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Sample records for vhl type 2b

  1. VHL type 2B mutations retain VBC complex form and function.

    Directory of Open Access Journals (Sweden)

    Kathryn E Hacker

    Full Text Available von Hippel-Lindau disease is characterized by a spectrum of hypervascular tumors, including renal cell carcinoma, hemangioblastoma, and pheochromocytoma, which occur with VHL genotype-specific differences in penetrance. VHL loss causes a failure to regulate the hypoxia inducible factors (HIF-1alpha and HIF-2alpha, resulting in accumulation of both factors to high levels. Although HIF dysregulation is critical to VHL disease-associated renal tumorigenesis, increasing evidence points toward gradations of HIF dysregulation contributing to the degree of predisposition to renal cell carcinoma and other manifestations of the disease.This investigation examined the ability of disease-specific VHL missense mutations to support the assembly of the VBC complex and to promote the ubiquitylation of HIF. Our interaction analysis supported previous observations that VHL Type 2B mutations disrupt the interaction between pVHL and Elongin C but maintain partial regulation of HIF. We additionally demonstrated that Type 2B mutant pVHL forms a remnant VBC complex containing the active members ROC1 and Cullin-2 which retains the ability to ubiquitylate HIF-1alpha.Our results suggest that subtypes of VHL mutations support an intermediate level of HIF regulation via a remnant VBC complex. These findings provide a mechanism for the graded HIF dysregulation and genetic predisposition for cancer development in VHL disease.

  2. VHL genetic alteration in CCRCC does not determine de-regulation of HIF, CAIX, hnRNP A2/B1 and osteopontin.

    LENUS (Irish Health Repository)

    Nyhan, Michelle J

    2012-01-31

    BACKGROUND: von Hippel-Lindau (VHL) tumour suppressor gene inactivation is associated with clear cell renal cell carcinoma (CCRCC) development. The VHL protein (pVHL) has been proposed to regulate the expression of several proteins including Hypoxia Inducible Factor-alpha (HIF-alpha), carbonic anhydrase (CA)IX, heterogeneous nuclear ribonucleoprotein (hnRNP) A2\\/B1 and osteopontin. pVHL has been characterized in vitro, however, clinical studies are limited. We evaluated the impact of VHL genetic alterations on the expression of several pVHL protein targets in paired normal and tumor tissue. METHODS: The VHL gene was sequenced in 23 CCRCC patients and VHL transcript levels were evaluated by real-time RT-PCR. Expression of pVHL\\'s protein targets were determined by Western blotting in 17 paired patient samples. RESULTS: VHL genetic alterations were identified in 43.5% (10\\/23) of CCRCCs. HIF-1alpha, HIF-2alpha and CAIX were up-regulated in 88.2% (15\\/17), 100% (17\\/17) and 88.2% (15\\/17) of tumors respectively and their expression is independent of VHL status. hnRNP A2\\/B1 and osteopontin expression was variable in CCRCCs and had no association with VHL genetic status. CONCLUSION: As expression of these proposed pVHL targets can be achieved independently of VHL mutation (and possibly by hypoxia alone), these data suggests that other pVHL targets may be more crucial in renal carcinogenesis.

  3. VHL Manifestations

    Science.gov (United States)

    ... Us Website References Search Patients / What is VHL? / Manifestations People who have VHL disease may experience tumors ... very important to check regularly for possible VHL manifestations throughout a person’s lifetime. Most of these VHL ...

  4. A patient with bilateral pheochromocytoma as part of a Von Hippel-Lindau (VHL syndrome type 2C

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    Rinkes Inne

    2007-10-01

    Full Text Available Abstract Background Von Hippel-Lindau (VHL disease is an autosomal dominant inherited disease. It is relatively recent that type 2C was identified as a separate group solely presenting with pheochromocytomas. As an illustration, an interesting case is presented of a pregnant woman with refractory hypertension. It proved to be the first manifestation of bilateral pheochromocytomas. The family history may indicate the diagnosis, but only identification of a germ line mutation in the DNA of a patient will confirm carriership. Case presentation A 27 year pregnant patient with intra uterine growth retardation presented with hypertension and pre-eclampsia. Magnetic resonance imaging revealed bilateral adrenal pheochromocytoma. She underwent laparoscopic adrenelectomy and a missense mutation (Gly93Ser in exon 1 of the VHL gene on chromosome 3 (p25 – p26 was shown in the patient, her father and her daughter confirming the diagnosis of VHL. Conclusion In almost all VHL families molecular genetic analysis of DNA will demonstrate an inherited mutation. Because of the involvement in several organs, periodic clinical evaluation should take place in a well coordinated, multidisciplinary setting. VHL disease can be classified into several subtypes. VHL type 2C patients present with pheochromocytomas without evidence of haemangioblastomas in the central nervous system and/or retina and a low risk of renal cell carcinoma. Therefore, in such families, periodic clinical screening can be focussed on pheochromocytomas.

  5. Differences in regulation of tight junctions and cell morphology between VHL mutations from disease subtypes

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    Isanova Bella

    2009-07-01

    Full Text Available Abstract Background In von Hippel-Lindau (VHL disease, germline mutations in the VHL tumor suppressor gene cause clear cell renal carcinomas, hemangioblastomas, and pheochromocytomas. The VHL gene product is part of an ubiquitin E3 ligase complex and hypoxia-inducible factor alpha (HIF-α is a key substrate, although additional VHL functions have been described. A genotype-phenotype relationship exists in VHL disease such that specific VHL mutations elicit certain subsets of these tumors. Here, we examine VHL genotype-phenotype correlations at the cellular level, focusing on the regulation of tight junctions and cell morphology. Methods Wild-type and various mutant VHL proteins representing VHL disease subtypes were stably expressed in 3 VHL-negative renal carcinoma cell lines. Using these cell lines, the roles of various VHL-associated cellular functions in regulation of cell morphology were investigated. Results As a whole, type 1 mutants varied greatly from type 2 mutants, demonstrating high levels of HIF-2α, cyclin D1 and α5 integrin, lower p27 levels, and a spindly, fibroblastic cellular appearance. Type 2 mutations demonstrated an epithelial morphology similar to wild-type VHL in the majority of the renal cell lines used. Knockdown of p27 in cells with wild-type VHL led to perturbations of both epithelial morphology and ZO-1 localization to tight junctions. ZO-1 localization correlated well with VHL disease subtypes, with greater mislocalization observed for genotypes associated with a higher risk of renal carcinoma. HIF-2α knockdown in 786-O partially restored ZO-1 localization, but did not restore an epithelial morphology. Conclusion VHL has both HIF-α dependent and HIF-α independent functions in regulating tight junctions and cell morphology that likely impact the clinical phenotypes seen in VHL disease.

  6. Dicty_cDB: VHL444 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available library) VHL444 (Link to dictyBase) - - - Contig-U15033-1 VHL444P (Link to Original site) VHL444F 595 VHL444Z...VHL444Z 674 VHL444P 1249 - - Show VHL444 Library VH (Link to library) Clone ID VHL444 (Link to dictyBase)...tsukuba.ac.jp/CSM/VH/VHL4-B/VHL444Q.Seq.d/ Representative seq. ID VHL444P (Link to Original site) Representative...Representative DNA sequence >VHL444 (VHL444Q) /CSM/VH/VHL4-B/VHL444Q.Seq.d/ CACTGTTGGCCTACTGGTATAGTTACA...significant alignments: (bits) Value VHL444 (VHL444Q) /CSM/VH/VHL4-B/VHL444Q.Seq.d/ 2420 0.0 VHN389 (VHN389Q)

  7. Phospholamban Is Downregulated by pVHL-Mediated Degradation through Oxidative Stress in Failing Heart

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    Shunichi Yokoe

    2017-10-01

    Full Text Available The E3 ubiquitin ligase, von Hippel–Lindau (VHL, regulates protein expression by polyubiquitination. Although the protein VHL (pVHL was reported to be involved in the heart function, the underlying mechanism is unclear. Here, we show that pVHL was upregulated in hearts from two types of genetically dilated cardiomyopathy (DCM mice models. In comparison with the wild-type mouse, both DCM mice models showed a significant reduction in the expression of phospholamban (PLN, a potent inhibitor of sarco(endoplasmic reticulum Ca2+-ATPase, and enhanced interaction between pVHL and PLN. To clarify whether pVHL is involved in PLN degradation in failing hearts, we used carbonylcyanide m-chlorophenylhydrazone (CCCP, a mitochondrial membrane potential (MMP-lowering reagent, to mimic the heart failure condition in PLN-expressing HEK293 cells and found that CCCP treatment resulted in PLN degradation and increased interaction between PLN and pVHL. However, these effects were reversed with the addition of N-acetyl-l-cysteine. Furthermore, the co-transfection of VHL and PLN in HEK293 cells decreased PLN expression under oxidative stress, whereas knockdown of VHL increased PLN expression both under normal and oxidative stress conditions. Together, we propose that oxidative stress upregulates pVHL expression to induce PLN degradation in failing hearts.

  8. Von Hippel-Lindau (VHL inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors.

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    Lee E Moore

    2011-10-01

    Full Text Available Renal tumor heterogeneity studies have utilized the von Hippel-Lindau VHL gene to classify disease into molecularly defined subtypes to examine associations with etiologic risk factors and prognosis. The aim of this study was to provide a comprehensive analysis of VHL inactivation in clear cell renal tumors (ccRCC and to evaluate relationships between VHL inactivation subgroups with renal cancer risk factors and VHL germline single nucleotide polymorphisms (SNPs. VHL genetic and epigenetic inactivation was examined among 507 sporadic RCC/470 ccRCC cases using endonuclease scanning and using bisulfite treatment and Sanger sequencing across 11 CpG sites within the VHL promoter. Case-only multivariate analyses were conducted to identify associations between alteration subtypes and risk factors. VHL inactivation, either through sequence alterations or promoter methylation in tumor DNA, was observed among 86.6% of ccRCC cases. Germline VHL SNPs and a haplotype were associated with promoter hypermethylation in tumor tissue (OR = 6.10; 95% CI: 2.28-16.35, p = 3.76E-4, p-global = 8E-5. Risk of having genetic VHL inactivation was inversely associated with smoking due to a higher proportion of wild-type ccRCC tumors [former: OR = 0.70 (0.20-1.31 and current: OR = 0.56 (0.32-0.99; P-trend = 0.04]. Alteration prevalence did not differ by histopathologic characteristics or occupational exposure to trichloroethylene. ccRCC cases with particular VHL germline polymorphisms were more likely to have VHL inactivation through promoter hypermethylation than through sequence alterations in tumor DNA, suggesting that the presence of these SNPs may represent an example of facilitated epigenetic variation (an inherited propensity towards epigenetic variation in renal tissue. A proportion of tumors from current smokers lacked VHL alterations and may represent a biologically distinct clinical entity from inactivated cases.

  9. Cushing Disease in a patient with Multiple Endocrine Neoplasia type 2B.

    Science.gov (United States)

    Kasturi, Kannan; Fernandes, Lucas; Quezado, Martha; Eid, Mary; Marcus, Leigh; Chittiboina, Prashant; Rappaport, Mark; Stratakis, Constantine A; Widemann, Brigitte; Lodish, Maya

    2017-06-01

    Multiple endocrine neoplasia type 2B (MEN2B) is a rare autosomal-dominant cancer syndrome characterized in part by metastatic medullary thyroid cancer (MTC) and pheochromocytoma. Cushing disease is a rare cause of endogenous hypercortisolism in children. We describe a 21-year-old African-American male who was diagnosed at age 10 with an ACTH-secreting pituitary microadenoma. At age 16 he developed medullary thyroid cancer and was found to have multiple endocrine neoplasia type 2B with the characteristic M918T mutation of the RET proto-oncogene. Following thyroidectomy, he was initiated on Vandetanib, a tyrosine kinase inhibitor, and has since had stable disease over the last 5 years. Our patient is the first individual with MEN2B to be described with Cushing disease. The RET oncogene may play a role in pituitary tumorigenesis; alternatively, the coexistence of these two entities may represent an extremely rare coincidence.

  10. Structural and functional characterizations of activin type 2B receptor (acvr2b) ortholog from the marine fish, gilthead sea bream, Sparus aurata: evidence for gene duplication of acvr2b in fish.

    Science.gov (United States)

    Funkenstein, Bruria; Krol, Ekaterina; Esterin, Elena; Kim, Yong-Soo

    2012-12-01

    Myostatin (MSTN), a negative regulator of muscle growth and a member of the transforming growth factor-β superfamily, can bind the two activin type 2 receptors (ACVR2). It has been previously shown that WT mice injected with ACVR2B extracellular domain (ACVR2B-ECD) had higher muscle mass. Likewise, fish larvae immersed in Pichia pastoris culture supernatant, containing goldfish Acvr2b-ECD, showed enhanced larval growth. However, it is not clear whether fish Mstn1 and Mstn2 signal through the same receptor and whether fish express more than one acvr2b gene. In the current study, three cDNAs encoding acvr2b (saacvr2b-1, saacvr2b-2a, and saacvr2b-2b) were cloned from gilthead sea bream. All three contain the short extracellular binding domain, a short transmembrane region, and a conserved catalytic domain of serine/threonine protein kinase. Bioinformatics analysis provided evidence for the existence of two acvr2b genes (acvr2b-1 and acvr2b-2) in several other fish species as well, probably as a result of gene or genome duplication. The two isoforms differ in their amino acid sequences. The direct inhibitory effect of Acvr2b-ECD on Mstn activity was tested in vitro. The saAcvr2b-1-ECD was expressed in the yeast P. pastoris. Evidence is provided for N-glycosylation of Acvr2b-1-ECD. The affinity-purified Acvr2b-1-ECD inhibited recombinant mouse/rat/human mature MSTN activity when determined in vitro using the CAGA-luciferase assay in A204 cells. A lower inhibitory activity was obtained when unprocessed purified, furin-digested, and activated saMstn1 was used. Results of this study demonstrate for the first time the existence of two acvr2b genes in fish. In addition, the study shows that bioactive fish Acvr2b-ECD can be produced from P. pastoris.

  11. Management of type 2b von Willebrand disease in the neonatal period.

    Science.gov (United States)

    Proud, Lindsay; Ritchey, A Kim

    2017-01-01

    Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting one in 1,000 people. Type 2b VWD is a less common subtype caused by a gain-of-function mutation in von Willebrand factor (VWF) that leads to the formation of large, ineffective VWF-platelet multimers in circulation. This unique pathophysiology creates diagnostic and treatment dilemmas. There is limited information on the management of type 2b VWD in the neonatal period. This report describes the management of a neonate with type 2b VWD with an emphasis on the added benefit of concomitant platelet transfusion and factor replacement therapy over factor replacement therapy alone. © 2016 Wiley Periodicals, Inc.

  12. The VHL-dependent regulation of microRNAs in renal cancer

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    Rawlings Lesley H

    2010-10-01

    Full Text Available Abstract Background The commonest histological type of renal cancer, clear cell renal cell carcinoma (cc RCC, is associated with genetic and epigenetic changes in the von Hippel-Lindau (VHL tumour suppressor. VHL inactivation leads to induction of hypoxia-inducible factors (HIFs and a hypoxic pattern of gene expression. Differential levels of specific microRNAs (miRNAs are observed in several tumours when compared to normal tissue. Given the central role of VHL in renal cancer formation, we examined the VHL-dependent regulation of miRNAs in renal cancer. Methods VHL-dependent miRNA expression in cc RCC was determined by microarray analysis of renal cell line RCC4 with mutated VHL (RCC4-VHL and reintroduced wild-type VHL (RCC4 + VHL. Five miRNAs highly upregulated in RCC4 + VHL and five miRNAs highly downregulated in RCC4 + VHL were studied further, in addition to miR-210, which is regulated by the HIF-VHL system. miRNA expression was also measured in 31 cc RCC tumours compared to adjacent normal tissue. Results A significant increase in miR-210, miR-155 and miR-21 expression was observed in the tumour tissue. miR-210 levels also showed a correlation with a HIF-regulated mRNA, carbonic anhydrase IX (CAIX, and with VHL mutation or promoter methylation. An inverse correlation was observed between miR-210 expression and patient survival, and a putative target of miR-210, iron-sulfur cluster assembly protein (ISCU1/2, shows reciprocal levels of mRNA expression in the tumours. Conclusions We have identified VHL-regulated miRNAs and found that for some the regulation is HIF-dependent and for others it is HIF-independent. This pattern of regulation was also seen in renal cancer tissue for several of these miRNAs (miR-210, miR-155, let-7i and members of the miR-17-92 cluster when compared with normal tissue. miR-210 showed marked increases in expression in renal cancer and levels correlated with patient survival. The inverse correlation between miR-210

  13. Multiple endocrine neoplasias type 2B and RET proto-oncogene

    Directory of Open Access Journals (Sweden)

    Martucciello Giuseppe

    2012-03-01

    Full Text Available Abstract Multiple Endocrine Neoplasia type 2B (MEN 2B is an autosomal dominant complex oncologic neurocristopathy including medullary thyroid carcinoma, pheochromocytoma, gastrointestinal disorders, marphanoid face, and mucosal multiple ganglioneuromas. Medullary thyroid carcinoma is the major cause of mortality in MEN 2B syndrome, and it often appears during the first years of life. RET proto-oncogene germline activating mutations are causative for MEN 2B. The 95% of MEN 2B patients are associated with a point mutation in exon 16 (M918/T. A second point mutation at codon 883 has been found in 2%-3% of MEN 2B cases. RET proto-oncogene is also involved in different neoplastic and not neoplastic neurocristopathies. Other RET mutations cause MEN 2A syndrome, familial medullary thyroid carcinoma, or Hirschsprung's disease. RET gene expression is also involved in Neuroblastoma. The main diagnosis standards are the acetylcholinesterase study of rectal mucosa and the molecular analysis of RET. In our protocol the rectal biopsy is, therefore, the first approach. RET mutation detection offers the possibility to diagnose MEN 2B predisposition at a pre-clinical stage in familial cases, and to perform an early total prophylactic thyroidectomy. The surgical treatment of MEN 2B is total thyroidectomy with cervical limphadenectomy of the central compartment of the neck. When possible, this intervention should be performed with prophylactic aim before 1 year of age in patients with molecular genetic diagnosis. Recent advances into the mechanisms of RET proto-oncogene signaling and pathways of RET signal transduction in the development of MEN 2 and MTC will allow new treatment possibilities.

  14. First detection of canine parvovirus type 2b from diarrheic dogs in Himachal Pradesh.

    Science.gov (United States)

    Sharma, Shalini; Dhar, Prasenjit; Thakur, Aneesh; Sharma, Vivek; Sharma, Mandeep

    2016-09-01

    The present study was conducted to detect the presence of canine parvovirus (CPV) among diarrheic dogs in Himachal Pradesh and to identify the most prevalent antigenic variant of CPV based on molecular typing and sequence analysis of VP2 gene. A total of 102 fecal samples were collected from clinical cases of diarrhea or hemorrhagic gastroenteritis from CPV vaccinated or non-vaccinated dogs. Samples were tested using CPV-specific polymerase chain reaction (PCR) targeting VP2 gene, multiplex PCR for detection of CPV-2a and CPV-2b antigenic variants, and a PCR for the detection of CPV-2c. CPV-2b isolate was cultured on Madin-Darby canine kidney (MDCK) cell lines and sequenced using VP2 structural protein gene. Multiple alignment and phylogenetic analysis was done using ClustalW and MEGA6 and inferred using the Neighbor-Joining method. No sample was found positive for the original CPV strain usually present in the vaccine. However, about 50% (52 out of 102) of the samples were found to be positive with CPV-2ab PCR assay that detects newer variants of CPV circulating in the field. In addition, multiplex PCR assay that identifies both CPV-2ab and CPV-2b revealed that CPV-2b was the major antigenic variant present in the affected dogs. A PCR positive isolate of CPV-2b was adapted to grow in MDCK cells and produced characteristic cytopathic effect after 5th passage. Multiple sequence alignment of VP2 structural gene of CPV-2b isolate (Accession number HG004610) used in the study was found to be similar to other sequenced isolates in NCBI sequence database and showed 98-99% homology. This study reports the first detection of CPV-2b in dogs with hemorrhagic gastroenteritis in Himachal Pradesh and absence of other antigenic types of CPV. Further, CPV-specific PCR assay can be used for rapid confirmation of circulating virus strains under field conditions.

  15. Progressive dysphagia in limb-girdle muscular dystrophy type 2B.

    LENUS (Irish Health Repository)

    Walsh, Richard

    2012-02-01

    Dysphagia has not been reported in genetically confirmed limb-girdle muscular dystrophy type 2B (LGMD2B). A 40-year-old woman reported exercise-induced calf pain at age 34, followed by progressive lower and upper limb weakness. At age 38, progressive dysphagia for solids, and subsequently liquids, ensued. Endoscopic and videofluoroscopic-radiological findings indicated a myopathic swallowing disorder. Molecular genetic analysis confirmed two dysferlin gene mutations consistent with a compound heterozygote state. Progressive dysphagia should be considered as part of the expanding dysferlinopathy phenotype.

  16. Identification of 3 novel VHL germ-line mutations in Danish VHL patients

    DEFF Research Database (Denmark)

    Dandanell, Mette; Friis-Hansen, Lennart Jan; Sunde, Lone

    2012-01-01

    von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome in which the patients develop retinal and central nervous system hemangioblastomas, pheochromocytomas and clear-cell renal tumors. The autosomal dominant disease is caused by mutations in the VHL gene.......von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome in which the patients develop retinal and central nervous system hemangioblastomas, pheochromocytomas and clear-cell renal tumors. The autosomal dominant disease is caused by mutations in the VHL gene....

  17. [Prenatal exclusion of von Hippel-Lindau syndrome in a Mexican family carrying a novel VHL gene mutation].

    Science.gov (United States)

    Chacón-Camacho, Oscar Francisco; Benitez-Granados, Jesús; Zenteno, Juan Carlos

    2014-03-01

    von Hippel-Lindau (VHL) disease is an autosomal dominant and familial multisystemic syndrome that is caused by the inactivation of the VHL gene and it is characterized by diverse types of high vasculated tumours of benign and malign nature. In this work we describe the clinical characteristics and the prenatal diagnosis of a woman with VHL. Describe the first exclusion prenatal case by DNA analysis of the VHL syndrome in Latinoamerican population. Analysis of a Mexican familial pedigree showed 5 affected subjects with VHL on 3 consecutive generations. The proband was a 7 weeks pregnancy woman who was referred to our service for familiar and personal history of this disease. Maternal DNA was obtained from peripheral blood leukocytes, while fetal DNA was isolated from amniotic liquid cells on the 15th week. The maternal and fetal DNA analysis were done by the Polymerase Chain reaction (PCR) and the direct nucleotide sequence of the VHL gene. A novel mutation (c. 161_168 dup GGAGGCCG) in the VHL gene was identified in maternal DNA. Fetal DNA analysis indicated that the fetus inherited the wild-type allele from the mother. A novel VHL gene mutation was identified in a familial case of the disease, expanding the mutational spectrum in this disorder. The molecular prenatal testing in the affected woman at 15 weeks of gestation, demonstrated that the fetus did nor inherited the mutated allele. To the best of our knowledge, this is the first example of prenatal-molecular exclusion on VHL syndrome in Latinoamerica population.

  18. Hypoxia-inducible factor-2α stabilizes the von Hippel-Lindau (VHL) disease suppressor, Myb-related protein 2.

    Science.gov (United States)

    Okumura, Fumihiko; Joo-Okumura, Akiko; Nakatsukasa, Kunio; Kamura, Takumi

    2017-01-01

    Ubiquitin ligase von Hippel-Lindau tumor suppressor (pVHL) negatively regulates protein levels of hypoxia-inducible factor-α (HIF-α). Loss of pVHL causes HIF-α accumulation, which contributes to the pathogenesis of von Hippel-Lindau (VHL) disease. In contrast, v-Myb avian myeloblastosis viral oncogene homolog-like 2 (MYBL2; B-Myb), a transcription factor, prevents VHL pathogenesis by regulating gene expression of HIF-independent pathways. Both HIF-α and B-Myb are targets of pVHL-mediated polyubiquitination and proteasomal degradation. Here, we show that knockdown of HIF-2α induces downregulation of B-Myb in 786-O cells, which are deficient in pVHL, and this downregulation is prevented by proteasome inhibition. In the presence of pVHL and under hypoxia-like conditions, B-Myb and HIF-2α are both upregulated, and the upregulation of B-Myb requires expression of HIF-2α. We also show that HIF-2α and B-Myb interact in the nucleus, and this interaction is mediated by the central region of HIF-2α and the C-terminal region of B-Myb. These data indicate that oncogenic HIF-2α stabilizes B-Myb to suppress VHL pathogenesis.

  19. First detection of canine parvovirus type 2b from diarrheic dogs in Himachal Pradesh

    Directory of Open Access Journals (Sweden)

    Shalini Sharma

    2016-09-01

    Full Text Available Aim: The present study was conducted to detect the presence of canine parvovirus (CPV among diarrheic dogs in Himachal Pradesh and to identify the most prevalent antigenic variant of CPV based on molecular typing and sequence analysis of VP2 gene. Materials and Methods: A total of 102 fecal samples were collected from clinical cases of diarrhea or hemorrhagic gastroenteritis from CPV vaccinated or non-vaccinated dogs. Samples were tested using CPV-specific polymerase chain reaction (PCR targeting VP2 gene, multiplex PCR for detection of CPV-2a and CPV-2b antigenic variants, and a PCR for the detection of CPV-2c. CPV-2b isolate was cultured on Madin-Darby canine kidney (MDCK cell lines and sequenced using VP2 structural protein gene. Multiple alignment and phylogenetic analysis was done using ClustalW and MEGA6 and inferred using the Neighbor-Joining method. Results: No sample was found positive for the original CPV strain usually present in the vaccine. However, about 50% (52 out of 102 of the samples were found to be positive with CPV-2ab PCR assay that detects newer variants of CPV circulating in the field. In addition, multiplex PCR assay that identifies both CPV-2ab and CPV-2b revealed that CPV-2b was the major antigenic variant present in the affected dogs. A PCR positive isolate of CPV-2b was adapted to grow in MDCK cells and produced characteristic cytopathic effect after 5th passage. Multiple sequence alignment of VP2 structural gene of CPV-2b isolate (Accession number HG004610 used in the study was found to be similar to other sequenced isolates in NCBI sequence database and showed 98-99% homology. Conclusion: This study reports the first detection of CPV-2b in dogs with hemorrhagic gastroenteritis in Himachal Pradesh and absence of other antigenic types of CPV. Further, CPV-specific PCR assay can be used for rapid confirmation of circulating virus strains under field conditions.

  20. Vaccination of dogs with canine parvovirus type 2b (CPV-2b) induces neutralising antibody responses to CPV-2a and CPV-2c.

    Science.gov (United States)

    Wilson, Stephen; Illambas, Joanna; Siedek, Elisabeth; Stirling, Catrina; Thomas, Anne; Plevová, Edita; Sture, Gordon; Salt, Jeremy

    2014-09-22

    Since the identification of canine parvovirus type 2, three variants have subsequently been observed differing from the historical CPV-2 and each other by 1-2 amino acids only. As a result there has been considerable research into differential diagnostics, with some researchers indicating there is a need for new vaccines containing different strains of CPV-2. In this study we investigated whether vaccination with a CPV-2b containing vaccine would induce cross-reactive antibody responses to the other CPV-2 variants. Two studies where dogs were vaccinated with a multivalent vaccine, subsequently challenged with CPV-2b and sera samples analysed are presented. Six week old pups with defined serological status were vaccinated twice, three weeks apart and challenged either 5 weeks (MDA override study) or one year after vaccination (duration of immunity study). Sera samples were collected before each vaccination and at periods throughout each study. In each study the antibody profiles were very similar; serological responses against CPV-2a, CPV-2b and CPV-2c were higher than those for CPV-2. Nevertheless, responses against CPV-2 were well above levels considered clinically protective. In each study dogs also showed a rapid increase in antibody titres following vaccination, reached a plateau following second vaccination with a slight decline to challenge after which rapid anamnestic responses were seen. Evaluation of the serological responses suggests vaccination with CPV-2b would cross-protect against CPV-2a and CPV-2c, as well as against CPV-2 which is now extinct in the field. In conclusion we have demonstrated that vaccination of minimum aged dogs with a multivalent vaccine containing the CPV-2b variant strain will induce serological responses which are cross-reactive against all currently circulating field strains, CPV-2a and CPV-2c, and the now extinct field strain CPV-2. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Dicty_cDB: VHL663 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available VH (Link to library) VHL663 (Link to dictyBase) - - - Contig-U15767-1 VHL663P (Link... to Original site) VHL663F 574 VHL663Z 702 VHL663P 1256 - - Show VHL663 Library VH (Link to library) Clone ID VHL663 (Link to dict...yBase) Atlas ID - NBRP ID - dictyBase ID - Link to Contig Contig-U15767-1 Original site URL http://dict...WPDGFKYFFVDNQAGDSESAKSGKNLPIQRDIELNWNGEAYEYSNSNYFPINGQG FNDVSYPV--- ---SYATGKCEPDSSLCNDNNICTIDICVHEGILDGLPQG...ik rqelvgqmvlsifl*itklviqnlpnlvkifqfkeiss*igmekhmniviqitsqltdkv smm*aiq--- ---SYATGKCEPDSSLCNDNNICTIDICVHEGI

  2. Dicty_cDB: VHL434 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available VH (Link to library) VHL434 (Link to dictyBase) - - - Contig-U16336-1 VHL434P (Link... to Original site) VHL434F 546 VHL434Z 778 VHL434P 1304 - - Show VHL434 Library VH (Link to library) Clone ID VHL434 (Link to dict...yBase) Atlas ID - NBRP ID - dictyBase ID - Link to Contig Contig-U16336-1 Original site URL http://dict...EVMSCNKFSSKRIGYLAASQSFNEGTDVIVLATHQIRKDFLS SNQSEAYLALNCLSNICTTDLARELANDILTLLSTQKTHILKRAITVLYKIFLRYPES-- - --...GFDISWASFKIVEVMSCNKFSSKRIGYLAASQSFNEGTDVIVLATHQIRKDFLS SNQSEAYLALNCLSNICTTDLARELANDILTLLSTQKTHILKRAITVLYKIFL

  3. Playing Tag with HIF: The VHL Story

    Directory of Open Access Journals (Sweden)

    Sherri K. Leung

    2002-01-01

    Full Text Available Inactivation of the von Hippel-Lindau (VHL tumour suppressor gene product pVHL is the cause of inherited VHL disease and is associated with sporadic kidney cancer. pVHL is found in a multiprotein complex with elongins B/C, Cul2, and Rbx1 forming an E3 ubiquitin ligase complex called VEC. This modular enzyme targets the α subunits of hypoxia-inducible factor (HIF for ubiquitin-mediated destruction. Consequently, tumour cells lacking functional pVHL overproduce the products of HIF-target genes such as vascular endothelial growth factor (VEGF, which promotes angiogenesis. This likely accounts for the hypervascular nature of VHL-associated neoplasms. Although pVHL has been linked to the cell-cycle, differentiation, and the regulation of extracellular matrix assembly, microenvironment pH, and tissue invasiveness, this review will focus on the recent insights into the molecular mechanisms governing the E3 ubiquitin ligase function of VEC.

  4. AMSR-E/Aqua L2B Global Swath Rain Rate/Type GSFC Profiling Algorithm V002

    Data.gov (United States)

    National Aeronautics and Space Administration — The AMSR-E/Aqua Level-2B rain product includes instantaneous rain rate and rain type over ice-free and snow-free land and ocean between 70 degrees north and south...

  5. Identification of the Lipodepsipeptide MDN-0066, a Novel Inhibitor of VHL/HIF Pathway Produced by a New Pseudomonas Species.

    Directory of Open Access Journals (Sweden)

    Bastien Cautain

    Full Text Available Throughout recent history, metabolites of microbial origin have had an extraordinary impact on the welfare of humanity. In fact, natural products have largely been--and still are--considered an exceedingly valuable platform for the discovery of new drugs against diverse pathologies. Such value is partly due to their higher complexity and chemical diversity as compared to those of synthetic and combinatorial compounds. Mutations in the Von Hippel-Lindau (vhl gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types. The primary cause of morbidity and mortality for these patients arises from progression of Renal Cell Carcinoma (RCC or end-stage renal disease. Inactivation of the Von Hippel-Lindau (vhl tumor suppressor gene arises in the majority of Renal Cell Carcinoma (RCC as well as in other types of cancer and is associated with a high degree of vascularization and poor prognosis. Loss of pVHL function thus represents a pathognomonic molecular defect for therapeutic exploitation. In this study, renal carcinoma cell lines with naturally occurring vhl mutations (RCC4 VA and their genetically matched wild-type vhl (RCC4 VHL counterparts were seeded onto 96-well plates and treated with a collection of 1,040 organic extracts obtained from 130 bacterial strains belonging to at least 25 genera of the phyla Actinobacteria, Firmicutes, Proteobacteria and Bacteroidetes. This strategy allowed us to identify several extracts obtained from bacterial strain F-278,770T, the type strain of the recently proposed new species Pseudomonas granadensis, showing biological activities not associated with previously known bioactive metabolites. The fractionation and structural elucidation of one of these extracts led to the discovery of a new lipodepsipeptide (MDN-0066 with specific toxicity in pVHL deficient cells that is not detectable in cells with pVHL expression rescue. This specific toxicity is associated with

  6. Identification of the Lipodepsipeptide MDN-0066, a Novel Inhibitor of VHL/HIF Pathway Produced by a New Pseudomonas Species.

    Science.gov (United States)

    Cautain, Bastien; de Pedro, Nuria; Schulz, Christian; Pascual, Javier; Sousa, Thiciana da S; Martin, Jesús; Pérez-Victoria, Ignacio; Asensio, Francisco; González, Ignacio; Bills, Gerald F; Reyes, Fernando; Genilloud, Olga; Vicente, Francisca

    2015-01-01

    Throughout recent history, metabolites of microbial origin have had an extraordinary impact on the welfare of humanity. In fact, natural products have largely been--and still are--considered an exceedingly valuable platform for the discovery of new drugs against diverse pathologies. Such value is partly due to their higher complexity and chemical diversity as compared to those of synthetic and combinatorial compounds. Mutations in the Von Hippel-Lindau (vhl) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types. The primary cause of morbidity and mortality for these patients arises from progression of Renal Cell Carcinoma (RCC) or end-stage renal disease. Inactivation of the Von Hippel-Lindau (vhl) tumor suppressor gene arises in the majority of Renal Cell Carcinoma (RCC) as well as in other types of cancer and is associated with a high degree of vascularization and poor prognosis. Loss of pVHL function thus represents a pathognomonic molecular defect for therapeutic exploitation. In this study, renal carcinoma cell lines with naturally occurring vhl mutations (RCC4 VA) and their genetically matched wild-type vhl (RCC4 VHL) counterparts were seeded onto 96-well plates and treated with a collection of 1,040 organic extracts obtained from 130 bacterial strains belonging to at least 25 genera of the phyla Actinobacteria, Firmicutes, Proteobacteria and Bacteroidetes. This strategy allowed us to identify several extracts obtained from bacterial strain F-278,770T, the type strain of the recently proposed new species Pseudomonas granadensis, showing biological activities not associated with previously known bioactive metabolites. The fractionation and structural elucidation of one of these extracts led to the discovery of a new lipodepsipeptide (MDN-0066) with specific toxicity in pVHL deficient cells that is not detectable in cells with pVHL expression rescue. This specific toxicity is associated with apoptosis

  7. Towards a Standardized Line List for G 191-B2B and other DA Type Objects

    Science.gov (United States)

    Preval, S. P.; Barstow, M. A.; Holberg, J. B.; Dickinson, N. J.

    2013-01-01

    We present a comprehensive analysis of the far UV spectrum of G 191-B2B over the range of 900-1700Å using co-added data from the FUSE and STIS archives. While previous identifications made by Holberg et al. (2003) are reaffirmed in this work, it is found that many previously unidentified lines can now be attributed to Fe, Ni, and a few lighter metals. Future work includes extending this detailed analysis to a wider range of DA objects, in the expectation that a more complete analysis of their atmospheres can be realised.

  8. Von Hippel-Lindau disease (vHL)

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Bisgaard, Søs Marie Luise; Harbud, Vibeke

    2013-01-01

    These clinical guidelines outline the criteria and recommendations for diagnostic and genetic work-up of families suspected of von Hippel-Lindau disease (vHL), as well as recommendations for prophylactic surveillance for vHL patients. The guideline has been composed by the Danish Coordination Group...... for vHL which is comprised of Danish doctors and specialists interested in vHL. The recommendations are based on longstanding clinical experience, Danish original research, and extensive review of the international literature. vHL is a hereditary multi-tumour disease caused by germline mutations...... cell carcinoma), the adrenal glands (pheochromocytoma), the pancreas, as well as in other organs. As many different organs can be affected, several medical specialities often take part in both diagnosis and treatment of manifestations. vHL should be suspected in individuals with a family history...

  9. Accelerated inactivation of the L-type calcium current due to a mutation in CACNB2b underlies Brugada syndrome

    DEFF Research Database (Denmark)

    Cordeiro, Jonathan M; Marieb, Mark; Pfeiffer, Ryan

    2009-01-01

    S in which loss of function is caused by accelerated inactivation of I(Ca). The proband, a 32 year old male, displayed a Type I ST segment elevation in two right precordial ECG leads following a procainamide challenge. EP study was positive with induction of polymorphic VT/VF. Interrogation of implanted ICD...... significantly faster in mutant channels between 0 and + 20 mV. Action potential voltage clamp experiments showed that total charge was reduced by almost half compared to WT. We report the first BrS mutation in CaCNB2b resulting in accelerated inactivation of L-type calcium channel current. Our results suggest...

  10. The effect of exercise on von Willebrand factor and ADAMTS-13 in individuals with type 1 and type 2B von Willebrand disease

    NARCIS (Netherlands)

    Stakiw, J.; Bowman, M.; Hegadorn, C.; Pruss, C.; Notley, C.; Groot, E.; Lenting, P. J.; Rapson, D.; Lillicrap, D.; James, P.

    Background: The effect of exercise on von Willebrand factor (VWF) and ADAMTS-13 levels in individuals with von Willebrand disease (VWD) has never been reported. Objectives: The aim was to quantify the effect of a standardized exercise protocol on individuals with type 1 and type 2B VWD.

  11. Potential value of EUS in pancreatic surveillance of VHL patients

    NARCIS (Netherlands)

    van Asselt, Sophie Josephien; Brouwers, Adrienne H; van Dullemen, Hendrik M; van der Jagt, Eric J; Bongaerts, Alfons H; Koopmans, Klaas P; Kema, Ido; Zonnenberg, Bernard A; Timmers, Henri Jlm; de Herder, Wouter; Sluiter, Wim; de Vries, Elisabeth G E; Links, T P

    Background: Patients with von Hippel-Lindau (VHL) disease are prone to develop pancreatic neuroendocrine tumors (pNETs). However, the best imaging technique for early detection of pNETs in VHL is currently unknown. In a head-to-head comparison, we evaluated endoscopic ultrasound (EUS) and

  12. Von Hippel-Lindau disease (vHL)

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Bisgaard, Søs Marie Luise; Harbud, Vibeke

    2013-01-01

    These clinical guidelines outline the criteria and recommendations for diagnostic and genetic work-up of families suspected of von Hippel-Lindau disease (vHL), as well as recommendations for prophylactic surveillance for vHL patients. The guideline has been composed by the Danish Coordination Group...... for vHL which is comprised of Danish doctors and specialists interested in vHL. The recommendations are based on longstanding clinical experience, Danish original research, and extensive review of the international literature. vHL is a hereditary multi-tumour disease caused by germline mutations...... of the disease, and/or in individuals with a vHL-associated manifestation; i.e. a hemangioblastoma in the retina or the central nervous system, familial or bilateral pheochromocytomas, familial, multiple, or early onset renal cell carcinomas, and in individuals with an endolymphatic sac tumour in the inner ear...

  13. Reproduction in porcine circovirus type 2 (PCV2) seropositive gilts inseminated with PCV2b spiked semen.

    Science.gov (United States)

    Sarli, Giuseppe; Morandi, Federico; Panarese, Serena; Bacci, Barbara; Ferrara, Domenico; Bianco, Carlo; Fusaro, Laura; Bacci, Maria Laura; Galeati, Giovanna; Dottori, Michele; Bonilauri, Paolo; Lelli, Davide; Leotti, Giorgio; Vila, Thais; Joisel, Francois; Allan, Gordon; Benazzi, Cinzia; Ostanello, Fabio

    2012-08-31

    Since 1999, field evidence of transplacental infection by porcine circovirus type 2 (PCV2) and reproductive failure has been reported in pigs. The objective of this study was to evaluate the clinical and pathological consequences of PCV2 infection in conventional PCV2-seropositive gilts by insemination with PCV2b-spiked semen. Six PCV2 seropositive gilts were inseminated with PCV2b-supplemented semen (infected) and three animals with semen and cell culture medium (controls). Only three out of the six infected animals were pregnant by ultrasonography on day 29 after insemination, while two out of the three controls were pregnant. One control gilt aborted on day 23 after insemination but not due to PVC2. Viraemia was demonstrated in four out of six infected and in one control gilt that became infected with PCV2a. Anti-PCV2 antibody titres showed dynamic variations in the infected group throughout the study. Among infected gilts, the animal with the lowest anti-PCV2 titre (1/100) at the beginning of the experiment and another that reached a similar low value during the experiment showed evident seroconversion over time and had also PCV2 positive foetuses. One placenta displayed mild focal necrosis of the chorionic epithelium positively stained by immunohistochemistry for PCV2 antigen. PCV2-seropositive gilts can be infected with PCV2 after intrauterine exposure and low maternal antibody titre may increase the probability of a foetal infection.

  14. Reproduction in porcine circovirus type 2 (PCV2 seropositive gilts inseminated with PCV2b spiked semen

    Directory of Open Access Journals (Sweden)

    Sarli Giuseppe

    2012-08-01

    Full Text Available Abstract Background Since 1999, field evidence of transplacental infection by porcine circovirus type 2 (PCV2 and reproductive failure has been reported in pigs. The objective of this study was to evaluate the clinical and pathological consequences of PCV2 infection in conventional PCV2-seropositive gilts by insemination with PCV2b-spiked semen. Results Six PCV2 seropositive gilts were inseminated with PCV2b-supplemented semen (infected and three animals with semen and cell culture medium (controls. Only three out of the six infected animals were pregnant by ultrasonography on day 29 after insemination, while two out of the three controls were pregnant. One control gilt aborted on day 23 after insemination but not due to PVC2. Viraemia was demonstrated in four out of six infected and in one control gilt that became infected with PCV2a. Anti-PCV2 antibody titres showed dynamic variations in the infected group throughout the study. Among infected gilts, the animal with the lowest anti-PCV2 titre (1/100 at the beginning of the experiment and another that reached a similar low value during the experiment showed evident seroconversion over time and had also PCV2 positive foetuses. One placenta displayed mild focal necrosis of the chorionic epithelium positively stained by immunohistochemistry for PCV2 antigen. Conclusions PCV2-seropositive gilts can be infected with PCV2 after intrauterine exposure and low maternal antibody titre may increase the probability of a foetal infection.

  15. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy.

    Science.gov (United States)

    Verhoeven, Kristien; De Jonghe, Peter; Coen, Katrien; Verpoorten, Nathalie; Auer-Grumbach, Michaela; Kwon, Jennifer M; FitzPatrick, David; Schmedding, Eric; De Vriendt, Els; Jacobs, An; Van Gerwen, Veerle; Wagner, Klaus; Hartung, Hans-Peter; Timmerman, Vincent

    2003-03-01

    Charcot-Marie-Tooth type 2B (CMT2B) is clinically characterized by marked distal muscle weakness and wasting and a high frequency of foot ulcers, infections, and amputations of the toes because of recurrent infections. CMT2B maps to chromosome 3q13-q22. We refined the CMT2B locus to a 2.5-cM region and report two missense mutations (Leu129Phe and Val162Met) in the small GTP-ase late endosomal protein RAB7 which causes the CMT2B phenotype in three extended families and in three patients with a positive family history. The alignment of RAB7 orthologs shows that both missense mutations target highly conserved amino acid residues. RAB7 is ubiquitously expressed, and we found expression in sensory and motor neurons.

  16. Small activating RNA induced expression of VHL gene in renal cell carcinoma.

    Science.gov (United States)

    Kang, Moo Rim; Park, Ki Hwan; Lee, Chang Woo; Lee, Myeong Youl; Han, Sang-Bae; Li, Long-Cheng; Kang, Jong Soon

    2018-02-06

    Recent studies have reported that chemically synthesized double-stranded RNAs (dsRNAs), also known as small activating RNA (saRNAs), can specifically induce gene expression by targeting promoter sequences by a mechanism termed RNA activation (RNAa). In the present study, we designed 4 candidate saRNAs targeting the Von Hippel-Lindau (VHL) gene promoter. Among these saRNAs, dsVHL-821 significantly inhibited cell growth by up-regulating VHL at both the mRNA and protein levels in renal cell carcinoma 769-P cells. Functional analysis showed that dsVHL-821 induced apoptosis by increasing p53, decreasing Bcl-xL, activating caspase 3/7 and poly-ADP-ribose polymerase in a dose-dependent manner. Chromatin immunoprecipitation analysis revealed that dsVHL-821 increased the enrichment of Ago2 and RNA polymerase II at the dsVHL-821 target site. In addition, Ago2 depletion significantly suppressed dsVHL-821-induced up-regulation of VHL gene expression and related effects. Single transfection of dsVHL-821 caused long-lasting (14 days) VHL up-regulation. Furthermore, the activation of VHL by dsVHL-821 was accompanied by an increase in dimethylation of histone 3 at lysine 4 (H3K4me2) and acetylation of histone 4 (H4ac) and a decrease in dimethylation of histone 3 at lysine 9 (H3K9me2) and lysine 27 (H3K27me2) in the dsVHL-821 target region. Taken together, these results demonstrate that dsVHL-821, a novel saRNA for VHL, induces the expression of the VHL gene by epigenetic changes, leading to inhibition of cell growth and induction of apoptosis, and suggest that targeted activation of VHL by dsVHL-821 may be explored as a novel treatment of renal cell carcinoma. Copyright © 2018 Elsevier Ltd. All rights reserved.

  17. Novel homozygous VHL mutation in exon 2 is associated with congenital polycythemia but not with cancer.

    Science.gov (United States)

    Lanikova, Lucie; Lorenzo, Felipe; Yang, Chunzhang; Vankayalapati, Hari; Drachtman, Richard; Divoky, Vladimir; Prchal, Josef T

    2013-05-09

    Germline von Hippel-Lindau (VHL) gene mutations underlie dominantly inherited familial VHL tumor syndrome comprising a predisposition for renal cell carcinoma, pheochromocytoma/paraganglioma, cerebral hemangioblastoma, and endolymphatic sac tumors. However, recessively inherited congenital polycythemia, exemplified by Chuvash polycythemia, has been associated with 2 separate 3' VHL gene mutations in exon 3. It was proposed that different positions of loss-of-function VHL mutations are associated with VHL syndrome cancer predisposition and only C-terminal domain-encoding VHL mutations would cause polycythemia. However, now we describe a new homozygous VHL exon 2 mutation of the VHL gene:(c.413C>T):P138L, which is associated in the affected homozygote with congenital polycythemia but not in her, or her-heterozygous relatives, with cancer or other VHL syndrome tumors. We show that VHL(P138L) has perturbed interaction with hypoxia-inducible transcription factor (HIF)1α. Further, VHL(P138L) protein has decreased stability in vitro. Similarly to what was reported in Chuvash polycythemia and some other instances of HIFs upregulation, VHL(P138L) erythroid progenitors are hypersensitive to erythropoietin. Interestingly, the level of RUNX1/AML1 and NF-E2 transcripts that are specifically upregulated in acquired polycythemia vera were also upregulated in VHL(P138L) granulocytes.

  18. Management Strategies and Outcomes for VHL-related Craniospinal Hemangioblastomas

    Directory of Open Access Journals (Sweden)

    Christ Ordookhanian

    2017-08-01

    Full Text Available Hemangioblastomas are rare and benign tumors accounting for less than 2% of all central nervous system (CNS tumors. The vast majority of hemangioblastomas occur sporadically, whereas a small number of cases, especially in younger patients, are associated with Von Hippel–Lindau (VHL syndrome. It is thought that loss of tumor suppressor function of the VHL gene results in stabilization of hypoxia-inducible factor alpha with downstream activation of cellular proliferative and angiogenic genes that promote tumorigenesis. VHL-related hemangioblastomas predominantly occur in the cerebellum and spine. Lesions are often diagnosed on contrast-enhanced craniospinal MRIs, and the diagnosis of VHL occurs through assessment for germline VHL mutations. Surgical resection remains the primary treatment modality for symptomatic or worrisome lesions, with excellent local control rates and neurological outcomes. Stereotactic radiotherapy can be employed in patients who are deemed high risk for surgery, have multiple lesions, or have non-resectable lesions. Given the tendency for development of either new or multiple lesions, close radiographic surveillance is often recommended for asymptomatic lesions.

  19. Role of VEGFA, CXCR4 and VHL mutation in tumour behaviour

    NARCIS (Netherlands)

    Kruizinga, Roeliene

    2014-01-01

    De ziekte van Von Hippel Lindau (VHL) is een zeldzaam kankersyndroom. Patiënten met deze ziekte krijgen zowel goedaardige als kwaadaardige tumoren in verschillende organen. VHL-patiënten hebben een niet goed werkend VHL-eiwit waardoor er meer CXCR4, een chemokine receptor, en VEGFA, een

  20. Surveillance in von Hippel-Lindau disease (vHL)

    DEFF Research Database (Denmark)

    Poulsen, Marie Louise Mølgaard; Budtz-Jørgensen, E; Bisgaard, M L

    2010-01-01

    54 living vHL-mutation carriers, risks of intercurrent manifestations in-between surveillance examinations were determined and clinical consequences of surveillance findings evaluated. Current recommendations of annual ophthalmic and abdominal examinations corresponded to acceptably low intercurrent...... for the patient. Also, pre-symptomatic surveillance increased cumulative incidence of clinical vHL diagnosis from 46% to 72% and from 89% to 94% by age 30 and 50 years, respectively. The present results promote optimization of surveillance, expectantly improving clinical vHL outcomes....

