmentally acceptable insecticides. Neonicotinoid insecticides selectively targeting insect nAChRs have important applications in crop protection and animal health. Members of this class exhibit strikingly diverse actions on their nAChR targets. Here we review the chemistry and diverse actions of neonicotinoids on insect and mammalian nAChRs. Electrophysiological studies on native nAChRs and on wild-type and mutagenized recombinant nAChRs have shown that basic residues particular to loop D of insect nAChRs are likely to interact electrostatically with the nitro group of neonicotinoids. In 2008, the crystal structures were published showing neonicotinoids docking into the acetylcholine binding site of molluscan acetylcholine binding proteins with homology to the ligand binding domain (LBD) of nAChRs. The crystal structures showed that 1) glutamine in loop D, corresponding to the basic residues of insect nAChRs, hydrogen bonds with the NO2 group of imidacloprid and 2) neonicotinoid-unique stacking and CH-π bonds at the LBD. A neonicotinoid-resistant strain obtained by laboratory-screening has been found to result from target site mutations, and possible reasons for this are also suggested by the crystal structures. The prospects of designing neonicotinoids that are safe not only for mammals but also for beneficial insects such as honey bees (Apis mellifera) are discussed in terms of interactions with non-α nAChR subunits. PMID:19321668

  19. Transplantation of Xenopus laevis tissues to determine the ability of motor neurons to acquire a novel target.

    Directory of Open Access Journals (Sweden)

    Karen L Elliott

    Full Text Available The evolutionary origin of novelties is a central problem in biology. At a cellular level this requires, for example, molecularly resolving how brainstem motor neurons change their innervation target from muscle fibers (branchial motor neurons to neural crest-derived ganglia (visceral motor neurons or ear-derived hair cells (inner ear and lateral line efferent neurons. Transplantation of various tissues into the path of motor neuron axons could determine the ability of any motor neuron to innervate a novel target. Several tissues that receive direct, indirect, or no motor innervation were transplanted into the path of different motor neuron populations in Xenopus laevis embryos. Ears, somites, hearts, and lungs were transplanted to the orbit, replacing the eye. Jaw and eye muscle were transplanted to the trunk, replacing a somite. Applications of lipophilic dyes and immunohistochemistry to reveal motor neuron axon terminals were used. The ear, but not somite-derived muscle, heart, or liver, received motor neuron axons via the oculomotor or trochlear nerves. Somite-derived muscle tissue was innervated, likely by the hypoglossal nerve, when replacing the ear. In contrast to our previous report on ear innervation by spinal motor neurons, none of the tissues (eye or jaw muscle was innervated when transplanted to the trunk. Taken together, these results suggest that there is some plasticity inherent to motor innervation, but not every motor neuron can become an efferent to any target that normally receives motor input. The only tissue among our samples that can be innervated by all motor neurons tested is the ear. We suggest some possible, testable molecular suggestions for this apparent uniqueness.

  20. Ethyl Pyruvate: An Anti-Microbial Agent that Selectively Targets Pathobionts and Biofilms

    OpenAIRE

    Debebe, Tewodros; Kr?ger, Monika; Huse, Klaus; Kacza, Johannes; M?hlberg, Katja; K?nig, Brigitte; Birkenmeier, Gerd

    2016-01-01

    The microbiota has a strong influence on health and disease in humans. A causative shift favoring pathobionts is strongly linked to diseases. Therefore, anti-microbial agents selectively targeting potential pathogens as well as their biofilms are urgently demanded. Here we demonstrate the impact of ethyl pyruvate, so far known as ROS scavenger and anti-inflammatory agent, on planktonic microbes and biofilms. Ethyl pyruvate combats preferably the growth of pathobionts belonging to bacteria and...

  1. Selective Targeting of Antiviral and Immunomodulating Agents in the Treatment of Arenavirus Infections

    Science.gov (United States)

    1987-10-01

    designated by other authorized documents. aCURqY CLASIFICATION OF THIS PAGE R T M A PForm Approved REPORT DOCUMEN[ATION PAGE OMB No. 0704-0188 la...protected mice from viral infections in which the liver or lung served as the primary site of virus infection. Liposome-encapsulated ribavirin was more...report summarizes our findings using liposomes as carriers for the selective targeting of antiviral and immunomodulating agents in viral infections

  2. Designing the nanobiointerface of fluorescent nanodiamonds: highly selective targeting of glioma cancer cells.

    Science.gov (United States)

    Slegerova, Jitka; Hajek, Miroslav; Rehor, Ivan; Sedlak, Frantisek; Stursa, Jan; Hruby, Martin; Cigler, Petr

    2015-01-14

    Core-shell nanoparticles based on fluorescent nanodiamonds coated with a biocompatible N-(2-hydroxypropyl)methacrylamide copolymer shell were developed for background-free near-infrared imaging of cancer cells. The particles showed excellent colloidal stability in buffers and culture media. After conjugation with a cyclic RGD peptide they selectively targeted integrin αvβ3 receptors on glioblastoma cells with high internalization efficacy.

  3. Mitochondrial permeability transition pore as a selective target for anti-cancer therapy

    Directory of Open Access Journals (Sweden)

    Dong Hoon eSuh

    2013-03-01

    Full Text Available Mitochondrial outer membrane permeabilization (MOMP is the ultimate step in dozens of lethal apoptotic signal transduction pathways which converge on mitochondria. One of the representative systems proposed to be responsible for the MOMP is the mitochondrial permeability transition pore (MPTP. Although the molecular composition of the MPTP is not clearly understood, the MPTP attracts much interest as a promising target for resolving two conundrums regarding cancer treatment: tumor selectivity and resistance to treatment. The regulation of the MPTP is closely related to metabolic reprogramming in cancer cells including mitochondrial alterations. Restoration of deregulated apoptotic machinery in cancer cells by tumor-specific modulation of the MPTP could therefore be a promising anti-cancer strategy. Currently, a number of MPTP-targeting agents are under pre-clinical and clinical studies. Here, we reviewed the structure and regulation of the MPTP as well as the current status of the development of promising MPTP-targeting drugs.

  4. The TESS Input Catalog and Selection of Targets for the TESS Transit Search

    Science.gov (United States)

    Pepper, Joshua; Stassun, Keivan G.; Paegert, Martin; Oelkers, Ryan; De Lee, Nathan Michael; Torres, Guillermo; TESS Target Selection Working Group

    2018-01-01

    The TESS mission will photometrically survey millions of the brightest stars over almost the entire the sky to detect transiting exoplanets. A key step to enable that search is the creation of the TESS Input Catalog (TIC), a compiled catalog of 700 million stars and galaxies with observed and calculated parameters. From the TIC we derive the Candidate Target List (CTL) to identify target stars for the 2-minute TESS postage stamps. The CTL is designed to identify the best stars for the detection of small planets, which includes all bright cool dwarf stars in the sky. I will describe the target selection strategy, the distribution of stars in the current CTL, and how both the TIC and CTL will expand and improve going forward.

  5. Retroviral DNA integration: viral and cellular determinants of target-site selection.

    Directory of Open Access Journals (Sweden)

    Mary K Lewinski

    2006-06-01

    Full Text Available Retroviruses differ in their preferences for sites for viral DNA integration in the chromosomes of infected cells. Human immunodeficiency virus (HIV integrates preferentially within active transcription units, whereas murine leukemia virus (MLV integrates preferentially near transcription start sites and CpG islands. We investigated the viral determinants of integration-site selection using HIV chimeras with MLV genes substituted for their HIV counterparts. We found that transferring the MLV integrase (IN coding region into HIV (to make HIVmIN caused the hybrid to integrate with a specificity close to that of MLV. Addition of MLV gag (to make HIVmGagmIN further increased the similarity of target-site selection to that of MLV. A chimeric virus with MLV Gag only (HIVmGag displayed targeting preferences different from that of both HIV and MLV, further implicating Gag proteins in targeting as well as IN. We also report a genome-wide analysis indicating that MLV, but not HIV, favors integration near DNase I-hypersensitive sites (i.e., +/- 1 kb, and that HIVmIN and HIVmGagmIN also favored integration near these features. These findings reveal that IN is the principal viral determinant of integration specificity; they also reveal a new role for Gag-derived proteins, and strengthen models for integration targeting based on tethering of viral IN proteins to host proteins.

  6. Chlorin e6 Conjugated Interleukin-6 Receptor Aptamers Selectively Kill Target Cells Upon Irradiation

    Directory of Open Access Journals (Sweden)

    Sven Kruspe

    2014-01-01

    Full Text Available Photodynamic therapy (PDT uses the therapeutic properties of light in combination with certain chemicals, called photosensitizers, to successfully treat brain, breast, prostate, and skin cancers. To improve PDT, current research focuses on the development of photosensitizers to specifically target cancer cells. In the past few years, aptamers have been developed to directly deliver cargo molecules into target cells. We conjugated the photosensitizer chlorin e6 (ce6 with a human interleukin-6 receptor (IL-6R binding RNA aptamer, AIR-3A yielding AIR-3A-ce6 for application in high efficient PDT. AIR-3A-ce6 was rapidly and specifically internalized by IL-6R presenting (IL-6R+ cells. Upon light irradiation, targeted cells were selectively killed, while free ce6 did not show any toxic effect. Cells lacking the IL-6R were also not affected by AIR-3A-ce6. With this approach, we improved the target specificity of ce6-mediated PDT. In the future, other tumor-specific aptamers might be used to selectively localize photosensitizers into cells of interest and improve the efficacy and specificity of PDT in cancer and other diseases.

  7. Merger and Acquisition Target Selection Based on Interval Neutrosophic Multigranulation Rough Sets over Two Universes

    Directory of Open Access Journals (Sweden)

    Chao Zhang

    2017-07-01

    Full Text Available As a significant business activity, merger and acquisition (M&A generally means transactions in which the ownership of companies, other business organizations or their operating units are transferred or combined. In a typical M&A procedure, M&A target selection is an important issue that tends to exert an increasingly significant impact on different business areas. Although some research works based on fuzzy methods have been explored on this issue, they can only deal with incomplete and uncertain information, but not inconsistent and indeterminate information that exists universally in the decision making process. Additionally, it is advantageous to solve M&A problems under the group decision making context. In order to handle these difficulties in M&A target selection background, we introduce a novel rough set model by combining interval neutrosophic sets (INSs with multigranulation rough sets over two universes, called an interval neutrosophic (IN multigranulation rough set over two universes. Then, we discuss the definition and some fundamental properties of the proposed model. Finally, we establish decision making rules and computing approaches for the proposed model in M&A target selection background, and the effectiveness of the decision making approach is demonstrated by an illustrative case analysis.

  8. Efficient and Adaptive Node Selection for Target Tracking in Wireless Sensor Network

    Directory of Open Access Journals (Sweden)

    Juan Feng

    2016-01-01

    Full Text Available In target tracking wireless sensor network, choosing the proper working nodes can not only minimize the number of active nodes, but also satisfy the tracking reliability requirement. However, most existing works focus on selecting sensor nodes which are the nearest to the target for tracking missions and they did not consider the correlation of the location of the sensor nodes so that these approaches can not meet all the goals of the network. This work proposes an efficient and adaptive node selection approach for tracking a target in a distributed wireless sensor network. The proposed approach combines the distance-based node selection strategy and particle filter prediction considering the spatial correlation of the different sensing nodes. Moreover, a joint distance weighted measurement is proposed to estimate the information utility of sensing nodes. Experimental results show that EANS outperformed the state-of-the-art approaches by reducing the energy cost and computational complexity as well as guaranteeing the tracking accuracy.

  9. A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli.

    Science.gov (United States)

    Urfer, Matthias; Bogdanovic, Jasmina; Lo Monte, Fabio; Moehle, Kerstin; Zerbe, Katja; Omasits, Ulrich; Ahrens, Christian H; Pessi, Gabriella; Eberl, Leo; Robinson, John A

    2016-01-22

    Increasing antibacterial resistance presents a major challenge in antibiotic discovery. One attractive target in Gram-negative bacteria is the unique asymmetric outer membrane (OM), which acts as a permeability barrier that protects the cell from external stresses, such as the presence of antibiotics. We describe a novel β-hairpin macrocyclic peptide JB-95 with potent antimicrobial activity against Escherichia coli. This peptide exhibits no cellular lytic activity, but electron microscopy and fluorescence studies reveal an ability to selectively disrupt the OM but not the inner membrane of E. coli. The selective targeting of the OM probably occurs through interactions of JB-95 with selected β-barrel OM proteins, including BamA and LptD as shown by photolabeling experiments. Membrane proteomic studies reveal rapid depletion of many β-barrel OM proteins from JB-95-treated E. coli, consistent with induction of a membrane stress response and/or direct inhibition of the Bam folding machine. The results suggest that lethal disruption of the OM by JB-95 occurs through a novel mechanism of action at key interaction sites within clusters of β-barrel proteins in the OM. These findings open new avenues for developing antibiotics that specifically target β-barrel proteins and the integrity of the Gram-negative OM. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Selective heating of soft tissue-bone interfaces during scanned focussed ultrasound hyperthermia

    International Nuclear Information System (INIS)

    Hynynen, K.; De Young, D.; Roemer, R.; Kundrat, M.

    1987-01-01

    Bone heating has been a frequent problem with clinical hyperthermia treatments induced by plane ultrasonic transducers. In this study, detailed temperature distributions were measured in dogs' (5 dogs) thigh muscles and bone in vivo while focussed ultrasound was applied to elevate the muscle temperature next to the bone. Significantly higher temperature elevations were measured at the bone surface than in the target volume in front of the bone. The temperature distribution was sharp decreasing fast inside the bone and also in front of it. By using more sharply focussed and multiple beams the temperature elevation at the bone surface was reduced and by suitable choice of the distance between the bone surface and the acoustical focus almost uniform temperature could be induced in the overlying muscle tissue from the surface down to the bone - the bone surface being in the same temperature as the muscle. Similar result was obtained by using single, higher frequency focussed beam (3.58 MHz). Also the utilization of nonlinear ultrasonic propagation appeared to reduce bone heating. The results showed that by carefully planning ultrasound hyperthermia treatments, tissues close to bone can be heated without extensive temperature elevation at bone surface

  11. Target Selection and Deselection at the Berkeley StructuralGenomics Center

    Energy Technology Data Exchange (ETDEWEB)

    Chandonia, John-Marc; Kim, Sung-Hou; Brenner, Steven E.

    2005-03-22

    At the Berkeley Structural Genomics Center (BSGC), our goalis to obtain a near-complete structural complement of proteins in theminimal organisms Mycoplasma genitalium and M. pneumoniae, two closelyrelated pathogens. Current targets for structure determination have beenselected in six major stages, starting with those predicted to be mosttractable to high throughput study and likely to yield new structuralinformation. We report on the process used to select these proteins, aswell as our target deselection procedure. Target deselection reducesexperimental effort by eliminating targets similar to those recentlysolved by the structural biology community or other centers. We measurethe impact of the 69 structures solved at the BSGC as of July 2004 onstructure prediction coverage of the M. pneumoniae and M. genitaliumproteomes. The number of Mycoplasma proteins for which thefold couldfirst be reliably assigned based on structures solved at the BSGC (24 M.pneumoniae and 21 M. genitalium) is approximately 25 percent of the totalresulting from work at all structural genomics centers and the worldwidestructural biology community (94 M. pneumoniae and 86M. genitalium)during the same period. As the number of structures contributed by theBSGC during that period is less than 1 percent of the total worldwideoutput, the benefits of a focused target selection strategy are apparent.If the structures of all current targets were solved, the percentage ofM. pneumoniae proteins for which folds could be reliably assigned wouldincrease from approximately 57 percent (391 of 687) at present to around80 percent (550 of 687), and the percentage of the proteome that could beaccurately modeled would increase from around 37 percent (254 of 687) toabout 64 percent (438 of 687). In M. genitalium, the percentage of theproteome that could be structurally annotated based on structures of ourremaining targets would rise from 72 percent (348 of 486) to around 76percent (371 of 486), with the

  12. Targeting of liver tumour in rats by selective delivery of holmium-166 loaded microspheres: a biodistribution study

    Energy Technology Data Exchange (ETDEWEB)

    Nijsen, F.; Rook, D.; Zonnenberg, B.; Klerk, J. de; Rijk, P. van; Schip, F. van het [Dept. of Nuclear Medicine, University Medical Center, Utrecht (Netherlands); Brandt, C. [Animal Inst., Utrecht Univ. (Netherlands); Meijer, R. [Dept. of Radiology, Univ. Medical Center, Utrecht (Netherlands); Dullens, H. [Dept. of Pathology, Univ. Medical Center, Utrecht (Netherlands); Hennink, W. [Dept. of Pharmaceutics, Utrecht Univ. (Netherlands)

    2001-06-01

    Intra-arterial administration of beta-emitting particles that become trapped in the vascular bed of a tumour and remain there while delivering high doses, represents a unique approach in the treatment of both primary and metastatic liver tumours. Studies on selective internal radiation therapy of colorectal liver metastases using yttrium-90 glass microspheres have shown encouraging results. This study describes the biodistribution of 40-{mu}m poly lactic acid microspheres loaded with radioactive holmium-166, after intra-arterial administration into the hepatic artery of rats with implanted liver tumours. Radioactivity measurements showed >95% retention of injected activity in the liver and its resident tumour. The average activity detected in other tissues was {<=}0.1%ID/g, with incidental exceptions in the lungs and stomach. Very little {sup 166}Ho activity was detected in kidneys (<0.1%ID/g), thereby indicating the stability of the microspheres in vivo. Tumour targeting was very effective, with a mean tumour to liver ratio of 6.1{+-}2.9 for rats with tumour (n=15) versus 0.7{+-}0.5 for control rats (n=6; P<0.001). These ratios were not significantly affected by the use of adrenaline. Histological analysis showed that five times as many large (>10) and medium-sized (4-9) clusters of microspheres were present within tumour and peritumoural tissue, compared with normal liver. Single microspheres were equally dispersed throughout the tumour, as well as normal liver parenchyma. (orig.)

  13. Improvement of potato tolerance to salinity using tissue culture techniques and irradiation with in vitro selection

    International Nuclear Information System (INIS)

    Al-Safadi, B.; Arabi, M. I. E.

    2005-06-01

    A mutation breeding program was conducted to improve potato (Solanum tuberosum) tolerance to salinity. In vitro cultured explants from potato cvs. Draga, Diamant, Spunta were irradiated with gamma doses 25, 30, and 35 Gy.Growing shoots were cut and re-cultured every 2 weeks until the 4th generation (MV 4 ) to make sure no chimeral tissues still existed in the mutant material. Plantlets were subsequently propagated to obtain enough explants for in vitro selection pressure. Around 3000 plantlets from the three cultivars were subjected to selection pressure. MV 4 explants were cultured on MS medium supplemented with the NaCl in varying concentrations ranging between 50 to 200 mM. Surviving plantlets were propagated and re-cultured on a similar medium to insure their tolerance to salinity. Tolerant plantlets were acclimatized and transferred to pots and grown under glasshouse conditions. Plants were later subjected to another selection pressure, by irrigating them using water containing NaCl in concentrations ranging between 50-250 mM in addition to controls irrigated with normal water. Cultivar Spunta produced the highest number of tolerant plants. Four plants of Spunta appeared to be tolerant to salinity whereas only one plant from Diamant and was tolerant and no plants from cultivar Draga were tolerant. Mutant plants varied in number of produced minitubers from 8 - 14. Also, weight of these minitubers varied from less than 1 to 31 grams. (author)

  14. Selective targeting of brain tumors with gold nanoparticle-induced radiosensitization.

    Directory of Open Access Journals (Sweden)

    Daniel Y Joh

    Full Text Available Successful treatment of brain tumors such as glioblastoma multiforme (GBM is limited in large part by the cumulative dose of Radiation Therapy (RT that can be safely given and the blood-brain barrier (BBB, which limits the delivery of systemic anticancer agents into tumor tissue. Consequently, the overall prognosis remains grim. Herein, we report our pilot studies in cell culture experiments and in an animal model of GBM in which RT is complemented by PEGylated-gold nanoparticles (GNPs. GNPs significantly increased cellular DNA damage inflicted by ionizing radiation in human GBM-derived cell lines and resulted in reduced clonogenic survival (with dose-enhancement ratio of ~1.3. Intriguingly, combined GNP and RT also resulted in markedly increased DNA damage to brain blood vessels. Follow-up in vitro experiments confirmed that the combination of GNP and RT resulted in considerably increased DNA damage in brain-derived endothelial cells. Finally, the combination of GNP and RT increased survival of mice with orthotopic GBM tumors. Prior treatment of mice with brain tumors resulted in increased extravasation and in-tumor deposition of GNP, suggesting that RT-induced BBB disruption can be leveraged to improve the tumor-tissue targeting of GNP and thus further optimize the radiosensitization of brain tumors by GNP. These exciting results together suggest that GNP may be usefully integrated into the RT treatment of brain tumors, with potential benefits resulting from increased tumor cell radiosensitization to preferential targeting of tumor-associated vasculature.

  15. Implications of structural genomics target selection strategies: Pfam5000, whole genome, and random approaches

    Energy Technology Data Exchange (ETDEWEB)

    Chandonia, John-Marc; Brenner, Steven E.

    2004-07-14

    The structural genomics project is an international effort to determine the three-dimensional shapes of all important biological macromolecules, with a primary focus on proteins. Target proteins should be selected according to a strategy which is medically and biologically relevant, of good value, and tractable. As an option to consider, we present the Pfam5000 strategy, which involves selecting the 5000 most important families from the Pfam database as sources for targets. We compare the Pfam5000 strategy to several other proposed strategies that would require similar numbers of targets. These include including complete solution of several small to moderately sized bacterial proteomes, partial coverage of the human proteome, and random selection of approximately 5000 targets from sequenced genomes. We measure the impact that successful implementation of these strategies would have upon structural interpretation of the proteins in Swiss-Prot, TrEMBL, and 131 complete proteomes (including 10 of eukaryotes) from the Proteome Analysis database at EBI. Solving the structures of proteins from the 5000 largest Pfam families would allow accurate fold assignment for approximately 68 percent of all prokaryotic proteins (covering 59 percent of residues) and 61 percent of eukaryotic proteins (40 percent of residues). More fine-grained coverage which would allow accurate modeling of these proteins would require an order of magnitude more targets. The Pfam5000 strategy may be modified in several ways, for example to focus on larger families, bacterial sequences, or eukaryotic sequences; as long as secondary consideration is given to large families within Pfam, coverage results vary only slightly. In contrast, focusing structural genomics on a single tractable genome would have only a limited impact in structural knowledge of other proteomes: a significant fraction (about 30-40 percent of the proteins, and 40-60 percent of the residues) of each proteome is classified in small

  16. Fiber-optic Raman probe couples ball lens for depth-selected Raman measurements of epithelial tissue.

    Science.gov (United States)

    Mo, Jianhua; Zheng, Wei; Huang, Zhiwei

    2010-06-28

    In this study, we present a fiber-optic ball lens Raman probe design for improving depth-selected Raman measurements of epithelial tissue. The Monte Carlo simulation results show that tissue Raman collection efficiency can be improved by properly selecting the refractive index and the diameter of the ball lens for the Raman probe design and the depth-selectivity of Raman measurements can also be improved by either increasing the refractive index or reducing the diameter of the ball lens. An appropriate arrangement of the Raman probe-tissue distance can also optimize the collection efficiency for depth-resolved Raman measurements. Experimental evaluation of a ball lens Raman probe design on a two-layer tissue phantom confirms the potential of the ball lens Raman probe design for efficient depth-selected measurement on epithelial tissue. This work suggests that the fiber-optic Raman probe coupled with a ball lens can facilitate the depth-selected Raman measurements of epithelial tissue, which may improve the diagnosis of epithelial precancer and early cancer at the molecular level.

  17. Body condition score as a selection tool for targeted selective treatment-based nematode control strategies in Merino ewes.

    Science.gov (United States)

    Cornelius, M P; Jacobson, C; Besier, R B

    2014-12-15

    Sheep nematode control utilising refugia-based strategies have been shown to delay anthelmintic resistance, but the optimal indices to select individuals to be left untreated under extensive sheep grazing conditions are not clear. This experiment tested the hypothesis that high body condition can indicate ability of mature sheep to better cope with worms and therefore remain untreated in a targeted treatment programme. Adult Merino ewes from flocks on two private farms located in south-west Western Australia (Farm A, n = 271, and Farm B, n = 258) were measured for body condition score (BCS), body weight and worm egg counts (WEC) on four occasions between May and December (pre-lambing, lamb marking, lamb weaning and post-weaning). Half of the ewes in each flock received anthelmintic treatments to suppress WEC over the experimental period and half remained untreated (unless critical limits were reached). Response to treatment was analysed in terms of BCS change and percentage live weight change. No effect of high or low initial WEC groups was shown for BCS response, and liveweight responses were inconsistent. A relatively greater BCS response to treatment was observed in ewes in low BCS pre-lambing compared to better-conditioned ewes on one farm where nutrition was sub-optimal and worm burdens were high. Sheep in low body condition pre-lambing were more than three times more likely to fall into a critically low BCS (<2.0) if left untreated. Recommendations can be made to treat ewes in lower BCS and leave a proportion of the higher body condition sheep untreated in a targeted selective treatment programme, to provide a population of non-resistant worms to delay the development of resistance. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Treatment of Prolapsing Hemorrhoids in HIV-Infected Patients with Tissue-Selecting Technique

    Directory of Open Access Journals (Sweden)

    Zhe Fan

    2017-01-01

    Full Text Available The aim of this retrospective study was to evaluate the outcome of a tissue-selecting therapy stapler (TST for prolapsing hemorrhoids in HIV-infected patients. Sixty-two patients with stage III-IV hemorrhoidal prolapse were treated with TST by a single surgeon between June and November 2014. The TST group comprised 32 patients (4 females, and the TST + HIV group comprised 30 HIV-infected patients (3 females. Age, gender, and preoperative examination as well as intraoperative and postoperative features were assessed. There was no marked difference in hemorrhoidal prolapse between the TST and HIV + TST groups, except for patient satisfaction at 12 months. TST is an effective and safe technique for treatment of prolapsing hemorrhoids in HIV-infected patients.

  19. Targeting MED1 LxxLL Motifs for Tissue-Selective Treatment of Human Breast Cancer

    Science.gov (United States)

    2014-09-01

    development, with some of such siRNAs in early-stage clinical trials for treatment of diseases including pachyonchyia congenita, menopausal osteoporosis ...approval of Pegaptanib (Macugen, Eyetech Pharmaceutics/Pfizer) by the US Food and Drug Administration (FDA) for the treatment of age- related macular...protein known to function in angiogenesis and neovascularization in age- related macular degeneration (AMD) and diabetic macular edema (DME) (24, 25

  20. Targeting MED1 LxxLL Motifs for Tissue-Selective Treatment of Human Breast Cancer

    Science.gov (United States)

    2013-09-01

    Cell 2000; 101: 25-33. [34] Matzke MA and Birchler JA. RNAi-mediated pathways in the nucleus. Nat Rev Genet 2005; 6: 24-35. [35] Tolia NH and...that displace cocaine from the membrane-bound nicotinic acetylcholine receptor. Proc Natl Acad Sci U S A 1998; 95: 14051-14056. [63] Ulrich H...December 2012 Oncogene (2013), 1–2 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc such as the genetic loss

  1. The Time-domain Spectroscopic Survey: Target Selection for Repeat Spectroscopy

    Science.gov (United States)

    MacLeod, Chelsea L.; Green, Paul J.; Anderson, Scott F.; Eracleous, Michael; Ruan, John J.; Runnoe, Jessie; Nielsen Brandt, William; Badenes, Carles; Greene, Jenny; Morganson, Eric; Schmidt, Sarah J.; Schwope, Axel; Shen, Yue; Amaro, Rachael; Lebleu, Amy; Filiz Ak, Nurten; Grier, Catherine J.; Hoover, Daniel; McGraw, Sean M.; Dawson, Kyle; Hall, Patrick B.; Hawley, Suzanne L.; Mariappan, Vivek; Myers, Adam D.; Pâris, Isabelle; Schneider, Donald P.; Stassun, Keivan G.; Bershady, Matthew A.; Blanton, Michael R.; Seo, Hee-Jong; Tinker, Jeremy; Fernández-Trincado, J. G.; Chambers, Kenneth; Kaiser, Nick; Kudritzki, R.-P.; Magnier, Eugene; Metcalfe, Nigel; Waters, Chris Z.

    2018-01-01

    As astronomers increasingly exploit the information available in the time domain, spectroscopic variability in particular opens broad new channels of investigation. Here we describe the selection algorithms for all targets intended for repeat spectroscopy in the Time Domain Spectroscopic Survey (TDSS), part of the extended Baryon Oscillation Spectroscopic Survey within the Sloan Digital Sky Survey (SDSS)-IV. Also discussed are the scientific rationale and technical constraints leading to these target selections. The TDSS includes a large “repeat quasar spectroscopy” (RQS) program delivering ∼13,000 repeat spectra of confirmed SDSS quasars, and several smaller “few-epoch spectroscopy” (FES) programs targeting specific classes of quasars as well as stars. The RQS program aims to provide a large and diverse quasar data set for studying variations in quasar spectra on timescales of years, a comparison sample for the FES quasar programs, and an opportunity for discovering rare, serendipitous events. The FES programs cover a wide variety of phenomena in both quasars and stars. Quasar FES programs target broad absorption line quasars, high signal-to-noise ratio normal broad line quasars, quasars with double-peaked or very asymmetric broad emission line profiles, binary supermassive black hole candidates, and the most photometrically variable quasars. Strongly variable stars are also targeted for repeat spectroscopy, encompassing many types of eclipsing binary systems, and classical pulsators like RR Lyrae. Other stellar FES programs allow spectroscopic variability studies of active ultracool dwarf stars, dwarf carbon stars, and white dwarf/M dwarf spectroscopic binaries. We present example TDSS spectra and describe anticipated sample sizes and results.

  2. Mitochondrial targeted coenzyme Q, superoxide, and fuel selectivity in endothelial cells.

    Directory of Open Access Journals (Sweden)

    Brian D Fink

    Full Text Available Previously, we reported that the "antioxidant" compound "mitoQ" (mitochondrial-targeted ubiquinol/ubiquinone actually increased superoxide production by bovine aortic endothelial (BAE cell mitochondria incubated with complex I but not complex II substrates.To further define the site of action of the targeted coenzyme Q compound, we extended these studies to include different substrate and inhibitor conditions. In addition, we assessed the effects of mitoquinone on mitochondrial respiration, measured respiration and mitochondrial membrane potential in intact cells, and tested the intriguing hypothesis that mitoquinone might impart fuel selectivity in intact BAE cells. In mitochondria respiring on differing concentrations of complex I substrates, mitoquinone and rotenone had interactive effects on ROS consistent with redox cycling at multiple sites within complex I. Mitoquinone increased respiration in isolated mitochondria respiring on complex I but not complex II substrates. Mitoquinone also increased oxygen consumption by intact BAE cells. Moreover, when added to intact cells at 50 to 1000 nM, mitoquinone increased glucose oxidation and reduced fat oxidation, at doses that did not alter membrane potential or induce cell toxicity. Although high dose mitoquinone reduced mitochondrial membrane potential, the positively charged mitochondrial-targeted cation, decyltriphenylphosphonium (mitoquinone without the coenzyme Q moiety, decreased membrane potential more than mitoquinone, but did not alter fuel selectivity. Therefore, non-specific effects of the positive charge were not responsible and the quinone moiety is required for altered nutrient selectivity.In summary, the interactive effects of mitoquinone and rotenone are consistent with redox cycling at more than one site within complex I. In addition, mitoquinone has substrate dependent effects on mitochondrial respiration, increases repiration by intact cells, and alters fuel selectivity favoring

  3. Correlation between the state of periodontal tissues and selected risk factors for periodontitis and myocardial infarction.

    Science.gov (United States)

    Górska, Renata; Dembowska, Elżbieta; Konopka, Tomasz P; Wysokińska-Miszczuk, Joanna; Pietruska, Małgorzata; Ganowicz, Ewa

    2017-01-01

    The current level of knowledge indicates a relationship between periodontitis and diabetes and/or cardiovascular diseases (CVD). Periodontitis can be not only a risk factor for these diseases, but also a condition modifying other primary risk factors associated with the occurrence of cardiovascular complications (lipid disorders, arterial hypertension, etc.) or diabetes. The aim of the study was an analysis of the correlation between the state of periodontal tissues and selected risk factors for myocardial infarction (MI) in patients after recent myocardial infarction. The study included 417 patients (92 women, 325 men) hospitalized due to recent MI. The inclusion criteria were MI history and age below 70 years. The state of periodontal tissues (plaque index, bleeding on probing, pocket depth and clinical attachment loss, CPI index) and selected risk factors for periodontitis and CVD were recorded. An analysis of the results showed no statistically significant correlation between the depth, the number, percentage of periodontal pockets and the average clinical attachment level on one hand and BMI on the other hand. Whereas a statistically significant correlation was observed between tobacco smoking and the degree of severity of periodontal diseases measured by the average pocket depth, the number and percentage of pockets above 4 mm and the average clinical attachment loss, as well as between hypertension and the state of oral hygiene and between diabetes and the number of preserved teeth and the number of pockets above 4 mm. The degree of severity of periodontal disease can impact hypertension and diabetes, which could potentially influence the occurrence and course of CVD.

  4. Fiber-optic Raman probe couples ball lens for depth-selected Raman measurements of epithelial tissue

    OpenAIRE

    Mo, Jianhua; Zheng, Wei; Huang, Zhiwei

    2010-01-01

    In this study, we present a fiber-optic ball lens Raman probe design for improving depth-selected Raman measurements of epithelial tissue. The Monte Carlo simulation results show that tissue Raman collection efficiency can be improved by properly selecting the refractive index and the diameter of the ball lens for the Raman probe design and the depth-selectivity of Raman measurements can also be improved by either increasing the refractive index or reducing the diameter of the ball lens. An a...

  5. Sequential Retraction Segregates SGN Processes during Target Selection in the Cochlea.

    Science.gov (United States)

    Druckenbrod, Noah R; Goodrich, Lisa V

    2015-12-09

    A hallmark of the nervous system is the presence of precise patterns of connections between different types of neurons. Many mechanisms can be used to establish specificity, including homophilic adhesion and synaptic refinement, but the range of strategies used across the nervous system remains unclear. To broaden the understanding of how neurons find their targets, we studied the developing murine cochlea, where two classes of spiral ganglion neurons (SGNs), type I and type II, navigate together to the sensory epithelium and then diverge to contact inner hair cells (IHCs) or outer hair cells (OHCs), respectively. Neurons with type I and type II morphologies are apparent before birth, suggesting that target selection might be accomplished by excluding type I processes from the OHC region. However, because type I processes appear to overshoot into type II territory postnatally, specificity may also depend on elimination of inappropriate synapses. To resolve these differences, we analyzed the morphology and dynamic behaviors of individual fibers and their branches as they interact with potential partners. We found that SGN processes continue to be segregated anatomically in the postnatal cochlea. Although type I-like fibers branched locally, few branches contacted OHCs, arguing against synaptic elimination. Instead, time-lapse imaging studies suggest a prominent role for retraction, first positioning processes to the appropriate region and then corralling branches during a subsequent period of exuberant growth and refinement. Thus, sequential stages of retraction can help to achieve target specificity, adding to the list of mechanisms available for sculpting neural circuits. During development, different types of neurons must form connections with specific synaptic targets, thereby creating the precise wiring diagram necessary for adult function. Although studies have revealed multiple mechanisms for target selection, we still know little about how different

  6. Targeting of breast metastases using a viral gene vector with tumour-selective transcription.

    LENUS (Irish Health Repository)

    Rajendran, Simon

    2012-01-31

    BACKGROUND: Adeno-associated virus (AAV) vectors have significant potential as gene delivery vectors for cancer gene therapy. However, broad AAV2 tissue tropism results in nonspecific gene expression. MATERIALS AND METHODS: We investigated use of the C-X-C chemokine receptor type 4 (CXCR4) promoter to restrict AAV expression to tumour cells, in subcutaneous MCF-7 xenograft mouse models of breast cancer and in patient samples, using bioluminescent imaging and flow cytometric analysis. RESULTS: Higher transgene expression levels were observed in subcutaneous MCF-7 tumours relative to normal tissue (muscle) using the CXCR4 promoter, unlike a ubiquitously expressing Cytomegalovirus promoter construct, with preferential AAVCXCR4 expression in epithelial tumour and CXCR4-positive cells. Transgene expression following intravenously administered AAVCXCR4 in a model of liver metastasis was detected specifically in livers of tumour bearing mice. Ex vivo analysis using patient samples also demonstrated higher AAVCXCR4 expression in tumour compared with normal liver tissue. CONCLUSION: This study demonstrates for the first time, the potential for systemic administration of AAV2 vector for tumour-selective gene therapy.

  7. CdSe/ZnS Quantum Dots-Labeled Mesenchymal Stem Cells for Targeted Fluorescence Imaging of Pancreas Tissues and Therapy of Type 1 Diabetic Rats.

    Science.gov (United States)

    Liu, Haoqi; Tang, Wei; Li, Chao; Lv, Pinlei; Wang, Zheng; Liu, Yanlei; Zhang, Cunlei; Bao, Yi; Chen, Haiyan; Meng, Xiangying; Song, Yan; Xia, Xiaoling; Pan, Fei; Cui, Daxiang; Shi, Yongquan

    2015-12-01

    Mesenchymal stem cells (MSCs) have been used for therapy of type 1 diabetes mellitus. However, the in vivo distribution and therapeutic effects of transplanted MSCs are not clarified well. Herein, we reported that CdSe/ZnS quantum dots-labeled MSCs were prepared for targeted fluorescence imaging and therapy of pancreas tissues in rat models with type 1 diabetes. CdSe/ZnS quantum dots were synthesized, their biocompatibility was evaluated, and then, the appropriate concentration of quantum dots was selected to label MSCs. CdSe/ZnS quantum dots-labeled MSCs were injected into mouse models with type 1 diabetes via tail vessel and then were observed by using the Bruker In-Vivo F PRO system, and the blood glucose levels were monitored for 8 weeks. Results showed that prepared CdSe/ZnS quantum dots owned good biocompatibility. Significant differences existed in distribution of quantum dots-labeled MSCs between normal control rats and diabetic rats (p quantum dots-labeled MSC injection. Statistical differences existed between the blood glucose levels of the diabetic rat control group and MSC-injected diabetic rat group (p < 0.01), and the MSC-injected diabetic rat group displayed lower blood glucose levels. In conclusion, CdSe/ZnS-labeled MSCs can target in vivo pancreas tissues in diabetic rats, and significantly reduce the blood glucose levels in diabetic rats, and own potential application in therapy of diabetic patients in the near future.

  8. Optimization of radiotherapy to target volumes with concave outlines: target-dose homogenization and selective sparing of critical structures by constrained matrix inversion

    Energy Technology Data Exchange (ETDEWEB)

    Colle, C.; Van den Berge, D.; De Wagter, C.; Fortan, L.; Van Duyse, B.; De Neve, W.

    1995-12-01

    The design of 3D-conformal dose distributions for targets with concave outlines is a technical challenge in conformal radiotherapy. For these targets, it is impossible to find beam incidences for which the target volume can be isolated from the tissues at risk. Commonly occurring examples are most thyroid cancers and the targets located at the lower neck and upper mediastinal levels related to some head and neck. A solution to this problem was developed, using beam intensity modulation executed with a multileaf collimator by applying a static beam-segmentation technique. The method includes the definition of beam incidences and beam segments of specific shape as well as the calculation of segment weights. Tests on Sherouse`s GRATISTM planning system allowed to escalate the dose to these targets to 65-70 Gy without exceeding spinal cord tolerance. Further optimization by constrained matrix inversion was investigated to explore the possibility of further dose escalation.