  1. Efficient charge separation based on type-II g-C3N4/TiO2-B nanowire/tube heterostructure photocatalysts.

    Science.gov (United States)

    Chen, Hongmei; Xie, Yinghao; Sun, Xiaoqin; Lv, Meilin; Wu, Fangfang; Zhang, Lei; Li, Li; Xu, Xiaoxiang

    2015-08-07

    Separation of photo-generated charges has played a crucial role in controlling the actual performance of a photocatalytic system. Here we have successfully fabricated g-C3N4/TiO2-B nanowire/tube heterostructures through facile urea degradation reactions. Owing to the effective separation of photo-generated charges associated with the type-II band alignment and intimate interfacial contacts between g-C3N4 and TiO2-B nanowires/tubes, such heterostructures demonstrate an improved photocatalytic activity over individual moieties. Synthetic conditions such as hydrothermal temperatures for the preparation of TiO2-B and the weight ratio of TiO2-B to urea were systematically investigated. A high crystallinity of TiO2-B as well as the proper growth of g-C3N4 on its surface are critical factors for a better performance. Our simple synthetic method and the prolonged lifetime of photo-generated charges signify the importance of type-II heterostructures in the photocatalytic applications.

  2. Ectopic Cushing syndrome secondary to metastatic medullary thyroid cancer in a child with multiple endocrine neoplasia syndrome type 2B: clues to early diagnosis of the paraneoplastic syndromes.

    Science.gov (United States)

    Singer, Kanakadurga; Heiniger, Nicholas; Thomas, Inas; Worden, Francis P; Menon, Ram K; Chen, Ming

    2014-09-01

    We describe a 13-year-old male with multiple endocrine neoplasia syndrome type 2B with medullary thyroid carcinoma who was diagnosed with ectopic adrenocorticotropin-dependent Cushing syndrome. This report highlights the importance of monitoring for paraneoplastic syndrome in MEN and clues to the diagnosis of this complication provided by growth patterns.

  3. Genetic analysis of the phenobarbital regulation of the cytochrome P-450 2b-9 and aldehyde dehydrogenase type 2 mRNAs in mouse liver.

    OpenAIRE

    Damon, M.; Fautrel, A; Guillouzo, A.; Corcos, L.

    1996-01-01

    The aim of this study was to investigate the effect of the genetic background on the phenobarbital inducibility of cytochrome P-450 2b-9, cytochrome P-450 2b-10 and aldehyde dehydrogenase type 2 mRNAs in mice. We analysed the basal expression and the phenobarbital inducibility of both cytochrome P-450 mRNAs by semi-quantitative specific reverse transcription-PCR analyses in five inbred mouse strains (A/J,BALB/cByJ,C57BL/6J, DBA/2J and SWR/J). Male mice constitutively expressed cytochrome P-45...

  4. Alkylated indacenodithieno[3,2-b]thiophene-based all donor ladder-type conjugated polymers for organic thin film transistors

    KAUST Repository

    Lu, Rimei

    2018-01-29

    We report the synthesis of a series of indacenodithieno[3,2-b]thiophene (IDTT) based conjugated polymers by copolymerization with three different electron rich co-monomers [thiophene (T), thieno[3,2-b]thiophene (TT) and dithieno[3,2-b:2\\',3\\'-d]thiophene (DTT)] under Stille coupling conditions. The resulting all-donor polymers show very good solubility in common solvents and exhibit similar optical, thermal and electronic properties. However, the performance of these semiconductors in thin film transistor devices varied and was highly dependent on the nature of the co-monomer. All polymers exhibited unipolar p-type charge transport behaviour, with the mobility values following the trend of IDTT-TT>IDTT-DTT>IDTT-T. The peak saturation mobility value of IDTT-TT was extracted to be 1.1 cm2V-1s-1, amongst the highest mobility for all-donor conjugated polymers reported to date.

  5. Endemic polycythemia in Russia: mutation in the VHL gene.

    Science.gov (United States)

    Ang, Sonny O; Chen, Hua; Gordeuk, Victor R; Sergueeva, Adelina I; Polyakova, Lydia A; Miasnikova, Galina Y; Kralovics, Robert; Stockton, David W; Prchal, Josef T

    2002-01-01

    Chuvash polycythemia (CP) is an autosomal recessive condition that is endemic in the Russian mid-Volga River region of Chuvashia. We previously found that CP patients may have increased serum erythropoietin (EPO) levels, ruled out linkage to both the EPO and EPO receptor (EPOR) gene loci, and hypothesized that the defect may lie in the oxygen homeostasis pathway. We now report a study of five multiplex Chuvash families which confirms that CP is associated with significant elevations of serum EPO levels and rules out a location for the CP gene on chromosome 11 as had been reported by other investigators or a mutation of the HIF-1 alpha gene. Using a genome-wide screen, we localized a region on chromosome 3 with a LOD score >2. After sequencing three candidate genes, we identified a C to T transition at nucleotide 598 (an R200W mutation) in the von Hippel-Lindau (VHL) gene. The VHL protein (pVHL) downregulates the alpha subunit of hypoxia-inducible factor 1 (HIF-1 alpha), the main regulator of hypoxia adaptation, by targeting the protein for degradation. In the simplest scenario, disruption of pVHL function causes a failure to degrade HIF-1 alpha resulting in accumulation of HIF-1 alpha, upregulation of downstream target genes such as EPO, and the clinical manifestation of polycythemia. These findings strongly suggest that CP is a congenital disorder of oxygen homeostasis.

  6. Von Hippel-Lindau disease (vHL)

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Bisgaard, Søs Marie Luise; Harbud, Vibeke

    2013-01-01

    cell carcinoma), the adrenal glands (pheochromocytoma), the pancreas, as well as in other organs. As many different organs can be affected, several medical specialities often take part in both diagnosis and treatment of manifestations. vHL should be suspected in individuals with a family history...

  7. Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B.

    Directory of Open Access Journals (Sweden)

    Soo-Kyung Choi

    Full Text Available Multiple endocrine neoplasia type 2B (MEN2B is a highly aggressive thyroid cancer syndrome. Since almost all sporadic cases are caused by the same nucleotide substitution in the RET proto-oncogene, the calculated disease incidence is 100-200 times greater than would be expected based on the genome average mutation frequency. In order to determine whether this increased incidence is due to an elevated mutation rate at this position (true mutation hot spot or a selective advantage conferred on mutated spermatogonial stem cells, we studied the spatial distribution of the mutation in 14 human testes. In donors aged 36-68, mutations were clustered with small regions of each testis having mutation frequencies several orders of magnitude greater than the rest of the testis. In donors aged 19-23 mutations were almost non-existent, demonstrating that clusters in middle-aged donors grew during adulthood. Computational analysis showed that germline selection is the only plausible explanation. Testes of men aged 75-80 were heterogeneous with some like middle-aged and others like younger testes. Incorporating data on age-dependent death of spermatogonial stem cells explains the results from all age groups. Germline selection also explains MEN2B's male mutation bias and paternal age effect. Our discovery focuses attention on MEN2B as a model for understanding the genetic and biochemical basis of germline selection. Since RET function in mouse spermatogonial stem cells has been extensively studied, we are able to suggest that the MEN2B mutation provides a selective advantage by altering the PI3K/AKT and SFK signaling pathways. Mutations that are preferred in the germline but reduce the fitness of offspring increase the population's mutational load. Our approach is useful for studying other disease mutations with similar characteristics and could uncover additional germline selection pathways or identify true mutation hot spots.

  8. Von Hippel-Lindau disease (vHL)

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Bisgaard, Søs Marie Luise; Harbud, Vibeke

    2013-01-01

    in the VHL gene. vHL is inherited in an autosomal dominant manner. Predisposed individuals are advised to undergo prophylactic examinations, as they are at lifelong risk of developing multiple cysts and tumours, especially in the cerebellum, the spinal cord, the retina (hemangioblastomas), the kidneys (renal...... are recommended to start in infancy with annual paediatric examinations and ophthalmoscopy until the age of five years. From five to 14 years, annual plasma-metanephrine and plasma-normetanephrine tests, as well as annual hearing examinations are added. Also, an MRI (Magnetic Resonance Imaging) examination....../MRI of the abdomen, e) annual plasma-metanephrine, plasma-normetanephrine, and plasma-chromogranin A tests, and f) annual hearing examination at a department of audiology. It is advised that one doctor takes on the responsibility of coordination of and referral to the many examinations, and the communication...

  9. Development of radiotracers for imaging NR2B subtype NMDA receptors with positron emission tomography; Developpement de radiotraceurs pour la visualisation des recepteurs NMDA de sous-type NR2B par tomographie par emission de positons

    Energy Technology Data Exchange (ETDEWEB)

    Labas, R

    2007-07-01

    The aim of this thesis was to develop new radioactive tracers for imaging NR2B subtype NMDA receptors with positron emission tomography. Several compounds including 4-(4-fluoro-benzyl)piperidine and presenting interesting in vivo biological properties were the object of a labelling with a positrons emitter atom ({sup 11}C or {sup 18}F)

  10. Composite paraganglioma-ganglioneuroma concomitant with adrenal metastasis of medullary thyroid carcinoma in a patient with multiple endocrine neoplasia type 2B: A case report.

    Science.gov (United States)

    Yamasaki, Mutsushi; Sato, Yoshiyasu; Nomura, Takeo; Sato, Fuminori; Uchino, Shinya; Mimata, Hiromitsu

    2017-02-01

    Multiple endocrine neoplasia type 2 (MEN2) is an autosomal-dominant cancer syndrome with major components of medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. MEN2B is the most aggressive and rarest of the MEN2 variants. Pheochromocytoma in MEN2 is virtually always located in the adrenal medulla, but MEN2-associated extra-adrenal pheochromocytomas (paraganglioma) are rare. A 59-year-old man who has been diagnosed with MEN2B consulted our hospital for surgical treatment of a 10-mm left adrenal mass and a 30-mm retroperitoneal mass. He had paroxysmal elevations in blood pressure and in urinary metanephrine and vanillylmandelic acid values. Laparoscopic excision of the left adrenal gland and retroperitoneal mass was performed. We experienced an extremely rare case of composite paraganglioma-ganglioneuroma concomitant with adrenal metastasis of medullary thyroid carcinoma in a patient with MEN2B. © 2016 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd.

  11. Phase II trial of pegylated interferon alfa-2b in young patients with neurofibromatosis type 1 and unresectable plexiform neurofibromas.

    Science.gov (United States)

    Jakacki, Regina I; Dombi, Eva; Steinberg, Seth M; Goldman, Stewart; Kieran, Mark W; Ullrich, Nicole J; Pollack, Ian F; Goodwin, Anne; Manley, Peter E; Fangusaro, Jason; Allen, Rudy; Widemann, Brigitte C

    2017-02-01

    There is no proven medical therapy for plexiform neurofibromas (PNs). We undertook a phase II trial of pegylated interferon (PI) to evaluate response and time to progression (TTP). PI was administered as a subcutaneous injection to patients with neurofibromatosis type 1‒related PN, stratified by the presence of symptoms (asymptomatic: stratum 1, symptomatic: stratum 2) or documented imaging progression (stratum 3). Patients in strata 1 and 2 received PI for up to one year if stable, 2 years for those with clinical (stratum 2) or imaging response (≥20% decrease in volume). Patients on stratum 3 continued PI until progression. PI was considered active in stratum 3 if TTP doubled compared with the placebo arm of a previous randomized trial using tipifarnib. Enrolled were 82 evaluable patients (median age 10 y; range 1.6 to 21.4). Fatigue and/or worsening of behavioral issues were the most common toxicities requiring dose modification. Across all strata, imaging responses were seen in 4 patients (5%). Three of 26 symptomatic patients on stratum 2 met the criteria for clinical response without corresponding imaging changes. In stratum 3, median TTP was 29.4 months versus 11.8 for the placebo arm of the previous trial (P=.031). The slope of tumor growth on PI slowed significantly compared with the slope before starting PI (P=.044). In patients with active PN, PI results in more than doubling of the TTP compared with placebo. Imaging changes in symptomatic patients were not associated with changes in clinical status.

  12. Lactobacillus delbrueckii UFV-H2b20 induces type 1 cytokine production by mouse cells in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    E. Neumann

    2009-04-01

    Full Text Available Lactobacillus delbrueckii UFV-H2b20 has been shown to increase clearance of bacteria injected into the blood of germ-free mice. Moreover, it induces the production of type 1 cytokines by human peripheral mononuclear cells. The objective of the present study was to investigate the production of inflammatory cytokines [interleukin-12 (IL-12 p40, tumor necrosis factor-α (TNF-α, and interferon-γ (IFN-γ] triggered in vitro by live, heat-killed or lysozyme-treated L. delbrueckii UFV-H2b20 and in vivo by a live preparation. Germ-free, L. delbrueckii-monoassociated and lipopolysaccharide (LPS-resistant C3H/HeJ mice were used as experimental models. UFV-H2b20 induced the production of IL-12 p40 and TNF-α by peritoneal cells and IFN-γ by spleen cells from germ-free or monoassociated Swiss/NIH mice and LPS-hyporesponsive mice (around 40 ng/mL for IL-12 p40, 200 pg/mL for TNF-α and 10 ng/mL for IFN-γ. Heat treatment of L. delbrueckii did not affect the production of these cytokines. Lysozyme treatment decreased IL-12 p40 production by peritoneal cells from C3H/HeJ mice, but did not affect TNF-α production by these cells or IFN-γ production by spleen cells from the same mouse strain. TNF-α production by peritoneal cells from Swiss/NIH L. delbrueckii-monoassociated mice was inhibited by lysozyme treatment. When testing IL-12 p40 and IFN-γ levels in sera from germ-free or monoassociated Swiss/NIH mice systemically challenged with Escherichia coli we observed that IL-12 p40 was produced at marginally higher levels by monoassociated mice than by germ-free mice (40 vs 60 ng/mL, but IFN-γ was produced earlier and at higher levels by monoassociated mice (monoassociated 4 and 14 ng/mL 4 and 8 h after infection, germfree 0 and 7.5 ng/mL at the same times. These results show that L. delbrueckii UFV-H2b20 stimulates the production of type 1 cytokines in vitro and in vivo, therefore suggesting that L. delbrueckii might have adjuvant properties in infection

  13. Difference in CXCR4 expression between sporadic and VHL-related hemangioblastoma

    NARCIS (Netherlands)

    Kruizinga, Roeliene C; van Marion, Denise M S; den Dunnen, Wilfred F A; de Groot, Jan C; Hoving, Eelco W; Oosting, Sjoukje F; Timmer-Bosscha, Hetty; Derks, Rosalie P H; Cornelissen, Chantal; van der Luijt, Rob B; Links, Thera P; de Vries, Elisabeth G E; Walenkamp, Annemiek M E

    2016-01-01

    Central nervous system hemangioblastomas occur sporadically and in patients with von Hippel-Lindau (VHL) disease due to a VHL germline mutation. This mutation leads to enhanced transcription of chemokine receptor 4 (CXCR4), its ligand (CXCL12) and vascular endothelial growth factor A (VEGFA). We

  14. Prevalence, birth incidence, and penetrance of von Hippel-Lindau disease (vHL) in Denmark

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Galanakis, Michael Carter Bisgaard; Budtz-Jørgensen, Esben

    2017-01-01

    . We further used national health registers to identify individuals who fulfilled the clinical diagnostic vHL criteria based on their registered diagnostic codes, but had not been diagnosed with vHL. We also assessed the medical histories of first-degree relatives to identify familial cases. This study...

  15. Completion of the DNA sequence of mouse adenovirus type 1: sequence of E2B, L1, and L2 (18-51 map units).

    Science.gov (United States)

    Meissner, J D; Hirsch, G N; LaRue, E A; Fulcher, R A; Spindler, K R

    1997-09-01

    The DNA sequence of 9991 nt, corresponding to 18-51 map units of mouse adenovirus type 1 (MAV-1), was determined, completing the sequence of the Larsen strain of MAV-1. The length of the complete MAV-1 genome is 30,946 nucleotides, consistent with previous experimental estimates. The 18-51 map unit region encodes early region 2B proteins necessary for adenoviral replication as well as late region L1 and L2 structural and packaging proteins. Sequence comparison in this region with human adenoviruses indicates broad similarities, including colinear preservation of all recognized open reading frames (ORFs), with highest amino acid identity occurring in the DNA polymerase and polypeptide III (penton base subunit) ORFs. Virus-associated (VA) RNA is not encoded in the region where VA RNAs are found in the human adenoviruses, between E2B and L1, nor is it encoded anywhere in the entire MAV-1 genome. The MAV-1 polypeptide III lacks the arginine-glycine-aspartic acid (RGD) motif which is involved in an association with cell-surface integrins. Only one RGD sequence is found in an identified coding region in the entire MAV-1 genome. Similar to the porcine adenovirus, this RGD sequence is found in the C-terminus of the MAV-1 fiber protein.

  16. Ising-Type Ferromagnetic Ground State Driven by Anisotropic c-f Hybridization in CeRu2Al2B

    Science.gov (United States)

    Matsuno, Haruki; Kotegawa, Hisashi; Matsuoka, Eiichi; Tomiyama, Yo; Sugawara, Hitoshi; Tou, Hideki

    2014-10-01

    The magnetic correlations between Ce 4f electrons and conduction electrons in the new tetragonal compound CeRu2Al2B have been investigated by 27Al nuclear magnetic resonance (NMR). The 27Al NMR spin-lattice relaxation rate 1/T1 exhibits a large magnetic anisotropy for field directions. Within a localized moment picture, the Ce 4f spin-fluctuation rates Γ|| for the c-axis and Γ⊥ for the c-plane are evaluated by taking account of the magnetic anisotropy. The relation of Γ allel ≫ Γ bot , which holds in the entire temperature range, indicates that the c-f hybridization between the ligand conduction electrons and the Ce 4f electrons with the Γ 7(1) crystal electric field ground state is anisotropic. From the temperature dependence of Γ, it is found that the Kondo effect dominates the Ruderman-Kittel-Kasuya-Yosida (RKKY) interaction at high temperatures, whereas below 60 K the RKKY interaction overcomes the Kondo effect and causes the magnetic order. These results indicate that the anisotropic c-f hybridization plays a vital role in realization of the Ising-type ferromagnetic magnetic ground state in CeRu2Al2B.

  17. B2B marketing

    OpenAIRE

    Pospíšilová, Lucie

    2010-01-01

    The main goal of this bachelor thesis is to apply theoretical knowledge in B2B marketing to the example of marketing processes in a particular company, to evaluate the current situation of its activities with regard to B2B principles and to suggest relevant recommendations. The theoretical part focuses on specific characteristics of B2B marketing, describes its differences from marketing on consumer markets, deals with buying behaviour of organizations and specifies particular features of mar...

  18. GRIN2B encephalopathy

    DEFF Research Database (Denmark)

    Platzer, Konrad; Yuan, Hongjie; Schuetz, Hannah

    2017-01-01

    BACKGROUND: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. METHODS: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research c...

  19. THE DEVELOPED RESOURCE DEFINITION OF GAS-INSULATED SWITCH TYPE H G F 100/2 B, C GEC ALSTHOM FOR A FUZZY MODEL

    Directory of Open Access Journals (Sweden)

    S. V. Domoroshchyn

    2016-12-01

    Full Text Available The purpose of the work is the development of fuzzy model gas-insulated switch type HGF 100/2 B,C GEC ALSTHOM to determine the total mined-out resource. Research methods. The study was conducted through expert interviews, that became the basis for the construction of the fuzzy model of gas-insulated circuit breaker to determine the total mined-out resource. This model is implemented in MATLAB Fuzzy Logic Toolbox using the mathematical apparatus of fuzzy sets and fuzzy logic. The obtained results. The authors developed the fuzzy model which obtained the numerical value of the total resource developed gas-insulated circuit breaker with the influence of aggregate factors such as the condition of mechanical and switching systems, the state of arc suppression medium and isolation. Scientific novelty.The authors developed the new fuzzy model of gas-insulated circuit breaker to determine the total developed resource, which uses the information available for measurement or observation. Practical significance. This model is used for gas-insulated switch type GEC ALSTHOM HGF 100/2C operated on the Dnipro HPS-1, ODD-330 kV, cell L -211/1. The developed fuzzy model of assessment of the gas-insulated switch technical condition can be applied to all switches of this type.

  20. Caffeine reduces 11β-hydroxysteroid dehydrogenase type 2 expression in human trophoblast cells through the adenosine A(2B receptor.

    Directory of Open Access Journals (Sweden)

    Saina Sharmin

    Full Text Available Maternal caffeine consumption is associated with reduced fetal growth, but the underlying molecular mechanisms are unknown. Since there is evidence that decreased placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2 is linked to fetal growth restriction, we hypothesized that caffeine may inhibit fetal growth partly through down regulating placental 11β-HSD2. As a first step in examining this hypothesis, we studied the effects of caffeine on placental 11β-HSD2 activity and expression using our established primary human trophoblast cells as an in vitro model system. Given that maternal serum concentrations of paraxanthine (the primary metabolite of caffeine were greater in women who gave birth to small-for-gestational age infants than to appropriately grown infants, we also studied the effects of paraxanthine. Our main findings were: (1 both caffeine and paraxanthine decreased placental 11β-HSD2 activity, protein and mRNA in a concentration-dependent manner; (2 this inhibitory effect was mediated by the adenosine A(2B receptor, since siRNA-mediated knockdown of this receptor prevented caffeine- and paraxanthine-induced inhibition of placental 11β-HSD2; and (3 forskolin (an activator of adenyl cyclase and a known stimulator of 11β-HSD2 abrogated the inhibitory effects of both caffeine and paraxanthine, which provides evidence for a functional link between exposure to caffeine and paraxanthine, decreased intracellular levels of cAMP and reduced placental 11β-HSD2. Taken together, these findings reveal that placental 11β-HSD2 is a novel molecular target through which caffeine may adversely affect fetal growth. They also uncover a previously unappreciated role for the adenosine A(2B receptor signaling in regulating placental 11β-HSD2, and consequently fetal development.

  1. Effects of the GluN2B-NMDA receptor antagonist Ro 25-6981 on two types of behavioral flexibility in rats.

    Science.gov (United States)

    Clark, Emma; Antoniak, Kristen; Feniquito, Alyssandra; Dringenberg, Hans C

    2017-02-15

    Recent evidence has implicated N-methyl-d-aspartate receptors (NMDARs) in several aspects of learning and behavioral flexibility in rodents. Here, we examined the effects of treatment with Ro 25-6981, a selective antagonist of NMDARs containing GluN2B subunits, on two types of behavioral flexibility in rats, spatial reversal learning and set-shifting (spatial vs. motor strategy). To examine spatial reversal learning, rats were trained to swim to a hidden platform in a water maze over four days. On the following day, the platform was moved to a new location in the maze. Administration of Ro 25-6981 (10mg/kg) selectively impaired the early phase of reversal learning, but all rats learned to navigate to the new platform location over 12 trials. To examine set-shifting, independent groups of rats were trained to either swim to a fixed location (spatial strategy) or use a motor response (e.g., "turn left"; motor strategy) to find a hidden escape platform in a cross-shaped water maze apparatus; after task acquisition, rats were trained on the second, novel strategy (set-shift) following treatment with either Ro 25-6981 (10mg/kg) or saline. Administration of Ro 25-6981 had no effect on the ability of rats to perform the set-shift and use the new strategy to locate the escape platform. These results suggest that, in rats, spatial reversal learning, but not set-shifting, is sensitive to Ro-25-6981 treatment. Thus, NMDARs-GluN2B signaling may play a selective role in some forms of behavioral plasticity, particularly for situations involving the updating of information in the spatial domain. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. The co-influence of VWD type 2B/2M mutations in the A1 domain and platelet GPIbα on the rate of cleavage to VWF by ADAMTS13.

    Science.gov (United States)

    Ma, Zhenni; Su, Jian; Zhang, Jingyu; Ling, Jing; Yin, Jie; Bai, Xia; Ruan, Changgeng

    2015-11-01

    In plasma, the size of the von Willebrand factor (VWF) multimer is down-regulated by ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13). The binding of platelets or glycoprotein (GP) Ibα recombinant fragment to VWF domain A1 may increase the cleavage by ADAMTS13 to VWF. Both type 2B and type 2M von Willebrand disease (VWD) result in bleeding disorders with the diathesis of increased and decreased binding affinity between GPIbα and VWF, respectively. However, the influence of 2B/2M VWD mutations in the A1 domain and GPIbα on cleavage by ADAMTS13 to VWF needs further study. Different types of full-length human recombinant VWF (rVWF) were expressed, including three type 2B mutations (P1337L, H1268D, and R1308C), one type 2M mutation (D1302G), and wild type (WT). The three characterized types of rVWF were digested by ADAMTS13 under static conditions or high-shear stress. The interaction of rVWF and ADAMTS13 was also tested by plate-binding assays. Under static (natured) conditions or high-shear stress, type 2B mutants exhibited a higher susceptibility to ADAMTS13 than rVWF-WT, whereas type 2M mutant was normal. While under static (denatured) conditions or high-shear stress (with GPIbα fragment) rVWF-WT showed an even higher susceptibility to ADAMTS13 than the two type 2B mutants studied. Type 2B mutations localized in the A1 domain could enhance the sensitivity to ADAMTS13-mediated proteolysis. When GPIbα participated, there was a dramatically increased proteolytic cleavage of VWF by ADAMTS13 to rVWF-WT, excluding some type 2B mutants. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. The molecular, temporal and region-specific requirements of the beta isoform of Calcium/Calmodulin-dependent protein kinase type 2 (CAMK2B) in mouse locomotion

    OpenAIRE

    Kool, Martijn J.; Jolet E. van de Bree; Bodde, Hanna E.; Ype Elgersma; van Woerden, Geeske M.

    2016-01-01

    Genetic approaches using temporal and brain region-specific restricted gene deletions have provided a wealth of insight in the brain regions and temporal aspects underlying spatial and associative learning. However, for locomotion such extensive studies are still scarce. Previous studies demonstrated that Camk2b ?/? mice, which lack the ? isoform of Calcium/Calmodulin-dependent protein kinase 2 (CAMK2B), show very severe locomotion deficits. However, where these locomotion deficits originate ...

  4. In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4

    Directory of Open Access Journals (Sweden)

    Thi Thanh Hanh Nguyen

    2013-12-01

    Full Text Available The discovery of potent therapeutic compounds against dengue virus is urgently needed. The NS2B-NS3 protease (NS2B-NS3pro of dengue fever virus carries out all enzymatic activities needed for polyprotein processing and is considered to be amenable to antiviral inhibition by analogy. Virtual screening of 300,000 compounds using Autodock 3 on the GVSS platform was conducted to identify novel inhibitors against the NS2B-NS3pro. Thirty-six compounds were selected for in vitro assay against NS2B-NS3pro expressed in Pichia pastoris. Seven novel compounds were identified as inhibitors with IC50 values of 3.9 ± 0.6–86.7 ± 3.6 μM. Three strong NS2B-NS3pro inhibitors were further confirmed as competitive inhibitors with Ki values of 4.0 ± 0.4, 4.9 ± 0.3, and 3.4 ± 0.1 μM, respectively. Hydrophobic and hydrogen bond interactions between amino acid residues in the NS3pro active site with inhibition compounds were also identified.

  5. OsACA6, a P-type 2B Ca(2+) ATPase functions in cadmium stress tolerance in tobacco by reducing the oxidative stress load.

    Science.gov (United States)

    Shukla, Devesh; Huda, Kazi Md Kamrul; Banu, Mst Sufara Akhter; Gill, Sarvajeet Singh; Gill, Sarvjeet Singh; Tuteja, Renu; Tuteja, Narendra

    2014-10-01

    The present study demonstrates the first direct evidence of the novel role of OsACA6 in providing Cd (2+) stress tolerance in transgenic tobacco by maintaining cellular ion homeostasis and modulating ROS-scavenging pathway. Cadmium, a non-essential toxic heavy metal, interferes with the plant growth and development. It reaches the leaves through xylem and may become part of the food chain, thus causing detrimental effects to human health. Therefore, there is an urgent need to develop strategies for engineering plants for Cd(2+) tolerance and less accumulation. The members of P-type ATPases family transport metal ions including Cd(2+), and thus play important role an ion homeostasis. The present study elucidates the role of P-type 2B Ca(2+) ATPase (OsACA6) in Cd(2+) stress tolerance. The transcript levels of OsACA6 were up-regulated upon Cd(2+), Zn(2+) and Mn(2+) exposure. Transgenic tobacco expressing OsACA6 showed tolerance towards Cd(2+) stress as demonstrated by several physiological indices including root length, biomass, chlorophyll, malondialdehyde and hydrogen peroxide content. The roots of the transgenic lines accumulated more Cd(2+) as compared to shoot. Further, confocal laser scanning microscopy showed that Cd(2+) exposure altered Ca(2+) uptake in OsACA6 transgenic plants. OsACA6 expression in tobacco also protected the transgenic plants from oxidative stress by enhancing the activity of enzymatic (SOD, CAT, APX, GR) and non-enzymatic (GSH and AsA) antioxidant machinery. Transgenic lines also tolerated Zn(2+) and Mn(2+) stress; however, tolerance for these ions was not as significant as observed for Cd(2+) exposure. Thus, overexpression of OsACA6 confers Cd(2+) stress tolerance in transgenic lines by maintaining cellular ion homeostasis and modulating reactive oxygen species (ROS)-scavenging pathway. The results of the present study will help to develop strategies for engineering Cd(2+) stress tolerance in economically important crop plants.

  6. Genetic diversity of the VP1/VP2 gene of canine parvovirus type 2b amplified from clinical specimens in Brazil Diversidade genética no gene VP1/VP2 do parvovirus canino tipo 2b amplificado de material clínico no Brasil

    Directory of Open Access Journals (Sweden)

    Cesar A. D. Pereira

    2000-10-01

    Full Text Available We evaluated the genetic diversity in the VP1/VP2 gene of CPV type 2b isolates from symptomatic dogs in Brazil. A total of 21 isolates collected from 1990 through 1995 previously typed as CPV2b by PCR assay were studied. Overall we found a high degree of similarity among sequences from different CPV clinical isolates collected. Genetic analysis of this selected region gave no indication of a specific Brazilian parvovirus lineage.Neste estudo foi avaliada a diversidade genética no gene VP1/VP2 do parvovírus canino tipo 2b a partir de amostras isoladas de cães sintomáticos no Brasil. Foram estudadas 21 amostras coletadas no período de 1990 à 1995, previamente caracterizadas como CPV 2b pela técnica de PCR. Observou-se alto grau de similaridade entre as seqüências estudadas e a análise genética da região selecionada não indicou a presença de uma linhagem brasileira específica.

  7. GRIN2B encephalopathy

    DEFF Research Database (Denmark)

    Platzer, Konrad; Yuan, Hongjie; Schütz, Hannah

    2017-01-01

    presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense...... treatment response in the respective patients still remains to be demonstrated. CONCLUSIONS: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment...

  8. The phenotype of polycythemia due to Croatian homozygous VHL (571C>G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C>T:R200W).

    Science.gov (United States)

    Tomasic, Nikica Ljubas; Piterkova, Lucie; Huff, Chad; Bilic, Ernest; Yoon, Donghoon; Miasnikova, Galina Y; Sergueeva, Adelina I; Niu, Xiaomei; Nekhai, Sergei; Gordeuk, Victor; Prchal, Josef T

    2013-04-01

    Mutations of VHL (a negative regulator of hypoxia-inducible factors) have position-dependent distinct cancer phenotypes. Only two known inherited homozygous VHL mutations exist and they cause polycythemia: Chuvash R200W and Croatian H191D. We report a second polycythemic Croatian H191D homozygote distantly related to the first propositus. Three generations of both families were genotyped for analysis of shared ancestry. Biochemical and molecular tests were performed to better define their phenotypes, with an emphasis on a comparison with Chuvash polycythemia. The VHL H191D mutation did not segregate in the family defined by the known common ancestors of the two subjects, suggesting a high prevalence in Croatians, but haplotype analysis indicated an undocumented common ancestor ∼six generations ago as the founder of this mutation. We show that erythropoietin levels in homozygous VHL H191D individuals are higher than in VHL R200W patients of similar ages, and their native erythroid progenitors, unlike Chuvash R200W, are not hypersensitive to erythropoietin. This observation contrasts with a report suggesting that polycythemia in VHL R200W and H191D homozygotes is due to the loss of JAK2 regulation from VHL R200W and H191D binding to SOCS1. In conclusion, our studies further define the hematologic phenotype of VHL H191D and provide additional evidence for phenotypic heterogeneity associated with the positional effects of VHL mutations.

  9. Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma

    Directory of Open Access Journals (Sweden)

    David A. Rowbotham

    2014-01-01

    Full Text Available Pheochromocytomas (PCC are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A for degradation, thus preventing a hypoxic response. VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described <10% VHL mutation rate cannot account for the high frequency of hypoxic response observed. Indeed, little is known about genetic mechanisms disrupting other complex component genes. Here, we show that, in a panel of 171 PCC tumors, 59.6% harbored gene copy number loss (CNL of at least one complex component. CNL significantly reduced gene expression and was associated with enrichment of gene targets controlled by HIF1. Interestingly, we show that VHL-related renal clear cell carcinoma harbored disruption of VHL alone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation.

  10. Obtaining thin films of compounds of constant composition of the A/sup 2/B/sup 6/ type by the chemical assembly method

    Energy Technology Data Exchange (ETDEWEB)

    Aleskovskii, V.B.; Drozd, V.E.; Gubaidullin, V.I.; Romanychev, A.I.

    1987-05-01

    The chemical assembly method has been developed and studied in the syntesis of oxides of a number of elements on different substrates. The goal of this work was to obtain thin films of the semiconductor compounds ZnS, ZnSe, CdS, and CdSe by this method. As the substrate, the authors used plates of silica, mica, quartz glass, gallium arsenide, sodium chloride. The thickness of the synthesized layers was measured ellipsometrically. The authors simultaneously measured the mass of these layers using piezoelectric resonator weights. The authors determined the thickness of the synthesized layers of the listed compounds A/sup 2/B/sup 6/ as a function of the number of chemical assembly reaction cycles at different temperatures.

  11. Tb{sub 2}Ni{sub 2}Mg{sub 3}: a new structure type derived from the Ru{sub 3}Al{sub 2}B{sub 2} type

    Energy Technology Data Exchange (ETDEWEB)

    Solokha, P. [Ivan Franko National Univ. of Lviv (Ukraine). Dept. of Inorganic Chemistry; De Negri, S.; Saccone, A. [Genova Univ. (Italy). Sezione di Chimica Inorganica e Metallurgia; Pavlyuk, V. [Ivan Franko National Univ. of Lviv (Ukraine). Dept. of Inorganic Chemistry; Jan Dlugosz Univ., Czestochowa (Poland). Inst. of Chemistry and Environment Protection; Marciniak, B. [Jan Dlugosz Univ., Czestochowa (Poland). Inst. of Chemistry and Environment Protection; Tedenac, J.C. [Montpellier II Univ., 34 (France). Lab. de Phisico-chimie de la Matiere Condensee; LPMC UMR CNRS, 34 - Montpellier (France)

    2007-02-15

    Single crystals of diterbium dinickel trimagnesium, Tb{sub 2}Ni{sub 2}Mg{sub 3}, were synthesized from the elements by induction melting. The novel compound crystallizes in the space group Cmmm with one Mg atom of site symmetry mmm and the Tb, Ni and other Mg atom in m2m positions. This ternary compound represents a new structure type that is derived from Ru{sub 3}Al{sub 2}B{sub 2} by way of Wyckoff site distribution. The twolayer structure of Tb{sub 2}Ni{sub 2}Mg{sub 3} is a new representative of a homologous linear structure series of general formula R'{sub k+n}X{sub 2n}R''{sub 200m+k} based on structural fragments of the {alpha}-Fe, CsCl and AlB{sub 2} structure types. The Tb atoms in the structure are enclosed in 17-vertex polyhedra, while rhombododecahedra and distorted rhombododecahedra surround the Mg atoms, and equatorially tricapped trigonal prisms form around the Ni atoms. All interatomic distances indicate metallic type bonding. (orig.)

  12. VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma.

    Science.gov (United States)

    Lessi, Francesca; Mazzanti, Chiara Maria; Tomei, Sara; Di Cristofano, Claudio; Minervini, Andrea; Menicagli, Michele; Apollo, Alessandro; Masieri, Lorenzo; Collecchi, Paola; Minervini, Riccardo; Carini, Marco; Bevilacqua, Generoso

    2014-03-01

    Von Hipple-Lindau gene (VHL) inactivation represents the most frequent abnormality in clear cell renal cell carcinoma (ccRCC). Hypoxia-inducible factor-1α (HIF-1α) expression is regulated by O2 level. In normal O2 conditions, VHL binds HIF-1α and allows HIF-1α proteasomal degradation. A single-nucleotide polymorphism (SNP) has been found located in the oxygen-dependent degradation domain at codon 582 (C1772T, rs11549465, Pro582Ser). In hypoxia, VHL/HIF-1α interaction is abolished and HIF-1α activates target genes in the nucleus. This study analyzes the impact of genetic alterations and protein expression of VHL and the C1772T SNP of HIF-1α gene (HIF-1α) on prognosis in early-stage ccRCC (pT1a, pT1b, and pT2). Mutational analysis of the entire VHL sequence and the genotyping of HIF-1α C1772T SNP were performed together with VHL promoter methylation analysis and loss of heterozygosis (LOH) analysis at (3p25) locus. Data obtained were correlated with VHL and HIF-1α protein expression and with tumor-specific survival (TSS). VHL mutations, methylation status, and LOH were detected in 51, 11, and 12% of cases, respectively. Our results support the association between biallelic alterations and/or VHL silencing with a worse TSS. Moreover, we found a significant association between the HIF-1α C1772C genotype and a worse TSS. The same association was found when testing the presence of HIF-1α protein in the nucleus. Our results highlight the role of VHL/HIF-1α pathway in RCC and support the molecular heterogeneity of early-stage ccRCC. More important, we show the involvement of HIF-1α C1772T SNP in ccRCC progression.

  13. Interferon Alfa-2b Injection

    Science.gov (United States)

    Interferon alfa-2b injection is used to treat a number of conditions.Interferon alfa-2b injection is used alone or in combination ... Hodgkin's lymphoma (NHL; a slow-growing blood cancer). Interferon alfa-2b is in a class of medications called ...

  14. The insertion/deletion variation in the α2B-adrenoceptor does not seem to modify the risk for acute myocardial infarction, but may modify the risk for hypertension in sib-pairs from families with type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Orho-Melander Marju

    2003-11-01

    Full Text Available Abstract Background An insertion/deletion polymorphism in the α2B-adrenoceptor (AR has been associated with the risk for acute myocardial infarction (AMI and sudden cardiac death. In this study we tested whether this polymorphism is associated with the risk for AMI among members of families with type 2 diabetes. Methods 154 subjects with a history of AMI were matched for age and sex with one of their siblings who did not have a history of AMI. The prevalence of the genotypes of the α2B-AR insertion/deletion polymorphism was compared between the siblings using McNemar's test. We also explored the data to see whether this genetic variation affects the risk for hypertension by using logistic regression models in the two subpopulations of subjects, with and without a history of AMI. Results Among all study subjects, 73 (24% carried the α2B-AR deletion/deletion genotype, 103 (33% carried the insertion/insertion genotype, and 132 (43% were heterozygous. The distribution of genotypes of the α2B-AR insertion/deletion variation in the group of subjects with a history of AMI and their phenotype-discordant siblings did not statistically significantly differ from that expected by random distribution (p = 0.52: the deletion/deletion genotype was carried by 34 subjects with AMI (22%, and by 39 subjects without AMI (25%. Neither did we observe any significant difference in deletion allele frequencies of the α2B-AR insertion/deletion polymorphism between patients with a history of AMI (0.44 and their sib-pair controls (0.46, p = 0.65. In an exploratory analysis, the α2B-AR deletion/deletion genotype was associated with increased odds for hypertension compared with subjects carrying any of the other genotypes. Conclusions The deletion/deletion genotype of the α2B-AR does not emerge in this study as a risk factor for AMI among members of families with type 2 diabetes; however, it might be involved in the development of hypertension.

  15. Raman spectra of Cu{sub 2}B{sup II}C{sup IV}X{sub 4}{sup VI} magnetic quaternary semiconductor compounds with tetragonal stannite type structure

    Energy Technology Data Exchange (ETDEWEB)

    Rincón, C., E-mail: crincon@ula.ve; Quintero, M.; Power, Ch.; Moreno, E.; Quintero, E.; Morocoima, M. [Centro de Estudios de Semiconductores, Departamento de Física, Facultad de Ciencias, Universidad de Los Andes, Mérida (Venezuela, Bolivarian Republic of); Henao, J. A.; Macías, M. A. [Grupo de Investigación en Química Estructural, Facultad de Ciencias, Escuela de Química, Universidad Industrial de Santander, Apartado Aéreo 678, Bucaramanga (Colombia)

    2015-05-28

    A comparative study of the Raman spectra of Cu{sub 2}B{sup II}C{sup IV}S{sub 4}{sup VI} and Cu{sub 2}B{sup II}C{sup IV}Se{sub 4}{sup VI}(where B = Mn or Fe) magnetic quaternary semiconductor compounds with stannite-type structure (I4{sup ¯}2m) has been done. Most of the fourteen Raman lines expected for these materials were observed in the spectra. The two strongest lines observed have been assigned to the IR inactive A{sub 1}{sup 1} and A{sub 1}{sup 2} stannite modes that originated from the motion of the S or Se anion around the Cu and C{sup IV} cations remaining at rest. The shift in the frequency of these two lines of about 150 cm{sup −1} to lower energies observed in Cu{sub 2}B{sup II}C{sup IV}Se{sub 4}{sup VI} compounds as compared to those in Cu{sub 2}B{sup II}C{sup IV}S{sub 4}{sup VI} ones, can then be explained as due to the anion mass effect. Based on the fact that values of these frequencies depend mainly on anion mass and bond-stretching forces between nearest-neighbor atoms, the vibrational frequencies v{sup ¯}(A{sub 1}{sup 2}) and v{sup ¯}(A{sub 1}{sup 2}) of both modes for several Cu{sub 2}B{sup II}C{sup IV}X{sub 4}{sup VI} stannite compounds (where X = S, Se, or Te) very close to the experimental data reported for these materials were calculated from a simple model that relates these stretching forces to the anion-cation bond-distances.

  16. A novel subunit vaccine co-expressing GM-CSF and PCV2b Cap protein enhances protective immunity against porcine circovirus type 2 in piglets.

    Science.gov (United States)

    Zhang, Huawei; Qian, Ping; Peng, Bo; Shi, Lin; Chen, Huanchun; Li, Xiangmin

    2015-05-15

    Porcine circovirus type 2 (PCV2) causes porcine circovirus-associated disease. Capsid (Cap) protein of PCV2 is the principal immunogenic protein that induces neutralizing antibodies and protective immunity. GM-CSF is an immune adjuvant that enhances responses to vaccines. In this study, recombinant baculoviruses Ac-Cap and Ac-Cap-GM-CSF expressing the Cap protein alone and co-expressing the Cap protein and porcine GM-CSF, respectively, were constructed successfully. The target proteins were analyzed by western blotting and IFA. Further, these proteins were confirmed by electron microscopy, which showed that Cap proteins could self-assemble into virus-like particles having diameters of 17-25nm. Animal experiments showed that pigs immunized with Cap-GM-CSF subunit vaccine showed significantly higher levels of PCV2-specific antibodies and neutralizing antibodies than pigs immunized with the Cap subunit vaccine and a commercial vaccine (Ingelvac CircoFLEX; PGM-CSF subunit vaccine showed significantly higher average daily weight gain after wild-type PCV2 challenge than pigs receiving the other three vaccines (PGM-CSF was a powerful immunoadjuvant for PCV2 subunit vaccines because it enhanced humoral immune response and improved immune protection against PCV2 infection in pigs. Thus, the novel Cap-GM-CSF subunit vaccine has the potential to be used as an effective and safe vaccine candidate against PCV2 infection. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Pancreatic Cancer Stage 2B

    Science.gov (United States)

    ... hyphen, e.g. -historical Searches are case-insensitive Pancreatic Cancer Stage 2B Add to My Pictures View /Download : ... 1500x1200 View Download Large: 3000x2400 View Download Title: Pancreatic Cancer Stage 2B Description: Stage IIB pancreatic cancer; drawing ...

  18. Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution

    DEFF Research Database (Denmark)

    Fisher, Rosalie; Horswell, Stuart; Rowan, Andrew

    2014-01-01

    with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies......Background : Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution. Results : We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient...... are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient...

  19. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL

    DEFF Research Database (Denmark)

    Staller, Peter; Sulitkova, Jitka; Lisztwan, Joanna

    2003-01-01

    Organ-specific metastasis is governed, in part, by interactions between chemokine receptors on cancer cells and matching chemokines in target organs. For example, malignant breast cancer cells express the chemokine receptor CXCR4 and commonly metastasize to organs that are an abundant source...... regulates CXCR4 expression owing to its capacity to target hypoxia-inducible factor (HIF) for degradation under normoxic conditions. This process is suppressed under hypoxic conditions, resulting in HIF-dependent CXCR4 activation. An analysis of clear cell renal carcinoma that manifests mutation of the VHL...... gene in most cases revealed an association of strong CXCR4 expression with poor tumour-specific survival. These results suggest a mechanism for CXCR4 activation during tumour cell evolution and imply that VHL inactivation acquired by incipient tumour cells early in tumorigenesis confers not only...

  20. VHL negatively regulates SARS coronavirus replication by modulating nsp16 ubiquitination and stability.

    Science.gov (United States)

    Yu, Xiao; Chen, Shuliang; Hou, Panpan; Wang, Min; Chen, Yu; Guo, Deyin

    2015-04-03

    Eukaryotic cellular and most viral RNAs carry a 5'-terminal cap structure, a 5'-5' triphosphate linkage between the 5' end of the RNA and a guanosine nucleotide (cap-0). SARS coronavirus (SARS-CoV) nonstructural protein nsp16 functions as a methyltransferase, to methylate mRNA cap-0 structure at the ribose 2'-O position of the first nucleotide to form cap-1 structures. However, whether there is interplay between nsp16 and host proteins was not yet clear. In this report, we identified several potential cellular nsp16-interacting proteins from a human thymus cDNA library by yeast two-hybrid screening. VHL, one of these proteins, was proven to interact with nsp16 both in vitro and in vivo. Further studies showed that VHL can inhibit SARS-CoV replication by regulating nsp16 ubiquitination and promoting its degradation. Our results have revealed the role of cellular VHL in the regulation of SARS-CoV replication. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism.

    Science.gov (United States)

    Dirckx, Naomi; Tower, Robert J; Mercken, Evi M; Vangoitsenhoven, Roman; Moreau-Triby, Caroline; Breugelmans, Tom; Nefyodova, Elena; Cardoen, Ruben; Mathieu, Chantal; Van der Schueren, Bart; Confavreux, Cyrille B; Clemens, Thomas L; Maes, Christa

    2018-02-12

    The skeleton has emerged as an important regulator of systemic glucose homeostasis, with osteocalcin and insulin representing prime mediators of the interplay between bone and energy metabolism. However, genetic evidence indicates that osteoblasts can influence global energy metabolism through additional, as yet unknown, mechanisms. Here, we report that constitutive or postnatally induced deletion of the hypoxia signaling pathway component von Hippel-Lindau (VHL) in skeletal osteolineage cells of mice led to high bone mass as well as hypoglycemia and increased glucose tolerance, not accounted for by osteocalcin or insulin. In vitro and in vivo data indicated that Vhl-deficient osteoblasts displayed massively increased glucose uptake and glycolysis associated with upregulated HIF-target gene expression, resembling the Warburg effect that typifies cancer cells. Overall, the glucose consumption by the skeleton was increased in the mutant mice, as revealed by 18F-FDG radioactive tracer experiments. Moreover, the glycemia levels correlated inversely with the level of skeletal glucose uptake, and pharmacological treatment with the glycolysis inhibitor dichloroacetate (DCA), which restored glucose metabolism in Vhl-deficient osteogenic cells in vitro, prevented the development of the systemic metabolic phenotype in the mutant mice. Altogether, these findings reveal a novel link between cellular glucose metabolism in osteoblasts and whole-body glucose homeostasis, controlled by local hypoxia signaling in the skeleton.

  2. Elevated homocysteine, glutathione and cysteinylglycine concentrations in patients homozygous for the Chuvash polycythemia VHL mutation

    Science.gov (United States)

    Sergueeva, Adelina I.; Miasnikova, Galina Y.; Okhotin, Daniel J.; Levina, Alla A.; Debebe, Zufan; Ammosova, Tatiana; Niu, Xiaomei; Romanova, Elena A.; Nekhai, Sergei; DiBello, Patricia M.; Jacobsen, Donald W.; Prchal, Josef T.; Gordeuk, Victor R.

    2010-01-01

    In Chuvash polycythemia, homozygous von Hippel-Lindau (VHL) 598C>T leads to increased hypoxia inducible factor-1α and 2α, thromboses and lower systemic blood pressures. Circulating homocysteine, glutathione, γ-glutamyltransferase and cysteinylglycine concentrations were higher in 34 VHL598C>T homozygotes than in 37 normal controls and cysteine was lower. Multivariate analysis showed elevated homocysteine independently associated with higher mean systemic blood pressures and elevated glutathione was associated with lower pressures to a similar degree. Among VHL598C>T homozygotes, homocysteine was elevated with low and normal folate concentrations, consistent with a possible defect in the remethylation pathway. The elevated glutathione and γ-glutamyltranserase levels correlated positively with cysteinylglycine, consistent with possible upregulation of a glutathione synthetic enzyme and γ-glutamyltransferase. Cysteinylglycine correlated inversely with cysteine, consistent with possible reduced cysteinyldipeptidase activity. We conclude that up-regulated hypoxia-sensing may influence multiple steps in thiol metabolism. The effects of the resultant elevated levels of homocysteine and glutathione on systemic blood pressure may largely balance each other out. PMID:18223282

  3. Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex.

    Science.gov (United States)

    Cardote, Teresa A F; Gadd, Morgan S; Ciulli, Alessio

    2017-06-06

    Cullin RING E3 ubiquitin ligases (CRLs) function in the ubiquitin proteasome system to catalyze the transfer of ubiquitin from E2 conjugating enzymes to specific substrate proteins. CRLs are large dynamic complexes and attractive drug targets for the development of small-molecule inhibitors and chemical inducers of protein degradation. The atomic details of whole CRL assembly and interactions that dictate subunit specificity remain elusive. Here we present the crystal structure of a pentameric CRL2VHL complex, composed of Cul2, Rbx1, Elongin B, Elongin C, and pVHL. The structure traps a closed state of full-length Cul2 and a new pose of Rbx1 in a trajectory from closed to open conformation. We characterize hotspots and binding thermodynamics at the interface between Cul2 and pVHL-EloBC and identify mutations that contribute toward a selectivity switch for Cul2 versus Cul5 recognition. Our findings provide structural and biophysical insights into the whole Cul2 complex that could aid future drug targeting. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  4. Homology modeling and molecular dynamics simulation of the HIF2α degradation-related HIF2α-VHL complex.

    Science.gov (United States)

    Dong, Xiaotian; Su, Xiaoru; Yu, Jiong; Liu, Jingqi; Shi, Xiaowei; Pan, Qiaoling; Yang, Jinfeng; Chen, Jiajia; Li, Lanjuan; Cao, Hongcui

    2017-01-01

    Hypoxia-inducible factor 2 alpha (HIF2α), prolyl hydroxylase domain protein 2 (PHD2), and the von Hippel Lindau tumor suppressor protein (pVHL) are three principal proteins in the oxygen-sensing pathway. Under normoxic conditions, a conserved proline in HIF2α is hydroxylated by PHD2 in an oxygen-dependent manner, and then pVHL binds and promotes the degradation of HIF2α. However, the crystal structure of the HIF2α-pVHL complex has not yet been established, and this has limited research on the interaction between HIF and pVHL. Here, we constructed a structural model of a 23-residue HIF2α peptide (528-550)-pVHL-ElonginB-ElonginC complex by using homology modeling and molecular dynamics simulations. We also applied these methods to HIF2α mutants (HYP531PRO, F540L, A530 V, A530T, and G537R) to reveal structural defects that explain how these mutations weaken the interaction with pVHL. Homology modeling and molecular dynamics simulations were used to construct a three-dimensional (3D) structural model of the HIF2α-VHL complex. Subsequently, MolProbity, an active validation tool, was used to analyze the reliability of the model. Molecular mechanics energies combined with the generalized Born and surface area continuum solvation (MM-GBSA) and solvated interaction energy (SIE) methods were used to calculate the binding free energy between HIF2a and pVHL, and the stability of the simulation system was evaluated by using root mean square deviation (RMSD) analysis. We also determined the secondary structure of the system by using the definition of secondary structure of proteins (DSSP) algorithm. Finally, we investigated the structural significance of specific point mutations known to have clinical implications. We established a reliable structural model of the HIF2α-pVHL complex, which is similar to the crystal structure of HIF1α in 1LQB. Furthermore, we compared the structural model of the HIF2α-pVHL complex and the HIF2α (HYP531P, F540L, A530V, A530T, and G537

  5. LOSS OF JAK2 REGULATION VIA VHL-SOCS1 E3 UBIQUITIN HETEROCOMPLEX UNDERLIES CHUVASH POLYCYTHEMIA

    Science.gov (United States)

    Russell, Ryan C.; Sufan, Roxana I.; Zhou, Bing; Heir, Pardeep; Bunda, Severa; Sybingco, Stephanie S.; Greer, Samantha N.; Roche, Olga; Heathcote, Samuel A.; Chow, Vinca W.K.; Boba, Lukasz M.; Richmond, Terri D.; Hickey, Michele M.; Barber, Dwayne L.; Cheresh, David A.; Simon, M. Celeste; Irwin, Meredith S.; Kim, William Y.; Ohh, Michael

    2011-01-01

    SUMMARY Chuvash polycythemia (CP) is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the von Hippel-Lindau (VHL) gene whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark features of CP such as hypersensitivity to erythropoietin are unclear. Here, we show that VHL directly binds suppressor of cytokine signalling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated (p)JAK2 for ubiquitin-mediated destruction. In contrast, CP-associated VHL mutants have altered affinity for SOCS1 and fail to engage and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reverses the disease phenotype in vhlR200W/R200W knock-in mice, a model that faithfully recapitulates human CP. These results reveal VHL as a SOCS1-cooperative negative regulator of JAK2 and provide compelling biochemical and preclinical evidence for JAK2- targeted therapy in CP patients. PMID:21685897

  6. Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia.

    Science.gov (United States)

    Russell, Ryan C; Sufan, Roxana I; Zhou, Bing; Heir, Pardeep; Bunda, Severa; Sybingco, Stephanie S; Greer, Samantha N; Roche, Olga; Heathcote, Samuel A; Chow, Vinca W K; Boba, Lukasz M; Richmond, Terri D; Hickey, Michele M; Barber, Dwayne L; Cheresh, David A; Simon, M Celeste; Irwin, Meredith S; Kim, William Y; Ohh, Michael

    2011-06-19

    Chuvash polycythemia is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the VHL (von Hippel-Lindau) gene, whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark abnormalities of Chuvash polycythemia, such as hypersensitivity to erythropoietin, are unclear. Here we show that VHL directly binds suppressor of cytokine signaling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction. In contrast, Chuvash polycythemia-associated VHL mutants have altered affinity for SOCS1 and do not engage with and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reversed the disease phenotype in Vhl(R200W/R200W) knock-in mice, an experimental model that recapitulates human Chuvash polycythemia. These results show that VHL is a SOCS1-cooperative negative regulator of JAK2 and provide biochemical and preclinical support for JAK2-targeted therapy in individuals with Chuvash polycythemia.

  7. pVHL co-ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear-cell renal cell carcinoma

    DEFF Research Database (Denmark)

    Struckmann, K; Mertz, Kd; Steu, S

    2008-01-01

    Loss of pVHL function, characteristic for clear-cell renal cell carcinoma (ccRCC), causes increased expression of CXCR4 chemokine receptor, which triggers expression of metastasis-associated MMP2/MMP9 in different human cancers. The impact of pVHL on MMP2/MMP9 expression and their relationship...

  8. Dicty_cDB: VHL343 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available region, section 4; and merlin (NF2) gene, exons 2 through 16 and complete cds. 34 4.0 3 AC133850 |AC133850.1...ence. 34 4.0 6 AY123429 |AY123429.1 Papio anubis anubis neurofibromatosis type 2

  9. Vhl deletion in renal epithelia causes HIF-1?-dependent, HIF-2?-independent angiogenesis and constitutive diuresis

    OpenAIRE

    Schönenberger, Désirée; Rajski, Michal; Harlander, Sabine; Frew, Ian J

    2016-01-01

    One of the earliest requirements for the formation of a solid tumor is the establishment of an adequate blood supply. Clear cell renal cell carcinomas (ccRCC) are highly vascularized tumors in which the earliest genetic event is most commonly the biallelic inactivation of the VHL tumor suppressor gene, leading to constitutive activation of the HIF-1α and HIF-2α transcription factors, which are known angiogenic factors. However it remains unclear whether either or both HIF-1α or HIF-2α stabili...

  10. The homozygous VHL(D126N) missense mutation is associated with dramatically elevated erythropoietin levels, consequent polycythemia, and early onset severe pulmonary hypertension.

    Science.gov (United States)

    Sarangi, Susmita; Lanikova, Lucie; Kapralova, Katarina; Acharya, Suchitra; Swierczek, Sabina; Lipton, Jeffrey M; Wolfe, Lawrence; Prchal, Josef T

    2014-11-01

    von Hippel-Lindau (VHL) protein is the principal negative regulator of hypoxia sensing mediated by transcription factors. Mutations in exon 3 of the VHL gene lead to Chuvash (VHL(R200W)) and Croatian (VHL(H191D)) polycythemias. Here, we describe an infant of Bangladesh ethnicity with a novel homozygous VHL(D126N) mutation with congenital polycythemia and dramatically elevated erythropoietin (EPO) levels, who developed severe fatal pulmonary hypertension. In contrast to Chuvash polycythemia, erythroid progenitors (BFU-Es) did not reveal a marked EPO hypersensitivity. Further, NF-E2 and RUNX1 transcripts that correlate with BFU-Es EPO hypersensitivity in polycythemic mutations were not elevated. © 2014 Wiley Periodicals, Inc.

  11. A Ladder-type Heteroheptacene 12H-Dithieno[2',3':4,5]thieno[3,2-b:2',3'-h]fluorene Based D-A Copolymer with Strong Intermolecular Interactions toward Efficient Polymer Solar Cells.

    Science.gov (United States)

    Yang, Mingyan; Lau, Tsz-Ki; Xiao, Shengqiang; Gao, Jianhong; Wang, Wei; Lu, Xinhui; Zhang, Shoujie; Wu, Jiansheng; Zhan, Chun; You, Wei

    2017-10-11

    Ladder-type electron-donating units for D-A copolymers applied in polymer solar cells usually comprise multiple tetrahedral carbon bridges bonded with out-of-plane alkyl chains for desirable solubility for device processing. However, molecular packing of resultant copolymers in the solid state and charge transport within devices are also impeded in spite of with multiple fused aromatic backbones. To mitigate this issue, a structurally well-defined ladder-type electron-donating heteroheptacene, 12H-dithieno[2',3':4,5]thieno[3,2-b:2',3'-h]fluorene (DTTF) with an extended conjugated backbone and a single tetrahedral carbon bridge attached with two bulky alkyl chains was designed and synthesized. The copolymerization of DTTF with 4,7-bis(4-hexylthiophen-2-yl)benzo[c][1,2,5]thiadiazole (DTBT) afforded a soluble D-A copolymer (PDTTF-DTBT) with a medium optical band gap of 1.72 eV and low-lying HOMO level at -5.36 eV. PDTTF-DTBT unprecedentedly exhibits strong intermolecular stacking ability and presents preferential face-on orientation on both ZnO and PEDOT:PSS layers. The improved packing order and appropriate phase separation of both the copolymer and PC71BM in the bulk heterojunction blend on the ZnO layer over on the PEDOT:PSS layer lead to much improved power conversion efficiency of ∼8.2% in the inverted solar cell device, among the highest for reported ladder-type D-A copolymers. The research demonstrates that it is an effective method to incorporate a single tetrahedral carbon bridge to the molecular center of a ladder-type heteroacene with heavily extended π-conjugation to prepare D-A copolymers toward highly efficient PSCs.

  12. Microtubular stability affects pVHL-mediated regulation of HIF-1alpha via the p38/MAPK pathway in hypoxic cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Miao Teng

    Full Text Available BACKGROUND: Our previous research found that structural changes of the microtubule network influence glycolysis in cardiomyocytes by regulating the hypoxia-inducible factor (HIF-1α during the early stages of hypoxia. However, little is known about the underlying regulatory mechanism of the changes of HIF-1α caused by microtubule network alternation. The von Hippel-Lindau tumor suppressor protein (pVHL, as a ubiquitin ligase, is best understood as a negative regulator of HIF-1α. METHODOLOGY/PRINCIPAL FINDINGS: In primary rat cardiomyocytes and H9c2 cardiac cells, microtubule-stabilization was achieved by pretreating with paclitaxel or transfection of microtubule-associated protein 4 (MAP4 overexpression plasmids and microtubule-depolymerization was achieved by pretreating with colchicine or transfection of MAP4 siRNA before hypoxia treatment. Recombinant adenovirus vectors for overexpressing pVHL or silencing of pVHL expression were constructed and transfected in primary rat cardiomyocytes and H9c2 cells. With different microtubule-stabilizing and -depolymerizing treaments, we demonstrated that the protein levels of HIF-1α were down-regulated through overexpression of pVHL and were up-regulated through knockdown of pVHL in hypoxic cardiomyocytes. Importantly, microtubular structure breakdown activated p38/MAPK pathway, accompanied with the upregulation of pVHL. In coincidence, we found that SB203580, a p38/MAPK inhibitor decreased pVHL while MKK6 (Glu overexpression increased pVHL in the microtubule network altered-hypoxic cardiomyocytes and H9c2 cells. CONCLUSIONS/SIGNIFICANCE: This study suggests that pVHL plays an important role in the regulation of HIF-1α caused by the changes of microtubular structure and the p38/MAPK pathway participates in the process of pVHL change following microtubule network alteration in hypoxic cardiomyocytes.

  13. The Virtual Observatory Service TheoSSA: Establishing a Database of Synthetic Stellar Flux Standards I. NLTE Spectral Analysis of the DA-Type White Dwarf G191-B2B *,**,***,****

    Science.gov (United States)

    Rauch, T.; Werner, K.; Bohlin, R.; Kruk, J. W.

    2013-01-01

    Hydrogen-rich, DA-type white dwarfs are particularly suited as primary standard stars for flux calibration. State-of-the-art NLTE models consider opacities of species up to trans-iron elements and provide reliable synthetic stellar-atmosphere spectra to compare with observations. Aims. We will establish a database of theoretical spectra of stellar flux standards that are easily accessible via a web interface. Methods. In the framework of the Virtual Observatory, the German Astrophysical Virtual Observatory developed the registered service TheoSSA. It provides easy access to stellar spectral energy distributions (SEDs) and is intended to ingest SEDs calculated by any model-atmosphere code. In case of the DA white dwarf G191-B2B, we demonstrate that the model reproduces not only its overall continuum shape but also the numerous metal lines exhibited in its ultraviolet spectrum. Results. TheoSSA is in operation and contains presently a variety of SEDs for DA-type white dwarfs. It will be extended in the near future and can host SEDs of all primary and secondary flux standards. The spectral analysis of G191-B2B has shown that our hydrostatic models reproduce the observations best at Teff =60 000 +/- 2000K and log g=7.60 +/- 0.05.We newly identified Fe vi, Ni vi, and Zn iv lines. For the first time, we determined the photospheric zinc abundance with a logarithmic mass fraction of -4.89 (7.5 × solar). The abundances of He (upper limit), C, N, O, Al, Si, O, P, S, Fe, Ni, Ge, and Sn were precisely determined. Upper abundance limits of about 10% solar were derived for Ti, Cr, Mn, and Co. Conclusions. The TheoSSA database of theoretical SEDs of stellar flux standards guarantees that the flux calibration of all astronomical data and cross-calibration between different instruments can be based on the same models and SEDs calculated with different model-atmosphere codes and are easy to compare.

  14. Characteristics of scientific production in Special Education in Virtual Health Library (VHL: a bibliometric study

    Directory of Open Access Journals (Sweden)

    Luciana Pizzani

    2010-12-01

    Full Text Available Objective: To characterize, through bibliometric approach, the scientific literature in this Special Education in the databases of the Virtual Health Library (VHL. The VHL is coordinated by BIREME - Specialized Center of the Pan American Health Organization whose objective is to promote the dissemination and use of scientific information in health. Method: The research methodology was performed by observing the following steps: a literature review on education special and bibliometrics, data collection from the site of BIREME about the presence of special education in the databases, organization, processing and bibliometric analysis of data collected using the software MS Excel and Vantage Point. Results: indicators produced allow signal that the predominant language of scientific production was the Portuguese and the majority of records were written individually, the themes addressed were psychology and developmental psychology. Conclusion: These bibliometric indicators characterizing the state of the art of scientific literature in Special Education at the various bases Data Bireme and also showed a field of interconnections between Health Sciences and Special Education.

  15. Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor α

    Science.gov (United States)

    Uematsu, Keiji; Byrne, Stuart D.; Hirano, Mie; Joo-Okumura, Akiko; Nishikimi, Akihiko; Shuin, Taro; Fukui, Yoshinori; Nakatsukasa, Kunio

    2016-01-01

    pVHL, the protein product of the von Hippel-Lindau (VHL) tumor suppressor gene, is a ubiquitin ligase that targets hypoxia-inducible factor α (HIF-α) for proteasomal degradation. Although HIF-α activation is necessary for VHL disease pathogenesis, constitutive activation of HIF-α alone did not induce renal clear cell carcinomas and pheochromocytomas in mice, suggesting the involvement of an HIF-α-independent pathway in VHL pathogenesis. Here, we show that the transcription factor B-Myb is a pVHL substrate that is degraded via the ubiquitin-proteasome pathway and that vascular endothelial growth factor (VEGF)- and/or platelet-derived growth factor (PDGF)-dependent tyrosine 15 phosphorylation of B-Myb prevents its degradation. Mice injected with B-Myb knockdown 786-O cells developed dramatically larger tumors than those bearing control cell tumors. Microarray screening of B-Myb-regulated genes showed that the expression of HIF-α-dependent genes was not affected by B-Myb knockdown, indicating that B-Myb prevents HIF-α-dependent tumorigenesis through an HIF-α-independent pathway. These data indicate that the regulation of B-Myb by pVHL plays a critical role in VHL disease. PMID:27090638

  16. Marketing Optimization for B2B Market

    OpenAIRE

    Kaynova Tatyana V.

    2012-01-01

    The article presents market definition B2B, the necessity to optimize marketing B2B market, provides a system for B2B-marketing and developed stages of its formation. On this basis it was identified key factors of customer loyalty and are the stages of development of loyalty programs for customers market B2B.

  17. The virtual observatory service TheoSSA: Establishing a database of synthetic stellar flux standards. I. NLTE spectral analysis of the DA-type white dwarf G191-B2B

    Science.gov (United States)

    Rauch, T.; Werner, K.; Bohlin, R.; Kruk, J. W.

    2013-12-01

    Context. Hydrogen-rich, DA-type white dwarfs are particularly suited as primary standard stars for flux calibration. State-of-the-art NLTE models consider opacities of species up to trans-iron elements and provide reliable synthetic stellar-atmosphere spectra to compare with observations. Aims: We will establish a database of theoretical spectra of stellar flux standards that are easily accessible via a web interface. Methods: In the framework of the Virtual Observatory, the German Astrophysical Virtual Observatory developed the registered service TheoSSA. It provides easy access to stellar spectral energy distributions (SEDs) and is intended to ingest SEDs calculated by any model-atmosphere code. In case of the DA white dwarf G191-B2B, we demonstrate that the model reproduces not only its overall continuum shape but also the numerous metal lines exhibited in its ultraviolet spectrum. Results: TheoSSA is in operation and contains presently a variety of SEDs for DA-type white dwarfs. It will be extended in the near future and can host SEDs of all primary and secondary flux standards. The spectral analysis of G191-B2B has shown that our hydrostatic models reproduce the observations best at and log g = 7.60 ± 0.05. We newly identified Fe vi, Ni vi, and Zn iv lines. For the first time, we determined the photospheric zinc abundance with a logarithmic mass fraction of -4.89 (7.5 × solar). The abundances of He (upper limit), C, N, O, Al, Si, O, P, S, Fe, Ni, Ge, and Sn were precisely determined. Upper abundance limits of about 10% solar were derived for Ti, Cr, Mn, and Co. Conclusions: The TheoSSA database of theoretical SEDs of stellar flux standards guarantees that the flux calibration of all astronomical data and cross-calibration between different instruments can be based on the same models and SEDs calculated with different model-atmosphere codes and are easy to compare. Based on observations with the NASA/ESA Hubble Space Telescope, obtained at the Space Telescope

  18. 75 FR 30687 - Airworthiness Directives; Turbomeca Arriel 2B1 Turboshaft Engines

    Science.gov (United States)

    2010-06-02

    ... 2B1 Turboshaft Engines AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Final rule. SUMMARY..., Engine Certification Office, FAA, Engine & Propeller Directorate, 12 New England Executive Park... Information The MCAI applies to the ARRIEL 2B1 and 2B1A engines. The ARRIEL 2B1A engine is not type...

  19. Immunogold electron microscopic evidence of differential regulation of GluN1, GluN2A, and GluN2B, NMDA-type glutamate receptor subunits in rat hippocampal CA1 synapses during benzodiazepine withdrawal.

    Science.gov (United States)

    Das, Paromita; Zerda, Ricardo; Alvarez, Francisco J; Tietz, Elizabeth I

    2010-11-01

    Benzodiazepine withdrawal-anxiety is associated with enhanced α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR)-mediated glutamatergic transmission in rat hippocampal CA1 synapses due to enhanced synaptic insertion and phosphorylation of GluA1 homomers. Interestingly, attenuation of withdrawal-anxiety is associated with a reduction in N-methyl-D-aspartate receptor (NMDAR)-mediated currents and subunit expression, secondary to AMPA receptor potentiation. Therefore, in this study ultrastructural evidence for possible reductions in NMDAR GluN1, GluN2A, and GluN2B subunits was sought at CA1 stratum radiatum synapses in proximal dendrites using postembedding immunogold labeling of tissues from rats withdrawn for 2 days from 1-week daily oral administration of the benzodiazepine, flurazepam (FZP). GluN1-immunogold density and the percentage of immunopositive synapses were significantly decreased in tissues from FZP-withdrawn rats. Similar decreases were observed for GluN2B subunits; however, the relative lateral distribution of GluN2B-immunolabeling within the postsynaptic density did not change after BZ withdrawal. In contrast to the GluN2B subunit, the percentage of synapses labeled with the GluN2A subunit antibody and the density of immunogold labeling for this subunit was unchanged. The spatial localization of immunogold particles associated with each NMDAR subunit was consistent with a predominantly postsynaptic localization. The data therefore provide direct evidence for reduced synaptic GluN1/GluN2B receptors and preservation of GluN1/GluN2A receptors in the CA1 stratum radiatum region during BZ withdrawal. Based on collective findings in this benzodiazepine withdrawal-anxiety model, we propose a functional model illustrating the changes in glutamate receptor populations at excitatory synapses during benzodiazepine withdrawal. © 2010 Wiley-Liss, Inc.

  20. Inactivation of Vhl in Osteochondral Progenitor Cells Causes High Bone Mass Phenotype and Protects Against Age-Related Bone Loss in Adult Mice

    Science.gov (United States)

    Weng, Tujun; Xie, Yangli; Huang, Junlan; Luo, Fengtao; Yi, Lingxian; He, Qifen; Chen, Di; Chen, Lin

    2014-01-01

    Previous studies have shown that disruption of von Hippel–Lindau gene (Vhl) coincides with activation of hypoxia-inducible factor α (HIFα) signaling in bone cells and plays an important role in bone development, homeostasis, and regeneration. It is known that activation of HIF1α signaling in mature osteoblasts is central to the coupling between angiogenesis and bone formation. However, the precise mechanisms responsible for the coupling between skeletal angiogenesis and osteogenesis during bone remodeling are only partially elucidated. To evaluate the role of Vhl in bone homeostasis and the coupling between vascular physiology and bone, we generated mice lacking Vhl in osteochondral progenitor cells (referred to as Vhl cKO mice) at postnatal and adult stages in a tamoxifen-inducible manner and changes in skeletal morphology were assessed by micro–computed tomography (µCT), histology, and bone histomorphometry. We found that mice with inactivation of Vhl in osteochondral progenitor cells at the postnatal stage largely phenocopied that of mice lacking Vhl in mature osteoblasts, developing striking and progressive accumulation of cancellous bone with increased microvascular density and bone formation. These were accompanied with a significant increase in osteoblast proliferation, upregulation of differentiation marker Runx2 and osteocalcin, and elevated expression of vascular endothelial growth factor (VEGF) and phosphorylation of Smad1/5/8. In addition, we found that Vhl deletion in osteochondral progenitor cells in adult bone protects mice from aging-induced bone loss. Our data suggest that the VHL-mediated signaling in osteochondral progenitor cells plays a critical role in bone remodeling at postnatal/adult stages through coupling osteogenesis and angiogenesis. © 2014 American Society for Bone and Mineral Research. PMID:23999831

  1. Scope of Internal Marketing in B2B Companies

    OpenAIRE

    Nigam, Niharika

    2007-01-01

    Abstract Previous studies have focused on "internal marketing" from services marketing perspective. There is, therefore, a great dearth of in-depth research on its application to other business types. This research attempts to find the scope of internal marketing in B2B companies. The purpose of this research is to closely examine the elements, their linkage, tools and applications of Internal marketing when applied to B2B settings. Internal marketing, the application of marketing managem...

  2. Rare presentation of familial paraganglioma without evidence of mutation in the SDH, RET and VHL genes: towards further genetic heterogeneity.

    Science.gov (United States)

    Persu, Alexandre; Amyere, Mustapha; Gutierrez-Roelens, Ilse; Rustin, Pierre; Sempoux, Christine; Lecouvet, Frédéric E; Van Beers, Bernard E; Horsmans, Yves; De Plaen, Jean-François; MarcHamoir; Vikkula, Miikka

    2009-01-01

    Mutations in genes encoding succinate dehydrogenase and its anchoring subunits (SDH genes) are at the origin of hereditary head and neck paraganglioma (PGL) and a subset of apparently sporadic pheochromocytoma. We describe a family including three patients harbouring bilateral head and neck PGL diagnosed before 25 years of age. Multiple hypervascular hepatic lesions were subsequently discovered in two of them. In both, liver biopsy confirmed the diagnosis of PGL. In addition, in one patient, MRI disclosed multiple target-like lesions of the spine, highly suggestive of metastatic PGL. Family history was compatible with autosomal dominant inheritance with possible maternal imprinting. Combined single-strand conformation polymorphism and heteroduplex analysis followed by sequencing did not show any mutation of the coding parts of SDHB, SDHC, SDHD, RET or VHL genes. Screening of copy number alterations and loss of heterozygosity in the three affected family members showed no deletion or amplification of the SDH, RET and VHL genes. Furthermore, succinate dehydrogenase activity measured in a liver PGL sample was not significantly decreased in the affected patient as compared with controls, underscoring the exclusion of the SDH genes. To our knowledge, this is the first reported family of hereditary head and neck PGL with metastatic dissemination in the liver and the spine. A large body of evidence supports the absence of mutations in SDH, RET and VHL genes, which suggests the existence of a yet unknown gene at the origin of this particular form of familial PGL.

  3. ERK5/BMK1 Is a Novel Target of the Tumor Suppressor VHL: Implication in Clear Cell Renal Carcinoma12

    Science.gov (United States)

    Arias-González, Laura; Moreno-Gimeno, Inmaculada; del Campo, Antonio Rubio; Serrano-Oviedo, Leticia; Valero, María Llanos; Esparís-Ogando, Azucena; de la Cruz-Morcillo, Miguel Ángel; Melgar-Rojas, Pedro; García-Cano, Jesús; Cimas, Francisco José; Hidalgo, María José Ruiz; Prado, Alfonso; Callejas-Valera, Juan Luis; Nam-Cha, Syong Hyun; Giménez-Bachs, José Miguel; Salinas-Sánchez, Antonio S; Pandiella, Atanasio; del Peso, Luis; Sánchez-Prieto, Ricardo

    2013-01-01

    Extracellular signal-regulated kinase 5 (ERK5), also known as big mitogen-activated protein kinase (MAPK) 1, is implicated in a wide range of biologic processes, which include proliferation or vascularization. Here, we show that ERK5 is degraded through the ubiquitin-proteasome system, in a process mediated by the tumor suppressor von Hippel-Lindau (VHL) gene, through a prolyl hydroxylation-dependent mechanism. Our conclusions derive from transient transfection assays in Cos7 cells, as well as the study of endogenous ERK5 in different experimental systems such as MCF7, HMEC, or Caki-2 cell lines. In fact, the specific knockdown of ERK5 in pVHL-negative cell lines promotes a decrease in proliferation and migration, supporting the role of this MAPK in cellular transformation. Furthermore, in a short series of fresh samples from human clear cell renal cell carcinoma, high levels of ERK5 correlate with more aggressive and metastatic stages of the disease. Therefore, our results provide new biochemical data suggesting that ERK5 is a novel target of the tumor suppressor VHL, opening a new field of research on the role of ERK5 in renal carcinomas. PMID:23730213

  4. ERK5/BMK1 Is a Novel Target of the Tumor Suppressor VHL: Implication in Clear Cell Renal Carcinoma

    Directory of Open Access Journals (Sweden)

    Laura Arias-González

    2013-06-01

    Full Text Available Extracellular signal-regulated kinase 5 (ERK5, also known as big mitogen-activated protein kinase (MAPK 1, is implicated in a wide range of biologic processes, which include proliferation or vascularization. Here, we show that ERK5 is degraded through the ubiquitin-proteasome system, in a process mediated by the tumor suppressor von Hippel-Lindau (VHL gene, through a prolyl hydroxylation-dependent mechanism. Our conclusions derive from transient transfection assays in Cos7 cells, as well as the study of endogenous ERK5 in different experimental systems such as MCF7, HMEC, or Caki-2 cell lines. In fact, the specific knockdown of ERK5 in pVHL-negative cell lines promotes a decrease in proliferation and migration, supporting the role of this MAPK in cellular transformation. Furthermore, in a short series of fresh samples from human clear cell renal cell carcinoma, high levels of ERK5 correlate with more aggressive and metastatic stages of the disease. Therefore, our results provide new biochemical data suggesting that ERK5 is a novel target of the tumor suppressor VHL, opening a new field of research on the role of ERK5 in renal carcinomas.

  5. Identification of Somatic Mutations in the von Hippel–Lindau (VHL Gene in a Patient With Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Wen-Chung Wang

    2009-11-01

    Full Text Available One of the known causal molecular events in renal cell carcinoma is somatic mutation in the von Hippel–Lindau (VHL gene. Our study describes a 51-year-old Taiwanese man who had bilateral renal cell carcinoma. The patient underwent radical nephrectomy without postoperative chemotherapy or radiotherapy, and is still alive after renal transplantation without tumor recurrence after > 5 years. To clarify his predisposition for bilateral tumors, we performed molecular genetic analysis of the VHL gene in this study. Polymerase chain reaction–single-strand conformation polymorphism and direct sequencing were performed on DNA of blood samples and paraffin-embedded tumor specimens from this patient. DNA from peripheral blood lymphocytes tested negative for germline mutations. However, there were two heterozygous alleles in the promoter and 3′ untranslated regions of this gene. Nonetheless, the DNA from his tumors showed loss of heterozygosity (LOH in these two loci. In addition to the LOH, we identified some different somatic mutations in his tumor tissues: C287T and G460A in the right-sided tumor, and G244A and G390A in the left-sided tumor. The possible roles of these genetic polymorphisms and point mutations in his renal tumorigenesis are discussed. This report provides new insights into renal cell carcinoma that result from VHL gene alterations in Taiwan.

  6. Gender-dependent associations of CDKN2A/2B, KCNJ11, POLI, SLC30A8, and TCF7L2 variants with type 2 diabetes in (North African) Tunisian Arabs.

    Science.gov (United States)

    Turki, Amira; Al-Zaben, Ghadeer S; Khirallah, Moncef; Marmouch, Hela; Mahjoub, Touhami; Almawi, Wassim Y

    2014-03-01

    We investigated the impact of gender on T2DM association with confirmed susceptibility loci. CDKN2A/2B rs10811661, KCNJ11 rs5219, and TCF7L2 rs7903146 were associated with T2DM in females, while POLI rs488846 was associated with T2DM among males; the association of SLC30A8 rs13266634 and TCF7L2 rs4506565, rs12243326, and rs12255372 with T2DM was gender-independent. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  7. Role of VHL, HIF1A and SDH on the expression of miR-210: Implications for tumoral pseudo-hypoxic fate.

    Science.gov (United States)

    Merlo, Anna; Bernardo-Castiñeira, Cristóbal; Sáenz-de-Santa-María, Inés; Pitiot, Ana S; Balbín, Milagros; Astudillo, Aurora; Valdés, Nuria; Scola, Bartolomé; Del Toro, Raquel; Méndez-Ferrer, Simón; Piruat, José I; Suarez, Carlos; Chiara, María-Dolores

    2017-01-24

    The hypoxia-inducible factor 1α (HIF-1α) and its microRNA target, miR-210, are candidate tumor-drivers of metabolic reprogramming in cancer. Neuroendocrine neoplasms such as paragangliomas (PGLs) are particularly appealing for understanding the cancer metabolic adjustments because of their associations with deregulations of metabolic enzymes, such as succinate dehydrogenase (SDH), and the von Hippel Lindau (VHL) gene involved in HIF-1α stabilization. However, the role of miR-210 in the pathogenesis of SDH-related tumors remains an unmet challenge. Herein is described an in vivo genetic analysis of the role of VHL, HIF1A and SDH on miR-210 by using knockout murine models, siRNA gene silencing, and analyses of human tumors. HIF-1α knockout abolished hypoxia-induced miR-210 expression in vivo but did not alter its constitutive expression in paraganglia. Normoxic miR-210 levels substantially increased by complete, but not partial, VHL silencing in paraganglia of knockout VHL-mice and by over-expression of p76del-mutated pVHL. Similarly, VHL-mutated PGLs, not those with decreased VHL-gene/mRNA dosage, over-expressed miR-210 and accumulate HIF-1α in most tumor cells. Ablation of SDH activity in SDHD-null cell lines or reduction of the SDHD or SDHB protein levels elicited by siRNA-induced gene silencing did not induce miR-210 whereas the presence of SDH mutations in PGLs and tumor-derived cell lines was associated with mild increase of miR-210 and the presence of a heterogeneous, HIF-1α-positive and HIF-1α-negative, tumor cell population. Thus, activation of HIF-1α is likely an early event in VHL-defective PGLs directly linked to VHL mutations, but it is a late event favored but not directly triggered by SDHx mutations. This combined analysis provides insights into the mechanisms of HIF-1α/miR-210 regulation in normal and tumor tissues potentially useful for understanding the pathogenesis of cancer and other diseases sharing similar underpinnings.

  8. Investigation of Class 2b Trucks

    Energy Technology Data Exchange (ETDEWEB)

    Davis, S.C.

    2002-04-03

    The popularity of trucks in the class 2 category--that is, those with a 6,000 to 10,000 pounds (lbs) gross vehicle weight rating (GVWR)--has increased since the late 1970s/early 1980s. The purpose of this research is to identify and examine vehicles in the upper portion of the class 2 weight range (designated as vehicle class 2b) and to assess their impact. Vehicles in class 2b (8,500-10,000 lbs GVWR) include pickup trucks, sport utility vehicles (SUVs), and large vans (i.e., not minivans). Oak Ridge National Laboratory researched each individual truck model to determine which models were class 2b trucks and arrived at four methodologies to derive sales volumes. Two methods--one for calendar year and one for model year sales--were recommended for producing believable and reliable results. The study indicates that 521,000 class 2b trucks were sold in calendar year 1999--6.4% of sales of all trucks under 10,000 lbs. Eighty-two percent of class 2b trucks sold in 1999 were pickups; one third of class 2b trucks sold in 1999 were diesel. There were 5.8 million class 2b trucks on the road in 2000, which amounts to 7.8% of all trucks under 10,000 lbs. Twenty-four percent of the class 2b truck population is diesel. Estimates show that class 2b trucks account for 8% of annual miles traveled by trucks under 10,000 lbs and 9% of fuel use. Data on class 2b trucks are scarce. As the Tier 2 standards, which apply to passenger vehicles in the 8,500-10,000 lb GVWR category, become effective, additional data on class 2b trucks may become available--not only emissions data, but data in all areas. At the moment, distinguishing class 2b trucks from class 2 trucks in general is a substantial task requiring data on an individual model level.

  9. Differential Tissue-Specific Function of Adora2b in Cardioprotection.

    Science.gov (United States)

    Seo, Seong-wook; Koeppen, Michael; Bonney, Stephanie; Gobel, Merit; Thayer, Molly; Harter, Patrick N; Ravid, Katya; Eltzschig, Holger K; Mittelbronn, Michel; Walker, Lori; Eckle, Tobias

    2015-08-15

    The adenosine A2b receptor (Adora2b) has been implicated in cardioprotection from myocardial ischemia. As such, Adora2b was found to be critical in ischemic preconditioning (IP) or ischemia/reperfusion (IR) injury of the heart. Whereas Adora2b is present on various cells types, the tissue-specific role of Adora2b in cardioprotection is still unknown. To study the tissue-specific role of Adora2b signaling on inflammatory cells, endothelia, or myocytes during myocardial ischemia in vivo, we intercrossed floxed Adora2b mice with Lyz2-Cre(+), VE-cadherin-Cre(+), or myosin-Cre(+) transgenic mice, respectively. Mice were exposed to 60 min of myocardial ischemia with or without IP (four times for 5 min) followed by 120 min of reperfusion. Cardioprotection by IP was abolished in Adora2b(f/f)-VE-cadherin-Cre(+) or Adora2b(f/f)-myosin-Cre(+), indicating that Adora2b signaling on endothelia or myocytes mediates IP. In contrast, primarily Adora2b signaling on inflammatory cells was necessary to provide cardioprotection in IR injury, indicated by significantly larger infarcts and higher troponin levels in Adora2b(f/f)-Lyz2-Cre(+) mice only. Cytokine profiling of IR injury in Adora2b(f/f)-Lyz2-Cre(+) mice pointed toward polymorphonuclear neutrophils (PMNs). Analysis of PMNs from Adora2b(f/f)-Lyz2-Cre(+) confirmed PMNs as one source of identified tissue cytokines. Finally, adoptive transfer of Adora2b(-/-) PMNs revealed a critical role of Adora2b on PMNs in cardioprotection from IR injury. Adora2b signaling mediates different types of cardioprotection in a tissue-specific manner. These findings have implications for the use of Adora2b agonists in the treatment or prevention of myocardial injury by ischemia. Copyright © 2015 by The American Association of Immunologists, Inc.

  10. Kidney Tumor in a von Hippel-Lindau (VHL) Patient With Intensely Increased Activity on 68Ga-DOTA-TATE PET/CT.

    Science.gov (United States)

    Papadakis, Georgios Z; Millo, Corina; Sadowski, Samira M; Bagci, Ulas; Patronas, Nicholas J

    2016-12-01

    Renal and pancreatic cysts and tumors are the most common visceral manifestations of von Hippel-Lindau (VHL) disease, a heritable multisystem cancer syndrome characterized by development of a variety of malignant and benign tumors. We report a case of a VHL patient with multiple renal cystic and complex cystic/solid lesions. The patient underwent Ga-DOTA-TATE-PET/CT showing intensely increased activity by a solid lesion which demonstrated enhancement on both CT and MRI scans, raising high suspicion for malignancy. The presented case indicates application of SSTR-imaging using Ga-DOTA-conjugated peptides in VHL-patients and emphasizes the need for cautious interpretation of renal parenchyma Ga-DOTATATE activity.

  11. Customer Relationship Management in B2B

    OpenAIRE

    VRCHOTA, Tomáš

    2016-01-01

    This thesis is focused on CRM systems for small and medium-sized enterprises operating in the B2B market. The main goal was to identify the needs and possibilities of the use of CRM systems in small and medium-sized enterprises operating in the B2B market and propose the appropriate CRM systems for this target group. Needs of small and medium-sized enterprises were explored by qualitative research by individual structured interviews. In the next part of the thesis I selected 33 CRM systems wh...

  12. 2000 Johnston Site 2B-P

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Underwater Site 2B-P was established at Johnston Atoll by Dr. James Maragos, U.S. Fish & Wildlife Service, on June 30, 2000. With a start point (meter 0) at...

  13. Recombinant adenovirus type 5 HIV gag/pol/nef vaccine in South Africa: unblinded, long-term follow-up of the phase 2b HVTN 503/Phambili study.

    Science.gov (United States)

    Gray, Glenda E; Moodie, Zoe; Metch, Barbara; Gilbert, Peter B; Bekker, Linda-Gail; Churchyard, Gavin; Nchabeleng, Maphoshane; Mlisana, Koleka; Laher, Fatima; Roux, Surita; Mngadi, Kathryn; Innes, Craig; Mathebula, Matsontso; Allen, Mary; McElrath, M Julie; Robertson, Michael; Kublin, James; Corey, Lawrence

    2014-05-01

    The HVTN 503/Phambili study, which assessed the efficacy of the Merck Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine in South Africa, was stopped when futility criteria in the Step study (assessing the same vaccine in the Americas, Caribbean, and Australia) were met. Here we report long-term follow-up data. HVTN 503/Phambili was a double-blind, placebo-controlled, randomised trial that recruited HIV-1 uninfected, sexually active adults aged 18-35 years from five sites in South Africa. Eligible participants were randomly assigned (1:1) by computer-generated random numbers to either vaccine or placebo, stratified by site and sex. Cox proportional hazards models were used to estimate HIV-1 infection in the modified intention-to-treat cohort, all of whom were unmasked early in follow-up. The trial is registered with ClinicalTrials.gov, number NCT00413725 and the South African National Health Research Database, number DOH-27-0207-1539. Between Jan 24, 2007, and Sept 19, 2007, 801 participants (26·7%) of a planned 3000 were randomly assigned (400 to vaccine, 401 to placebo); 216 (27%) received only one injection, 529 (66%) received only two injections, and 56 (7%) received three injections. At a median follow-up of 42 months (IQR 31-42), 63 vaccine recipients (16%) had HIV-1 infection compared with 37 placebo recipients (9%; adjusted HR 1·70, 95% CI 1·13-2·55; p=0·01). Risk for HIV-1 infection did not differ according to the number of vaccinations received, sex, circumcision, or adenovirus type 5 (Ad5) serostatus. Differences in risk behaviour at baseline or during the study, or annualised dropout rate (7·7% [95% CI 6·2-9·5] for vaccine recipients vs 8·8% [7·1-10·7] for placebo recipients; p=0·40) are unlikely explanations for the increased rate of HIV-1 infections seen in vaccine recipients. The increased risk of HIV-1 acquisition in vaccine recipients, irrespective of number of doses received, warrants further investigation to understand the biological

  14. Spectroscopic confirmation of DES12S2b

    Science.gov (United States)

    Cenko, S. B.; Clubb, K. I.; Aldering, G.; Bloom, J. S.; Kim, A.; Nugent, P.; Perlmutter, S.; Thomas, R. C.; Desai, S.; Paech, K.; Smith, R. C.; Kessler, R.; Covarrubias, R. A.; Cane, R.; Fischer, J. A.; Gilhool, S.; Gladney, L.; Gupta, R.; Mosher, J.; Sako, M.; Brown, P. J.; Krisciunas, K.; Marshall, J.; Suntzeff, N.; Campbell, H.; D'Andrea, C.; Nichol, R.; Papadopoulos, A.; Sullivan, M.; March, M.; Smith, M.; Barbary, K.; Bernstein, J. P.; Biswas, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D.; Frieman, J.; Marriner, J.; Wester, W.

    2013-02-01

    We report optical spectroscopy of a supernova candidate discovered by the Dark Energy Survey (ATel #4668). The spectrum (450-960 nm) of DES12S2b was obtained using Deimos on Keck II. A fit of the spectrum with SNID (Blondin & Tonry, 2007, ApJ, 666, 1024) reveals this event to be a Type Ia SN at z=0.37, near maximum light.

  15. WTS-2 b: Too close for comfort?

    Directory of Open Access Journals (Sweden)

    Kovács G.

    2013-04-01

    Full Text Available We report the discovery of WTS-2 b, a typical hot Jupiter in an unusually close 1.02-day orbit to a K-dwarf star. This is the second planet to be discovered in the infrared light curves of the WFCAM Transit Survey (WTS and is only one-and-a-half times the separation from its host star at which is would be destroyed by Roche lobe overflow. The predicted remaining lifetime of the planet is just 38 Myrs, assuming a tidal dissipation quality factor of Q'* = 106. The magnitude of Q'* is largely unconstrained by observations, thus WTS-2 b provides a useful calibration point for theories describing how frictional processes within a host star affect the tidal orbital evolution of its companion giant planets. It is expected that stars with large convective envelopes are more efficient at dissipating the orbital energy of the planet, and WTS-2 b provides an observational constraint in the sparsely populated K-dwarf regime. In addition, despite its relatively faint magnitude, the favourable size ratio of the WTS-2 star-planet system and the predicted hot equilibrium temperature of the planet will make it possible to characterise the planet's atmosphere via secondary eclipse measurements using existing ground-based instrumentation.

  16. B2B oriented on-line applications generator

    OpenAIRE

    Vintilă Bogdan-Cătălin

    2008-01-01

    B2B applications are presented. Quality characteristics of B2B applications are defined. B2B application structure is defined. The application for contracts is developed. The advantages are identified.

  17. To be or not B2B?

    CERN Document Server

    Symons, L J

    2001-01-01

    La question du commerce électronique interentreprises par le web (Business to Business, B2B) est posée actuellement par les grands groupes industriels impliqués dans le commerce mondial. Les prévisions sont imposantes, le B2B atteindra le C.A. de 3000 milliards de dollars en 2003. Les conditions d'accès, la façon de procéder des deux organisateurs (ARIBA et COMMERCE ONE) des plus grandes places de marchés actuelles, sont décrites. La base de l'énorme pyramide est le catalogue électronique multilingue UNSPSC (United Nations Standard Products and Services Classification) et l'organisation ECCMA (Electronic Commerce Code Management Association) qui gère le développement des UNSPSC codes en 8 langues. Dans ce contexte, l'auteur (re)-déclare qu'un des efforts principaux à fournir par le CERN est la création de son propre catalogue électronique. Dans la Division ST, une aide partielle à ce vaste programme pourrait être apportée par la normalisation des codes et désignations des pièces de maint...

  18. Thyrotoxicosis with pegylated interferon alfa-2b.

    Science.gov (United States)

    Lowndes, Sarah A; Asher, Ruth; Middleton, Mark R

    2010-11-01

    Despite adequate surgery, a diagnosis of stage III melanoma carries a high risk of relapse, and hence mortality. Interferon alfa is the only treatment that has currently been shown to alter the natural history of the disease, delaying relapse-free survival, particularly in patients with micrometastatic disease. There is also recent evidence of a prognostic advantage conferred by the development of autoimmune conditions in patients receiving adjuvant interferon therapy. We present the case of a 27-year-old woman with stage IIIa melanoma who was entered into the European Organisation for the Research and Treatment of Cancer 18991 trial of 5-year adjuvant treatment with pegylated interferon (peginterferon) alfa-2b. The patient developed thyrotoxicosis 3 months after commencing treatment, which required treatment with propylthiouracil. The degree of thyrotoxicosis corresponded closely to the dose of peginterferon alfa-2b given. However, in this patient, the hyperthyroidism resolved spontaneously after 4 years when peginterferon treatment was still ongoing. Seven years following the initial diagnosis, the patient has not had disease relapse. Hyperthyroidism is less common than hypothyroidism as a consequence of interferon therapy, and this case is atypical in that it resolved spontaneously during interferon therapy but is in accordance with the recent evidence of a positive association between interferon-associated autoimmunity and prognosis.

  19. Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHL(R200W) mutation (Chuvash polycythemia).

    Science.gov (United States)

    Sable, Craig A; Aliyu, Zakari Y; Dham, Niti; Nouraie, Mehdi; Sachdev, Vandana; Sidenko, Stanislav; Miasnikova, Galina Y; Polyakova, Lydia A; Sergueeva, Adelina I; Okhotin, Daniel J; Bushuev, Vladimir; Remaley, Alan T; Niu, Xiaomei; Castro, Oswaldo L; Gladwin, Mark T; Kato, Gregory J; Prchal, Josef T; Gordeuk, Victor R

    2012-02-01

    Patients with Chuvash polycythemia, (homozygosity for the R200W mutation in the von Hippel Lindau gene (VHL)), have elevated levels of hypoxia inducible factors HIF-1 and HIF-2, often become iron-deficient secondary to phlebotomy, and have elevated estimated pulmonary artery pressure by echocardiography. The objectives of this study were to provide a comprehensive echocardiographic assessment of cardiovascular physiology and to identify clinical, hematologic and cardiovascular risk factors for elevation of tricuspid regurgitation velocity in children and adults with Chuvash polycythemia. This cross-sectional observational study of 120 adult and pediatric VHL(R200W) homozygotes and 31 controls at outpatient facilities in Chuvashia, Russian Federation included echocardiography assessment of pulmonary artery pressure (tricuspid regurgitation velocity), cardiac volume, and systolic and diastolic function, as well as hematologic and clinical parameters. We determined the prevalence and risk factors for elevation of tricuspid regurgitation velocity in this population and its relationship to phlebotomy. The age-adjusted mean ± SE tricuspid regurgitation velocity was higher in VHL(R200W) homozygotes than controls with normal VHL alleles (2.5±0.03 vs. 2.3±0.05 m/sec, P=0.005). The age-adjusted left ventricular diastolic diameter (4.8±0.05 vs. 4.5±0.09 cm, P=0.005) and left atrial diameter (3.4±0.04 vs. 3.2±0.08 cm, P=0.011) were also greater in the VHL(R200W) homozygotes, consistent with increased blood volume, but the elevation in tricuspid regurgitation velocity persisted after adjustment for these variables. Among VHL(R200W) homozygotes, phlebotomy therapy was associated with lower serum ferritin concentration, and low ferritin independently predicted higher tricuspid regurgitation velocity (standardized beta=0.29; P=0.009). Children and adults with Chuvash polycythemia have higher estimated right ventricular systolic pressure, even after adjustment for

  20. Functional characterization of cytochromes P450 2B from the desert woodrat Neotoma lepida

    Energy Technology Data Exchange (ETDEWEB)

    Wilderman, P. Ross, E-mail: pwilderman@ucsd.edu [Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA (United States); Jang, Hyun-Hee [Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA (United States); Malenke, Jael R. [Department of Biology, University of Utah, Salt Lake City, UT (United States); Salib, Mariam; Angermeier, Elisabeth; Lamime, Sonia [Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA (United States); Dearing, M. Denise [Department of Biology, University of Utah, Salt Lake City, UT (United States); Halpert, James R. [Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA (United States)

    2014-02-01

    Mammalian detoxification processes have been the focus of intense research, but little is known about how wild herbivores process plant secondary compounds, many of which have medicinal value or are drugs. cDNA sequences that code for three enzymes of the cytochrome P450 (CYP) 2B subfamily, here termed 2B35, 2B36, and 2B37 have been recently identified from a wild rodent, the desert woodrat (Malenke et al., 2012). Two variant clones of each enzyme were engineered to increase protein solubility and to facilitate purification, as reported for CYP2B enzymes from multiple species. When expressed in Escherichia coli each of the woodrat proteins gave the characteristic maximum at 450 nm in a reduced carbon monoxide difference spectrum but generally expressed at lower levels than rat CYP2B1. Two enzymes, 2B36 and 2B37, showed dealkylation activity with the model substrates 7-ethoxy-4-(trifluoromethyl)coumarin and 7-benzyloxyresorufin, whereas 2B35 was inactive. Binding of the monoterpene (+)-α-pinene produced a Type I shift in the absorbance spectrum of each enzyme. Mutation of 2B37 at residues 114, 262, or 480, key residues governing ligand interactions with other CYP2B enzymes, did not significantly change expression levels or produce the expected functional changes. In summary, two catalytic and one ligand-binding assay are sufficient to distinguish among CYP2B35, 2B36, and 2B37. Differences in functional profiles between 2B36 and 2B37 are partially explained by changes in substrate recognition site residue 114, but not 480. The results advance our understanding of the mechanisms of detoxification in wild mammalian herbivores and highlight the complexity of this system. - Highlights: • Three CYP2B enzymes from Neotoma lepida were cloned, engineered, and expressed. • A mix of catalytic and binding assays yields unique results for each enzyme. • Mutational analysis indicates CYP{sub 2}B substrate recognition remains to be clarified. • Reported N. lepida gene

  1. Neutron diffraction studies of Ho1-xYxNi2B2C compounds

    DEFF Research Database (Denmark)

    Chang, L.J.; Tomy, C.V.; Paul, D.M.K.