  9. Selective preparation of hard dental tissue: classical and laser treatments comparison

    Science.gov (United States)

    Dostálova, Tat'jana; Jelínkova, Helena; Němec, Michal; Koranda, Petr; Miyagi, Mitsunobu; Iwai, Katsumasa; Shi, Yi-Wei; Matsuura, Yuji

    2006-02-01

    For the purpose of micro-selective preparation which is part of the modern dentistry four various methods were examined: ablation by Er:YAG laser radiation (free-running or Q-switching regime), preparation of tissues by ultrasonic round ball tip, and by the classical dental drilling machine using diamond round bur. In the case of Er:YAG laser application the interaction energy 40 mJ in pulse of 200 us yielding to the interaction intensity 62 kW/cm2, and 20 mJ in pulse of 100 ns yielding to the interaction intensity 62 MW/cm2 was used for the case of free running, and Q-switch regime, respectively. For comparisson with the classical methods the ultrasound preparation tip (Sonixflex cariex TC, D - Sonicsys micro) and dental driller together with usual preparation burrs and standard handpiece were used. For the interaction experiment the samples of extracted human teeth and ebony cut into longitudinal sections and polished were used. The thickness of the prepared samples ranged from 5 to 7 mm. The methods were compared from the point of prepared cavity shape (SEM), inner surface, and possibility of selective removal of carries. The composite filling material was used to reconstruct the cavities. The dye penetrating analysis was performed.

  10. An evolutionary view of plant tissue culture: somaclonal variation and selection.

    Science.gov (United States)

    Wang, Qin-Mei; Wang, Li

    2012-09-01

    Plants regenerated from in vitro cultures possess an array of genetic and epigenetic changes. This phenomenon is known as 'somaclonal variation' and the frequency of somaclonal variation (SV) is usually elevated far beyond that expected in nature. Initially, the relationship between time in culture and detected SV was found to support the widespread belief that SV accumulates with culture age. However, a few studies indicated that older cultures yielded regenerants with less SV. What leads to this seemed contradiction? In this article, we have proposed a novel in vitro callus selection hypothesis, differentiation bottleneck (D-bottleneck) and dedifferentiation bottleneck (Dd-bottleneck), which consider natural selection theory to be fit for cell population in vitro. The results of multiplication races between the cells with the true-to-type phenotype and the deleterious cells determine the increase/decrease of SV frequencies in calli or regenerants as in vitro culture time goes on. The possibility of interpreting the complex situation of time-related SV by the evolutionary theory is discussed in this paper. In addition, the SV threshold, space-determined hypothesis and D-bottleneck are proposed to interpret the loss of the regenerability through a long period of plant tissue culture (PTC).

  11. Antisense oligonucleotides targeting translation inhibitory elements in 5' UTRs can selectively increase protein levels.

    Science.gov (United States)

    Liang, Xue-Hai; Sun, Hong; Shen, Wen; Wang, Shiyu; Yao, Joyee; Migawa, Michael T; Bui, Huynh-Hoa; Damle, Sagar S; Riney, Stan; Graham, Mark J; Crooke, Rosanne M; Crooke, Stanley T

    2017-09-19

    A variety of diseases are caused by deficiencies in amounts or activity of key proteins. An approach that increases the amount of a specific protein might be of therapeutic benefit. We reasoned that translation could be specifically enhanced using trans-acting agents that counter the function of negative regulatory elements present in the 5' UTRs of some mRNAs. We recently showed that translation can be enhanced by antisense oligonucleotides (ASOs) that target upstream open reading frames. Here we report the amount of a protein can also be selectively increased using ASOs designed to hybridize to other translation inhibitory elements in 5' UTRs. Levels of human RNASEH1, LDLR, and ACP1 and of mouse ACP1 and ARF1 were increased up to 2.7-fold in different cell types and species upon treatment with chemically modified ASOs targeting 5' UTR inhibitory regions in the mRNAs encoding these proteins. The activities of ASOs in enhancing translation were sequence and position dependent and required helicase activity. The ASOs appear to improve the recruitment of translation initiation factors to the target mRNA. Importantly, ASOs targeting ACP1 mRNA significantly increased the level of ACP1 protein in mice, suggesting that this approach has therapeutic and research potentials. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  12. The group A streptococcal collagen-like protein 1, Scl1, mediates biofilm formation by targeting the EDA-containing variant of cellular fibronectin expressed in wounded tissue

    Science.gov (United States)

    Oliver-Kozup, Heaven; Martin, Karen H.; Schwegler-Berry, Diane; Green, Brett J.; Betts, Courtney; Shinde, Arti V.; Van De Water, Livingston; Lukomski, Slawomir

    2012-01-01

    Summary Wounds are known to serve as portals of entry for group A Streptococcus (GAS). Subsequent tissue colonization is mediated by interactions between GAS surface proteins and host extracellular matrix components. We recently reported that the streptococcal collagen-like protein-1, Scl1, selectively binds the cellular form of fibronectin (cFn) and also contributes to GAS biofilm formation on abiotic surfaces. One structural feature of cFn, which is predominantly expressed in response to tissue injury, is the presence of a spliced variant containing extra domain A (EDA/EIIIA). We now report that GAS biofilm formation is mediated by the Scl1 interaction with EDA-containing cFn. Recombinant Scl1 proteins that bound cFn also bound recombinant EDA within the C-C′ loop region recognized by the α9β1 integrin. The extracellular 2-D matrix derived from human dermal fibroblasts supports GAS adherence and biofilm formation. Altogether, this work identifies and characterizes a novel molecular mechanism by which GAS utilizes Scl1 to specifically target an extracellular matrix component that is predominantly expressed at the site of injury in order to secure host tissue colonization. PMID:23217101

  13. Mature Epitope Density - A strategy for target selection based on immunoinformatics and exported prokaryotic proteins

    DEFF Research Database (Denmark)

    Santos, Anderson R; Pereira, Vanessa Bastos; Barbosa, Eudes

    2013-01-01

    . However, currently available tools do not account for the concentration of epitope products in the mature protein product and its relation to the reliability of target selection. RESULTS: We developed a computational strategy based on measuring the epitope's concentration in the mature protein, called...... Mature Epitope Density (MED). Our method, though simple, is capable of identifying promising vaccine targets. Our online software implementation provides a computationally light and reliable analysis of bacterial exoproteins and their potential for vaccines or diagnosis projects against pathogenic....... Half of the 60 proteins were classified as highest scored by the MED statistic, while the other half were classified as lowest scored. Among the lowest scored proteins, ~13% were confirmed as not related to antigenicity or not contributing to the bacterial pathogenicity, and 70% of the highest scored...

  14. Differential selective constraints shaping codon usage pattern of housekeeping and tissue-specific homologous genes of rice and arabidopsis.

    Science.gov (United States)

    Mukhopadhyay, Pamela; Basak, Surajit; Ghosh, Tapash Chandra

    2008-12-01

    Intra-genomic variation between housekeeping and tissue-specific genes has always been a study of interest in higher eukaryotes. To-date, however, no such investigation has been done in plants. Availability of whole genome expression data for both rice and Arabidopsis has made it possible to examine the evolutionary forces in shaping codon usage pattern in both housekeeping and tissue-specific genes in plants. In the present work, we have taken 4065 rice-Arabidopsis homologous gene pairs to study evolutionary forces responsible for codon usage divergence between housekeeping and tissue-specific genes. In both rice and Arabidopsis, it is mutational bias that regulates error minimization in highly expressed genes of both housekeeping and tissue-specific genes. Our results show that, in comparison to tissue-specific genes, housekeeping genes are under strong selective constraint in plants. However, in tissue-specific genes, lowly expressed genes are under stronger selective constraint compared with highly expressed genes. We demonstrated that constraint acting on mRNA secondary structure is responsible for modulating codon usage variations in rice tissue-specific genes. Thus, different evolutionary forces must underline the evolution of synonymous codon usage of highly expressed genes of housekeeping and tissue-specific genes in rice and Arabidopsis.

  15. Dynamics of wound healing signaling as a potential therapeutic target for radiation-induced tissue damage.

    Science.gov (United States)

    Chung, Yih-Lin; Pui, Newman N M

    2015-01-01

    We hypothesized the histone deacetylase inhibitor phenylbutyrate (PB) has beneficial effects on radiation-induced injury by modulating the expression of DNA repair and wound healing genes. Hamsters received a radiosurgical dose of radiation (40 Gy) to the cheek and were treated with varying PB dosing regimens. Gross alteration of the irradiated cheeks, eating function, histological changes, and gene expression during the course of wound healing were compared between treatment groups. Pathological analysis showed decreased radiation-induced mucositis, facilitated epithelial cell growth, and preventing ulcerative wound formation, after short-term PB treatment, but not after vehicle or sustained PB. The radiation-induced wound healing gene expression profile exhibited a sequential transition from the inflammatory and DNA repair phases to the tissue remodeling phase in the vehicle group. Sustained PB treatment resulted in a prolonged wound healing gene expression profile and delayed the wound healing process. Short-term PB shortened the duration of inflammatory cytokine expression, triggered repeated pulsed expression of cell cycle and DNA repair-regulating genes, and promoted earlier oscillatory expression of tissue remodeling genes. Distinct gene expression patterns between sustained and short-term treatment suggest dynamic profiling of wound healing gene expression can be an important part of a biological therapeutic strategy to mitigate radiation-related tissue injury. © 2015 by the Wound Healing Society.

  16. Real-time target selection optimization to enhance alignment of gas chromatograms.

    Science.gov (United States)

    Dearing, Thomas I; Nadeau, Jeremy S; Rohrback, Brian G; Ramos, L Scott; Synovec, Robert E

    2011-01-15

    An improved method for real-time selection of the target for the alignment of gas chromatographic data is described. Further outlined is a simple method to determine the accuracy of the alignment procedure. The target selection method proposed uses a moving window of aligned chromatograms to generate a target, herein referred to as the window target method (WTM). The WTM was initially tested using a series of 100 simulated chromatograms, and additionally evaluated using a series of 55 diesel fuel gas chromatograms obtained with four fuel samples. The WTM was evaluated via a comparison to a related method (the nearest neighbor method (NNM)). The results using the WTM with simulated chromatograms showed a significant improvement in the correlation coefficient and the accuracy of alignment when compared to the alignments performed using the NNM. A significant improvement in real-time alignment accuracy, as assessed by a correlation coefficient metric, was achieved with the WTM (starting at ∼ 1.0 and declining to only ∼ 0.985 for the 100th sample), relative to the NNM (starting at ∼ 1.0 and declining to ∼ 0.4 for the 100th sample) for the simulated chromatogram study. The results determined when using the WTM with the diesel fuels also showed an improvement in correlation coefficient and accuracy of the within-class alignments as compared to the results obtained from the NNM. In practice, the WTM could be applied to the real-time analysis of process and feedstock industrial streams to enable real-time decision making from the more precisely aligned chromatographic data. Copyright © 2010 Elsevier B.V. All rights reserved.

  17. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours

    DEFF Research Database (Denmark)

    Lasko, Loren M; Jakob, Clarissa G; Edalji, Rohinton P

    2017-01-01

    The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved...... model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases....... also been implicated in human pathological conditions (including cancer). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products, bi-substrate analogues and the widely used small molecule C646, lack potency or selectivity. Here, we describe A-485, a potent...

  18. Criteria for selection of target materials and design of high-efficiency-release targets for radioactive ion beam generation

    CERN Document Server

    Alton, G D; Liu, Y

    1999-01-01

    In this report, we define criteria for choosing target materials and for designing, mechanically stable, short-diffusion-length, highly permeable targets for generation of high-intensity radioactive ion beams (RIBs) for use at nuclear physics and astrophysics research facilities based on the ISOL principle. In addition, lists of refractory target materials are provided and examples are given of a number of successful targets, based on these criteria, that have been fabricated and tested for use at the Holifield Radioactive Ion Beam Facility (HRIBF).

  19. Evodiamine selectively targets cancer stem-like cells through the p53-p21-Rb pathway

    International Nuclear Information System (INIS)

    Han, Seula; Woo, Jong Kyu; Jung, Yuchae; Jeong, Dawoon; Kang, Minsook; Yoo, Young-Ji; Lee, Hani; Oh, Seung Hyun; Ryu, Jae-Ha; Kim, Woo-Young

    2016-01-01

    In spite of the recent improvements, the resistance to chemotherapy/radiotherapy followed by relapse is the main hurdle for the successful treatment of breast cancer, a leading cause of death in women. A small population of breast cancer cells that have stem-like characteristics (cancer stem-like cells; CSLC) may contribute to this resistance and relapse. Here, we report on a component of a traditional Chinese medicine, evodiamine, which selectively targets CSLC of breast cancer cell lines MCF7 and MDAMB 231 at a concentration that does show a little or no cytotoxic effect on bulk cancer cells. While evodiamine caused the accumulation of bulk cancer cells at the G2/M phase, it did not hold CSLC in a specific cell cycle phase but instead, selectively killed CSLC. This was not due to the culture of CSLC in suspension or without FBS. A proteomic analysis and western blotting revealed that evodiamine changed the expression of cell cycle regulating molecules more efficiently in CSLC cells than in bulk cancer cells. Surprisingly, evodiamine selectively activated p53 and p21 and decreased inactive Rb, the master molecules in G1/S checkpoint. These data collectively suggest a novel mechanism involving CSLC-specific targeting by evodiamine and its possible use to the therapy of breast cancer. - Highlights: • Evodiamine selectively kills breast cancer stem like cells at G1 phase. • Evodiamine utilizes different mechanism of cell cycle modulation in CSLC and in bulk cancer cells. • Evodiamine activate the p53, p21 and Rb pathway.

  20. Rapid and targeted introgression of genes into popular wheat cultivars using marker-assisted background selection.

    Directory of Open Access Journals (Sweden)

    Harpinder S Randhawa

    Full Text Available A marker-assisted background selection (MABS-based gene introgression approach in wheat (Triticum aestivum L. was optimized, where 97% or more of a recurrent parent genome (RPG can be recovered in just two backcross (BC generations. A four-step MABS method was developed based on 'Plabsim' computer simulations and wheat genome structure information. During empirical optimization of this method, double recombinants around the target gene were selected in a step-wise fashion during the two BC cycles followed by selection for recurrent parent genotype on non-carrier chromosomes. The average spacing between carrier chromosome markers was <4 cM. For non-carrier chromosome markers that flanked each of the 48 wheat gene-rich regions, this distance was approximately 12 cM. Employed to introgress seedling stripe rust (Puccinia striiformis f. sp. tritici resistance gene Yr15 into the spring wheat cultivar 'Zak', marker analysis of 2,187 backcross-derived progeny resulted in the recovery of a BC(2F(2ratio3 plant with 97% of the recurrent parent genome. In contrast, only 82% of the recurrent parent genome was recovered in phenotypically selected BC(4F(7 plants developed without MABS. Field evaluation results from 17 locations indicated that the MABS-derived line was either equal or superior to the recurrent parent for the tested agronomic characteristics. Based on these results, MABS is recommended as a strategy for rapidly introgressing a targeted gene into a wheat genotype in just two backcross generations while recovering 97% or more of the recurrent parent genotype.

  1. Evodiamine selectively targets cancer stem-like cells through the p53-p21-Rb pathway

    Energy Technology Data Exchange (ETDEWEB)

    Han, Seula [The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul (Korea, Republic of); Woo, Jong Kyu [College of Pharmacy, Gachon University, Incheon (Korea, Republic of); Jung, Yuchae; Jeong, Dawoon; Kang, Minsook; Yoo, Young-Ji; Lee, Hani [The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul (Korea, Republic of); Oh, Seung Hyun [College of Pharmacy, Gachon University, Incheon (Korea, Republic of); Ryu, Jae-Ha [The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul (Korea, Republic of); Kim, Woo-Young, E-mail: wykim@sookmyung.ac.kr [The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul (Korea, Republic of)

    2016-01-22

    In spite of the recent improvements, the resistance to chemotherapy/radiotherapy followed by relapse is the main hurdle for the successful treatment of breast cancer, a leading cause of death in women. A small population of breast cancer cells that have stem-like characteristics (cancer stem-like cells; CSLC) may contribute to this resistance and relapse. Here, we report on a component of a traditional Chinese medicine, evodiamine, which selectively targets CSLC of breast cancer cell lines MCF7 and MDAMB 231 at a concentration that does show a little or no cytotoxic effect on bulk cancer cells. While evodiamine caused the accumulation of bulk cancer cells at the G2/M phase, it did not hold CSLC in a specific cell cycle phase but instead, selectively killed CSLC. This was not due to the culture of CSLC in suspension or without FBS. A proteomic analysis and western blotting revealed that evodiamine changed the expression of cell cycle regulating molecules more efficiently in CSLC cells than in bulk cancer cells. Surprisingly, evodiamine selectively activated p53 and p21 and decreased inactive Rb, the master molecules in G1/S checkpoint. These data collectively suggest a novel mechanism involving CSLC-specific targeting by evodiamine and its possible use to the therapy of breast cancer. - Highlights: • Evodiamine selectively kills breast cancer stem like cells at G1 phase. • Evodiamine utilizes different mechanism of cell cycle modulation in CSLC and in bulk cancer cells. • Evodiamine activate the p53, p21 and Rb pathway.

  2. Targeted Delivery of Neutralizing Anti-C5 Antibody to Renal Endothelium Prevents Complement-Dependent Tissue Damage

    Directory of Open Access Journals (Sweden)

    Paolo Durigutto

    2017-09-01

    Full Text Available Complement activation is largely implicated in the pathogenesis of several clinical conditions and its therapeutic neutralization has proven effective in preventing tissue and organ damage. A problem that still needs to be solved in the therapeutic control of complement-mediated diseases is how to avoid side effects associated with chronic neutralization of the complement system, in particular, the increased risk of infections. We addressed this issue developing a strategy based on the preferential delivery of a C5 complement inhibitor to the organ involved in the pathologic process. To this end, we generated Ergidina, a neutralizing recombinant anti-C5 human antibody coupled with a cyclic-RGD peptide, with a distinctive homing property for ischemic endothelial cells and effective in controlling tissue damage in a rat model of renal ischemia/reperfusion injury (IRI. As a result of its preferential localization on renal endothelium, the molecule induced complete inhibition of complement activation at tissue level, and local protection from complement-mediated tissue damage without affecting circulating C5. The ex vivo binding of Ergidina to surgically removed kidney exposed to cold ischemia supports its therapeutic use to prevent posttransplant IRI leading to delay of graft function. Moreover, the finding that the ex vivo binding of Ergidina was not restricted to the kidney, but was also seen on ischemic heart, suggests that this RGD-targeted anti-C5 antibody may represent a useful tool to treat organs prior to transplantation. Based on this evidence, we propose preliminary data showing that Ergidina is a novel targeted drug to prevent complement activation on the endothelium of ischemic kidney.

  3. New Therapeutic and Diagnostic Opportunities for Injured Tissue-Specific Targeting of Complement Inhibitors and Imaging Modalities

    Science.gov (United States)

    Holers, V. Michael; Tomlinson, Stephen; Kulik, Liudmila; Atkinson, Carl; Rohrer, Bärbel; Banda, Nirmal; Thurman, Joshua M.

    2016-01-01

    Despite substantial opportunity and commercial interest in developing drugs that modulate the complement system in a broad range of non-orphan indications, several obstacles remain to be overcome. Among these issues is the biophysical nature of complement proteins, whose circulating levels are typically very high and whose turnover rates are relatively rapid, especially in the setting of chronic inflammatory conditions. This situation necessitates the use of very high levels of therapeutic compounds in order to achieve both multi-pathway and multiple effector mechanism inhibition. In addition, one must avoid infectious complications or the systemic impairment of the other important physiological functions of complement. Herein we focus on the development of a novel therapeutic strategy based on injured tissue-specific targeting of complement inhibitors using the antigen-combining domains of a small subset of natural IgM antibodies, which as endogenous antibodies specifically recognize sites of local damage across a broad range of tissues and locally activate complement C3, resulting in C3 fragment covalent fixation. Because the use of such recombinant tissue-targeting inhibitors precludes the utility of measuring systemic levels of complement biomarkers or function, since a goal of this targeting strategy is to leave those processes intact and unimpeded, we also briefly describe a new method designed to quantitatively measure using imaging modalities the inhibition of generation of fixed C3 fragments at sites of inflammation/injury. In addition to the ability to determine whether complement activation is locally constrained with the use of inhibitors, there is also a broader application of this imaging approach to inflammatory and autoimmune diseases characterized by local complement activation. PMID:27282113

  4. Reagent Precoated Targets for Rapid In-Tissue Derivatization of the Anti-Tuberculosis Drug Isoniazid Followed by MALDI Imaging Mass Spectrometry

    Science.gov (United States)

    Manier, M. Lisa; Reyzer, Michelle L.; Goh, Anne; Dartois, Veronique; Via, Laura E.; Barry, Clifton E.; Caprioli, Richard M.

    2011-08-01

    Isoniazid (INH) is an important component of front-line anti-tuberculosis therapy with good serum pharmacokinetics but unknown ability to penetrate tuberculous lesions. However, endogenous background interferences hinder our ability to directly analyze INH in tissues. Chemical derivatization has been successfully used to measure isoniazid directly from tissue samples using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS). MALDI targets were pretreated with trans-cinnamaldehyde (CA) prior to mounting tissue slices. Isoniazid present in the tissues was efficiently derivatized and the INH-CA product measured by MS/MS. Precoating of MALDI targets allows the tissues to be directly thaw-mounted and derivatized, thus simplifying the preparation. A time-course series of tissues from tuberculosis infected/INH dosed animals were assayed and the MALDI MS/MS response correlates well with the amount of INH determined to be in the tissues by high-performance liquid chromatography (HPLC)-MS/MS.

  5. Selective optical scattering characterisation of tissue malignancy using Mueller matrix polarimetry: a simulation study

    Science.gov (United States)

    Fathima, Adeeba; Sujatha, N.

    2016-04-01

    Quantitative Mueller polarimetry optically characterizes a medium and is reflected upon by the ultrastructural changes in it. Tissue morphology changes occur during advent of diseases like cancer neoplasia. This alters the Mueller matrix characterizing the tissue as an optical element. The nucleus size undergoes an approximate doubling during the development of cancer. Cell crowding during cancer increases the number density of the nuclei per unit volume. Modeling the cell nuclei as main scattering centers, a systematic computational study on how Mueller matrix elements vary for an increase in scatterer size and number density is performed. Simulation on polarized light transport of wavelength 633nm through a slab of size 3 mm comprising of spherical scatterers in a medium of refractive index 1.33 is carried out. Light propagation is modeled using Monte Carlo method and meridian plane method is adopted for tracking the polarization state change. The stokes vector of the outgoing light is tracked to calculate the Mueller matrix images of the light backscattered from the slab. The Mueller matrix elements as well as depolarization factors are derived. The depolarization index increases with scatterer size. Along with nucleus size, change in the cell number density is also expected in the different stages of the cancer growth. Volume fraction of the scatterers in medium is varied as an indicator of this number density change. Behavior of Mueller matrix with respect to change in scattering coefficient due to variation in scatterer size and volume fraction is studied. It is observed that the depolarization index derived from Mueller matrix has selective discrimination towards the change in scattering coefficient caused due to size change and volume fraction change respectively.

  6. Tissue-Specific Gain of RTK Signalling Uncovers Selective Cell Vulnerability during Embryogenesis.

    Directory of Open Access Journals (Sweden)

    Yannan Fan

    Full Text Available The successive events that cells experience throughout development shape their intrinsic capacity to respond and integrate RTK inputs. Cellular responses to RTKs rely on different mechanisms of regulation that establish proper levels of RTK activation, define duration of RTK action, and exert quantitative/qualitative signalling outcomes. The extent to which cells are competent to deal with fluctuations in RTK signalling is incompletely understood. Here, we employ a genetic system to enhance RTK signalling in a tissue-specific manner. The chosen RTK is the hepatocyte growth factor (HGF receptor Met, an appropriate model due to its pleiotropic requirement in distinct developmental events. Ubiquitously enhanced Met in Cre/loxP-based Rosa26(stopMet knock-in context (Del-R26(Met reveals that most tissues are capable of buffering enhanced Met-RTK signalling thus avoiding perturbation of developmental programs. Nevertheless, this ubiquitous increase of Met does compromise selected programs such as myoblast migration. Using cell-type specific Cre drivers, we genetically showed that altered myoblast migration results from ectopic Met expression in limb mesenchyme rather than in migrating myoblasts themselves. qRT-PCR analyses show that ectopic Met in limbs causes molecular changes such as downregulation in the expression levels of Notum and Syndecan4, two known regulators of morphogen gradients. Molecular and functional studies revealed that ectopic Met expression in limb mesenchyme does not alter HGF expression patterns and levels, but impairs HGF bioavailability. Together, our findings show that myoblasts, in which Met is endogenously expressed, are capable of buffering increased RTK levels, and identify mesenchymal cells as a cell type vulnerable to ectopic Met-RTK signalling. These results illustrate that embryonic cells are sensitive to alterations in the spatial distribution of RTK action, yet resilient to fluctuations in signalling levels of an

  7. Selective Targeting of SH2 Domain–Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies

    Energy Technology Data Exchange (ETDEWEB)

    Kükenshöner, Tim; Schmit, Nadine Eliane; Bouda, Emilie; Sha, Fern; Pojer, Florence; Koide, Akiko; Seeliger, Markus; Koide, Shohei; Hantschel, Oliver

    2017-05-01

    The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck). Interactome analysis of intracellularly expressed monobodies revealed that they bind SFKs but no other SH2-containing proteins. Three crystal structures of monobody–SH2 complexes unveiled different and only partly overlapping binding modes, which rationalized the observed selectivity and enabled structure-based mutagenesis to modulate inhibition mode and selectivity. In line with the critical roles of SFK SH2 domains in kinase autoinhibition and T-cell receptor signaling, monobodies binding the Src and Hck SH2 domains selectively activated respective recombinant kinases, whereas an Lck SH2-binding monobody inhibited proximal signaling events downstream of the T-cell receptor complex. Our results show that SFK SH2 domains can be targeted with unprecedented potency and selectivity using monobodies. They are excellent tools for dissecting SFK functions in normal development and signaling and to interfere with aberrant SFK signaling networks in cancer cells.

  8. Hepatoblastoma: A Need for Cell Lines and Tissue Banks to Develop Targeted Drug Therapies

    Directory of Open Access Journals (Sweden)

    Rishi Raj Rikhi

    2016-03-01

    Full Text Available Limited research exists regarding the most aggressive forms of hepatoblastoma. Cell lines of the rare subtypes of hepatoblastoma with poor prognosis are not only difficult to attain, but are challenging to characterize histologically. A community approach to educating parents and families of the need for donated tissue is necessary for scientists to have access to resources for murine models and drug discovery. Herein we describe the currently available resources, the today’s existing gaps in research, and the path to move forward for uniform cure of hepatoblastoma.

  9. Tissue distribution and tumor uptake of folate receptor–targeted epothilone folate conjugate, BMS-753493, in CD2F1 mice after systemic administration

    Directory of Open Access Journals (Sweden)

    Hong Shen

    2016-09-01

    Full Text Available To assess targeting of an epothilone folate conjugate (BMS-753493 to the folate receptor (FR-overexpressed tumor in mice bearing both FR+ and FR– tumors, a series of experiments were conducted by quantitative whole-body autoradiography (QWBA and LC–MS/MS following i.v. administration of BMS-753493 or its active moiety, BMS-748285 in mice bearing FR+ (98M109 and FR– (M109 tumors. QWBA showed [3H]BMS-753493–derived radioactivity was extensively distributed to various tissues. The FR over-expressing 98M109 tumors showed consistently higher level of radioactivity than FR-negative tumors (i.e., M109 tumors up to 48 h post dose of [3H]BMS-753493, despite the magnitude of difference between the tumors is relatively small (generally 3~5-fold. The radioactivity level in 98M109 tumors was 2~12-fold of normal tissues except intestine/content at 48 h post dose. No selective radioactivity uptake into 98M109 tumors over M109 or normal tissues was observed after i.v. administration of the active epothilone, [3H]BMS-748285. LC–MS/MS measurements demonstrated that the concentrations of BMS-748285, presumably from hydrolysis of the folate conjugate, in 98M109 tumors were greater than those in M109 tumors after i.v. administration of BMS-753493 (2–3-fold whereas no differential uptake in the tumors following BMS-748285 administration. Those data were consistent with radioactivity determinations. Those results demonstrated that the folate conjugation in BMS-753493 enabled moderately preferential distribution of the active epothilone to FR over-expressing 98M109 tumors, thereby supporting targeted delivery of cytotoxics through the folate receptor.

  10. Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting

    Directory of Open Access Journals (Sweden)

    Brian C. Palmer

    2016-12-01

    Full Text Available Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases.

  11. Peptide-modified liposomes for selective targeting of bombesin receptors overexpressed by cancer cells: a potential theranostic agent

    Science.gov (United States)

    Accardo, Antonella; Salsano, Giuseppina; Morisco, Anna; Aurilio, Michela; Parisi, Antonio; Maione, Francesco; Cicala, Carla; Tesauro, Diego; Aloj, Luigi; De Rosa, Giuseppe; Morelli, Giancarlo

    2012-01-01

    Objectives Drug delivery systems consisting of liposomes displaying a cell surface receptor-targeting peptide are being developed to specifically deliver chemotherapeutic drugs to tumors overexpressing a target receptor. This study addresses novel liposome composition approaches to specifically target tissues overexpressing bombesin (BN) receptors. Methods A new amphiphilic peptide derivative (MonY-BN) containing the BN(7–14) peptide, the DTPA (diethylenetriaminepentaacetate) chelating agent, a hydrophobic moiety with two C18 alkyl chains, and polyethylene glycol spacers, has been synthesized by solid-phase methods. Liposomes have been generated by co-aggregation of MonY-BN with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). The structural and biological properties of these new target-selective drug-delivery systems have been characterized. Results Liposomes with a DSPC/MonY-BN (97/3 molar ratio) composition showed a diameter of 145.5 ± 31.5 nm and a polydispersity index of 0.20 ± 0.05. High doxorubicin (Dox) loading was obtained with the remote pH gradient method using citrate as the inner buffer. Specific binding to PC-3 cells of DSPC/MonY-BN liposomes was obtained (2.7% ± 0.3%, at 37°C), compared with peptide-free DSPC liposomes (1.4% ± 0.2% at 37°C). Incubation of cells with DSPC/ MonY-BN/Dox showed significantly lower cell survival compared with DSPC/Dox-treated cells, in the presence of 100 ng/mL and 300 ng/mL drug amounts, in cytotoxicity experiments. Intravenous treatment of PC-3 xenograft-bearing mice with DSPC/MonY-BN/Dox at 10 mg/kg Dox dose produced higher tumour growth inhibition (60%) compared with nonspecific DSPC/ Dox liposomes (36%) relative to control animals. Conclusion The structural and loading properties of DSPC/MonY-BN liposomes along with the observed in-vitro and in-vivo activity are encouraging for further development of this approach for target-specific cancer chemotherapy. PMID:22619538

  12. Selective Photothermolysis to target Sebaceous Glands: Theoretical Estimation of Parameters and Preliminary Results Using a Free Electron Laser

    Energy Technology Data Exchange (ETDEWEB)

    Fernanda Sakamoto, Apostolos Doukas, William Farinelli, Zeina Tannous, Michelle D. Shinn, Stephen Benson, Gwyn P. Williams, H. Dylla, Richard Anderson

    2011-12-01

    The success of permanent laser hair removal suggests that selective photothermolysis (SP) of sebaceous glands, another part of hair follicles, may also have merit. About 30% of sebum consists of fats with copious CH2 bond content. SP was studied in vitro, using free electron laser (FEL) pulses at an infrared CH2 vibrational absorption wavelength band. Absorption spectra of natural and artificially prepared sebum were measured from 200 nm to 3000 nm, to determine wavelengths potentially able to target sebaceous glands. The Jefferson National Accelerator superconducting FEL was used to measure photothermal excitation of aqueous gels, artificial sebum, pig skin, human scalp and forehead skin (sebaceous sites). In vitro skin samples were exposed to FEL pulses from 1620 to 1720 nm, spot diameter 7-9.5 mm with exposure through a cold 4C sapphire window in contact with the skin. Exposed and control tissue samples were stained using H and E, and nitroblue tetrazolium chloride staining (NBTC) was used to detect thermal denaturation. Natural and artificial sebum both had absorption peaks near 1210, 1728, 1760, 2306 and 2346 nm. Laser-induced heating of artificial sebum was approximately twice that of water at 1710 and 1720 nm, and about 1.5x higher in human sebaceous glands than in water. Thermal camera imaging showed transient focal heating near sebaceous hair follicles. Histologically, skin samples exposed to {approx}1700 nm, {approx}100-125 ms pulses showed evidence of selective thermal damage to sebaceous glands. Sebaceous glands were positive for NBTC staining, without evidence of selective loss in samples exposed to the laser. Epidermis was undamaged in all samples. Conclusions: SP of sebaceous glands appears to be feasible. Potentially, optical pulses at {approx}1720 nm or {approx}1210 nm delivered with large beam diameter and appropriate skin cooling in approximately 0.1 s may provide an alternative treatment for acne.

  13. Targeted photodynamic therapy of established soft-tissue infections in mice

    Science.gov (United States)

    Gad, Faten; Zahra, Touqir; Hasan, Tayyaba; Hamblin, Michael R.

    2004-06-01

    The worldwide rise in antibiotic resistance necessitates the development of novel antimicrobial strategies. Although many workers have used photodynamic therapy (PDT) to kill bacteria in vitro, the use of this approach has seldom been reported in vivo in animal models of infection. We have previously described the first use of PDT to treat excisional wound infections by Gram-negative bacteria in living mice. However these infected wound models used a short time after infection (30 min) before PDT. We now report on the use of PDT to treat an established soft-tissue infection in mice. We used Staphylococcus aureus stably transformed with a Photorhabdus luminescens lux operon (luxABCDE) that was genetically modified to be functional in Gram-positive bacteria. These engineered bacteria emitted bioluminescence allowing the progress of the infection to be monitored in both space and time with a lowlight imaging charged couple device (CCD) camera. One million cells were injected into one or both thigh muscles of mice that had previously been rendered neutropenic by cyclophosphamide administration. Twenty-four hours later the bacteria had multiplied more than one hundred-fold, and poly-L-lysine chlorin(e6) conjugate or free chlorin(e6) was injected into one area of infected muscle and imaged with the CCD camera. Thirty-minutes later red light from a diode laser was delivered as a surface spot or by interstitial fiber into the infection. There was a lightdose dependent loss of bioluminescence (to resistant soft-tissue infections.

  14. Does Angling Technique Selectively Target Fishes Based on Their Behavioural Type?

    Directory of Open Access Journals (Sweden)

    Alexander D M Wilson

    Full Text Available Recently, there has been growing recognition that fish harvesting practices can have important impacts on the phenotypic distributions and diversity of natural populations through a phenomenon known as fisheries-induced evolution. Here we experimentally show that two common recreational angling techniques (active crank baits versus passive soft plastics differentially target wild largemouth bass (Micropterus salmoides and rock bass (Ambloplites rupestris based on variation in their behavioural tendencies. Fish were first angled in the wild using both techniques and then brought back to the laboratory and tested for individual-level differences in common estimates of personality (refuge emergence, flight-initiation-distance, latency-to-recapture and with a net, and general activity in an in-lake experimental arena. We found that different angling techniques appear to selectively target these species based on their boldness (as characterized by refuge emergence, a standard measure of boldness in fishes but not other assays of personality. We also observed that body size was independently a significant predictor of personality in both species, though this varied between traits and species. Our results suggest a context-dependency for vulnerability to capture relative to behaviour in these fish species. Ascertaining the selective pressures angling practices exert on natural populations is an important area of fisheries research with significant implications for ecology, evolution, and resource management.

  15. Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1

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    Hirotada Tajiri

    2017-05-01

    Full Text Available Oncogenic Ras plays a key role in cancer initiation but also contributes to malignant phenotypes by stimulating nutrient uptake and promoting invasive migration. Because these latter cellular responses require Rac-mediated remodeling of the actin cytoskeleton, we hypothesized that molecules involved in Rac activation may be valuable targets for cancer therapy. We report that genetic inactivation of the Rac-specific guanine nucleotide exchange factor DOCK1 ablates both macropinocytosis-dependent nutrient uptake and cellular invasion in Ras-transformed cells. By screening chemical libraries, we have identified 1-(2-(3′-(trifluoromethyl-[1,1′-biphenyl]-4-yl-2-oxoethyl-5-pyrrolidinylsulfonyl-2(1H-pyridone (TBOPP as a selective inhibitor of DOCK1. TBOPP dampened DOCK1-mediated invasion, macropinocytosis, and survival under the condition of glutamine deprivation without impairing the biological functions of the closely related DOCK2 and DOCK5 proteins. Furthermore, TBOPP treatment suppressed cancer metastasis and growth in vivo in mice. Our results demonstrate that selective pharmacological inhibition of DOCK1 could be a therapeutic approach to target cancer cell survival and invasion.

  16. Update on the Pfam5000 Strategy for Selection of StructuralGenomics Targets

    Energy Technology Data Exchange (ETDEWEB)

    Chandonia, John-Marc; Brenner, Steven E.

    2005-06-27

    Structural Genomics is an international effort to determine the three-dimensional shapes of all important biological macromolecules, with a primary focus on proteins. Target proteins should be selected according to a strategy that is medically and biologically relevant, of good financial value, and tractable. In 2003, we presented the ''Pfam5000'' strategy, which involves selecting the 5,000 most important families from the Pfam database as sources for targets. In this update, we show that although both the Pfam database and the number of sequenced genomes have increased in size, the expected benefits of the Pfam5000 strategy have not changed substantially. Solving the structures of proteins from the 5,000 largest Pfam families would allow accurate fold assignment for approximately 65 percent of all prokaryotic proteins (covering 54 percent of residues) and 63 percent of eukaryotic proteins (42 percent of residues). Fewer than 2,300 of the largest families on this list remain to be solved, making the project feasible in the next five years given the expected throughput to be achieved in the production phase of the Protein Structure Initiative.

  17. Does Angling Technique Selectively Target Fishes Based on Their Behavioural Type?

    Science.gov (United States)

    Wilson, Alexander D M; Brownscombe, Jacob W; Sullivan, Brittany; Jain-Schlaepfer, Sofia; Cooke, Steven J

    2015-01-01

    Recently, there has been growing recognition that fish harvesting practices can have important impacts on the phenotypic distributions and diversity of natural populations through a phenomenon known as fisheries-induced evolution. Here we experimentally show that two common recreational angling techniques (active crank baits versus passive soft plastics) differentially target wild largemouth bass (Micropterus salmoides) and rock bass (Ambloplites rupestris) based on variation in their behavioural tendencies. Fish were first angled in the wild using both techniques and then brought back to the laboratory and tested for individual-level differences in common estimates of personality (refuge emergence, flight-initiation-distance, latency-to-recapture and with a net, and general activity) in an in-lake experimental arena. We found that different angling techniques appear to selectively target these species based on their boldness (as characterized by refuge emergence, a standard measure of boldness in fishes) but not other assays of personality. We also observed that body size was independently a significant predictor of personality in both species, though this varied between traits and species. Our results suggest a context-dependency for vulnerability to capture relative to behaviour in these fish species. Ascertaining the selective pressures angling practices exert on natural populations is an important area of fisheries research with significant implications for ecology, evolution, and resource management.

  18. Selective apoptotic killing of malignant hemopoietic cells by antibody-targeted delivery of an amphipathic peptide.

    Science.gov (United States)

    Marks, Alexandra J; Cooper, Margaret S; Anderson, Robert J; Orchard, Kim H; Hale, Geoffrey; North, Janet M; Ganeshaguru, Kanagasabai; Steele, Andrew J; Mehta, Atul B; Lowdell, Mark W; Wickremasinghe, R Gitendra

    2005-03-15

    The alpha-helical amphipathic peptide D-(KLAKLAK)2 is toxic to eukaryotic cells if internalized by a suitable targeting mechanism. We have targeted this peptide to malignant hemopoietic cells via conjugation to monoclonal antibodies, which recognize lineage-specific cell surface molecules. An anti-CD19/peptide conjugate efficiently killed 3/3 B lymphoid lines. However, an anti-CD33/peptide conjugate was cytotoxic to only one of three CD33-positive myeloid leukemia lines. The IC50 towards susceptible lines were in the low nanomolar range. Conjugates were highly selective and did not kill cells that did not express the appropriate cell surface cognate of the antibody moiety. Anti-CD19/peptide conjugates efficiently killed cells from patients with chronic lymphocytic leukemia but anti-CD33/peptide reagents were less effective against fresh acute myeloid leukemia cells. We therefore suggest that amphipathic peptides may be of value as targeted therapeutic agents for the treatment of a subset of hematologic malignancies.

  19. Scientific objectives and selection of targets for the SMART-1 Infrared Spectrometer (SIR)

    Science.gov (United States)

    Basilevsky, A. T.; Keller, H. U.; Nathues, A.; Mall, U.; Hiesinger, H.; Rosiek, M.