    1996-01-01

    Neutron diffraction measurements have been carried out to investigate the nature of magnetic ordering in Ho(1-x)Y(x)Ni(2)B(2)C (x = 0, 0.1 and 0.2) compounds. HoNi(2)B(2)C shows a complex type of magnetic ordering below the superconducting transition, with a commensurate antiferromagnetic ordering...

  2. ONLINE ACQUISITIONS IN B2B MODEL

    Directory of Open Access Journals (Sweden)

    Constantin SASU

    2016-12-01

    Full Text Available Within the present paper, we propose to review some of the main aspects documented by the academic research so far with regard to the online purchasing behaviour in the B2B online environment (more specifically, in the case of the small and medium-sized companies. Preliminary conclusions reveal that, at least in the case studies, the dominant feature is that the geographic delimitation creates a potential obstacle when it comes to applying a general principle governing the small and medium-sized enterprises. Despite this, we consider that some theoretical elements can be acknowledged, elements from which future research can start to develop theories and hypothesis aimed at better explaining the phenomenon. Furthermore, the fact that the studies are rarely involving the same sector, makes it impossible to generalise the process.

  3. Fascin 2b is a component of stereocilia that lengthens actin-based protrusions.

    Directory of Open Access Journals (Sweden)

    Shih-Wei Chou

    Full Text Available Stereocilia are actin-filled protrusions that permit mechanotransduction in the internal ear. To identify proteins that organize the cytoskeleton of stereocilia, we scrutinized the hair-cell transcriptome of zebrafish. One promising candidate encodes fascin 2b, a filamentous actin-bundling protein found in retinal photoreceptors. Immunolabeling of zebrafish hair cells and the use of transgenic zebrafish that expressed fascin 2b fused to green fluorescent protein demonstrated that fascin 2b localized to stereocilia specifically. When filamentous actin and recombinant fusion protein containing fascin 2b were combined in vitro to determine their dissociation constant, a K(d≈0.37 µM was observed. Electron microscopy showed that fascin 2b-actin filament complexes formed parallel actin bundles in vitro. We demonstrated that expression of fascin 2b or espin, another actin-bundling protein, in COS-7 cells induced the formation of long filopodia. Coexpression showed synergism between these proteins through the formation of extra-long protrusions. Using phosphomutant fascin 2b proteins, which mimicked either a phosphorylated or a nonphosphorylated state, in COS-7 cells and in transgenic hair cells, we showed that both formation of long filopodia and localization of fascin 2b to stereocilia were dependent on serine 38. Overexpression of wild-type fascin 2b in hair cells was correlated with increased stereociliary length relative to controls. These findings indicate that fascin 2b plays a key role in shaping stereocilia.

  4. Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology

    DEFF Research Database (Denmark)

    Clayton, Emma L.; Mizielinska, Sarah; Edgar, James R.

    2015-01-01

    in human CHMP2B mutation brain than in neurodegenerative disease or age-matched control brains. These data suggest that lysosomal storage pathology is the major neuronal pathology in FTD caused by CHMP2B mutation. Recent evidence suggests that two other genes associated with FTD, GRN and TMEM106B......Mutations in the charged multivesicular body protein 2B (CHMP2B) cause frontotemporal dementia (FTD). We report that mice which express FTD-causative mutant CHMP2B at physiological levels develop a novel lysosomal storage pathology characterised by large neuronal autofluorescent aggregates....... The aggregates are an early and progressive pathology that occur at 3 months of age and increase in both size and number over time. These autofluorescent aggregates are not observed in mice expressing wild-type CHMP2B, or in non-transgenic controls, indicating that they are a specific pathology caused by mutant...

  5. Telecom 2-B and 2-C (TC2B and TC2C)

    Science.gov (United States)

    Dulac, J.; Alvarez, H.

    1991-01-01

    The DSN (Deep Space Network) mission support requirements for Telecom 2-B and 2-C (TC2B and TC2C) are summarized. These Telecom missions will provide high-speed data link applications, telephone, and television service between France and overseas territories as a follow-on to TC2A. Mission objectives are outlined and the DSN support requirements are defined through the presentation of tables and narratives describing the spacecraft flight profile; DSN support coverage; frequency assignments; support parameters for telemetry, command and support systems; and tracking support responsibility.

  6. Human Papillomavirus 16 E6 Contributes HIF-1α Induced Warburg Effect by Attenuating the VHL-HIF-1α Interaction

    Directory of Open Access Journals (Sweden)

    Yi Guo

    2014-05-01

    Full Text Available Cervical cancer is still one of the leading causes of cancer deaths in women worldwide, especially in the developing countries. It is a major metabolic character of cancer cells to consume large quantities of glucose and derive more energy by glycolysis even in the presence of adequate oxygen, which is called Warburg effect that can be exaggerated by hypoxia. The high risk subtype HPV16 early oncoprotein E6 contributes host cell immortalization and transformation through interacting with a number of cellular factors. Hypoxia-inducible factor 1α (HIF-1α, a ubiquitously expressed transcriptional regulator involved in induction of numerous genes associated with angiogenesis and tumor growth, is highly increased by HPV E6. HIF-1α is a best-known target of the von Hippel-Lindau tumor suppressor (VHL as an E3 ligase for degradation. In the present work, we found that HPV16 E6 promotes hypoxia induced Warburg effect through hindering the association of HIF-1α and VHL. This disassociation attenuates VHL-mediated HIF-1α ubiquitination and causes HIF-1α accumulation. These results suggest that oncoprotein E6 plays a major role in the regulation of Warburg effect and can be a valuable therapeutic target for HPV-related cancer.

  7. Duplication of the VHL and IRAK2 genes in a patient with mental retardation/multiple congenital anomalies, epilepsy and ectomorphic habitus.

    Science.gov (United States)

    Chabchoub, E; Michils, G; Vermeesch, J R; De Cock, P; Lagae, L; Fryns, J P

    2010-01-01

    Partial 3p duplications are very rare. Often they are reported in translocations involving other chromosomes, whereas deletions encompassing the VHL gene in 3p25.3 predispose to Van-Hippel Lindau syndrome. We report here a paternally-inherited microduplication of 3p25.3 detected by array comparative genomic hybridisation (aCGH) in a 17 year-old male patient presenting with mental retardation and multiple congenital anomalies (MR/MCA), epilepsy and ectomorphic habitus. He has no tumour and there is no history of familial cancer. We refined the duplication by Multiplex Ligation-dependent Probe Amplification (MLPA) to a 251 kb region encompassing the VHL and IRAK2 genes. The duplication is likely to be causal. Interestingly, duplication of IRAK2 can cause epilepsy. Disruption of the GHRL gene can explain the ectomorphic habitus. To our knowledge, this is the smallest 3p duplication encompassing the VHL region. Its prognosis is unknown and a long-term follow-up is essential for an early diagnosis of malignancy.

  8. 75 FR 5689 - Airworthiness Directives; Turbomeca Arriel 2B and 2B1 Turboshaft Engines

    Science.gov (United States)

    2010-02-04

    ...-35-AD; Amendment 39-16189; AD 2010-03-06] RIN 2120-AA64 Airworthiness Directives; Turbomeca Arriel 2B... the following new AD: 2010-03-06 Turbomeca: Amendment 39-16189. Docket No. FAA-2009-0889; Directorate...

  9. Effect of the π-conjugation length on the properties and photovoltaic performance of A–π–D–π–A type oligothiophenes with a 4,8-bis(thienylbenzo[1,2-b:4,5-b′]dithiophene core

    Directory of Open Access Journals (Sweden)

    Ni Yin

    2016-08-01

    Full Text Available Benzo[1,2-b:4,5-b′]dithiophene (BDT is an excellent building block for constructing π-conjugated molecules for the use in organic solar cells. In this paper, four 4,8-bis(5-alkyl-2-thienylbenzo[1,2-b:4,5-b′]dithiophene (TBDT-containing A–π–D–π–A-type small molecules (COOP-nHT-TBDT, n = 1, 2, 3, 4, having 2-cyano-3-octyloxy-3-oxo-1-propenyl (COOP as terminal group and regioregular oligo(3-hexylthiophene (nHT as the π-conjugated bridge unit were synthesized. The optical and electrochemical properties of these compounds were systematically investigated. All these four compounds displayed broad absorption bands over 350–600 nm. The optical band gap becomes narrower (from 1.94 to 1.82 eV and the HOMO energy levels increased (from −5.68 to −5.34 eV with the increase of the length of the π-conjugated bridge. Organic solar cells using the synthesized compounds as the electron donor and PC61BM as the electron acceptor were fabricated and tested. Results showed that compounds with longer oligothiophene π-bridges have better power conversion efficiency and higher device stability. The device based on the quaterthiophene-bridged compound 4 gave a highest power conversion efficiency of 5.62% with a VOC of 0.93 V, JSC of 9.60 mA·cm−2, and a FF of 0.63.

  10. PODAAC-QSX12-L2B00

    Data.gov (United States)

    National Aeronautics and Space Administration — This dataset has been superseded by Version 3: http://podaac.jpl.nasa.gov/dataset/QSCAT_LEVEL_2B_OWV_COMP_12 . This QuikSCAT Level 2B dataset contains...

  11. TRUST IN B2B E-MARKETPLACES

    Directory of Open Access Journals (Sweden)

    SEBASTIAN KOT

    2011-01-01

    Full Text Available The paper presents background of B2B exchanges and review of their forms and functionalities. The benefits and fails reasons are noticed. European enterprises interest in B2B trade is next aspect of consideration. Finally, the trust barriers of B2B exchanges are presented.

  12. Component Based System Framework for Dynamic B2B Interaction

    NARCIS (Netherlands)

    Hu jinmin, Jinmin; Grefen, P.W.P.J.

    Business-to-Business (B2B) collaboration is becoming a pivotal way to bring today's enterprises to success in the dynamically changing e-business environment. Though many business-to-business protocols are developed to support B2B interaction, none are generally accepted. A B2B system should support

  13. 7 CFR 301.85-2b - Exempted articles. 1

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 5 2010-01-01 2010-01-01 false Exempted articles. 1 301.85-2b Section 301.85-2b... § 301.85-2b Exempted articles. 1 1 The articles hereby exempted remain subject to applicable restrictions under other quarantines and other provisions of this subpart. (a) The following articles are...

  14. 7 CFR 301.80-2b - Exempted articles. 1

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 5 2010-01-01 2010-01-01 false Exempted articles. 1 301.80-2b Section 301.80-2b....80-2b Exempted articles. 1 1 The articles hereby exempted remain subject to applicable restrictions under other quarantines. (a) The following articles are exempt from the certification and permit and...

  15. H2A and H2B tails are essential to properly reconstitute nucleosome core particles.

    Science.gov (United States)

    Bertin, Aurélie; Durand, Dominique; Renouard, Madalena; Livolant, Françoise; Mangenot, Stéphanie

    2007-11-01

    The conformation of recombinant Nucleosome Core Particles (NCPs) lacking H2A and H2B histone tails (gH2AgH2B) are studied. The migration of these particles in acrylamide native gels is slowed down compared to intact reconstituted NCPs. gH2AgH2B NCPs are also much more sensitive to nuclease digestion than intact NCPs. Small angle X-ray scattering (SAXS) experiments point out that the absence of H2A and H2B tails produces small but significant conformational changes of the octamers conformation (without wrapped DNA), whereas gH2AgH2B NCP conformations are significantly altered. A separation of about 25-30 bp from the core could account for the experimental curves, but other types of DNA superhelix deformation cannot be excluded. The distorted gH2AgH2B octamer may not allow the correct winding of DNA around the core. The absence of the H2A and H2B tails would further prevent the secondary sliding of the DNA around the core and therefore impedes the stabilisation of the particle. Cryo-electron microscopy on the same particles also shows a detachment of DNA portions from the particle core. The effect is even stronger because the vitrification of the samples worsens the instability of gH2AgH2B NCPs.

  16. Emergence of canine parvovirus subtype 2b (CPV-2b) infections in Australian dogs.

    Science.gov (United States)

    Clark, Nicholas J; Seddon, Jennifer M; Kyaw-Tanner, Myat; Al-Alawneh, John; Harper, Gavin; McDonagh, Phillip; Meers, Joanne

    2017-12-16

    Tracing the temporal dynamics of pathogens is crucial for developing strategies to detect and limit disease emergence. Canine parvovirus (CPV-2) is an enteric virus causing morbidity and mortality in dogs around the globe. Previous work in Australia reported that the majority of cases were associated with the CPV-2a subtype, an unexpected finding since CPV-2a was rapidly replaced by another subtype (CPV-2b) in many countries. Using a nine-year dataset of CPV-2 infections from 396 dogs sampled across Australia, we assessed the population dynamics and molecular epidemiology of circulating CPV-2 subtypes. Bayesian phylogenetic Skygrid models and logistic regressions were used to trace the temporal dynamics of CPV-2 infections in dogs sampled from 2007 to 2016. Phylogenetic models indicated that CPV-2a likely emerged in Australia between 1973 and 1988, while CPV-2b likely emerged between 1985 and 1998. Sequences from both subtypes were found in dogs across continental Australia and Tasmania, with no apparent effect of climate variability on subtype occurrence. Both variant subtypes exhibited a classical disease emergence pattern of relatively high rates of evolution during early emergence followed by subsequent decreases in evolutionary rates over time. However, the CPV-2b subtype maintained higher mutation rates than CPV-2a and continued to expand, resulting in an increase in the probability that dogs will carry this subtype over time. Ongoing monitoring programs that provide molecular epidemiology surveillance will be necessary to detect emergence of new variants and make informed recommendations to develop reliable detection and vaccine methods. Copyright © 2017. Published by Elsevier B.V.

  17. Analysis list: Kdm2b [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Kdm2b Embryonic fibroblast,Pluripotent stem cell + mm9 http://dbarchive.bioscienced...bc.jp/kyushu-u/mm9/target/Kdm2b.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Kdm2b.5.tsv http...://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Kdm2b.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Kdm2...b.Embryonic_fibroblast.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Kdm2

  18. Analysis list: Gtf2b [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Gtf2b Blood,Cardiovascular,Liver + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/m...m9/target/Gtf2b.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Gtf2b.5.tsv http://dbarchive.bioscience...dbc.jp/kyushu-u/mm9/target/Gtf2b.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Gtf2b.Blo...od.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Gtf2b.Cardiovascular.t...sv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Gtf2b.Liver.tsv http://dbarchive.biosciencedbc.jp/kyu

  19. Intestinal Npt2b Plays a Major Role in Phosphate Absorption and Homeostasis

    OpenAIRE

    Sabbagh, Yves; O'Brien, Stephen P.; Song, Wenping; Boulanger, Joseph H; Stockmann, Adam; Arbeeny, Cynthia; Schiavi, Susan C.

    2009-01-01

    Intestinal phosphate absorption occurs through both a paracellular mechanism involving tight junctions and an active transcellular mechanism involving the type II sodium-dependent phosphate cotransporter NPT2b (SLC34a2). To define the contribution of NPT2b to total intestinal phosphate absorption, we generated an inducible conditional knockout mouse, Npt2b−/− (Npt2bfl/fl:Cre+/−). Npt2b−/− animals had increased fecal phosphate excretion and hypophosphaturia, but serum phosphate remained unchan...

  20. CYP2B6 rs2279343 polymorphism is associated with smoking cessation success in bupropion therapy.

    Science.gov (United States)

    Tomaz, Paulo Roberto Xavier; Santos, Juliana Rocha; Issa, Jaqueline Scholz; Abe, Tânia Ogawa; Gaya, Patrícia Viviane; Krieger, José Eduardo; Pereira, Alexandre Costa; Santos, Paulo Caleb Júnior Lima

    2015-09-01

    Previous studies suggested that polymorphisms in the CYP2B6 gene (which encodes an isoenzyme that metabolizes bupropion) and in the ANKK1 gene (which is located in the ANKK1/DRD2 gene cluster) might influence response to therapy. Thus, the aim of the present study was to evaluate whether the CYP2B6 and ANKK1 polymorphisms are associated with the response to smoking cessation therapies in patients from a smoking cessation assistance program. The cohort study enrolled 478 smokers who received behavioral counseling and drug therapy (bupropion, nicotine replacement therapy, and/or varenicline). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. Fagerström test for nicotine dependence (FTND) and Issa situational smoking scores were analyzed for nicotine dependence (ND). The ANKK1 rs1800497, CYP2B6*4 (rs2279343), CYP2B6*5 (rs3211371), and CYP2B6*9 (rs3745274) polymorphisms were genotyped by high resolution melting analysis or by restriction fragment length polymorphism. Patients with CYP2B6 rs2279343 wild-type AA genotype had higher success rate (48.0 %) compared with patients carrying AG or GG genotypes (CYP2B6*4 variant) (35.5 %) on bupropion therapy. The AA genotype was associated with higher OR for success during bupropion therapy (OR = 1.92, 95 % CI = 1.08-3.42, p = 0.03) in a multivariate model. We did not observe significant differences in the FTND and Issa scores according to the studied polymorphisms. We showed that patients with CYP2B6*4 (rs2279343) variant had lower success rate with bupropion. Likely, the CYP2B6*4 variant, which leads to a rapid predicted metabolic phenotype for the isoenzyme, influences the pharmacological activity of bupropion. Our finding suggests that CYP2B6*4 may be an important genetic marker for individualized bupropion pharmacotherapy.

  1. PTK2b function during fertilization of the mouse oocyte

    Energy Technology Data Exchange (ETDEWEB)

    Luo, Jinping [Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160 (United States); McGinnis, Lynda K. [Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Carlton, Carol [Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Beggs, Hilary E. [Department of Ophthalmology, University of California, San Francisco, CA (United States); Kinsey, William H., E-mail: wkinsey@kumc.edu [Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

    2014-08-01

    Highlights: • PTK2b is expressed in oocytes and is activated following fertilization. • PTK2b suppression in oocytes prevents fertilization, but not parthenogenetic activation. • PTK2b suppression prevents the oocyte from fusing with or incorporating bound sperm. • PTK2b suppressed oocytes that fail to fertilize do not exhibit calcium oscillations. - Abstract: Fertilization triggers rapid changes in intracellular free calcium that serve to activate multiple signaling events critical to the initiation of successful development. Among the pathways downstream of the fertilization-induced calcium transient is the calcium-calmodulin dependent protein tyrosine kinase PTK2b or PYK2 kinase. PTK2b plays an important role in fertilization of the zebrafish oocyte and the objective of the present study was to establish whether PTK2b also functions in mammalian fertilization. PTK2b was activated during the first few hours after fertilization of the mouse oocyte during the period when anaphase resumption was underway and prior to the pronuclear stage. Suppression of PTK2b kinase activity in oocytes blocked sperm incorporation and egg activation although sperm-oocyte binding was not affected. Oocytes that failed to incorporate sperm after inhibitor treatment showed no evidence of a calcium transient and no evidence of anaphase resumption suggesting that egg activation did not occur. The results indicate that PTK2b functions during the sperm-egg fusion process or during the physical incorporation of sperm into the egg cytoplasm and is therefore critical for successful development.

  2. Haplotypes frequencies of CYP2B6 in Malaysia

    Directory of Open Access Journals (Sweden)

    N Musa

    2012-01-01

    Full Text Available Background: Drugs with complex pharmacology are used in the management of drug use disorder (DUD and HIV/AIDS in Malaysia and in parts of South-East Asia. Their multiethnic populations suggest complexity due to the genetic polymorphism, such as CYP2B6 that metabolizes methadone and anti-retroviral. Aims: Our aim was to explore the genetic polymorphism of CYP2B6 among Malays, Chinese, Indians, and opiate-dependent individuals in Malaysia. Settings and Design: The study utilized DNA from our previous studies on CYPs and new recruitments from opiate-dependent individuals. Materials and Methods: For the new recruitment, after obtaining consent and baseline demography, 5 ml blood was obtained from patients attending methadone maintenance therapy (MMT Clinics. Genomic DNA was extracted using standard methods. 10 nucleotide changes associated with CYP2B6FNx0110, CYP2B6FNx012, CYP2B6FNx0117, CYP2B6FNx0111, CYP2B6FNx018, CYP2B6FNx0114, CYP2B6FNx019, CYP2B6FNx014, CYP2B6FNx016, CYP2B6FNx0127, and CYP2B6FNx0120 were determined using multiplex nested allele-specific PCR. Statistical Analysis: Descriptive statistics were used to summarize demographic data. Differences in allele frequencies between populations were tested using Chi-squared test and were corrected using the Bonferroni test. Results: CYP2B6 polymorphism in Malaysia is variable with trends that suggest an ethnic difference. Reduced activity CYP2B6FNx016 occurred in 13% to 26% among Malays, Chinese, Indians and opiate-dependent individuals. Another ′reduced activity′, CYP2B6FNx012 allele, was found at much lower percentages in the groups. Conclusions: The relative commonness of reduced-activity CYP2B6 alleles in our study called for attention in terms of dosage requirements for MMT and ARV in Malaysia. It also implored follow-up association studies to determine its relevance and consequences in personalized medicine for drug use disorder and HIV/AIDS.

  3. Analysis list: GTF2B [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available GTF2B Blood,Uterus + hg19 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/GT...F2B.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/GTF2B.5.tsv http://dbarchive.biosciencedbc....jp/kyushu-u/hg19/target/GTF2B.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/GTF2B.Blood.tsv,http://dbarchive.bioscience...dbc.jp/kyushu-u/hg19/colo/GTF2B.Uterus.tsv http://dbarchive.bioscience...dbc.jp/kyushu-u/hg19/colo/Blood.gml,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/Uterus.gml ...

  4. Harnessing marketing automation for B2B content marketing

    OpenAIRE

    Järvinen, Joel; Taiminen, Heini

    2016-01-01

    The growing importance of the Internet to B2B customer purchasing decisions has motivated B2B sellers to create digital content that leads potential buyers to interact with their company. This trend has engendered a new paradigm referred to as ‘content marketing.’ This study investigates the organizational processes for developing valuable and timely content to meet customer needs and for integrating content marketing with B2B selling processes. The results of this single case study demonstra...

  5. Impaired Ventilatory and Thermoregulatory Responses to Hypoxic Stress in Newborn Phox2b Heterozygous Knock-Out Mice

    Science.gov (United States)

    Ramanantsoa, Nelina; Matrot, Boris; Vardon, Guy; Lajard, Anne-Marie; Voituron, Nicolas; Dauger, Stéphane; Denjean, André; Hilaire, Gérard; Gallego, Jorge

    2011-01-01

    The Phox2b genesis necessary for the development of the autonomic nervous system, and especially, of respiratory neuronal circuits. In the present study, we examined the role of Phox2b in ventilatory and thermoregulatory responses to hypoxic stress, which are closely related in the postnatal period. Hypoxic stress was generated by strong thermal stimulus, combined or not with reduced inspired O2. To this end, we exposed 6-day-old Phox2b+/− pups and their wild-type littermates (Phox2b+/+) to hypoxia (10% O2) or hypercapnia (8% CO2) under thermoneutral (33°C) or cold (26°C) conditions. We found that Phox2b+/− pups showed less normoxic ventilation (VE) in the cold than Phox2b+/+ pups. Phox2b+/− pups also showed lower oxygen consumption (VO2) in the cold, reflecting reduced thermogenesis and a lower body temperature. Furthermore, while the cold depressed ventilatory responses to hypoxia and hypercapnia in both genotype groups, this effect was less pronounced in Phox2b+/− pups. Finally, because serotonin (5-HT) neurons are pivotal to respiratory and thermoregulatory circuits and depend on Phox2b for their differentiation, we studied 5-HT metabolism using high pressure liquid chromatography, and found that it was altered in Phox2b+/− pups. We conclude that Phox2b haploinsufficiency alters the ability of newborns to cope with metabolic challenges, possibly due to 5-HT signaling impairments. PMID:21977017

  6. Cmv2b-AGO interaction is required for the suppression of RDR-dependent antiviral silencing in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Yuan-Yuan Fang

    2016-08-01

    Full Text Available Using a transient plant system, it was previously found that the suppression of Cucumber mosaic virus (CMV 2b protein relies on its double-strand (ds RNA binding capacity, but it is independent of its interaction with ARGONAUTE (AGO proteins. Thus, the biological meaning of the 2b-AGO interaction in the context of virus infection remains elusive. In this study, we created infectious clones of CMV mutants that expressed the 2b functional domains of dsRNA or AGO binding and tested the effect of these CMV mutants on viral pathogenicity. We found that the mutant CMV2b(1-76 expressing the 2b dsRNA-binding domain exhibited the same virulence as wild-type CMV in infection with either wild-type Arabidopsis or rdr1/6 plants with RDR1- and RDR6-deficient mutations. However, remarkably reduced viral RNA levels and increased virus (vsiRNAs were detected in CMV2b(1-76-infected Arabidopsis in comparison to CMV infection, which demonstrated that the 2b(1-76 deleted AGO-binding domain failed to suppress the RDR1/RDR6-dependent degradation of viral RNAs. The mutant CMV2b(8-111 expressing mutant 2b, in which the N-terminal 7 amino acid (aa was deleted, exhibited slightly reduced virulence, but not viral RNA levels, in both wild-type and rdr1/6 plants, which indicated that 2b retained the AGO-binding activity acquired the counter-RDRs degradation of viral RNAs. The deletion of the N-terminal 7 aa of 2b affected virulence due to the reduced affinity for long dsRNA. The mutant CMV2b(18-111 expressing mutant 2b lacked the N-terminal 17 aa but retained its AGO-binding activity greatly reduced virulence and viral RNA level. Together with the instability of both 2b(18-111-EGFP and RFP-AGO4 proteins when co-expressed in Nicotiana benthamiana leaves, our data demonstrates that the effect of 2b-AGO interaction on counter-RDRs antiviral defense required the presence of 2b dsRNA-binding activity. Taken together, our findings demonstrate that the dsRNA-binding activity of the

  7. VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKC{delta}-driven migration.

    Science.gov (United States)

    Razorenova, Olga V; Finger, Elizabeth C; Colavitti, Renata; Chernikova, Sophia B; Boiko, Alexander D; Chan, Charles K F; Krieg, Adam; Bedogni, Barbara; LaGory, Edward; Weissman, Irving L; Broome-Powell, Marianne; Giaccia, Amato J

    2011-02-01

    A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis in scirrhous and lung adenocarcinomas as well as in prostate cancer. In this study, we established a molecular mechanism linking VHL loss to induction of the CDCP1 gene through the HIF-1/2 pathway in renal cancer. Also, we report that Fyn, which forms a complex with CDCP1 and mediates its signaling to PKCδ, is a HIF-1 target gene. Mechanistically, we found that CDCP1 specifically regulates phosphorylation of PKCδ, but not of focal adhesion kinase or Crk-associated substrate. Signal transduction from CDCP1 to PKCδ leads to its activation, increasing migration of CC-RCC. Furthermore, patient survival can be stratified by CDCP1 expression at the cell surface of the tumor. Taken together, our data indicates that CDCP1 protein might serve as a therapeutic target for CC-RCC.

  8. B2B or Not to Be: Does B2B E-Commerce Increase Labour Productivity?

    OpenAIRE

    Bertschek, Irene; Fryges, Helmut; Kaiser, Ulrich

    2004-01-01

    We implement an endogeneous switching-regression model for labour productivity and firms' decision to use business-to-business (B2B) e-commerce. Our approach allows B2B usage to affect any parameter of the labour productivity equation and to properly take account of strategic complementarities between the input factors and B2B usage. Empirical evidence from 1,394 German firms shows that firms using B2B e-commerce have a significantly higher output elasticity with respect to ICT-investment and...

  9. Mechanochemical synthesis and characterization of pure Co2B ...

    Indian Academy of Sciences (India)

    Cobalt boride (Co 2 B) is a significant transition metal boride having a wide range of usage area due to its high oxidation, abrasion and corrosion resistance as well as its superior electrochemical, magnetic and anisotropicproperties. In this study, pure Co2B nanocrystals were synthesized with Co, B 2 O 3 and Mg as starting ...

  10. Frontotemporal dementia caused by CHMP2B mutations

    DEFF Research Database (Denmark)

    Isaacs, A M; Johannsen, P; Holm, I

    2011-01-01

    CHMP2B mutations are a rare cause of autosomal dominant frontotemporal dementia (FTD). The best studied example is frontotemporal dementia linked to chromosome 3 (FTD-3) which occurs in a large Danish family, with a further CHMP2B mutation identified in an unrelated Belgian familial FTD patient...

  11. ORM-based semantics of B2B transactions.

    NARCIS (Netherlands)

    Balsters, H.; van Blommestein, F.; Meersman, R; Herrero, P; Dillon, T

    2009-01-01

    After widespread implementation of Enterprise Resource Planning and Personal Information Management, the next wave in the application of ICT is headed towards business to business (B2B) communication. B2B has a number of specific aspects, one of them being negotiation. This aspect has been largely

  12. Building Customized University-to-Business (U2B) Partnerships

    Science.gov (United States)

    Irvine, George; Verma, Lisa

    2013-01-01

    Continuing education (CE) units throughout the United States have successfully built University-to-Business (U2B) partnerships to provide greater value to their community partners and to increase revenue for the university. Our experience in building U2B partnerships and feedback from our partners--businesses, corporations, state agencies, and…

  13. PODAAC-RSX12-L2B11

    Data.gov (United States)

    National Aeronautics and Space Administration — This dataset contains the RapidScat Level 2B 12.5km Version 1.1 science-quality ocean surface wind vectors. The Level 2B wind vectors are binned on a 12.5 km Wind...

  14. Genetic and bibliographic information: HTR2B [GenLibi

    Lifescience Database Archive (English)

    Full Text Available HTR2B 5-hydroxytryptamine (serotonin) receptor 2B human alcoholism (MeSH) Disorders... of Environmental Origin (C21) > Substance-Related Disorders (C21.739) > Alcohol-Related Disorders (C21.739.100) > Alcoholism (C21.739.100.250) 01A0634580 ...

  15. PODAAC-QSX25-L2B02

    Data.gov (United States)

    National Aeronautics and Space Administration — This dataset has been superseded by Version 3: http://podaac.jpl.nasa.gov/dataset/QSCAT_LEVEL_2B_OWV_COMP_12 . This QuikSCAT Level 2B dataset contains the Version 2...

  16. Improved Refolding Efficacy of Recombinant Human Interferon α-2b ...

    African Journals Online (AJOL)

    Purpose: To increase the refolding yield of Recombinant Human Interferon α-2b in order to achieve a highly potent product. Methods: Interferon α-2b inclusion body was dissolved in tris-HCl buffer containing 6 M guanidine-HCl and CuSO4. Different refolding buffers were employed for refolding the target protein.

  17. Expression and purification of recombinant Shiga toxin 2B from ...

    African Journals Online (AJOL)

    The two step purification trains were used to purify native Stx2B. First step purification was Ni-immobilized metal ion affinity chromatography (IMAC) column, followed by second step using HaloLink resin. The native Stx2B was obtained after column cleavage of halo-tag using HaloTEV protease. Maximum protein expression ...

  18. Frontotemporal dementia caused by CHMP2B mutations

    DEFF Research Database (Denmark)

    Isaacs, A M; Johannsen, P; Holm, I

    2011-01-01

    CHMP2B mutations are a rare cause of autosomal dominant frontotemporal dementia (FTD). The best studied example is frontotemporal dementia linked to chromosome 3 (FTD-3) which occurs in a large Danish family, with a further CHMP2B mutation identified in an unrelated Belgian familial FTD patient....... These mutations lead to C-terminal truncations of the CHMP2B protein and we will review recent advances in our understanding of the molecular effects of these mutant truncated proteins on vesicular fusion events within the endosome-lysosome and autophagy degradation pathways. We will also review the clinical...... features of FTD caused by CHMP2B truncation mutations as well as new brain imaging and neuropathological findings. Finally, we collate the current data on CHMP2B missense mutations, which have been reported in FTD and motor neuron disease....

  19. Superconductivity in the intermetallic borocarbides YPd2B2C, YPt2B2C and LaPt2B2C

    Science.gov (United States)

    Durajski, A. P.; Paliwoda, M. K.; Szczȩśniak, R.

    2016-11-01

    We report a detailed study of the thermodynamic properties of the conventional phonon-mediated superconductors YPd2B2C, YPt2B2C and LaPt2B2C. Our calculations conducted within the framework of the Migdal-Eliashberg formalism show that the experimental values of the critical temperature cannot be properly reproduced using commonly accepted value of Coulomb pseudopotential. Moreover, we proved that the values of universal ratios of conventional superconductivity appearing in the Bardeen-Copper-Schrieffer (BCS) theory are inconsistent with our results obtained from the investigated borocarbides. The observed differences are connected with the strong/medium-coupling and retardation effects existing in the studied systems.

  20. 75 FR 26681 - Airworthiness Directives; Turbomeca S.A. Arriel 2B and 2B1 Turboshaft Engines

    Science.gov (United States)

    2010-05-12

    ... initial and repetitive borescope inspection of the engine for rearward displacement of the high-pressure... Directives; Turbomeca S.A. Arriel 2B and 2B1 Turboshaft Engines AGENCY: Federal Aviation Administration (FAA... limit axial displacement of the HP blade relative to the disk in case of blade lock rupture or opening...

  1. Current status of BL-2B at photon factory

    Energy Technology Data Exchange (ETDEWEB)

    Nambu, Akira, E-mail: akia.nambu.tw@hitachi.com; Ueda, Kazuhiro [Central Research Laboratory, Hitachi, ltd. 1-280 Higashi-Koigakubo, Kokubunji, Tokyo, 185-8601 (Japan); Horiba, Koji; Tsuchiya, Kimichika; Kumigashira, Hiroshi; Amemiya, Kenta [KEK-PF 1-1 Oho, Tsukuba, Ibaraki, 305-0801 (Japan)

    2016-07-27

    A new soft x-ray beamline BL-2B at Photon Factory of High Energy Accelerator Research Organization (KEK-PF) covers energy range from vacuum ultraviolet (30 eV) to soft x-ray (4000 eV). This wide energy range could be achieved by employing two undulators and two monochromators. Two different energy range undulators were installed tandem to a 9-meter straight section of PF storage ring. The 1{sup st} undulator is for VUV (30 eV) to SX (280 eV), while the other one is for SX (280 eV) to HX (4000 eV). It is also necessary to be equipped with two different monochrometors for energy above and under 2000 eV; grating monochrometor and double crystal monochrometor. One of the main purposes of this bemaline is spectroscopic study of light elements contained in several functional materials. The beamline is designed for photoemission spectroscopy (PES), X-ray absorption fine structure (XAFS) and other types of experiments. The performance of the new beamline is reported and typical examples of its application to material science are demonstrated.

  2. Phenotypic and Transcriptomic Analysis of Nicotiana benthamiana Expressing Cucumber mosaic virus 2b gene

    Directory of Open Access Journals (Sweden)

    Seong-Han Sohn

    2015-09-01

    Full Text Available Cucumber mosaic virus possesses 2b gene known as a suppressor of post-transcriptional gene silencing (PTGS. To investigate its function and effect in plant, transgenic Nicotiana benethamiana expressing 2b gene was developed and analyzed in phenotypic characteristics and differential gene expression (DEG comparing with wild-type. Eight lines of transgenic plants (T0 were obtained with difficulty and showed severe deformed phenotypes in leaves, flowers, petioles and etc. Moreover, transgenic plants were hardly able to set seeds, but small amounts of seeds were barely produced in some of transgene-hemizygous plants. DEG analysis showed that transgenic plant ectopically accumulated diverse RNA transcripts at higher levels than wild-type probably due to the disturbance in RNA metabolism, especially of RNA decay, caused by 2b-mediated inhibition of PTGS. These ectopic accumulations of RNAs disrupt protein and RNA homeostasis and then subsequently lead to abnormal phenotypes of transgenic plants.

  3. Pharmacokinetics of interferon alpha-2b in healthy volunteers.

    Science.gov (United States)

    Radwanski, E; Perentesis, G; Jacobs, S; Oden, E; Affrime, M; Symchowicz, S; Zampaglione, N

    1987-01-01

    In a three-way crossover design, 12 healthy male volunteers received 5 X 10(6) IU/m2 body surface area interferon alpha-2b(IFN alpha-2b) by intravenous (IV) infusion over 30 minutes, intramuscular (IM) injections, and subcutaneous (SC) injections. Blood and urine samples were collected at specified times, and analysis of IFN alpha-2b concentrations was performed by immunoradiometric assay. "Flulike" symptoms were the most frequently reported adverse experiences and were independent of the route of administration. After a 30-minute IV infusion, IFN alpha-2b disappeared rapidly from serum, with distribution and elimination phase half-lives of 0.1 hour and 1.7 hours, respectively. Interferon alpha-2b was absorbed slowly after IM and SC administration, with similar absorption half-lives of 5.8 and 5.5 hours, respectively. The observed maximal concentrations after IM and SC administration were 42.1 IU/mL at six hours and 45.8 IU/mL at eight hours, respectively. Interferon alpha-2b was eliminated with half-lives of 2.2 hours after IM administration and 2.9 hours after SC administration. The areas under the serum concentration-time curves for the SC and IM doses were higher than those obtained for the IV infusion. Measurable amounts of IFN alpha-2b were not found in urine regardless of the route of administration.

  4. Applying conceptual design to B2B sales negotiations

    DEFF Research Database (Denmark)

    Illi, Mikko; Ylirisku, Salu

    This paper addresses the challenge of perceiving B2B sales negotiation in a manner that would open up new possibilities for the improvement of the practice. B2B sales agents work under high pressure in developing relevant and appealing proposals when negotiating for a deal with a customer. The key...... problem that will be addressed is the building of understanding of a customer’s current needs and requirements, and then trying to devise an appropriate proposal to match these. The work of the sales agents in B2B sales negotiations is highly complex, as they need to understand both the modular machinery...... on the ways in which design sense making artefacts may drive also B2B sales agents’ work....

  5. PODAAC-RSX12-L2B12

    Data.gov (United States)

    National Aeronautics and Space Administration — This dataset contains the RapidScat Level 2B 12.5km Version 1.2 science-quality ocean surface wind vectors, which are intended as a replacement and continuation of...

  6. B2B Models for DoD Acquisition

    National Research Council Canada - National Science Library

    Kamel, Magdi N

    2008-01-01

    A central vision of B2B e-commerce is that of an electronic marketplace that would bring suppliers together with major buyers of goods and services for the purpose of conducting "frictionless commerce...

  7. PODAAC-RSX12-L2B13

    Data.gov (United States)

    National Aeronautics and Space Administration — This dataset contains the RapidScat Level 2B 12.5km Version 1.3 science-quality ocean surface wind vectors, which are intended as a replacement and continuation of...

  8. PODAAC-QSX12-L2B31

    Data.gov (United States)

    National Aeronautics and Space Administration — This dataset contains the latest reprocessed version 3.1 of the Level 2B science-quality ocean surface wind vector retrievals from the QuikSCAT scatterometer. The...

  9. PODAAC-QSX12-L2B01

    Data.gov (United States)

    National Aeronautics and Space Administration — This dataset contains the latest reprocessed version 3 of the Level 2B science-quality ocean surface wind vector retrievals from the QuikSCAT scatterometer. The...

  10. Synthesis and reactivity of dimolybdathiaborane cluster [(Cp Mo) 2 B ...

    Indian Academy of Sciences (India)

    Chemistry and reactivity of dimolybdathiaborane, [(Cp∗Mo)2B4SH6], 1, obtained from the reaction of 2-mercaptobenzothiazole, [Cp∗MoCl4] and [LiBH4.thf], has been explored with dinuclear metal carbonyl [Fe2(CO)9]. As a result, reaction of 1 with [Fe2(CO)9] yielded heterometallathiaborane, [(Cp∗Mo)2B4H6SFe(CO)3], ...

  11. PTK2b function during fertilization of the mouse oocyte.

    Science.gov (United States)

    Luo, Jinping; McGinnis, Lynda K; Carlton, Carol; Beggs, Hilary E; Kinsey, William H

    2014-08-01

    Fertilization triggers rapid changes in intracellular free calcium that serve to activate multiple signaling events critical to the initiation of successful development. Among the pathways downstream of the fertilization-induced calcium transient is the calcium-calmodulin dependent protein tyrosine kinase PTK2b or PYK2 kinase. PTK2b plays an important role in fertilization of the zebrafish oocyte and the objective of the present study was to establish whether PTK2b also functions in mammalian fertilization. PTK2b was activated during the first few hours after fertilization of the mouse oocyte during the period when anaphase resumption was underway and prior to the pronuclear stage. Suppression of PTK2b kinase activity in oocytes blocked sperm incorporation and egg activation although sperm-oocyte binding was not affected. Oocytes that failed to incorporate sperm after inhibitor treatment showed no evidence of a calcium transient and no evidence of anaphase resumption suggesting that egg activation did not occur. The results indicate that PTK2b functions during the sperm-egg fusion process or during the physical incorporation of sperm into the egg cytoplasm and is therefore critical for successful development. Published by Elsevier Inc.

  12. [Eukaryotic translation initiation factor 2B and leukoencephalopathy with vanishing white matter].

    Science.gov (United States)

    Pan, Yan Xia; Wu, Ye; Niu, Zheng Ping; Jiang, Yu Wu

    2009-10-18

    Leukoencephalopathy with vanishing white matter (VWM) is one of the most prevalent inherited white matter disorders in childhood, and it's the only known hereditary human disease due to the direct defects in protein synthesis process, with the gene defects in EIF2B1-5, encoding the five subunits of eukaryotic translation initiation factor (eIF2B alpha, beta, gamma, delta and epsilon ) respectively. eIF2B is essential for the protein translation initiation process, and its action is realized via eukaryotic translation initiation factor2 (eIF2). Phosphorylation of eIF2alpha and eIF2Bepsilon is an important way to regulate eIF2B function, and thus play a key role in control of the protein translation level under physiological condition. Mutant eIF2B results in functional defects and decrease of the overall protein translation in cells, but in increase the translation of proteins with multiple upstream open reading frames, such as activating transcription factor 4 (AFT4), which leads to the susceptibility to unfolded protein response under stress, and the following apoptosis. The exact pathogenic mechanisms of VWM are far from well understood. It's suggested that level of AFT4 in cells with eIF2B mutations is higher than in wild type cells under physiological condition, which makes the mutant cells more susceptible to endoplasmic reticulum (ER) stress and unfolded protein response (UPR). Under stress, the defect eIF2B leads to a vicious cycle of UPR activation, which may underlie the neurological aggravation in VWM patients after minor stress, a specific clinical feature of VWM. Elucidating the pathogenesis of VWM will be helpful to further understand the protein translation process in eukaryotic cells, and provide a clue for possible therapeutic targets and treatment strategies in the future.

  13. Synthesis of 9H-Indeno [1, 2-b] Pyrazine and 11H-Indeno [1, 2-b ...

    African Journals Online (AJOL)

    NICO

    Synthesis of 9H-Indeno [1, 2-b] Pyrazine and. 11H-Indeno [1, 2-b] Quinoxaline Derivatives in. One-step Reaction from 2-Bromo-4-chloro-1-indanone. S. Jasouri1,2, J. Khalafy1,*, M. Badali2 and R.H. Prager3. 1Department of Chemistry, Urmia University, Urmia 57154, Iran. 2Daana Pharmaceutical Co., P.O. Box 5181, Tabriz ...

  14. Pharmacogenetics of Cytochrome P450 2B6 (CYP2B6: Advances on Polymorphisms, Mechanisms, and Clinical Relevance

    Directory of Open Access Journals (Sweden)

    Ulrich M Zanger

    2013-03-01

    Full Text Available Cytochrome P450 2B6 (CYP2B6 belongs to the minor drug metabolizing P450s in human liver. Expression is highly variable both between individuals and within individuals, owing to nongenetic factors, genetic polymorphisms, inducibility and irreversible inhibition by many compounds. Drugs metabolized mainly by CYP2B6 include artemisinin, bupropion, cyclophosphamide, efavirenz, ketamine, and methadone. CYP2B6 is one of the most polymorphic CYP genes in humans and variants have been shown to affect transcriptional regulation, splicing, mRNA and protein expression, and catalytic activity. Some variants appear to affect several functional levels simultaneously, thus, combined in haplotypes, leading to complex interactions between substrate-dependent and -independent mechanisms. The most common functionally deficient allele is CYP2B6*6 [Q172H, K262R], which occurs at frequencies of 15 to over 60% in different populations. The allele leads to lower expression in liver due to erroneous splicing. Recent investigations suggest that the amino acid changes contribute complex substrate-dependent effects at the activity level, although data from recombinant systems used by different researchers are not well in agreement with each other. Another important variant, CYP2B6*18 [I328T], occurs predominantly in Africans (4 to 12% and does not express functional protein. A large number of uncharacterized variants are currently emerging from different ethnicities in the course of the 1000 Genomes Project. The CYP2B6 polymorphism is clinically relevant for HIV-infected patients treated with the reverse transcriptase inhibitor efavirenz, but it is increasingly being recognized for other drug substrates. This review summarizes recent advances on the functional and clinical significance of CYP2B6 and its genetic polymorphism, with particular emphasis on the comparison of kinetic data obtained with different substrates for variants expressed in different recombinant

  15. Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance

    Science.gov (United States)

    Zanger, Ulrich M.; Klein, Kathrin

    2013-01-01

    Cytochrome P450 2B6 (CYP2B6) belongs to the minor drug metabolizing P450s in human liver. Expression is highly variable both between individuals and within individuals, owing to non-genetic factors, genetic polymorphisms, inducibility, and irreversible inhibition by many compounds. Drugs metabolized mainly by CYP2B6 include artemisinin, bupropion, cyclophosphamide, efavirenz, ketamine, and methadone. CYP2B6 is one of the most polymorphic CYP genes in humans and variants have been shown to affect transcriptional regulation, splicing, mRNA and protein expression, and catalytic activity. Some variants appear to affect several functional levels simultaneously, thus, combined in haplotypes, leading to complex interactions between substrate-dependent and -independent mechanisms. The most common functionally deficient allele is CYP2B6*6 [Q172H, K262R], which occurs at frequencies of 15 to over 60% in different populations. The allele leads to lower expression in liver due to erroneous splicing. Recent investigations suggest that the amino acid changes contribute complex substrate-dependent effects at the activity level, although data from recombinant systems used by different researchers are not well in agreement with each other. Another important variant, CYP2B6*18 [I328T], occurs predominantly in Africans (4–12%) and does not express functional protein. A large number of uncharacterized variants are currently emerging from different ethnicities in the course of the 1000 Genomes Project. The CYP2B6 polymorphism is clinically relevant for HIV-infected patients treated with the reverse transcriptase inhibitor efavirenz, but it is increasingly being recognized for other drug substrates. This review summarizes recent advances on the functional and clinical significance of CYP2B6 and its genetic polymorphism, with particular emphasis on the comparison of kinetic data obtained with different substrates for variants expressed in different recombinant expression systems. PMID

  16. Antagonistic effects of extracts from Artemisia rupetris L. and Leontopodium leontopodioides to CC chemokine receptor 2b (CCR2b).

    Science.gov (United States)

    Yu, Qin-Wei; Hu, Jie; Wang, Hao; Chen, Xin; Zhao, Fang; Gao, Peng; Yang, Qiu-Bin; Sun, Dan-Dan; Zhang, Lu-Yong; Yan, Ming

    2016-05-01

    The present study was designed to establish a suitable assay to explore CCR2b receptor antagonists from the natural products of Artemisia rupetris and Leontopodium leontopodioides. An aequorin assay was developed as a cell-based assay suitable for 384-well microplate and used for screening CCR2b receptor antagonists from natural products. Through establishing suitable conditions, the assay was shown to be suitable for screening of CCR2b receptor antagonists. Seven compounds were identified in preliminary screening. Five of them showed evident dose-response relationship in secondary screening. The structure-activity relationship study suggested that 7-position hydroxyl group of flavonoids was necessary, a polar group should be introduced on the 3-position, and the substituents on 2-position benzene ring of flavonoids have little influence on the potentency of the inhibition activity on CCR2b receptor. The ortho-position dihydroxyl structure in quinic acid compounds may be important. In conclusion, Compounds HR-1, 5, 7, and AR-20, 35 showed activity as antagonist of CCR2b receptor, which shed lights on the development of novel drugs as CCR2b receptor antagonists for preventing inflammation related diseases. Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  17. Lithium insertion in nanostructured TiO(2)(B) architectures.