    2004-12-01

    The European SMART-1 mission to the Moon, primarily a testbed for innovative technologies, was launched in September 2003 and will reach the Moon in 2005. On board are several scientific instruments, including the point-spectrometer SMART-1 Infrared Spectrometer (SIR). Taking into account the capabilities of the SMART-1 mission and the SIR instrument in particular, as well as the open questions in lunar science, a selection of targets for SIR observations has been compiled. SIR can address at least five topics: (1) Surface/regolith processes; (2) Lunar volcanism; (3) Lunar crust structure; (4) Search for spectral signatures of ices at the lunar poles; and (5) Ground truth and study of geometric effects on the spectral shape. For each topic we will discuss specific observation modes, necessary to achieve our scientific goals. The majority of SIR targets will be observed in the nadir-tracking mode. More than 100 targets, which require off-nadir pointing and off-nadir tracking, are planned. It is expected that results of SIR observations will significantly increase our understanding of the Moon. Since the exact arrival date and the orbital parameters of the SMART-1 spacecraft are not known yet, a more detailed planning of the scientific observations will follow in the near future.

  20. Matrix metalloproteinases and their tissue inhibitors after selective laser trabeculoplasty in pseudoexfoliative secondary glaucoma

    Directory of Open Access Journals (Sweden)

    Strobbe Ernesto

    2008-10-01

    Full Text Available Abstract Background The aim of this study was to assess changes in metalloproteinases (MMP-2 and tissue inhibitor of metalloproteinases (TIMP-2 following selective laser trabeculoplasty (SLT in patients with pseudoexfoliative glaucoma (PEXG. Methods We enrolled 15 patients with PEXG and cataracts (PEXG-C group and good intraocular pressure (IOP controlled with β-blockers and dorzolamide eye drops who were treated by cataract phacoemulsification and 15 patients with pseudoexfoliative glaucoma (PEXG-SLT group. The PEXG-SLT patients underwent a trabeculectomy for uncontrolled IOP in the eye that showed increased IOP despite the maximum drug treatment with β-blockers and dorzolamide eye drops and after ineffective selective laser trabeculoplasty (SLT. The control group consisted of 15 subjects with cataracts. Aqueous humor was aspirated during surgery from patients with PEXG-C, PEXG-SLT and from matched control patients with cataracts during cataract surgery or trabeculectomy. The concentrations of MMP-2 and TIMP-2 in the aqueous humor were assessed with commercially available ELISA kits. Results In PEXG-SLT group in the first 10 days after SLT treatment a significant reduction in IOP was observed: 25.8 ± 1.9 vs 18.1.0 ± 1.4 mm/Hg (p The MMP-2 in PEXG-C was 57.77 ± 9.25 μg/ml and in PEXG-SLT was 58.52 ± 9.66 μg/ml (p Conclusion This case series suggest that IOP elevation after SLT can be a serious adverse event in some PEXG patients. The IOP increase in these cases would be correlated to the failure to decrease the TIMP-2/MMP-2 ratio. Trial registration Current Controlled Trials ISRCTN79745214

  1. How active ingredient localisation in plant tissues determines the targeted pest spectrum of different chemistries

    DEFF Research Database (Denmark)

    Buchholz, Anke; Trapp, Stefan

    2016-01-01

    adsorption into leaf cells and thus a favourable distribution into apoplast and xylem sap. Slightly lipophilic bases get trapped in vacuoles, which is a less suited place to control hemipteran pests but appropriate to control mites. Non-favourable cellular localisation led to a strong reduction...... information sets revealed that the intracellular localisation of active ingredients determines the performance of test compounds against different target pests because of different feeding behaviours: mites feed on mesophyll, and aphids and whiteflies mostly in the vascular system. Polar compounds have a slow...

  2. Selective Vitamin D Receptor Activation as Anti-Inflammatory Target in Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    J. Donate-Correa

    2014-01-01

    Full Text Available Paricalcitol, a selective vitamin D receptor (VDR activator used for treatment of secondary hyperparathyroidism in chronic kidney disease (CKD, has been associated with survival advantages, suggesting that this drug, beyond its ability to suppress parathyroid hormone, may have additional beneficial actions. In this prospective, nonrandomised, open-label, proof-of-concept study, we evaluated the hypothesis that selective vitamin D receptor activation with paricalcitol is an effective target to modulate inflammation in CKD patients. Eight patients with an estimated glomerular filtration rate between 15 and 44 mL/min/1.73 m2 and an intact parathyroid hormone (PTH level higher than 110 pg/mL received oral paricalcitol (1 μg/48 hours as therapy for secondary hyperparathyroidism. Nine patients matched by age, sex, and stage of CKD, but a PTH level <110 pg/mL, were enrolled as a control group. Our results show that five months of paricalcitol administration were associated with a reduction in serum concentrations of hs-CRP (13.9%, P<0.01, TNF-α (11.9%, P=0.01, and IL-6 (7%, P<0.05, with a nonsignificant increase of IL-10 by 16%. In addition, mRNA expression levels of the TNFα and IL-6 genes in peripheral blood mononuclear cells decreased significantly by 30.8% (P=0.01 and 35.4% (P=0.01, respectively. In conclusion, selective VDR activation is an effective target to modulate inflammation in CKD.

  3. Mining the epigenetic landscape of tissue polarity in search of new targets for cancer therapy.

    Science.gov (United States)

    Atrian, Farzaneh; Lelièvre, Sophie A

    2015-01-01

    The epigenetic nature of cancer encourages the development of inhibitors of epigenetic pathways. Yet, the clinical use for solid tumors of approved epigenetic drugs is meager. We argue that this situation might improve upon understanding the coinfluence between epigenetic pathways and tissue architecture. We present emerging information on the epigenetic control of the polarity axis, a central feature of epithelial architecture created by the orderly distribution of multiprotein complexes at cell-cell and cell-extracellular matrix contacts and altered upon cancer onset (with apical polarity loss), invasive progression (with basolateral polarity loss) and metastatic development (with basoapical polarity imbalance). This information combined with the impact of polarity-related proteins on epigenetic mechanisms of cancer enables us to envision how to guide the choice of drugs specific for distinct epigenetic modifiers, in order to halt cancer development and counter the consequences of polarity alterations.

  4. The Respiratory Pathogen Moraxella catarrhalis Targets Collagen for Maximal Adherence to Host Tissues

    Directory of Open Access Journals (Sweden)

    Birendra Singh

    2016-03-01

    Full Text Available Moraxella catarrhalis is a human respiratory pathogen that causes acute otitis media in children and is associated with exacerbations in patients suffering from chronic obstructive pulmonary disease (COPD. The first step in M. catarrhalis colonization is adherence to the mucosa, epithelial cells, and extracellular matrix (ECM. The objective of this study was to evaluate the role of M. catarrhalis interactions with collagens from various angles. Clinical isolates (n = 43 were tested for collagen binding, followed by a detailed analysis of protein-protein interactions using recombinantly expressed proteins. M. catarrhalis-dependent interactions with collagen produced by human lung fibroblasts and tracheal tissues were studied by utilizing confocal immunohistochemistry and high-resolution scanning electron microscopy. A mouse smoke-induced chronic obstructive pulmonary disease (COPD model was used to estimate the adherence of M. catarrhalis in vivo. We found that all M. catarrhalis clinical isolates tested adhered to fibrillar collagen types I, II, and III and network-forming collagens IV and VI. The trimeric autotransporter adhesins ubiquitous surface protein A2 (UspA2 and UspA2H were identified as major collagen-binding receptors. M. catarrhalis wild type adhered to human tracheal tissue and collagen-producing lung fibroblasts, whereas UspA2 and UspA2H deletion mutants did not. Moreover, in the COPD mouse model, bacteria devoid of UspA2 and UspA2H had a reduced level of adherence to the respiratory tract compared to the adherence of wild-type bacteria. Our data therefore suggest that the M. catarrhalis UspA2 and UspA2H-dependent interaction with collagens is highly critical for adherence in the host and, furthermore, may play an important role in the establishment of disease.

  5. A Kinetic Aggregation Assay Enabling Selective and Sensitive Aβ Amyloid Quantification in Cells and Tissues

    Science.gov (United States)

    Du, Deguo; Murray, Amber N.; Cohen, Ehud; Kim, Hyun-Eui; Simkovsky, Ryan; Dillin, Andrew; Kelly, Jeffery W.

    2011-01-01

    The process of amyloid-β (Aβ) fibril formation is genetically and pathologically linked to Alzheimer's disease (AD). Thus, a selective and sensitive method for the quantification of Aβ amyloid fibrils in complex biological samples enables a variety of hypotheses to be tested. Herein we report the basis for a quantitative in vitro kinetic aggregation assay that detects seeding-competent Aβ aggregates in mammalian cell culture media, in Caenorhabditis elegans lysate and in mouse brain homogenate. Sonicated, proteinase K treated Aβ-fibril-containing tissue homogenates or cell culture media were added to an initially monomeric Aβ1–40 reporter peptide to seed an in vitro nucleated aggregation reaction. The reduction in the half time (t50) of the amyloid growth phase is proportional to the quantity of seeding-competent Aβ aggregates present in the biological sample. An ion exchange resin amyloid isolation strategy from complex biological samples is demonstrated as an alternative to improve the sensitivity and linearity of the kinetic aggregation assay. PMID:21268584

  6. Selection of suitable prodrug candidates for in vivo studies via in vitro studies; the correlation of prodrug stability in between cell culture homogenates and human tissue homogenates.

    Science.gov (United States)

    Tsume, Yasuhiro; Amidon, Gordon L

    2012-01-01

    To determine the correlations/discrepancies of drug stabilities between in the homogenates of human culture cells and of human tissues. Amino acid/dipeptide monoester prodrugs of floxuridine were chosen as the model drugs. The stabilities (half-lives) of floxuridine prodrugs in human tissues (pancreas, liver, and small intestine) homogenates were obtained and compared with ones in cell culture homogenates (AcPC-1, Capan-2, and Caco-2 cells) as well as human liver microsomes. The correlations of prodrug stability in human small bowel tissue homogenate vs. Caco-2 cell homogenate, human liver tissue homogenate vs. human liver microsomes, and human pancreatic tissue homogenate vs. pancreatic cell, AsPC-1 and Capan-2, homogenates were examined. The stabilities of floxuridine prodrugs in human small bowel homogenate exhibited the great correlation to ones in Caco-2 cell homogenate (slope = 1.0-1.3, r2 = 0.79-0.98). The stability of those prodrugs in human pancreas tissue homogenate also exhibited the good correlations to ones in AsPC-1 and Capan-2 cells homogenates (slope = 0.5-0.8, r2 = 0.58-0.79). However, the correlations of prodrug stabilities between in human liver tissue homogenates and in human liver microsomes were weaker than others (slope = 1.3-1.9, r2 = 0.07-0.24). The correlations of drug stabilities in cultured cell homogenates and in human tissue homogenates were compared. Those results exhibited wide range of correlations between in cell homogenate and in human tissue homogenate (r2 = 0.07 - 0.98). Those in vitro studies in cell homogenates would be good tools to predict drug stabilities in vivo and to select drug candidates for further developments. In the series of experiments, 5'-O-D-valyl-floxuridine and 5'-O-L-phenylalanyl-L-tyrosyl-floxuridine would be selected as candidates of oral drug targeting delivery for cancer chemotherapy due to their relatively good stabilities compared to other tested prodrugs.

  7. The major targets of acute norovirus infection are immune cells in the gut-associated lymphoid tissue.

    Science.gov (United States)

    Grau, Katrina R; Roth, Alexa N; Zhu, Shu; Hernandez, Abel; Colliou, Natacha; DiVita, Bayli B; Philip, Drake T; Riffe, Cara; Giasson, Benoit; Wallet, Shannon M; Mohamadzadeh, Mansour; Karst, Stephanie M

    2017-12-01

    Noroviruses are the leading cause of food-borne gastroenteritis outbreaks and childhood diarrhoea globally, estimated to be responsible for 200,000 deaths in children each year 1-4 . Thus, reducing norovirus-associated disease is a critical priority. Development of vaccines and therapeutics has been hindered by the limited understanding of basic norovirus pathogenesis and cell tropism. While macrophages, dendritic cells, B cells and stem-cell-derived enteroids can all support infection of certain noroviruses in vitro 5-7 , efforts to define in vivo norovirus cell tropism have generated conflicting results. Some studies detected infected intestinal immune cells 8-12 , other studies detected epithelial cells 13 , and still others detected immune and epithelial cells 14-16 . Major limitations of these studies are that they were performed on tissue sections from immunocompromised or germ-free hosts, chronically infected hosts where the timing of infection was unknown, or following non-biologically relevant inoculation routes. Here, we report that the dominant cellular targets of a murine norovirus inoculated orally into immunocompetent mice are macrophages, dendritic cells, B cells and T cells in the gut-associated lymphoid tissue. Importantly, we also demonstrate that a norovirus can infect T cells, a previously unrecognized target, in vitro. These findings represent the most extensive analyses to date of in vivo norovirus cell tropism in orally inoculated, immunocompetent hosts at the peak of acute infection and thus they significantly advance our basic understanding of norovirus pathogenesis.

  8. Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology.

    Science.gov (United States)

    Galdeano, Carles; Ciulli, Alessio

    2016-09-01

    Targeting epigenetic proteins is a rapidly growing area for medicinal chemistry and drug discovery. Recent years have seen an explosion of interest in developing small molecules binding to bromodomains, the readers of acetyl-lysine modifications. A plethora of co-crystal structures has motivated focused fragment-based design and optimization programs within both industry and academia. These efforts have yielded several compounds entering the clinic, and many more are increasingly being used as chemical probes to interrogate bromodomain biology. High selectivity of chemical probes is necessary to ensure biological activity is due to an on-target effect. Here, we review the state-of-the-art of bromodomain-targeting compounds, focusing on the structural basis for their on-target selectivity or lack thereof. We also highlight chemical biology approaches to enhance on-target selectivity.

  9. Intracellular distribution of the vitamin D receptor in the brain: comparison with classic target tissues and redistribution with development.

    Science.gov (United States)

    Eyles, D W; Liu, P Y; Josh, P; Cui, X

    2014-05-30

    Apart from its role in regulating calcium there is growing evidence that vitamin D is a neuroactive steroid capable of regulating multiple pathways important for both brain development and mature brain function. Vitamin D induces its genomic effects through its nuclear receptor the vitamin D receptor (VDR). Although there is abundant evidence for this receptor's presence in the mammalian brain from studies employing immunohistochemistry, Western blot or quantitative RNA studies there remains some dispute regarding the validity of these studies. In this study we provide unambiguous confirmation for the VDR in adult rodent brain using proteomic techniques. However Western blot experiments show that compared to more classic target organs such as the gut and kidney, VDR expression is quantitatively lower in the brain. In addition we have examined VDR subcellular distribution in the gut, kidney and brain from both embryonic and adult tissues. We show that in all embryonic tissues VDR distribution is mostly nuclear, however by adulthood it appears that at least in the gut and kidney, VDR presence in the plasma membrane is more prominent perhaps reflecting some change in VDR function with the maturation of these tissues. Finally the subcellular distribution of VDR in the embryo did not appear to be altered by vitamin D deficiency indicating that perhaps there are other mechanisms at play in vivo to stabilize this receptor in the absence of its ligand. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

  10. A precisely substituted benzopyran targets androgen refractory prostate cancer cells through selective modulation of estrogen receptors

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Rajeev; Verma, Vikas; Sharma, Vikas; Jain, Ashish; Singh, Vishal [Division of Endocrinology, CSIR—Central Drug Research Institute, Lucknow 226 031 (India); Sarswat, Amit [Division of Medicinal & Process Chemistry, CSIR—Central Drug Research Institute, Lucknow 226 031 (India); Maikhuri, Jagdamba P. [Division of Endocrinology, CSIR—Central Drug Research Institute, Lucknow 226 031 (India); Sharma, Vishnu L. [Division of Medicinal & Process Chemistry, CSIR—Central Drug Research Institute, Lucknow 226 031 (India); Gupta, Gopal, E-mail: g_gupta@cdri.res.in [Division of Endocrinology, CSIR—Central Drug Research Institute, Lucknow 226 031 (India)

    2015-03-15

    Dietary consumption of phytoestrogens like genistein has been linked with lower incidence of prostate cancer. The estradiol-like benzopyran core of genistein confers estrogen receptor-β (ER-β) selectivity that imparts weak anti-proliferative activity against prostate cancer cells. DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2H-1-benzopyran (BP), a SERM designed with benzopyran core, targeted androgen independent prostate cancer (PC-3) cells 14-times more potently than genistein, ~ 25% more efficiently than tamoxifen and 6.5-times more actively than ICI-182780, without forfeiting significant specificity in comparison to genistein. BP increased apoptosis (annexin-V and TUNEL labeling), arrested cell cycle, and significantly increased caspase-3 activity along with mRNA expressions of estrogen receptor (ER)-β and FasL (qPCR) in PC-3 cells. In classical ERE-luc reporter assay BP behaved as a potent ER-α antagonist and ER-β agonist. Accordingly, it decreased expression of ER-α target PS2 (P < 0.01) and increased expression of ER-β target TNF-α (P < 0.05) genes in PC-3. ER-β deficient PC-3 (siRNA-transfected) was resistant to apoptotic and anti-proliferative actions of SERMs, including stimulation of FasL expression by BP. BP significantly inhibited phosphorylation of Akt and ERK-1/2, JNK and p38 in PC-3 (immunoblotting), and thus adopted a multi-pathway mechanism to exert a more potent anti-proliferative activity against prostate cancer cells than natural and synthetic SERMs. Its precise ER-subtype specific activity presents a unique lead structure for further optimization. - Highlights: • BP with benzopyran core of genistein was identified for ER-β selective action. • BP was 14-times more potent than genistien in targeting prostate cancer cells. • It behaved as a potent ER-β agonist and ER-α antagonist in gene reporter assays. • BP's anti-proliferative action was inhibited significantly in ER-β deficient cells. • BP — a unique lead

  11. ICAM-1–targeted thrombomodulin mitigates tissue factor–driven inflammatory thrombosis in a human endothelialized microfluidic model

    Science.gov (United States)

    Johnston, Ian H.; Villa, Carlos H.; Gollomp, Kandace; Esmon, Charles T.; Cines, Douglas B.; Poncz, Mortimer

    2017-01-01

    Diverse human illnesses are characterized by loss or inactivation of endothelial thrombomodulin (TM), predisposing to microvascular inflammation, activation of coagulation, and tissue ischemia. Single-chain antibody fragment (scFv)/TM) fusion proteins, previously protective against end-organ injury in murine models of inflammation, are attractive candidates to treat inflammatory thrombosis. However, animal models have inherent differences in TM and coagulation biology, are limited in their ability to resolve and control endothelial biology, and do not allow in-depth testing of “humanized” scFv/TM fusion proteins, which are necessary for translation to the clinical domain. To address these challenges, we developed a human whole-blood, microfluidic model of inflammatory, tissue factor (TF)–driven coagulation that features a multichannel format for head-to-head comparison of therapeutic approaches. In this model, fibrin deposition, leukocyte adhesion, and platelet adhesion and aggregation showed a dose-dependent response to tumor necrosis factor-α activation and could be quantified via real-time microscopy. We used this model to compare hTM/R6.5, a humanized, intracellular adhesion molecule 1 (ICAM-1)–targeted scFv/TM biotherapeutic, to untargeted antithrombotic agents, including soluble human TM (shTM), anti–TF antibodies, and hirudin. The targeted hTM/R6.5 more effectively inhibited TF-driven coagulation in a protein C (PC)–dependent manner and demonstrated synergy with supplemental PC. These results support the translational prospects of ICAM-targeted scFv/TM and illustrate the utility of the microfluidic system as a platform to study humanized therapeutics at the interface of endothelium and whole blood under flow. PMID:29296786

  12. A novel DPSO-SVM system for variable interval selection of endometrial tissue sections by near infrared spectroscopy.

    Science.gov (United States)

    Wang, Guiyun; Ma, Mingyu; Zhang, Zhuoyong; Xiang, Yuhong; Harrington, Peter de B

    2013-08-15

    A novel method combining a discrete particle swarm optimization (DPSO) with a support vector machine (SVM) was proposed for the variable interval selection of tissue sections of endometrial carcinoma by near infrared spectroscopy. The DPSO-SVM algorithm includes a multi-stage screening. In each screening step, the DPSO was repeated 50 times using random sampling, and the frequencies that the variable intervals were selected among the 50 repeats were used to select the most probable intervals. The variable intervals with high probabilities were selected and further used in the next screening. Finally, the subset of variable intervals with the highest classification rate was considered as the optimal variable intervals. A synthetic data set mimicking the near infrared (NIR) spectra of tissue samples was applied to evaluate the performance of the DPSO-SVM. For the synthetic data, the classification rates were 74.9 ± 0.9% and 100% for the full spectral range and the six variable intervals selected by the DPSO-SVM. For the real endometrial tissue data, the entire spectral data gave an average accuracy of 69.5 ± 0.5%, while the 20 variable intervals gave 98.5 ± 0.3%. The results showed that the informative variables from the NIR spectra could be selected and high classification accuracy was achieved by the proposed approach. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours

    Energy Technology Data Exchange (ETDEWEB)

    Lasko, Loren M.; Jakob, Clarissa G.; Edalji, Rohinton P.; Qiu, Wei; Montgomery, Debra; Digiammarino, Enrico L.; Hansen, T. Matt; Risi, Roberto M.; Frey, Robin; Manaves, Vlasios; Shaw, Bailin; Algire, Mikkel; Hessler, Paul; Lam, Lloyd T.; Uziel, Tamar; Faivre, Emily; Ferguson, Debra; Buchanan, Fritz G.; Martin, Ruth L.; Torrent, Maricel; Chiang, Gary G.; Karukurichi, Kannan; Langston, J. William; Weinert, Brian T.; Choudhary, Chunaram; de Vries, Peter; Van Drie, John H.; McElligott, David; Kesicki, Ed; Marmorstein, Ronen; Sun, Chaohong; Cole, Philip A.; Rosenberg, Saul H.; Michaelides, Michael R.; Lai, Albert; Bromberg, Kenneth D. (AbbVie); (UCopenhagen); (Petra Pharma); (UPENN); (JHU); (Van Drie); (Faraday)

    2017-09-27

    The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription1 and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind2. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer3). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products4, bi-substrate analogues5 and the widely used small molecule C6466,7, lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.

  14. Ethyl Pyruvate: An Anti-Microbial Agent that Selectively Targets Pathobionts and Biofilms.

    Science.gov (United States)

    Debebe, Tewodros; Krüger, Monika; Huse, Klaus; Kacza, Johannes; Mühlberg, Katja; König, Brigitte; Birkenmeier, Gerd

    The microbiota has a strong influence on health and disease in humans. A causative shift favoring pathobionts is strongly linked to diseases. Therefore, anti-microbial agents selectively targeting potential pathogens as well as their biofilms are urgently demanded. Here we demonstrate the impact of ethyl pyruvate, so far known as ROS scavenger and anti-inflammatory agent, on planktonic microbes and biofilms. Ethyl pyruvate combats preferably the growth of pathobionts belonging to bacteria and fungi independent of the genera and prevailing drug resistance. Surprisingly, this anti-microbial agent preserves symbionts like Lactobacillus species. Moreover, ethyl pyruvate prevents the formation of biofilms and promotes matured biofilms dissolution. This potentially new anti-microbial and anti-biofilm agent could have a tremendous positive impact on human, veterinary medicine and technical industry as well.

  15. Ethyl Pyruvate: An Anti-Microbial Agent that Selectively Targets Pathobionts and Biofilms.

    Directory of Open Access Journals (Sweden)

    Tewodros Debebe

    Full Text Available The microbiota has a strong influence on health and disease in humans. A causative shift favoring pathobionts is strongly linked to diseases. Therefore, anti-microbial agents selectively targeting potential pathogens as well as their biofilms are urgently demanded. Here we demonstrate the impact of ethyl pyruvate, so far known as ROS scavenger and anti-inflammatory agent, on planktonic microbes and biofilms. Ethyl pyruvate combats preferably the growth of pathobionts belonging to bacteria and fungi independent of the genera and prevailing drug resistance. Surprisingly, this anti-microbial agent preserves symbionts like Lactobacillus species. Moreover, ethyl pyruvate prevents the formation of biofilms and promotes matured biofilms dissolution. This potentially new anti-microbial and anti-biofilm agent could have a tremendous positive impact on human, veterinary medicine and technical industry as well.

  16. Acute resistance exercise modulates microRNA expression profiles: Combined tissue and circulatory targeted analyses.

    Directory of Open Access Journals (Sweden)

    Randall F D'Souza

    Full Text Available A subset of short non-coding RNAs, microRNAs (miRs, have been identified in the regulation of skeletal muscle hypertrophy and atrophy. Expressed within cells, miRs are also present in circulation (c-miR and have a putative role in cross-tissue signalling. The aim of this study was to examine the impact of a single bout of high intensity resistance exercise (RE on skeletal muscle and circulatory miRs harvested simultaneously. Resistance trained males (n = 9, 24.6 ± 4.9 years undertook a single bout of high volume RE with venous blood and muscle biopsies collected before, 2 and 4hr post-exercise. Real time polymerase chain reaction (Rt-PCR analyses was performed on 30 miRs that have previously been shown to be required for skeletal muscle function. Of these, 6 miRs were significantly altered within muscle following exercise; miR-23a, -133a, -146a, -206, -378b and 486. Analysis of these same miRs in circulation demonstrated minimal alterations with exercise, although c-miR-133a (~4 fold, p = 0.049 and c-miR-149 (~2.4 fold; p = 0.006 were increased 4hr post-exercise. Thus a single bout of RE results in the increased abundance of a subset of miRs within the skeletal muscle, which was not evident in plasma. The lack a qualitative agreement in the response pattern of intramuscular and circulating miR expression suggests the analysis of circulatory miRs is not reflective of the miR responses within skeletal muscle after exercise.

  17. A review on powder-based additive manufacturing for tissue engineering: selective laser sintering and inkjet 3D printing

    Science.gov (United States)

    Farid Seyed Shirazi, Seyed; Gharehkhani, Samira; Mehrali, Mehdi; Yarmand, Hooman; Metselaar, Hendrik Simon Cornelis; Adib Kadri, Nahrizul; Azuan Abu Osman, Noor

    2015-06-01

    Since most starting materials for tissue engineering are in powder form, using powder-based additive manufacturing methods is attractive and practical. The principal point of employing additive manufacturing (AM) systems is to fabricate parts with arbitrary geometrical complexity with relatively minimal tooling cost and time. Selective laser sintering (SLS) and inkjet 3D printing (3DP) are two powerful and versatile AM techniques which are applicable to powder-based material systems. Hence, the latest state of knowledge available on the use of AM powder-based techniques in tissue engineering and their effect on mechanical and biological properties of fabricated tissues and scaffolds must be updated. Determining the effective setup of parameters, developing improved biocompatible/bioactive materials, and improving the mechanical/biological properties of laser sintered and 3D printed tissues are the three main concerns which have been investigated in this article.

  18. A review on powder-based additive manufacturing for tissue engineering: selective laser sintering and inkjet 3D printing.

    Science.gov (United States)

    Shirazi, Seyed Farid Seyed; Gharehkhani, Samira; Mehrali, Mehdi; Yarmand, Hooman; Metselaar, Hendrik Simon Cornelis; Adib Kadri, Nahrizul; Osman, Noor Azuan Abu

    2015-06-01

    Since most starting materials for tissue engineering are in powder form, using powder-based additive manufacturing methods is attractive and practical. The principal point of employing additive manufacturing (AM) systems is to fabricate parts with arbitrary geometrical complexity with relatively minimal tooling cost and time. Selective laser sintering (SLS) and inkjet 3D printing (3DP) are two powerful and versatile AM techniques which are applicable to powder-based material systems. Hence, the latest state of knowledge available on the use of AM powder-based techniques in tissue engineering and their effect on mechanical and biological properties of fabricated tissues and scaffolds must be updated. Determining the effective setup of parameters, developing improved biocompatible/bioactive materials, and improving the mechanical/biological properties of laser sintered and 3D printed tissues are the three main concerns which have been investigated in this article.

  19. Detection of Sendai virus receptor, the ganglioside GDla, in target tissue (mouse lung)

    International Nuclear Information System (INIS)

    Markwell, M.A.K.; Sato, E.

    1986-01-01

    Previously the authors had shown that the gangliosides GDla, GTlb, and GQlb derived from brain function as receptors for the paramyxovirus Sendai virus by their ability to induce infection when incubated with receptor-deficient cells. Analyses of MDBK, HeLa, and MDCK cells in culture demonstrated that these putative receptors were present in host cells in the quantities required for infection. The primary site of infection for Sendai virus in the whole animal is the respiratory tract, culminating in the lung. Therefore, the ganglioside content of this target organ was analyzed to determine the endogenous receptor population available to Sendai virus. The total ganglioside fraction of lung was resolved into individual species by HPTLC. Gangliosides of the gangliotetraose series were identified by the specific binding of 125 I-labeled tetanus and cholera toxins before and after exposure with sialidase. In this manner one of the major resorcinol-positive bands was identified as GDla. Evidence of the more complex ganglioside receptors for Sendai virus was also seen

  20. NuMA is required for the selective induction of p53 target genes.

    Science.gov (United States)

    Ohata, Hirokazu; Miyazaki, Makoto; Otomo, Ryo; Matsushima-Hibiya, Yuko; Otsubo, Chihiro; Nagase, Takahiro; Arakawa, Hirofumi; Yokota, Jun; Nakagama, Hitoshi; Taya, Yoichi; Enari, Masato

    2013-06-01

    The p53 tumor suppressor protein is a transcription factor controlling various outcomes, such as growth arrest and apoptosis, through the regulation of different sets of target genes. The nuclear mitotic apparatus protein (NuMA) plays important roles in spindle pole organization during mitosis and in chromatin regulation in the nucleus during interphase. Although NuMA has been shown to colocalize with several nuclear proteins, including high-mobility-group proteins I and Y and GAS41, the role of NuMA during interphase remains unclear. Here we report that NuMA binds to p53 to modulate p53-mediated transcription. Acute and partial ablation of NuMA attenuates the induction of the proarrested p21 gene following DNA damage, subsequently causing impaired cell cycle arrest. Interestingly, NuMA knockdown had little effect on the induction of the p53-dependent proapoptotic PUMA gene. Furthermore, NuMA is required for the recruitment of cyclin-dependent kinase 8 (Cdk8), a component of the Mediator complex and a promoter of p53-mediated p21 gene function. These data demonstrate that NuMA is critical for the target selectivity of p53-mediated transcription.

  1. Non-invasive brain stimulation targeting the right fusiform gyrus selectively increases working memory for faces.

    Science.gov (United States)

    Brunyé, Tad T; Moran, Joseph M; Holmes, Amanda; Mahoney, Caroline R; Taylor, Holly A

    2017-04-01

    The human extrastriate cortex contains a region critically involved in face detection and memory, the right fusiform gyrus. The present study evaluated whether transcranial direct current stimulation (tDCS) targeting this anatomical region would selectively influence memory for faces versus non-face objects (houses). Anodal tDCS targeted the right fusiform gyrus (Brodmann's Area 37), with the anode at electrode site PO10, and cathode at FP2. Two stimulation conditions were compared in a repeated-measures design: 0.5mA versus 1.5mA intensity; a separate control group received no stimulation. Participants completed a working memory task for face and house stimuli, varying in memory load from 1 to 4 items. Individual differences measures assessed trait-based differences in facial recognition skills. Results showed 1.5mA intensity stimulation (versus 0.5mA and control) increased performance at high memory loads, but only with faces. Lower overall working memory capacity predicted a positive impact of tDCS. Results provide support for the notion of functional specialization of the right fusiform regions for maintaining face (but not non-face object) stimuli in working memory, and further suggest that low intensity electrical stimulation of this region may enhance demanding face working memory performance particularly in those with relatively poor baseline working memory skills. Published by Elsevier Inc.

  2. First report of in vitro selection of RNA aptamers targeted to recombinant Loxosceles laeta spider toxins.

    Science.gov (United States)

    Sapag, Amalia; Salinas-Luypaert, Catalina; Constenla-Muñoz, Carlos

    2014-03-26

    Loxoscelism is the envenomation caused by the bite of Loxosceles spp. spiders. It entails severe necrotizing skin lesions, sometimes accompanied by systemic reactions and even death. There are no diagnostic means and treatment is mostly palliative. The main toxin, found in several isoforms in the venom, is sphingomyelinase D (SMD), a phospholipase that has been used to generate antibodies intended for medical applications. Nucleic acid aptamers are a promising alternative to antibodies. Aptamers may be isolated from a combinatorial mixture of oligonucleotides by iterative selection of those that bind to the target. In this work, two Loxosceles laeta SMD isoforms, Ll1 and Ll2, were produced in bacteria and used as targets with the aim of identifying RNA aptamers that inhibit sphingomyelinase activity. Six RNA aptamers capable of eliciting partial but statistically significant inhibitions of the sphingomyelinase activity of recombinant SMD-Ll1 and SMD-Ll2 were obtained: four aptamers exert ~17% inhibition of SMD-Ll1, while two aptamers result in ~25% inhibition of SMD-Ll2 and ~18% cross inhibition of SMD-Ll1. This work is the first attempt to obtain aptamers with therapeutic and diagnostic potential for loxoscelism and provides an initial platform to undertake the development of novel anti Loxosceles venom agents.

  3. First report of in vitro selection of RNA aptamers targeted to recombinant Loxosceles laeta spider toxins

    Directory of Open Access Journals (Sweden)

    Amalia Sapag

    2014-01-01

    Full Text Available BACKGROUND: Loxoscelism is the envenomation caused by the bite of Loxosceles spp. spiders. It entails severe necrotizing skin lesions, sometimes accompanied by systemic reactions and even death. There are no diagnostic means and treatment is mostly palliative. The main toxin, found in several isoforms in the venom, is sphingomyelinase D (SMD, a phospholipase that has been used to generate antibodies intended for medical applications. Nucleic acid aptamers are a promising alternative to antibodies. Aptamers may be isolated from a combinatorial mixture of oligonucleotides by iterative selection of those that bind to the target. In this work, two Loxosceles laeta SMD isoforms, Ll1 and Ll2, were produced in bacteria and used as targets with the aim of identifying RNA aptamers that inhibit sphingomyelinase activity. RESULTS: Six RNA aptamers capable of eliciting partial but statistically significant inhibitions of the sphingomyelinase activity of recombinant SMD-Ll1 and SMD-Ll2 were obtained: four aptamers exert ~17% inhibition of SMD-Ll1, while two aptamers result in ~25% inhibition of SMD-Ll2 and ~18% cross inhibition of SMD-Ll1. CONCLUSIONS: This work is the first attempt to obtain aptamers with therapeutic and diagnostic potential for loxoscelism and provides an initial platform to undertake the development of novel anti Loxoscelesvenom agents.

  4. The Breakthrough Listen Search for Intelligent Life: Target Selection of Nearby Stars and Galaxies

    Science.gov (United States)

    Isaacson, Howard; Siemion, Andrew P. V.; Marcy, Geoffrey W.; Lebofsky, Matt; Price, Danny C.; MacMahon, David; Croft, Steve; DeBoer, David; Hickish, Jack; Werthimer, Dan; Sheikh, Sofia; Hellbourg, Greg; Enriquez, J. Emilio

    2017-05-01

    We present the target selection for the Breakthrough Listen search for extraterrestrial intelligence during the first year of observations at the Green Bank Telescope, Parkes Telescope, and Automated Planet Finder. On the way to observing 1,000,000 nearby stars in search of technological signals, we present three main sets of objects we plan to observe in addition to a smaller sample of exotica. We chose the 60 nearest stars, all within 5.1 pc from the Sun. Such nearby stars offer the potential to observe faint radio signals from transmitters that have a power similar to those on Earth. We add a list of 1649 stars drawn from the Hipparcos catalog that span the Hertzprung-Russell diagram, including all spectral types along the main sequence, subgiants, and giant stars. This sample offers diversity and inclusion of all stellar types, but with thoughtful limits and due attention to main sequence stars. Our targets also include 123 nearby galaxies composed of a “morphological-type-complete” sample of the nearest spirals, ellipticals, dwarf spherioidals, and irregulars. While their great distances hamper the detection of technological electromagnetic radiation, galaxies offer the opportunity to observe billions of stars simultaneously and to sample the bright end of the technological luminosity function. We will also use the Green Bank and Parkes telescopes to survey the plane and central bulge of the Milky Way. Finally, the complete target list includes several classes of exotica, including white dwarfs, brown dwarfs, black holes, neutron stars, and asteroids in our solar system.

  5. Dipeptidyl peptidase IV as a potential target for selective prodrug activation and chemotherapeutic action in cancers.

    Science.gov (United States)

    Dahan, Arik; Wolk, Omri; Yang, Peihua; Mittal, Sachin; Wu, Zhiqian; Landowski, Christopher P; Amidon, Gordon L

    2014-12-01

    The efficacy of chemotherapeutic drugs is often offset by severe side effects attributable to poor selectivity and toxicity to normal cells. Recently, the enzyme dipeptidyl peptidase IV (DPPIV) was considered as a potential target for the delivery of chemotherapeutic drugs. The purpose of this study was to investigate the feasibility of targeting chemotherapeutic drugs to DPPIV as a strategy to enhance their specificity. The expression profile of DPPIV was obtained for seven cancer cell lines using DNA microarray data from the DTP database, and was validated by RT-PCR. A prodrug was then synthesized by linking the cytotoxic drug melphalan to a proline-glycine dipeptide moiety, followed by hydrolysis studies in the seven cell lines with a standard substrate, as well as the glycyl-prolyl-melphalan (GP-Mel). Lastly, cell proliferation studies were carried out to demonstrate enzyme-dependent activation of the candidate prodrug. The relative RT-PCR expression levels of DPPIV in the cancer cell lines exhibited linear correlation with U95Av2 Affymetrix data (r(2) = 0.94), and with specific activity of a standard substrate, glycine-proline-p-nitroanilide (r(2) = 0.96). The significantly higher antiproliferative activity of GP-Mel in Caco-2 cells (GI₅₀ = 261 μM) compared to that in SK-MEL-5 cells (GI₅₀ = 807 μM) was consistent with the 9-fold higher specific activity of the prodrug in Caco-2 cells (5.14 pmol/min/μg protein) compared to SK-MEL-5 cells (0.68 pmol/min/μg protein) and with DPPIV expression levels in these cells. Our results demonstrate the great potential to exploit DPPIV as a prodrug activating enzyme for efficient chemotherapeutic drug targeting.

  6. A structural annotation resource for the selection of putative target proteins in the malaria parasite

    Directory of Open Access Journals (Sweden)

    Joubert Fourie

    2008-05-01

    Full Text Available Abstract Background Protein structure plays a pivotal role in elucidating mechanisms of parasite functioning and drug resistance. Moreover, protein structure aids the determination of protein function, which can together with the structure be used to identify novel drug targets in the parasite. However, various structural features in Plasmodium falciparum proteins complicate the experimental determination of protein structures. Limited similarity to proteins in the Protein Data Bank and the shortage of solved protein structures in the malaria parasite necessitate genome-scale structural annotation of P. falciparum proteins. Additionally, the annotation of a range of structural features facilitates the identification of suitable targets for experimental and computational studies. Methods An integrated structural annotation system was developed and applied to P. falciparum, Plasmodium vivax and Plasmodium yoelii. The annotation included searches for sequence similarity, patterns and domains in addition to the following predictions: secondary structure, transmembrane helices, protein disorder, low complexity, coiled-coils and small molecule interactions. Subsequently, candidate proteins for further structural studies were identified based on the annotated structural features. Results The annotation results are accessible through a web interface, enabling users to select groups of proteins which fulfil multiple criteria pertaining to structural and functional features 1. Analysis of features in the P. falciparum proteome showed that protein-interacting proteins contained a higher percentage of predicted disordered residues than non-interacting proteins. Proteins interacting with 10 or more proteins have a disordered content concentrated in the range of 60–100%, while the disorder distribution for proteins having only one interacting partner, was more evenly spread. Conclusion A series of P. falciparum protein targets for experimental structure

  7. Single domain antibodies in tissue engineering

    OpenAIRE

    Rodrigues, E.D.

    2014-01-01

    The aim of this thesis is to demonstrate the potential of VHH in tissue engineering applications, with a focus on bone and cartilage tissue regeneration. After a general introduction to this thesis in chapter 1, the selection of VHH targeting growth factors is described in chapter 2. VHH were selected to target growth factors relevant in skeletal tissue engineering and VHH were found to modulate BMP activity with high affinity. Chapter 3 describes the immobilization of VHH and its potential t...

  8. Human Memory B Cells TargetingStaphylococcus aureusExotoxins Are Prevalent with Skin and Soft Tissue Infection.

    Science.gov (United States)

    Pelzek, Adam J; Shopsin, Bo; Radke, Emily E; Tam, Kayan; Ueberheide, Beatrix M; Fenyö, David; Brown, Stuart M; Li, Qianhao; Rubin, Ada; Fulmer, Yi; Chiang, William K; Hernandez, David N; El Bannoudi, Hanane; Sause, William E; Sommerfield, Alexis; Thomsen, Isaac P; Miller, Andy O; Torres, Victor J; Silverman, Gregg J

    2018-03-13

    Staphylococcus aureus is a Gram-positive opportunistic pathogen that causes superficial and invasive infections in the hospital and community. High mortality from infection emphasizes the need for improved methods for prevention and treatment. Although S. aureus possesses an arsenal of virulence factors that contribute to evasion of host defenses, few studies have examined long-term humoral and B-cell responses. Adults with acute-phase skin and soft tissue infections were recruited; blood samples were obtained; and S. aureus isolates, including methicillin-resistant strains, were subjected to genomic sequence analysis. In comparisons of acute-phase sera with convalescent-phase sera, a minority (37.5%) of patients displayed 2-fold or greater increases in antibody titers against three or more S. aureus antigens, whereas nearly half exhibited no changes, despite the presence of toxin genes in most infecting strains. Moreover, enhanced antibody responses waned over time, which could reflect a defect in B-cell memory or long-lived plasma cells. However, memory B cells reactive with a range of S. aureus antigens were prevalent at both acute-phase and convalescent-phase time points. While some memory B cells exhibited toxin-specific binding, those cross-reactive with structurally related leucocidin subunits were dominant across patients, suggesting the targeting of conserved epitopes. Memory B-cell reactivity correlated with serum antibody levels for selected S. aureus exotoxins, suggesting a relationship between the cellular and humoral compartments. Overall, although there was no global defect in the representation of anti- S. aureus memory B cells, there was evidence of restrictions in the range of epitopes recognized, which may suggest potential therapeutic approaches for augmenting host defenses. IMPORTANCE The contribution of B-cell memory and long-term antibody responses to host defenses against S. aureus exotoxins remains poorly understood. Our studies

  9. β-escin selectively targets the glioblastoma-initiating cell population and reduces cell viability.

    Science.gov (United States)

    Harford-Wright, Elizabeth; Bidère, Nicolas; Gavard, Julie

    2016-10-11

    Glioblastoma multiforme (GBM) is a highly aggressive tumour of the central nervous system and is associated with an extremely poor prognosis. Within GBM exists a subpopulation of cells, glioblastoma-initiating cells (GIC), which possess the characteristics of progenitor cells, have the ability to initiate tumour growth and resist to current treatment strategies. We aimed at identifying novel specific inhibitors of GIC expansion through use of a large-scale chemical screen of approved small molecules. Here, we report the identification of the natural compound β-escin as a selective inhibitor of GIC viability. Indeed, β-escin was significantly cytotoxic in nine patient-derived GIC, whilst exhibiting no substantial effect on the other human cancer or control cell lines tested. In addition, β-escin was more effective at reducing GIC growth than current clinically used cytotoxic agents. We further show that β-escin triggers caspase-dependent cell death combined with a loss of stemness properties. However, blocking apoptosis could not rescue the β-escin-induced reduction in sphere formation or stemness marker activity, indicating that β-escin directly modifies the stem identity of GIC, independent of the induction of cell death. Thus, this study has repositioned β-escin as a promising potential candidate to selectively target the aggressive population of initiating cells within GBM.

  10. Identifying Human Genome-Wide CNV, LOH and UPD by Targeted Sequencing of Selected Regions.

    Directory of Open Access Journals (Sweden)

    Wei Li

    Full Text Available Copy-number variations (CNV, loss of heterozygosity (LOH, and uniparental disomy (UPD are large genomic aberrations leading to many common inherited diseases, cancers, and other complex diseases. An integrated tool to identify these aberrations is essential in understanding diseases and in designing clinical interventions. Previous discovery methods based on whole-genome sequencing (WGS require very high depth of coverage on the whole genome scale, and are cost-wise inefficient. Another approach, whole exome genome sequencing (WEGS, is limited to discovering variations within exons. Thus, we are lacking efficient methods to detect genomic aberrations on the whole genome scale using next-generation sequencing technology. Here we present a method to identify genome-wide CNV, LOH and UPD for the human genome via selectively sequencing a small portion of genome termed Selected Target Regions (SeTRs. In our experiments, the SeTRs are covered by 99.73%~99.95% with sufficient depth. Our developed bioinformatics pipeline calls genome-wide CNVs with high confidence, revealing 8 credible events of LOH and 3 UPD events larger than 5M from 15 individual samples. We demonstrate that genome-wide CNV, LOH and UPD can be detected using a cost-effective SeTRs sequencing approach, and that LOH and UPD can be identified using just a sample grouping technique, without using a matched sample or familial information.

  11. Optimal Decision Rules for Biomarker-Based Subgroup Selection for a Targeted Therapy in Oncology

    Directory of Open Access Journals (Sweden)

    Johannes Krisam

    2015-05-01

    Full Text Available Throughout recent years, there has been a rapidly increasing interest regarding the evaluation of so-called targeted therapies. These therapies are assumed to show a greater benefit in a pre-specified subgroup of patients—commonly identified by a predictive biomarker—as compared to the total patient population of interest. This situation has led to the necessity to develop biostatistical methods allowing an efficient evaluation of such treatments. Among others, adaptive enrichment designs have been proposed as a solution. These designs allow the selection of the most promising patient population based on an efficacy analysis at interim and restricting recruitment to these patients afterwards. As has recently been shown, the performance of the applied interim decision rule in such a design plays a crucial role in ensuring a successful trial. In this work, we investigate the situation when the primary outcome of the trial is a binary variable. Optimal decision rules are derived which incorporate the uncertainty about the treatment effects. These optimal decision rules are evaluated with respect to their performance in an adaptive enrichment design in terms of correct selection probability and power, and are compared to proposed ad hoc decision rules. Our methods are illustrated by means of a clinical trial example.

  12. Delivery of antigen to nasal-associated lymphoid tissue microfold cells through secretory IgA targeting local dendritic cells confers protective immunity.

    Science.gov (United States)

    Rochereau, Nicolas; Pavot, Vincent; Verrier, Bernard; Jospin, Fabienne; Ensinas, Agathe; Genin, Christian; Corthésy, Blaise; Paul, Stéphane

    2016-01-01

    Transmission of mucosal pathogens relies on their ability to bind to the surfaces of epithelial cells, to cross this thin barrier, and to gain access to target cells and tissues, leading to systemic infection. This implies that pathogen-specific immunity at mucosal sites is critical for the control of infectious agents using these routes to enter the body. Although mucosal delivery would ensure the best onset of protective immunity, most of the candidate vaccines are administered through the parenteral route. The present study evaluates the feasibility of delivering the chemically bound p24gag (referred to as p24 in the text) HIV antigen through secretory IgA (SIgA) in nasal mucosae in mice. We show that SIgA interacts specifically with mucosal microfold cells present in the nasal-associated lymphoid tissue. p24-SIgA complexes are quickly taken up in the nasal cavity and selectively engulfed by mucosal dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin-positive dendritic cells. Nasal immunization with p24-SIgA elicits both a strong humoral and cellular immune response against p24 at the systemic and mucosal levels. This ensures effective protection against intranasal challenge with recombinant vaccinia virus encoding p24. This study represents the first example that underscores the remarkable potential of SIgA to serve as a carrier for a protein antigen in a mucosal vaccine approach targeting the nasal environment. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  13. Identification of genomic variants putatively targeted by selection during dog domestication.

    Science.gov (United States)

    Cagan, Alex; Blass, Torsten

    2016-01-12

    Dogs [Canis lupus familiaris] were the first animal species to be domesticated and continue to occupy an important place in human societies. Recent studies have begun to reveal when and where dog domestication occurred. While much progress has been made in identifying the genetic basis of phenotypic differences between dog breeds we still know relatively little about the genetic changes underlying the phenotypes that differentiate all dogs from their wild progenitors, wolves [Canis lupus]. In particular, dogs generally show reduced aggression and fear towards humans compared to wolves. Therefore, selection for tameness was likely a necessary prerequisite for dog domestication. With the increasing availability of whole-genome sequence data it is possible to try and directly identify the genetic variants contributing to the phenotypic differences between dogs and wolves. We analyse the largest available database of genome-wide polymorphism data in a global sample of dogs 69 and wolves 7. We perform a scan to identify regions of the genome that are highly differentiated between dogs and wolves. We identify putatively functional genomic variants that are segregating or at high frequency [> = 0.75 Fst] for alternative alleles between dogs and wolves. A biological pathways analysis of the genes containing these variants suggests that there has been selection on the 'adrenaline and noradrenaline biosynthesis pathway', well known for its involvement in the fight-or-flight response. We identify 11 genes with putatively functional variants fixed for alternative alleles between dogs and wolves. The segregating variants in these genes are strong candidates for having been targets of selection during early dog domestication. We present the first genome-wide analysis of the different categories of putatively functional variants that are fixed or segregating at high frequency between a global sampling of dogs and wolves. We find evidence that selection has been strongest

  14. Virotherapy targeting cyclin E overexpression in tumors with adenovirus-enhanced cancer-selective promoter.

    Science.gov (United States)

    Cheng, Pei-Hsin; Rao, Xiao-Mei; Duan, Xiaoxian; Li, Xiao-Feng; Egger, Michael E; McMasters, Kelly M; Zhou, H Sam

    2015-02-01

    Oncolytic virotherapy can selectively destroy cancer cells and is a potential approach in cancer treatment. A strategy to increase tumor-specific selectivity is to control the expression of a key regulatory viral gene with a tumor-specific promoter. We have previously found that cyclin E expression is augmented in cancer cells after adenovirus (Ad) infection. Thus, the cyclin E promoter that is further activated by Ad in cancer cells may have unique properties for enhancing oncolytic viral replication. We have shown that high levels of viral E1a gene expression are achieved in cancer cells infected with Ad-cycE, in which the endogenous Ad E1a promoter was replaced with the cyclin E promoter. Ad-cycE shows markedly selective oncolytic efficacy in vitro and destroys various types of cancer cells, including those resistant to ONYX-015/dl1520. Furthermore, Ad-cycE shows a strong capacity to repress A549 xenograft tumor growth in nude mice and significantly prolongs survival. This study suggests the potential of Ad-cycE in cancer therapy and indicates the advantages of using promoters that can be upregulated by virus infection in cancer cells in development of oncolytic viruses. Key messages: Cyclin E promoter activity is high in cancer cells and enhanced by adenovirus infection. Cyclin E promoter is used to control the E1a gene of a tumor-specific oncolytic adenovirus. Ad-cycE efficiently targets cancer cells and induces oncolysis. Ad-cycE significantly repressed xenograft tumor and prolonged survival.

  15. Selective Estrogen Receptor Modulators and the Tissue-Selective Estrogen Complex: Analysis of Cell Type-Specific Effects Using In Vivo Imaging of a Reporter Mouse Model.

    Science.gov (United States)

    Torre, Sara Della; Ciana, Paolo

    2016-01-01

    Selective estrogen receptor modulators (SERMs) are a class of compounds that act differentially on the estrogen receptor (ER) in various tissues with a mixed agonist/antagonistic activity (agonistic in some tissues while antagonist in others). This peculiarity represents a challenge for developing new hormone replacement therapies (HRTs) and highlights the need of new tools to evaluate the specific effects of a given SERM in different organs/tissues of an entire organism and with time. Reporter mice represent invaluable tools in pharmacology to analyze specific signaling in physiological conditions and monitor the effects of drugs acting on these signals in a spatio-temporal dimension. Here, we describe an in vivo protocol to examine the effects of different SERMs on estrogen receptor activity by using the ERE-Luc reporter model, a mouse that reports ER transcriptional activity.

  16. SEARCH FOR TARGET TISSUE IN THE EYE ORBIT FOR AUTOIMMUNE AGGRESSION OF THYROID ANTIBODIES IN ENDOCRINE OPHTHALMOPATHY

    Directory of Open Access Journals (Sweden)

    V. G. Likhvantseva

    2017-01-01

    Full Text Available We searched for a possible target tissue in eye orbit for thyroid autoantibodies in endocrine ophthalmopathy (Graves’ disease, using correlation analysis method. We examined a group of 139 patients (278 eye orbits with thyroid-associated ophthalmopathy associated with diffuse toxic goiter. Serological parameters (antibodies to thyroid-stimulating hormone receptor; thyroglobulin, thyroid peroxidase were compared with instrumental diagnostic data (multi-layer CT, ultrasonography of eye orbit, and exophthalmometer, as well as clinical symptoms. Statistical correlation analysis enabled us to show different degrees of association between thyroid antibodies and clinical manifestations of Graves’ disease and eye orbit involvement. Especially, carriers of antibodies to TSH receptor and thyroglobulin (as compared to seronegative patients exhibited higher exophthalmos scores (19.16±0.26 mm, p < 0.001, and 19.41±0.40 mm, p < 0.05, respectively, and with total muscle index (2.42±0.05, p < 0.01, and 2.42±0.08, respectively. Meanwhile, eyelids in carriers of antibodies to TSH receptor and thyroid peroxidase proved to be more swollen (p < 0.001, p < 0.05, respectively. Carriage of antibodies to thyroglobulin was associated with synchronous involvement of two structures of the eye orbit: extraocular muscles and retrobulbar tissue, which is reflected by increase in the average ntegral exophthalmos index within the group.

  17. Control of neurotransmission, behaviour and development, by photo-dynamic manipulation of tissue redox state of brain targets.

    Science.gov (United States)

    Kataoka, Y; Morii, H; Imamura, K; Cui, Y; Kobayashi, M; Watanabe, Y

    2000-12-01

    Reversible manipulation of local neurotransmission in brain areas, using controlled spatial and temporal resolution, is one of the powerful techniques used to investigate integrative aspects of brain function. We have developed a novel technique for rapidly inactivating local synaptic transmission, from outside the brain, within seconds or minutes via oxidation of target tissue using a photosensitive dye followed by photoirradiation (photo-dynamic tissue oxidation; PDTO). PDTO applied through a defined slit, sharply suppressed excitatory synaptic transmission in rat hippocampal slices and also suppressed in vivo hippocampal neurotransmission reversibly. Furthermore, we manipulated the voluntary movement of gerbils in free-field activity by application of PDTO to the striatum. Also, in freely moving kittens, the development of the visual cortex was manipulated by long-lasting application of PDTO to the eye. Thus, PDTO enables external manipulation of in vivo or in vitro neurotransmission in various clearly defined regions on the submillimeter scale. Suppression of neurotransmission occurred only within the photo-oxidized area which can be histochemically visualized.

  18. Hypothalamus metabolomic profiling to elucidate the tissue-targeted biochemical basis of febrile response in yeast-induced pyrexia rats.

    Science.gov (United States)

    Liu, Haiyu; Zhang, Li; Zhao, Baosheng; Zhang, Zhixin; Qin, Lingling; Zhang, Qingqing; Wang, Qing; Lu, Zhiwei; Gao, Xiaoyan

    2015-04-25

    In the previous reports regarding thermoregulation, the hypothalamus is thought to be the primary centre in the central nervous system for controlling the body temperature. However, to date, there has not been sufficient evidence to reveal its thermoregulatory mechanism. In the current study, we utilised a tissue-targeted metabolomics strategy to elucidate the underlying biochemical mechanisms of thermoregulation in the fever process by analysing the global metabolic profile of the hypothalamus in yeast-induced pyrexia rats. Data acquisition was completed using the HPLC-LTQ-Orbitrap/MS in both positive and negative ion mode. Principal component analysis was used to observe the cluster characteristics between the control group and the pyrexia group. Potential biomarkers were screened using orthogonal partial least-squares-discriminant analysis. Seventeen potential biomarkers were identified in the hypothalamus samples to discriminate the control and pyrexia groups, including amino acids, nucleic acids, vitamins, carbohydrates, and phospholipids. As a result, purine metabolism was enhanced pronouncedly, and perturbation of lipid metabolism was also observed. Meanwhile, amino acid metabolism and energy metabolism were also activated significantly. In conclusion, the study indicated that hypothalamus-targeted metabolomics could provide a powerful tool to further understand the pathogenesis of febrile response. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. GLUT1-mediated selective tumor targeting with fluorine containing platinum(II) glycoconjugates.

    Science.gov (United States)

    Liu, Ran; Fu, Zheng; Zhao, Meng; Gao, Xiangqian; Li, Hong; Mi, Qian; Liu, Pengxing; Yang, Jinna; Yao, Zhi; Gao, Qingzhi

    2017-06-13

    Increased glycolysis and overexpression of glucose transporters (GLUTs) are physiological characteristics of human malignancies. Based on the so-called Warburg effect, 18flurodeoxyglucose-positron emission tomography (FDG-PET) has successfully developed as clinical modality for the diagnosis and staging of many cancers. To leverage this glucose transporter mediated metabolic disparity between normal and malignant cells, in the current report, we focus on the fluorine substituted series of glucose, mannose and galactose-conjugated (trans-R,R-cyclohexane-1,2-diamine)-2-flouromalonato-platinum(II) complexes for a comprehensive evaluation on their selective tumor targeting. Besides highly improved water solubility, these sugar-conjugates presented improved cytotoxicity than oxaliplatin in glucose tranporters (GLUTs) overexpressing cancer cell lines and exhibited no cross-resistance to cisplatin. For the highly water soluble glucose-conjugated complex (5a), two novel in vivo assessments were conducted and the results revealed that 5a was more efficacious at a lower equitoxic dose (70% MTD) than oxaliplatin (100% MTD) in HT29 xenograft model, and it was significantly more potent than oxaliplatin in leukemia-bearing DBA/2 mice as well even at equimolar dose levels (18% vs 90% MTD). GLUT inhibitor mediated cell viability analysis, GLUT1 knockdown cell line-based cytotoxicity evaluation, and platinum accumulation study demonstrated that the cellular uptake of the sugar-conjugates was regulated by GLUT1. The higher intrinsic DNA reactivity of the sugar-conjugates was confirmed by kinetic study of platinum(II)-guanosine adduct formation. The mechanistic origin of the antitumor effect of the fluorine complexes was found to be forming the bifunctional Pt-guanine-guanine (Pt-GG) intrastrand cross-links with DNA. The results provide a rationale for Warburg effect targeted anticancer drug design.

  20. Uranium exploration target selection for proterozoic iron oxide/breccia complex type deposits in India

    International Nuclear Information System (INIS)

    Dwivedy, K.K.; Sinha, K.K.

    1997-01-01

    Multimetal iron oxide/breccia complex (IOBC) type deposits exemplified by Olympic Dam in Australia, fall under low grade, large tonnage deposits. A multidisciplinary integrated exploration programme consisting of airborne surveys, ground geological surveys, geophysical and geochemical investigations and exploratory drilling, supported adequately by the state of the art analytical facilities, data processing using various software and digital image processing has shown moderate success in the identification of target areas for this type of deposits in the Proterozoic terrains of India. Intracratonic, anorogenic, continental rift to continental margin environment have been identified in a very wide spectrum of rock associations. The genesis and evolution of such associations during the Middle Proterozoic period have been reviewed and applied for target selection in the (i) Son-Narmada rift valley zone; (ii) areas covered by Dongargarh Supergroup of rocks in Madhya Pradesh; (iii) areas exposing ferruginous breccia in the western part of the Singhbhum Shear Zone (SSZ) around Lotapahar; (iv) Siang Group of rocks in Arunachal Pradesh; (v) Crystalline rocks of Garo Hills around Anek; and (vi) Chhotanagpur Gneissic complex in the Bahia-Ulatutoli tract of Ranchi Plateau. Of theses six areas, the Son-Narmada rift area appears to be the most promising area for IOBC type deposits. Considering occurrences of the uranium anomalies near Meraraich, Kundabhati, Naktu and Kudar and positive favourability criteria observed in a wide variety of rocks spatially related to the rifts and shears, certain sectors in Son-Narmada rift zone have been identified as promising for intense subsurface exploration. 20 refs, 4 figs, 1 tab

  1. A Novel Sensor Selection and Power Allocation Algorithm for Multiple-Target Tracking in an LPI Radar Network

    Directory of Open Access Journals (Sweden)

    Ji She

    2016-12-01

    Full Text Available Radar networks are proven to have numerous advantages over traditional monostatic and bistatic radar. With recent developments, radar networks have become an attractive platform due to their low probability of intercept (LPI performance for target tracking. In this paper, a joint sensor selection and power allocation algorithm for multiple-target tracking in a radar network based on LPI is proposed. It is found that this algorithm can minimize the total transmitted power of a radar network on the basis of a predetermined mutual information (MI threshold between the target impulse response and the reflected signal. The MI is required by the radar network system to estimate target parameters, and it can be calculated predictively with the estimation of target state. The optimization problem of sensor selection and power allocation, which contains two variables, is non-convex and it can be solved by separating power allocation problem from sensor selection problem. To be specific, the optimization problem of power allocation can be solved by using the bisection method for each sensor selection scheme. Also, the optimization problem of sensor selection can be solved by a lower complexity algorithm based on the allocated powers. According to the simulation results, it can be found that the proposed algorithm can effectively reduce the total transmitted power of a radar network, which can be conducive to improving LPI performance.

  2. Preparation and characterization of anti-HIV nanodrug targeted to microfold cell of gut-associated lymphoid tissue.

    Science.gov (United States)

    Roy, Upal; Ding, Hong; Pilakka-Kanthikeel, Sudheesh; Raymond, Andrea D; Atluri, Venkata; Yndart, Adriana; Kaftanovskaya, Elena M; Batrakova, Elena; Agudelo, Marisela; Nair, Madhavan

    2015-01-01

    The human immunodeficiency virus 1 (HIV-1) still remains one of the leading life-threatening diseases in the world. The introduction of highly active antiretroviral therapy has significantly reduced disease morbidity and mortality. However, most of the drugs have variable penetrance into viral reservoir sites, including gut-associated lymphoid tissue (GALT). Being the largest lymphoid organ, GALT plays a key role in early HIV infection and host-pathogen interaction. Many different treatment options have been proposed to eradicate the virus from GALT. However, it becomes difficult to deliver traditional drugs to the GALT because of its complex physiology. In this regard, we developed a polymer-based Pluronic nanocarrier containing anti-HIV drug called efavirenz (EFV) targeting Microfold cells (M-cells) in the GALT. M-cells are specialized epithelial cells that are predominantly present in the GALT. In this work, we have exploited this paracellular transport property of M-cells for targeted delivery of Pluronic nanocarrier tagged EFV, bioconjugated with anti-M-cell-specific antibodies to the GALT (nanodrug). Preliminary characterization showed that the nanodrug (EFV-F12-COOH) is of 140 nm size with 0.3 polydispersion index, and the zeta potential of the particles was -19.38±2.2 mV. Further, drug dissolution study has shown a significantly improved sustained release over free drugs. Binding potential of nanodrug with M-cell was also confirmed with fluorescence microscopy and in vitro uptake and release studies. The anti-HIV activity of the nanodrug was also significantly higher compared to that of free drug. This novel formulation was able to show sustained release of EFV and inhibit the HIV-1 infection in the GALT compared to the free drug. The present study has potential for our in vivo targeted nanodrug delivery system by combining traditional enteric-coated capsule technique via oral administration.

  3. Biotherapeutic target or sink: analysis of the macrophage mannose receptor tissue distribution in murine models of lysosomal storage diseases.

    Science.gov (United States)

    Zhang, Xin Sheen; Brondyk, William; Lydon, John T; Thurberg, Beth L; Piepenhagen, Peter A

    2011-06-01

    Lysosomal storage diseases (LSDs) are metabolic disorders caused by enzyme deficiencies that lead to lysosomal accumulation of undegraded substrates. Enzyme replacement therapies (ERT) have been developed as treatments for patients with Gaucher, Niemann-Pick, Fabry, and Pompe diseases. Depending on the disease, the corresponding therapeutic enzyme is designed to be internalized by diseased cells through receptor-mediated endocytosis via macrophage mannose receptors (MMR) or mannose-6-phosphate receptors (M6PR). Enzymes developed to treat Gaucher and Niemann-Pick diseases are meant to target MMR-expressing cells, and in the case of Cerezyme [recombinant human β-glucocerebrosidase (rhβGC)] for treating Gaucher disease, glycans on the enzyme are modified to increase specificity toward this receptor. Due to heterogeneity in glycosylation on enzymes intended to target the M6PR, however, there may also be some unintended targeting to MMR-expressing cells, which could act as unwanted sinks. Examples include Fabrazyme [recombinant human α-galactosidase A (rhαGal)] for treating Fabry disease and Myozyme [recombinant human acid α-glucosidase (rhGAA)] for treating Pompe disease. It is therefore of great interest to better understand the cell type and tissue distribution of MMR in murine LSD models used to evaluate ERT efficacy and mechanism of action. In this study, we generated affinity-purified polyclonal antibody against murine MMR and used it to carry out a systematic examination of MMR protein localization in murine models of Gaucher, Niemann-Pick, Fabry, and Pompe diseases. Using immunohistochemistry, immunofluorescence, and confocal microscopy, we examined MMR distribution in liver, spleen, lung, kidney, heart, diaphragm, quadriceps, and triceps in these animal models and compared them with MMR distribution in wild-type mice.

  4. Using Deep Learning for Targeted Data Selection, Improving Satellite Observation Utilization for Model Initialization

    Science.gov (United States)

    Lee, Y. J.; Bonfanti, C. E.; Trailovic, L.; Etherton, B.; Govett, M.; Stewart, J.

    2017-12-01

    At present, a fraction of all satellite observations are ultimately used for model assimilation. The satellite data assimilation process is computationally expensive and data are often reduced in resolution to allow timely incorporation into the forecast. This problem is only exacerbated by the recent launch of Geostationary Operational Environmental Satellite (GOES)-16 satellite and future satellites providing several order of magnitude increase in data volume. At the NOAA Earth System Research Laboratory (ESRL) we are researching the use of machine learning the improve the initial selection of satellite data to be used in the model assimilation process. In particular, we are investigating the use of deep learning. Deep learning is being applied to many image processing and computer vision problems with great success. Through our research, we are using convolutional neural network to find and mark regions of interest (ROI) to lead to intelligent extraction of observations from satellite observation systems. These targeted observations will be used to improve the quality of data selected for model assimilation and ultimately improve the impact of satellite data on weather forecasts. Our preliminary efforts to identify the ROI's are focused in two areas: applying and comparing state-of-art convolutional neural network models using the analysis data from the National Center for Environmental Prediction (NCEP) Global Forecast System (GFS) weather model, and using these results as a starting point to optimize convolution neural network model for pattern recognition on the higher resolution water vapor data from GOES-WEST and other satellite. This presentation will provide an introduction to our convolutional neural network model to identify and process these ROI's, along with the challenges of data preparation, training the model, and parameter optimization.

  5. Interval MULTIMOORA method with target values of attributes based on interval distance and preference degree: biomaterials selection

    Science.gov (United States)

    Hafezalkotob, Arian; Hafezalkotob, Ashkan

    2017-12-01

    A target-based MADM method covers beneficial and non-beneficial attributes besides target values for some attributes. Such techniques are considered as the comprehensive forms of MADM approaches. Target-based MADM methods can also be used in traditional decision-making problems in which beneficial and non-beneficial attributes only exist. In many practical selection problems, some attributes have given target values. The values of decision matrix and target-based attributes can be provided as intervals in some of such problems. Some target-based decision-making methods have recently been developed; however, a research gap exists in the area of MADM techniques with target-based attributes under uncertainty of information. We extend the MULTIMOORA method for solving practical material selection problems in which material properties and their target values are given as interval numbers. We employ various concepts of interval computations to reduce degeneration of uncertain data. In this regard, we use interval arithmetic and introduce innovative formula for interval distance of interval numbers to create interval target-based normalization technique. Furthermore, we use a pairwise preference matrix based on the concept of degree of preference of interval numbers to calculate the maximum, minimum, and ranking of these numbers. Two decision-making problems regarding biomaterials selection of hip and knee prostheses are discussed. Preference degree-based ranking lists for subordinate parts of the extended MULTIMOORA method are generated by calculating the relative degrees of preference for the arranged assessment values of the biomaterials. The resultant rankings for the problem are compared with the outcomes of other target-based models in the literature.

  6. Study of selected trace elements in cancerous and non-cancerous human breast tissues using neutron activation analysis

    International Nuclear Information System (INIS)

    Ebrahim, A. M.

    2006-03-01

    This study was performed to investigate the influence of cancer on selected trace elements among sudanese patients with confirmed breast cancer. Eighty samples of cancerous and normal tissues (total of one hundred and sixty) were obtained from the same breast of the same subject from different hospitals in Khartoum State. Samples were freeze dried and analyzed using neutron activation analysis (NAA). Neutron irradiations were performed at Egypt second research reactor with a maximum thermal flux of 2.37 Χ 10 14 n cm -2 s -1 . To examine if there was any difference in the concentrations of elements from normal and malignant tissues; Wilcox on signed ranks test was used. It was found that Al, Mn, Mg, Se, Zn, and Cr elements from the malignant tissues are significantly elevated (p 0.05). The results obtained have shown consistency with results obtained by some previous studies, however, no data could be found for the elements Mg, Cr, and Sc.(Author)

  7. Examination of radioactive contamination in the soil-plant system and their transfer to selected animal tissues

    International Nuclear Information System (INIS)

    Chibowski, S.; Gladysz, A.

    1999-01-01

    This paper investigates gamma emitter radioactivity in a system consisting of soil and plants. Some selected sample of tissues of animals fed with the plants from these sites were also measured. In soil and plant samples artificial ( 137 Cs and 134 Cs) and natural (thorium and uranium series) isotopes were detected. Despite the relatively high content of the natural isotopes in plants and their seeds, their accumulation in animal tissues was not detected.The 40 K isotope was transferred in the chain soil-plant-animal in the highest degree. From the group of the natural isotopes, only 212 Pb was detected in examined animal tissue samples. Other natural isotopes were below detection level. In the samples heavy metal content was also examined. In any sample no element concentration was noticed above trade acceptable limit. (author)

  8. A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action

    Science.gov (United States)

    Campaner, Elena; Rustighi, Alessandra; Zannini, Alessandro; Cristiani, Alberto; Piazza, Silvano; Ciani, Yari; Kalid, Ori; Golan, Gali; Baloglu, Erkan; Shacham, Sharon; Valsasina, Barbara; Cucchi, Ulisse; Pippione, Agnese Chiara; Lolli, Marco Lucio; Giabbai, Barbara; Storici, Paola; Carloni, Paolo; Rossetti, Giulia; Benvenuti, Federica; Bello, Ezia; D'Incalci, Maurizio; Cappuzzello, Elisa; Rosato, Antonio; Del Sal, Giannino

    2017-06-01

    The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs. By a mechanism-based screening, we have identified a novel covalent PIN1 inhibitor, KPT-6566, able to selectively inhibit PIN1 and target it for degradation. We demonstrate that KPT-6566 covalently binds to the catalytic site of PIN1. This interaction results in the release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells. Accordingly, KPT-6566 treatment impairs PIN1-dependent cancer phenotypes in vitro and growth of lung metastasis in vivo.

  9. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH.

    Science.gov (United States)

    Yun, Jihye; Mullarky, Edouard; Lu, Changyuan; Bosch, Kaitlyn N; Kavalier, Adam; Rivera, Keith; Roper, Jatin; Chio, Iok In Christine; Giannopoulou, Eugenia G; Rago, Carlo; Muley, Ashlesha; Asara, John M; Paik, Jihye; Elemento, Olivier; Chen, Zhengming; Pappin, Darryl J; Dow, Lukas E; Papadopoulos, Nickolas; Gross, Steven S; Cantley, Lewis C

    2015-12-11

    More than half of human colorectal cancers (CRCs) carry either KRAS or BRAF mutations and are often refractory to approved targeted therapies. We found that cultured human CRC cells harboring KRAS or BRAF mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wild-type cells. High-dose vitamin C impairs tumor growth in Apc/Kras(G12D) mutant mice. These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations. Copyright © 2015, American Association for the Advancement of Science.

  10. Green tea extract selectively targets nanomechanics of live metastatic cancer cells

    Science.gov (United States)

    Cross, Sarah E.; Jin, Yu-Sheng; Lu, Qing-Yi; Rao, JianYu; Gimzewski, James K.

    2011-05-01

    Green tea extract (GTE) is known to be a potential anticancer agent (Yang et al 2009 Nat. Rev. Cancer 9 429-39) with various biological activities (Lu et al 2005 Clin. Cancer Res. 11 1675-83 Yang et al 1998 Carcinogenesis 19 611-6) yet the precise mechanism of action is still unclear. The biomechanical response of GTE treated cells taken directly from patient's body samples was measured using atomic force microscopy (AFM) (Binnig et al 1986 Phys. Rev. Lett. 56 930). We found significant increase in stiffness of GTE treated metastatic tumor cells, with a resulting value similar to untreated normal mesothelial cells, whereas mesothelial cell stiffness after GTE treatment is unchanged. Immunofluorescence analysis showed an increase in cytoskeletal-F-actin in GTE treated tumor cells, suggesting GTE treated tumor cells display mechanical, structural and morphological features similar to normal cells, which appears to be mediated by annexin-I expression, as determined by siRNA analysis of an in vitro cell line model. Our data indicates that GTE selectively targets human metastatic cancer cells but not normal mesothelial cells, a finding that is significantly advantageous compared to conventional chemotherapy agents.

  11. A Predictive Model for Selective Targeting of the Warburg Effect through GAPDH Inhibition with a Natural Product.

    Science.gov (United States)

    Liberti, Maria V; Dai, Ziwei; Wardell, Suzanne E; Baccile, Joshua A; Liu, Xiaojing; Gao, Xia; Baldi, Robert; Mehrmohamadi, Mahya; Johnson, Marc O; Madhukar, Neel S; Shestov, Alexander A; Chio, Iok I Christine; Elemento, Olivier; Rathmell, Jeffrey C; Schroeder, Frank C; McDonnell, Donald P; Locasale, Jason W

    2017-10-03

    Targeted cancer therapies that use genetics are successful, but principles for selectively targeting tumor metabolism that is also dependent on the environment remain unknown. We now show that differences in rate-controlling enzymes during the Warburg effect (WE), the most prominent hallmark of cancer cell metabolism, can be used to predict a response to targeting glucose metabolism. We establish a natural product, koningic acid (KA), to be a selective inhibitor of GAPDH, an enzyme we characterize to have differential control properties over metabolism during the WE. With machine learning and integrated pharmacogenomics and metabolomics, we demonstrate that KA efficacy is not determined by the status of individual genes, but by the quantitative extent of the WE, leading to a therapeutic window in vivo. Thus, the basis of targeting the WE can be encoded by molecular principles that extend beyond the status of individual genes. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Microbial metabolomics: Replacing trial-and-error by the unbiased selection and ranking of targets

    NARCIS (Netherlands)

    Werf, M.J. van der; Jellema, R.H.; Hankemeier, T.

    2005-01-01

    Microbial production strains are currently improved using a combination of random and targeted approaches. In the case of a targeted approach, potential bottlenecks, feed-back inhibition, and side-routes are removed, and other processes of interest are targeted by overexpressing or knocking-out the

  13. Targeting of captopril to the kidney : towards selective renal ACE inhibition

    NARCIS (Netherlands)

    Kok, Robbert Jan

    1998-01-01

    The present thesis deals with the targeting of the angiotensin converting enzyme (ACE) inhibiting drug captopril to the kidney. Drug targeting is a technique that aims at a more specific action of drugs by restricting their distribution to a specific part of the body. In other words, the targeting

  14. Deciding Where to Attend: Priming of Pop-Out Drives Target Selection

    Science.gov (United States)

    Brascamp, Jan W.; Blake, Randolph; Kristjansson, Arni

    2011-01-01

    With attention and eye-movements humans orient to targets of interest. This orienting occurs faster when the same target repeats: priming of pop-out (PoP). While reaction times (RTs) can be important, PoP's real function could be to steer "where" to orient, a possibility underexposed in many current paradigms, as these predesignate a target to…

  15. Attention Blinks for Selection, Not Perception or Memory: Reading Sentences and Reporting Targets

    Science.gov (United States)

    Potter, Mary C.; Wyble, Brad; Olejarczyk, Jennifer

    2011-01-01

    In whole report, a sentence presented sequentially at the rate of about 10 words/s can be recalled accurately, whereas if the task is to report only two target words (e.g., red words), the second target suffers an attentional blink if it appears shortly after the first target. If these two tasks are carried out simultaneously, is there an…

  16. New Strategies for the Next Generation of Matrix-Metalloproteinase Inhibitors: Selectively Targeting Membrane-Anchored MMPs with Therapeutic Antibodies

    Directory of Open Access Journals (Sweden)

    Laetitia Devy

    2011-01-01

    Full Text Available MMP intervention strategies have met with limited clinical success due to severe toxicities. In particular, treatment with broad-spectrum MMP-inhibitors (MMPIs caused musculoskeletal pain and inflammation. Selectivity may be essential for realizing the clinical potential of MMPIs. Here we review discoveries pinpointing membrane-bound MMPs as mediators of mechanisms underlying cancer and inflammation and as possible therapeutic targets for prevention/treatment of these diseases. We discuss strategies to target these therapeutic proteases using highly selective inhibitory agents (i.e., human blocking antibodies against individual membrane-bound MMPs.

  17. Identification and quantification of selected chemicals in laser pyrolysis products of mammalian tissues

    Science.gov (United States)

    Spleiss, Martin; Weber, Lothar W.; Meier, Thomas H.; Treffler, Bernd

    1995-01-01

    Liver and muscle tissue have been irradiated with a surgical CO2-laser. The prefiltered fumes were adsorbed on different sorbents (activated charcoal type NIOSH and Carbotrap) and desorbed with different solvents (carbondisulphide and acetone). Analysis was done by gas chromatography/mass spectrometry. An updated list of identified substances is shown. Typical Maillard reaction products as found in warmed over flavour as aldehydes, aromatics, heterocyclic and sulphur compounds were detected. Quantification of some toxicological relevant substances is presented. The amounts of these substances are given in relation to the laser parameters and different tissues for further toxicological assessment.

  18. Prone versus supine positioning for whole and partial-breast radiotherapy: A comparison of non-target tissue dosimetry

    International Nuclear Information System (INIS)

    Kirby, Anna M.; Evans, Philip M.; Donovan, Ellen M.; Convery, Helen M.; Haviland, Joanna S.; Yarnold, John R.

    2010-01-01

    Purpose: To compare non-target tissue (including left-anterior-descending coronary-artery (LAD)) dosimetry of prone versus supine whole (WBI) and partial-breast irradiation (PBI). Methods and materials: Sixty-five post-lumpectomy breast cancer patients underwent CT-imaging supine and prone. On each dataset, the whole-breast clinical-target-volume (WB-CTV), partial-breast CTV (tumour-bed + 15 mm), ipsilateral-lung and chest-wall were outlined. Heart and LAD were outlined in left-sided cases (n = 30). Tangential-field WBI and PBI plans were generated for each position. Mean LAD, heart, and ipsilateral-lung doses (x mean ), maximum LAD (LAD max ) doses, and the volume of chest-wall receiving 50 Gy (V 50Gy ) were compared. Results: Two-hundred and sixty plans were generated. Prone positioning reduced heart and LAD doses in 19/30 WBI cases (median reduction in LAD mean = 6.2 Gy) and 7/30 PBI cases (median reduction in LAD max = 29.3 Gy) (no difference in 4/30 cases). However, prone positioning increased cardiac doses in 8/30 WBI (median increase in LAD mean = 9.5 Gy) and 19/30 PBI cases (median increase in LAD max = 22.9 Gy) (no difference in 3/30 cases). WB-CTV > 1000cm 3 was associated with improved cardiac dosimetry in the prone position for WBI (p = 0.04) and PBI (p = 0.04). Prone positioning reduced ipsilateral-lung mean in 65/65 WBI and 61/65 PBI cases, and chest-wall V 50Gy in all WBI cases. PBI reduced normal-tissue doses compared to WBI in all cases, regardless of the treatment position. Conclusions: In the context of tangential-field WBI and PBI, prone positioning is likely to benefit left-breast-affected women of larger breast volume, but to be detrimental in left-breast-affected women of smaller breast volume. Right-breast-affected women are likely to benefit from prone positioning regardless of breast volume.