    Science.gov (United States)

    Dylla, Anthony G; Henkelman, Graeme; Stevenson, Keith J

    2013-05-21

    Electric vehicles and grid storage devices have potentialto become feasible alternatives to current technology, but only if scientists can develop energy storage materials that offer high capacity and high rate capabilities. Chemists have studied anatase, rutile, brookite and TiO2(B) (bronze) in both bulk and nanostructured forms as potential Li-ion battery anodes. In most cases, the specific capacity and rate of lithiation and delithiation increases as the materials are nanostructured. Scientists have explained these enhancements in terms of higher surface areas, shorter Li(+) diffusion paths and different surface energies for nanostructured materials allowing for more facile lithiation and delithiation. Of the most studied polymorphs, nanostructured TiO2(B) has the highest capacity with promising high rate capabilities. TiO2(B) is able to accommodate 1 Li(+) per Ti, giving a capacity of 335 mAh/g for nanotubular and nanoparticulate TiO2(B). The TiO2(B) polymorph, discovered in 1980 by Marchand and co-workers, has been the focus of many recent studies regarding high power and high capacity anode materials with potential applications for electric vehicles and grid storage. This is due to the material's stability over multiple cycles, safer lithiation potential relative to graphite, reasonable capacity, high rate capability, nontoxicity, and low cost (Bruce, P. G.; Scrosati, B.; Tarascon, J.-M. Nanomaterials for Rechargeable Lithium Batteries. Angew. Chem., Int. Ed.2008, 47, 2930-2946). One of the most interesting properties of TiO2(B) is that both bulk and nanostructured forms lithiate and delithiate through a surface redox or pseudocapacitive charging mechanism, giving rise to stable high rate charge/discharge capabilities in the case of nanostructured TiO2(B). When other polymorphs of TiO2 are nanostructured, they still mainly intercalate lithium through a bulk diffusion-controlled mechanism. TiO2(B) has a unique open crystal structure and low energy Li

  18. Generation of an induced pluripotent stem cell line from a patient with hereditary multiple endocrine neoplasia 2B (MEN2B) syndrome with "highest risk" RET mutation.

    Science.gov (United States)

    Bennaceur-Griscelli, A; Hadoux, J; Féraud, O; Opolon, P; Divers, D; Gobbo, E; Schlumberger, M; Griscelli, F; Turhan, A G

    2017-08-01

    Multiple Endocrine Neoplasia Type 2B (MEN2B) is a cancer-predisposing syndrome that affects patients with germline RET mutations. The clinical spectrum of the syndrome includes medullary thyroid carcinoma (MTC) and pheochromocytoma. Currently, there is no satisfactory model recapitulating all the features of the disease especially at the level of stem cells. We generated induced pluripotent stem cells (iPSCs) from a patient with RET mutation at codon 918 who developed pheochromocytoma and MTC. These iPSC had normal karyotype, harboured the RET(M918T) mutation and expressed pluripotency hallmarks. A comprehensive pathological assessment of teratoma was performed after injection in immunodeficient mice. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  19. ORM-Based Semantics of B2B Transactions

    Science.gov (United States)

    Balsters, H.; van Blommestein, F.

    After widespread implementation of Enterprise Resource Planning and Personal Information Management, the next wave in the application of ICT is headed towards business to business (B2B) communication. B2B has a number of specific aspects, one of them being negotiation. This aspect has been largely neglected by present implementations of standard EDI- or XML-messaging and by B2B webservice implementations. In this paper a precise model is given of the negotiation process. The requirements of a potential Buyer and the offer of a potential Seller are matched and, if the negotiation is successful, a contract is concluded. The negotiation process model is represented in ORM, extended with dynamic constraints. Our model may be implemented in the databases of the trading partners and in message- or service definitions.

  20. Flow Simulation of N2B Hybrid Wing Body Configuration

    Science.gov (United States)

    Kim, Hyoungjin; Liou, Meng-Sing

    2012-01-01

    The N2B hybrid wing body aircraft was conceptually designed to meet environmental and performance goals for the N+2 generation transport set by the subsonic fixed wing project. In this study, flow fields around the N2B configuration is simulated using a Reynolds-averaged Navier-Stokes flow solver using unstructured meshes. Boundary conditions at engine fan face and nozzle exhaust planes are provided by response surfaces of the NPSS thermodynamic engine cycle model. The present flow simulations reveal challenging design issues arising from boundary layer ingestion offset inlet and nacelle-airframe interference. The N2B configuration can be a good test bed for application of multidisciplinary design optimization technology.

  1. Implication of 5-HT(2B) receptors in the serotonin syndrome.

    Science.gov (United States)

    Diaz, Silvina Laura; Maroteaux, Luc

    2011-09-01

    The serotonin (5-HT) syndrome occurs in humans after antidepressant overdose or combination of drugs inducing a massive increase in extracellular 5-HT. Several 5-HT receptors are known to participate in this syndrome in humans and animal models. The 5-HT(2B) receptor has been proposed as a positive modulator of serotonergic activity, but whether it is involved in 5-HT syndrome has not yet been studied. We analyzed here, a putative role of 5-HT(2B) receptors in this disorder by forced swimming test (FST) and behavioral assessment in the open field. In FST, genetic (5-HT(2B)(-/-) mice) or pharmacological (antagonist RS127445 at 0.5 mg/kg) ablation of 5-HT(2B) receptors facilitated selective 5-HT reuptake inhibitors (SSRI)-induced increase of immobility time as well as expression of other symptoms related to 5-HT syndrome like hind limb abduction and Straub tail. Increase in immobility was also developed in FST by both wild type (WT) and 5-HT(2B)(-/-) mice after the administration of 5-HT(1A), 5-HT(2A) or 5-HT(2C) receptor agonists, 8-OH-DPAT (5 mg/kg), DOI (1 mg/kg), or WAY161503 (5 mg/kg), respectively. In contrast, the 5-HT(2B) receptor agonist BW723C86 (3 mg/kg) or 5-HT(1B) receptor agonist CGS12066A (2 mg/kg) decreased immobility time in both genotypes. The 5-HT syndrome induced by fluoxetine at high doses was blocked in WT and 5-HT(2B)(-/-) mice by administration of 5-HT(1A) and 5-HT(2C) receptor antagonists (WAY100635 0.5 mg/kg and SB242084 0.5 mg/kg) but not by the 5-HT(2A) receptor antagonist MDL100907 (1 mg/kg). By behavioral assessment, we confirmed that 5-HT(2B)(-/-) mice were more prone to develop 5-HT syndrome symptoms after administration of high dose of SSRIs or the 5-HT precursor 5-Hydroxytryptophan, 5-HTP, even if increases in 5-HT plasma levels were similar in both genotypes. This evidence suggests that the presence of 5-HT(2B) receptors hinders acute 5-HT toxicity once high levels of 5-HT are attained. Therefore, differential agonism

  2. B2B-asiantuntijayritys ja sosiaalinen media

    OpenAIRE

    Sahlman, Katriina

    2012-01-01

    Tämän tutkimuksen tarkoituksena on selvittää, miten B2B-asiantuntijayritykset toimivat sosiaalisessa mediassa, miten ne hyödyntävät sitä palvelujensa ja brändinsä markkinointiin sekä lopulta liiketoimintansa edistämiseen. Tutkimus suoritettiin haastattelumuotoisena, laadullisena tutkimuksena. Tutkimukseen haastateltiin yhdeksää B2B-asiantuntijayrityksissä toimivaa, sosiaalista mediaa työkseen tai sen parissa työskentelevää henkilöä, jotka myös vapaa-ajallaan aktiivisesti käyttävät sosiaal...

  3. Zinc mediated dimer of human interferon-alpha 2b revealed by X-ray crystallography.

    Science.gov (United States)

    Radhakrishnan, R; Walter, L J; Hruza, A; Reichert, P; Trotta, P P; Nagabhushan, T L; Walter, M R

    1996-12-15

    The human alpha-interferon (huIFN-alpha) family displays broad spectrum antiviral, antiproliferative and immunomodulatory activities on a variety of cell types. The diverse biological activities of the IFN-alpha's are conveyed to cells through specific interactions with cell-surface receptors. Despite considerable effort, no crystal structure of a member of this family has yet been reported, because the quality of the protein crystals have been unsuitable for crystallographic studies. Until now, structural models of the IFN-alpha's have been based on the structure of murine IFN-beta (muIFN-beta). These models are likely to be inaccurate, as the amino acid sequence of muIFN-beta differs significantly from the IFN-alpha's at proposed receptor-binding sites. Structural information on a huIFN-alpha subtype would provide an improved basis for modeling the structures of the entire IFN-alpha family. The crystal structure of recombinant human interferon-alpha 2b (huIFN-alpha 2b) has been determined at 2.9 A resolution. HuIFN-alpha 2b exists in the crystal as a noncovalent dimer, which associates in a novel manner. Unlike other structurally characterized cytokines, extensive interactions in the dimer interface are mediated by a zinc ion (Zn2+). The overall fold of huIFN-alpha 2b is most similar to the structure of muIFN-beta. Unique to huIFN-alpha 2b is a 3(10) helix in the AB loop which is held to the core of the molecule by a disulfide bond. The structure of huIFN-alpha 2b provides an accurate model for analysis of the > 15 related type 1 interferon molecules. HuIFN-alpha 2b displays considerable structural similarity with muIFN-beta, interleukin-10 and interferon-gamma, which also bind related class 2 cytokine receptors. From these structural comparisons and numerous studies on the effects of mutations on biological activity, we have identified protein surfaces that appear to be important in receptor activation. This study also reveals the potential biological importance

  4. genetic overexpression of NR2B subunit enhances social recognition memory for different strains and species.

    Directory of Open Access Journals (Sweden)

    Stephanie A Jacobs

    Full Text Available The ability to learn and remember conspecifics is essential for the establishment and maintenance of social groups. Many animals, including humans, primates and rodents, depend on stable social relationships for survival. Social learning and social recognition have become emerging areas of interest for neuroscientists but are still not well understood. It has been established that several hormones play a role in the modulation of social recognition including estrogen, oxytocin and arginine vasopression. Relatively few studies have investigated how social recognition might be improved or enhanced. In this study, we investigate the role of the NMDA receptor in social recognition memory, specifically the consequences of altering the ratio of the NR2B:NR2A subunits in the forebrain regions in social behavior. We produced transgenic mice in which the NR2B subunit of the NMDA receptor was overexpressed postnatally in the excitatory neurons of the forebrain areas including the cortex, amygdala and hippocampus. We investigated the ability of both our transgenic animals and their wild-type littermate to learn and remember juvenile conspecifics using both 1-hr and 24-hr memory tests. Our experiments show that the wild-type animals and NR2B transgenic mice preformed similarly in the 1-hr test. However, transgenic mice showed better performances in 24-hr tests of recognizing animals of a different strain or animals of a different species. We conclude that NR2B overexpression in the forebrain enhances social recognition memory for different strains and animal species.

  5. Prognostic Value of a CYP2B6 Gene Polymorphism in Patients with Acute Myeloid Leukemia.

    Science.gov (United States)

    Alazhary, Nevin M; Shafik, Roxan E; Shafik, Hanan E; Kamel, Mahmoud M

    2015-01-01

    The objectives of this study aimed to detect a CYP2B6 polymorphism in de novo cases of acute myeloid leukemia patients and identify any role in disease progression and outcome. DNA was isolated from peripheral blood of 82 newly diagnosed acute myeloid leukemia cases and the CYP2B6 G15631T gene polymorphism was assayed by PCR restriction fragment length polymorphism (PCR-RFLP). The frequency of the GG genotype (wild type) was 48 (58.5%) and that of the mutant type T allele was 34 (41.9%). GT genotype heterozygous variants were found in 28 (34%), and TT genotype homozygous variants in 6 (7.3%) cases. We found no significant association between the CYP2B6 G15631T polymorphism and complete response (CR) (p-value=0.768), FAB classification (p-value=0.51), cytogenetic analysis (p-value=0.673), and overall survival (p-value=0.325). Also, there were no significant links with early toxic death (p-value=0.92) or progression- free survival (PFS) (p-value=0.245). Our results suggest that the CYP2B6 polymorphism has no role in disease progression, therapeutic outcome, patient free survival, early toxic death and overall survival in acute myeloid leukemia patients.

  6. Improved Refolding Efficacy of Recombinant Human Interferon α-2b ...

    African Journals Online (AJOL)

    helix from 23.7 % at ... synthesis overwhelm the folding machinery or the cell's capacity .... Table 3: Secondary structure of refolded rhIFN α-2b determined by CD spectropolarimetry at different pH values. pH. Helix (%). Beta Sheet (%). Turn (%).

  7. Mechanochemical synthesis and characterization of pure Co2B ...

    Indian Academy of Sciences (India)

    3Department of Industrial Design Engineering, Gazi University, Ankara 06500, Turkey. MS received 5 January 2016; accepted 2 February 2016. Abstract. Cobalt boride (Co2B) is a significant transition metal boride having a wide range of usage area due to its high oxidation, abrasion and corrosion resistance as well as its ...

  8. Intelligent Information Integration in B2B Electronic Commerce

    NARCIS (Netherlands)

    Fensel, Dieter; Omelayenko, Borys; Ding, Ying; Klein, Michel; Flett, Alan; Schulten, Ellen; Botquin, Guy; Brown, Mike; Dabiri, Gloria

    2002-01-01

    Internet and web technology penetrates many aspects of our daily life. Its importance as a medium for business transactions will grow exponentially during the next few years. In terms of the involved market volume, the B2B area will hereby be the most interesting area. Also, it will be the place,

  9. Association analysis of polymorphism in KIAA1717, HUMMLC2B ...

    African Journals Online (AJOL)

    Association analysis of polymorphism in KIAA1717, HUMMLC2B, DECR1 and FTO genes with meat quality traits of the Berkshire breed. ... associated with meat color (CIE a and b) and backfat thickness; and a SNP in FTO was associated with meat color (CIE L, a and b), protein content, drip loss, and water-holding capacity.

  10. Marketing-sales interface configurations in B2B firms

    NARCIS (Netherlands)

    Biemans, Wim G.; Brencic, Maja Makovec; Malshe, Avinash; Makovec Brenciv, M.

    As the body of knowledge on marketing-sales interface expands, there is a greater need to investigate the specific aspects of marketing-sales configurations in B2B firms. Using a qualitative methodology and interview data collected from over 100 sales and marketing professionals from the US, The

  11. Vortex lattice transitions in YNi 2 B 2 C

    Indian Academy of Sciences (India)

    We have performed extensive small-angle neutron scattering (SANS) diffraction studies of the vortex lattice in single crystal YNi2B2C for B | | c . High-resolution SANS, combined with a field-oscillation vortex lattice preparation technique, allows us to separate Bragg scattered intensities from two orthogonal domains and ...

  12. Persistent Electrochemical Performance in Epitaxial VO2(B).

    Science.gov (United States)

    Lee, Shinbuhm; Sun, Xiao-Guang; Lubimtsev, Andrew A; Gao, Xiang; Ganesh, Panchapakesan; Ward, Thomas Z; Eres, Gyula; Chisholm, Matthew F; Dai, Sheng; Lee, Ho Nyung

    2017-04-12

    Discovering high-performance energy storage materials is indispensable for renewable energy, electric vehicle performance, and mobile computing. Owing to the open atomic framework and good room temperature conductivity, bronze-phase vanadium dioxide [VO2(B)] has been regarded as a highly promising electrode material for Li ion batteries. However, previous attempts were unsuccessful to show the desired cycling performance and capacity without chemical modification. Here, we show with epitaxial VO2(B) films that one can accomplish the theoretical limit for capacity with persistent charging-discharging cyclability owing to the high structural stability and unique open pathways for Li ion conduction. Atomic-scale characterization by scanning transmission electron microscopy and density functional theory calculations also reveal that the unique open pathways in VO2(B) provide the most stable sites for Li adsorption and diffusion. Thus, this work ultimately demonstrates that VO2(B) is a highly promising energy storage material and has no intrinsic hindrance in achieving superior cyclability with a very high power and capacity in a Li-ion conductor.

  13. Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17.

    Science.gov (United States)

    Hu, Dong G; Selth, Luke A; Tarulli, Gerard A; Meech, Robyn; Wijayakumara, Dhilushi; Chanawong, Apichaya; Russell, Roslin; Caldas, Carlos; Robinson, Jessica L L; Carroll, Jason S; Tilley, Wayne D; Mackenzie, Peter I; Hickey, Theresa E

    2016-10-01

    Glucuronidation is an enzymatic process that terminally inactivates steroid hormones, including estrogens and androgens, thereby influencing carcinogenesis in hormone-dependent cancers. While estrogens drive breast carcinogenesis via the estrogen receptor alpha (ERα), androgens play a critical role as prohormones for estrogen biosynthesis and ligands for the androgen receptor (AR). In this study, the expression and regulation of two androgen-inactivating enzymes, the UDP-glucuronosyltransferases UGT2B15 and UGT2B17, was assessed in breast cancer. In large clinical cohorts, high UGT2B15 and UGT2B17 levels positively influenced disease-specific survival in distinct molecular subgroups. Expression of these genes was highest in cases positive for ERα. In cell line models, ERα, AR, and the transcription factor FOXA1 cooperated to increase transcription via tandem binding events at their proximal promoters. ERα activity was dependent on FOXA1, facilitated by AR activation, and potently stimulated by estradiol as well as estrogenic metabolites of 5α-dihydrotestosterone. AR activity was mediated via binding to an estrogen receptor half-site 3' to the FOXA1 and ERα-binding sites. Although AR and FOXA1 bound the UGT promoters in AR-positive/ERα-negative breast cancer cell lines, androgen treatment did not influence basal transcription levels. Ex vivo culture of human breast tissue and ERα(+) tumors provided evidence for upregulation of UGT2B15 and UGT2B17 by estrogen or androgen treatment. ERα binding was evident at the promoters of these genes in a small cohort of primary tumors and distant metastases. Collectively, these data provide insight into sex steroid receptor-mediated regulation of androgen-inactivating enzymes in ERα(+) breast cancer, which may have subtype-specific consequences for disease progression and outcomes. Cancer Res; 76(19); 5881-93. ©2016 AACR. ©2016 American Association for Cancer Research.

  14. Il B2B e il paradigma dei costi di transazione (B2B and the Transaction Costs Paradigm

    Directory of Open Access Journals (Sweden)

    Pierluigi Sabbatini

    2001-06-01

    Full Text Available Business to Business (B2B Internet commerce causes a significant contraction of transaction costs. According to the Coase paradigm, we would thus expect a deverticalization of the industry and broader scope for anonymous market mechanisms. In reality, such expectations are not fully borne out by the facts. When the industrial structure is concentrated the B2Bgenerally loses its independence, and is owned by the firms which most contribute to its development, e.g. the ones able to bring the liquidity to it. The B2B governance mechanism established by these firms gives hierarchical mechanisms a role which they do not usually play in extensive, anonymous markets.

  15. Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS.

    Directory of Open Access Journals (Sweden)

    Laura E Cox

    Full Text Available BACKGROUND: Amyotrophic lateral sclerosis (ALS, a common late-onset neurodegenerative disease, is associated with fronto-temporal dementia (FTD in 3-10% of patients. A mutation in CHMP2B was recently identified in a Danish pedigree with autosomal dominant FTD. Subsequently, two unrelated patients with familial ALS, one of whom also showed features of FTD, were shown to carry missense mutations in CHMP2B. The initial aim of this study was to determine whether mutations in CHMP2B contribute more broadly to ALS pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Sequencing of CHMP2B in 433 ALS cases from the North of England identified 4 cases carrying 3 missense mutations, including one novel mutation, p.Thr104Asn, none of which were present in 500 neurologically normal controls. Analysis of clinical and neuropathological data of these 4 cases showed a phenotype consistent with the lower motor neuron predominant (progressive muscular atrophy (PMA variant of ALS. Only one had a recognised family history of ALS and none had clinically apparent dementia. Microarray analysis of motor neurons from CHMP2B cases, compared to controls, showed a distinct gene expression signature with significant differential expression predicting disassembly of cell structure; increased calcium concentration in the ER lumen; decrease in the availability of ATP; down-regulation of the classical and p38 MAPK signalling pathways, reduction in autophagy initiation and a global repression of translation. Transfection of mutant CHMP2B into HEK-293 and COS-7 cells resulted in the formation of large cytoplasmic vacuoles, aberrant lysosomal localisation demonstrated by CD63 staining and impairment of autophagy indicated by increased levels of LC3-II protein. These changes were absent in control cells transfected with wild-type CHMP2B. CONCLUSIONS/SIGNIFICANCE: We conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases

  16. CDKN2B gene rs1063192 polymorphism decreases the risk of glaucoma.

    Science.gov (United States)

    Hu, Zhenxian; He, Chenliang

    2017-03-28

    The aim of this meta-analysis was to evaluate the association between cyclin-dependent kinase Inhibitor-2B (CDKN2B) gene rs1063192 polymorphism and glaucoma risk. We searched the databases of PubMed, and Embase. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by using fixed-effect or random-effect models. A total of 14 case-control studies involving 11,316 cases and 24,055 controls were included. Meta-analysis showed that CDKN2B gene rs1063192 polymorphism was associated with a decreased risk of glaucoma. Stratification analysis of ethnicity indicated that rs1063192 polymorphism decreased the risk of glaucoma among Caucasians and Asians. Stratification analysis by type of glaucoma revealed that rs1063192 polymorphism conferred a protective factor of primary open-angle glaucoma (POAG) and non-POAG. Stratification by source of controls uncovered an association between rs1063192 polymorphism and glaucoma in groups of population-based controls. In conclusion, this meta-analysis indicates that CDKN2B gene rs1063192 polymorphism is significantly associated with a decreased risk of glaucoma.

  17. Oncolytic gene therapy with recombinant vaccinia strain GLV-2b372 efficiently kills hepatocellular carcinoma.

    Science.gov (United States)

    Ady, Justin W; Johnsen, Clark; Mojica, Kelly; Heffner, Jacqueline; Love, Damon; Pugalenthi, Amudhan; Belin, Laurence J; Chen, Nanhai G; Yu, Yong A; Szalay, Aladar A; Fong, Yuman

    2015-08-01

    Hepatocellular carcinoma (HCC) commonly presents at a late stage when surgery is no longer a curative option. As such, novel therapies for advanced HCC are needed. Oncolytic viruses are a viable option for cancer therapy owing to their ability to specifically infect, replicate within, and kill cancer cells. In this study, we have investigated the ability of GLV-2b372, a novel light-emitting recombinant vaccinia virus derived from a wild-type Lister strain, to kill HCC. Four human HCC cell lines were assayed in vitro for infectivity and cytotoxicity. Viral replication was quantified via standard viral plaque assays. Flank HCC xenografts generated in athymic nude mice were treated with intratumoral GLV-2b372 to assess for tumor growth inhibition and viral biodistribution. Infectivity occurred in a time- and concentration-dependent manner with 70% cell death in all cell lines by day 5. All cell lines supported efficient viral replication. At 25 days after infection, flank tumor volumes decreased by 50% whereas controls increased by 400%. Tumor tissue demonstrated substantial GLV-2b372 infection at 24 hours, 48 hours, and 2 weeks. We demonstrate that GLV-2b372 efficiently kills human HCC in vitro and in vivo and is a viable treatment option for patients with HCC. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Development of New B2B Venture Corporate Brand Identity

    DEFF Research Database (Denmark)

    Törmälä, Minna; Gyrd-Jones, Richard I.

    2017-01-01

    capital of the organisation or the founder. We challenge this view in this paper from a conceptual and empirical perspective. Combining narrative theory and performativity theory this article suggests brand identity develops as a narrative performance. The study employs a narrative case analysis...... of interviews and archival data generated during a three-year period to examine the development of corporate brand over time. This study shows that the development of corporate brand identity and the context of the development of new B2B venture are closely intertwined processes and provides a framework......The development and role of brand identity in new B2B ventures is not well explored despite the challenge for such organisations in establishing reputational legitimacy. Previous research defines corporate brand identity as stable and endogenous to the organisation based either on the reputational...

  19. Hashimoto encephalopathy with pegylated interferon alfa-2b and ribavirin.

    Science.gov (United States)

    Deutsch, Melanie; Koskinas, John; Tzannos, Konstatinos; Vassilopoulos, Dimitrios; Mailis, Antonis; Tolis, George; Hadziyannis, Stephanos

    2005-10-01

    To report an instance of Hashimoto encephalopathy probably resulting from pegylated interferon alfa-2b and ribavirin. A 36-year-old woman with a 10-year history of autoimmune thyroiditis presented with symptoms and signs consistent with Hashimoto encephalopathy during therapy with pegylated interferon alfa-2b and ribavirin for chronic hepatitis C. Hashimoto encephalopathy is a rare autoimmune condition that occurs in patients with Hashimoto thyroiditis and high titers of antithyroid antibodies. It is characterized by a variety of nonspecific neuropsychiatric symptoms, increased cerebrospinal fluid protein level, and abnormal brain imaging and electroencephalogram. Prompt response to corticosteroids is observed in most cases. As of August 29, 2005, this is the first report of such an association. An objective causality assessment revealed that the Hashimoto encephalopathy was probably caused by the patient's medications. Hashimoto encephalopathy may rarely be triggered by interferon alfa therapy in susceptible patients.

  20. Structured Crowdsourcing: A B2B Innovation Roadmap

    DEFF Research Database (Denmark)

    Edgeman, Rick; Engell, Toke; Jensen, Nik Grewy

    Crowdsourcing is an increasingly popular source of both ideas and funding. Crowdsourcing in a B2B context is less well understood and, as such, much of our discussion will highlight business-to-business crowdsourcing. More generally discussion will address crowdsourcing relative to innovation...... from crowd-sourcing efforts. The roadmap emphasizes on early stages in the overall innovation management activity that is related to development and specification of the task to be crowdsourced, the identification of the crowd, the creation of the environment to connect the crowdsourcer, the task...... and the crowd, motivation of the crowd, and actual activities in reaching the crowd. Managing the input from the crowd is regarded as a later stage in the overall innovation management but also as a focal point in the arguments for improving B2B crowdsourcing. In crowd selection processes this paper aims...

  1. Synthesis, crystal structure, spectrum properties, and electronic structure of a new three-borate Ba{sub 4}Na{sub 2}Zn{sub 4}(B{sub 3}O{sub 6}){sub 2}(B{sub 12}O{sub 24}) with two isolated types of blocks: 3[3Δ] and 3[2Δ + 1T

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xuean, E-mail: xueanchen@bjut.edu.cn [College of Materials Science and Engineering, Beijing University of Technology, Ping Le Yuan 100, Beijing 100124 (China); Chen, Yanjun; Sun, Chong; Chang, Xinan [College of Materials Science and Engineering, Beijing University of Technology, Ping Le Yuan 100, Beijing 100124 (China); Xiao, Weiqiang [Institute of Microstructure and Property of Advanced Materials, Beijing University of Technology, Beijing 100124 (China)

    2013-08-15

    Graphical abstract: Ba{sub 4}Na{sub 2}Zn{sub 4}(B{sub 3}O{sub 6}){sub 2}(B{sub 12}O{sub 24}) contains complicated porous anionic layers composed of ZnO{sub 4} tetrahedra, [B{sub 3}O{sub 6}]{sup 3−} rings with notation of 3[3Δ], and [B{sub 12}O{sub 24}]{sup 12−} groups built up from four BO{sub 4} tetrahedra and eight BO{sub 3} triangles with notation of 2 × {2 × (3[2Δ + 1T])}. The anionic layers stack along c-axis, with the intralayer open channels and interlayer void spaces occupied by Na{sup +} or Ba{sup 2+} cations to balance charge. Highlights: •Ba{sub 4}Na{sub 2}Zn{sub 4}(B{sub 3}O{sub 6}){sub 2}(B{sub 12}O{sub 24}) has been prepared by solid state reaction method. •It has a layered structure consisting of ZnO{sub 4} tetrahedra, [B{sub 3}O{sub 6}]{sup 3−} rings, and [B{sub 12}O{sub 24}]{sup 12−} groups. •The IR spectrum confirmed the presence of both BO{sub 3} and BO{sub 4} groups. •UV–vis diffuse reflectance spectrum revealed a band gap of about 3.13 eV. •Band structure calculations indicated that it is an indirect band material. -- Abstract: A new barium sodium zincoborate, Ba{sub 4}Na{sub 2}Zn{sub 4}(B{sub 3}O{sub 6}){sub 2}(B{sub 12}O{sub 24}), has been prepared by solid state reaction method below 750 °C. Single-crystal XRD analysis showed that it crystallizes in the triclinic space group P1{sup ¯} with a = 7.0288(14) Å, b = 7.0687(14) Å, c = 17.501(4) Å, α = 91.92(3)°, β = 96.46(3)°, γ = 119.72(3)°, Z = 1. The crystal structure exhibits complicated porous anionic layers composed of ZnO{sub 4} tetrahedra, [B{sub 3}O{sub 6}]{sup 3−} rings with notation of 3[3Δ], and [B{sub 12}O{sub 24}]{sup 12−} groups built up from four BO{sub 4} tetrahedra and eight BO{sub 3} triangles with notation of 2 × {2 × (3[2Δ + 1T])}. The anionic layers stack along c-axis, with the intralayer open channels and interlayer void spaces occupied by Na{sup +} or Ba{sup 2+} cations to balance charge. The IR spectrum further confirmed the

  2. Social media usage: an investigation of B2B salespeople

    OpenAIRE

    Roberta J. Schultz; Charles H. Schwepker, Jr; David J. Good

    2012-01-01

    A great deal has been written recently in the practitioner press about the strategic importance and usage of social media. However, as practitioners only release limited information about the internal advantages such a tool provides, research in this emerging field remains extremely limited about its usage in the sales area. In this context, the purpose of this paper is to propose and empirically assess a model of social media usage among business-to-business (B2B) salespeople. A survey of 27...

  3. Expression and purification of recombinant Shiga toxin 2B from ...

    African Journals Online (AJOL)

    sunny t

    expression of Stx2B economically was obtained using 1 mM IPTG for 4 h at 37°C. Protein identity was confirmed by a band at ~11.4 kDa using ... of recombinant Shiga toxin B subunit (rStxB) protein in. BALB/c mice was evaluated. Animal ..... tag-based purification of PKCƔ Kinase free tag protein. (Ohana et al., 2011) which ...

  4. Redefining B2B Relationship Marketing: Insight from postmodern Alibaba

    OpenAIRE

    Cockayne, David

    2016-01-01

    The cultural and philosophical movement of modernism has defined contemporary marketing knowledge, constructing a powerful narrative that has conceptually bound, yet semantically separated business to consumer (B2C) and business to business (B2B) marketing knowledge. Perceived paradigm shifts towards relationships, and the birth of relationship marketing are argued to be no more than an evolution of modern marketing, yet at the heart of relational constructs sit the very features modernism se...

  5. Expression and purification of recombinant Shiga toxin 2B from ...

    African Journals Online (AJOL)

    sunny t

    both Stx1 and Stx2 in the HeLa cell cytotoxicity assay. ... The prokaryotic plasmid pH6HTN His6HaloTag® T7 (4,014 kb,. Promega, USA) was .... The cell has been confirmed to be transformed in the gene (stx2B) in the correct orientation insertion. The transformed cells were grown to test the ability of the host cell containing.

  6. Mass Customized Technical Textiles in the B2B Sector

    Science.gov (United States)

    Gebhardt, R.; Barteld, M.; Grafmüller, L.; Mosig, T.; Weiß, M.

    2017-10-01

    Mass Customization is a great opportunity for textile companies for both staying competitive in high-wage countries and offering inexpensive, customized products. Within the area of Technical Textiles, this study focuses on the B2B sector and shows the status quo, potentials and strengths. Both management and technological issues are addressed. For the former, business models and the value co-creation process are dealt with, for the latter, the focus is on modelling.

  7. Phonon linewidths in YNi2B2C

    Indian Academy of Sciences (India)

    a = b = 3.51 Å and c = 10.53 Å. The single-crystal sample of YN2B2C weighing. 2.26 g was mounted in a standard orange cryostat at LLB and in a closed-cycle .... perturbation approach was used for calculating properties of the lattice dynamics and electron-phonon coupling. Details can be found in R Heid and K-P Bohnen, ...

  8. Agent-based services for B2B electronic commerce

    Science.gov (United States)

    Fong, Elizabeth; Ivezic, Nenad; Rhodes, Tom; Peng, Yun

    2000-12-01

    The potential of agent-based systems has not been realized yet, in part, because of the lack of understanding of how the agent technology supports industrial needs and emerging standards. The area of business-to-business electronic commerce (b2b e-commerce) is one of the most rapidly developing sectors of industry with huge impact on manufacturing practices. In this paper, we investigate the current state of agent technology and the feasibility of applying agent-based computing to b2b e-commerce in the circuit board manufacturing sector. We identify critical tasks and opportunities in the b2b e-commerce area where agent-based services can best be deployed. We describe an implemented agent-based prototype system to facilitate the bidding process for printed circuit board manufacturing and assembly. These activities are taking place within the Internet Commerce for Manufacturing (ICM) project, the NIST- sponsored project working with industry to create an environment where small manufacturers of mechanical and electronic components may participate competitively in virtual enterprises that manufacture printed circuit assemblies.

  9. NUMERICAL SIMULATIONS OF MAP IOP2B WITH AROME

    OpenAIRE

    Seity, Y.

    2005-01-01

    Abstract: The goal of this study is to use the large amount of measurements collected during the MAP IOP2B, to validate a new Numerical Weather Prediction system : AROME. We also evaluate AROME by comparison with ALADIN and Meso-NH simulations of this IOP. The AROME 2.5 km results are sensitive to the choice of the coupling model. AROME 2.5 km coupled with AROME 10 km is able in pseudo-operational conditions (long time step and coupled with forecasts) to reproduce the main features of the ...

  10. 40 CFR Table 2b to Subpart E of... - Reactivity Factors for Aliphatic Hydrocarbon Solvent Mixtures

    Science.gov (United States)

    2010-07-01

    ... Hydrocarbon Solvent Mixtures 2B Table 2B to Subpart E of Part 59 Protection of Environment ENVIRONMENTAL... Hydrocarbon Solvent Mixtures Bin Averageboiling point * (degrees F) Criteria Reactivityfactor 1 80-205 Alkanes... + Dry Point) / 2 (b) Aromatic Hydrocarbon Solvents ...

  11. USING UML SCENARIOS IN B2B SYSTEMS

    Directory of Open Access Journals (Sweden)

    A. Jakimi

    2010-05-01

    Full Text Available Scenarios has become a popular technique for requirements elicitation and specification building. Since scenarios capture only partial descriptions of the system behavior, an approach for scenario composition and/or integration is needed to produce more complete specifications. The Unified Modeling Language (UML, which has become a standard notation for object-oriented modeling, provides a suitable framework for scenario acquisition using Use Case diagrams and Sequence or Collaboration diagrams. In this paper, we suggest an algorithmic and tool support for composing and integrating scenarios that are represented in form of sequence diagrams. We suggest four operators (;: sequential operator, ||: concurrent operator, ?: conditional operator and  * :iteration operator to compose a set of scenarios that describe a use case of a given system. In this paper, we suggest also to apply the scenario approach to B2B systems (Business to Business. We propose to develop B2B systems as a three activities process deriving formal specifications and code skeletons from UML scenarios. Activities of this proposed process are generally automatic and are supported by a set of developed algorithms and tools.

  12. RE{sub 2}B{sub 8}O{sub 15} (RE = La, Pr, Nd). Syntheses of three new rare earth borates isotypic to Ce{sub 2}B{sub 8}O{sub 15}

    Energy Technology Data Exchange (ETDEWEB)

    Glaetzle, Matthias; Hoerder, Gregor J.; Huppertz, Hubert [Innsbruck Univ. (Austria). Inst. fuer Allgemeine, Anorganische und Theoretische Chemie

    2016-08-01

    The rare earth borates RE{sub 2}B{sub 8}O{sub 15} (RE = La, Pr, Nd) were synthesized in a Walker-type multianvil apparatus under conditions of 5.5 GPa and 1100 C. Starting from the corresponding rare earth oxides and boron oxide, the syntheses yielded crystalline products of all new compounds that allowed crystal structure analyses based on single-crystal X-ray diffraction data for La{sub 2}B{sub 8}O{sub 15} and Nd{sub 2}B{sub 8}O{sub 15}. The compound Pr{sub 2}B{sub 8}O{sub 15} could be characterized via X-ray powder diffractometry. The results show that the new compounds crystallize isotypically to Ce{sub 2}B{sub 8}O{sub 15} in the monoclinic space group P2/c. The infrared spectra of RE{sub 2}B{sub 8}O{sub 15} (RE = La, Pr, Nd) have also been studied.

  13. A Fast Healthcare Interoperability Resources (FHIR) layer implemented over i2b2.

    Science.gov (United States)

    Boussadi, Abdelali; Zapletal, Eric

    2017-08-14

    Standards and technical specifications have been developed to define how the information contained in Electronic Health Records (EHRs) should be structured, semantically described, and communicated. Current trends rely on differentiating the representation of data instances from the definition of clinical information models. The dual model approach, which combines a reference model (RM) and a clinical information model (CIM), sets in practice this software design pattern. The most recent initiative, proposed by HL7, is called Fast Health Interoperability Resources (FHIR). The aim of our study was to investigate the feasibility of applying the FHIR standard to modeling and exposing EHR data of the Georges Pompidou European Hospital (HEGP) integrating biology and the bedside (i2b2) clinical data warehouse (CDW). We implemented a FHIR server over i2b2 to expose EHR data in relation with five FHIR resources: DiagnosisReport, MedicationOrder, Patient, Encounter, and Medication. The architecture of the server combines a Data Access Object design pattern and FHIR resource providers, implemented using the Java HAPI FHIR API. Two types of queries were tested: query type #1 requests the server to display DiagnosticReport resources, for which the diagnosis code is equal to a given ICD-10 code. A total of 80 DiagnosticReport resources, corresponding to 36 patients, were displayed. Query type #2, requests the server to display MedicationOrder, for which the FHIR Medication identification code is equal to a given code expressed in a French coding system. A total of 503 MedicationOrder resources, corresponding to 290 patients, were displayed. Results were validated by manually comparing the results of each request to the results displayed by an ad-hoc SQL query. We showed the feasibility of implementing a Java layer over the i2b2 database model to expose data of the CDW as a set of FHIR resources. An important part of this work was the structural and semantic mapping between the

  14. KAT2B Is Required for Pancreatic Beta Cell Adaptation to Metabolic Stress by Controlling the Unfolded Protein Response

    Directory of Open Access Journals (Sweden)

    Nabil Rabhi

    2016-05-01

    Full Text Available The endoplasmic reticulum (ER unfolded protein response (UPRer pathway plays an important role in helping pancreatic β cells to adapt their cellular responses to environmental cues and metabolic stress. Although altered UPRer gene expression appears in rodent and human type 2 diabetic (T2D islets, the underlying molecular mechanisms remain unknown. We show here that germline and β cell-specific disruption of the lysine acetyltransferase 2B (Kat2b gene in mice leads to impaired insulin secretion and glucose intolerance. Genome-wide analysis of Kat2b-regulated genes and functional assays reveal a critical role for Kat2b in maintaining UPRer gene expression and subsequent β cell function. Importantly, Kat2b expression is decreased in mouse and human diabetic β cells and correlates with UPRer gene expression in normal human islets. In conclusion, Kat2b is a crucial transcriptional regulator for adaptive β cell function during metabolic stress by controlling UPRer and represents a promising target for T2D prevention and treatment.

  15. Darier disease mutation E917K of SERCA2b relieves the inhibitory influence of the 11th transmembrane segment

    DEFF Research Database (Denmark)

    Mikkelsen, Stine; Holdensen, Anne Nyholm; Vangheluwe, Peter

    Mutation E917K of the Sarco(endo)plasmic Reticulum Ca2+-ATPase isoform 2b (SERCA2b) causes Darier disease, an autosomal dominantly inherited skin disease also denoted as Keratosis Follicularis or Darier-White disease. SERCA is encoded by three genes ATP2A1, ATP2A2 and ATP2A3 giving rise...... to the proteins SERCA1, SERCA2 and SERCA3. SERCA2 is spliced into three variants SERCA2a, SERCA2b and SERCA2c, the only difference between SERCA2a and SERCA2b is the extended C-terminus of SERCA2b (49 amino acids) which forms an extra 11th transmembrane segment (compared with the 10 transmembrane segments of all...... other SERCA proteins). SERCA2b is expressed in all cell types and is known as the “house keeping” SERCA isoform. It has a characteristic low catalytic turnover rate and increased Ca2+ affinity compared with SERCA2a and the well characterized SERCA1a isoform. Glutamate 917 is located in the cytoplasmic...

  16. Cucumber mosaic virus and its 2b RNA silencing suppressor modify plant-aphid interactions in tobacco

    Science.gov (United States)

    Ziebell, Heiko; Murphy, Alex M.; Groen, Simon C.; Tungadi, Trisna; Westwood, Jack H.; Lewsey, Mathew G.; Moulin, Michael; Kleczkowski, Adam; Smith, Alison G.; Stevens, Mark; Powell, Glen; Carr, John P.

    2011-01-01

    The cucumber mosaic virus (CMV) 2b protein not only inhibits anti-viral RNA silencing but also quenches transcriptional responses of plant genes to jasmonic acid, a key signalling molecule in defence against insects. This suggested that it might affect interactions between infected plants and aphids, insects that transmit CMV. We found that infection of tobacco with a 2b gene deletion mutant (CMVΔ2b) induced strong resistance to aphids (Myzus persicae) while CMV infection fostered aphid survival. Using electrical penetration graph methodology we found that higher proportions of aphids showed sustained phloem ingestion on CMV-infected plants than on CMVΔ2b-infected or mock-inoculated plants although this did not increase the rate of growth of individual aphids. This indicates that while CMV infection or certain viral gene products might elicit aphid resistance, the 2b protein normally counteracts this during a wild-type CMV infection. Our findings suggest that the 2b protein could indirectly affect aphid-mediated virus transmission. PMID:22355702

  17. Relationship Quality as Predictor of B2B Customer Loyalty

    Directory of Open Access Journals (Sweden)

    Shaimaa S. B. Ahmed Doma

    2013-02-01

    Full Text Available Relationship marketing has become extremely important recently due to the fierce competition in today's marketplace. Companies are required to build long-term profitable relationship with customers and to achieve customer loyalty. Also, switching behaviors frequently occur among most of targeted customers. Fewer studies, however, discuss the effects of relationship quality efforts on customer loyalty. Therefore, this study is aimed to investigate the impact of relationship quality on customer loyalty in B2B context in the Egyptian shipping services sector. Building on prior research, we propose relationship quality as a higher construct comprising trust, commitment and satisfaction. An analytical model is developed as a guideline to test the relationships between relationship quality dimensions and customer loyalty.

  18. Semantic ETL into i2b2 with Eureka!

    Science.gov (United States)

    Post, Andrew R; Krc, Tahsin; Rathod, Himanshu; Agravat, Sanjay; Mansour, Michel; Torian, William; Saltz, Joel H

    2013-01-01

    Clinical phenotyping is an emerging research information systems capability. Research uses of electronic health record (EHR) data may require the ability to identify clinical co-morbidities and complications. Such phenotypes may not be represented directly as discrete data elements, but rather as frequency, sequential and temporal patterns in billing and clinical data. These patterns' complexity suggests the need for a robust yet flexible extract, transform and load (ETL) process that can compute them. This capability should be accessible to investigators with limited ability to engage an IT department in data management. We have developed such a system, Eureka! Clinical Analytics. It extracts data from an Excel spreadsheet, computes a broad set of phenotypes of common interest, and loads both raw and computed data into an i2b2 project. A web-based user interface allows executing and monitoring ETL processes. Eureka! is deployed at our institution and is available for deployment in the cloud.

  19. Strategic Insights from Mystery Shopping in B2B Relationships

    DEFF Research Database (Denmark)

    Mattsson, Jan

    2012-01-01

    This paper describes how mystery shopping can be used to gain valuable strategic input in B2B service relationships. We account for a longitudinal case study framed as a natural experiment (duration 18 months) in a Swedish group of consultancy companies offering a wide selection of industrial...... services to large Scandinavian corporations. We account for and analyse the process of building a mystery shopping procedure to get strategic insights from engineers delivering temporary consultancy services to these clients. After a successful trial period with three mystery shoppers the experiment (a...... guideline covering the themes of map, smoke and mirror as metaphors) has been extended to comprise a larger group of engineers and may be taken up in a company-wide way. The experiment was deemed effective in developing both a procedure for mystery shopping and a new way to train the consultants....

  20. Semantic ETL into i2b2 with Eureka!

    Science.gov (United States)

    Post, Andrew R.; Krc, Tahsin; Rathod, Himanshu; Agravat, Sanjay; Mansour, Michel; Torian, William; Saltz, Joel H.

    Clinical phenotyping is an emerging research information systems capability. Research uses of electronic health record (EHR) data may require the ability to identify clinical co-morbidities and complications. Such phenotypes may not be represented directly as discrete data elements, but rather as frequency, sequential and temporal patterns in billing and clinical data. These patterns’ complexity suggests the need for a robust yet flexible extract, transform and load (ETL) process that can compute them. This capability should be accessible to investigators with limited ability to engage an IT department in data management. We have developed such a system, Eureka! Clinical Analytics. It extracts data from an Excel spreadsheet, computes a broad set of phenotypes of common interest, and loads both raw and computed data into an i2b2 project. A web-based user interface allows executing and monitoring ETL processes. Eureka! is deployed at our institution and is available for deployment in the cloud. PMID:24303265

  1. Matchmaking Framework for B2B E-Marketplaces

    Directory of Open Access Journals (Sweden)

    Fekete ZOLTAN ALPAR

    2010-01-01

    Full Text Available In the recent years trading on the Internet become more popular. Online businesses gradually replace more and more from the conventional business. Much commercial information is exchanged on the internet, especially using the e-marketplaces. The demand and supply matching process becomes complex and difficult on last twenty years since the e-marketplaces play an important role in business management. Companies can achieve significant cost reduction by using e-marketplaces in their trade activities and by using matchmaking systems on finding the corresponding supply for their demand and vice versa. In the literature were proposed many approaches for matchmaking. In this paper we present a conceptual framework of matchmaking in B2B e-marketplaces environment.

  2. Rap2B promotes proliferation, migration, and invasion of human breast cancer through calcium-related ERK1/2 signaling pathway.

    Science.gov (United States)

    Di, Jiehui; Huang, Hui; Qu, Debao; Tang, Juangjuan; Cao, Wenjia; Lu, Zheng; Cheng, Qian; Yang, Jing; Bai, Jin; Zhang, Yanping; Zheng, Junnian

    2015-07-23

    Rap2B, a member of GTP-binding proteins, is widely upregulated in many types of tumors and promotes migration and invasion of human suprarenal epithelioma. However, the function of Rap2B in breast cancer is unknown. Expression of Rap2B was examined in breast cancer cell lines and human normal breast cell line using Western blot analysis. Using the CCK-8 cell proliferation assay, cell cycle analysis, and transwell migration assay, we also elucidated the role of Rap2B in breast cancer cell proliferation, migration, and invasion. Results showed that the expression of Rap2B is higher in tumor cells than in normal cells. Flow cytometry and Western blot analysis revealed that Rap2B elevates the intracellular calcium level and further promotes extracellular signal-related kinase (ERK) 1/2 phosphorylation. By contrast, calcium chelator BAPTM/AM and MEK inhibitor (U0126) can reverse Rap2B-induced ERK1/2 phosphorylation. Furthermore, Rap2B knockdown inhibits cell proliferation, migration, and invasion abilities via calcium related-ERK1/2 signaling. In addition, overexpression of Rap2B promotes cell proliferation, migration and invasion abilities, which could be neutralized by BAPTM/AM and U0126. Taken together, these findings shed light on Rap2B as a therapeutic target for breast cancer.

  3. Cardiovascular magnetic resonance of cardiomyopathy in limb girdle muscular dystrophy 2B and 2I

    Science.gov (United States)

    2011-01-01

    Background Limb girdle muscular dystrophies (LGMD) are inclusive of 7 autosomal dominant and 14 autosomal recessive disorders featuring progressive muscle weakness and atrophy. Studies of cardiac function have not yet been well-defined in deficiencies of dysferlin (LGMD2B) and fukutin related protein (LGMD2I). In this study of patients with these two forms of limb girdle muscular dystrophy, cardiovascular magnetic resonance (CMR) was used to more specifically define markers of cardiomyopathy including systolic dysfunction, myocardial fibrosis, and diastolic dysfunction. Methods Consecutive patients with genetically-proven LGMD types 2I (n = 7) and 2B (n = 9) and 8 control subjects were enrolled. All subjects underwent cardiac magnetic resonance (CMR) on a standard 1.5 Tesla clinical scanner with cine imaging for left ventricular (LV) volume and ejection fraction (EF) measurement, vector velocity analysis of cine data to calculate myocardial strain, and late post-gadolinium enhancement imaging (LGE) to assess for myocardial fibrosis. Results Sixteen LGMD patients (7 LGMD2I, 9 LGMD2B), and 8 control subjects completed CMR. All but one patient had normal LV size and systolic function; one (type 2I) had severe dilated cardiomyopathy. Of 15 LGMD patients with normal systolic function, LGE imaging revealed focal myocardial fibrosis in 7 (47%). Peak systolic circumferential strain rates were similar in patients vs. controls: εendo was -23.8 ± 8.5vs. -23.9 ± 4.2%, εepi was -11.5 ± 1.7% vs. -10.1 ± 4.2% (p = NS for all). Five of 7 LGE-positive patients had grade I diastolic dysfunction [2I (n = 2), 2B (n = 3)]. that was not present in any LGE-negative patients or controls. Conclusions LGMD2I and LGMD2B generally result in mild structural and functional cardiac abnormalities, though severe dilated cardiomyopathy may occur. Long-term studies are warranted to evaluate the prognostic significance of subclinical fibrosis detected by CMR in these patients. PMID:21816046

  4. Cardiovascular magnetic resonance of cardiomyopathy in limb girdle muscular dystrophy 2B and 2I

    Directory of Open Access Journals (Sweden)

    Habib Philip

    2011-08-01

    Full Text Available Abstract Background Limb girdle muscular dystrophies (LGMD are inclusive of 7 autosomal dominant and 14 autosomal recessive disorders featuring progressive muscle weakness and atrophy. Studies of cardiac function have not yet been well-defined in deficiencies of dysferlin (LGMD2B and fukutin related protein (LGMD2I. In this study of patients with these two forms of limb girdle muscular dystrophy, cardiovascular magnetic resonance (CMR was used to more specifically define markers of cardiomyopathy including systolic dysfunction, myocardial fibrosis, and diastolic dysfunction. Methods Consecutive patients with genetically-proven LGMD types 2I (n = 7 and 2B (n = 9 and 8 control subjects were enrolled. All subjects underwent cardiac magnetic resonance (CMR on a standard 1.5 Tesla clinical scanner with cine imaging for left ventricular (LV volume and ejection fraction (EF measurement, vector velocity analysis of cine data to calculate myocardial strain, and late post-gadolinium enhancement imaging (LGE to assess for myocardial fibrosis. Results Sixteen LGMD patients (7 LGMD2I, 9 LGMD2B, and 8 control subjects completed CMR. All but one patient had normal LV size and systolic function; one (type 2I had severe dilated cardiomyopathy. Of 15 LGMD patients with normal systolic function, LGE imaging revealed focal myocardial fibrosis in 7 (47%. Peak systolic circumferential strain rates were similar in patients vs. controls: εendo was -23.8 ± 8.5vs. -23.9 ± 4.2%, εepi was -11.5 ± 1.7% vs. -10.1 ± 4.2% (p = NS for all. Five of 7 LGE-positive patients had grade I diastolic dysfunction [2I (n = 2, 2B (n = 3]. that was not present in any LGE-negative patients or controls. Conclusions LGMD2I and LGMD2B generally result in mild structural and functional cardiac abnormalities, though severe dilated cardiomyopathy may occur. Long-term studies are warranted to evaluate the prognostic significance of subclinical fibrosis detected by CMR in these patients.