  19. Chemical biology based on target-selective degradation of proteins and carbohydrates using light-activatable organic molecules.

    Science.gov (United States)

    Toshima, Kazunobu

    2013-05-01

    Proteins and carbohydrates play crucial roles in a wide range of biological processes, including serious diseases. The development of novel and innovative methods for selective control of specific proteins and carbohydrates functions has attracted much attention in the field of chemical biology. In this account article, the development of novel chemical tools, which can degrade target proteins and carbohydrates by irradiation with a specific wavelength of light under mild conditions without any additives, is introduced. This novel class of photochemical agents promise bright prospects for finding not only molecular-targeted bioprobes for understanding of the structure-activity relationships of proteins and carbohydrates but also novel therapeutic drugs targeting proteins and carbohydrates.

  20. Aronia melanocarpa Treatment and Antioxidant Status in Selected Tissues in Wistar Rats

    Directory of Open Access Journals (Sweden)

    Renata Francik

    2014-01-01

    Full Text Available Aronia juice is considered to be a source of compounds with high antioxidative potential. We conducted a study on the impact of compounds in the Aronia juice on oxidative stress in plasma and brain tissues. The influence of Aronia juice on oxidative stress parameters was tested with the use of a model with a high content of fructose and nonsaturated fats. Therefore, the activity of enzymatic (catalase, CAT, and paraoxonase, PON and nonenzymatic (thiol groups, SH, and protein carbonyl groups, PCG oxidative stress markers, which indicate changes in the carbohydrate and protein profiles, was marked in brain tissue homogenates. Adding Aronia caused statistically significant increase in the CAT activity in plasma in all tested diets, while the PON activity showed a statistically significant increase only in case of high fat diet. In animals fed with Aronia juice supplemented with carbohydrates or fat, statistically significant increase in the PON activity and the decrease in the CAT activity in brain tissue were observed. In case of the high fat diet, an increase in the number of SH groups and a decrease in the number of PCG groups in brain tissue were observed.

  1. Impact of Uncertain Head Tissue Conductivity in the Optimization of Transcranial Direct Current Stimulation for an Auditory Target

    Science.gov (United States)

    Wagner, Sven; Burger, Martin; van Rienen, Ursula; Wolters, Carsten H

    2015-01-01

    Objective Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique to modify neural excitability. Using multi-array tDCS, we investigate the influence of inter-individually varying head tissue conductivity profiles on optimal electrode configurations for an auditory cortex stimulation. Approach In order to quantify the uncertainty of the optimal electrode configurations, multi-variate generalized Polynomial Chaos (gPC) expansions of the model solutions are used based on uncertain conductivity profiles of the compartments skin, skull, gray matter, and white matter. Stochastic measures, probability density functions, and sensitivity of the quantities of interest are investigated for each electrode and the current density at the target with the resulting stimulation protocols visualized on the head surface. Main results We demonstrate that the optimized stimulation protocols are only comprised of a few active electrodes, with tolerable deviations in the stimulation amplitude of the anode. However, large deviations in the order of the uncertainty in the conductivity profiles could be noted in the stimulation protocol of the compensating cathodes. Regarding these main stimulation electrodes, the stimulation protocol was most sensitive to uncertainty in skull conductivity. Finally, the probability that the current density amplitude in the auditory cortex target region is supra-threshold was below 50%. Significance The results suggest that an uncertain conductivity profile in computational models of tDCS can have a substantial influence on the prediction of optimal stimulation protocols for stimulation of the auditory cortex. The investigations carried out in this study present a possibility to predict the probability of providing a therapeutic effect with an optimized electrode system for future auditory clinical and experimental procedures of tDCS applications. PMID:26170066

  2. Proteomic Identification of Target Proteins of Thiodigalactoside in White Adipose Tissue from Diet-Induced Obese Rats

    Directory of Open Access Journals (Sweden)

    Hilal Ahmad Parray

    2015-06-01

    Full Text Available Previously, galectin-1 (GAL1 was found to be up-regulated in obesity-prone subjects, suggesting that use of a GAL1 inhibitor could be a novel therapeutic approach for treatment of obesity. We evaluated thiodigalactoside (TDG as a potent inhibitor of GAL1 and identified target proteins of TDG by performing comparative proteome analysis of white adipose tissue (WAT from control and TDG-treated rats fed a high fat diet (HFD using two dimensional gel electrophoresis (2-DE combined with MALDI-TOF-MS. Thirty-two spots from a total of 356 matched spots showed differential expression between control and TDG-treated rats, as identified by peptide mass fingerprinting. These proteins were categorized into groups such as carbohydrate metabolism, tricarboxylic acid (TCA cycle, signal transduction, cytoskeletal, and mitochondrial proteins based on functional analysis using Protein Annotation Through Evolutionary Relationship (PANTHER and Database for Annotation, Visualization, Integrated Discovery (DAVID classification. One of the most striking findings of this study was significant changes in Carbonic anhydrase 3 (CA3, Voltage-dependent anion channel 1 (VDAC1, phosphatidylethanolamine-binding protein 1 (PEBP1, annexin A2 (ANXA2 and lactate dehydrogenase A chain (LDHA protein levels between WAT from control and TDG-treated groups. In addition, we confirmed increased expression of thermogenic proteins as well as reduced expression of lipogenic proteins in response to TDG treatment. These results suggest that TDG may effectively prevent obesity, and TDG-responsive proteins can be used as novel target proteins for obesity treatment.

  3. Using 99TcM-tripeptoid library as an example of radio-combinatorial screening in vivo for the discovery of tissue targeting drug

    International Nuclear Information System (INIS)

    Zeng Jun; Liu Ciyi; Xie Wenhui; Hu Silong; Jin Muxiu

    2004-01-01

    Libraries against a molecular target in vitro is an artificially idealized system that are not the real picture in vivo where biomolecules coexist to maintain life activities. Furthermore, the diagnostic and therapeutic efficiency of drug depends highly on the drug distribution in target tissues (tumor for example) both specifically and accumulatively. Radio-labeling technology can make a unique opportunity of tracing large number of compounds in a combinatorial way in vivo simultaneously, sensitively, quantitatively, dynamically, and noninvasively. Methods: The C-terminal amide tripeptide libraries were synthesized on Rink Amide-MBHA resin in the OXX aO1OXaO1O2O positional scanning format and iterative protoco. A technetium (V) oxo core[(TcO)3+] was bound to the N4-triligands of tripeptide libraries via four deprotonated amide nitrogen atoms to form a structure of 99Tcm-tripeptoid libraries. The radio-combinatorial screening (RCS) in vivo was then carded out after SD rats and A549 tumor bearing mice received i.v. with 99Tcm-tripeptoid libraries. Results: Using 99Tcm-tripeptoid libraries as an example, a new method of radio-combinatorial screening (RCS) in vivo was demonstrated successful in generation, optimization, and design of tissue targeting leads. Signals of tissue distribution and metabolism of libraries were recorded by g counting or imaging. From library of 8,000 99Tcm-tripeptoid members, the tissue targeting leads had been identified by RCS. Those included 99Tcm-DSG, 99Tcm-VAA, 99Tcm-VIG, and 99Tcm-RES that had specific tissue targeting in kidney, stomach, liver, and tumor respectively. The percent injected dose per gram tissue (%ID/g) of 99Tcm labeled leads in their target tissues was highly structure-dependent Because the nontarget tissue binding and the metabolism of 99Tcm-tripeptoid libraries was simultaneously monitored so successfully by RCS that the background activity was limited to the lowest level when a 99Tcm labeled lead finally generated

  4. Effectiveness of a selective alcohol prevention program targeting personality risk factors: Results of interaction analyses.

    Science.gov (United States)

    Lammers, Jeroen; Goossens, Ferry; Conrod, Patricia; Engels, Rutger; Wiers, Reinout W; Kleinjan, Marloes

    2017-08-01

    To explore whether specific groups of adolescents (i.e., scoring high on personality risk traits, having a lower education level, or being male) benefit more from the Preventure intervention with regard to curbing their drinking behaviour. A clustered randomized controlled trial, with participants randomly assigned to a 2-session coping skills intervention or a control no-intervention condition. Fifteen secondary schools throughout The Netherlands; 7 schools in the intervention and 8 schools in the control condition. 699 adolescents aged 13-15; 343 allocated to the intervention and 356 to the control condition; with drinking experience and elevated scores in either negative thinking, anxiety sensitivity, impulsivity or sensation seeking. Differential effectiveness of the Preventure program was examined for the personality traits group, education level and gender on past-month binge drinking (main outcome), binge frequency, alcohol use, alcohol frequency and problem drinking, at 12months post-intervention. Preventure is a selective school-based alcohol prevention programme targeting personality risk factors. The comparator was a no-intervention control. Intervention effects were moderated by the personality traits group and by education level. More specifically, significant intervention effects were found on reducing alcohol use within the anxiety sensitivity group (OR=2.14, CI=1.40, 3.29) and reducing binge drinking (OR=1.76, CI=1.38, 2.24) and binge drinking frequency (β=0.24, p=0.04) within the sensation seeking group at 12months post-intervention. Also, lower educated young adolescents reduced binge drinking (OR=1.47, CI=1.14, 1.88), binge drinking frequency (β=0.25, p=0.04), alcohol use (OR=1.32, CI=1.06, 1.65) and alcohol use frequency (β=0.47, p=0.01), but not those in the higher education group. Post hoc latent-growth analyses revealed significant effects on the development of binge drinking (β=-0.19, p=0.02) and binge drinking frequency (β=-0.10, p=0

  5. Selective reactivation of human herpesvirus 6 in patients with autoimmune connective tissue diseases.

    Science.gov (United States)

    Broccolo, Francesco; Drago, Francesco; Cassina, Giulia; Fava, Andrea; Fusetti, Lisa; Matteoli, Barbara; Ceccherini-Nelli, Luca; Sabbadini, Maria Grazia; Lusso, Paolo; Parodi, Aurora; Malnati, Mauro S

    2013-11-01

    Viral infections have been associated with autoimmune connective tissue diseases. To evaluate whether active infection by Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus (HHV)-6, -7, -8, as well as parvovirus B19 (B19V) occur in patients with autoimmune connective tissue diseases, viral DNA loads were assessed in paired samples of serum and peripheral blood mononuclear cells (PBMCs) of 115 patients affected by different disorders, including systemic sclerosis, systemic, and discoid lupus erythematosus, rheumatoid arthritis, and dermatomyositis. Two additional groups, patients affected by inflammatory diseases (n=51) and healthy subjects (n=58) were studied as controls. The titers of anti-HHV-6 and anti-EBV antibodies were also evaluated. Cell-free HHV-6 serum viremia was detected in a significantly higher proportion of connective tissue diseases patients compared to controls (P<0.0002); a significant association between HHV-6 reactivation and the active disease state was found only for lupus erythematosus (P=0.021). By contrast, the rate of cell-free EBV viremia was similar in patients and controls groups. Cell-free CMV, HHV-8, and B19V viremia was not detected in any subject. Anti-HHV-6 and anti-EBV early antigen IgG titers were both significantly higher in autoimmune diseases patients as compared to healthy controls, although they were not associated with the presence of viremia. EBV, HHV-6, -7 prevalence and viral load in PBMCs of patients with connective tissue diseases and controls were similar. These data suggest that HHV-6 may act as a pathogenic factor predisposing patients to the development of autoimmune connective tissue diseases or, conversely, that these disorders may predispose patients to HHV-6 reactivation. © 2013 Wiley Periodicals, Inc.

  6. From Target Selection to Post-Stimulation Analysis: Example of an Unconventional Faulted Reservoir

    Science.gov (United States)

    LeCalvez, J. H.; Williams, M.; Xu, W.; Stokes, J.; Moros, H.; Maxwell, S. C.; Conners, S.

    2011-12-01

    As the global balance of supply and demand forces the hydrocarbon industry toward unconventional resources, technology- and economics-driven shale oil and gas production is gaining momentum throughout many basins worldwide. Production from such unconventional plays is facilitated by massive hydraulic fracturing treatments aimed at increasing permeability and reactivating natural fractures. Large-scale faulting and fracturing partly control stress distribution, hence stimulation-derived hydraulically-induced fracture systems development. Therefore, careful integrated approaches to target selection, treatment staging, and stimulation methods need to be used to economically maximize ultimate hydrocarbon recovery. We present a case study of a multistage, multilateral stimulation project in the Fort Worth Basin, Texas. Wells had to be drilled within city limits in a commercially developing building area. Well locations and trajectories were determined in and around large-scale faults using 3D surface seismic with throws varying from seven to thirty meters. As a result, three horizontal wells were drilled in the Lower Barnett Shale section, 150 m apart with the central well landed about 25 m shallower than the outside laterals. Surface seismic indicates that the surface locations are on top of a major fault complex with the lateral sections drilling away from the major fault system and through a smaller fault. Modeling of the borehole-based microseismic monitoring options led to the selection of an optimum set of configurations given the operational restrictions faced: monitoring would mainly take place using a horizontal array to be tractored downhole and moved according to the well and stage to be monitored. Wells were completed using a perf-and-plug approach allowing for each stimulation stage to obtain a precise orientation of the various three-component accelerometers of the monitoring array as well as the calibration of the velocity model used to process the

  7. Nicotine facilitates nicotinic acetylcholine receptor targeting to mitochondria but makes them less susceptible to selective ligands.

    Science.gov (United States)

    Uspenska, Kateryna; Lykhmus, Olena; Gergalova, Galyna; Chernyshov, Volodymyr; Arias, Hugo R; Komisarenko, Sergiy; Skok, Maryna

    2017-08-24

    Several nicotinic acetylcholine receptor (nAChR) subtypes are expressed in mitochondria to regulate the internal pathway of apoptosis in ion channel-independent manner. However, the mechanisms of nAChR activation in mitochondria and targeting to mitochondria are still unknown. Nicotine has been shown to favor nAChR pentamer assembly, folding, and maturation on the way of biosynthesis. The idea of the present work was to determine whether nicotine affects the content, glycosylation, and function of mitochondrial nAChRs. Experiments were performed in isolated liver mitochondria from mice, that either consumed or not nicotine with the drinking water (200μL/L) for 7days. Mitochondria detergent lysates were studied by sandwich or lectin ELISA for the presence and carbohydrate composition of different nAChR subunits. Intact mitochondria were examined by flow cytometry for the binding of fluorescently labeled α-cobratoxin and were tested in functional assay of cytochrome c release under the effect of either Ca 2+ or wortmannin in the presence or absence of nAChR-selective ligands, including PNU-282987 (1nM), dihydro-β-erythroidine (DhβE, 1μM), PNU-120596 (0.3, 3, or 10μM) and desformylflustrabromine hydrochloride (dFBr, 0.001, 0.3, or 1μM). It was found that nicotine consumption increased the ratio of mitochondrial vs non-mitochondrial nAChRs in the liver, enhanced fucosylation of mitochondrial nAChRs, but prevented the binding of α-cobratoxin and the cytochrome c release-attenuating effects of nAChR-specific agonists, antagonists, or positive allosteric modulators. It is concluded that nicotine consumption in vivo favors nAChR glycosylation and trafficking to mitochondria but makes them less susceptible to the effects of specific ligands. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Development of novel agents for idiopathic pulmonary fibrosis: progress in target selection and clinical trial design.

    Science.gov (United States)

    O'Riordan, Thomas G; Smith, Victoria; Raghu, Ganesh

    2015-10-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease. Until recently, the standard therapy for this disease has been essentially supportive, with the exception of a minority of patients who were eligible for lung transplantation. The development pathway for novel medications for IPF has been complicated. There have been several challenges, including an incomplete understanding of the pathogenesis, unpredictable clinical course, lack of validated biomarkers, the low clinical predictive value of animal models of lung injury, and the need to commit to large clinical trials of long duration to obtain initial evidence of clinical efficacy. Despite these challenges, the combination of recent advances in translational medicine and the unprecedented increase in clinical data accumulated from recent large clinical trials has stimulated an increase in the number of clinical development programs for IPF. Clinical programs are increasingly characterized by rational target selection, preclinical optimization of therapeutic molecules, and an emphasis on efficient clinical trial design. A lower rate of functional decline in patients treated with pirfenidone and nintedanib was demonstrated in large clinical trials. In October 2014, these two drugs became the first agents to be approved by the US Food and Drug Administration for the treatment of IPF. (Pirfenidone had already been approved in several countries outside the United States.) In November 2014, the European Medicines Agency approved the use of nintedanib for IPF. The landscape for management of IPF has markedly changed with the advent of approved therapeutic options for IPF. In this article, we review the strategies that are being used to increase the likelihood of success in clinical development programs of novel disease-modifying agents in IPF.

  9. NBR1-mediated selective autophagy targets insoluble ubiquitinated protein aggregates in plant stress responses.

    Directory of Open Access Journals (Sweden)

    Jie Zhou

    Full Text Available Plant autophagy plays an important role in delaying senescence, nutrient recycling, and stress responses. Functional analysis of plant autophagy has almost exclusively focused on the proteins required for the core process of autophagosome assembly, but little is known about the proteins involved in other important processes of autophagy, including autophagy cargo recognition and sequestration. In this study, we report functional genetic analysis of Arabidopsis NBR1, a homolog of mammalian autophagy cargo adaptors P62 and NBR1. We isolated two nbr1 knockout mutants and discovered that they displayed some but not all of the phenotypes of autophagy-deficient atg5 and atg7 mutants. Like ATG5 and ATG7, NBR1 is important for plant tolerance to heat, oxidative, salt, and drought stresses. The role of NBR1 in plant tolerance to these abiotic stresses is dependent on its interaction with ATG8. Unlike ATG5 and ATG7, however, NBR1 is dispensable in age- and darkness-induced senescence and in resistance to a necrotrophic pathogen. A selective role of NBR1 in plant responses to specific abiotic stresses suggest that plant autophagy in diverse biological processes operates through multiple cargo recognition and delivery systems. The compromised heat tolerance of atg5, atg7, and nbr1 mutants was associated with increased accumulation of insoluble, detergent-resistant proteins that were highly ubiquitinated under heat stress. NBR1, which contains an ubiquitin-binding domain, also accumulated to high levels with an increasing enrichment in the insoluble protein fraction in the autophagy-deficient mutants under heat stress. These results suggest that NBR1-mediated autophagy targets ubiquitinated protein aggregates most likely derived from denatured or otherwise damaged nonnative proteins generated under stress conditions.

  10. Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis.

    Science.gov (United States)

    Wring, Stephen; Gaukel, Eric; Nare, Bakela; Jacobs, Robert; Beaudet, Beth; Bowling, Tana; Mercer, Luke; Bacchi, Cyrus; Yarlett, Nigel; Randolph, Ryan; Parham, Robin; Rewerts, Cindy; Platner, Jacob; Don, Robert

    2014-01-01

    SUMMARY This review presents a progression strategy for the discovery of new anti-parasitic drugs that uses in vitro susceptibility, time-kill and reversibility measures to define the therapeutically relevant exposure required in target tissues of animal infection models. The strategy is exemplified by the discovery of SCYX-7158 as a potential oral treatment for stage 2 (CNS) Human African Trypanosomiasis (HAT). A critique of current treatments for stage 2 HAT is included to provide context for the challenges of achieving target tissue disposition and the need for establishing pharmacokinetic-pharmacodynamic (PK-PD) measures early in the discovery paradigm. The strategy comprises 3 stages. Initially, compounds demonstrating promising in vitro activity and selectivity for the target organism over mammalian cells are advanced to in vitro metabolic stability, barrier permeability and tissue binding assays to establish that they will likely achieve and maintain therapeutic concentrations during in-life efficacy studies. Secondly, in vitro time-kill and reversibility kinetics are employed to correlate exposure (based on unbound concentrations) with in vitro activity, and to identify pharmacodynamic measures that would best predict efficacy. Lastly, this information is used to design dosing regimens for pivotal pharmacokinetic-pharmacodyamic studies in animal infection models.

  11. CdSe/ZnS Quantum Dots-Labeled Mesenchymal Stem Cells for Targeted Fluorescence Imaging of Pancreas Tissues and Therapy of Type 1 Diabetic Rats

    Science.gov (United States)

    Liu, Haoqi; Tang, Wei; Li, Chao; Lv, Pinlei; Wang, Zheng; Liu, Yanlei; Zhang, Cunlei; Bao, Yi; Chen, Haiyan; Meng, Xiangying; Song, Yan; Xia, Xiaoling; Pan, Fei; Cui, Daxiang; Shi, Yongquan

    2015-06-01

    Mesenchymal stem cells (MSCs) have been used for therapy of type 1 diabetes mellitus. However, the in vivo distribution and therapeutic effects of transplanted MSCs are not clarified well. Herein, we reported that CdSe/ZnS quantum dots-labeled MSCs were prepared for targeted fluorescence imaging and therapy of pancreas tissues in rat models with type 1 diabetes. CdSe/ZnS quantum dots were synthesized, their biocompatibility was evaluated, and then, the appropriate concentration of quantum dots was selected to label MSCs. CdSe/ZnS quantum dots-labeled MSCs were injected into mouse models with type 1 diabetes via tail vessel and then were observed by using the Bruker In-Vivo F PRO system, and the blood glucose levels were monitored for 8 weeks. Results showed that prepared CdSe/ZnS quantum dots owned good biocompatibility. Significant differences existed in distribution of quantum dots-labeled MSCs between normal control rats and diabetic rats ( p therapy of diabetic patients in the near future.

  12. Target-triggered transcription machinery for ultra-selective and sensitive fluorescence detection of nucleoside triphosphates in one minute.

    Science.gov (United States)

    Dong, Jiantong; Wu, Tongbo; Xiao, Yu; Chen, Lu; Xu, Lei; Li, Mengyuan; Zhao, Meiping

    2018-02-15

    Nucleoside triphosphates (NTPs) play important roles in living organisms. However, no fluorescent assays are currently available to simply and rapidly detect multiple NTPs with satisfactory selectivity, sensitivity and low cost. Here we demonstrate for the first time a target-triggered in-vitro transcription machinery for ultra-selective, sensitive and instant fluorescence detection of multiple NTPs. The machinery assembles RNA polymerase, DNA template and non-target NTPs to convert the target NTP into equivalent RNA signal sequences which are monitored by the fluorescence enhancement of molecular beacon. The machinery offers excellent selectivity for the target NTP against NDP, NMP and dNTP. Notably, to accelerate the kinetics of the machinery while maintain its high specificity, we investigated the sequence of DNA templates systematically and established a set of guidelines for the design of the optimum DNA templates, which allowed for instant detection of the target NTP at fmol level in less than 1min. Furthermore, the machinery could be transformed into logic gates to study the coeffects of two NTPs in biosynthesis and real-time monitoring systems to reflect the distribution of NTP in nucleotide pools. These results provide very useful and low-cost tools for both biochemical tests and point-of-care analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Receptor-isoform-selective insulin analogues give tissue-preferential effects

    DEFF Research Database (Denmark)

    Vienberg, Sara Gry; Bouman, Stephan D; Sørensen, Heidi

    2011-01-01

    The relative expression patterns of the two IR (insulin receptor) isoforms, +/- exon 11 (IR-B/IR-A respectively), are tissue-dependent. Therefore we have developed insulin analogues with different binding affinities for the two isoforms to test whether tissue-preferential biological effects can...... be attained. In rats and mice, IR-B is the most prominent isoform in the liver (> 95%) and fat (> 90%), whereas in muscles IR-A is the dominant isoform (> 95%). As a consequence, the insulin analogue INS-A, which has a higher relative affinity for human IR-A, had a higher relative potency [compared with HI...... (human insulin)] for glycogen synthesis in rat muscle strips (26%) than for glycogen accumulation in rat hepatocytes (5%) and for lipogenesis in rat adipocytes (4%). In contrast, the INS-B analogue, which has an increased affinity for human IR-B, had higher relative potencies (compared with HI...

  14. Targeted Integration of Single-Copy Transgenes in Drosophila melanogaster Tissue-Culture Cells Using Recombination-Mediated Cassette Exchange.

    Science.gov (United States)

    Manivannan, Sathiya N; Jacobsen, Thomas L; Lyon, Peter; Selvaraj, Bhavani; Halpin, Peter; Simcox, Amanda

    2015-12-01

    Transfection of transgenes into Drosophila cultured cells is a standard approach for studying gene function. However, the number of transgenes present in the cell following transient transfection or stable random integration varies, and the resulting differences in expression level affect interpretation. Here we developed a system for Drosophila cell lines that allows selection of cells with a single-copy transgene inserted at a specific genomic site using recombination-mediated cassette exchange (RMCE). We used the φC31 integrase and its target sites attP and attB for RMCE. Cell lines with an attP-flanked genomic cassette were transfected with donor plasmids containing a transgene of interest (UAS-x), a dihydrofolate reductase (UAS-DHFR) gene flanked by attB sequences, and a thymidine kinase (UAS-TK) gene in the plasmid backbone outside the attB sequences. In cells undergoing RMCE, UAS-x and UAS-DHFR were exchanged for the attP-flanked genomic cassette, and UAS-TK was excluded. These cells were selected using methotrexate, which requires DHFR expression, and ganciclovir, which causes death in cells expressing TK. Pure populations of cells with one copy of a stably integrated transgene were efficiently selected by cloning or mass culture in ∼6 weeks. Our results show that RMCE avoids the problems associated with current methods, where transgene number is not controlled, and facilitates the rapid generation of Drosophila cell lines in which expression from a single transgene can be studied. Copyright © 2015 by the Genetics Society of America.

  15. Efficacy Trial of a Selective Prevention Program Targeting Both Eating Disorder Symptoms and Unhealthy Weight Gain among Female College Students

    Science.gov (United States)

    Stice, Eric; Rohde, Paul; Shaw, Heather; Marti, C. Nathan

    2012-01-01

    Objective: Evaluate a selective prevention program targeting both eating disorder symptoms and unhealthy weight gain in young women. Method: Female college students at high-risk for these outcomes by virtue of body image concerns (N = 398; M age = 18.4 years, SD = 0.6) were randomized to the Healthy Weight group-based 4-hr prevention program,…

  16. Chromosomal aberrations in bladder cancer: fresh versus formalin fixed paraffin embedded tissue and targeted FISH versus wide microarray-based CGH analysis.

    Directory of Open Access Journals (Sweden)

    Elena Panzeri

    Full Text Available Bladder carcinogenesis is believed to follow two alternative pathways driven by the loss of chromosome 9 and the gain of chromosome 7, albeit other nonrandom copy number alterations (CNAs were identified. However, confirmation studies are needed since many aspects of this model remain unclear and considerable heterogeneity among cases has emerged. One of the purposes of this study was to evaluate the performance of a targeted test (UroVysion assay widely used for the detection of Transitional Cell Carcinoma (TCC of the bladder, in two different types of material derived from the same tumor. We compared the results of UroVysion test performed on Freshly Isolated interphasic Nuclei (FIN and on Formalin Fixed Paraffin Embedded (FFPE tissues from 22 TCCs and we didn't find substantial differences. A second goal was to assess the concordance between array-CGH profiles and the targeted chromosomal profiles of UroVysion assay on an additional set of 10 TCCs, in order to evaluate whether UroVysion is an adequately sensitive method for the identification of selected aneuploidies and nonrandom CNAs in TCCs. Our results confirmed the importance of global genomic screening methods, that is array based CGH, to comprehensively determine the genomic profiles of large series of TCCs tumors. However, this technique has yet some limitations, such as not being able to detect low level mosaicism, or not detecting any change in the number of copies for a kind of compensatory effect due to the presence of high cellular heterogeneity. Thus, it is still advisable to use complementary techniques such as array-CGH and FISH, as the former is able to detect alterations at the genome level not excluding any chromosome, but the latter is able to maintain the individual data at the level of single cells, even if it focuses on few genomic regions.

  17. Restoration for the future: Setting endpoints and targets and selecting indicators of progress and success

    Science.gov (United States)

    Daniel C. Dey; Callie Jo Schweitzer; John M. Kabrick

    2014-01-01

    Setting endpoints and targets in forest restoration is a complicated task that is best accomplished in cooperative partnerships that account for the ecology of the system, production of desired ecosystem goods and services, economics and well-being of society, and future environments. Clearly written and quantitative endpoints and intermediary targets need to be...

  18. Acquisitions as lotteries? : The selection of target-firm risk and its impact on merger outcomes

    NARCIS (Netherlands)

    Schneider, C.A.R.; Spalt, Oliver

    2017-01-01

    From 1987 to 2008, riskier firms were more likely to be taken over. Yet, on average, the acquirer declined in value by 2.8% when it bought a "risky target" (the third tercile, having an annualized idiosyncratic volatility of 61% or more), but only by 0.6% when it bought a "safe target" (the first

  19. Target-specific NMR detection of protein-ligand interactions with antibody-relayed 15N-group selective STD.

    Science.gov (United States)

    Hetényi, Anasztázia; Hegedűs, Zsófia; Fajka-Boja, Roberta; Monostori, Éva; Kövér, Katalin E; Martinek, Tamás A

    2016-12-01

    Fragment-based drug design has been successfully applied to challenging targets where the detection of the weak protein-ligand interactions is a key element. 1 H saturation transfer difference (STD) NMR spectroscopy is a powerful technique for this work but it requires pure homogeneous proteins as targets. Monoclonal antibody (mAb)-relayed 15 N-GS STD spectroscopy has been developed to resolve the problem of protein mixtures and impure proteins. A 15 N-labelled target-specific mAb is selectively irradiated and the saturation is relayed through the target to the ligand. Tests on the anti-Gal-1 mAb/Gal-1/lactose system showed that the approach is experimentally feasible in a reasonable time frame. This method allows detection and identification of binding molecules directly from a protein mixture in a multicomponent system.

  20. Use of diagnostic dynamic contrast-enhanced (DCE)-MRI for targeting of soft tissue tumour biopsies at 3T: preliminary results

    International Nuclear Information System (INIS)

    Noebauer-Huhmann, Iris-Melanie; Amann, Gabriele; Krssak, Martin; Panotopoulos, Joannis; Funovics, Philipp; Windhager, Reinhard; Szomolanyi, Pavol; Weber, Michael; Czerny, Christian; Nemec, Stefan; Breitenseher, Martin; Grabner, Guenther; Bogner, Wolfgang; Dominkus, Martin; Trattnig, Siegfried

    2015-01-01

    To test the feasibility and accuracy of MR-guided soft tissue tumour biopsy at 3T, using the dynamic contrast-enhanced (DCE) information from staging MRI for intralesional targeting. After obtaining written informed consent for this institutional review board-approved study, 53 patients with suspected soft tissue tumours prospectively underwent preoperative staging MRI at 3T, including DCE, and subsequent MR-guided core needle biopsy. In 44/53 cases, DCE was heterogeneous and was used for intralesional biopsy targeting. Surgical, whole-specimen histology was used as the gold standard in 43/44 patients and revealed 42 soft tissue tumours (24 men; 18 women; mean age, 52 years; range, 19 - 84). Final surgical histology revealed eight benign lesions, six tumours of intermediate dignity, and 28 malignancies. All malignancies had shown heterogeneous DCE. The diagnostic yield of the biopsies was 100 % (42/42). Histological accuracy rates of biopsy were 100 % in predicting the dignity (42/42; 95 % CI [0.916 - 1.000]), 95.2 % for the tissue-specific entity (40/42; 95 % CI [0.847 - 0.987]), and 90.5 % for the tumour grade (38/42; 95 % CI [0.779 - 0.962]). Our preliminary study indicates that biopsy of soft tissue tumours can be performed accurately and safely with DCE targeted MR-guidance at 3T, using a combined staging/biopsy MRI protocol. (orig.)

  1. Use of diagnostic dynamic contrast-enhanced (DCE)-MRI for targeting of soft tissue tumour biopsies at 3T: preliminary results

    Energy Technology Data Exchange (ETDEWEB)

    Noebauer-Huhmann, Iris-Melanie [Medical University of Vienna, Department of Biomedical Imaging and Image-guided Therapy, Division of Neuroradiology and Musculoskeletal Radiology, Vienna (Austria); Medical University of Vienna, High Field MR Center, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Medical University of Vienna/Vienna General Hospital, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Amann, Gabriele [Medical University of Vienna, Clinical Institute for Pathology, Vienna (Austria); Krssak, Martin [Medical University of Vienna, High Field MR Center, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Medical University of Vienna, Department of Internal Medicine III, Endocrinology and Metabolism, Vienna (Austria); Panotopoulos, Joannis; Funovics, Philipp; Windhager, Reinhard [Medical University of Vienna, Department of Orthopaedics, Vienna (Austria); Szomolanyi, Pavol [Medical University of Vienna, High Field MR Center, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Slovak Academy of Sciences, Department of Imaging Methods, Institute of Measurement Science, Bratislava (Slovakia); Weber, Michael; Czerny, Christian; Nemec, Stefan [Medical University of Vienna, Department of Biomedical Imaging and Image-guided Therapy, Division of Neuroradiology and Musculoskeletal Radiology, Vienna (Austria); Breitenseher, Martin [Landesklinikum Waldviertel Horn, Horn (Austria); Grabner, Guenther; Bogner, Wolfgang [Medical University of Vienna, High Field MR Center, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Dominkus, Martin [Orthopaedics Hospital Speising, Vienna (Austria); Trattnig, Siegfried [Medical University of Vienna, High Field MR Center, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Austrian Cluster for Tissue Regeneration, Vienna (Austria)

    2015-07-15

    To test the feasibility and accuracy of MR-guided soft tissue tumour biopsy at 3T, using the dynamic contrast-enhanced (DCE) information from staging MRI for intralesional targeting. After obtaining written informed consent for this institutional review board-approved study, 53 patients with suspected soft tissue tumours prospectively underwent preoperative staging MRI at 3T, including DCE, and subsequent MR-guided core needle biopsy. In 44/53 cases, DCE was heterogeneous and was used for intralesional biopsy targeting. Surgical, whole-specimen histology was used as the gold standard in 43/44 patients and revealed 42 soft tissue tumours (24 men; 18 women; mean age, 52 years; range, 19 - 84). Final surgical histology revealed eight benign lesions, six tumours of intermediate dignity, and 28 malignancies. All malignancies had shown heterogeneous DCE. The diagnostic yield of the biopsies was 100 % (42/42). Histological accuracy rates of biopsy were 100 % in predicting the dignity (42/42; 95 % CI [0.916 - 1.000]), 95.2 % for the tissue-specific entity (40/42; 95 % CI [0.847 - 0.987]), and 90.5 % for the tumour grade (38/42; 95 % CI [0.779 - 0.962]). Our preliminary study indicates that biopsy of soft tissue tumours can be performed accurately and safely with DCE targeted MR-guidance at 3T, using a combined staging/biopsy MRI protocol. (orig.)

  2. Tissue- and stage-specific Wnt target gene expression is controlled subsequent to beta-catenin recruitment to cis-regulatory modules

    NARCIS (Netherlands)

    Nakamura, Y.; de Paiva Alves, E.; Veenstra, G.J.C.; Hoppler, S.

    2016-01-01

    Key signalling pathways, such as canonical Wnt/beta-catenin signalling, operate repeatedly to regulate tissue- and stage-specific transcriptional responses during development. Although recruitment of nuclear beta-catenin to target genomic loci serves as the hallmark of canonical Wnt signalling,

  3. HDR monotherapy for prostate cancer: A simulation study to determine the effect of catheter displacement on target coverage and normal tissue irradiation

    NARCIS (Netherlands)

    I.-K.K. Kolkman-Deurloo (Inger-Karina); M.A. Roos (Martin); S. Aluwini (Shafak)

    2011-01-01

    textabstractPurpose: The aim of this study was to systematically analyse the effect of catheter displacements both on target coverage and normal tissue irradiation in fractionated high dose rate (HDR) prostate brachytherapy, using a simulation study, and to define tolerances for catheter

  4. Chemical elements in the muscle tissues of European eel (Anguilla anguilla) from selected lakes in Latvia.

    Science.gov (United States)

    Rudovica, Vita; Bartkevics, Vadims

    2015-10-01

    Fish is a significant source of essential nutrients, as well as toxic elements in the human diet. Concentration of 17 elements was determined in muscles of eels (Anguilla anguilla) collected from five fishing lakes in the territory of Latvia. The concentration of main elements determined in muscle tissues varied within the following ranges: for Pb, 0.019-0.047; Cd, 0.0051-0.011; Hg, 0.13-0.36; Cu, 0.76-0.92; Zn, 28-42; and As, 0.13-0.23 mg kg(-1) wet weight. A positive correlation was revealed between the concentration of Hg in muscles and fish length in inland lakes. Concentration of metals in muscle tissues of eels from brackish coastal and inland lakes was without statistically significant difference. This research demonstrated that the elemental content of Cd and Pb in muscles of the examined fish was lower than the maximum allowed threshold set by the European Union legislation. Mercury content was over the threshold limit for all the analyzed eels if to compare with the Water Framework Directive Environmental Quality Standards. On other side, only 7% of analyzed fish have indicated values that are over threshold limits for mercury established by the European Union food legislation. The current study contributes to the implementation of Water Framework Directive in Latvia by collection of information necessary for the further protection measures of waters. To our knowledge, this study provides the first data on multielemental bioaccumulation in muscle tissues of European eels collected from fishing lakes of Latvia.

  5. MicroRNA-145 Inhibits Cell Migration and Invasion and Regulates Epithelial-Mesenchymal Transition (EMT) by Targeting Connective Tissue Growth Factor (CTGF) in Esophageal Squamous Cell Carcinoma.

    Science.gov (United States)

    Han, Qiang; Zhang, Hua-Yong; Zhong, Bei-Long; Wang, Xiao-Jing; Zhang, Bing; Chen, Hua

    2016-10-23

    BACKGROUND This study investigated the mechanism of miR-145 in targeting connective tissue growth factor (CTGF), which affects the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of ESCC cells. MATERIAL AND METHODS A total of 50 ESCC tissues and their corresponding normal adjacent esophageal tissue samples were collected. Then, miR-145 expression in both ESCC clinical specimens and cell lines was detected using quantitative real-time PCR. CTGF protein was detected using immunohistochemistry. Dual luciferase reporter gene assay was employed to assess the effect of miR-145 on the 3'UTR luciferase activity of CTGF. Eca109 cells were transfected with miR-145 mimics and CTGF siRNA, respectively, and changes in cellular proliferation, migration, and invasion were detected via MTT assay, wound-healing assay, and Transwell assay, respectively. Western blotting assay was used to detect the expression of marker genes related to EMT. RESULTS MiR-145 was significantly down-regulated in ESCC tissues and cell lines compared with normal tissues and cell lines (Ptissues was than in normal adjacent esophageal tissues (Ptissues and cell lines, while the protein expression of CTGF exhibited the opposite trend. MiR-145 inhibited the proliferation, migration, invasiveness, and the EMT process of ESCC cells through targeted regulation of CTGF expression.

  6. Effect of selected heavy metals on the histopathology of different tissues of earthworm Eudrillus eugeniae.

    Science.gov (United States)

    Sharma, Vishal J; Satyanarayan, Shanta

    2011-09-01

    Laboratory-scale experiments were conducted to determine the effect of heavy metals viz. copper (Cu), cadmium (Cd), chromium (Cr), lead (Pb), and zinc (Zn) on the different vital tissues of earthworm Eudrillus eugeniae such as head, gizzard, clitellum, and intestine after the worms were placed in municipal solid waste (MSW) substrate spiked with heavy metals in the concentration range of 0.05 g/kg to 1.0 g/kg of the waste for Cu, Cr, PB, and Zn and 0.05 g/kg for Cd. The experiments were conducted for 100 days with periodic observations and sample collection for investigation after every 10th day. Copper and lead metals were found to cause more deleterious effect in head, gizzard, and intestine. Chromium metal caused cellular damage to the intestinal region. In comparison, cadmium metal severity was more than copper, lead, and chromium metal. Zinc metal did not show deleterious effect on tissues. In general, earthworms can be used as biomarkers in toxicity studies related to heavy metals at cellular levels.

  7. Comparing the selection and placement of best management practices in improving water quality using a multiobjective optimization and targeting method.