  5. Il B2B e il paradigma dei costi di transazione (B2B and the Transaction Costs Paradigm

    Directory of Open Access Journals (Sweden)

    Pierluigi Sabbatini

    2012-04-01

    Full Text Available Business to Business (B2B Internet commerce causes a significant contraction of transaction costs. According to the Coase paradigm, we would thus expect a deverticalization of the industry and broader scope for anonymous market mechanisms. In reality, such expectations are not fully borne out by the facts. When the industrial structure is concentrated the B2Bgenerally loses its independence, and is owned by the firms which most contribute to its development, e.g. the ones able to bring the liquidity to it. The B2B governance mechanism established by these firms gives hierarchical mechanisms a role which they do not usually play in extensive, anonymous markets.         JEL Codes: D23, L86Keywords: Cost, Transaction Costs, Transactions

  6. Getting started with Oracle SOA B2B Integration a hands-on tutorial

    CERN Document Server

    Bhatia, Krishnaprem; Perlovsky, Alan

    2013-01-01

    This hands on tutorial gives you the best possible start you could hope for with Oracle B2B. Learn using real life scenarios and examples to give you a solid footing of B2B.This book is for B2B architects, consultants and developers who would like to design and develop B2B integrations using Oracle B2B. This book assumes no prior knowledge of Oracle B2B and explains all concepts from scratch using illustrations, real world examples and step-by-step instructions. The book covers enough depth and details to be useful for both beginner and advanced B2B users.

  7. B2-B2.5 code benchmarking

    Energy Technology Data Exchange (ETDEWEB)

    Dekeyser, W.; Baelmans, M; Voskoboynikov, S.; Rozhansky, V.; Reiter, D.; Wiesen, S.; Kotov, V.; Boerner, P.

    2011-01-15

    ITER-IO currently (and since about 15 years) employs the SOLPS4.xxx code for its divertor design, currently version SOLPS4.3. SOLPS.xxx is a special variant of the B2-EIRENE code, which was originally developed by an European consortium (FZ Juelich, AEA Culham, ERM Belgium/KU Leuven) in the late eighties and early nineties of the last century under NET contracts. Until today even the very similar edge plasma codes within the SOLPS family, if run on a seemingly identical choice of physical parameters, still sometimes disagree significantly with each other. It is obvious that in computational engineering applications, as they are carried out for the various ITER divertor aspects with SOLPS4.3 for more than a decade now, any transition from one to another code must be fully backward compatible, or, at least, the origin of differences in the results must be identified and fully understood quantitatively. In this report we document efforts undertaken in 2010 to ultimately eliminate the third issue. For the kinetic EIRENE part within SOLPS this backward compatibility (back until 1996) was basically achieved (V. Kotov, 2004-2006) and SOLPS4.3 is now essentially up to date with the current EIRENE master maintained at FZ Juelich. In order to achieve a similar level of reproducibility for the plasma fluid (B2, B2.5) part, we follow a similar strategy, which is quite distinct from the previous SOLPS benchmark attempts: the codes are ''disintegrated'' and pieces of it are run on smallest (i.e. simplest) problems. Only after full quantitative understanding is achieved, the code model is enlarged, integrated, piece by piece again, until, hopefully, a fully backward compatible B2 / B2.5 ITER edge plasma simulation will be achieved. The status of this code dis-integration effort and its findings until now (Nov. 2010) are documented in the present technical note. This work was initiated in a small workshop by the three partner teams of KU Leuven, St. Petersburg

  8. Adenosine promotes alternative macrophage activation via A2A and A2B receptors

    Science.gov (United States)

    Csóka, Balázs; Selmeczy, Zsolt; Koscsó, Balázs; Németh, Zoltán H.; Pacher, Pál; Murray, Peter J.; Kepka-Lenhart, Diane; Morris, Sidney M.; Gause, William C.; Leibovich, S. Joseph; Haskó, György

    2012-01-01

    Adenosine has been implicated in suppressing the proinflammatory responses of classically activated macrophages induced by Th1 cytokines. Alternative macrophage activation is induced by the Th2 cytokines interleukin (IL)-4 and IL-13; however, the role of adenosine in governing alternative macrophage activation is unknown. We show here that adenosine treatment of IL-4- or IL-13-activated macrophages augments the expression of alternative macrophage markers arginase-1, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), and macrophage galactose-type C-type lectin-1. The stimulatory effect of adenosine required primarily A2B receptors because the nonselective adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) increased both arginase activity (EC50=261.8 nM) and TIMP-1 production (EC50=80.67 nM), and both pharmacologic and genetic blockade of A2B receptors prevented the effect of NECA. A2A receptors also contributed to the adenosine augmentation of IL-4-induced TIMP-1 release, as both adenosine and NECA were less efficacious in augmenting TIMP-1 release by A2A receptor-deficient than control macrophages. Of the transcription factors known to drive alternative macrophage activation, CCAAT-enhancer-binding protein β was required, while cAMP response element-binding protein and signal transducer and activator of transcription 6 were dispensable in mediating the effect of adenosine. We propose that adenosine receptor activation suppresses inflammation and promotes tissue restitution, in part, by promoting alternative macrophage activation.—Csóka, B., Selmeczy, Z., Koscsó, B., Németh, Z. H., Pacher, P., Murray, P. J., Kepka-Lenhart, D., Morris S. M., Jr., Gause, W. C., Leibovich, S. J., Haskó, G. Adenosine promotes alternative macrophage activation via A2A and A2B receptors. PMID:21926236

  9. Oral application of freeze-dried yeast particles expressing the PCV2b Cap protein on their surface induce protection to subsequent PCV2b challenge in vivo.

    Science.gov (United States)

    Patterson, Robert; Eley, Thomas; Browne, Christopher; Martineau, Henny M; Werling, Dirk

    2015-11-17

    Porcine circovirus type 2 (PCV2) is now endemic in every major pig producing country, causing PCV-associated disease (PCVAD), linked with large scale economic losses. Current vaccination strategies are based on the capsid protein of the virus and are reasonably successful in preventing PCVAD but fail to induce sterile immunity. Additionally, vaccinating whole herds is expensive and time consuming. In the present study a "proof of concept" vaccine trial was employed to test the effectiveness of powdered freeze-dried recombinant Saccharomyces cerevisiae yeast stably expressing the capsid protein of PCV2b on its surface as an orally applied vaccine. PCV2-free pigs were given 3 doses of vaccine or left un-vaccinated before challenge with a defined PCV2b strain. Rectal temperatures were measured and serum and faeces samples were collected weekly. At the end of the study, pigs were euthanized, tissue samples taken and tested for PCV2b load by qPCR and immunohistochemistry. The peak of viraemia in sera and faeces of unvaccinated pigs was higher than that of vaccinated pigs. Additionally more sIgA was found in faeces of vaccinated pigs than unvaccinated. Vaccination was associated with lower serum concentrations of TNFα and IL-1β but higher concentrations of IFNα and IFNγ in comparison to the unvaccinated animals. At the end of the trial, a higher viral load was found in several lymphatic tissues and the ileum of unvaccinated pigs in comparison to vaccinated pigs. The difference between groups was especially apparent in the ileum. The results presented here demonstrate a possible use for recombinant S. cerevisiae expressing viral proteins as an oral vaccine against PCV2. A powdered freeze-dried recombinant S. cerevisiae used as an oral vaccine could be mixed with feed and may offer a cheap and less labour intensive alternative to inoculation with the additional advantage that no cooling chain would be required for vaccine transport and storage. Copyright © 2015 The

  10. Hanstholm phase 2B. Offshore wave energy test 1994 - 1996

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-11-01

    The wave power converter consists of a float 2.5 meter in diameter, connected by a rope to a seabed-mounted piston pump, installed on 25 meter deep water 2,5 km offshore Hanstholm, Denmark. The converter is designed to absorb an average maximum power of 1 kW. Measured data in real sea conditions are compared to results based on computer simulations and previous tank testing. Losses caused by rope elasticity and hysteresis, friction in the pump and back flow through the valves are assessed. The economic perspectives of a large wave power plant are presented, based on a revised prototype incorporating the results and experience gained during the test period. The wave energy conversion test `Hanstholm phase 2B` has showed, that it it technically possible to exploit the offshore wave energy resource. This source of energy could become attractive for commercial enterprise. The wave power converter demonstrated a reliable performance over a period of nine months. It produced energy under all wave conditions and survived storm waves of 9,6 m. A 300 MW wave power plant in the Danish part of the North sea is estimated to produce electricity at a cost between 2,1 - 2,4 DKK/kWh. The electrical transmission to shore contribute to approximately 20% of the cost. New data predict a potential of 23 kW per meter wave front. The energy plan Energy 21 proposed by the Danish Department of Energy, includes a scenario incorporating wave energy in the energy system year 2030. A strategy for the development of wave energy, has been proposed as part of the project OWEC-1 supported by the European Joule R and D programme. A proposal for future Danish initiatives to develop second generation point absorber systems is outlined. (ARW) 29 refs.

  11. Beyond the exchange--the future of B2B.

    Science.gov (United States)

    Wise, R; Morrison, D

    2000-01-01

    Using the Internet to facilitate business-to-business commerce promises many benefits, such as dramatic cost reductions and greater access to buyers and sellers. Yet little is known about how B2B e-commerce will evolve. The authors argue that changes in the financial services industry over the past two decades provide important clues. Exchanges, they say, are not the primary source of value in information-intensive markets; value tends to accumulate among a diverse group of specialists that focus on such tasks as packaging, standard setting, arbitrage, and information management. Because scale and liquidity are vitally important to efficient trading, today's exchanges will consolidate into a relatively small set of mega-exchanges. Originators will handle the origination and aggregation of complex transactions before sending them on to mega-exchanges for execution. E-speculators, seeking to capitalize on an abundance of market information, will tend to concentrate where relatively standardized products can be transferred easily among a large group of buyers. In many markets, a handful of independent solution providers with well-known brand names and solid reputations will thrive alongside mega-exchanges. Sell-side asset exchanges will create the networks and provide the tools to allow suppliers to trade orders among themselves, sometimes after initial transactions with customers are made on the mega-exchanges. For many companies, traditional skills in such areas as product development, manufacturing, and marketing may become relatively less important, while the ability to understand and capitalize on market dynamics may become considerably more important.

  12. New imidazo[1,2-b]pyrazoles as anticancer agents: synthesis, biological evaluation and structure activity relationship analysis.

    Science.gov (United States)

    Grosse, Sandrine; Mathieu, Véronique; Pillard, Christelle; Massip, Stéphane; Marchivie, Mathieu; Jarry, Christian; Bernard, Philippe; Kiss, Robert; Guillaumet, Gérald

    2014-09-12

    Synthesis and functionalization strategies of the imidazo[1,2-b]pyrazole core were developed giving a rapid access to three series of novel imidazo[1,2-b]pyrazole type derivatives: C-2/C-6/C-7 trisubstituted, C-2/C-3/C-6 tri(hetero)arylated and C-2/C-3/C-6/C-7 tetrasubstituted imidazo[1,2-b]pyrazoles. 39 of the synthetized products were evaluated for in vitro anticancer activity using the MTT colorimetric assay against 5 human and 1 murine cancer cell lines. Promising in vitro growth inhibitory activities were exhibited by some of the target compounds. Of the 39 evaluated products, 4 displayed an IC50 ≤ 10 μM in the 6 cell lines analyzed (compounds 4d, 4g, 9a, 11a). A structure activity relationship analysis is also reported in this paper. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  13. Distinct biological properties of two RET isoforms activated by MEN 2A and MEN 2B mutations.

    Science.gov (United States)

    Rossel, M; Pasini, A; Chappuis, S; Geneste, O; Fournier, L; Schuffenecker, I; Takahashi, M; van Grunsven, L A; Urdiales, J L; Rudkin, B B; Lenoir, G M; Billaud, M

    1997-01-23

    Germline mutations of the RET proto-oncogene, which codes for a receptor tyrosine kinase, cause multiple endocrine neoplasia type 2A (MEN 2A) and 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). MEN 2 mutations have been shown to result in RET oncogenic activation. The RET gene encodes several isoforms whose biological properties, when altered by MEN 2 mutations, have not been thoroughly addressed yet. In this study, we have introduced a MEN 2A mutation (Cys634-->Arg) and the unique MEN 2B mutation (Met918-->Thr) in two RET isoforms of 1114 and 1072 amino acids which differ in the carboxy-terminus part. Herein, we report that each RET isoform activated by MEN 2A or MEN 2B mutation was transforming in fibroblasts and induced neuronal differentiation of pheochromocytoma PC12 cells. However, among the different RET-MEN 2 mutants, the long RET isoform activated by the MEN 2B mutation stimulated the most prominent neurite outgrowth in PC12 cells, while the short RET isoform counterpart elicited a very weak differentiation effect in PC12 cells. We further demonstrate that the morphological changes of PC12 cells caused by constitutively activated RET oncoproteins involved the engagement of a Ras-dependent pathway. These findings provide evidence that the biological properties of RET-MEN 2 mutants depend on the interplay between the RET isoforms and the nature of the activating MEN 2 mutation.

  14. Efficient cell culture system for hepatitis C virus genotype 2B

    DEFF Research Database (Denmark)

    2014-01-01

    The present inventors developed hepatitis C virus 2b/2a intergenotypic recombinants in which the JFH1 structural genes (Core, E1 and E2), p7 and the complete NS2 were replaced by the corresponding genes of the genotype 2b reference strain J8. Sequence analysis of recovered 2b/2a recombinants from 2...... transfection experiments revealed that 2b/2a was genetically stable. Conclusion: The developed 2b/2a viruses provide a robust in vitro tool for research in HCV genotype 2b, including vaccine studies and functional analysis....

  15. E-hubs: the new B2B (business-to-business) marketplaces.

    Science.gov (United States)

    Kaplan, S; Sawhney, M

    2000-01-01

    Electronic hubs--Internet-based intermediaries that host electronic marketplaces and mediate transactions among businesses--are generating a lot of interest. Companies like Ariba, Chemdex, and Commerce One have already attained breathtaking stock market capitalizations. Venture capitalists are pouring money into more business-to-business start-ups. Even industrial stalwarts like GM and Ford are making plans to set up their own Web markets. As new entrants with new business models pour into the business-to-business space, it's increasingly difficult to make sense of the landscape. This article provides a blueprint of the e-hub arena. The authors start by looking at the two dimensions of purchasing: what businesses buy--manufacturing inputs or operating inputs--and how they buy--through systematic sourcing or spot sourcing. They classify B2B e-hubs into four categories: MRO hubs, yield managers, exchanges, and catalog hubs, and they discuss each type in detail. Drilling deeper into this B2B matrix, the authors look at how e-hubs create value--through aggregation and matching--and explain when each mechanism works best. They also examine the biases of e-hubs. Although many e-hubs are neutral--they're operated by independent third parties--some favor the buyers or sellers. The authors explain the differences and discuss the pros and cons of each position. The B2B marketplace is changing rapidly. This framework helps buyers, sellers, and market makers navigate the landscape by explaining what the different hubs do and how they add the most value.

  16. 75 FR 59065 - Airworthiness Directives; Turboméca S.A. Arriel 2B and 2B1 Turboshaft Engines

    Science.gov (United States)

    2010-09-27

    .... Arriel 2B and 2B1 Turboshaft Engines AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Final... of these dampers has demonstrated to limit axial displacement of the HP blade relative to the disk in.... We are issuing this AD to prevent an uncommanded in-flight engine shutdown which could result in an...

  17. Methadone pharmacogenetics: CYP2B6 polymorphisms determine plasma concentrations, clearance and metabolism

    Science.gov (United States)

    Kharasch, Evan D.; Regina, Karen J.; Blood, Jane; Friedel, Christina

    2015-01-01

    Background Interindividual variability in methadone disposition remains unexplained, and methadone accidental overdose in pain therapy is a significant public health problem. Cytochrome P4502B6 (CYP2B6) is the principle determinant of clinical methadone elimination. The CYP2B6 gene is highly polymorphic, with several variant alleles. CYP2B6.6, the protein encoded by the CYP2B6*6 polymorphism, deficiently catalyzes methadone metabolism in vitro. This investigation determined the influence of CYP2B6*6, and other allelic variants encountered, on methadone concentrations, clearance, and metabolism. Methods Healthy volunteers in genotype cohorts CYP2B6*1/*1 (n=21), CYP2B6*1/*6 (n=20), and CYP2B6*6/*6 (n=17), and also CYP2B6*1/*4 (n=1), CYP2B6*4/*6 (n=3), CYP2B6*5/*5 (n=2) subjects received single doses of intravenous and oral methadone. Plasma and urine methadone and metabolite concentrations were determined by tandem mass spectrometry. Results Average S-methadone apparent oral clearance was 35 and 45% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1, and R-methadone apparent oral clearance was 25 and 30% lower. R- and S-methadone apparent oral clearance was 3- and 4-fold greater in CYP2B6*4 carriers. Intravenous and oral R- and S-methadone metabolism was significantly lower in CYP2B6*6 carriers compared with CYP2B6*1 homozygotes, and greater in CYP2B6*4 carriers. Methadone metabolism and clearance were lower in African-Americans due to the CYP2B6*6 genetic polymorphism. Conclusions CYP2B6 polymorphisms influence methadone plasma concentrations, due to altered methadone metabolism and thus clearance. Genetic influence is greater for oral than intravenous, and S- than R-methadone. CYP2B6 pharmacogenetics explains, in part, interindividual variability in methadone elimination. CYP2B6 genetic effects on methadone metabolism and clearance may identify subjects at risk for methadone toxicity and drug interactions. PMID:26389554

  18. Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Dorval, K M; Wigg, K G; Crosbie, J; Tannock, R; Kennedy, J L; Ickowicz, A; Pathare, T; Malone, M; Schachar, R; Barr, C L

    2007-07-01

    The glutamatergic signaling pathway represents an ideal candidate susceptibility system for attention-deficit/hyperactivity disorder (ADHD). Disruption of specific N-methyl-D-aspartate-type glutamate receptor subunit genes (GRIN1, 2A-D) in mice leads to significant alterations in cognitive and/or locomotor behavior including impairments in latent learning, spatial memory tasks and hyperactivity. Here, we tested for association of GRIN2B variants with ADHD, by genotyping nine single nucleotide polymorphisms (SNPs) in 205 nuclear families identified through probands with ADHD. Transmission of alleles from heterozygous parents to affected offspring was examined using the transmission/disequilibrium test. Quantitative trait analyses for the ADHD symptom dimensions [inattentive (IA) and hyperactive/impulsive (HI)] and cognitive measures of verbal working memory and verbal short-term memory were performed using the fbat program. Three SNPs showed significantly biased transmission (P memory or verbal working memory. Our data suggest an association between variations in the GRIN2B subunit gene and ADHD as measured categorically or as a quantitatively distributed trait.

  19. Li2b2-Façade: Simulation of i2b2 Data Warehouse Server and Client for Interaction with Other Systems.

    Science.gov (United States)

    Majeed, Raphael W; Xu, Tingyan; Stöhr, Mark R; Röhrig, Rainer

    2017-01-01

    Since its release in 2004, the i2b2 data warehouse software has become a valuable tool for clinical researchers. Physicians can use its browser-based query frontend intuitively without additional training or reading through documentation. While the i2b2 software describes it's API as "REST", it is neither stateless nor does it follow the common guidelines for RESTful APIs. Thus, interfacing other software with i2b2's custom RPC-style XML-API is a very cumbersome process. To overcome these issues, we developed a lightweight software abstraction layer "lightweight i2b2 façade" (li2b2-façade).

  20. In adenosine A2B knockouts acute treatment with inorganic nitrate improves glucose disposal, oxidative stress and AMPK signaling in the liver

    Directory of Open Access Journals (Sweden)

    Maria ePeleli

    2015-08-01

    Full Text Available Rationale: Accumulating studies suggest that nitric oxide (NO deficiency and oxidative stress are central pathological mechanisms in type 2 diabetes. Recent findings demonstrate therapeutic effects by boosting a nitrate-nitrite-NO pathway, an alternative pathway for NO formation. This study aimed at investigating the acute effects of inorganic nitrate on glucose and insulin signaling in adenosine A2B receptor knockout mice (A2B-/-, a genetic model of impaired metabolic regulation.Methods: Acute effects of nitrate treatment were investigated in aged wild-type (WT and A2B-/- mice. One hour after injection with nitrate or placebo, metabolic regulation was evaluated by glucose and insulin tolerance tests. NADPH oxidase-mediated superoxide production and AMPK phosphorylation were measured in livers obtained from non-treated or glucose-treated mice, with or without prior nitrate injection. Plasma was used to determine insulin resistance (HOMA-IR and NO signaling.Results: A2B-/- displayed increased body weight, reduced glucose clearance and attenuated overall insulin responses compared with age-matched WT. Nitrate treatment increased circulating levels of nitrate, nitrite and cGMP in A2B-/-, and improved glucose clearance. In WT mice, however, nitrate treatment did not influence glucose clearance. HOMA-IR increased following glucose injection in A2B-/-, but remained at basal levels in mice pretreated with nitrate. NADPH oxidase activity in livers from A2B-/-, but not WT mice, was reduced by nitrate. Livers from A2B-/- displayed reduced AMPK phosphorylation compared with WT mice, and this was increased by nitrate treatment. Injection with the anti-diabetic agent metformin induced similar therapeutic effects in the A2B-/- as observed with nitrate. Conclusion: The A2B-/- mouse is a genetic model of metabolic syndrome. Acute treatment with nitrate improved the metabolic profile, at least partly via reduction in oxidative stress and improved AMPK signaling

  1. Incidence and prevalence of multiple endocrine neoplasia 2B in Denmark: a nationwide study

    DEFF Research Database (Denmark)

    Mathiesen, Jes Sloth; Kroustrup, Jens Peter; Vestergaard, Peter

    2017-01-01

    Extract: Multiple endocrine neoplasia 2B (MEN2B) is an autosomal dominant inherited cancer syndrome associating medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), ganglioneuromatosis of the aerodigestive tract and facial, ophthalmologic and skeletal abnormalities. MEN2B is caused by the ...

  2. CDKN2B methylation is associated with carotid artery calcification in ischemic stroke patients

    OpenAIRE

    Shuyu Zhou; Yumeng Zhang; Li Wang; Zhizhong Zhang; Biyang Cai; Keting Liu; Hao Zhang; Minhui Dai; Lingli Sun; Xiaomeng Xu; Huan Cai; Xinfeng Liu; Guangming Lu; Gelin Xu

    2016-01-01

    Background Cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) near chromosome 9p21 have been associated with both atherosclerosis and artery calcification, but the underlying mechanisms remained largely unknown. Considering that CDKN2A/2B is a frequently reported site for DNA methylation, this study aimed to evaluate whether carotid artery calcification (CarAC) is related to methylation levels of CDKN2A/2B in patients with ischemic stroke. Methods DNA methylation levels of CDKN2A/2B were mea...

  3. Homozygous mutation of the PHOX2B gene in congenital central hypoventilation syndrome (Ondine's Curse).

    Science.gov (United States)

    Trochet, Delphine; de Pontual, Loïc; Estêvao, Maria Helena; Mathieu, Yves; Munnich, Arnold; Feingold, J; Goridis, Christo; Lyonnet, Stanislas; Amiel, Jeanne

    2008-05-01

    Homozygosity for a dominant allele is relatively rare and preferentially observed in communities with high inbreeding. According to the definition of true dominance, similar phenotypes should be observed in patients heterozygous and homozygous for a dominant mutation. However, the homozygous phenotype usually tends to be more severe than the heterozygous one. In these cases, the wild-type and mutant alleles are semi-dominant. Here we report a patient with a Congenital Central Hypoventilation Syndrome (CCHS) phenotype and homozygosity for a PHOX2B gene mutation leading to an alanine expansion shorter than the threshold hitherto observed in CCHS patients with a heterozygous mutation. This observation adds the concept of mutational threshold per se to the discussion about dominant and recessive alleles.

  4. Splicing-related single nucleotide polymorphism of RAB, member of RAS oncogene family like 2B (RABL2B) jeopardises semen quality in Chinese Holstein bulls.

    Science.gov (United States)

    Wang, Xiuge; Cui, Xiaohui; Zhang, Yan; Hao, Haisheng; Ju, Zhihua; Liu, Deyu; Jiang, Qiang; Yang, Chunhong; Sun, Yan; Wang, Changfa; Huang, Jinming; Zhu, Huabin

    2017-11-01

    RAB, member of RAS oncogene family like 2B (RABL2B) is a member of a poorly characterised clade of the RAS GTPase superfamily, which plays an essential role in male fertility, sperm intraflagellar transport and tail assembly. In the present study, we identified a novel RABL2B splice variant in bovine testis and spermatozoa. This splice variant, designated RABL2B-TV, is characterised by exon 2 skipping. Moreover, a single nucleotide polymorphism (SNP), namely c.125G>A, was found within the exonic splicing enhancer (ESE) motif, indicating that the SNP caused the production of the RABL2B-TV aberrant splice variant. This was demonstrated by constructing a pSPL3 exon capturing vector with different genotypes and transfecting these vectors into murine Leydig tumour cell line (MLTC-1) cells. Expression of the RABL2B-TV transcript was lower in semen from high- versus low-performance bulls. Association analysis showed that sperm deformity rate was significantly lower in Chinese Holstein bulls with the GG or GA genotype than in bulls with the AA genotype (Pquality in bulls with different RABL2B genotypes is generated via an alternative splicing mechanism caused by a functional SNP within the ESE motif.

  5. Copy Number Variation of UGT 2B Genes in Indian Families Using Whole Genome Scans

    Directory of Open Access Journals (Sweden)

    Avinash M. Veerappa

    2016-01-01

    Full Text Available Background and Objectives. Uridine diphospho-glucuronosyltransferase 2B (UGT2B is a family of genes involved in metabolizing steroid hormones and several other xenobiotics. These UGT2B genes are highly polymorphic in nature and have distinct polymorphisms associated with specific regions around the globe. Copy number variations (CNVs status of UGT2B17 in Indian population is not known and their disease associations have been inconclusive. It was therefore of interest to investigate the CNV profile of UGT2B genes. Methods. We investigated the presence of CNVs in UGT2B genes in 31 members from eight Indian families using Affymetrix Genome-Wide Human SNP Array 6.0 chip. Results. Our data revealed >50% of the study members carried CNVs in UGT2B genes, of which 76% showed deletion polymorphism. CNVs were observed more in UGT2B17 (76.4% than in UGT2B15 (17.6%. Molecular network and pathway analysis found enrichment related to steroid metabolic process, carboxylesterase activity, and sequence specific DNA binding. Interpretation and Conclusion. We report the presence of UGT2B gene deletion and duplication polymorphisms in Indian families. Network analysis indicates the substitutive role of other possible genes in the UGT activity. The CNVs of UGT2B genes are very common in individuals indicating that the effect is neutral in causing any suspected diseases.

  6. Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation.

    Science.gov (United States)

    Xie, H-J; Yasar, U; Lundgren, S; Griskevicius, L; Terelius, Y; Hassan, M; Rane, A

    2003-01-01

    The role of polymorphic CYP2B6 in cyclophosphamide (CPA) bioactivation was investigated in human liver microsomes. A total of 67 human liver specimens were first genotyped with respect to the CYP2B6*5 and CYP2B6*6 variant alleles. CYP2B6 apoprotein levels in 55 liver microsomal preparations were assessed by immunoblotting. 4-Hydroxy-CPA and hydroxy-bupropion were quantified by using HPLC and LC-MS, respectively. 7-Ethoxy-4-trifluoromethyl coumarin O-deethylase activity was measured fluorometrically. The frequencies of CYP2B6*5 and CYP2B6*6 mutant alleles were 9.0 and 16.4%, respectively. CYP2B6 protein expression was detected in 80% of the samples, with a large variation (0.003-2.234, arbitrary units). There was a high correlation between CYP2B6 apoprotein content and CPA 4-hydroxylation (n=55, r=0.81, P<0.0001). When based on the CYP2B6 apoprotein levels, the *6 carriers had significantly higher CPA 4-hydroxylation (P<0.05). CPA 4-hydroxylation also correlated significantly with other CYP2B6-specific reactions (n=20, P<0.0001). V(max) and K(m) for CPA 4-hydroxylation in recombinant CYP2B6 enzyme were 338 nmol/min/nmol enzyme and 1.4 mM, respectively. CYP2B6 showed much higher in vitro intrinsic clearance than previously observed in recombinant CYP2C19 and CYP2C9 variants in yeast expression system. Our results demonstrate that the polymorphic CYP2B6 is a major enzyme in the bioactivation of CPA. Moreover, we identified a strong impact of CYP2B6*6 on CPA 4-hydroxylation.

  7. A gain-of-function mutation in Tnni2 impeded bone development through increasing Hif3a expression in DA2B mice.

    Directory of Open Access Journals (Sweden)

    Xiaoquan Zhu

    2014-10-01

    Full Text Available Distal arthrogryposis type 2B (DA2B is an important genetic disorder in humans. However, the mechanisms governing this disease are not clearly understood. In this study, we generated knock-in mice carrying a DA2B mutation (K175del in troponin I type 2 (skeletal, fast (TNNI2, which encodes a fast-twitch skeletal muscle protein. Tnni2K175del mice (referred to as DA2B mice showed typical DA2B phenotypes, including limb abnormality and small body size. However, the current knowledge concerning TNNI2 could not explain the small body phenotype of DA2B mice. We found that Tnni2 was expressed in the osteoblasts and chondrocytes of long bone growth plates. Expression profile analysis using radii and ulnae demonstrated that Hif3a expression was significantly increased in the Tnni2K175del mice. Chromatin immunoprecipitation assays indicated that both wild-type and mutant tnni2 protein can bind to the Hif3a promoter using mouse primary osteoblasts. Moreover, we showed that the mutant tnni2 protein had a higher capacity to transactivate Hif3a than the wild-type protein. The increased amount of hif3a resulted in impairment of angiogenesis, delay in endochondral ossification, and decrease in chondrocyte differentiation and osteoblast proliferation, suggesting that hif3a counteracted hif1a-induced Vegf expression in DA2B mice. Together, our data indicated that Tnni2K175del mutation led to abnormally increased hif3a and decreased vegf in bone, which explain, at least in part, the small body size of Tnni2K175del mice. Furthermore, our findings revealed a new function of tnni2 in the regulation of bone development, and the study of gain-of-function mutation in Tnni2 in transgenic mice opens a new avenue to understand the pathological mechanism of human DA2B disorder.

  8. The effects of anti-hypertensive drugs and the mechanism of hypertension in vascular smooth muscle cell-specific ATP2B1 knockout mice.

    Science.gov (United States)

    Okuyama, Yuki; Hirawa, Nobuhito; Fujita, Megumi; Fujiwara, Akira; Ehara, Yosuke; Yatsu, Keisuke; Sumida, Koichiro; Kagimoto, Minako; Katsumata, Mari; Kobayashi, Yusuke; Saka, Sanae; Umemura, Satoshi; Tamura, Kouichi

    2018-02-01

    ATP2B1 is a gene associated with hypertension. We reported previously that mice lacking ATP2B1 in vascular smooth muscle cells (VSMC ATP2B1 KO mice) exhibited high blood pressure and increased intracellular calcium concentration. The present study was designed to investigate whether lack of the ATP2B1 gene causes a higher response to calcium channel blockers (CCBs) than to other types of anti-hypertensive drugs. Both VSMC ATP2B1 KO and control mice were administered anti-hypertensive drugs while monitoring blood pressure shifts. We also examined the association of nitric oxide synthase (NOS) activity in those mice to investigate whether another mechanism of hypertension existed. VSMC ATP2B1 KO mice exhibited significantly greater anti-hypertensive effects with a single injection of nicardipine, but the effects of an angiotensin II receptor blocker (ARB), an α-blocker and amlodipine on blood pressure were all similar to control mice. However, long-term treatment with amlodipine, but not an ARB, significantly decreased the blood pressure of KO mice compared with control mice. Both mRNA and protein expression levels of the L-type calcium channel were significantly upregulated in KO VSMCs. There were no alterations in neural NOS protein expression of VSMCs or in urinary NO production between the two groups. VSMC ATP2B1 KO mice had a higher response to CCBs for blood pressure-lowering effects than other anti-hypertensive drugs. These results mean that increased intracellular calcium concentration in VSMCs due to lack of ATP2B1 and subsequent activation of L-type calcium channels mainly affects blood pressure and suggests increased susceptibility to CCBs in this type of hypertension.

  9. TiO2-B Nanoribbons Anchored with NiO Nanosheets as Hybrid Anode Materials for Rechargeable Lithium ion Batteries

    DEFF Research Database (Denmark)

    Zhang, J. Y.; Shen, J.X.; Wang, T.L.

    2015-01-01

    A new type of TiO2-B nanoribbon anchored with NiO nanosheets (TiO2@NiO) is synthesized via a hydrothermal process and a subsequent homogeneous precipitation method. XRD analysis indicates that TiO2-B and cubic NiO phases exist in the composites. According to SEM images, the morphology of the TiO2...

  10. 76 FR 28637 - Airworthiness Directives; Eurocopter France Model AS350B, B1, B2, B3, BA, and EC130 B4 Helicopters

    Science.gov (United States)

    2011-05-18

    ... Model AS350B, B1, B2, B3, BA, and EC130 B4 Helicopters AGENCY: Federal Aviation Administration (FAA..., 2009, for the Model EC130 B4 helicopters. The Model AS350 BB helicopter is not type certificated in the...) None. Applicability (c) This AD applies to Model AS350B, B1, B2, B3, BA, and EC130 B4 helicopters with...

  11. Elevated adenosine signaling via adenosine A2B receptor induces normal and sickle erythrocyte sphingosine kinase 1 activity

    Science.gov (United States)

    Sun, Kaiqi; Zhang, Yujin; Bogdanov, Mikhail V.; Wu, Hongyu; Song, Anren; Li, Jessica; Dowhan, William; Idowu, Modupe; Juneja, Harinder S.; Molina, Jose G.; Blackburn, Michael R.; Kellems, Rodney E.

    2015-01-01

    Erythrocyte possesses high sphingosine kinase 1 (SphK1) activity and is the major cell type supplying plasma sphingosine-1-phosphate, a signaling lipid regulating multiple physiological and pathological functions. Recent studies revealed that erythrocyte SphK1 activity is upregulated in sickle cell disease (SCD) and contributes to sickling and disease progression. However, how erythrocyte SphK1 activity is regulated remains unknown. Here we report that adenosine induces SphK1 activity in human and mouse sickle and normal erythrocytes in vitro. Next, using 4 adenosine receptor-deficient mice and pharmacological approaches, we determined that the A2B adenosine receptor (ADORA2B) is essential for adenosine-induced SphK1 activity in human and mouse normal and sickle erythrocytes in vitro. Subsequently, we provide in vivo genetic evidence that adenosine deaminase (ADA) deficiency leads to excess plasma adenosine and elevated erythrocyte SphK1 activity. Lowering adenosine by ADA enzyme therapy or genetic deletion of ADORA2B significantly reduced excess adenosine-induced erythrocyte SphK1 activity in ADA-deficient mice. Finally, we revealed that protein kinase A-mediated extracellular signal-regulated kinase 1/2 activation functioning downstream of ADORA2B underlies adenosine-induced erythrocyte SphK1 activity. Overall, our findings reveal a novel signaling network regulating erythrocyte SphK1 and highlight innovative mechanisms regulating SphK1 activity in normal and SCD. PMID:25587035

  12. Neurotoxic, cytotoxic, apoptotic and antiproliferative effects of some marine algae extracts on the NA2B cell line.

    Science.gov (United States)

    Kurt, O; Özdal-Kurt, F; Akçora, C M; Özkut, M; Tuğlu, M I

    2018-02-01

    Oxidative stress contributes to cancer pathologies and to apoptosis. Marine algae exhibit cytotoxic, antiproliferative and apoptotic effects; their metabolites have been used to treat many types of cancer. We investigated in culture extracts of Petalonia fascia, Jania longifurca and Halimeda tuna to determine their effects on mouse neuroblastoma cell line, NA2B. NA2B cells were treated with algae extracts, and the survival and proliferation of NA2B cells were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of algae extracts on oxidative stress in NA2B cells also were investigated using nitric oxide synthase (NOS) immunocytochemistry and apoptosis was assessed using terminal deoxynucleotidyl transferase dUTP nick end labeling. We observed significant neurite inhibition with moderate damage by the neurotoxicity-screening test (NST) at IC 50 dilutions of the extracts. MTT demonstrated that J. longifurca extracts were more toxic than P. fascia and H. tuna extracts. We found an increase of endothelial and inducible NOS immunostaining for oxidative stress and TUNEL analysis revealed increased apoptosis after application of extract. Our findings suggest that the algae we tested may have potential use for treatment of cancer.

  13. Mutagenesis of the yellow fever virus NS2B protein: effects on proteolytic processing, NS2B-NS3 complex formation, and viral replication.

    Science.gov (United States)

    Chambers, T J; Nestorowicz, A; Amberg, S M; Rice, C M

    1993-11-01

    To study the role of specific regions of the yellow fever virus NS2B protein in proteolytic processing and association with the NS3 proteinase domain, a series of mutations were created in the hydrophobic regions and in a central conserved hydrophilic region proposed as a domain important for NS2B function. The effects of these mutations on cis cleavage at the 2B/3 cleavage site and on processing at other consensus cleavage sites for the NS3 proteinase in the nonstructural region were then characterized by cell-free translation and transient expression in BHK cells. Association between NS2B and the NS3 proteinase domain and the effects of mutations on complex formation were investigated by nondenaturing immunoprecipitation of these proteins expressed in infected cells, by cell-free translation, or by recombinant vaccinia viruses. Mutations within the hydrophobic regions had subtle effects on proteolytic processing, whereas mutations within the conserved domain dramatically reduced cleavage efficiency or abolished all cleavages. The conserved domain of NS2B is also implicated in formation of an NS2B-NS3 complex on the basis of the ability of mutations in this region to eliminate both association of these two proteins and trans-cleavage activity. In addition, mutations which either eliminated proteolytic processing or had no apparent effect on processing were found to abolish recovery of infectious virus following RNA transfection. These results suggest that the conserved region of NS2B is a domain essential for the function of the NS3 proteinase. Hydrophobic regions of NS2B whose structural integrity may not be essential for proteolytic processing may have additional functions during viral replication.

  14. Overexpression of SULT2B1b Promotes Angiogenesis in Human Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Wen Chen

    2016-03-01

    Full Text Available Background/Aims: Overexpression of cytosolic sulfotransferase 2B1b (SULT2B1b has been commonly found in colorectal and hepatocellular carcinoma, suggesting that SULT2B1b might act as a potential oncogenic protein. However, its clinical significance and biological role in gastric cancer progression remain largely unknown. Methods: Expressions of SULT2B1b in clinical gastric cancer (GC samples were examined using qRT-PCR and Western blot. Results: SULT2B1b was markedly overexpressed in human GC samples, and positively correlated with vessel density and associated with poor clinical features. We also demonstrated that overexpression of SULT2B1b resulted in increased tumor angiogenesis and tumor growth in mouse GC models. In addition, ablation of SULT2B1b in human GC cells lines BGC823 and MKN45 decreased the capability of the cells to recruit endothelial cells. Moreover, depletion of SULT2B1b in GC cells reduced VEGF-A expression by downregulating SP1 and AP2. Conclusion: Our results suggested that the SULT2B1b-mediated angiogenic pathway could serve as biomarkers for GC diagnosis and prognosis, and suppressing SULT2B1b-mediated angiogenic signaling might be a promising strategy for developing novel GC treatment.

  15. Biodegradation of BOD and ammonia-free using bacterial consortium in aerated fixed film bioreactor (AF2B)

    Science.gov (United States)

    Prayitno, Rulianah, Sri; Saroso, Hadi; Meilany, Diah

    2017-06-01

    BOD and Ammonia-free (NH3-N) are pollutants of hospital wastewater which often exceed the quality standards. It is because biological processes in wastewater treatment plant (WWTP) have not been effective in degrading BOD and NH3-N. Therefore, a study on factors that influence the biodegradation of BOD and NH3-N by choosing the type of bacteria to improve the mechanisms of biodegradation processes is required. Bacterial consortium is a collection of several types of bacteria obtained from isolation process, which is known to be more effective than a single bacterial in degrading pollutants. On the other hand, AF2B is a type of reactor in wastewater treatment system. The AF2B contains a filter media that has a large surface area so that the biodegradation process of pollutants by microorganism can be improved. The objective of this research is to determine the effect of volume of starter and air supplies on decreasing BOD and NH3-N in hospital wastewater using bacterial consortium in the AF2B on batch process. The research was conducted in three stages: the making of the growth curve of the bacterial consortium, bacterial consortium acclimatization, and hospital wastewater treatment in the AF2B with batch process. The variables used are the volume of starter (65%, 75%, and 85% in volume) and air supplies (2.5, 5, and 7.5 L/min). Meanwhile, the materials used are hospital wastewater, bacterial consortium (Pseudomonas diminuta, Pseudomonas capica, Bacillius sp, and Nitrobacter sp), blower, and AF2B. AF2B is a plastic basin containing a filter media with a wasp-nest shape used as a medium for growing the bacterial consortium. In the process of making the growth curve, a solid form of bacterial consortium was dissolved in sterilized water, then grown in a nutrient broth (NB). Then, shaking and sampling were done at any time to determine the path growth of bacterial consortium. In the acclimatization process, bacterial isolates were grown using hospital wastewater as a

  16. B2B marketingová komunikace společnosti John Deere

    OpenAIRE

    Szabó, Attila

    2013-01-01

    The aim of this master's thesis is to evaluate the implementation of the B2B marketing strategy of John Deere on a specific example. The theoretical part of the thesis focuses on defining the basics of modern marketing communications. Next it deals with defining the concept of B2B marketing and related strategies. The practical part focuses on the characterisation of the agricultural machinery industry and the slovak agricultural sector. Further it includes the introduction of other B2B marke...

  17. Doc2b synchronizes secretion from chromaffin cells by stimulating fast and inhibiting sustained release

    DEFF Research Database (Denmark)

    da Silva Pinheiro, Paulo César; de Wit, Heidi; Walter, Alexander M

    2013-01-01

    Synaptotagmin-1 and -7 constitute the main calcium sensors mediating SNARE-dependent exocytosis in mouse chromaffin cells, but the role of a closely related calcium-binding protein, Doc2b, remains enigmatic. We investigated its role in chromaffin cells using Doc2b knock-out mice and high temporal...... resolution measurements of exocytosis. We found that the calcium dependence of vesicle priming and release triggering remained unchanged, ruling out an obligatory role for Doc2b in those processes. However, in the absence of Doc2b, release was shifted from the readily releasable pool to the subsequent...

  18. Insights into CYP2B6-mediated drug–drug interactions

    Directory of Open Access Journals (Sweden)

    William D. Hedrich

    2016-09-01

    Full Text Available Mounting evidence demonstrates that CYP2B6 plays a much larger role in human drug metabolism than was previously believed. The discovery of multiple important substrates of CYP2B6 as well as polymorphic differences has sparked increasing interest in the genetic and xenobiotic factors contributing to the expression and function of the enzyme. The expression of CYP2B6 is regulated primarily by the xenobiotic receptors constitutive androstane receptor (CAR and pregnane X receptor (PXR in the liver. In addition to CYP2B6, these receptors also mediate the inductive expression of CYP3A4, and a number of important phase II enzymes and drug transporters. CYP2B6 has been demonstrated to play a role in the metabolism of 2%–10% of clinically used drugs including widely used antineoplastic agents cyclophosphamide and ifosfamide, anesthetics propofol and ketamine, synthetic opioids pethidine and methadone, and the antiretrovirals nevirapine and efavirenz, among others. Significant inter-individual variability in the expression and function of the human CYP2B6 gene exists and can result in altered clinical outcomes in patients receiving treatment with CYP2B6-substrate drugs. These variances arise from a number of sources including genetic polymorphism, and xenobiotic intervention. In this review, we will provide an overview of the key players in CYP2B6 expression and function and highlight recent advances made in assessing clinical ramifications of important CYP2B6-mediated drug–drug interactions.

  19. Insights into CYP2B6-mediated drug-drug interactions.

    Science.gov (United States)

    Hedrich, William D; Hassan, Hazem E; Wang, Hongbing

    2016-09-01

    Mounting evidence demonstrates that CYP2B6 plays a much larger role in human drug metabolism than was previously believed. The discovery of multiple important substrates of CYP2B6 as well as polymorphic differences has sparked increasing interest in the genetic and xenobiotic factors contributing to the expression and function of the enzyme. The expression of CYP2B6 is regulated primarily by the xenobiotic receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) in the liver. In addition to CYP2B6, these receptors also mediate the inductive expression of CYP3A4, and a number of important phase II enzymes and drug transporters. CYP2B6 has been demonstrated to play a role in the metabolism of 2%-10% of clinically used drugs including widely used antineoplastic agents cyclophosphamide and ifosfamide, anesthetics propofol and ketamine, synthetic opioids pethidine and methadone, and the antiretrovirals nevirapine and efavirenz, among others. Significant inter-individual variability in the expression and function of the human CYP2B6 gene exists and can result in altered clinical outcomes in patients receiving treatment with CYP2B6-substrate drugs. These variances arise from a number of sources including genetic polymorphism, and xenobiotic intervention. In this review, we will provide an overview of the key players in CYP2B6 expression and function and highlight recent advances made in assessing clinical ramifications of important CYP2B6-mediated drug-drug interactions.

  20. Targeting Sulfotransferase (SULT) 2B1b as a regulator of Cholesterol Metabolism in Prostate Cancer

    Science.gov (United States)

    2016-10-01

    SULT2B1b activity pro- motes hepatocellular carcinoma cell growth in vitro and in vivo, and SULT2B1b expression correlates with poor prognosis and...rescues cell growth in LNCaP with SULT2B1b KD. A) Western blot showing expression levels of indicated proteins . Cells were harvested 60 hours after...induces cell death. SULT2B1b KD also decreases androgen receptor (AR) activity and expression at mRNA and protein levels. While AR overexpression hasno

  1. Emotional disorders in adult mice heterozygous for the transcription factor Phox2b.

    Science.gov (United States)

    Bollen, Bieke; Ramanantsoa, Nelina; Naert, Arne; Matrot, Boris; Van den Bergh, Omer; D'Hooge, Rudi; Gallego, Jorge

    2015-03-15

    Phox2b is an essential transcription factor for the development of the autonomic nervous system. Mice carrying one invalidated Phox2b allele (Phox2b(+/-)) show mild autonomic disorders including sleep apneas, and impairments in chemosensitivity and thermoregulation that recover within 10days of postnatal age. Because Phox2b is not expressed above the pons nor in the cerebellum, this mutation is not expected to affect brain development and cognitive functioning directly. However, the transient physiological disorders in Phox2b(+/-) mice might impair neurodevelopment. To examine this possibility, we conducted a behavioral test battery of emotional, motor, and cognitive functioning in adult Phox2b(+/-) mice and their wildtype littermates (Phox2b(+/+)). Adult Phox2b(+/-) mice showed altered exploratory behavior in the open field and in the elevated plus maze, both indicative of anxiety. Phox2b(+/-) mice did not show cognitive or motor impairments. These results suggest that also mild autonomic control deficits may disturb long-term emotional development. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Administration of soluble activin receptor 2B increases bone and muscle mass in a mouse model of osteogenesis imperfecta

    Science.gov (United States)

    DiGirolamo, Douglas J.; Singhal, Vandana; Chang, Xiaoli; Lee, Se-Jin; Germain-Lee, Emily L.