    Science.gov (United States)

    Chiang, Li-Chi; Chaubey, Indrajeet; Maringanti, Chetan; Huang, Tao

    2014-03-11

    Suites of Best Management Practices (BMPs) are usually selected to be economically and environmentally efficient in reducing nonpoint source (NPS) pollutants from agricultural areas in a watershed. The objective of this research was to compare the selection and placement of BMPs in a pasture-dominated watershed using multiobjective optimization and targeting methods. Two objective functions were used in the optimization process, which minimize pollutant losses and the BMP placement areas. The optimization tool was an integration of a multi-objective genetic algorithm (GA) and a watershed model (Soil and Water Assessment Tool-SWAT). For the targeting method, an optimum BMP option was implemented in critical areas in the watershed that contribute the greatest pollutant losses. A total of 171 BMP combinations, which consist of grazing management, vegetated filter strips (VFS), and poultry litter applications were considered. The results showed that the optimization is less effective when vegetated filter strips (VFS) are not considered, and it requires much longer computation times than the targeting method to search for optimum BMPs. Although the targeting method is effective in selecting and placing an optimum BMP, larger areas are needed for BMP implementation to achieve the same pollutant reductions as the optimization method.

  8. Comparing the Selection and Placement of Best Management Practices in Improving Water Quality Using a Multiobjective Optimization and Targeting Method

    Directory of Open Access Journals (Sweden)

    Li-Chi Chiang

    2014-03-01

    Full Text Available Suites of Best Management Practices (BMPs are usually selected to be economically and environmentally efficient in reducing nonpoint source (NPS pollutants from agricultural areas in a watershed. The objective of this research was to compare the selection and placement of BMPs in a pasture-dominated watershed using multiobjective optimization and targeting methods. Two objective functions were used in the optimization process, which minimize pollutant losses and the BMP placement areas. The optimization tool was an integration of a multi-objective genetic algorithm (GA and a watershed model (Soil and Water Assessment Tool—SWAT. For the targeting method, an optimum BMP option was implemented in critical areas in the watershed that contribute the greatest pollutant losses. A total of 171 BMP combinations, which consist of grazing management, vegetated filter strips (VFS, and poultry litter applications were considered. The results showed that the optimization is less effective when vegetated filter strips (VFS are not considered, and it requires much longer computation times than the targeting method to search for optimum BMPs. Although the targeting method is effective in selecting and placing an optimum BMP, larger areas are needed for BMP implementation to achieve the same pollutant reductions as the optimization method.

  9. Iterative optimization yields Mcl-1-targeting stapled peptides with selective cytotoxicity to Mcl-1-dependent cancer cells.

    Science.gov (United States)

    Rezaei Araghi, Raheleh; Bird, Gregory H; Ryan, Jeremy A; Jenson, Justin M; Godes, Marina; Pritz, Jonathan R; Grant, Robert A; Letai, Anthony; Walensky, Loren D; Keating, Amy E

    2018-01-30

    Bcl-2 family proteins regulate apoptosis, and aberrant interactions of overexpressed antiapoptotic family members such as Mcl-1 promote cell transformation, cancer survival, and resistance to chemotherapy. Discovering potent and selective Mcl-1 inhibitors that can relieve apoptotic blockades is thus a high priority for cancer research. An attractive strategy for disabling Mcl-1 involves using designer peptides to competitively engage its binding groove, mimicking the structural mechanism of action of native sensitizer BH3-only proteins. We transformed Mcl-1-binding peptides into α-helical, cell-penetrating constructs that are selectively cytotoxic to Mcl-1-dependent cancer cells. Critical to the design of effective inhibitors was our introduction of an all-hydrocarbon cross-link or "staple" that stabilizes α-helical structure, increases target binding affinity, and independently confers binding specificity for Mcl-1 over related Bcl-2 family paralogs. Two crystal structures of complexes at 1.4 Å and 1.9 Å resolution demonstrate how the hydrophobic staple induces an unanticipated structural rearrangement in Mcl-1 upon binding. Systematic sampling of staple location and iterative optimization of peptide sequence in accordance with established design principles provided peptides that target intracellular Mcl-1. This work provides proof of concept for the development of potent, selective, and cell-permeable stapled peptides for therapeutic targeting of Mcl-1 in cancer, applying a design and validation workflow applicable to a host of challenging biomedical targets.

  10. Selection of reference genes for gene expression studies in pig tissues using SYBR green qPCR

    DEFF Research Database (Denmark)

    Hillig, Ann-Britt Nygaard; Jørgensen, Claus Bøttcher; Cirera, Susanna

    2007-01-01

    Background: Real-time quantitative PCR (qPCR) is a method for rapid and reliable quantification of mRNA transcription. Internal standards such as reference genes are used to normalise mRNA levels between different samples for an exact comparison of mRNA transcription level. Selection of high...... quality reference genes is of crucial importance for the interpretation of data generated by real-time qPCR. Results: In this study nine commonly used reference genes were investigated in 17 different pig tissues using real-time qPCR with SYBR green. The genes included beta-actin (ACTB), beta-2...

  11. In vitro HIV-1 selective integration into the target sequence and decoy-effect of the modified sequence.

    Directory of Open Access Journals (Sweden)

    Tatsuaki Tsuruyama

    Full Text Available Although there have been a few reports that the HIV-1 genome can be selectively integrated into the genomic DNA of cultured host cell, the biochemistry of integration selectivity has not been fully understood. We modified the in vitro integration reaction protocol and developed a reaction system with higher efficiency. We used a substrate repeat, 5'-(GTCCCTTCCCAGT(n(ACTGGGAAGGGAC(n-3', and a modified sequence DNA ligated into a circular plasmid. CAGT and ACTG (shown in italics in the above sequence in the repeat units originated from the HIV-1 proviral genome ends. Following the incubation of the HIV-1 genome end cDNA and recombinant integrase for the formation of the pre-integration (PI complex, substrate DNA was reacted with this complex. It was confirmed that the integration selectively occurred in the middle segment of the repeat sequence. In addition, integration frequency and selectivity were positively correlated with repeat number n. On the other hand, both frequency and selectivity decreased markedly when using sequences with deletion of CAGT in the middle position of the original target sequence. Moreover, on incubation with the deleted DNAs and original sequence, the integration efficiency and selectivity for the original target sequence were significantly reduced, which indicated interference effects by the deleted sequence DNAs. Efficiency and selectivity were also found to vary discontinuously with changes in manganese dichloride concentration in the reaction buffer, probably due to its influence on the secondary structure of substrate DNA. Finally, integrase was found to form oligomers on the binding site and substrate DNA formed a loop-like structure. In conclusion, there is a considerable selectivity in HIV-integration into the specified sequence; however, similar DNA sequences can interfere with the integration process, and it is therefore difficult for in vivo integration to occur selectively in the actual host genome DNA.

  12. Targeting the Binding Interface on a Shared Receptor Subunit of a Cytokine Family Enables the Inhibition of Multiple Member Cytokines with Selectable Target Spectrum*

    Science.gov (United States)

    Nata, Toshie; Basheer, Asjad; Cocchi, Fiorenza; van Besien, Richard; Massoud, Raya; Jacobson, Steven; Azimi, Nazli; Tagaya, Yutaka

    2015-01-01

    The common γ molecule (γc) is a shared signaling receptor subunit used by six γc-cytokines. These cytokines play crucial roles in the differentiation of the mature immune system and are involved in many human diseases. Moreover, recent studies suggest that multiple γc-cytokines are pathogenically involved in a single disease, thus making the shared γc-molecule a logical target for therapeutic intervention. However, the current therapeutic strategies seem to lack options to treat such cases, partly because of the lack of appropriate neutralizing antibodies recognizing the γc and, more importantly, because of the inherent and practical limitations in the use of monoclonal antibodies. By targeting the binding interface of the γc and cytokines, we successfully designed peptides that not only inhibit multiple γc-cytokines but with a selectable target spectrum. Notably, the lead peptide inhibited three γc-cytokines without affecting the other three or non-γc-cytokines. Biological and mutational analyses of our peptide provide new insights to our current understanding on the structural aspect of the binding of γc-cytokines the γc-molecule. Furthermore, we provide evidence that our peptide, when conjugated to polyethylene glycol to gain stability in vivo, efficiently blocks the action of one of the target cytokines in animal models. Collectively, our technology can be expanded to target various combinations of γc-cytokines and thereby will provide a novel strategy to the current anti-cytokine therapies against immune, inflammatory, and malignant diseases. PMID:26183780

  13. Transient analysis mode participation for modal survey target mode selection using MSC/NASTRAN DMAP

    Science.gov (United States)

    Barnett, Alan R.; Ibrahim, Omar M.; Sullivan, Timothy L.; Goodnight, Thomas W.

    1994-01-01

    Many methods have been developed to aid analysts in identifying component modes which contribute significantly to component responses. These modes, typically targeted for dynamic model correlation via a modal survey, are known as target modes. Most methods used to identify target modes are based on component global dynamic behavior. It is sometimes unclear if these methods identify all modes contributing to responses important to the analyst. These responses are usually those in areas of hardware design concerns. One method used to check the completeness of target mode sets and identify modes contributing significantly to important component responses is mode participation. With this method, the participation of component modes in dynamic responses is quantified. Those modes which have high participation are likely modal survey target modes. Mode participation is most beneficial when it is used with responses from analyses simulating actual flight events. For spacecraft, these responses are generated via a structural dynamic coupled loads analysis. Using MSC/NASTRAN DMAP, a method has been developed for calculating mode participation based on transient coupled loads analysis results. The algorithm has been implemented to be compatible with an existing coupled loads methodology and has been used successfully to develop a set of modal survey target modes.

  14. Transient analysis mode participation for modal survey target mode selection using MSC/NASTRAN DMAP

    Science.gov (United States)

    Barnett, Alan R.; Ibrahim, Omar M.; Sullivan, Timothy L.; Goodnight, Thomas W.

    1994-03-01

    Many methods have been developed to aid analysts in identifying component modes which contribute significantly to component responses. These modes, typically targeted for dynamic model correlation via a modal survey, are known as target modes. Most methods used to identify target modes are based on component global dynamic behavior. It is sometimes unclear if these methods identify all modes contributing to responses important to the analyst. These responses are usually those in areas of hardware design concerns. One method used to check the completeness of target mode sets and identify modes contributing significantly to important component responses is mode participation. With this method, the participation of component modes in dynamic responses is quantified. Those modes which have high participation are likely modal survey target modes. Mode participation is most beneficial when it is used with responses from analyses simulating actual flight events. For spacecraft, these responses are generated via a structural dynamic coupled loads analysis. Using MSC/NASTRAN DMAP, a method has been developed for calculating mode participation based on transient coupled loads analysis results. The algorithm has been implemented to be compatible with an existing coupled loads methodology and has been used successfully to develop a set of modal survey target modes.

  15. Selecting Targets for Tumor Imaging: An Overview of Cancer-Associated Membrane Proteins

    Directory of Open Access Journals (Sweden)

    Martin C. Boonstra

    2016-01-01

    Full Text Available Tumor targeting is a booming business: The global therapeutic monoclonal antibody market accounted for more than $78 billion in 2012 and is expanding exponentially. Tumors can be targeted with an extensive arsenal of monoclonal antibodies, ligand proteins, peptides, RNAs, and small molecules. In addition to therapeutic targeting, some of these compounds can also be applied for tumor visualization before or during surgery, after conjugation with radionuclides and/or near-infrared fluorescent dyes. The majority of these tumor-targeting compounds are directed against cell membrane-bound proteins. Various categories of targetable membrane-bound proteins, such as anchoring proteins, receptors, enzymes, and transporter proteins, exist. The functions and biological characteristics of these proteins determine their location and distribution on the cell membrane, making them more, or less, accessible, and therefore, it is important to understand these features. In this review, we evaluate the characteristics of cancer-associated membrane proteins and discuss their overall usability for cancer targeting, especially focusing on imaging applications.

  16. An efficient method for native protein purification in the selected range from prostate cancer tissue digests

    Energy Technology Data Exchange (ETDEWEB)

    Ahmad, Rumana; Nicora, Carrie D.; Shukla, Anil K.; Smith, Richard D.; Qian, Wei-Jun; Liu, Alvin Y.

    2016-12-01

    Prostate cancer (CP) cells differ from their normal counterpart in gene expression. Genes encoding secreted or extracellular proteins with increased expression in CP may serve as potential biomarkers. For their detection and quantification, assays based on monoclonal antibodies are best suited for development in a clinical setting. One approach to obtain antibodies is to use recombinant proteins as immunogen. However, the synthesis of recombinant protein for each identified candidate is time-consuming and expensive. It is also not practical to generate high quality antibodies to all identified candidates individually. Furthermore, non-native forms (e.g., recombinant) of proteins may not always lead to useful antibodies. Our approach was to purify a subset of proteins from CP tissue specimens for use as immunogen.

  17. Somatic homologous recombination in plants is promoted by a geminivirus in a tissue-selective manner.

    Science.gov (United States)

    Richter, K S; Kleinow, T; Jeske, H

    2014-03-01

    Four transgenic Arabidopsis thaliana lines carrying different reporter gene constructs based on split glucuronidase genes were used to monitor the frequency of somatic homologous recombination after geminivirus infections. Euphorbia mosaic virus and Cleome leaf crumple virus were chosen as examples, because they induce only mild symptoms and are expected to induce less general stress responses than other geminiviruses. After comparing the different plant lines and viruses as well as optimizing the infection procedure, Euphorbia mosaic virus enhanced recombination rates significantly in the transgenic reporter line 1445. The effect was tissue-specific in cells of the leaf veins as expected for this phloem-limited virus. The advantage for geminiviruses to activate a general recombination pathway is discussed with reference to an increased fitness by generating virus recombinants which have been observed frequently as an epidemiologic driving force. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Selection of an Appropriate Protein Extraction Method to Study the Phosphoproteome of Maize Photosynthetic Tissue.

    Directory of Open Access Journals (Sweden)

    Inês M Luís

    Full Text Available Often plant tissues are recalcitrant and, due to that, methods relying on protein precipitation, such as TCA/acetone precipitation and phenol extraction, are usually the methods of choice for protein extraction in plant proteomic studies. However, the addition of precipitation steps to protein extraction methods may negatively impact protein recovery, due to problems associated with protein re-solubilization. Moreover, we show that when working with non-recalcitrant plant tissues, such as young maize leaves, protein extraction methods with precipitation steps compromise the maintenance of some labile post-translational modifications (PTMs, such as phosphorylation. Therefore, a critical issue when studying PTMs in plant proteins is to ensure that the protein extraction method is the most appropriate, both at qualitative and quantitative levels. In this work, we compared five methods for protein extraction of the C4-photosynthesis related proteins, in the tip of fully expanded third-leaves. These included: TCA/Acetone Precipitation; Phenol Extraction; TCA/Acetone Precipitation followed by Phenol Extraction; direct extraction in Lysis Buffer (a urea-based buffer; and direct extraction in Lysis Buffer followed by Cleanup with a commercial kit. Protein extraction in Lysis Buffer performed better in comparison to the other methods. It gave one of the highest protein yields, good coverage of the extracted proteome and phosphoproteome, high reproducibility, and little protein degradation. This was also the easiest and fastest method, warranting minimal sample handling. We also show that this method is adequate for the successful extraction of key enzymes of the C4-photosynthetic metabolism, such as PEPC, PPDK, PEPCK, and NADP-ME. This was confirmed by MALDI-TOF/TOF MS analysis of excised spots of 2DE analyses of the extracted protein pools. Staining for phosphorylated proteins in 2DE revealed the presence of several phosphorylated isoforms of PEPC, PPDK

  19. Selection of a breast cancer subpopulation-specific antibody using phage display on tissue sections

    DEFF Research Database (Denmark)

    Larsen, Simon Asbjørn; Meldgaard, Theresa; Fridriksdottir, Agla J

    2015-01-01

    Breast cancer tumors are composed of heterogeneous cell populations. These populations display a high variance in morphology, growth and metastatic propensity. They respond differently to therapeutic interventions, and some may be more prone to cause recurrence. Studying individual subpopulations...... of breast cancer may provide crucial knowledge for the development of individualized therapy. However, this process is challenged by the availability of biomarkers able to identify subpopulations specifically. Here, we demonstrate an approach for phage display selection of recombinant antibody fragments...

  20. Targeting hunter distribution based on host resource selection and kill sites to manage disease risk

    DEFF Research Database (Denmark)

    Dugal, Cherie; van Beest, Floris; Vander Wal, Eric

    2013-01-01

    of these cohorts were positively associated with landscape- level forest cover and increasing distance to streams and negatively associated with high road density. Local-level forest was positively associated with collared animal locations and hunter-kill sites; however, selection was stronger for collared......Endemic and emerging diseases are rarely uniform in their spatial distribution or prevalence among cohorts of wildlife. Spatial models that quantify risk-driven differences in resource selection and hunter mortality of animals at fine spatial scales can assist disease management by identifying high......-risk areas and individuals. We used resource selection functions (RSFs) and selection ratios (SRs) to quantify sex- and age-specific resource selection patterns of collared (n = 67) and hunter-killed (n = 796) nonmigratory elk (Cervus canadensis manitobensis) during the hunting season between 2002 and 2012...

  1. SPIDERS: selection of spectroscopic targets using AGN candidates detected in all-sky X-ray surveys

    Science.gov (United States)

    Dwelly, T.; Salvato, M.; Merloni, A.; Brusa, M.; Buchner, J.; Anderson, S. F.; Boller, Th.; Brandt, W. N.; Budavári, T.; Clerc, N.; Coffey, D.; Del Moro, A.; Georgakakis, A.; Green, P. J.; Jin, C.; Menzel, M.-L.; Myers, A. D.; Nandra, K.; Nichol, R. C.; Ridl, J.; Schwope, A. D.; Simm, T.

    2017-07-01

    SPIDERS (SPectroscopic IDentification of eROSITA Sources) is a Sloan Digital Sky Survey IV (SDSS-IV) survey running in parallel to the Extended Baryon Oscillation Spectroscopic Survey (eBOSS) cosmology project. SPIDERS will obtain optical spectroscopy for large numbers of X-ray-selected active galactic nuclei (AGN) and galaxy cluster members detected in wide-area eROSITA, XMM-Newton and ROSAT surveys. We describe the methods used to choose spectroscopic targets for two sub-programmes of SPIDERS X-ray selected AGN candidates detected in the ROSAT All Sky and the XMM-Newton Slew surveys. We have exploited a Bayesian cross-matching algorithm, guided by priors based on mid-IR colour-magnitude information from the Wide-field Infrared Survey Explorer survey, to select the most probable optical counterpart to each X-ray detection. We empirically demonstrate the high fidelity of our counterpart selection method using a reference sample of bright well-localized X-ray sources collated from XMM-Newton, Chandra and Swift-XRT serendipitous catalogues, and also by examining blank-sky locations. We describe the down-selection steps which resulted in the final set of SPIDERS-AGN targets put forward for spectroscopy within the eBOSS/TDSS/SPIDERS survey, and present catalogues of these targets. We also present catalogues of ˜12 000 ROSAT and ˜1500 XMM-Newton Slew survey sources that have existing optical spectroscopy from SDSS-DR12, including the results of our visual inspections. On completion of the SPIDERS programme, we expect to have collected homogeneous spectroscopic redshift information over a footprint of ˜7500 deg2 for >85 per cent of the ROSAT and XMM-Newton Slew survey sources having optical counterparts in the magnitude range 17 < r < 22.5, producing a large and highly complete sample of bright X-ray-selected AGN suitable for statistical studies of AGN evolution and clustering.

  2. Comparative analysis of FoxP3(+) regulatory T cells in the target tissues and blood in chronic graft versus host disease.

    Science.gov (United States)

    Imanguli, M M; Cowen, E W; Rose, J; Dhamala, S; Swaim, W; Lafond, S; Yagi, B; Gress, R E; Pavletic, S Z; Hakim, F T

    2014-10-01

    Activation and migration of regulatory T cells (Treg) into tissue is critical in control of inflammation, but has not been examined extensively in chronic graft versus host disease (cGVHD). In parallel studies of tissues and blood, we determined that FoxP3(+) T cells increased in proportion to T effectors (Teff) in tissue infiltrates in oral and cutaneous lichenoid cGVHD. These FoxP3(+) cells expressed distinguishing phenotypic and functional markers of Treg (CD3(+), CD4(+), CD27(+), ICOS(+) and CD39(+)), not found on FoxP3(-) Teff. Both Teff and FoxP3(+) Treg expressed T-bet and the chemokine receptor CXCR3, however, consistent with a common mechanism of chemokine-mediated migration into tissue. Furthermore, functional markers (ICOS and CD39) and chemokine receptors (CXCR3) were both present in a higher proportion of FoxP3(+) cells in tissues than in peripheral blood, consistent with recruitment and activation of Treg in cGVHD target tissues. Finally, the 'activated' CD45RA(-)FoxP3(hi) subset of Treg cells, which highly express functional markers, were found in comparable frequencies in cGVHD patients and normal controls, despite a significant deficit in naive 'resting' Treg. These findings are consistent with Treg capacity to upregulate functional markers and traffick into tissue in cGVHD.

  3. Monte Carlo model to describe depth selective fluorescence spectra of epithelial tissue: applications for diagnosis of oral precancer.

    Science.gov (United States)

    Pavlova, Ina; Weber, Crystal Redden; Schwarz, Richard A; Williams, Michelle; El-Naggar, Adel; Gillenwater, Ann; Richards-Kortum, Rebecca

    2008-01-01

    We present a Monte Carlo model to predict fluorescence spectra of the oral mucosa obtained with a depth-selective fiber optic probe as a function of tissue optical properties. A model sensitivity analysis determines how variations in optical parameters associated with neoplastic development influence the intensity and shape of spectra, and elucidates the biological basis for differences in spectra from normal and premalignant oral sites. Predictions indicate that spectra of oral mucosa collected with a depth-selective probe are affected by variations in epithelial optical properties, and to a lesser extent, by changes in superficial stromal parameters, but not by changes in the optical properties of deeper stroma. The depth selective probe offers enhanced detection of epithelial fluorescence, with 90% of the detected signal originating from the epithelium and superficial stroma. Predicted depth-selective spectra are in good agreement with measured average spectra from normal and dysplastic oral sites. Changes in parameters associated with dysplastic progression lead to a decreased fluorescence intensity and a shift of the spectra to longer emission wavelengths. Decreased fluorescence is due to a drop in detected stromal photons, whereas the shift of spectral shape is attributed to an increased fraction of detected photons arising in the epithelium.

  4. Joint Selection of Transmitters and Receivers in Distributed Multi-input Multi-output Radar Network for Multiple Targets Tracking

    Directory of Open Access Journals (Sweden)

    Lu Yanxi

    2017-02-01

    Full Text Available Only a subset of transmitters and receivers in a distributed Multi-Input Multi-Output (MIMO radar network is allowed to actively track a target at a particular instance due to the limited time and energy resource of a MIMO radar network. It is therefore desirable to obtain an efficient method to overcome the resource constraints while optimizing the tracking performance. In this study, posterior Cramer-Rao lower bound is used as the performance metric and the selection problem is formulated as a Boolean programming problem aiming at optimizing the worst tracking performance of multiple targets. It is later relaxed to a semidefinite programming and solved by the block coordinate descend method. Numerical results show that proposed method superior to the fixed selection method. In addition, with less computation complexity, the proposed method obtains nearly equivalent performance compared with exhaustive search method.

  5. Cooperative interactions between CBP and TORC2 confer selectivity to CREB target gene expression

    DEFF Research Database (Denmark)

    Ravnskjær, Kim; Kester, Henri; Liu, Yi

    2007-01-01

    , but have minimal effects on CRE-dependent transcription. Here, we show that the latent cytoplasmic coactivator TORC2 mediates target gene activation in response to cAMP signaling by associating with CBP/p300 and increasing its recruitment to a subset of CREB target genes. TORC2 is not activated in response...... to stress signals, however; and in its absence, P-CREB is unable to stimulate CRE-dependent transcription, due to a block in CBP recruitment. The effect of TORC2 on CBP/p300 promoter occupancy appears pivotal because a gain of function mutant CREB polypeptide with increased affinity for CBP restored CRE...

  6. Method for selecting hollow microspheres for use in laser fusion targets

    Science.gov (United States)

    Farnum, Eugene H.; Fries, R. Jay; Havenhill, Jerry W.; Smith, Maurice Lee; Stoltz, Daniel L.

    1976-01-01

    Hollow microspheres having thin and very uniform wall thickness are useful as containers for the deuterium and tritium gas mixture used as a fuel in laser fusion targets. Hollow microspheres are commercially available; however, in commercial lots only a very small number meet the rigid requirements for use in laser fusion targets. Those meeting these requirements may be separated from the unsuitable ones by subjecting the commercial lot to size and density separations and then by subjecting those hollow microspheres thus separated to an external pressurization at which those which are aspherical or which have nonuniform walls are broken and separating the sound hollow microspheres from the broken ones.

  7. Characterization of IgG monoclonal antibody targeted to both tissue cyst and sporocyst walls of Toxoplasma gondii

    Science.gov (United States)

    Toxoplasma gondii infects approximately one third of the human population and animals habiting terrestrial and aquatic environments. Its environmentally resistant oocysts are excreted by felids, and the stage encysted in tissues (tissue cysts), are important in the horizontal transmission of T. gon...

  8. Algal Bioremediation of Waste Waters from Land-Based Aquaculture Using Ulva: Selecting Target Species and Strains

    OpenAIRE

    Lawton, Rebecca J.; Mata, Leonardo; de Nys, Rocky; Paul, Nicholas A.

    2013-01-01

    The optimised reduction of dissolved nutrient loads in aquaculture effluents through bioremediation requires selection of appropriate algal species and strains. The objective of the current study was to identify target species and strains from the macroalgal genus Ulva for bioremediation of land-based aquaculture facilities in Eastern Australia. We surveyed land-based aquaculture facilities and natural coastal environments across three geographic locations in Eastern Australia to determine wh...

  9. K-targeted metabolomic analysis extends chemical subtraction to DESIGNER extracts: selective depletion of extracts of hops (Humulus lupulus).

    Science.gov (United States)

    Ramos Alvarenga, René F; Friesen, J Brent; Nikolić, Dejan; Simmler, Charlotte; Napolitano, José G; van Breemen, Richard; Lankin, David C; McAlpine, James B; Pauli, Guido F; Chen, Shao-Nong

    2014-12-26

    This study introduces a flexible and compound targeted approach to Deplete and Enrich Select Ingredients to Generate Normalized Extract Resources, generating DESIGNER extracts, by means of chemical subtraction or augmentation of metabolites. Targeting metabolites based on their liquid-liquid partition coefficients (K values), K targeting uses countercurrent separation methodology to remove single or multiple compounds from a chemically complex mixture, according to the following equation: DESIGNER extract = total extract ± target compound(s). Expanding the scope of the recently reported depletion of extracts by immunoaffinity or solid phase liquid chromatography, the present approach allows a more flexible, single- or multi-targeted removal of constituents from complex extracts such as botanicals. Chemical subtraction enables both chemical and biological characterization, including detection of synergism/antagonism by both the subtracted targets and the remaining metabolite mixture, as well as definition of the residual complexity of all fractions. The feasibility of the DESIGNER concept is shown by K-targeted subtraction of four bioactive prenylated phenols, isoxanthohumol (1), 8-prenylnaringenin (2), 6-prenylnaringenin (3), and xanthohumol (4), from a standardized hops (Humulus lupulus L.) extract using specific solvent systems. Conversely, adding K-targeted isolates allows enrichment of the original extract and hence provides an augmented DESIGNER material. Multiple countercurrent separation steps were used to purify each of the four compounds, and four DESIGNER extracts with varying depletions were prepared. The DESIGNER approach innovates the characterization of chemically complex extracts through integration of enabling technologies such as countercurrent separation, K-by-bioactivity, the residual complexity concepts, as well as quantitative analysis by (1)H NMR, LC-MS, and HiFSA-based NMR fingerprinting.

  10. Genetic Manipulation of Lactococcus lactis by Using Targeted Group II Introns: Generation of Stable Insertions without Selection

    Science.gov (United States)

    Frazier, Courtney L.; San Filippo, Joseph; Lambowitz, Alan M.; Mills, David A.

    2003-01-01

    Despite their commercial importance, there are relatively few facile methods for genomic manipulation of the lactic acid bacteria. Here, the lactococcal group II intron, Ll.ltrB, was targeted to insert efficiently into genes encoding malate decarboxylase (mleS) and tetracycline resistance (tetM) within the Lactococcus lactis genome. Integrants were readily identified and maintained in the absence of a selectable marker. Since splicing of the Ll.ltrB intron depends on the intron-encoded protein, targeted invasion with an intron lacking the intron open reading frame disrupted TetM and MleS function, and MleS activity could be partially restored by expressing the intron-encoded protein in trans. Restoration of splicing from intron variants lacking the intron-encoded protein illustrates how targeted group II introns could be used for conditional expression of any gene. Furthermore, the modified Ll.ltrB intron was used to separately deliver a phage resistance gene (abiD) and a tetracycline resistance marker (tetM) into mleS, without the need for selection to drive the integration or to maintain the integrant. Our findings demonstrate the utility of targeted group II introns as a potential food-grade mechanism for delivery of industrially important traits into the genomes of lactococci. PMID:12571038

  11. Nuclear pore component Nup98 is a potential tumor suppressor and regulates posttranscriptional expression of select p53 target genes.

    Science.gov (United States)

    Singer, Stephan; Zhao, Ruiying; Barsotti, Anthony M; Ouwehand, Anette; Fazollahi, Mina; Coutavas, Elias; Breuhahn, Kai; Neumann, Olaf; Longerich, Thomas; Pusterla, Tobias; Powers, Maureen A; Giles, Keith M; Leedman, Peter J; Hess, Jochen; Grunwald, David; Bussemaker, Harmen J; Singer, Robert H; Schirmacher, Peter; Prives, Carol

    2012-12-14

    The p53 tumor suppressor utilizes multiple mechanisms to selectively regulate its myriad target genes, which in turn mediate diverse cellular processes. Here, using conventional and single-molecule mRNA analyses, we demonstrate that the nucleoporin Nup98 is required for full expression of p21, a key effector of the p53 pathway, but not several other p53 target genes. Nup98 regulates p21 mRNA levels by a posttranscriptional mechanism in which a complex containing Nup98 and the p21 mRNA 3'UTR protects p21 mRNA from degradation by the exosome. An in silico approach revealed another p53 target (14-3-3σ) to be similarly regulated by Nup98. The expression of Nup98 is reduced in murine and human hepatocellular carcinomas (HCCs) and correlates with p21 expression in HCC patients. Our study elucidates a previously unrecognized function of wild-type Nup98 in regulating select p53 target genes that is distinct from the well-characterized oncogenic properties of Nup98 fusion proteins. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Tumor targeting using {sup 67}Ga-DOTA-Bz-folate - investigations of methods to improve the tissue distribution of radiofolates

    Energy Technology Data Exchange (ETDEWEB)

    Mueller, Cristina, E-mail: cristina.mueller@psi.ch [Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI (Switzerland); Vlahov, Iontcho R.; Santhapuram, Hari Krishna R.; Leamon, Christopher P. [Endocyte Inc., West Lafayette, IN 47906 (United States); Schibli, Roger [Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI (Switzerland); Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich (Switzerland)

    2011-07-15

    Introduction: Use of folic acid radioconjugates for folate receptor (FR) targeting is a promising strategy for imaging purposes as well as for potential therapy of cancer and inflammatory diseases due to the frequent FR overexpression found on cancer cells and activated macrophages. Herein, we report on preclinical results using a novel DOTA-Bz-EDA-folate conjugate radiolabeled with [{sup 67}Ga]-gallium. Methods: DOTA-Bz-EDA-folate was prepared by conjugation of ethylenediamine-({gamma})-folate with 2-(p-isothiocyanobenzyl)-DOTA. Radiolabeling was carried out with {sup 67}GaCl{sub 3} according to standard procedures. Biodistribution studies of the tracer were performed in mice bearing FR-positive KB tumor xenografts. The effects on radiofolate biodistribution with coadministered renal uptake-blocking amino acids, diuretic agents, antifolates as well as different routes of administration were likewise investigated. Supportive imaging studies were performed using a small-animal single photon emission computed tomography (SPECT)/CT scanner. Results: {sup 67}Ga-DOTA-Bz-EDA-folate showed a high and specific accumulation in tumors (6.30%{+-}0.75% ID/g, 1 h pi and 6.08%{+-}0.89% ID/g, 4 h pi). Nonspecific radioactivity uptake in nontargeted tissues was negligible, but significant accumulation was found in FR-positive kidneys, which resulted in unfavorably low tumor-to-kidney ratios (<0.1). Coadministered amino acids or diuretics did not effectively reduce renal accumulation; in contrast, predosed pemetrexed did significantly reduce kidney uptake (<29% of control values). The SPECT/CT studies confirmed the excellent tumor-to-background contrast of {sup 67}Ga-radiofolate and the favorable reduction in kidney uptake (with improved imaging quality) resulting from pemetrexed administration. Conclusion: Conventional methods to reduce kidney uptake of radiofolates fail. However, the novel {sup 67}Ga-radiolabeled DOTA-Bz-EDA-folate can effectively be used to image FR

  13. Methods for Reducing Normal Tissue Complication Probabilities in Oropharyngeal Cancer: Dose Reduction or Planning Target Volume Elimination

    Energy Technology Data Exchange (ETDEWEB)

    Samuels, Stuart E.; Eisbruch, Avraham; Vineberg, Karen; Lee, Jae; Lee, Choonik; Matuszak, Martha M.; Ten Haken, Randall K.; Brock, Kristy K., E-mail: kbrock@med.umich.edu

    2016-11-01

    Purpose: Strategies to reduce the toxicities of head and neck radiation (ie, dysphagia [difficulty swallowing] and xerostomia [dry mouth]) are currently underway. However, the predicted benefit of dose and planning target volume (PTV) reduction strategies is unknown. The purpose of the present study was to compare the normal tissue complication probabilities (NTCP) for swallowing and salivary structures in standard plans (70 Gy [P70]), dose-reduced plans (60 Gy [P60]), and plans eliminating the PTV margin. Methods and Materials: A total of 38 oropharyngeal cancer (OPC) plans were analyzed. Standard organ-sparing volumetric modulated arc therapy plans (P70) were created and then modified by eliminating the PTVs and treating the clinical tumor volumes (CTVs) only (C70) or maintaining the PTV but reducing the dose to 60 Gy (P60). NTCP dose models for the pharyngeal constrictors, glottis/supraglottic larynx, parotid glands (PGs), and submandibular glands (SMGs) were analyzed. The minimal clinically important benefit was defined as a mean change in NTCP of >5%. The P70 NTCP thresholds and overlap percentages of the organs at risk with the PTVs (56-59 Gy, vPTV{sub 56}) were evaluated to identify the predictors for NTCP improvement. Results: With the P60 plans, only the ipsilateral PG (iPG) benefited (23.9% vs 16.2%; P<.01). With the C70 plans, only the iPG (23.9% vs 17.5%; P<.01) and contralateral SMG (cSMG) (NTCP 32.1% vs 22.9%; P<.01) benefited. An iPG NTCP threshold of 20% and 30% predicted NTCP benefits for the P60 and C70 plans, respectively (P<.001). A cSMG NTCP threshold of 30% predicted for an NTCP benefit with the C70 plans (P<.001). Furthermore, for the iPG, a vPTV{sub 56} >13% predicted benefit with P60 (P<.001) and C70 (P=.002). For the cSMG, a vPTV{sub 56} >22% predicted benefit with C70 (P<.01). Conclusions: PTV elimination and dose-reduction lowered the NTCP of the iPG, and PTV elimination lowered the NTCP of the cSMG. NTCP thresholds and the

  14. Highly stable aptamers selected from a 2'-fully modified fGmH RNA library for targeting biomaterials.

    Science.gov (United States)

    Friedman, Adam D; Kim, Dongwook; Liu, Rihe

    2015-01-01

    When developed as targeting ligands for the in vivo delivery of biomaterials to biological systems, RNA aptamers immediately face numerous obstacles, in particular nuclease degradation and post-selection 2' modification. This study aims to develop a novel class of highly stable, 2'-fully modified RNA aptamers that are ideal for the targeted delivery of biomaterials. We demonstrated the facile transcription of a fGmH (2'-F-dG, 2'-OMe-dA/dC/dU) RNA library with unexpected hydrophobicity, the direct selection of aptamers from a fGmH RNA library that bind Staphylococcus aureus Protein A (SpA) as a model target, and the superior nuclease and serum stability of these aptamers compared to 2'-partially modified RNA variants. Characterizations of fGmH RNA aptamers binding to purified SpA and to endogenous SpA present on the surface of S. aureus cells demonstrate fGmH RNA aptamer selectivity and stability. Significantly, fGmH RNA aptamers were able to functionalize, stabilize, and specifically deliver aggregation-prone silver nanoparticles (AgNPs) to S. aureus with SpA-dependent antimicrobial effects. This study describes a novel aptamer class with considerable potential to improve the in vivo applicability of nucleic acid-based affinity molecules to biomaterials.

  15. Tissue-Selective Salvage of the White Matter by Successful Endovascular Stroke Therapy.

    Science.gov (United States)

    Kleine, Justus F; Kaesmacher, Mirjam; Wiestler, Benedikt; Kaesmacher, Johannes

    2017-10-01

    White matter (WM) is less vulnerable to ischemia than gray matter. In ischemic stroke caused by acute large-vessel occlusion, successful recanalization might therefore sometimes selectively salvage the WM, leading to infarct patterns confined to gray matter. This study examines occurrence, determinants, and clinical significance of such effects. Three hundred twenty-two patients with acute middle cerebral artery occlusion subjected to mechanical thrombectomy were included. Infarct patterns were categorized into WM - (sparing the WM) and WM + (involving WM). National Institutes of Health Stroke Scale-based measures of neurological outcome, including National Institutes of Health Stroke Scale improvement or National Institutes of Health Stroke Scale worsening, good functional midterm outcome (day 90-modified Rankin Scale score of ≤2), the occurrence of malignant swelling, and in-hospital mortality were predefined outcome measures. WM - infarcts occurred in 118 of 322 patients and were associated with successful recanalization and better collateral grades ( P <0.05). Shorter symptom-onset to recanalization times were also associated with WM - infarcts in univariate analysis, but not when adjusted for collateral grades. WM - infarcts were independently associated with good neurological outcome (adjusted odds ratio, 3.003; 95% confidence interval, 1.186-7.607; P =0.020) and good functional midterm outcome (adjusted odds ratio, 8.618; 95% confidence interval, 2.409-30.828; P =0.001) after correcting for potential confounders, including final infarct volume. Only 2.6% of WM - patients, but 20.5% of WM + patients exhibited neurological worsening, and none versus 12.8% developed malignant swelling ( P <0.001), contributing to lower mortality in this group (2.5% versus 10.3%; P =0.014). WM infarction commonly commences later than gray matter infarction after acute middle cerebral artery occlusion. Successful recanalization can therefore salvage completely the WM at risk in

  16. Selection and Characterization of Single Chain Antibody Fragments Specific for Hsp90 as a Potential Cancer Targeting Molecule

    Directory of Open Access Journals (Sweden)

    Edyta Petters

    2015-08-01

    Full Text Available Heat shock proteins play an essential role in facilitating malignant transformation and they have been recognized as important factors in human cancers. One of the key elements of the molecular chaperones machinery is Hsp90 and it has recently become a target for anticancer therapeutic approaches. The potential and importance of Hsp90-directed agents becomes apparent when one realizes that disruption of Hsp90 function may influence over 200 oncogenic client proteins. Here, we described the selection and characterization of Hsp90-specific antibody fragments from commercially available Tomlinson I and J phage display libraries. The affinities of Hsp90-binding scFv variants were measured using SPR method. Then, based on the best clone selected, we performed the affinity maturation procedure and obtained valuable Hsp90-specific clones. The selected binders were expressed and applied for immunostaining, ELISA and SPR analysis using model cancer cell lines. All performed experiments confirmed the ability of selected antibodies to interact with the Hsp90. Therefore, the presented Hsp90-specific scFv, might be a starting point for the development of a novel antibody-based strategy targeting cancer.

  17. Mechanistic Insight into Salt Tolerance of Acacia auriculiformis: The Importance of Ion Selectivity, Osmoprotection, Tissue Tolerance, and Na+ Exclusion

    Science.gov (United States)

    Rahman, Md. M.; Rahman, Md. A.; Miah, Md. G.; Saha, Satya R.; Karim, M. A.; Mostofa, Mohammad G.