    2015-01-01

    Osteogenesis imperfecta (OI) comprises a group of heritable connective tissue disorders generally defined by recurrent fractures, low bone mass, short stature and skeletal fragility. Beyond the skeletal complications of OI, many patients also report intolerance to physical activity, fatigue and muscle weakness. Indeed, recent studies have demonstrated that skeletal muscle is also negatively affected by OI, both directly and indirectly. Given the well-established interdependence of bone and skeletal muscle in both physiology and pathophysiology and the observations of skeletal muscle pathology in patients with OI, we investigated the therapeutic potential of simultaneous anabolic targeting of both bone and skeletal muscle using a soluble activin receptor 2B (ACVR2B) in a mouse model of type III OI (oim). Treatment of 12-week-old oim mice with ACVR2B for 4 weeks resulted in significant increases in both bone and muscle that were similar to those observed in healthy, wild-type littermates. This proof of concept study provides encouraging evidence for a holistic approach to treating the deleterious consequences of OI in the musculoskeletal system. PMID:26161291

  3. Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.

    Science.gov (United States)

    Wu, Ye; Pan, Yanxia; Du, Li; Wang, Jingmin; Gu, Qiang; Gao, Zhijie; Li, Jie; Leng, Xuerong; Qin, Jiong; Wu, Xiru; Jiang, Yuwu

    2009-02-01

    Vanishing white matter (VWM) disease, inherited in an autosomal recessive manner, is one of the most prevalent inherited leukoencephalopathies in childhood. It is a hereditary human disease resulting from the direct defects during protein synthesis, with the gene defects in EIF2B1-5 (identified in 2001-2002) encoding the five subunits of eukaryotic translation initiation factor (eIF2B alpha, beta, gamma, delta and epsilon), respectively. Most of the published studies were carried out in the white population. The analysis of clinical features and EIF2B mutation screening were performed in 11 Chinese patients for the first time. Mutations were identified exclusively in EIF2B5 and EIF2B3 in these patients, with six novel mutations, including five missense mutations (EIF2B5: c.185A>T, p.D62V; c.1004G>C, p.C335S; c.1126A>G, p.N376D; EIF2B3: c.140G>A, p.G47E; c.1037T>C, p.I346T) and one deletion leading to amino-acid deletion (EIF2B5: c.1827-1838del, p.S610-D613del). EIF2B3 mutation, accounting for 20% of the total number of mutations found in this study, is more prevalent than expected according to an earlier report (7%). A hot spot mutation in EIF2B3 was identified in this study. A unique EIF2B mutation spectrum in Chinese VWM patients was shown. A systemic study to assess mutation spectrum in different populations needs to be carried out.

  4. Responses to peginterferon alfa-2a vs alfa-2b plus ribavirin in a Mexican population with chronic hepatitis C.

    Science.gov (United States)

    Sandoval-Ramirez, Jorge Luis; Mata-Marín, José Antonio; Huerta García, Gloria; Gaytán-Martínez, Jesús Enrique

    2015-03-15

    The WHO estimates that 180 million people are chronically infected with hepatitis C virus (HCV) throughout the world. Despite the emergence of new therapies, the combination of pegylated interferon and ribavirin remains the accepted standard of care in low-income countries, including Mexico. Two types of peginterferon are available (peginterferon alfa-2a and peginterferon alfa-2b), and both are recommended for the treatment of HCV, although there is controversy over which treatment option is most effective. This was a retrospective cohort study at a infectious disease center in Mexico City. Patients were included if they had received peginterferon alfa-2a or peginterferon alfa-2b plus ribavirin. Age, sex, body mass index, AST platelet ratio index, HCV RNA viral load, levels of alanine aminotransferase, aspartate aminotransferase, bilirubin, albumin, and hemoglobin, and platelet and leukocyte counts of the subjects were assessed before treatment and at weeks 4, 12, 24, 48, and 6 months post treatment. Eighty-seven patients met the inclusion criteria. A sustained virological response (SVR) occurred in 33 (38%) of them, 11 (33%) given peginterferon alfa-2a and 22 (67%) given peginterferon alfa-2b (p = 0.17). Seventeen patients (20%) relapsed, 7 (41%) of those given peginterferon alfa-2a and 10 (59%) of those given peginterferon alfa-2b (p = 0.76); 27 (31%) patients were non-responders (p = 0.09). The rates of anemia, thrombocytopenia, and leukopenia were similar in both groups. Similar SVR rates and frequencies of adverse events were observed. Either type of interferon can be used to treat HCV infection in the Mexican population.

  5. 77 FR 28764 - Temporary Non-agricultural Employment of H-2B Aliens in the United States

    Science.gov (United States)

    2012-05-16

    ... H-2B Aliens in the United States AGENCY: Employment and Training Administration, Labor. ] ACTION... Aliens in the United States, published February 21, 2012 (the 2012 H-2B Final Rule). The 2012 H-2B Final...

  6. Neutron diffraction studies of magnetic ordering in superconducting ErNi2B2C and TmNi2B2C in an applied magnetic field

    DEFF Research Database (Denmark)

    Toft, Katrine Nørgaard

    The field-induced magnetic structures of ErNi2B2C and TmNi2B2C in are especially interesting because the field suppresses the superconducting order parameter and therefore the magnetic properties can be studied while varying the strength ofsuperconductivity. ErNi2B2C: For magnetic fields along all...... three symmetry directions, the observed magnetic structures have a period corresponding to the Fermi surface nesting structure. The phase diagrams present all the observed magnetic structures.Two results remain unresolved: 1. When applying the magnetic field along [010], the minority domain (QNB = (0,Q......,0) with moments perpendicular to the field) shows no signs of hysteresis. I expected it to be a meta-stable state, which would be graduallysuppressed by a magnetic field, and when decreasing the field it would not reappear until some small field of approximately 0.1 T. 2. When the field is applied...

  7. Data of evolutionary structure change: 1CERP-2B4RR [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1CERP-2B4RR 1CER 2B4R P R -MKVGINGFGRIGRQVFRILHSRG-VEVALINDLT-DNKTLAHLLKYDSIYHRFPG...1CER P 1CERP LHSRG-VEVAL ...1CER P 1CERP INDLT-DNKTL ...1CER P 1CERP DLPHK---DLRRA...1CER P 1CERP DAKLT-KALGN

  8. Data of evolutionary structure change: 1CERP-2B4RO [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1CERP-2B4RO 1CER 2B4R P O -MKVGINGFGRIGRQVFRILHSRG-VEVALINDLT-DNKTLAHLLKYDSIYHRFPG...1CER P 1CERP LHSRG-VEVAL ...1CER P 1CERP INDLT-DNKTL ...1CER P 1CERP DLPHK---DLRRA...1CER P 1CERP TKALG-NMVKV

  9. Data of evolutionary structure change: 1CERP-2B4TQ [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1CERP-2B4TQ 1CER 2B4T P Q MKVGINGFGRIGRQVFRILHSRG-VEVALINDLT-DNKTLAHLLKYDSIYHRFPGE...1CER P 1CERP LHSRG-VEVAL ...1CER P 1CERP INDLT-DNKTL ...1CER P 1CERP DLPHK---DLRRA...1CER P 1CERP DAKLT-KALGN

  10. Data of evolutionary structure change: 1CERP-2B4TO [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1CERP-2B4TO 1CER 2B4T P O MKVGINGFGRIGRQVFRILHSRG-VEVALINDLT-DNKTLAHLLKYDSIYHRFPGE...1CER P 1CERP LHSRG-VEVAL ...1CER P 1CERP INDLT-DNKTL ...1CER P 1CERP DLPHK---DLRRA...1CER P 1CERP DAKLT-KALGN

  11. Data of evolutionary structure change: 1CERP-2B4RP [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1CERP-2B4RP 1CER 2B4R P P -MKVGINGFGRIGRQVFRILHSRG-VEVALINDLT-DNKTLAHLLKYDSIYHRFPG...1CER P 1CERP LHSRG-VEVAL ...1CER P 1CERP INDLT-DNKTL ...1CER P 1CERP DLPHK---DLRRA...1CER P 1CERP DAKLT-KALGN

  12. Data of evolutionary structure change: 1CERP-2B4TR [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1CERP-2B4TR 1CER 2B4T P R MKVGINGFGRIGRQVFRILHSRG-VEVALINDLT-DNKTLAHLLKYDSIYHRFPGE...1CER P 1CERP LHSRG-VEVAL ...1CER P 1CERP INDLT-DNKTL ...1CER P 1CERP DLPHK---DLRRA...1CER P 1CERP DAKLT-KALGN

  13. Data of evolutionary structure change: 15C8H-32C2B [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available ain>H 15C8H FNIKD-TYMHW ...> GGG- EEEEture> ATOM 1815 CA PHE H 27 28.7...tryIDChain>32C2B YSISSDYAWNW ucture> EEture...pdbChain> 32C2B GYISY-SGSTS >EEEE - EEE...ce>AQIDPANGNTK >EEEE EEE> ATOM 2

  14. SRC Inhibition Reduces NR2B Surface Expression and Synaptic Plasticity in the Amygdala

    Science.gov (United States)

    Sinai, Laleh; Duffy, Steven; Roder, John C.

    2010-01-01

    The Src protein tyrosine kinase plays a central role in the regulation of N-methyl-d-aspartate receptor (NMDAR) activity by regulating NMDAR subunit 2B (NR2B) surface expression. In the amygdala, NMDA-dependent synaptic plasticity resulting from convergent somatosensory and auditory inputs contributes to emotional memory; however, the role of Src…

  15. Water‐Data Report 413721083124001 Pool 2B at Ottawa NWR-2009

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Water levels and water quality parameters recorded on Pool 2B. Water-Data Report 2009 413721083124001 Pool 2B at Ottawa NWR LOCATION: Lat. 41°37'21.08"N, long...

  16. Water‐Data Report 413721083124001 Pool 2B at Ottawa NWR-2012

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Water levels and water quality parameters recorded on Pool 2B. Water-Data Report 2012 413721083124001 Pool 2B at Ottawa NWR LOCATION: Lat. 41°37'21.08"N, long...

  17. Water‐Data Report 413721083124001 Pool 2B at Ottawa NWR-2011

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Water levels and water quality parameters recorded on Pool 2B. Water-Data Report 2011 413721083124001 Pool 2B at Ottawa NWR LOCATION: Lat. 41°37'21.08"N, long...

  18. Water‐Data Report 413721083124001 Pool 2B at Ottawa NWR-2010

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Water levels and water quality parameters recorded on Pool 2B. Water-Data Report 2010 413721083124001 Pool 2B at Ottawa NWR LOCATION: Lat. 41°37'21.08"N, long...

  19. RSCAT_LEVEL_2B_OWV_COMP_12_V1.1:1

    Data.gov (United States)

    National Aeronautics and Space Administration — This dataset contains the RapidScat Level 2B 12.5km Version 1.1 science-quality ocean surface wind vectors. The Level 2B wind vectors are binned on a 12.5 km Wind...

  20. Data of evolutionary structure change: 2B9RA-2BPMD [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 2B9RA-2BPMD 2B9R 2BPM A D -VKDIYAYLRQLEAAQAVRPKYLLGR-EVTGNMRAILID...line>THR CA 261 GLY CA 332 ASN CA 307 2BPM... D 2BPMD YMKKQPDITNS .../line> ASP CA 206 VAL CA 247 GLU CA 298 2BPM... D 2BPMD

  1. 75 FR 13451 - Airworthiness Directives; Turbomeca Arriel 2B1 Turboshaft Engines

    Science.gov (United States)

    2010-03-22

    ... 2B1 Turboshaft Engines AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Notice of proposed... Arriel 2B1 turboshaft engines. This proposed AD results from mandatory continuing airworthiness...-2251. FOR FURTHER INFORMATION CONTACT: Kevin Dickert, Aerospace Engineer, Engine Certification Office...

  2. Effect of Npt2b deletion on intestinal and renal inorganic phosphate (Pi) handling.

    Science.gov (United States)

    Ikuta, Kayo; Segawa, Hiroko; Sasaki, Shohei; Hanazaki, Ai; Fujii, Toru; Kushi, Aoi; Kawabata, Yuka; Kirino, Ruri; Sasaki, Sumire; Noguchi, Miwa; Kaneko, Ichiro; Tatsumi, Sawako; Ueda, Otoya; Wada, Naoko A; Tateishi, Hiromi; Kakefuda, Mami; Kawase, Yosuke; Ohtomo, Shuichi; Ichida, Yasuhiro; Maeda, Akira; Jishage, Kou-Ichi; Horiba, Naoshi; Miyamoto, Ken-Ichi

    2017-11-11

    Hyperphosphatemia is common in chronic kidney disease and is associated with morbidity and mortality. The intestinal Na+-dependent phosphate transporter Npt2b is thought to be an important molecular target for the prevention of hyperphosphatemia. The role of Npt2b in the net absorption of inorganic phosphate (Pi), however, is controversial. In the present study, we made tamoxifen-inducible Npt2b conditional knockout (CKO) mice to analyze systemic Pi metabolism, including intestinal Pi absorption. Although the Na+-dependent Pi transport in brush-border membrane vesicle uptake levels was significantly decreased in the distal intestine of Npt2b CKO mice compared with control mice, plasma Pi and fecal Pi excretion levels were not significantly different. Data obtained using the intestinal loop technique showed that Pi uptake in Npt2b CKO mice was not affected at a Pi concentration of 4 mM, which is considered the typical luminal Pi concentration after meals in mice. Claudin, which may be involved in paracellular pathways, as well as claudin-2, 12, and 15 protein levels were significantly decreased in the Npt2b CKO mice. Thus, Npt2b deficiency did not affect Pi absorption within the range of Pi concentrations that normally occurs after meals. These findings indicate that abnormal Pi metabolism may also be involved in tight junction molecules such as Cldns that are affected by Npt2b deficiency.

  3. Identification of Phox2b-regulated genes by expression profiling of cranial motoneuron precursors

    Directory of Open Access Journals (Sweden)

    Reiprich Simone

    2008-06-01

    Full Text Available Abstract Background Branchiomotor neurons comprise an important class of cranial motor neurons that innervate the branchial-arch-derived muscles of the face, jaw and neck. They arise in the ventralmost progenitor domain of the rhombencephalon characterized by expression of the homeodomain transcription factors Nkx2.2 and Phox2b. Phox2b in particular plays a key role in the specification of branchiomotor neurons. In its absence, generic neuronal differentiation is defective in the progenitor domain and no branchiomotor neurons are produced. Conversely, ectopic expression of Phox2b in spinal regions of the neural tube promotes cell cycle exit and neuronal differentiation and, at the same time, induces genes and an axonal phenotype characteristic for branchiomotor neurons. How Phox2b exerts its pleiotropic functions, both as a proneural gene and a neuronal subtype determinant, has remained unknown. Results To gain further insights into the genetic program downstream of Phox2b, we searched for novel Phox2b-regulated genes by cDNA microarray analysis of facial branchiomotor neuron precursors from heterozygous and homozygous Phox2b mutant embryos. We selected for functional studies the genes encoding the axonal growth promoter Gap43, the Wnt antagonist Sfrp1 and the transcriptional regulator Sox13, which were not previously suspected to play roles downstream of Phox2b and whose expression was affected by Phox2b misexpression in the spinal cord. While Gap43 did not produce an obvious phenotype when overexpressed in the neural tube, Sfrp1 induced the interneuron marker Lhx1,5 and Sox13 inhibited neuronal differentiation. We then tested whether Sfrp1 and Sox13, which are down-regulated by Phox2b in the facial neuron precursors, would antagonize some aspects of Phox2b activity. Co-expression of Sfrp1 prevented Phox2b from repressing Lhx1,5 and alleviated the commissural axonal phenotype. When expressed together with Sox13, Phox2b was still able to promote

  4. Nonlinear Elasticity of Borocarbide Superconductor YNi2B2C: A First-Principles Study

    Directory of Open Access Journals (Sweden)

    Lili Liu

    2017-01-01

    Full Text Available First-principles calculations combined with homogeneous deformation methods are used to investigate the second- and third-order elastic constants of YNi2B2C with tetragonal structure. The predicted lattice constants and second-order elastic constants of YNi2B2C agree well with the available data. The effective second-order elastic constants are obtained from the second- and third-order elastic constants for YNi2B2C. Based on the effective second-order elastic constants, Pugh’s modulus ratio, Poisson’s ratio, and Vickers hardness of YNi2B2C under high pressure are further investigated. It is shown that the ductility of YNi2B2C increases with increasing pressure.

  5. CDKN2B methylation is associated with carotid artery calcification in ischemic stroke patients

    Directory of Open Access Journals (Sweden)

    Shuyu Zhou

    2016-12-01

    Full Text Available Abstract Background Cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B near chromosome 9p21 have been associated with both atherosclerosis and artery calcification, but the underlying mechanisms remained largely unknown. Considering that CDKN2A/2B is a frequently reported site for DNA methylation, this study aimed to evaluate whether carotid artery calcification (CarAC is related to methylation levels of CDKN2A/2B in patients with ischemic stroke. Methods DNA methylation levels of CDKN2A/2B were measured in 322 ischemic stroke patients using peripheral blood leukocytes. Methylation levels of 36 CpG sites around promoter regions of CDKN2A/2B were examined with BiSulfite Amplicon Sequencing. CarAC was quantified with Agatston score based on results of computed tomography angiography. Generalized liner model was performed to explore the association between methylation levels and CarAC. Results Of the 322 analyzed patients, 187 (58.1% were classified as with and 135 (41.9% without evident CarAC. The average methylation levels of CDKN2B were higher in patents with CarAC than those without (5.7 vs 5.4, p = 0.001. After adjustment for potential confounders, methylation levels of CDKN2B were positively correlated with cube root transformed calcification scores (β = 0.591 ± 0.172, p = 0.001 in generalized liner model. A positive correlation was also detected between average methylation levels of CDKN2B and cube root transformed calcium volumes (β = 0.533 ± 0.160, p = 0.001. Conclusions DNA methylation of CDKN2B may play a potential role in artery calcification.

  6. Expression, purification, and crystallization of Schizosaccharomyces pombe eIF2B.

    Science.gov (United States)

    Kashiwagi, Kazuhiro; Shigeta, Tomoaki; Imataka, Hiroaki; Ito, Takuhiro; Yokoyama, Shigeyuki

    2016-03-01

    Tight control of protein synthesis is necessary for cells to respond and adapt to environmental changes rapidly. Eukaryotic translation initiation factor (eIF) 2B, the guanine nucleotide exchange factor for eIF2, is a key target of translation control at the initiation step. The nucleotide exchange activity of eIF2B is inhibited by the stress-induced phosphorylation of eIF2. As a result, the level of active GTP-bound eIF2 is lowered, and protein synthesis is attenuated. eIF2B is a large multi-subunit complex composed of five different subunits, and all five of the subunits are the gene products responsible for the neurodegenerative disease, leukoencephalopathy with vanishing white matter. However, the overall structure of eIF2B has remained unresolved, due to the difficulty in preparing a sufficient amount of the eIF2B complex. To overcome this problem, we established the recombinant expression and purification method for eIF2B from the fission yeast Schizosaccharomyces pombe. All five of the eIF2B subunits were co-expressed and reconstructed into the complex in Escherichia coli cells. The complex was successfully purified with a high yield. This recombinant eIF2B complex contains each subunit in an equimolar ratio, and the size exclusion chromatography analysis suggests it forms a heterodecamer, consistent with recent reports. This eIF2B increased protein synthesis in the reconstituted in vitro human translation system. In addition, disease-linked mutations led to subunit dissociation. Furthermore, we crystallized this functional recombinant eIF2B, and the crystals diffracted to 3.0 Å resolution.

  7. Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B

    Directory of Open Access Journals (Sweden)

    Yu Zhang

    2017-03-01

    Full Text Available The truncated mutant form of the charged multivesicular body protein 2B (CHMP2B is causative for frontotemporal dementia linked to chromosome 3 (FTD3. CHMP2B is a constituent of the endosomal sorting complex required for transport (ESCRT and, when mutated, disrupts endosome-to-lysosome trafficking and substrate degradation. To understand the underlying molecular pathology, FTD3 patient induced pluripotent stem cells (iPSCs were differentiated into forebrain-type cortical neurons. FTD3 neurons exhibited abnormal endosomes, as previously shown in patients. Moreover, mitochondria of FTD3 neurons displayed defective cristae formation, accompanied by deficiencies in mitochondrial respiration and increased levels of reactive oxygen. In addition, we provide evidence for perturbed iron homeostasis, presenting an in vitro patient-specific model to study the effects of iron accumulation in neurodegenerative diseases. All phenotypes observed in FTD3 neurons were rescued in CRISPR/Cas9-edited isogenic controls. These findings illustrate the relevance of our patient-specific in vitro models and open up possibilities for drug target development.

  8. Research of B2B e-Business Application and Development Technology Based on SOA

    Science.gov (United States)

    Xian, Li Liang

    Today, the B2B e-business systems in most enterprises usually have multiple heterogeneous and independent systems which are based on different platforms and operate in different functional departments. To deal with the increased services in future, an enterprise needs to expand its system continuously. This, however, will cause great inconvenience to the future system maintenance. To implement e-business successfully, a unified internal e-business integration environment must be established to integrate the internal system and thus realize a unified internal mechanism within the enterprise e-business system. The SOA (service-oriented architecture), however, can well meet the above requirements. The integration of SOA-based applications can reduce the dependency of different types of IT systems, reduce the cost of system maintenance and the complexity of the IT system operation, increase the flexibility of the system deployment, and at the same time exclude the barrier of service innovation. Research and application of SOA-based enterprise application systems has become a very important research project at present. Based on SOA, this document designs an enterprise e-business application model and realizes a flexible and expandable e-business platform.

  9. Laser surface treatment of S235JRC carbon steel with Co{sub 2}B nanocrystals

    Energy Technology Data Exchange (ETDEWEB)

    Simsek, Tuncay [Hacettepe Univ., Ankara (Turkey). Dept. of Physics Engineering; Baris, Mustafa [Eti Maden Works General Management, Ankara (Turkey). Dept. of Technology Development; Akkurt, Adnan [Gazi Univ., Ankara (Turkey). Dept. of Industrial Design Engineering

    2017-06-15

    In this study, Co{sub 2}B nanocrystals, which were synthesized in a planetary type mill by using the mechanochemical method, were pre-coated on the surface of S235JRC low carbon steel substrates, and then the surfaces were clad using a CO{sub 2} laser. In the experiments, laser scan speed was kept constant and laser power was specified as the variable parameter. The microstructure and phases of the coatings were investigated by using X-ray diffractometry, scanning electron microscopy, and optical microscopy. The mechanical properties of the coatings were characterized using micro-hardness, ball-on-disc wear, and scratch testing. The thickness of the coatings depending on the laser power was measured in the range 35-71 μm. The hardness and the wear resistance of the coatings were approximately 3 times higher compared to the base metal due to FeN{sub 0.0760}, Fe{sub 15.1}C, FeCo, and B{sub 2}C{sub 5}N{sub 2} phases of the coatings. The most durable coatings against wear were obtained at 174 W and 220 W laser powers.

  10. Recombinant human interferon alpha 2b prevents and reverses experimental pulmonary hypertension.

    Directory of Open Access Journals (Sweden)

    Eileen M Bauer

    Full Text Available Pulmonary hypertension (PH is a progressive and fatal disease with no cure. Vascular remodeling in PH involves intraluminal growth of endothelial and smooth muscle cells, leading to obliterative vascular lesions. Cell growth in these lesions is quasi-neoplastic, with evidence of monoclonality, apoptosis resistance and cancer-like metabolic derangements. Herein we tested the effect of human interferon alpha 2b (IFNα, a pleiotropic cytokine and anti-cancer therapeutic, on the development and progression of PH in the rat SU5416/hypoxia (SUH model and mouse hypoxia model of the disease. In both models IFNα attenuated the development of PH and reversed established PH as assessed by measuring right ventricular systolic pressure and right ventricular hypertrophy. The effect of IFNα was dependent on the type I interferon receptor (IFNAR since mice lacking a subunit of the IFNAR were not protected by IFNα. Morphometric analysis of pulmonary aterioles from hypoxic mice or SUH rats showed that IFNα inhibited pulmonary vascular remodeling in both models and that IFNα reversed remodeling in SUH rats with established disease. Immunohistochemical staining revealed that IFNα decreased the number of PCNA and Tunel positive cells in the wall of pulmonary arterioles. In vitro, IFNα inhibited proliferation of human pulmonary artery smooth muscle cells and as well as human pulmonary artery endothelial cell proliferation and apoptosis. Together these findings demonstrate that IFNα reverses established experimental PH and provide a rationale for further exploration of the use of IFNα and other immunotherpies in PH.

  11. Metformin Represses Drug-Induced Expression of CYP2B6 by Modulating the Constitutive Androstane Receptor Signaling

    Science.gov (United States)

    Yang, Hui; Garzel, Brandy; Heyward, Scott; Moeller, Timothy; Shapiro, Paul

    2014-01-01

    Metformin is currently the most widely used drug for the treatment of type 2 diabetes. Mechanistically, metformin interacts with many protein kinases and transcription factors that alter the expression of numerous downstream target genes governing lipid metabolism, cell proliferation, and drug metabolism. The constitutive androstane receptor (CAR, NR1i3), a known xenobiotic sensor, has recently been recognized as a novel signaling molecule, in that its activation could be regulated by protein kinases in addition to the traditional ligand binding. We show that metformin could suppress drug-induced expression of CYP2B6 (a typical target gene of CAR) by modulating the phosphorylation status of CAR. In human hepatocytes, metformin robustly suppressed the expression of CYP2B6 induced by both indirect (phenobarbital) and direct CITCO [6-(4-chlorophenyl)imidazo[2,1-b]1,3thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime] activators of human CAR. Mechanistic investigation revealed that metformin specifically enhanced the phosphorylation of threonine-38 of CAR, which blocks CAR nuclear translocation and activation. Moreover, we showed that phosphorylation of CAR by metformin was primarily an AMP-activated protein kinase– and extracellular signal-regulated kinase 1/2–dependent event. Additional two-hybrid and coimmunoprecipitation assays demonstrated that metformin could also disrupt CITCO-mediated interaction between CAR and the steroid receptor coactivator 1 or the glucocorticoid receptor-interacting protein 1. Our results suggest that metformin is a potent repressor of drug-induced CYP2B6 expression through specific inhibition of human CAR activation. Thus, metformin may affect the metabolism and clearance of drugs that are CYP2B6 substrates. PMID:24252946

  12. The A2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease.

    Science.gov (United States)

    Karmouty-Quintana, Harry; Zhong, Hongyan; Acero, Luis; Weng, Tingting; Melicoff, Ernestina; West, James D; Hemnes, Anna; Grenz, Almut; Eltzschig, Holger K; Blackwell, Timothy S; Xia, Yang; Johnston, Richard A; Zeng, Dewan; Belardinelli, Luiz; Blackburn, Michael R

    2012-06-01

    Development of pulmonary hypertension is a common and deadly complication of interstitial lung disease. Little is known regarding the cellular and molecular mechanisms that lead to pulmonary hypertension in patients with interstitial lung disease, and effective treatment options are lacking. The purpose of this study was to examine the adenosine 2B receptor (A(2B)R) as a regulator of vascular remodeling and pulmonary hypertension secondary to pulmonary fibrosis. To accomplish this, cellular and molecular changes in vascular remodeling were monitored in mice exposed to bleomycin in conjunction with genetic removal of the A(2B)R or treatment with the A(2B)R antagonist GS-6201. Results demonstrated that GS-6201 treatment or genetic removal of the A(2B)R attenuated vascular remodeling and hypertension in our model. Furthermore, direct A(2B)R activation on vascular cells promoted interleukin-6 and endothelin-1 release. These studies identify a novel mechanism of disease progression to pulmonary hypertension and support the development of A(2B)R antagonists for the treatment of pulmonary hypertension secondary to interstitial lung disease.

  13. Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b

    Directory of Open Access Journals (Sweden)

    Lee Robert E

    2006-01-01

    Full Text Available Abstract Background There have been indications that common Angiotensin Receptor Blockers (ARBs may be exerting anti-inflammatory actions by directly modulating the immune system. We decided to use molecular modelling to rapidly assess which of the potential targets might justify the expense of detailed laboratory validation. We first studied the VDR nuclear receptor, which is activated by the secosteroid hormone 1,25-dihydroxyvitamin-D. This receptor mediates the expression of regulators as ubiquitous as GnRH (Gonadatrophin hormone releasing hormone and the Parathyroid Hormone (PTH. Additionally we examined Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma, which affects the function of phagocytic cells, and the C-CChemokine Receptor, type 2b, (CCR2b, which recruits monocytes to the site of inflammatory immune challenge. Results Telmisartan was predicted to strongly antagonize (Ki≈0.04nmol the VDR. The ARBs Olmesartan, Irbesartan and Valsartan (Ki≈10 nmol are likely to be useful VDR antagonists at typical in-vivo concentrations. Candesartan (Ki≈30 nmol and Losartan (Ki≈70 nmol may also usefully inhibit the VDR. Telmisartan is a strong modulator of PPARgamma (Ki≈0.3 nmol, while Losartan (Ki≈3 nmol, Irbesartan (Ki≈6 nmol, Olmesartan and Valsartan (Ki≈12 nmol also seem likely to have significant PPAR modulatory activity. Olmesartan andIrbesartan (Ki≈9 nmol additionally act as antagonists of a theoretical modelof CCR2b. Initial validation of this CCR2b model was performed, and a proposed model for the AngiotensinII Type1 receptor (AT2R1 has been presented. Conclusion Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ligand binding and is an important tool in drug design. ARBs were designed to act as antagonists for AT2R1, and it was not surprising to discover their affinity for the structurally similar CCR2b. However, this study also found evidence that ARBs modulate the

  14. Serotonin 2B receptor signaling is required for craniofacial morphogenesis and jaw joint formation in Xenopus.

    Science.gov (United States)

    Reisoli, Elisa; De Lucchini, Stefania; Nardi, Irma; Ori, Michela

    2010-09-01

    Serotonin (5-HT) is a neuromodulator that plays many different roles in adult and embryonic life. Among the 5-HT receptors, 5-HT2B is one of the key mediators of 5-HT functions during development. We used Xenopus laevis as a model system to further investigate the role of 5-HT2B in embryogenesis, focusing on craniofacial development. By means of gene gain- and loss-of-function approaches and tissue transplantation assays, we demonstrated that 5-HT2B modulates, in a cell-autonomous manner, postmigratory skeletogenic cranial neural crest cell (NCC) behavior without altering early steps of cranial NCC development and migration. 5-HT2B overexpression induced the formation of an ectopic visceral skeletal element and altered the dorsoventral patterning of the branchial arches. Loss-of-function experiments revealed that 5-HT2B signaling is necessary for jaw joint formation and for shaping the mandibular arch skeletal elements. In particular, 5-HT2B signaling is required to define and sustain the Xbap expression necessary for jaw joint formation. To shed light on the molecular identity of the transduction pathway acting downstream of 5-HT2B, we analyzed the function of phospholipase C beta 3 (PLC) in Xenopus development and showed that PLC is the effector of 5-HT2B during craniofacial development. Our results unveiled an unsuspected role of 5-HT2B in craniofacial development and contribute to our understanding of the interactive network of patterning signals that is involved in the development and evolution of the vertebrate mandibular arch.

  15. Lentivirus-mediated downregulation of MAT2B inhibits cell proliferation and induces apoptosis in melanoma.

    Science.gov (United States)

    Lei, Yu; Zhang, Bo; Zhang, Yaohua; Zhao, Yuan; Sun, Jingying; Zhang, Xuejun; Yang, Sen

    2016-09-01

    Malignant melanoma is the most lethal of skin cancers and its pathogenesis is complex and heterogeneous. The efficacy of conventional therapeutic regimens for melanoma remains limited. Thus, it is important to explore novel effective therapeutic targets in the treatment of melanoma. The MAT2B gene encodes for the regulatory subunit of methionine adenosyltransferase (MAT). Recent studies have suggested that MAT2B may have functional roles other than modulating catalytic activity of MAT. In order to identify the roles of MAT2B in the tumorigenesis of malignant melanoma, we compared MAT2B expression profile in melanoma tissues with that in benign nevus samples. We employed lentivirus-mediated RNAi to downregulate the expression of MAT2B in malignant melanoma cell lines (A375 and Mel-RM), and investigated the effects of MAT2B on cell growth, colony-formation ability and apoptosis in vitro, as well as tumor growth of a xenograft model in vivo. The expression levels of BCL2 and XAF1 proteins, which were closely related to tumor cell apoptosis, were analyzed by western blot analysis. Our data showed that MAT2B was elevated in both primary and metastatic melanoma tissues compared with benign nevus samples. Lentivirus-mediated downregulation of MAT2B suppressed cell growth, colony formation and induced apoptosis in A375 and Mel-RM cell lines in vitro, affected protein expression of BCL2 and XAF1, extended the transplanted tumor growth in vivo. These results indicated that MAT2B was critical in the proliferation of melanoma cells and tumorigenicity. It may be considered as a potential anti-melanoma therapeutic target.

  16. High performance of solvothermally prepared VO2(B) as anode for aqueous rechargeable lithium batteries

    OpenAIRE

    Milošević Sanja; Stojković Ivana; Mitrić Miodrag; Cvjetićanin Nikola

    2015-01-01

    The VO2 (B) was synthesized via a simple solvothermal route at 160oC in ethanol. The initial discharge capacity of VO2 (B) anode, in saturated aqueous solution of LiNO3, was 177 mAh g-1 at a current rate of 50 mA g-1. After 50 cycles capacity fade was 4%, but from 20th-50th cycle no capacity drop was observed. The VO2 (B) has shown very good cyclability at current rate of even 1000 mA g-1 with initial discharge capacity of 92 mAh g-1. The excellent electroc...

  17. Reversal of pathology in CHMP2B-mediated frontotemporal dementia patient cells using RNA interference

    DEFF Research Database (Denmark)

    Nielsen, Troels Tolstrup; Mizielinska, Sarah; Hasholt, Lis

    2012-01-01

    role in the pathogenesis of the disease. METHODS: In the present study, we used lentiviral vectors to efficiently knockdown CHMP2B by delivering microRNA embedded small hairpin RNAs. RESULTS: We show that CHMP2B can be efficiently knocked down in patient fibroblasts using an RNA interference approach...... and that the knockdown causes reversal of the abnormal endosomal phenotype observed in patient fibroblasts. CONCLUSIONS: This is the first description of a treatment that reverses the cellular pathology caused by mutant CHMP2B and suggests that RNA interference might be a feasible therapeutic strategy. Furthermore...

  18. Strategic B2B customer experience management: the importance of outcomes-based measures

    OpenAIRE

    Zolkiewski, Judy; Story, Victoria; Burton, Jamie; Chan, Paul; Gomes, Andre; Hunter-Jones, Philippa; O’Malley, Lisa; Peters, Linda D.; Raddats, Chris; Robinson, William

    2017-01-01

    Purpose\\ud \\ud The purpose of this paper is to critique the adequacy of efforts to capture the complexities of customer experience in a business-to-business (B2B) context using input–output measures. The paper introduces a strategic customer experience management framework to capture the complexity of B2B service interactions and discusses the value of outcomes-based measurement.\\ud Design/methodology/approach\\ud \\ud This is a theoretical paper that reviews extant literature related to B2B cu...

  19. B2B-yrityksen markkinointi, viestintä ja asiakaspalvelu sosiaalisessa mediassa

    OpenAIRE

    Liespuu, Mikael

    2014-01-01

    Tämän opinnäytetyön tarkoituksena oli tehdä tutkimus sosiaalisen median hyödyntämisestä B2B-yrityksessä. Tarkemmin lähestytään yrityksen markkinointia, viestintää sekä asiakaspalvelua sosiaalisessa mediassa. Sosiaalinen media mielletään usein kuluttajasuuntautuneeksi ja sitä se on aiemmin pääosin ollutkin. Tarkoituksena oli selvittää miten B2B-markkinoilla toimiva yritys saa enemmän irti sosiaalisesta mediasta. Ongelmana B2B-yritykselle sosiaalisen median osalta on se, että sosiaalisest...

  20. Amniotic membrane transplantation with topical interferon alfa-2b after excision of ocular surface squamous neoplasia

    Directory of Open Access Journals (Sweden)

    Hua-Tao Xie

    2018-01-01

    Full Text Available To evaluate the outcome of amniotic membrane transplantation (AMT after tumor excision followed by topical interferon alfa-2b (IFNα2b drops for primary ocular surface squamous neoplasia (OSSN. Twelve eyes of 12 patients with a mean age of 66±10y were included. The average follow-up was 23±10mo. All 12 patients had limbal involvement. Smooth ocular surface and transparent cornea were achieved in all cases. No sign of inflammation, neovascularization, symblepharon or recurrence was noted at the last follow-up. We conclude that AMT with topical IFNα2b drops restores a healthy ocular surface in OSSN without recurrence.

  1. Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations

    OpenAIRE

    Urwin, Hazel; Authier, Astrid; Nielsen, Jorgen E.; Metcalf, Daniel; Powell, Caroline; Froud, Kristina; Malcolm, Denise S.; Holm, Ida; Johannsen, Peter; Brown, Jeremy; Fisher, Elizabeth M.C.; van der Zee, Julie; Bruyland, Marc; Van Broeckhoven, Christine; Collinge, John

    2010-01-01

    Mutations in CHMP2B cause frontotemporal dementia (FTD) in a large Danish pedigree, which is termed FTD linked to chromosome 3 (FTD-3), and also in an unrelated familial FTD patient. CHMP2B is a component of the ESCRT-III complex, which is required for function of the multivesicular body (MVB), an endosomal structure that fuses with the lysosome to degrade endocytosed proteins. We report a novel endosomal pathology in CHMP2B mutation-positive patient brains and also identify and characterize ...

  2. Analysis of the Role of Social Media in B2B Marketing for Startups

    OpenAIRE

    Fomicheva, Yekaterina

    2015-01-01

    Social media is a new, yet very prominent concept in present marketing communication. It has been growing steadily and became popular among marketers both in business-to-customer (B2C) and business-to-business (B2B). However, there has been more research done on how to apply and utilize social media in the B2C scenario and there are fewer explanations about B2B cases. Therefore, it was interesting to do research and analysis on how B2B companies operate, what are the factors influencing socia...

  3. Adenosine Receptor Adora2b Plays a Mechanistic Role in the Protective Effect of the Volatile Anesthetic Sevoflurane during Liver Ischemia/Reperfusion.

    Science.gov (United States)

    Granja, Tiago F; Köhler, David; Schad, Jessica; de Oliveira, Claudia Bernardo; Konrad, Franziska; Hoch-Gutbrod, Michaela; Streienberger, Ariane; Rosenberger, Peter; Straub, Andreas

    2016-09-01

    Liver ischemia/reperfusion (IR) injury is characterized by hepatic tissue damage and an inflammatory response. This is accompanied by the formation and vascular sequestration of platelet-neutrophil conjugates (PNCs). Signaling through Adora2b adenosine receptors can provide liver protection. Volatile anesthetics may interact with adenosine receptors. This study investigates potential antiinflammatory effects of the volatile anesthetic sevoflurane during liver IR. Experiments were performed ex vivo with human blood and in a liver IR model with wild-type, Adora2a, and Adora2b mice. The effect of sevoflurane on platelet activation, PNC formation and sequestration, cytokine release, and liver damage (alanine aminotransferase release) was analyzed using flow cytometry, luminometry, and immunofluorescence. Adenosine receptor expression in liver tissue was analyzed using immunohistochemistry and real-time polymerase chain reaction. Ex vivo experiments indicate that sevoflurane inhibits platelet and leukocyte activation (n = 5). During liver IR, sevoflurane (2 Vol%) decreased PNC formation 2.4-fold in wild-type (P < 0.05) but not in Adora2b mice (n ≥ 5). Sevoflurane reduced PNC sequestration 1.9-fold (P < 0.05) and alanine aminotransferase release 3.5-fold (P < 0.05) in wild-type but not in Adora2b mice (n = 5). In Adora2a mice, sevoflurane also inhibited PNC formation and cytokine release. Sevoflurane diminished cytokine release (n ≥ 3) and increased Adora2b transcription and expression in liver tissue of wild-types (n = 4). Our experiments highlight antiinflammatory and tissue-protective properties of sevoflurane during liver IR and reveal a mechanistic role of Adora2b in sevoflurane-associated effects. The targeted use of sevoflurane not only as an anesthetic but also to prevent IR damage is a promising approach in the treatment of critically ill patients.

  4. Anti-factor XIII A subunit (FXIII-A) autoantibodies block FXIII-A2 B2 assembly and steal FXIII-A from native FXIII-A2 B2.

    Science.gov (United States)

    Souri, M; Osaki, T; Ichinose, A

    2015-05-01

    Autoimmune hemophilia-like disease (hemorrha-philia or hemorrhagic disorder) caused by anti-factor XIII antibodies (termed AH13) or 'autoimmune FXIII deficiency' is a life-threatening bleeding disorder. AH13 was thought to be rare worldwide. Because the number of diagnosed AH13 cases has recently been increasing, at least in Japan, we conducted a nationwide survey supported by the Japanese Ministry of Health, Labor, and Welfare, and explored the pathologic mechanism(s) of AH13. We diagnosed AH13 cases during the last 11 years according to the presence of anti-FXIII autoantibodies confirmed by a dot blot assay and ELISA, and characterized 33 of these both immunologically and biochemically. The AH13 cases were immunologically classified into three types, Aa, Ab, and B. Type Aa autoantibodies, observed in 27 cases, were directed against the native FXIII A subunit (FXIII-A), and blocked FXIII activation. The autoantibodies not only prevented assembly of new FXIII-A2 B2 heterotetramers, but also removed FXIII-A from native FXIII-A2 B2 heterotetramers by forming an FXIII-A-IgG complex. Type Ab autoantibodies, detected in three cases, preferentially bound to activated FXIII-A and inhibited its activity. Type Aa and Ab autoantibodies were 'neutralizing' FXIII antibodies (or FXIII inhibitors), and thus could be screened with functional assays. Type B antibodies, detected in two cases, were non-neutralizing anti-FXIII B subunit (FXIII-B) autoantibodies that possibly accelerated the clearance of FXIII, and thus could be diagnosed exclusively with immunologic methods. There are three major types of anti-FXIII autoantibody, with distinct targets and mechanisms that cause AH13. © 2015 International Society on Thrombosis and Haemostasis.

  5. Nitrous oxide produces antinociceptive response via alpha2B and/or alpha2C adrenoceptor subtypes in mice.

    Science.gov (United States)

    Guo, T Z; Davies, M F; Kingery, W S; Patterson, A J; Limbird, L E; Maze, M

    1999-02-01

    Opiate receptors in the periaqueductal gray region and alpha2 adrenoceptors in the spinal cord of the rat mediate the antinociceptive properties of nitrous oxide (N2O). The availability of genetically altered mice facilitates the detection of the precise protein species involved in the transduction pathway. In this study, the authors establish the similarity between rats and mice in the antinociceptive action of N2O and investigate which alpha2 adrenoceptor subtypes mediate this response. After obtaining institutional approval, antinociceptive dose-response and time-course to N2O was measured in wild-type and transgenic mice (D79N), with a nonfunctional alpha2A adrenoceptor using tail-flick latency. The antinociceptive effect of N2O was tested after pretreatment systemically with yohimbine (nonselective alpha2 antagonist), naloxone (opiate antagonist), L659,066 (peripheral alpha2-antagonist) and prazosin (alpha2B- and alpha2C-selective antagonist). The tail-flick latency to dexmedetomidine (D-med), a nonselective alpha2 agonist, was tested in wild-type and transgenic mice. N2O produced antinociception in both D79N transgenic and wild-type litter mates, although the response was less pronounced in the transgenic mice. Antinociception from N2O decreased over time with continuing exposure, and the decrement was more pronounced in the transgenic mice. The antinociceptive response could be dose dependently antagonized by opiate receptor and selective alpha2B-/alpha2C-receptor antagonists but not by a central nervous system-impermeant alpha2 antagonist (L659,066). Whereas dexmedetomidine exhibited no antinociceptive response in the D79N mice, the robust antinociceptive response in the wild-type litter mates could not be blocked by a selective alpha2B-/alpha2C-receptor antagonist. These data confirm that the antinociceptive response to an exogenous alpha2-agonist is mediated by an alpha2A adrenoceptor and that there appears to be a role for the alpha2B- or alpha2C

  6. Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics

    Science.gov (United States)

    Elhamine, Fatiha; Radke, Michael H.; Pfitzer, Gabriele; Granzier, Henk; Gotthardt, Michael; Stehle, Robert

    2014-01-01

    ABSTRACT Cardiac titin is the main determinant of sarcomere stiffness during diastolic relaxation. To explore whether titin stiffness affects the kinetics of cardiac myofibrillar contraction and relaxation, we used subcellular myofibrils from the left ventricles of homozygous and heterozygous N2B-knockout mice which express truncated cardiac titins lacking the unique elastic N2B region. Compared with myofibrils from wild-type mice, myofibrils from knockout and heterozygous mice exhibit increased passive myofibrillar stiffness. To determine the kinetics of Ca2+-induced force development (rate constant kACT), myofibrils from knockout, heterozygous and wild-type mice were stretched to the same sarcomere length (2.3 µm) and rapidly activated with Ca2+. Additionally, mechanically induced force-redevelopment kinetics (rate constant kTR) were determined by slackening and re-stretching myofibrils during Ca2+-mediated activation. Myofibrils from knockout mice exhibited significantly higher kACT, kTR and maximum Ca2+-activated tension than myofibrils from wild-type mice. By contrast, the kinetic parameters of biphasic force relaxation induced by rapidly reducing [Ca2+] were not significantly different among the three genotypes. These results indicate that increased titin stiffness promotes myocardial contraction by accelerating the formation of force-generating cross-bridges without decelerating relaxation. PMID:24982444

  7. Possible involvement of nuclear factor erythroid 2-related factor 2 in the gene expression of Cyp2b10 and Cyp2a5.

    Science.gov (United States)

    Ashino, Takashi; Ohkubo-Morita, Haruyo; Yamamoto, Masayuki; Yoshida, Takemi; Numazawa, Satoshi

    2014-01-01

    Cytochrome P450 gene expression is altered by various chemical compounds. In this study, we used nuclear factor erythroid 2-related factor 2 (Nrf2)-deficient (Nrf2(-⧸-)) mice to investigate the involvement of Nrf2 in Cyp2b10 and Cyp2a5 gene expression. Phorone, an Nrf2 activator, strongly increased Cyp2b10 and Cyp2a5 mRNA as well as Nrf2 target genes, including NAD(P)H-quinone oxidoreductase-1 and heme oxygenase-1, in wild-type mouse livers 8 h after treatment. The phorone-induced mRNA levels in Nrf2(-⧸-) mouse livers were lower than that in wild-type mouse livers. Nrf2(-⧸-) mice showed attenuated Cyp2b10 and Cyp2a5 induction by phenobarbital, a classical Cyp2b inducer. These findings suggest that the Nrf2 pathway is involved in Cyp2b10 and Cyp2a5 gene expression.

  8. Possible involvement of nuclear factor erythroid 2-related factor 2 in the gene expression of Cyp2b10 and Cyp2a5☆

    Science.gov (United States)

    Ashino, Takashi; Ohkubo-Morita, Haruyo; Yamamoto, Masayuki; Yoshida, Takemi; Numazawa, Satoshi

    2014-01-01

    Cytochrome P450 gene expression is altered by various chemical compounds. In this study, we used nuclear factor erythroid 2-related factor 2 (Nrf2)–deficient (Nrf2−⧸−) mice to investigate the involvement of Nrf2 in Cyp2b10 and Cyp2a5 gene expression. Phorone, an Nrf2 activator, strongly increased Cyp2b10 and Cyp2a5 mRNA as well as Nrf2 target genes, including NAD(P)H-quinone oxidoreductase-1 and heme oxygenase-1, in wild-type mouse livers 8 h after treatment. The phorone-induced mRNA levels in Nrf2−⧸− mouse livers were lower than that in wild-type mouse livers. Nrf2−⧸− mice showed attenuated Cyp2b10 and Cyp2a5 induction by phenobarbital, a classical Cyp2b inducer. These findings suggest that the Nrf2 pathway is involved in Cyp2b10 and Cyp2a5 gene expression. PMID:24494203

  9. Possible involvement of nuclear factor erythroid 2-related factor 2 in the gene expression of Cyp2b10 and Cyp2a5

    Directory of Open Access Journals (Sweden)

    Takashi Ashino

    2014-01-01

    Full Text Available Cytochrome P450 gene expression is altered by various chemical compounds. In this study, we used nuclear factor erythroid 2-related factor 2 (Nrf2–deficient (Nrf2−⧸− mice to investigate the involvement of Nrf2 in Cyp2b10 and Cyp2a5 gene expression. Phorone, an Nrf2 activator, strongly increased Cyp2b10 and Cyp2a5 mRNA as well as Nrf2 target genes, including NAD(PH-quinone oxidoreductase-1 and heme oxygenase-1, in wild-type mouse livers 8 h after treatment. The phorone-induced mRNA levels in Nrf2−⧸− mouse livers were lower than that in wild-type mouse livers. Nrf2−⧸− mice showed attenuated Cyp2b10 and Cyp2a5 induction by phenobarbital, a classical Cyp2b inducer. These findings suggest that the Nrf2 pathway is involved in Cyp2b10 and Cyp2a5 gene expression.

  10. Managing Innovation Through Social Media in B2B SME-Context

    DEFF Research Database (Denmark)

    Lutz, Salla; Madsen, Svend Ole; Brink, Tove

    2015-01-01

    This paper shed light on how social media application can enhance innovation management in SME B2B context. Our study employs a qualitative case study approach with four B2B SMEs for in-depth research in the period from October 2013 to October 2014. The B2B SME managers aim for open business model...... innovation. However, social media application is hindered due to lack of specific local knowledge, lack of knowledge on social media technicalities and bewilderedness on leadership approaches within the social media application. A contribution is hereby made to the B2B SME field, to the academic...... understanding an insight on social media application and open business model innovation....

  11. Data of evolutionary structure change: 1YDVA-1AW2B [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1YDVA-1AW2B 1YDV 1AW2 A B RKYFVAANWKCNGTLESIKSLTNSFNNLDFDPSKLDVVV...--- RHPVVMGNWKLNGSKEMVVDLLNGLNAELEGVTGVDVAVAPPALFVDLAERTLTEAGSAIILGA...confEVID> 0 1YDV A 1YDVA...> A 1YDVA IVKDTCGEKQA

  12. Pre-LBA ABLE-2A and ABLE-2B Expedition Data

    Data.gov (United States)

    National Aeronautics and Space Administration — The ABLE 2A and 2B (Atmospheric Boundary Layer Experiments) data consists of estimates of the rate of exchange of a wide variety of aerosols and gases between the...