    2017-01-01

    Salinity, one of the major environmental constraints, threatens soil health and consequently agricultural productivity worldwide. Acacia auriculiformis, being a halophyte, offers diverse benefits against soil salinity; however, the defense mechanisms underlying salt-tolerant capacity in A. auriculiformis are still elusive. In this study, we aimed to elucidate mechanisms regulating the adaptability of the multi-purpose perennial species A. auriculiformis to salt stress. The growth, ion homeostasis, osmoprotection, tissue tolerance and Na+ exclusion, and anatomical adjustments of A. auriculiformis grown in varied doses of seawater for 90 and 150 days were assessed. Results showed that diluted seawater caused notable reductions in the level of growth-related parameters, relative water content, stomatal conductance, photosynthetic pigments, proteins, and carbohydrates in dose- and time-dependent manners. However, the percent reduction of these parameters did not exceed 50% of those of control plants. Na+ contents in phyllodes and roots increased with increasing levels of salinity, whereas K+ contents and K+/Na+ ratio decreased significantly in comparison with control plants. A. auriculiformis retained more Na+ in the roots and maintained higher levels of K+, Ca2+ and Mg2+, and K+/Na+ ratio in phyllodes than roots through ion selective capacity. The contents of proline, total free amino acids, total sugars and reducing sugars significantly accumulated together with the levels of malondialdehyde and electrolyte leakage in the phyllodes, particularly at day 150th of salt treatment. Anatomical investigations revealed various anatomical changes in the tissues of phyllodes, stems and roots by salt stress, such as increase in the size of spongy parenchyma of phyllodes, endodermal thickness of stems and roots, and the diameter of root vascular bundle, relative to control counterparts. Furthermore, the estimated values for Na+ exclusion and tissue tolerance index suggested that

  18. Target guided synthesis using DNA nano-templates for selectively assembling a G-quadruplex binding c-MYC inhibitor

    Science.gov (United States)

    Panda, Deepanjan; Saha, Puja; Das, Tania; Dash, Jyotirmayee

    2017-07-01

    The development of small molecules is essential to modulate the cellular functions of biological targets in living system. Target Guided Synthesis (TGS) approaches have been used for the identification of potent small molecules for biological targets. We herein demonstrate an innovative example of TGS using DNA nano-templates that promote Huisgen cycloaddition from an array of azide and alkyne fragments. A G-quadruplex and a control duplex DNA nano-template have been prepared by assembling the DNA structures on gold-coated magnetic nanoparticles. The DNA nano-templates facilitate the regioselective formation of 1,4-substituted triazole products, which are easily isolated by magnetic decantation. The G-quadruplex nano-template can be easily recovered and reused for five reaction cycles. The major triazole product, generated by the G-quadruplex inhibits c-MYC expression by directly targeting the c-MYC promoter G-quadruplex. This work highlights that the nano-TGS approach may serve as a valuable strategy to generate target-selective ligands for drug discovery.

  19. Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism

    Science.gov (United States)

    di Leva, Francesco Saverio; Festa, Carmen; Renga, Barbara; Sepe, Valentina; Novellino, Ettore; Fiorucci, Stefano; Zampella, Angela; Limongelli, Vittorio

    2015-11-01

    Bile acids can regulate nutrient metabolism through the activation of the cell membrane receptor GPBAR1 and the nuclear receptor FXR. Developing an exogenous control over these receptors represents an attractive strategy for the treatment of enterohepatic and metabolic disorders. A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors. On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding. Here, taking advantage of our knowledge of the two targets, we have identified through a rational drug design study a series of amine lithocholic acid derivatives as selective GPBAR1 agonists. The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

  20. Many gases and many measures. Choice of targets and selection of measures in climate policy

    Energy Technology Data Exchange (ETDEWEB)

    Aaheim, H. Asbjoern

    1997-12-31

    This report studies a mix of measures to reduce emissions of CO{sub 2}, CH{sub 4} and N{sub 2}O. It starts with a discussion of so-called direct measures and relates them to charges on emissions of fossil fuels in order to assess conditions for an optimal combination of the two. It then establishes cost functions for direct measures based on Norwegian data and discusses the calculation model. It further describes the atemporal conditions, which are relevant for a policy with emission targets and studies the implications for the choice of direct and indirect measures as well as the emphasis on different gases. In the final section, the intertemporal approach is taken, where the targets are related to concentrations of greenhouse gases by their radiative forcing. 15 refs., 19 figs., 1 table

  1. Evaluation of Alternative Splicing Regulators as Targets for Selective Therapy of Triple Negative (Basal) Breast Carcinoma

    Science.gov (United States)

    2017-10-01

    are generating the experimental animals that combine the transgene with the knockout alleles. Under Task 4, we analyzed the expression of KHDRBS3 in...tumorigenesis process and identify potential therapeutic targets. This will be accomplished through series of experiments in vitro and on animal ...We have already produced KHDRBS3(-/+); C3.1-Tag animals and these are now bred with KHDRBS3(-/-) animals to place the transgene in complete

  2. Hunting Leadership Targets in Counterinsurgency and Counterterrorist Operations: Selected Perspectives and Experience

    Science.gov (United States)

    2007-06-01

    efficacy of leadership targeting spans a broad spec- trum from highly successful in the case of Peru and the Sendero Luminoso in the 1990s to the less...countries from Central America to Argentina. In the Andean Ridge area, Colombia and Peru have been particularly notable. Among the largest and most intense...followers as “ Presidente Gonzalo” and the “Fourth Sword of Marxism” (joining Marx, Lenin and Mao), he had embraced Maoism in his travels to China

  3. Cooperative interactions between CBP and TORC2 confer selectivity to CREB target gene expression.

    Science.gov (United States)

    Ravnskjaer, Kim; Kester, Henri; Liu, Yi; Zhang, Xinmin; Lee, Dong; Yates, John R; Montminy, Marc

    2007-06-20

    A number of hormones and growth factors stimulate gene expression by promoting the phosphorylation of CREB (P-CREB), thereby enhancing its association with the histone acetylase paralogs p300 and CBP (CBP/p300). Relative to cAMP, stress signals trigger comparable amounts of CREB phosphorylation, but have minimal effects on CRE-dependent transcription. Here, we show that the latent cytoplasmic coactivator TORC2 mediates target gene activation in response to cAMP signaling by associating with CBP/p300 and increasing its recruitment to a subset of CREB target genes. TORC2 is not activated in response to stress signals, however; and in its absence, P-CREB is unable to stimulate CRE-dependent transcription, due to a block in CBP recruitment. The effect of TORC2 on CBP/p300 promoter occupancy appears pivotal because a gain of function mutant CREB polypeptide with increased affinity for CBP restored CRE-mediated transcription in cells exposed to stress signals. Taken together, these results indicate that TORC2 is one of the long sought after cofactors that mediates the differential effects of cAMP and stress pathways on CREB target gene expression.

  4. Variable selection for confounder control, flexible modeling and Collaborative Targeted Minimum Loss-based Estimation in causal inference

    Science.gov (United States)

    Schnitzer, Mireille E.; Lok, Judith J.; Gruber, Susan

    2015-01-01

    This paper investigates the appropriateness of the integration of flexible propensity score modeling (nonparametric or machine learning approaches) in semiparametric models for the estimation of a causal quantity, such as the mean outcome under treatment. We begin with an overview of some of the issues involved in knowledge-based and statistical variable selection in causal inference and the potential pitfalls of automated selection based on the fit of the propensity score. Using a simple example, we directly show the consequences of adjusting for pure causes of the exposure when using inverse probability of treatment weighting (IPTW). Such variables are likely to be selected when using a naive approach to model selection for the propensity score. We describe how the method of Collaborative Targeted minimum loss-based estimation (C-TMLE; van der Laan and Gruber, 2010) capitalizes on the collaborative double robustness property of semiparametric efficient estimators to select covariates for the propensity score based on the error in the conditional outcome model. Finally, we compare several approaches to automated variable selection in low-and high-dimensional settings through a simulation study. From this simulation study, we conclude that using IPTW with flexible prediction for the propensity score can result in inferior estimation, while Targeted minimum loss-based estimation and C-TMLE may benefit from flexible prediction and remain robust to the presence of variables that are highly correlated with treatment. However, in our study, standard influence function-based methods for the variance underestimated the standard errors, resulting in poor coverage under certain data-generating scenarios. PMID:26226129

  5. Human circulating monocytes internalize 125I-insulin in a similar fashion to rat hepatocytes: relevance to receptor regulation in target and nontarget tissues

    International Nuclear Information System (INIS)

    Grunberger, G.; Robert, A.; Carpentier, J.L.; Dayer, J.M.; Roth, A.; Stevenson, H.C.; Orci, L.; Gorden, P.

    1985-01-01

    Circulating monocytes bind 125 I-insulin in a specific fashion and have been used to analyze the ambient receptor status in humans. When freshly isolated circulating monocytes are incubated with 125 I-insulin and examined by electron microscopic autoradiography, approximately 18% of the labeled material is internalized after 15 minutes at 37 degrees C. By 2 hours at 37 degrees C, approximately one half of the 125 I-insulin is internalized. Internalization occurs also at 15 degrees C but at a slower rate. Furthermore, the monocytes bind and internalize 125 I-insulin in a manner that mirrors that of major target tissues, such as rat hepatocytes. These data suggest that the insulin receptor of the circulating monocyte might be regulated by adsorptive endocytosis in a manner analogous to that of target tissue, such as the liver

  6. Adipose tissue biglycan as a potential anti-inflammatory target of sodium salicylate in mice fed a high fat diet

    Directory of Open Access Journals (Sweden)

    Adapala Venkata J

    2012-04-01

    Full Text Available Abstract Background Inflammation in adipose tissue (AT during obesity causes impaired AT function. Although multiple extracellular matrix (ECM proteins are expressed in AT their potential role in adipose tissue inflammation is unclear. Biglycan, a pro-inflammatory ECM gene, is highly enriched in adipose tissue. However, whether it is correlated with adipose tissue inflammation is unknown. We provide evidence in support of a strong association between biglycan expression and inflammatory status of adipose tissue. Methods C57BL6 mice were fed either a control (10% fat calories or a high fat diet (HFD (60% fat calories for 8 weeks. Adipose tissue was analyzed for the expression of biglycan, IL-6 and TNFα. Biglycan knockout or wild type were also fed a high fat diet for 8 weeks and the expression of inflammatory genes in the mesenteric adipose tissue was examined. To test anti-inflammatory treatment on biglycan expression, a group of mice were fed either the low fat or high fat diet for eight weeks supplemented with either saline or sodium salicylate @ 25mg/100ml in their drinking water. Results Mice on HFD had an increase in ECM genes (BGN and COL1A1, inflammatory genes (IL-6 and TNFα in both the subcutaneous and epididymal depots. However, correlation analysis only shows a positive correlation between biglycan, IL-6 and TNFα expression. In addition, lower expression of IL-6 and CD68 was found in the mesenteric adipose tissue of biglycan knockout mice compared to the wild type. Sodium salicylate treatment reduced subcutaneous adipose tissue expression of BGN, COL1A1, and COL6A1 and a concurrent downregulation of TNFα and IL-6 and TLR4 expression. Salicylate also lowered the serum TGFβ1 levels. Conclusion Biglycan expression correlates with adipose tissue inflammation, especially in the subcutaneous depot compared to the epididymal depot. This is supported by the greater effect of sodium salicylate in attenuating both inflammatory and ECM gene

  7. Frontoparietal theta activity supports behavioral decisions in movement-target selection.

    NARCIS (Netherlands)

    Rawle, C.J.; Miall, R.C.; Praamstra, P.

    2012-01-01

    There is recent EEG evidence describing task-related changes of theta power in spatial attention and reaching/pointing tasks. Here, we aim to better characterize this theta activity and determine whether it is associated with visuospatial memory or with visuospatial selection functions of the

  8. Tissue Selective Androgen Receptor Modulators (SARMs) Increase Pelvic Floor Muscle Mass in Ovariectomized Mice.

    Science.gov (United States)

    Ponnusamy, Suriyan; Sullivan, Ryan D; Thiyagarajan, Thirumagal; Tillmann, Heather; Getzenberg, Robert H; Narayanan, Ramesh

    2017-03-01

    Stress urinary incontinence (SUI), a prevalent condition, is represented by an involuntary leakage of urine that results, at least in part, from weakened or damaged pelvic floor muscles and is triggered by physical stress. Current treatment options are limited with no oral therapies available. The pelvic floor is rich in androgen receptor and molecules with anabolic activity including selective androgen receptor modulators (SARMs) may serve as therapeutic options for individuals with SUI. In this study, two SARMs (GTx-024 and GTx-027) were evaluated in a post-menopausal animal model in order to determine their effect on pelvic floor muscles. Female C57BL/6 mice were ovariectomized and their pelvic muscles allowed to regress. The animals were then treated with vehicle or doses of GTx-024 or GTx-027. Animal total body weight, lean body mass, and pelvic floor muscle weights were measured along with the expression of genes associated with muscle catabolism. Treatment with the SARMs resulted in a restoration of the pelvic muscles to the sham-operated weight. Coordinately, the induction of genes associated with muscle catabolism was inhibited. Although a trend was observed towards an increase in total lean body mass in the SARM-treated groups, no significant differences were detected. Treatment of an ovariectomized mouse model with SARMs resulted in an increase in pelvic floor muscles, which may translate to an improvement of symptoms associated with SUI and serves as the basis for evaluating their clinical use. J. Cell. Biochem. 118: 640-646, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  9. Fluoride Uptake Profiles of Selected European Toothpastes into Hard Tissues and Plaque.

    Science.gov (United States)

    Moore, Joel; Schneiderman, Eva; Farmer, Teresa; Zsiska, Marianne

    2017-09-01

    To compare the fluoridating potential of selected European toothpastes using a combination of enamel, dentin, and plaque in vitromodels. Four in vitromodels were included: 1) Enamel Fluoride (F) Uptake (EFU); 2) Dentin F Uptake (DFU); 3) Enamel Solubility Reduction (ESR); and 4) Plaque F Uptake (PFU). A core set of marketed products was included in all studies, plus a standard toothpaste (1100 ppm F as NaF/silica) and placebo control (the PFU study did not include a placebo control). Test dentifrices: [A] Fluocaril® Bi-Fluoré 250 (1500 ppm F as NaF+1000 ppm F as SMFP); [B] LacerAnticaries (2500 ppm F as SMFP); [C] Elmex® Caries Professional™ (1450 ppm F as SMFP+1.5% arginine); [D] Colgate® Triple Action (1450 ppm F as SMFP); [E] Placebo (0 ppm F); and [F] standard toothpaste (1100 ppm as NaF/silica). In all studies (EFU, DFU, ESR, and PFU), assessments were compared for each pair using the Tukey-Kramer HSD test (p F = B = C = D > E; DFU: A > F = B = C = D = E; PFU: A = B > F = C = D). In demineralization prevention, the Fluocaril dentifrice [A] also provided the greatest benefit (ESR: A = F = C = B = D > E). In all studies that included a placebo control, all of the F-containing dentifrices performed better than the placebo control. While these results demonstrate that all of the marketed products tested provide effective anticaries benefits, the Fluocaril Bi-Fluoré 250 dentifrice consistently delivered unsurpassed performance. It delivered the highest level of F to plaque, provided greater measures of efficacy in both remineralization and inhibition of demineralization, and delivered substantial improvement in fluoridation of dentin, suggesting the potential for delivering both coronal and root caries benefits.

  10. MAGEA4 expression in bone and soft tissue tumors: its utility as a target for immunotherapy and diagnostic marker combined with NY-ESO-1.

    Science.gov (United States)

    Iura, Kunio; Kohashi, Kenichi; Ishii, Takeaki; Maekawa, Akira; Bekki, Hirofumi; Otsuka, Hiroshi; Yamada, Yuichi; Yamamoto, Hidetaka; Matsumoto, Yoshihiro; Iwamoto, Yukihide; Oda, Yoshinao

    2017-07-26

    Cancer-testis (CT) antigens have promise as targets for immunotherapy, because of their restricted expression in tumor or testis tissue. MAGEA4 is both a MAGE family member and a CT antigen, and has attracted attention as a potential immunotherapeutic target. We investigated MAGEA4 expression by immunohistochemistry in bone and soft tissue tumor specimens that consisted of 35 malignant or intermediate and 24 benign histological subtypes, in order to evaluate its possible utility as an immunotherapy target and its potential use as a diagnostic marker when combined with another CT antigen, NY-ESO-1. Among these tumors, MAGEA4 was detected in 82.2% of synovial sarcomas, 67.7% of myxoid liposarcomas, 43.8% of osteosarcomas, 41.4% of angiosarcomas, 24.6% of malignant peripheral nerve sheath tumors (MPNSTs), and 21.4% of chondrosarcomas. NY-ESO-1 expression was found in 88.2% of myxoid liposarcomas, 61.1% of synovial sarcomas, 31.3% of osteosarcomas, 21.4% of pleomorphic liposarcomas, 16.7% of desmoplastic small round cell tumors, and 14.3% of chondrosarcomas. Benign tumors and non-tumorous tissue, except for testis tissue, did not express MAGEA4 or NY-ESO-1. Combined use of MAGEA4 and NY-ESO-1 increased the sensitivity, specificity, positive predictive values, and negative predictive values for distinguishing synovial sarcoma from spindle cell tumors and other mimicking tumors, compared to individual use of MAGEA4 or NY-ESO-1. Our results support the immunotherapy targeting MAGEA4 or NY-ESO-1 can be an ancillary therapy in the above-mentioned tumors, and the potential utility of MAGEA4 as an ancillary diagnostic marker for synovial sarcoma combined with NY-ESO-1.

  11. Drugability of extracellular targets: discovery of small molecule drugs targeting allosteric, functional, and subunit-selective sites on GPCRs and ion channels.

    Science.gov (United States)

    Grigoriadis, Dimitri E; Hoare, Samuel R J; Lechner, Sandra M; Slee, Deborah H; Williams, John A

    2009-01-01

    Beginning with the discovery of the structure of deoxyribose nucleic acid in 1953, by James Watson and Francis Crick, the sequencing of the entire human genome some 50 years later, has begun to quantify the classes and types of proteins that may have relevance to human disease with the promise of rapidly identifying compounds that can modulate these proteins so as to have a beneficial and therapeutic outcome. This so called 'drugable space' involves a variety of membrane-bound proteins including the superfamily of G-protein-coupled receptors (GPCRs), ion channels, and transporters among others. The recent number of novel therapeutics targeting membrane-bound extracellular proteins that have reached the market in the past 20 years however pales in magnitude when compared, during the same timeframe, to the advancements made in the technologies available to aid in the discovery of these novel therapeutics. This review will consider select examples of extracellular drugable targets and focus on the GPCRs and ion channels highlighting the corticotropin releasing factor (CRF) type 1 and gamma-aminobutyric acid receptors, and the Ca(V)2.2 voltage-gated ion channel. These examples will elaborate current technological advancements in drug discovery and provide a prospective framework for future drug development.

  12. The effect of uterine motion and uterine margins on target and normal tissue doses in intensity modulated radiation therapy of cervical cancer

    Science.gov (United States)

    Gordon, J. J.; Weiss, E.; Abayomi, O. K.; Siebers, J. V.; Dogan, N.

    2011-05-01

    In intensity modulated radiation therapy (IMRT) of cervical cancer, uterine motion can be larger than cervix motion, requiring a larger clinical target volume to planning target volume (CTV-to-PTV) margin around the uterine fundus. This work simulates different motion models and margins to estimate the dosimetric consequences. A virtual study used image sets from ten patients. Plans were created with uniform margins of 1 cm (PTVA) and 2.4 cm (PTVC), and a margin tapering from 2.4 cm at the fundus to 1 cm at the cervix (PTVB). Three inter-fraction motion models (MM) were simulated. In MM1, all structures moved with normally distributed rigid body translations. In MM2, CTV motion was progressively magnified as one moved superiorly from the cervix to the fundus. In MM3, both CTV and normal tissue motion were magnified as in MM2, modeling the scenario where normal tissues move into the void left by the mobile uterus. Plans were evaluated using static and percentile DVHs. For a conventional margin (PTVA), quasi-realistic uterine motion (MM3) reduces fundus dose by about 5 Gy and increases normal tissue volumes receiving 30-50 Gy by ~5%. A tapered CTV-to-PTV margin can restore fundus and CTV doses, but will increase normal tissue volumes receiving 30-50 Gy by a further ~5%.

  13. Vascular targeting to the SST2 receptor improves the therapeutic response to near-IR two-photon activated PDT for deep-tissue cancer treatment.

    Science.gov (United States)

    Starkey, Jean R; Pascucci, Elizabeth M; Drobizhev, Mikhail A; Elliott, Aleisha; Rebane, Aleksander K

    2013-10-01

    Broader clinical acceptance of photodynamic therapy is currently hindered by (a) poor depth efficacy, and (b) predisposition towards establishment of an angiogenic environment during the treatment. Improved depth efficacy is being sought by exploiting the NIR tissue transparency window and by photo-activation using two-photon absorption (2PA). Here, we use two-photon activation of PDT sensitizers, untargeted and targeted to SST2 receptors or EGF receptors, to achieve deep tissue treatment. Human tumor lines, positive or negative for SST2r expression were used, as well as murine 3LL cells and bovine aortic endothelial cells. Expression of SST2 receptors on cancer cells and tumor vasculature was evaluated in vitro and frozen xenograft sections. PDT effects on tumor blood flow were followed using in vivo scanning after intravenous injection of FITC conjugated dextran 150K. Dependence of the PDT efficacy on the laser pulse duration was evaluated. Effectiveness of targeting to vascular SST2 receptors was compared to that of EGF receptors, or no targeting. Tumor vasculature stained for SST2 receptors even in tumors from SST2 receptor negative cell lines, and SST2r targeted PDT led to tumor vascular shutdown. Stretching the pulse from ~120fs to ~3ps led to loss of the PDT efficacy especially at greater depth. PDT targeted to SST2 receptors was much more effective than untargeted PDT or PDT targeted to EGF receptors. The use of octreotate to target SST2 receptors expressed on tumor vessels is an excellent approach to PDT with few recurrences and some long term cures. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Selection and fabrication of a non-woven polycarbonate urethane cover for a tissue engineered airway stent.

    Science.gov (United States)

    Chen, Weiluan; Clauser, Johanna; Thiebes, Anja Lena; McGrath, Donnacha J; McHugh, Peter E; Steinseifer, Ulrich; Jockenhoevel, Stefan; Hennink, Wim E; Kok, Robbert Jan

    2016-11-30

    One of the major problems in end-stage bronchotracheal cancer is stenosis of the upper airways, either due to luminal ingrowth of the tumor or mucus plugging. Airway stents that suppress tumor ingrowth and sustain mucociliary transport can alleviate these problems in end-stage bronchial cancer. We evaluated different types of polymeric covers for a tissue engineered airway stent. The distinguishing feature of this stent concept is that respiratory epithelial cells can grow on the luminal surface of the stent which facilitates mucociliary clearance. To facilitate growth of epithelial cells at the air-liquid interface of the stent, we developed a polyurethane cover that allows transport of nutrients to the cells. Nonwoven polycarbonate urethane (PCU) covers were prepared by a spraying process and evaluated for their porosity and glucose permeability. Respiratory epithelial cells harvested from sheep trachea were cultured onto the selected PCU cover and remained viable at the air-liquid interface when cultured for 21days. Lastly, we evaluated the radial force of a PCU-covered nitinol stent, and showed the PCU covers did not adversely affect the mechanical properties of the stents for their intended application in the smaller bronchi. These in vitro data corroborate the design of a novel airway stent for palliative treatment of bronchotracheal stenosis by combination of stent-technology with tissue-engineered epithelial cells. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Selective pressurized liquid extraction technique capable of analyzing dioxins, furans, and PCBs in clams and crab tissue.

    Science.gov (United States)

    Subedi, Bikram; Aguilar, Lissette; Williams, E Spencer; Brooks, Bryan W; Usenko, Sascha

    2014-04-01

    A selective pressurized liquid extraction technique (SPLE) was developed for the analysis of polychlorodibenzo-p-dioxins, polychlorodibenzofurans (PCDD/Fs) and dioxin-like polychlorobiphenyls (dl-PCBs) in clam and crab tissue. The SPLE incorporated multiple cleanup adsorbents (alumina, florisil, silica gel, celite, and carbopack) within the extraction cell. Tissue extracts were analyzed by high resolution gas chromatography coupled with electron capture negative ionization mass spectrometry. Mean recovery (n = 3) and percent relative standard deviation for PCDD/Fs and dl-PCBs in clam and crabs was 89 ± 2.3 and 85 ± 4.0, respectively. The SPLE method was applied to clams and crabs collected from the San Jacinto River Waste Pits, a Superfund site in Houston, TX. The dl-PCBs concentrations in clams and crabs ranged from 50 to 2,450 and 5 to 800 ng/g ww, respectively. Sample preparation time and solvents were reduced by 92 % and 65 %, respectively, as compared to USEPA method 1613.

  16. Variable phenotypic penetrance of thrombosis in adult mice after tissue-selective and temporally controlled Thbd gene inactivation.

    Science.gov (United States)

    van Mens, Thijs E; Liang, Hai-Po H; Basu, Sreemanti; Hernandez, Irene; Zogg, Mark; May, Jennifer; Zhan, Min; Yang, Qiuhui; Foeckler, Jamie; Kalloway, Shawn; Sood, Rashmi; Karlson, Caren Sue; Weiler, Hartmut

    2017-06-27

    Thrombomodulin (Thbd) exerts pleiotropic effects on blood coagulation, fibrinolysis, and complement system activity by facilitating the thrombin-mediated activation of protein C and thrombin-activatable fibrinolysis inhibitor and may have additional thrombin- and protein C (pC)-independent functions. In mice, complete Thbd deficiency causes embryonic death due to defective placental development. In this study, we used tissue-selective and temporally controlled Thbd gene ablation to examine the function of Thbd in adult mice. Selective preservation of Thbd function in the extraembryonic ectoderm and primitive endoderm via the Meox2Cre-transgene enabled normal intrauterine development of Thbd-deficient (Thbd -/- ) mice to term. Half of the Thbd -/- offspring expired perinatally due to thrombohemorrhagic lesions. Surviving Thbd -/- animals only rarely developed overt thrombotic lesions, exhibited low-grade compensated consumptive coagulopathy, and yet exhibited marked, sudden-onset mortality. A corresponding pathology was seen in mice in which the Thbd gene was ablated after reaching adulthood. Supplementation of activated PC by transgenic expression of a partially Thbd-independent murine pC zymogen prevented the pathologies of Thbd -/- mice. However, Thbd -/- females expressing the PC transgene exhibited pregnancy-induced morbidity and mortality with near-complete penetrance. These findings suggest that Thbd function in nonendothelial embryonic tissues of the placenta and yolk sac affects through as-yet-unknown mechanisms the penetrance and severity of thrombosis after birth and provide novel opportunities to study the role of the natural Thbd-pC pathway in adult mice and during pregnancy.

  17. Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement

    Science.gov (United States)

    Altenhöfer, Sebastian; Radermacher, Kim A.; Kleikers, Pamela W.M.; Wingler, Kirstin

    2015-01-01

    Abstract Significance: Oxidative stress, an excess of reactive oxygen species (ROS) production versus consumption, may be involved in the pathogenesis of different diseases. The only known enzymes solely dedicated to ROS generation are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases with their catalytic subunits (NOX). After the clinical failure of most antioxidant trials, NOX inhibitors are the most promising therapeutic option for diseases associated with oxidative stress. Recent Advances: Historical NADPH oxidase inhibitors, apocynin and diphenylene iodonium, are un-specific and not isoform selective. Novel NOX inhibitors stemming from rational drug discovery approaches, for example, GKT137831, ML171, and VAS2870, show improved specificity for NADPH oxidases and moderate NOX isoform selectivity. Along with NOX2 docking sequence (NOX2ds)-tat, a peptide-based inhibitor, the use of these novel small molecules in animal models has provided preliminary in vivo evidence for a pathophysiological role of specific NOX isoforms. Critical Issues: Here, we discuss whether novel NOX inhibitors enable reliable validation of NOX isoforms' pathological roles and whether this knowledge supports translation into pharmacological applications. Modern NOX inhibitors have increased the evidence for pathophysiological roles of NADPH oxidases. However, in comparison to knockout mouse models, NOX inhibitors have limited isoform selectivity. Thus, their use does not enable clear statements on the involvement of individual NOX isoforms in a given disease. Future Directions: The development of isoform-selective NOX inhibitors and biologicals will enable reliable validation of specific NOX isoforms in disease models other than the mouse. Finally, GKT137831, the first NOX inhibitor in clinical development, is poised to provide proof of principle for the clinical potential of NOX inhibition. Antioxid. Redox Signal. 23, 406–427. PMID:24383718

  18. Virotherapy Targeting Cyclin E Overexpression in Tumors with Adenovirus-enhanced Cancer Selective Promoter

    Science.gov (United States)

    Cheng, Pei-Hsin; Rao, Xiao-Mei; Duan, Xiaoxian; Li, Xiao-Feng; Egger, Michael E.; McMasters, Kelly M.; Zhou, H. Sam

    2014-01-01

    Oncolytic virotherapy can selectively destroy cancer cells and is a potential approach in cancer treatment. A strategy to increase tumor-specific selectivity is to control the expression of a key regulatory viral gene with a tumor-specific promoter. We have previously found that cyclin E expression is augmented in cancer cells after adenovirus (Ad) infection. Thus, the cyclin E promoter that is further activated by Ad in cancer cells may have unique properties for enhancing oncolytic viral replication. We have shown that high levels of viral E1a gene expression are achieved in cancer cells infected with Ad-cycE, in which the endogenous Ad E1a promoter was replaced with the cyclin E promoter. Ad-cycE shows markedly selective oncolytic efficacy in vitro and destroys various types of cancer cells, including those resistant to ONYX-015/dl1520. Furthermore, Ad-cycE shows a strong capacity to repress A549 xenograft tumor growth in nude mice and significantly prolongs survival. This study suggests the potential of Ad-cycE in cancer therapy and indicates the advantages of using promoters that can be upregulated by virus infection in cancer cells in development of oncolytic viruses. PMID:25376708

  19. Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

    Science.gov (United States)

    Zalachoras, Ioannis; Houtman, René; Atucha, Erika; Devos, Rene; Tijssen, Ans M. I.; Hu, Pu; Lockey, Peter M.; Datson, Nicole A.; Belanoff, Joseph K.; Lucassen, Paul J.; Joëls, Marian; de Kloet, E. Ronald; Roozendaal, Benno; Hunt, Hazel; Meijer, Onno C.

    2013-01-01

    Glucocorticoid receptor (GR) antagonism may be of considerable therapeutic value in stress-related psychopathology such as depression. However, blockade of all GR-dependent processes in the brain will lead to unnecessary and even counteractive effects, such as elevated endogenous cortisol levels. Selective GR modulators are ligands that can act both as agonist and as antagonist and may be used to separate beneficial from harmful treatment effects. We have discovered that the high-affinity GR ligand C108297 is a selective modulator in the rat brain. We first demonstrate that C108297 induces a unique interaction profile between GR and its downstream effector molecules, the nuclear receptor coregulators, compared with the full agonist dexamethasone and the antagonist RU486 (mifepristone). C108297 displays partial agonistic activity for the suppression of hypothalamic corticotropin-releasing hormone (CRH) gene expression and potently enhances GR-dependent memory consolidation of training on an inhibitory avoidance task. In contrast, it lacks agonistic effects on the expression of CRH in the central amygdala and antagonizes GR-mediated reduction in hippocampal neurogenesis after chronic corticosterone exposure. Importantly, the compound does not lead to disinhibition of the hypothalamus–pituitary–adrenal axis. Thus, C108297 represents a class of ligands that has the potential to more selectively abrogate pathogenic GR-dependent processes in the brain, while retaining beneficial aspects of GR signaling. PMID:23613579

  20. Modelling the consequences of targeted selective treatment strategies on performance and emergence of anthelmintic resistance amongst grazing calves

    Directory of Open Access Journals (Sweden)

    Zoe Berk

    2016-12-01

    Full Text Available The development of anthelmintic resistance by helminths can be slowed by maintaining refugia on pasture or in untreated hosts. Targeted selective treatments (TST may achieve this through the treatment only of individuals that would benefit most from anthelmintic, according to certain criteria. However TST consequences on cattle are uncertain, mainly due to difficulties of comparison between alternative strategies. We developed a mathematical model to compare: 1 the most ‘beneficial’ indicator for treatment selection and 2 the method of selection of calves exposed to Ostertagia ostertagi, i.e. treating a fixed percentage of the population with the lowest (or highest indicator values versus treating individuals who exceed (or are below a given indicator threshold. The indicators evaluated were average daily gain (ADG, faecal egg counts (FEC, plasma pepsinogen, combined FEC and plasma pepsinogen, versus random selection of individuals. Treatment success was assessed in terms of benefit per R (BPR, the ratio of average benefit in weight gain to change in frequency of resistance alleles R (relative to an untreated population. The optimal indicator in terms of BPR for fixed percentages of calves treated was plasma pepsinogen and the worst ADG; in the latter case treatment was applied to some individuals who were not in need of treatment. The reverse was found when calves were treated according to threshold criteria, with ADG being the best target indicator for treatment. This was also the most beneficial strategy overall, with a significantly higher BPR value than any other strategy, but its degree of success depended on the chosen threshold of the indicator. The study shows strong support for TST, with all strategies showing improvements on calves treated selectively, compared with whole-herd treatment at 3, 8, 13 weeks post-turnout. The developed model appeared capable of assessing the consequences of other TST strategies on calf populations.

  1. Clinical Application of Targeted Deep Sequencing in Solid-Cancer Patients and Utility for Biomarker-Selected Clinical Trials.

    Science.gov (United States)

    Kim, Seung Tae; Kim, Kyoung-Mee; Kim, Nayoung K D; Park, Joon Oh; Ahn, Soomin; Yun, Jae-Won; Kim, Kyu-Tae; Park, Se Hoon; Park, Peter J; Kim, Hee Cheol; Sohn, Tae Sung; Choi, Dong Il; Cho, Jong Ho; Heo, Jin Seok; Kwon, Wooil; Lee, Hyuk; Min, Byung-Hoon; Hong, Sung No; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki; Park, Woong-Yang; Lee, Jeeyun

    2017-10-01

    Molecular profiling of actionable mutations in refractory cancer patients has the potential to enable "precision medicine," wherein individualized therapies are guided based on genomic profiling. The molecular-screening program was intended to route participants to different candidate drugs in trials based on clinical-sequencing reports. In this screening program, we used a custom target-enrichment panel consisting of cancer-related genes to interrogate single-nucleotide variants, insertions and deletions, copy number variants, and a subset of gene fusions. From August 2014 through April 2015, 654 patients consented to participate in the program at Samsung Medical Center. Of these patients, 588 passed the quality control process for the 381-gene cancer-panel test, and 418 patients were included in the final analysis as being eligible for any anticancer treatment (127 gastric cancer, 122 colorectal cancer, 62 pancreatic/biliary tract cancer, 67 sarcoma/other cancer, and 40 genitourinary cancer patients). Of the 418 patients, 55 (12%) harbored a biomarker that guided them to a biomarker-selected clinical trial, and 184 (44%) patients harbored at least one genomic alteration that was potentially targetable. This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase. This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase. © AlphaMed Press 2017.

  2. Application of Ultrasound to Selectively Localize Nanodroplets for Targeted Imaging and Therapy

    Directory of Open Access Journals (Sweden)

    Paul A. Dayton

    2006-07-01

    Full Text Available Lipid-coated perfluorocarbon nanodroplets are submicrometer-diameter liquid-filled droplets with proposed applications in molecularly targeted therapeutics and ultrasound (US imaging. Ultrasonic molecular imaging is unique in that the optimal application of these agents depends not only on the surface chemistry, but also on the applied US field, which can increase receptor-ligand binding and membrane fusion. Theory and experiments are combined to demonstrate the displacement of perfluorocarbon nanoparticles in the direction of US propagation, where a traveling US wave with a peak pressure on the order of megapascals and frequency in the megahertz range produces a particle translational velocity that is proportional to acoustic intensity and increases with increasing center frequency. Within a vessel with a diameter on the order of hundreds of micrometers or larger, particle velocity on the order of hundreds of micrometers per second is produced and the dominant mechanism for droplet displacement is shown to be bulk fluid streaming. A model for radiation force displacement of particles is developed and demonstrates that effective particle displacement should be feasible in the microvasculature. In a flowing system, acoustic manipulation of targeted droplets increases droplet retention. Additionally, we demonstrate the feasibility of US-enhanced particle internalization and therapeutic delivery.

  3. Oxamate, but Not Selective Targeting of LDH-A, Inhibits Medulloblastoma Cell Glycolysis, Growth and Motility

    Directory of Open Access Journals (Sweden)

    Cara J. Valvona

    2018-03-01

    Full Text Available Medulloblastoma is the most common malignant paediatric brain tumour and current therapies often leave patients with severe neurological disabilities. Four major molecular groups of medulloblastoma have been identified (Wnt, Shh, Group 3 and Group 4, which include additional, recently defined subgroups with different prognosis and genetic characteristics. Lactate dehydrogenase A (LDHA is a key enzyme in the aerobic glycolysis pathway, an abnormal metabolic pathway commonly observed in cancers, associated with tumour progression and metastasis. Studies indicate MBs have a glycolytic phenotype; however, LDHA has not yet been explored as a therapeutic target for medulloblastoma. LDHA expression was examined in medulloblastoma subgroups and cell lines. The effects of LDHA inhibition by oxamate or LDHA siRNA on medulloblastoma cell line metabolism, migration and proliferation were examined. LDHA was significantly overexpressed in Group 3 and Wnt MBs compared to non-neoplastic cerebellum. Furthermore, we found that oxamate significantly attenuated glycolysis, proliferation and motility in medulloblastoma cell lines, but LDHA siRNA did not. We established that aerobic glycolysis is a potential therapeutic target for medulloblastoma, but broader LDH inhibition (LDHA, B, and C may be more appropriate than LDHA inhibition alone.

  4. A targeted ferritin-microplasmin based thrombolytic nanocage selectively dissolves blood clots.

    Science.gov (United States)

    Seo, Junyoung; Al-Hilal, Taslim A; Jee, Jun-Goo; Kim, Yong-Lim; Kim, Ha-Jeong; Lee, Byung-Heon; Kim, Soyoun; Kim, In-San

    2018-04-01

    The use of thrombolytic therapies is limited by an increased risk of systemic hemorrhage due to lysis of hemostatic clots. We sought to develop a plasmin-based thrombolytic nanocage that efficiently dissolves the clot without causing systemic fibrinolysis or disrupting hemostatic clots. Here, we generated a double chambered short-length ferritin (sFt) construct that has an N-terminal region fused to multivalent clot targeting peptides (CLT: CNAGESSKNC) and a C-terminal end fused to a microplasmin (μPn); CLT recognizes fibrin-fibronectin complexes in clots, μPn efficiently dissolves clots, and the assembly of double chambered sFt (CLT-sFt-μPn) into nanocage structure protects the activated-μPn from its circulating inhibitors. Importantly, activated CLT-sFt-μPn thrombolytic nanocage showed a prolonged circulatory life over activated-μPn and efficiently lysed the preexisting clots in both arterial and venous thromboses models. Thus, CLT-sFt-μPn thrombolytic nanocage platform represents the prototype of a targeted clot-busting agent with high efficacy and safety over existing thrombolytic therapies. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. Target-selective homologous recombination cloning for high-throughput generation of monoclonal antibodies from single plasma cells.

    Science.gov (United States)

    Kurosawa, Nobuyuki; Yoshioka, Megumi; Isobe, Masaharu

    2011-04-13

    Molecular cloning of functional immunoglobulin genes from single plasma cells is one of the most promising technologies for the rapid development of monoclonal antibody drugs. However, the proper insertion of PCR-amplified immunoglobulin genes into expression vectors remains an obstacle to the high-throughput production of recombinant monoclonal antibodies. We developed a single-step cloning method, target-selective homologous recombination (TS-HR), in which PCR-amplified immunoglobulin variable genes were selectively inserted into vectors, even in the presence of nonspecifically amplified DNA. TS-HR utilizes Red/ET-mediated homologous recombination with a target-selective vector (TS-vector) with unique homology arms on its termini. Using TS-HR, immunoglobulin variable genes were cloned directly into expression vectors by co-transforming unpurified PCR products and the TS-vector into E. coli. Furthermore, the high cloning specificity of TS-HR allowed plasmids to be extracted from pools of transformed bacteria without screening single colonies for correct clones. We present a one-week protocol for the production of recombinant mouse monoclonal antibodies from large numbers of single plasma cells. The time requirements and limitations of traditional cloning procedures for the production of recombinant immunoglobulins have been significantly reduced with the development of the TS-HR cloning technique. © 2011 Kurosawa et al; licensee BioMed Central Ltd.

  6. Target-selective homologous recombination cloning for high-throughput generation of monoclonal antibodies from single plasma cells

    Directory of Open Access Journals (Sweden)

    Isobe Masaharu

    2011-04-01

    Full Text Available Abstract Background Molecular cloning of functional immunoglobulin genes from single plasma cells is one of the most promising technologies for the rapid development of monoclonal antibody drugs. However, the proper insertion of PCR-amplified immunoglobulin genes into expression vectors remains an obstacle to the high-throughput production of recombinant monoclonal antibodies. Results We developed a single-step cloning method, target-selective homologous recombination (TS-HR, in which PCR-amplified immunoglobulin variable genes were selectively inserted into vectors, even in the presence of nonspecifically amplified DNA. TS-HR utilizes Red/ET-mediated homologous recombination with a target-selective vector (TS-vector with unique homology arms on its termini. Using TS-HR, immunoglobulin variable genes were cloned directly into expression vectors by co-transforming unpurified PCR products and the TS-vector into E. coli. Furthermore, the high cloning specificity of TS-HR allowed plasmids to be extracted from pools of transformed bacteria without screening single colonies for correct clones. We present a one-week protocol for the production of recombinant mouse monoclonal antibodies from large numbers of single plasma cells. Conclusion The time requirements and limitations of traditional cloning procedures for the production of recombinant immunoglobulins have been significantly reduced with the development of the TS-HR cloning technique.

  7. PLS-based and regularization-based methods for the selection of relevant variables in non-targeted metabolomics data

    Directory of Open Access Journals (Sweden)

    Renata Bujak

    2016-07-01

    Full Text Available Non-targeted metabolomics constitutes a part of systems biology and aims to determine many metabolites in complex biological samples. Datasets obtained in non-targeted metabolomics studies are multivariate and high-dimensional due to the sensitivity of mass spectrometry-based detection methods as well as complexity of biological matrices. Proper selection of variables which contribute into group classification is a crucial step, especially in metabolomics studies which are focused on searching for disease biomarker candidates. In the present study, three different statistical approaches were tested using two metabolomics datasets (RH and PH study. Orthogonal projections to latent structures-discriminant analysis (OPLS-DA without and with multiple testing correction as well as least absolute shrinkage and selection operator (LASSO were tested and compared. For the RH study, OPLS-DA model built without multiple testing correction, selected 46 and 218 variables based on VIP criteria using Pareto and UV scaling, respectively. In the case of the PH study, 217 and 320 variables were selected based on VIP criteria using Pareto and UV scaling, respectively. In the RH study, OPLS-DA model built with multiple testing correction, selected 4 and 19 variables as statistically significant in terms of Pareto and UV scaling, respectively. For PH study, 14 and 18 variables were selected based on VIP criteria in terms of Pareto and UV scaling, respectively. Additionally, the concept and fundaments of the least absolute shrinkage and selection operator (LASSO with bootstrap procedure evaluating reproducibility of results, was demonstrated. In the RH and PH study, the LASSO selected 14 and 4 variables with reproducibility between 99.3% and 100%. However, apart from the popularity of PLS-DA and OPLS-DA methods in metabolomics, it should be highlighted that they do not control type I or type II error, but only arbitrarily establish a cut-off value for PLS-DA loadings

  8. α-Fetoprotein promoter-driven Cre/LoxP-switched RNA interference for hepatocellular carcinoma tissue-specific target therapy.

    Directory of Open Access Journals (Sweden)

    Yuan-Fei Peng

    Full Text Available RNA interference (RNAi has recently emerged as a potential treatment modality for hepatocellular carcinoma (HCC therapy, but the lack of cellular targets and sustained efficacy limits its application. The purpose of this study is to develop an HCC tissue-specific RNAi system and investigate its possibility for HCC treatment.Two different HCC-specific RNAi systems in which therapeutic miRNA or shRNA against target gene (Beclin 1 was directly or indirectly driven by alpha-fetoprotein promoter (AFP-miRNA and AFP-Cre/LoxP-shRNA were constructed. Human HCC cell lines (HepG2, Hep3B and HCCLM3 and non-HCC cell lines (L-02, Hela and SW1116 were infected with the systems. The effectiveness and tissue-specificity of the systems were examined by Q-PCR and western blot analysis. The efficacy of the systems was further tested in mouse model of HCC by intravenous or intratumoral administration. The feasibility of the system for HCC treatment was evaluated by applying the system as adjuvant therapy to enhance sorafenib treatment. An AFP-Cre/LoxP-shRNA system targeting Atg5 gene (AFP-Cre/LoxP-shRNA-Atg5 was constructed and its efficacy in sensitizing HCC cells (MHCC97L/PLC to sorafenib treatment was examined by apoptosis assay in vitro and tumorigenesis assay in vivo.The AFP-miRNA system could silence target gene (Beclin 1 but required a high titer which was lethal to target cells. The AFP-Cre/LoxP-shRNA system could efficiently knockdown target gene while maintain high HCC specificity. Intratumoral injection of the AFP-Cre/LoxP-shRNA system could efficiently silence target gene (Beclin 1 in vivo while intravenous administration could not. The AFP-Cre/LoxP-shRNA system target Atg5 gene could significantly sensitize MHCC97L/PLC cells to sorafenib-induced apoptosis in vitro and tumor growth suppression in vivo.An efficient HCC tissue-specific RNAi system (AFP-Cre/LoxP-shRNA was successfully established. The system provides a usable tool for HCC-specific RNAi

  9. Animal models for medications development targeting alcohol abuse using selectively bred rat lines: Neurobiological and pharmacological validity

    Science.gov (United States)

    Bell, Richard L.; Sable, Helen J.K.; Colombo, Giancarlo; Hyytia, Petri; Rodd, Zachary A.; Lumeng, Lawrence

    2012-01-01

    The purpose of this review paper is to present evidence that rat animal models of alcoholism provide an ideal platform for developing and screening medications that target alcohol abuse and dependence. The focus is on the 5 oldest international rat lines that have been selectively bred for a high alcohol-consumption phenotype. The behavioral and neurochemical phenotypes of these rat lines are reviewed and placed in the context of the clinical literature. The paper presents behavioral models for assessing the efficacy of pharmaceuticals for the treatment of alcohol abuse and dependence in rodents, with particular emphasis on rats. Drugs that have been tested for their effectiveness in reducing alcohol/ethanol consumption and/or self-administration by these rat lines and their putative site of action are summarized. The paper also presents some current and future directions for developing pharmacological treatments targeting alcohol abuse and dependence. PMID:22841890

  10. LuIII parvovirus selectively and efficiently targets, replicates in, and kills human glioma cells.

    Science.gov (United States)

    Paglino, Justin C; Ozduman, Koray; van den Pol, Anthony N

    2012-07-01

    Because productive infection by parvoviruses requires cell division and is enhanced by oncogenic transformation, some parvoviruses may have potential utility in killing cancer cells. To identify the parvovirus(es) with the optimal oncolytic effect against human glioblastomas, we screened 12 parvoviruses at a high multiplicity of infection (MOI). MVMi, MVMc, MVM-G17, tumor virus X (TVX), canine parvovirus (CPV), porcine parvovirus (PPV), rat parvovirus 1A (RPV1A), and H-3 were relatively ineffective. The four viruses with the greatest oncolytic activity, LuIII, H-1, MVMp, and MVM-G52, were tested for the ability, at a low MOI, to progressively infect the culture over time, causing cell death at a rate higher than that of cell proliferation. LuIII alone was effective in all five human glioblastomas tested. H-1 progressively infected only two of five; MVMp and MVM-G52 were ineffective in all five. To investigate the underlying mechanism of LuIII's phenotype, we used recombinant parvoviruses with the LuIII capsid replacing the MVMp capsid or with molecular alteration of the P4 promoter. The LuIII capsid enhanced efficient replication and oncolysis in MO59J gliomas cells; other gliomas tested required the entire LuIII genome to exhibit enhanced infection. LuIII selectively infected glioma cells over normal glial cells in vitro. In mouse models, human glioblastoma xenografts were selectively infected by LuIII when administered intratumorally; LuIII reduced tumor growth by 75%. LuIII also had the capacity to selectively infect subcutaneous or intracranial gliomas after intravenous inoculation. Intravenous or intracranial LuIII caused no adverse effects. Intracranial LuIII caused no infection of mature mouse neurons or glia in vivo but showed a modest infection of developing neurons.

  11. Increasing selective exposure to health messages by targeting person versus behavior schemas.

    Science.gov (United States)

    Pease, Meridith E; Brannon, Laura A; Pilling, Valerie K

    2006-01-01

    Schema correspondence theory (Brannon and Brock, 1994) was applied to the topic of selective exposure to health information. The following question was asked: When do people prefer to expose themselves to health-relevant information tailored to match their own needs and values (i.e., recipient self-schema matching) versus the values and goals that the healthy behavior brings to mind (i.e., behavior schema matching)? In general, recipient self-schema matched messages tended to be preferred over behavior schema matched messages. However, this tendency was attenuated to the extent that the behavior had a very well defined (prototypical) schema.

  12. A recombinant fusion toxin based on enzymatic inactive C3bot1 selectively targets macrophages.

    Directory of Open Access Journals (Sweden)

    Lydia Dmochewitz

    Full Text Available BACKGROUND: The C3bot1 protein (~23 kDa from Clostridium botulinum ADP-ribosylates and thereby inactivates Rho. C3bot1 is selectively taken up into the cytosol of monocytes/macrophages but not of other cell types such as epithelial cells or fibroblasts. Most likely, the internalization occurs by a specific endocytotic pathway via acidified endosomes. METHODOLOGY/PRINCIPAL FINDINGS: Here, we tested whether enzymatic inactive C3bot1E174Q serves as a macrophage-selective transport system for delivery of enzymatic active proteins into the cytosol of such cells. Having confirmed that C3bot1E174Q does not induce macrophage activation, we used the actin ADP-ribosylating C2I (∼50 kDa from Clostridium botulinum as a reporter enzyme for C3bot1E174Q-mediated delivery into macrophages. The recombinant C3bot1E174Q-C2I fusion toxin was cloned and expressed as GST-protein in Escherichia coli. Purified C3bot1E174Q-C2I was recognized by antibodies against C2I and C3bot and showed C2I-specific enzyme activity in vitro. When applied to cultured cells C3bot1E174Q-C2I ADP-ribosylated actin in the cytosol of macrophages including J774A.1 and RAW264.7 cell lines as well as primary cultured human macrophages but not of epithelial cells. Together with confocal fluorescence microscopy experiments, the biochemical data indicate the selective uptake of a recombinant C3-fusion toxin into the cytosol of macrophages. CONCLUSIONS/SIGNIFICANCE: In summary, we demonstrated that C3bot1E174Q can be used as a delivery system for fast, selective and specific transport of enzymes into the cytosol of living macrophages. Therefore, C3-based fusion toxins can represent valuable molecular tools in experimental macrophage pharmacology and cell biology as well as attractive candidates to develop new therapeutic approaches against macrophage-associated diseases.

  13. Selectivity and Efficiency of Late Transgene Expression by Transcriptionally Targeted Oncolytic Adenoviruses Are Dependent on the Transgene Insertion Strategy

    Science.gov (United States)

    Quirin, Christina; Rohmer, Stanimira; Fernández-Ulibarri, Inés; Behr, Michael; Hesse, Andrea; Engelhardt, Sarah; Erbs, Philippe; Enk, Alexander H.

    2011-01-01

    Abstract Key challenges facing cancer therapy are the development of tumor-specific drugs and potent multimodal regimens. Oncolytic adenoviruses possess the potential to realize both aims by restricting virus replication to tumors and inserting therapeutic genes into the virus genome, respectively. A major effort in this regard is to express transgenes in a tumor-specific manner without affecting virus replication. Using both luciferase as a sensitive reporter and genetic prodrug activation, we show that promoter control of E1A facilitates highly selective expression of transgenes inserted into the late transcription unit. This, however, required multistep optimization of late transgene expression. Transgene insertion via internal ribosome entry site (IRES), splice acceptor (SA), or viral 2A sequences resulted in replication-dependent expression. Unexpectedly, analyses in appropriate substrates and with matching control viruses revealed that IRES and SA, but not 2A, facilitated indirect transgene targeting via tyrosinase promoter control of E1A. Transgene expression via SA was more selective (up to 1,500-fold) but less effective than via IRES. Notably, we also revealed transgene-dependent interference with splicing. Hence, the prodrug convertase FCU1 (a cytosine deaminase–uracil phosphoribosyltransferase fusion protein) was expressed only after optimizing the sequence surrounding the SA site and mutating a cryptic splice site within the transgene. The resulting tyrosinase promoter-regulated and FCU1-encoding adenovirus combined effective oncolysis with targeted prodrug activation therapy of melanoma. Thus, prodrug activation showed potent bystander killing and increased cytotoxicity of the virus up to 10-fold. We conclude that armed oncolytic viruses can be improved substantially by comparing and optimizing strategies for targeted transgene expression, thereby implementing selective and multimodal cancer therapies. PMID:20939692

  14. Gene Electrotransfer of Plasmid with Tissue Specific Promoter Encoding shRNA against Endoglin Exerts Antitumor Efficacy against Murine TS/A Tumors by Vascular Targeted Effects.

    Directory of Open Access Journals (Sweden)

    Monika Stimac

    Full Text Available Vascular targeted therapies, targeting specific endothelial cell markers, are promising approaches for the treatment of cancer. One of the targets is endoglin, transforming growth factor-β (TGF-β co-receptor, which mediates proliferation, differentiation and migration of endothelial cells forming neovasculature. However, its specific, safe and long-lasting targeting remains the challenge. Therefore, in our study we evaluated the transfection efficacy, vascular targeted effects and therapeutic potential of the plasmid silencing endoglin with the tissue specific promoter, specific for endothelial cells marker endothelin-1 (ET (TS plasmid, in comparison to the plasmid with constitutive promoter (CON plasmid, in vitro and in vivo. Tissue specificity of TS plasmid was demonstrated in vitro on several cell lines, and its antiangiogenic efficacy was demonstrated by reducing tube formation of 2H11 endothelial cells. In vivo, on a murine mammary TS/A tumor model, we demonstrated good antitumor effect of gene electrotransfer (GET of either of both plasmids in treatment of smaller tumors still in avascular phase of growth, as well as on bigger tumors, already well vascularized. In support to the observations on predominantly vascular targeted effects of endoglin, histological analysis has demonstrated an increase in necrosis and a decrease in the number of blood vessels in therapeutic groups. A significant antitumor effect was observed in tumors in avascular and vascular phase of growth, possibly due to both, the antiangiogenic and the vascular disrupting effect. Furthermore, the study indicates on the potential use of TS plasmid in cancer gene therapy since the same efficacy as of CON plasmid was determined.

  15. Extending Data Worth Analyses to Select Multiple Observations Targeting Multiple Forecasts.

    Science.gov (United States)

    Vilhelmsen, Troels N; Ferré, Ty P A

    2017-09-15

    Hydrological models are often set up to provide specific forecasts of interest. Owing to the inherent uncertainty in data used to derive model structure and used to constrain parameter variations, the model forecasts will be uncertain. Additional data collection is often performed to minimize this forecast uncertainty. Given our common financial restrictions, it is critical that we identify data with maximal information content with respect to forecast of interest. In practice, this often devolves to qualitative decisions based on expert opinion. However, there is no assurance that this will lead to optimal design, especially for complex hydrogeological problems. Specifically, these complexities include considerations of multiple forecasts, shared information among potential observations, information content of existing data, and the assumptions and simplifications underlying model construction. In the present study, we extend previous data worth analyses to include: simultaneous selection of multiple new measurements and consideration of multiple forecasts of interest. We show how the suggested approach can be used to optimize data collection. This can be used in a manner that suggests specific measurement sets or that produces probability maps indicating areas likely to be informative for specific forecasts. Moreover, we provide examples documenting that sequential measurement election approaches often lead to suboptimal designs and that estimates of data covariance should be included when selecting future measurement sets. © 2017, National Ground Water Association.

  16. Targeting ferritin receptors for the selective delivery of imaging and therapeutic agents to breast cancer cells.

    Science.gov (United States)

    Geninatti Crich, S; Cadenazzi, M; Lanzardo, S; Conti, L; Ruiu, R; Alberti, D; Cavallo, F; Cutrin, J C; Aime, S

    2015-04-21

    In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 μg ml(-1) (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation.

  17. Single domain antibodies in tissue engineering

    NARCIS (Netherlands)

    Rodrigues, E.D.

    2014-01-01

    The aim of this thesis is to demonstrate the potential of VHH in tissue engineering applications, with a focus on bone and cartilage tissue regeneration. After a general introduction to this thesis in chapter 1, the selection of VHH targeting growth factors is described in chapter 2. VHH were

  18. Targeted tissue perfusion versus macrocirculation-guided standard care in patients with septic shock (TARTARE-2S)

    DEFF Research Database (Denmark)

    Pettilä, Ville; Merz, Tobias; Wilkman, Erika

    2016-01-01

    at least 200 patients with septic shock in four European intensive care units (ICUs) to test whether a tissue perfusion-guided treatment strategy based on capillary refill time, peripheral temperature, arterial lactate concentrations, and accepting lower MAP levels, leads to a faster resolution of shock...

  19. Vagal stimulation targets select populations of intrinsic cardiac neurons to control neurally induced atrial fibrillation.

    Science.gov (United States)

    Salavatian, Siamak; Beaumont, Eric; Longpré, Jean-Philippe; Armour, J Andrew; Vinet, Alain; Jacquemet, Vincent; Shivkumar, Kalyanam; Ardell, Jeffrey L

    2016-11-01

    Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)-sided VNS (15 Hz, 500 μs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory. Copyright © 2016 the American Physiological Society.

  20. FOXO3 Selectively Amplifies Enhancer Activity to Establish Target Gene Regulation

    Directory of Open Access Journals (Sweden)

    Astrid Eijkelenboom

    2013-12-01

    Full Text Available Forkhead box O (FOXO transcription factors regulate diverse cellular processes, affecting tumorigenesis, metabolism, stem cell maintenance, and lifespan. We show that FOXO3 transcription regulation mainly proceeds through the most active subset of enhancers. In addition to the general distinction between “open” and “closed” chromatin, we show that the level of activity marks (H3K27ac, RNAPII, enhancer RNAs of these open chromatin regions prior to FOXO3 activation largely determines FOXO3 DNA binding. Consequently, FOXO3 amplifies the levels of these activity marks and their absolute rather than relative changes associate best with FOXO3 target gene regulation. The importance of preexisting chromatin state in directing FOXO3 gene regulation, as shown here, provides a mechanism whereby FOXO3 can regulate cell-specific homeostasis. Genetic variation is reported to affect these chromatin signatures in a quantitative manner, and, in agreement, we observe a correlation between cancer-associated genetic variations and the amplitude of FOXO3 enhancer binding.

  1. Selective laser sintering fabrication of nano-hydroxyapatite/poly-ε-caprolactone scaffolds for bone tissue engineering applications

    Science.gov (United States)

    Xia, Yan; Zhou, Panyu; Cheng, Xiaosong; Xie, Yang; Liang, Chong; Li, Chao; Xu, Shuogui

    2013-01-01

    The regeneration of functional tissue in osseous defects is a formidable challenge in orthopedic surgery. In the present study, a novel biomimetic composite scaffold, here called nano-hydroxyapatite (HA)/poly-ε-caprolactone (PCL) was fabricated using a selective laser sintering technique. The macrostructure, morphology, and mechanical strength of the scaffolds were characterized. Scanning electronic microscopy (SEM) showed that the nano-HA/PCL scaffolds exhibited predesigned, well-ordered macropores and interconnected micropores. The scaffolds have a range of porosity from 78.54% to 70.31%, and a corresponding compressive strength of 1.38 MPa to 3.17 MPa. Human bone marrow stromal cells were seeded onto the nano-HA/PCL or PCL scaffolds and cultured for 28 days in vitro. As indicated by the level of cell attachment and proliferation, the nano-HA/PCL showed excellent biocompatibility, comparable to that of PCL scaffolds. The hydrophilicity, mineralization, alkaline phosphatase activity, and Alizarin Red S staining indicated that the nano-HA/PCL scaffolds are more bioactive than the PCL scaffolds in vitro. Measurements of recombinant human bone morphogenetic protein-2 (rhBMP-2) release kinetics showed that after nano-HA was added, the material increased the rate of rhBMP-2 release. To investigate the in vivo biocompatibility and osteogenesis of the composite scaffolds, both nano-HA/PCL scaffolds and PCL scaffolds were implanted in rabbit femur defects for 3, 6, and 9 weeks. The wounds were studied radiographically and histologically. The in vivo results showed that both nano-HA/PCL composite scaffolds and PCL scaffolds exhibited good biocompatibility. However, the nano-HA/PCL scaffolds enhanced the efficiency of new bone formation more than PCL scaffolds and fulfilled all the basic requirements of bone tissue engineering scaffolds. Thus, they show large potential for use in orthopedic and reconstructive surgery. PMID:24204147

  2. Identification of compounds that selectively target highly chemotherapy refractory neuroblastoma cancer stem cells.

    Science.gov (United States)

    Díaz-Carballo, David; Acikelli, Ali Haydar; Bardenheuer, Walter; Gustmann, Sebastian; Malak, Sascha; Stoll, Raphael; Kedziorski, Thorsten; Nazif, Mhd Ali; Jastrow, Holger; Wennemuth, Gunter; Dammann, Philip; Feigel, Martin; Strumberg, Dirk

    2014-09-01

    Relapse of cancer months or years after an apparently successful therapy is probably caused by cancer stem cells (CSCs) due to their intrinsic features like dormant periods, radiorefraction, and acquired multidrug resistance (MDR) phenotypes, among other mechanisms of cellular drug evasiveness. Thus, the lack of currently efficacious interventions remains a major problem in the treatment of malignancies, together with the inability of existing drugs to destroy specifically CSCs. Neuroblastomas per se are highly chemotherapy-refractory extracranial tumors in infants with very low survival rates. So far, no effective cytostatics against this kind of tumors are clinically available. Therefore, we have put much effort into the development of agents to efficiently combat this malignancy. For this purpose, we tested several compounds isolated from Cuban propolis on induced CSCs (iCSC) derived from LAN-1 neuroblastoma cells which expressed several characteristics of tumor-initiating cells both in in-vitro and in-vivo models. Some small molecules such as flavonoids and polycyclic polyprenylated acylphloroglucinols (PPAP) were isolated using successive RT-HPLC cycles and identified employing mass spectrometry and NMR spectroscopic techniques. Their cytotoxicity was first screened in sensitive cell systems by MTT proliferation assays and afterwards studied in less sensitive neuroblastoma iCSC models. We found several compounds with considerable anti-iCSC activity, most of them belonging to the PPAP class. The majority of the compounds act in a pleiotropic manner on the molecular biology of tumors although their specific targets remain unclear. Nevertheless, two substances, one of them a flavonoid, induced a strong disruption of tubulin polymerization. In addition, an unknown compound strongly inhibited replicative enzymes like toposimerases I/II and DNA polymerase. Here, we report for the first time cytotoxic activities of small molecules isolated from Caribbean propolis

  3. Vagal stimulation targets select populations of intrinsic cardiac neurons to control neurally induced atrial fibrillation

    Science.gov (United States)

    Salavatian, Siamak; Beaumont, Eric; Longpré, Jean-Philippe; Armour, J. Andrew; Vinet, Alain; Jacquemet, Vincent; Shivkumar, Kalyanam

    2016-01-01

    Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)-sided VNS (15 Hz, 500 μs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P < 0.001). Convergent LCNs were preferentially activated by MNS. Preemptive RCV reduced MNS-induced changes in LCN activity (by 70%) while mitigating MNS-induced AF (by 75%). Preemptive LCV reduced LCN activity by 60% while mitigating AF potential by 40%. IC neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory. PMID:27591222

  4. Olesoxime prevents microtubule-targeting drug neurotoxicity: selective preservation of EB comets in differentiated neuronal cells.

    Science.gov (United States)

    Rovini, Amandine; Carré, Manon; Bordet, Thierry; Pruss, Rebecca M; Braguer, Diane

    2010-09-15

    Microtubule-targeting agents (MTAs), anticancer drugs widely used in the clinic, often induce peripheral neuropathy, a main dose-limiting side effect. The mechanism for this neurotoxicity remains poorly understood and there are still no approved therapies for neuropathies triggered by MTAs. Olesoxime (cholest-4-en-3-one, oxime; TRO19622) has shown marked neuroprotective properties in animals treated with paclitaxel and vincristine. The purpose of this study was to investigate its mechanism of neuroprotection against MTA neurotoxicity by using rat and human differentiated neuronal cells. We first showed that olesoxime prevented neurite shrinkage induced by MTAs in differentiated PC-12 and SK-N-SH neuroblastoma cell lines by up to 90%. This neuroprotective effect was correlated with enhanced EB1 accumulation at microtubule plus-ends, increased growth cone microtubule growing rate (20%) and decreased microtubule attenuation duration (54%). The effects of olesoxime on EB comets were specific for differentiated neuronal cells and were not seen either in proliferating neuroblastoma cells, glioblastoma cells or primary endothelial cells. Importantly, olesoxime did not alter MTA cytotoxic properties in a wide range of MTA-sensitive tumor cells, a prerequisite for future clinical application. Finally, olesoxime also counteracted MTA inhibition of microtubule-dependent mitochondria trafficking. These results provide additional insight into the neuroprotective properties of olesoxime, highlighting a role for microtubule dynamics in preservation of neurite architecture and axoplasmic transport, which are both disturbed by MTAs. The neuron-specific protective properties of olesoxime support its further development to treat MTA-induced neuropathy. Copyright 2010 Elsevier Inc. All rights reserved.

  5. The Endosymbiotic Bacterium Wolbachia Selectively Kills Male Hosts by Targeting the Masculinizing Gene.

    Directory of Open Access Journals (Sweden)

    Takahiro Fukui

    2015-07-01

    Full Text Available Pathogens are known to manipulate the reproduction and development of their hosts for their own benefit. Wolbachia is an endosymbiotic bacterium that infects a wide range of insect species. Wolbachia is known as an example of a parasite that manipulates the sex of its host's progeny. Infection of Ostrinia moths by Wolbachia causes the production of all-female progeny, however, the mechanism of how Wolbachia accomplishes this male-specific killing is unknown. Here we show for the first time that Wolbachia targets the host masculinizing gene of Ostrinia to accomplish male-killing. We found that Wolbachia-infected O. furnacalis embryos do not express the male-specific splice variant of doublesex, a gene which acts at the downstream end of the sex differentiation cascade, throughout embryonic development. Transcriptome analysis revealed that Wolbachia infection markedly reduces the mRNA level of Masc, a gene that encodes a protein required for both masculinization and dosage compensation in the silkworm Bombyx mori. Detailed bioinformatic analysis also elucidated that dosage compensation of Z-linked genes fails in Wolbachia-infected O. furnacalis embryos, a phenomenon that is extremely similar to that observed in Masc mRNA-depleted male embryos of B. mori. Finally, injection of in vitro transcribed Masc cRNA into Wolbachia-infected embryos rescued male progeny. Our results show that Wolbachia-induced male-killing is caused by a failure of dosage compensation via repression of the host masculinizing gene. Our study also shows a novel strategy by which a pathogen hijacks the host sex determination cascade.

  6. Recent progress in defining mechanisms and potential targets for prevention of normal tissue injury after radiation therapy

    International Nuclear Information System (INIS)

    Anscher, Mitchell S.; Chen, Liguang; Rabbani, Zahid; Kang Song; Larrier, Nicole; Huang Hong; Samulski, Thaddeus V.; Dewhirst, Mark W.; Brizel, David M.; Folz, Rodney J.; Vujaskovic, Zeljko

    2005-01-01

    The ability to optimize treatments for cancer on the basis of relative risks for normal tissue injury has important implications in oncology, because higher doses of radiation might, in some diseases, improve both local control and survival. To achieve this goal, a thorough understanding of the molecular mechanisms responsible for radiation-induced toxicity will be essential. Recent research has demonstrated that ionizing radiation triggers a series of genetic and molecular events, which might lead to chronic persistent alterations in the microenvironment and an aberrant wound-healing response. Disrupted epithelial-stromal cell communication might also be important. With the application of a better understanding of fundamental biology to clinical practice, new approaches to treating and preventing normal tissue injury can focus on correcting these disturbed molecular processes

  7. Effectiveness of a selective, personality-targeted prevention program for adolescent alcohol use and misuse: a cluster randomized controlled trial.

    Science.gov (United States)

    Conrod, Patricia J; O'Leary-Barrett, Maeve; Newton, Nicola; Topper, Lauren; Castellanos-Ryan, Natalie; Mackie, Clare; Girard, Alain

    2013-03-01

    Selective school-based alcohol prevention programs targeting youth with personality risk factors for addiction and mental health problems have been found to reduce substance use and misuse in those with elevated personality profiles. To report 24-month outcomes of the Teacher-Delivered Personality-Targeted Interventions for Substance Misuse Trial (Adventure trial) in which school staff were trained to provide interventions to students with 1 of 4 high-risk (HR) profiles: anxiety sensitivity, hopelessness, impulsivity, and sensation seeking and to examine the indirect herd effects of this program on the broader low-risk (LR) population of students who were not selected for intervention. Cluster randomized controlled trial. Secondary schools in London, United Kingdom. A total of 1210 HR and 1433 LR students in the ninth grade (mean [SD] age, 13.7 [0.33] years). Schools were randomized to provide brief personality-targeted interventions to HR youth or treatment as usual (statutory drug education in class). Participants were assessed for drinking, binge drinking, and problem drinking before randomization and at 6-monthly intervals for 2 years. Two-part latent growth models indicated long-term effects of the intervention on drinking rates (β = -0.320, SE = 0.145, P = .03) and binge drinking rates (β = -0.400, SE = 0.179, P = .03) and growth in binge drinking (β = -0.716, SE = 0.274, P = .009) and problem drinking (β = -0.452, SE = 0.193, P = .02) for HR youth. The HR youth were also found to benefit from the interventions during the 24-month follow-up on drinking quantity (β = -0.098, SE = 0.047, P = .04), growth in drinking quantity (β = -0.176, SE = 0.073, P = .02), and growth in binge drinking frequency (β = -0.183, SE = 0.092, P = .047). Some herd effects in LR youth were observed, specifically on drinking rates (β = -0.259, SE = 0.132, P = .049) and growth of binge drinking (β = -0.244, SE = 0.073, P = .001), during the 24-month follow-up. Findings further

  8. Targeted selected reaction monitoring mass spectrometric immunoassay for insulin-like growth factor 1.

    Directory of Open Access Journals (Sweden)

    Eric E Niederkofler

    Full Text Available Insulin-like growth factor 1 (IGF1 is an important biomarker of human growth disorders that is routinely analyzed in clinical laboratories. Mass spectrometry-based workflows offer a viable alternative to standard IGF1 immunoassays, which utilize various pre-analytical preparation strategies. In this work we developed an assay that incorporates a novel sample preparation method for dissociating IGF1 from its binding proteins. The workflow also includes an immunoaffinity step using antibody-derivatized pipette tips, followed by elution, trypsin digestion, and LC-MS/MS separation and detection of the signature peptides in a selected reaction monitoring (SRM mode. The resulting quantitative mass spectrometric immunoassay (MSIA exhibited good linearity in the range of 1 to 1,500 ng/mL IGF1, intra- and inter-assay precision with CVs of less than 10%, and lowest limits of detection of 1 ng/mL. The linearity and recovery characteristics of the assay were also established, and the new method compared to a commercially available immunoassay using a large cohort of human serum samples. The IGF1 SRM MSIA is well suited for use in clinical laboratories.

  9. Potential targets for selection during the evolution of viviparity in cold-climate reptiles.

    Science.gov (United States)

    Li, Hong; Elphick, Melanie; Shine, Richard

    2017-01-01

    Viviparity (live-bearing) has evolved from oviparity (egg-laying) in more than 100 lineages of squamate reptiles (lizards and snakes). This transition generally has occurred in cool climates, where thermal differentials between eggs in the (cool) nest versus the (warm) maternal oviduct influence embryonic development, in ways that may enhance offspring fitness. To identify specific traits potentially under selection, we incubated eggs of a montane scincid lizard at conditions simulating natural nests, maternal body temperatures, and an intermediate stage (2-week uterine retention of eggs prior to laying). Incubation at maternal temperatures throughout incubation affected the hatchling lizard's activity level and boldness, as well as its developmental rate, morphology, and locomotor ability. A treatment that mimicked the initial stages of the transition toward viviparity had a major effect on some hatchling traits (locomotor speeds), a minor effect on others (tail length, total incubation period) and no effect on yet others (offspring behaviors). More generally, different aspects of the phenotype are sensitive to incubation conditions at different stages of development; thus, the evolution of reptilian viviparity may have been driven by a succession of advantages that accrued at different stages of embryogenesis.

  10. Assessment of a novel VEGF targeted agent using patient-derived tumor tissue xenograft models of colon carcinoma with lymphatic and hepatic metastases.

    Directory of Open Access Journals (Sweden)

    Ketao Jin

    Full Text Available The lack of appropriate tumor models of primary tumors and corresponding metastases that can reliably predict for response to anticancer agents remains a major deficiency in the clinical practice of cancer therapy. It was the aim of our study to establish patient-derived tumor tissue (PDTT xenograft models of colon carcinoma with lymphatic and hepatic metastases useful for testing of novel molecularly targeted agents. PDTT of primary colon carcinoma, lymphatic and hepatic metastases were used to create xenograft models. Hematoxylin and eosin staining, immunohistochemical staining, genome-wide gene expression analysis, pyrosequencing, qRT-PCR, and western blotting were used to determine the biological stability of the xenografts during serial transplantation compared with the original tumor tissues. Early passages of the PDTT xenograft models of primary colon carcinoma, lymphatic and hepatic metastases revealed a high degree of similarity with the original clinical tumor samples with regard to histology, immunohistochemistry, genes expression, and mutation status as well as mRNA expression. After we have ascertained that these xenografts models retained similar histopathological features and molecular signatures as the original tumors, drug sensitivities of the xenografts to a novel VEGF targeted agent, FP3 was evaluated. In this study, PDTT xenograft models of colon carcinoma with lymphatic and hepatic metastasis have been successfully established. They provide appropriate models for testing of novel molecularly targeted agents.

  11. Visual working memory modulates low-level saccade target selection: Evidence from rapidly generated saccades in the global effect paradigm

    Science.gov (United States)

    Hollingworth, Andrew; Matsukura, Michi; Luck, Steven J.

    2013-01-01

    In three experiments, we examined the influence of visual working memory (VWM) on the metrics of saccade landing position in a global effect paradigm. Participants executed a saccade to the more eccentric object in an object pair appearing on the horizontal midline, to the left or right of central fixation. While completing the saccade task, participants maintained a color in VWM for an unrelated memory task. Either the color of the saccade target matched the memory color (target match), the color of the distractor matched the memory color (distractor match), or the colors of neither object matched the memory color (no match). In the no-match condition, saccades tended to land at the midpoint between the two objects: the global, or averaging, effect. However, when one of the two objects matched VWM, the distribution of landing position shifted toward the matching object, both for target match and for distractor match. VWM modulation of landing position was observed even for the fastest quartile of saccades, with a mean latency as low as 112 ms. Effects of VWM on such rapidly generated saccades, with latencies in the express-saccade range, indicate that VWM interacts with the initial sweep of visual sensory processing, modulating perceptual input to oculomotor systems and thereby biasing oculomotor selection. As a result, differences in memory match produce effects on landing position similar to the effects generated by differences in physical salience. PMID:24190909

  12. Visual working memory modulates low-level saccade target selection: evidence from rapidly generated saccades in the global effect paradigm.

    Science.gov (United States)

    Hollingworth, Andrew; Matsukura, Michi; Luck, Steven J

    2013-11-04

    In three experiments, we examined the influence of visual working memory (VWM) on the metrics of saccade landing position in a global effect paradigm. Participants executed a saccade to the more eccentric object in an object pair appearing on the horizontal midline, to the left or right of central fixation. While completing the saccade task, participants maintained a color in VWM for an unrelated memory task. Either the color of the saccade target matched the memory color (target match), the color of the distractor matched the memory color (distractor match), or the colors of neither object matched the memory color (no match). In the no-match condition, saccades tended to land at the midpoint between the two objects: the global, or averaging, effect. However, when one of the two objects matched VWM, the distribution of landing position shifted toward the matching object, both for target match and for distractor match. VWM modulation of landing position was observed even for the fastest quartile of saccades, with a mean latency as low as 112 ms. Effects of VWM on such rapidly generated saccades, with latencies in the express-saccade range, indicate that VWM interacts with the initial sweep of visual sensory processing, modulating perceptual input to oculomotor systems and thereby biasing oculomotor selection. As a result, differences in memory match produce effects on landing position similar to the effects generated by differences in physical salience.

  13. Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.

    Science.gov (United States)

    Janas, Maja M; Schlegel, Mark K; Harbison, Carole E; Yilmaz, Vedat O; Jiang, Yongfeng; Parmar, Rubina; Zlatev, Ivan; Castoreno, Adam; Xu, Huilei; Shulga-Morskaya, Svetlana; Rajeev, Kallanthottathil G; Manoharan, Muthiah; Keirstead, Natalie D; Maier, Martin A; Jadhav, Vasant

    2018-02-19

    Small interfering RNAs (siRNAs) conjugated to a trivalent N-acetylgalactosamine (GalNAc) ligand are being evaluated in investigational clinical studies for a variety of indications. The typical development candidate selection process includes evaluation of the most active compounds for toxicity in rats at pharmacologically exaggerated doses. The subset of GalNAc-siRNAs that show rat hepatotoxicity is not advanced to clinical development. Potential mechanisms of hepatotoxicity can be associated with the intracellular accumulation of oligonucleotides and their metabolites, RNA interference (RNAi)-mediated hybridization-based off-target effects, and/or perturbation of endogenous RNAi pathways. Here we show that rodent hepatotoxicity observed at supratherapeutic exposures can be largely attributed to RNAi-mediated off-target effects, but not chemical modifications or the perturbation of RNAi pathways. Furthermore, these off-target effects can be mitigated by modulating seed-pairing using a thermally destabilizing chemical modification, which significantly improves the safety profile of a GalNAc-siRNA in rat and may minimize the occurrence of hepatotoxic siRNAs across species.

  14. Transcriptome analysis reveals in vitro cultured Withania somnifera leaf and root tissues as a promising source for targeted withanolide biosynthesis.

    Science.gov (United States)

    Senthil, Kalaiselvi; Jayakodi, Murukarthick; Thirugnanasambantham, Pankajavalli; Lee, Sang Choon; Duraisamy, Pradeepa; Purushotham, Preethi M; Rajasekaran, Kalaiselvi; Nancy Charles, Shobana; Mariam Roy, Irene; Nagappan, Arul Kumar; Kim, Gon Sup; Lee, Yun Sun; Natesan, Senthil; Min, Tae-Sun; Yang, Tae Jin

    2015-01-22

    The production of metabolites via in vitro culture is promoted by the availability of fully defined metabolic pathways. Withanolides, the major bioactive phytochemicals of Withania somnifera, have been well studied for their pharmacological activities. However, only a few attempts have been made to identify key candidate genes involved in withanolide biosynthesis. Understanding the steps involved in withanolide biosynthesis is essential for metabolic engineering of this plant to increase withanolide production. Transcriptome sequencing was performed on in vitro adventitious root and leaf tissues using the Illumina platform. We obtained a total of 177,156 assembled transcripts with an average unigene length of 1,033 bp. About 13% of the transcripts were unique to in vitro adventitious roots but no unique transcripts were observed in in vitro-grown leaves. A putative withanolide biosynthetic pathway was deduced by mapping the assembled transcripts to the KEGG database, and the expression of candidate withanolide biosynthesis genes -were validated by qRT PCR. The accumulation pattern of withaferin A and withanolide A varied according to the type of tissue and the culture period. Further, we demonstrated that in vitro leaf extracts exhibit anticancer activity against human gastric adenocarcinoma cell lines at sub G1 phase. We report here a validated large-scale transcriptome data set and the potential biological activity of in vitro cultures of W. somnifera. This study provides important information to enhance tiss