  13. Pre-LBA ABLE-2A and ABLE-2B Expedition Data

    Data.gov (United States)

    National Aeronautics and Space Administration — ABSTRACT: The ABLE 2A and 2B (Atmospheric Boundary Layer Experiments) data consists of estimates of the rate of exchange of a wide variety of aerosols and gases...

  14. Water‐Data Report 413721083124001 Pool 2B at Ottawa NWR-2014

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Water levels and water quality parameters recorded on Crane Creek are described in this report. Water-Data Report 2013 413721083124001 Pool 2B at Ottawa NWR...

  15. Interferon alfa-2b in the management of recurrent conjunctival papillomatosis.

    Science.gov (United States)

    Singh, Manpreet; Gautam, Natasha; Gupta, Adit; Kaur, Manpreet

    2016-10-01

    A 2-year-old boy presented with a recurrent strawberry-like reddish mass arising from the left caruncular region for 8 months. An incisional biopsy was performed elsewhere 2 months earlier, followed by an increase in size of mass, significant epiphora, and intermittent bleeding. On examination, exuberant exophytic gelatinous mass with multifocal origin was observed arising from inferior forniceal conjunctiva and caruncle. Clinical differential of multifocal conjunctival papilloma was kept, and topical interferon alfa-2b (INFα-2b) was started. No clinical reduction in mass or symptomatology was observed over 6 weeks. Excision biopsy with cryotherapy and subconjunctival injection of INFα-2b was performed over all foci. Conjunctival papilloma was confirmed on histopathology, and topical INFα-2b was continued in postoperative period for 3 months. At 14 months of follow-up, no recurrence, epiphora, or bleeding was noticed. We advocate a possible role of local INF therapy in managing and preventing recurrences of conjunctival papillomatosis.

  16. Protective effects of sesaminol on BEAS-2B cells impaired by cigarette smoke extract.

    Science.gov (United States)

    Dong, Ping; Fu, Xiao; Wang, Xiang; Wang, Wen-mei; Cao, Wen-ming; Zhang, Wei-yun

    2015-03-01

    The aim of this study is to investigate protective effects of sesaminol on the human bronchial epithelial (BEAS-2B) cell line against oxidative damage of cigarette smoke extract (CSE). BEAS-2B cells were pre-incubated with sesaminol for 12 h and then treated with various concentrations of CSE for 24 h. After that proliferation ability, levels of reactive oxygen species (ROS) and lactate dehydrogenase (LDH), cell apoptosis, activities of catalase (CAT) and superoxide dismutase (SOD), and mRNA levels of IL-8 and IL-6 were measured. The results showed that sesaminol significantly improved BEAS-2B cell viability, reduced the production of ROS and LDH of cells, inhibited cell apoptosis and increased CAT and SOD activities in CSE-treated cells. Sesaminol also inhibited the expression of IL-8 and IL-6 mRNA following CSE exposure. In conclusion, sesaminol may protect BEAS-2B cells against CSE-induced oxidative damage.

  17. Marine microbial biodiversity, bioinformatics and biotechnology (M2B3) data reporting and service standards.

    Science.gov (United States)

    Ten Hoopen, Petra; Pesant, Stéphane; Kottmann, Renzo; Kopf, Anna; Bicak, Mesude; Claus, Simon; Deneudt, Klaas; Borremans, Catherine; Thijsse, Peter; Dekeyzer, Stefanie; Schaap, Dick Ma; Bowler, Chris; Glöckner, Frank Oliver; Cochrane, Guy

    2015-01-01

    Contextual data collected concurrently with molecular samples are critical to the use of metagenomics in the fields of marine biodiversity, bioinformatics and biotechnology. We present here Marine Microbial Biodiversity, Bioinformatics and Biotechnology (M2B3) standards for "Reporting" and "Serving" data. The M2B3 Reporting Standard (1) describes minimal mandatory and recommended contextual information for a marine microbial sample obtained in the epipelagic zone, (2) includes meaningful information for researchers in the oceanographic, biodiversity and molecular disciplines, and (3) can easily be adopted by any marine laboratory with minimum sampling resources. The M2B3 Service Standard defines a software interface through which these data can be discovered and explored in data repositories. The M2B3 Standards were developed by the European project Micro B3, funded under 7(th) Framework Programme "Ocean of Tomorrow", and were first used with the Ocean Sampling Day initiative. We believe that these standards have value in broader marine science.

  18. The efficacy of topical interferon alpha 2b treatment in refractory vernal keratoconjunctivitis.

    Science.gov (United States)

    Turan-Vural, Ece; Acar, Banu Torun; Acar, Suphi

    2012-04-01

    This study aimed to investigate the efficacy and safety of a 2-month topical interferon alpha 2b treatment in patients with refractory vernal keratoconjunctivitis. Twelve (10 male, 2 female) patients with refractory vernal keratoconjunctivitis received topical treatment with one million IU/mL interferon alpha 2b 4 times a day for 2 months. Symptom and ophthalmological examination scores were assessed at baseline and during follow-up. No significant complications or side effects associated with the use of topical interferon alpha 2b were observed. Symptom scores for itching, tearing, photophobia, and total symptom score, and objective scores for corneal lesion, hyperemia, chemosis, papillary hypertrophy, secretion, and total examination score significantly improved during the 2-month treatment. Improvements were maintained after discontinuation of the treatment for most parameters. Topical interferon alpha 2b treatment seems to offer a safe and effective alternative for the treatment of refractory vernal keratoconjunctivitis for a brief period.

  19. Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations

    DEFF Research Database (Denmark)

    Urwin, Hazel; Authier, Astrid; Nielsen, Jørgen Erik

    2010-01-01

    Mutations in CHMP2B cause frontotemporal dementia (FTD) in a large Danish pedigree, which is termed FTD linked to chromosome 3 (FTD-3), and also in an unrelated familial FTD patient. CHMP2B is a component of the ESCRT-III complex, which is required for function of the multivesicular body (MVB......), an endosomal structure that fuses with the lysosome to degrade endocytosed proteins. We report a novel endosomal pathology in CHMP2B mutation-positive patient brains and also identify and characterize abnormal endosomes in patient fibroblasts. Functional studies demonstrate a specific disruption of endosome...... for neuronal function and the data presented therefore suggest a pathogenic mechanism for FTD caused by CHMP2B mutations....

  20. High performance of solvothermally prepared VO2(B as anode for aqueous rechargeable lithium batteries

    Directory of Open Access Journals (Sweden)

    Milošević Sanja

    2015-01-01

    Full Text Available The VO2 (B was synthesized via a simple solvothermal route at 160oC in ethanol. The initial discharge capacity of VO2 (B anode, in saturated aqueous solution of LiNO3, was 177 mAh g-1 at a current rate of 50 mA g-1. After 50 cycles capacity fade was 4%, but from 20th-50th cycle no capacity drop was observed. The VO2 (B has shown very good cyclability at current rate of even 1000 mA g-1 with initial discharge capacity of 92 mAh g-1. The excellent electrochemical performance of VO2 (B was attributed to the stability of micro-nano structures to repeated intercalation /deintercalation process, very good electronic conductivity as well as the very low charge transfer resistance in the aqueous electrolyte. [Projekat Ministarstva nauke Republike Srbije, br. III45014

  1. Aviation Environmental Design Tool (AEDT): technical manual, version 2b, service pack 3

    Science.gov (United States)

    2016-05-03

    The Federal Aviation Administration, Office of Environment and Energy (FAA-AEE) has developed the Aviation Environmental Design Tool (AEDT) version 2b software system with the support of the following development team: FAA, National Aeronautics and S...

  2. Characteristics of the brand building on the business (B2B) market

    National Research Council Canada - National Science Library

    Gligorijević Mirjana

    2011-01-01

    This paper analyzes the characteristics of the brand building in the business (B2B) market. Branding strategy at the business market is complex and difficult to implement because of the many limiting factors...

  3. OS2_OSCAT_LEVEL_2B_OWV_COMP_12_V2:1

    Data.gov (United States)

    National Aeronautics and Space Administration — This dataset consists of the version 2 Level 2B science-quality ocean surface wind vector retrievals from the Oceansat-2 scatterometer (OSCAT), which was designed...

  4. QSCAT_LEVEL_2B_OWV_COMP_12:1

    Data.gov (United States)

    National Aeronautics and Space Administration — This dataset contains the latest reprocessed version 3 of the Level 2B science-quality ocean surface wind vector retrievals from the QuikSCAT scatterometer. The...

  5. Data of evolutionary structure change: 1NP2B-2RGMB [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1NP2B-2RGMB 1NP2 2RGM B B ----------AEKFLWGVATSAYQIEGATQEDGRGPSIWDTFARRPGAIRDGSTGE...YRERIARAQ WLGGLSRAAFPKRFVFGTVTSAYQVEGMAASGGRGPSIWDAFAHTPGNVAGNQNGDVATDQYHRYKEDVNLMKSLNF...QTPTSYSADWQVTYVFAKNGKPIGPQANSNWLYIVPWGMYGCVNYIKQKYGNPTVVITENGMDQPANLSRDQYLRDTTRVHFYRSYLTQLKKAIDEGANV... 2RGM B 2RGMB 2RGM B 2RGMB

  6. Serotonin 2B Receptors in Mesoaccumbens Dopamine Pathway Regulate Cocaine Responses.

    Science.gov (United States)

    Doly, Stéphane; Quentin, Emily; Eddine, Raphaël; Tolu, Stefania; Fernandez, Sebastian P; Bertran-Gonzalez, Jesus; Valjent, Emmanuel; Belmer, Arnauld; Viñals, Xavier; Callebert, Jacques; Faure, Philippe; Meye, Frank J; Hervé, Denis; Robledo, Patricia; Mameli, Manuel; Launay, Jean-Marie; Maldonado, Rafael; Maroteaux, Luc

    2017-10-25

    Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT2B receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system. Despite these findings, it remains unknown whether 5-HT2B receptors directly modulate dopaminergic activity and the possible mechanisms involved. To answer these questions, we investigated the contribution of 5-HT2B receptors to cocaine-dependent behavioral responses. Male mice permanently lacking 5-HT2B receptors, even restricted to dopamine neurons, developed heightened cocaine-induced locomotor responses. Retrograde tracing combined with single-cell mRNA amplification indicated that 5-HT2B receptors are expressed by mesolimbic dopamine neurons. In vivo and ex vivo electrophysiological recordings showed that 5-HT2B-receptor inactivation in dopamine neurons affects their neuronal activity and increases AMPA-mediated over NMDA-mediated excitatory synaptic currents. These changes are associated with lower ventral striatum dopamine activity and blunted cocaine self-administration. These data identify the 5-HT2B receptor as a pharmacological intermediate and provide mechanistic insight into attenuated dopamine tone following exposure to drugs of abuse.SIGNIFICANCE STATEMENT Here we report that mice lacking 5-HT2B receptors totally or exclusively in dopamine neurons exhibit heightened cocaine-induced locomotor responses. Despite the sensitized state of these mice, we found that associated changes include lower ventral striatum dopamine activity and lower cocaine operant self-administration. We described the selective expression of 5-HT2B receptors in a subpopulation of dopamine

  7. Human UGT2B7 is the major isoform responsible for the glucuronidation of clopidogrel carboxylate.

    Science.gov (United States)

    Ji, Jin-Zi; Huang, Bei-Bei; Gu, Tong-Tong; Tai, Ting; Zhou, Huan; Jia, Yu-Meng; Mi, Qiong-Yu; Zhang, Meng-Ran; Xie, Hong-Guang

    2018-02-01

    Clopidogrel is predominantly hydrolyzed to clopidogrel carboxylic acid (CCA) by carboxylesterase 1, and subsequently CCA is glucuronidated to clopidogrel acyl glucuronide (CAG) by uridine diphosphate-glucuronosyltransferases (UGTs); however, the UGT isoenzymes glucuronidating CCA remain unidentified to date. In this study, the glucuronidation of CCA was screened with pooled human liver microsomes (HLMs) and 7 human recombinant UGT (rUGT) isoforms. Results indicated that rUGT2B7 exhibited the highest catalytical activity for the CCA glucuronidation as measured with a mean Vmax value of 120.9 pmol/min/mg protein, 3- to 12-fold higher than that of the other rUGT isoforms tested. According to relative activity factor approach, the relative contribution of rUGT2B7 to CCA glucuronidation was estimated to be 58.6%, with the minor contributions (3%) from rUGT1A9. Moreover, the glucuronidation of CCA followed Michaelis-Menten kinetics with a mean Km value of 372.9 μM and 296.4 μM for pooled HLMs and rUGT2B7, respectively, showing similar affinity for both. The formation of CAG was significantly inhibited by azidothymidine and gemfibrozil (well-characterized UGT2B7 substrates) in a concentration-dependent manner, or by fluconazole (a typical UGT2B7-selective inhibitor) in a time-dependent manner, for both HLMs and rUGT2B7, respectively. In addition, CCA inhibited azidothymidine glucuronidation (catalyzed almost exclusively by UGT2B7) by HLMs and rUGT2B7 in a concentration-dependent manner, indicating that CCA is a substrate of UGT2B7. These results reveal that UGT2B7 is the major enzyme catalyzing clopidogrel glucuronidation in the human liver, and that there is the potential for drug-drug interactions between clopidogrel and the other substrate drugs of UGT2B7. Copyright © 2017 John Wiley & Sons, Ltd.

  8. Drivers of relationships affecting B2B firms in an e-commerce environment

    OpenAIRE

    Irene Samanta; Mike Danson

    2014-01-01

    The advent of the internet has created numerous opportunities for B2B marketing professionals to enhance current marketing practices, including electronic relationships. However, the investigation of e-relationships and the factors that influence e-relationships in an internet environment is scant. Further, there appears to be no investigation of this phenomenon within the context of Greek B2B Medium-sized firms (MSF). Τhe research problem investigated in this research is: “Which drivers in B...

  9. Managers' perceptions of using of e-marketing in B2B relationships

    OpenAIRE

    Σαμαντά, Ειρήνη; Κυριαζόπουλος, Π.

    2008-01-01

    Researchers agree that the use of the Internet is increasingly expanding in business-tobusiness (B2B) relationships in order to improve effective communication, distribution, and streamline processes with customers and stakeholders. This study examines a sample of 30 firms operating in Greece and discusses the benefits from B2B collaboration by using e-marketing. The method used for the quantitative analysis is the factor analysis and ordinal symmetric measures; Kendall’s tau-b...

  10. Drivers of relationships affecting B2B firms in an e-commerce environment

    Directory of Open Access Journals (Sweden)

    Irene Samanta

    2014-09-01

    Full Text Available The advent of the internet has created numerous opportunities for B2B marketing professionals to enhance current marketing practices, including electronic relationships. However, the investigation of e-relationships and the factors that influence e-relationships in an internet environment is scant. Further, there appears to be no investigation of this phenomenon within the context of Greek B2B Medium-sized firms (MSF. Τhe research problem investigated in this research is: “Which drivers in B2B e-commerce use affect inter-firm relationships in medium-sized B2B firms?”. A framework for B2B e-commerce relationships in a changing and globalized environment was synthesised and integrated with the literature about relationship marketing to arrive at the following research issues: “How do relationship marketing drivers affect the management of B2B e-relationships?”. An explanatory quantitative research approach was used and quantitative data was collected from B2B firms in Greece, which represents a case of e-commerce progress during the last six years. Regarding social exchange, some important differences emerge where cooperation between B2B e-commerce firms is concerned. Suppliers engaged in electronic commerce are more committed and oriented to a long-term relationship than buyers, based on both previous and current experience with them. Confidence in the relationships, consistency and honesty with their obligations and the exchange of reliable, trustworthy information and advisory services between firms are important factors in the development and establishment of their e-relationships. The main contribution of this research is the development of a theoretical framework for e-relationships in medium-sized Β2Β firms. That framework is the first rigorously researched step towards understanding the importance of these powerful streams of relationship drivers in total, and the business activity of e-marketing and electronic relationships.

  11. Crystal structure of catalytic domain of the initiation factor 2B epsilon subunit

    DEFF Research Database (Denmark)

    Boesen, Thomas; Mohammad, Sarah S.; Pavitt, Graham D.

    , UMIST, PO Box 88, Manchester, M60 1QD, UK Eukaryotic initiation factor 2B (eIF2B) is the exchange factor of initiation factor 2 (eIF2) and catalyses the reaction where GDP bound to eIF2 is exchanged for GTP, a crucial step in translation. The crystal structure of the C-terminal catalytic domain of the e...

  12. Viroporin Activity of the Foot-and-Mouth Disease Virus Non-Structural 2B Protein.

    Directory of Open Access Journals (Sweden)

    Da Ao

    Full Text Available Viroporins are a family of low-molecular-weight hydrophobic transmembrane proteins that are encoded by various animal viruses. Viroporins form transmembrane pores in host cells via oligomerization, thereby destroying cellular homeostasis and inducing cytopathy for virus replication and virion release. Among the Picornaviridae family of viruses, the 2B protein encoded by enteroviruses is well understood, whereas the viroporin activity of the 2B protein encoded by the foot-and-mouth disease virus (FMDV has not yet been described. An analysis of the FMDV 2B protein domains by computer-aided programs conducted in this study revealed that this protein may contain two transmembrane regions. Further biochemical, biophysical and functional studies revealed that the protein possesses a number of features typical of a viroporin when it is overexpressed in bacterial and mammalian cells as well as in FMDV-infected cells. The protein was found to be mainly localized in the endoplasmic reticulum (ER, with both the N- and C-terminal domains stretched into the cytosol. It exhibited cytotoxicity in Escherichia coli, which attenuated 2B protein expression. The release of virions from cells infected with FMDV was inhibited by amantadine, a viroporin inhibitor. The 2B protein monomers interacted with each other to form both intracellular and extracellular oligomers. The Ca(2+ concentration in the cells increased, and the integrity of the cytoplasmic membrane was disrupted in cells that expressed the 2B protein. Moreover, the 2B protein induced intense autophagy in host cells. All of the results of this study demonstrate that the FMDV 2B protein has properties that are also found in other viroporins and may be involved in the infection mechanism of FMDV.

  13. CRM in the digital age: implementation of CRM in three contemporary B2B firms

    OpenAIRE

    Lipiäinen, Heini

    2015-01-01

    Purpose – The purpose of this study was to contribute to the current discussion on digitization in companies’ marketing from a customer relationship management (CRM) perspective by examining the role and objectives of CRM and the exploitation of social media to serve the objectives of CRM in contemporary business-to-business (B2B) companies. Design/methodology/approach – The data are collected through semi-structured themed interviews with key marketing/sales managers from three B2B...

  14. Innovation strategy for B2B mobile apps : a value-centric approach

    OpenAIRE

    Haugestad, Rune

    2015-01-01

    Purpose: The purpose of this empirical master study is to examine how innovation strategy, emphasizing Value-centric innovation strategies, can help to enhance mobile & tablet B2B/Business app Product-Life-Cycles. Furthermore, analyzing strategical aspects and how these impact; digital value creation & digital value capturing, app B2B marketing, disruption, diffusion, high growth user adoptions and app profit and profitability. The research takes a holistic approach to brin...

  15. Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans.

    Science.gov (United States)

    Heinz, Lisa; Kim, Gwang-Jin; Marrakchi, Slaheddine; Christiansen, Julie; Turki, Hamida; Rauschendorf, Marc-Alexander; Lathrop, Mark; Hausser, Ingrid; Zimmer, Andreas D; Fischer, Judith

    2017-06-01

    Ichthyoses are a clinically and genetically heterogeneous group of genodermatoses associated with abnormal scaling of the skin over the whole body. Mutations in nine genes are known to cause non-syndromic forms of autosomal-recessive congenital ichthyosis (ARCI). However, not all genetic causes for ARCI have been discovered to date. Using whole-exome sequencing (WES) and multigene panel screening, we identified 6 ARCI-affected individuals from three unrelated families with mutations in Sulfotransferase family 2B member 1 (SULT2B1), showing their causative association with ARCI. Cytosolic sulfotransferases form a large family of enzymes that are involved in the synthesis and metabolism of several steroids in humans. We identified four distinct mutations including missense, nonsense, and splice site mutations. We demonstrated the loss of SULT2B1 expression at RNA and protein levels in keratinocytes from individuals with ARCI by functional analyses. Furthermore, we succeeded in reconstructing the morphologic skin alterations in a 3D organotypic tissue culture model with SULT2B1-deficient keratinocytes and fibroblasts. By thin layer chromatography (TLC) of extracts from these organotypic cultures, we could show the absence of cholesterol sulfate, the metabolite of SULT2B1, and an increased level of cholesterol, indicating a disturbed cholesterol metabolism of the skin upon loss-of-function mutation in SULT2B1. In conclusion, our study reveals an essential role for SULT2B1 in the proper development of healthy human skin. Mutation in SULT2B1 leads to an ARCI phenotype via increased proliferation of human keratinocytes, thickening of epithelial layers, and altered epidermal cholesterol metabolism. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  16. Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy.

    Science.gov (United States)

    Cavero, Icilio; Guillon, Jean-Michel

    2014-01-01

    The rhythmic opening and tightly closing of cardiac valve leaflets are cardiac cyclic events imposing to blood a unidirectional course along the vascular tree. Drugs with 5-HT2B agonism properties can seriously compromise this biological function critical for hemodynamic efficiency as their intrinsic pro-fibrotic effects can, with time, make valvular coaptation blood regurgitant. Cardiac valve anatomy, physiology and pathology as well as 5-HT2B receptor properties (coupling, effects mediated, biased agonism) are briefly exposed. Approaches to unveil 5-HT2B receptor liability of drug candidates are detailed. In silico computational models can rapidly probe molecules for chemical signatures associated with 5-HT2B receptor affinity. In vitro radioligand competition assays allow quantifying receptor binding capacity (Ki, IC50), the pharmacological nature (agonism, antagonism) of which can be ascertained from cytosolic second messenger (inositol phosphates, Ca(++), MAPK2) changes. Potencies calculated from the latter data may exhibit variability as they are dependent upon the readout measured and the experimental conditions (e.g., receptor density level of cell material expressing human 5-HT2B receptors). The in vivo valvulopathy effects of 5-HT2B receptor agonists can be assessed by echocardiographic measurements and valve histology in rats chronically treated with the candidate drug. Finally, safety margins derived from from nonclinical and clinical data are evaluated in terms of the readout, usefulness and scientific reliability. The Safety Pharmacology toolbox for detecting possible 5-HT2B receptor agonism liabilities of candidate drugs requires meticulous optimization and validation of all its (in silico, in vitro and in vivo) components to perfect its human predictability power. In particular, since 5-HT2B receptor agonism is biased in nature, the most predictive readout(s) of valvular liability should be identified and prioritized in keeping with best scientific

  17. Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension.

    Science.gov (United States)

    Karmouty-Quintana, Harry; Philip, Kemly; Acero, Luis F; Chen, Ning-Yuan; Weng, Tingting; Molina, Jose G; Luo, Fayong; Davies, Jonathan; Le, Ngoc-Bao; Bunge, Isabelle; Volcik, Kelly A; Le, Thanh-Thuy T; Johnston, Richard A; Xia, Yang; Eltzschig, Holger K; Blackburn, Michael R

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a lethal, fibroproliferative disease. Pulmonary hypertension (PH) can develop secondary to IPF and increase mortality. Alternatively, activated macrophages (AAMs) contribute to the pathogenesis of both IPF and PH. Here we hypothesized that adenosine signaling through the ADORA2B on AAMs impacts the progression of these disorders and that conditional deletion of ADORA2B on myeloid cells would have a beneficial effect in a model of these diseases. Conditional knockout mice lacking ADORA2B on myeloid cells (Adora2B(f/f)-LysM(Cre)) were exposed to the fibrotic agent bleomycin (BLM; 0.035 U/g body weight, i.p.). At 14, 17, 21, 25, or 33 d after exposure, SpO2, bronchoalveolar lavage fluid (BALF), and histologic analyses were performed. On day 33, lung function and cardiovascular analyses were determined. Markers for AAM and mediators of fibrosis and PH were assessed. Adora2B(f/f)-LysM(Cre) mice presented with attenuated fibrosis, improved lung function, and no evidence of PH compared with control mice exposed to BLM. These findings were accompanied by reduced expression of CD206 and arginase-1, markers for AAMs. A 10-fold reduction in IL-6 and a 5-fold decrease in hyaluronan, both linked to lung fibrosis and PH, were also observed. These data suggest that activation of the ADORA2B on macrophages plays an active role in the pathogenesis of lung fibrosis and PH. © FASEB.

  18. DjhnRNPA2/B1-like gene is required for planarian regeneration and tissue homeostasis.

    Science.gov (United States)

    Dong, Zimei; Yang, Tong; Yang, Yibo; Dou, He; Chen, Guangwen

    2017-10-30

    The hnRNPs play important roles in physiological processes in eukaryotic organisms by regulation of pre-mRNA after transcription, including pre-mRNA splicing, mRNA stability, DNA replication and repair and telomere maintenance and so on. However, it remains unclear about the specific functions of these genes. In this study, the full-length cDNA sequence of hnRNPA2/B1-like was first cloned from Dugesia japonica, and its roles were investigated by WISH and RNAi. The results showed that: (1) DjhnRNPA2/B1-like was highly conserved during animal evolution; (2) DjhnRNPA2/B1-like mRNA was mainly distributed each side of the body in intact worms and regenerative blastemas, and its expression levels were up-regulated on days 0 and 5 after amputation; (3) the intact and regenerating worms gradually lysed or lost regeneration capacity after DjhnRNPA2/B1-like RNAi; and (4) DjhnRNPA2/B1-like expression is induced by temperature and heavy metal ion stress. The data suggests that DjhnRNPA2/B1-like is a multiple functional gene, it plays important roles in regeneration and homeostatic maintenance and it is also involved in stress responses in planarians. Our work provides basic data for the study of regenerative mechanism and stress responses in freshwater planarians. Copyright © 2017. Published by Elsevier B.V.

  19. Defective dendritic cell generation from monocytes is a potential reason for poor therapeutic efficacy of interferon α2b (IFNα2b) in cervical cancer.

    Science.gov (United States)

    Roy, Soumyabrata; Goswami, Shyamal; Bose, Anamika; Goswami, Kuntal Kanti; Sarkar, Koustav; Chakraborty, Krishnendu; Chakraborty, Tathagata; Pal, Smarajit; Haldar, Atanu; Basu, Parthasarathi; Biswas, Jaydip; Baral, Rathindranath

    2011-10-01

    Despite being a pleiotropic cytokine, the therapeutic potential of interferon α2b (IFNα2b) is debatable. Thus, the need for identifying predictive marker(s) for patients who are most likely to benefit from the treatment is pivotal for avoiding the exposure of nonresponsive patients to the toxicity of the treatment. To account for the attenuated efficacy of the drug, we have verified its dendritic cell (DC) maturating ability from monocytes of cervical cancer stage IIIB (CaCx-IIIB) patients. First, we evaluated the status of monocytes from CaCx-IIIB and healthy women by conducting flow cytometric studies of various activation markers and a cytokine analysis by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Immature DCs were then generated from these monocytes and matured with low-dose IFNα2b (1500 units/mL). A functional and phenotypic comparative analysis of these matured DCs was performed by flow cytometric, proliferative, cytotoxic, and enzyme-linked immunosorbent assays. Our study shows that monocytes isolated from CaCx-IIIB are impaired, and in vitro maturation with IFNα2b did not significantly improve the functional repertoire of DCs generated from these monocytes in comparison with healthy controls. This impairment of monocytes might be a plausible reason for the attenuated efficacy of this drug alone in treating CaCx-IIIB patients, and this imbalance of immune parameters associated with the stage of malignancy might be considered an effective marker to design a proper therapeutic regimen. Copyright © 2011 Mosby, Inc. All rights reserved.

  20. Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone- and buprenorphine-maintained subjects

    Science.gov (United States)

    Gelston, Eloise A; Coller, Janet K; Lopatko, Olga V; James, Heather M; Schmidt, Helmut; White, Jason M; Somogyi, Andrew A

    2012-01-01

    AIMS To compare the O-demethylation (CYP2D6-mediated), N-demethylation (CYP3A4-mediated) and 6-glucuronidation (UGT2B4/7-mediated) metabolism of codeine between methadone- and buprenorphine-maintained CYP2D6 extensive metabolizer subjects. METHODS Ten methadone- and eight buprenorphine-maintained subjects received a single 60 mg dose of codeine phosphate. Blood was collected at 3 h and urine over 6 h and assayed for codeine, norcodeine, morphine, morphine-3- and -6-glucuronides and codeine-6-glucuronide. RESULTS The urinary metabolic ratio for O-demethylation was significantly higher (P = 0.0044) in the subjects taking methadone (mean ± SD, 2.8 ± 3.1) compared with those taking buprenorphine (0.60 ± 0.43), likewise for 6-glucuronide formation (0.31 ± 0.24 vs. 0.053 ± 0.027; P codeine and norcodeine concentrations (P codeine-6-glucuronide concentrations (P < 0.008). CONCLUSION Methadone is associated with inhibition of CYP2D6 and UGTs 2B4 and 2B7 reactions in vivo, even though it is not a substrate for these enzymes. Plasma morphine was not altered, owing to the opposing effects of inhibition of both formation and elimination; however, morphine-6-glucuronide (analgesically active) concentrations were substantially reduced. Drug interactions with methadone are likely to include drugs metabolized by various UGTs and CYP2D6. PMID:22092298

  1. Competency-orientated brand cooperations of power supply companies in the B2B sector; Kompetenzorientierte Markenkooperationen von Energieversorgungsunternehmen im B2B-Kundenbereich

    Energy Technology Data Exchange (ETDEWEB)

    Peuser, M.M.

    2008-07-01

    On the basis of an extensive empirical study with B2B electricity users, the author of the book under consideration examines brand co-operations of power supply companies with companies not working in the area of energy production. Based on the view of various co-operation alternatives, impact relations and success-determining factors of influence in the area of B2B customers are identified. The term of the authority of an energy brand is discussed. Beside this, profiles of concrete brands of current power supply companies from the view of B2B customers are pointed out, and recommendations for the organization of brand co-operation and the structure of mark authority in practice are shown. This contribution is written for lecturers and students of the management economics with the emphasis of marketing and management as well as high-level personnel in the energy industry, who wants to develop strong mark authority by brand co-operation.

  2. Safety and antiviral activity of albinterferon alfa-2b in prior interferon nonresponders with chronic hepatitis C.

    Science.gov (United States)

    Nelson, David R; Rustgi, Vinod; Balan, Vijayan; Sulkowski, Mark S; Davis, Gary L; Muir, Andrew J; Lambiase, Louis R; Dickson, Rolland C; Weisner, Russell H; Fiscella, Michele; Cronin, Patrick W; Pulkstenis, Erik; McHutchison, John G; Subramanian, G Mani

    2009-02-01

    Pegylated interferon alfa-2a/2b is used in combination with ribavirin to treat patients with chronic hepatitis C (CHC), although many do not achieve a sustained virologic response (SVR). Albinterferon alfa-2b, a recombinant protein consisting of interferon alfa-2b fused to human albumin, may increase drug exposure. This phase 2 study evaluated the safety/efficacy of albinterferon in CHC patients who had not responded to interferon-based regimens. A total of 115 patients were assigned to 5 groups given 1200 microg albinterferon every 4 weeks or 900, 1200, 1500, or 1800 microg every 2 weeks, plus oral ribavirin, for 48 weeks. The primary efficacy end point was achievement of an SVR after 24 weeks. Treatment was extended to 72 weeks for 6 slow responders who were negative for hepatitis C virus RNA after 24 weeks. The types of adverse events were similar across groups; the overall discontinuation rate as a result of adverse events was 10.4%. Reductions in absolute neutrophil counts were less frequent in the every 4 weeks group and comparable among the every 2 weeks groups. The overall SVR rate was 17% (11% for previous nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection). An SVR occurred in 3 of 6 slow responders by 72 weeks. The greatest reductions in hepatitis C virus RNA in nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection were observed in the 1800-microg group. In patients with CHC who did not respond to interferon-based regimens, higher doses of albinterferon had significant early antiviral activity and a low incidence of adverse events, with the types of adverse events similar to those observed with interferon.

  3. Phenobarbital induction of CYP2B1, CYP2B2, and CYP3A1 in rat liver: genetic differences in a common regulatory mechanism.

    Science.gov (United States)

    Larsen, M C; Jefcoate, C R

    1995-08-20

    The phenobarbital induction of five responsive hepatic cytochrome P450 genes is highly strain selective, particularly in female rats (Fischer > Wistar Furth). We have shown that this strain variation represents a systematic difference in the endocrine-mediated suppression of phenobarbital induction which points to a common signaling process for each of these genes. Immunoblot analysis revealed that the strain-specific differences of phenobarbital responsiveness (10-fold for CYP2B1, CYP2B2, and CYP3A1 in females) are much smaller in male animals and are also greatly diminished by hypophysectomy. Partial depletion of thyroid hormone and growth hormone levels by methimazole treatment was equally as effective as hypophysectomy in elevating phenobarbital-induced levels of CYP2B1, CYP2B2, and CYP3A1 in Wistar Furth rats, while the Fischer strain was unaffected. Ovariectomy suppressed the phenobarbital induction of these genes in the Wistar Furth but not in the Fischer strain, while castration yielded a similar differential suppression in male rats which was reversed by testosterone propionate supplementation. Changes in CYP2B1 protein closely correlated with changes in 7-pentoxyresorufin-O-dealkylation activity, a functional marker for this P450. The strain-selective differences, although smaller, were also observed in the very low basal expression of these P450 genes, while the effects of hypophysectomy, ovariectomy, and castration occurred in a similar manner. However, methimazole was essentially ineffective relative to hypophysectomy in elevating basal expression of these genes. The low concentrations of residual growth hormone and thyroid hormone probably provide a more effective suppression in the basal than in the induced state. We conclude that multiple cytochrome P450 genes share a common phenobarbital induction pathway that, in part, alleviates the suppressive effects of thyroid hormone and growth hormone which are far greater in female Wistar Furth rats. This

  4. Biological responses according to the shape and size of carbon nanotubes in BEAS-2B and MESO-1 cells.

    Science.gov (United States)

    Haniu, Hisao; Saito, Naoto; Matsuda, Yoshikazu; Tsukahara, Tamotsu; Usui, Yuki; Maruyama, Kayo; Takanashi, Seiji; Aoki, Kaoru; Kobayashi, Shinsuke; Nomura, Hiroki; Tanaka, Manabu; Okamoto, Masanori; Kato, Hiroyuki

    2014-01-01

    This study aimed to investigate the influence of the shape and size of multi-walled carbon nanotubes (MWCNTs) and cup-stacked carbon nanotubes (CSCNTs) on biological responses in vitro. Three types of MWCNTs - VGCF(®)-X, VGCF(®)-S, and VGCF(®) (vapor grown carbon fibers; with diameters of 15, 80, and 150 nm, respectively) - and three CSCNTs of different lengths (CS-L, 20-80 μm; CS-S, 0.5-20 μm; and CS-M, of intermediate length) were tested. Human bronchial epithelial (BEAS-2B) and malignant pleural mesothelioma cells were exposed to the CNTs (1-50 μg/mL), and cell viability, permeability, uptake, total reactive oxygen species/superoxide production, and intracellular acidity were measured. CSCNTs were less toxic than MWCNTs in both cell types over a 24-hour exposure period. The cytotoxicity of endocytosed MWCNTs varied according to cell type/size, while that of CSCNTs depended on tube length irrespective of cell type. CNT diameter and length influenced cell aggregation and injury extent. Intracellular acidity increased independently of lysosomal activity along with the number of vacuoles in BEAS-2B cells exposed for 24 hours to either CNT (concentration, 10 μg/mL). However, total reactive oxygen species/superoxide generation did not contribute to cytotoxicity. The results demonstrate that CSCNTs could be suitable for biological applications and that CNT shape and size can have differential effects depending on cell type, which can be exploited in the development of highly specialized, biocompatible CNTs.

  5. Herb–drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Hai-Ying, E-mail: cmu4h-mhy@126.com [The Fourth Affiliated Hospital of China Medical University, Shenyang 110032 (China); Sun, Dong-Xue [School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016 (China); Cao, Yun-Feng [The First Affiliated Hospital of Liaoning Medical University, Jinzhou 121001 (China); Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023 (China); Ai, Chun-Zhi [Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023 (China); Qu, Yan-Qing [Thyroid Surgery, Yantaishan Hospital, Yantai, Shandong (China); Hu, Cui-Min [Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023 (China); Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057 (United States); Jiang, Changtao [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 (United States); Dong, Pei-Pei [Academy of Integrative Medicine, Dalian Medical University, Dalian 116044 (China); Sun, Xiao-Yu; Hong, Mo [Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023 (China); Tanaka, Naoki; Gonzalez, Frank J. [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 (United States); and others

    2014-05-15

    Herb–drug interaction strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons. The present study aims to investigate the inhibition potential of andrographolide derivatives towards one of the most important phase II DMEs UDP-glucuronosyltransferases (UGTs). Recombinant UGT isoforms (except UGT1A4)-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation were employed to firstly screen the andrographolide derivatives' inhibition potential. High specific inhibition of andrographolide derivatives towards UGT2B7 was observed. The inhibition type and parameters (K{sub i}) were determined for the compounds exhibiting strong inhibition capability towards UGT2B7, and human liver microsome (HLMs)-catalyzed zidovudine (AZT) glucuronidation probe reaction was used to furtherly confirm the inhibition behavior. In combination of inhibition parameters (K{sub i}) and in vivo concentration of andrographolide and dehydroandrographolide, the potential in vivo inhibition magnitude was predicted. Additionally, both the in vitro inhibition data and computational modeling results provide important information for the modification of andrographolide derivatives as selective inhibitors of UGT2B7. Taken together, data obtained from the present study indicated the potential herb–drug interaction between Andrographis paniculata and the drugs mainly undergoing UGT2B7-catalyzed metabolic elimination, and the andrographolide derivatives as potential candidates for the selective inhibitors of UGT2B7. - Highlights: • Specific inhibition of andrographolide derivatives towards UGT2B7. • Herb-drug interaction related withAndrographis paniculata. • Guidance for design of UGT2B7 specific inhibitors.

  6. Adenosine A2B receptor blockade slows growth of bladder and breast tumors.

    Science.gov (United States)

    Cekic, Caglar; Sag, Duygu; Li, Yuesheng; Theodorescu, Dan; Strieter, Robert M; Linden, Joel

    2012-01-01

    The accumulation of high levels of adenosine in tumors activates A(2A) and A(2B) receptors on immune cells and inhibits their ability to suppress tumor growth. Deletion of adenosine A(2A) receptors (A(2A)ARs) has been reported to activate antitumor T cells, stimulate dendritic cell (DC) function, and inhibit angiogenesis. In this study, we evaluated the effects of intermittent intratumor injection of a nonselective adenosine receptor antagonist, aminophylline (AMO; theophylline ethylenediamine) and, for the first time to our knowledge, a selective A(2B)AR antagonist, ATL801. AMO and ATL801 slowed the growth of MB49 bladder and 4T1 breast tumors in syngeneic mice and reduced by 85% metastasizes of breast cancer cells from mammary fat to lung. Based on experiments with A(2A)AR(-/-) or adenosine A(2B) receptor(-/-) mice, the effect of AMO injection was unexpectedly attributed to A(2B)AR and not to A(2A)AR blockade. AMO and ATL801 significantly increased tumor levels of IFN-γ and the IFN-inducible chemokine CXCL10, which is a ligand for CXCR3. This was associated with an increase in activated tumor-infiltrating CXCR3(+) T cells and a decrease in endothelial cell precursors within tumors. Tumor growth inhibition by AMO or ATL801 was eliminated in CXCR3(-/-) mice and RAG1(-/-) mice that lack mature T cells. In RAG1(-/-) mice, A(2B)AR deletion enhanced CD86 expression on CD11b(-) DCs. Bone marrow chimera experiments demonstrated that CXCR3 and A(2B)AR expression on bone marrow cells is required for the antitumor effects of AMO. The data suggest that blockade of A(2B)ARs enhances DC activation and CXCR3-dependent antitumor responses.

  7. A Post-Docking Role of Synaptotagmin 1-C2B Domain Bottom Residues R398/399 in Mouse Chromaffin Cells

    DEFF Research Database (Denmark)

    Kedar, Girish H; Munch, Anders S; van Weering, Jan R T

    2015-01-01

    Synaptotagmin-1 (Syt1) is the principal Ca2+ sensor for vesicle fusion and is also essential for vesicle docking in chromaffin cells. Docking depends on interactions of the Syt1-C2B domain with the t-SNARE SNAP25/Syntaxin1 complex and/or plasma membrane phospholipids. Here, we investigated the role...... of the positively charged “bottom” region of the C2B domain, proposed to help crosslink membranes, in vesicle docking and secretion in mouse chromaffin cells and in cell-free assays. We expressed a double mutation shown previously to interfere with lipid mixing between proteoliposomes and with synaptic transmission...... mutants. Finally, overexpressing the RQ-mutant in wild type cells produced no effect on either docking or secretion. We conclude that the positively charged bottom region in the C2B domain—and, by inference, Syt1-mediated membrane crosslinking—is required for triggering fusion, but not for docking...

  8. The Effect of CYP2B6, CYP2D6, and CYP3A4 Alleles on Methadone Binding: A Molecular Docking Study

    Directory of Open Access Journals (Sweden)

    Nik Nur Syazana Bt Nik Mohamed Kamal

    2013-01-01

    Full Text Available Current methadone maintenance therapy (MMT is yet to ensure 100% successful treatment as the optimum dosage has yet to be determined. Overdose leads to death while lower dose causes the opioid withdrawal effect. Single-nucleotide polymorphisms (SNP in cytochrome P450s (CYPs, the methadone metabolizers, have been showen to be the main factor for the interindividual variability of methadone clinical effects. In this study, we investigated the effect of SNPs in three major methadone metabolizers (CYP2B6, CYP2D6, and CYP3A4 on methadone binding affinity. Results showed that CYP2B6*11, CYP2B6*12, CYP2B6*18, and CYP3A4*12 have significantly higher binding affinity to R-methadone compared to wild type. S-methadone has higher binding affinity in CYP3A4*3, CYP3A4*11, and CYP3A4*12 compared to wild type. R-methadone was shown to be the active form of methadone; thus individuals with CYP alleles that binds better to R-methadone will have higher methadone metabolism rate. Therefore, a higher dosage of methadone is necessary to obtain the opiate effect compared to a normal individual and vice versa. These results provide an initial prediction on methadone metabolism rate for individuals with mutant type CYP which enables prescription of optimum methadone dosage for individuals with CYP alleles.

  9. Genetic characterization of Listeria monocytogenes food isolates and pathogenic potential within serovars 1/2a and 1/2b.

    Science.gov (United States)

    Cabrita, Paula; Correia, Sónia; Ferreira-Dias, Suzana; Brito, Luisa

    2004-08-01

    A total of 39 Listeria monocytogenes strains isolated from raw milk, smoked meat, chicken carcass and reference strains, belonging to serovars 1/2a, 4a, 1/2b, 3b and 4b, were analysed by RAPD and by polymorphisms of the virulent genes inlAB and iap. Ten isolates, belonging to serovars 1/2a and 1/2b and, collected from raw milk and smoked meat, were further tested for pathogenicity by IP injection into mice. The clustering of the 39 L. monocytogenes strains in 3 groups at 0.45 similarity level, based on molecular typing, was observed. Distribution of serovars in these clusters was in agreement with the proposed three Listeria monocytogenes lineages. Within serovar 1/2b, the 50% lethal dose (LD50) ranged from 8.4 x 10(4) to 1.7 x 10(6) cfu.ml(-1). One of the serovar 1/2b strains, isolated from smoked meat, exhibited the lowest virulence potential evaluated by LD50 and by mean time to death (MTD) and, from this point of view, was completely different from the other strains. Our results suggest the existence of heterogeneity in virulence levels within serovars 1/2a and 1/2b. However, when comparing the isolates based on genotyping, virulence indicators and food origin, no relation could be assessed.

  10. Electrophilic Halogenation of closo-1,2-C2B8H10.

    Science.gov (United States)

    Bakardjiev, Mario; Růžička, Aleš; Růžičková, Zdeňka; Holub, Josef; Tok, Oleg L; Štíbr, Bohumil

    2017-05-15

    Initial studies on electrophilic halogenation of the dicarbaborane closo-1,2-C2B8H10 (1) have been carried out to reveal that the substitution takes place at B7 and B10 vertexes, which are the most removed from the CH positions. The course of the halogenation is strongly dependent on the nature of the halogenation agent and reaction conditions. Individual reactions led to the isolation of the monosubstituted compounds 1,2-C2B8H9-10-X (2) (where X = F, I) and 1,2-C2B8H9-7-X (3) (where X = Cl, I). Disubstituted carboranes 1,2-C2B8H8-7,10-X2 (4) (where X = Cl, Br, I) were obtained under more forcing conditions. Individual halo derivatives were characterized by mass spectrometry and high-field NMR ((11)B, (1)H,(13)C) spectroscopy combined with two-dimensional [(11)B-(11)B]-COSY, (1)H{(11)B(selective)}, and [(11)B-(1)H]-correlation NMR techniques. All of the derivatives bearing a halogen substituent in the B10 position exhibit a remarkable antipodal (13)C and (1)H NMR shielding at the CH1 vertex, increasing in the order H < I < Br < Cl < F. The structures of 1,2-C2B8H8-7,10-X2 derivatives (where X = Cl, I, 4b,d) were established by X-ray diffraction analyses.

  11. Presymptomatic generalized brain atrophy in frontotemporal dementia caused by CHMP2B mutation

    DEFF Research Database (Denmark)

    Rohrer, Jonathan D; Ahsan, R Laila; Isaacs, Adrian M

    2009-01-01

    BACKGROUND/AIMS: CHMP2B mutations are a rare cause of familial frontotemporal dementia (FTD). The clinical syndrome is dominated by personality change and behavioural symptoms, but language, memory, calculation and praxis impairments are also seen early in the course of the disease. There are no ......BACKGROUND/AIMS: CHMP2B mutations are a rare cause of familial frontotemporal dementia (FTD). The clinical syndrome is dominated by personality change and behavioural symptoms, but language, memory, calculation and praxis impairments are also seen early in the course of the disease....... There are no detailed studies of brain imaging in CHMP2B mutation-associated FTD. This study aimed to investigate whether there were early or presymptomatic changes in this group of patients. METHODS: Subjects comprised 16 members of a Danish family with CHMP2B mutation-associated FTD. Nine subjects were presymptomatic...... mutation carriers with a control group of 7 mutation-negative family members. Volumetric MRI brain scans were performed on all subjects at two time points, and rates of volume change were compared between the two groups. RESULTS: We demonstrate that generalized atrophy occurs presymptomatically in CHMP2B...

  12. Charcot Marie Tooth 2B Peripheral Sensory Neuropathy: How Rab7 Mutations Impact NGF Signaling?

    Directory of Open Access Journals (Sweden)

    Harry Liu

    2017-02-01

    Full Text Available Charcot-Marie-Tooth 2B peripheral sensory neuropathy (CMT2B is a debilitating autosomal dominant hereditary sensory neuropathy. Patients with this disease lose pain sensation and frequently need amputation. Axonal dysfunction and degeneration of peripheral sensory neurons is a major clinical manifestation of CMT2B. However, the cellular and molecular pathogenic mechanisms remain undefined. CMT2B is caused by missense point mutations (L129F, K157N, N161T/I, V162M in Rab7 GTPase. Strong evidence suggests that the Rab7 mutation(s enhances the cellular levels of activated Rab7 proteins, thus resulting in increased lysosomal activity and autophagy. As a consequence, trafficking and signaling of neurotrophic factors such as nerve growth factor (NGF in the long axons of peripheral sensory neurons are particularly vulnerable to premature degradation. A “gain of toxicity” model has, thus, been proposed based on these observations. However, studies of fly photo-sensory neurons indicate that the Rab7 mutation(s causes a “loss of function”, resulting in haploinsufficiency. In the review, we summarize experimental evidence for both hypotheses. We argue that better models (rodent animals and human neurons of CMT2B are needed to precisely define the disease mechanisms.

  13. 5-HT2B Receptor Antagonists Inhibit Fibrosis and Protect from RV Heart Failure

    Directory of Open Access Journals (Sweden)

    Wiebke Janssen

    2015-01-01

    Full Text Available Objective. The serotonin (5-HT pathway was shown to play a role in pulmonary hypertension (PH, but its functions in right ventricular failure (RVF remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist or SB204741 (5-HT2B receptor antagonist on right heart function and structure upon pulmonary artery banding (PAB in mice. Methods. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid or SB204741 (5 mg/kg day. Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI, and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. Results. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Conclusion. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF.

  14. Development of Fluorescent Probes that Target Serotonin 5-HT2B Receptors.

    Science.gov (United States)

    Azuaje, Jhonny; López, Paula; Iglesias, Alba; de la Fuente, Rocío A; Pérez-Rubio, José M; García, Diego; Stępniewski, Tomasz Maciej; García-Mera, Xerardo; Brea, José M; Selent, Jana; Pérez, Dolores; Castro, Marián; Loza, María I; Sotelo, Eddy

    2017-09-07

    Some 5-HT2B fluorescent probes were obtained by tagging 1-(2,5-dimethoxy-4-iodophenyl)-propan-2-amine (DOI) with a subset of fluorescent amines. Some of the resulting fluorescent ligands showed excellent affinity and selectivity profiles at the 5-HT2B receptors (e.g. 12b), while retain the agonistic functional behaviour of the model ligand (DOI). The study highlighted the most salient features of the structure-activity relationship in this series and these were substantiated by a molecular modelling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human 5-HT2B receptor. One of the fluorescent ligands developed in this work, compound 12i, specifically labelled CHO-K1 cells expressing 5-HT2B receptors and not parental CHO-K1 cells in a concentration-dependent manner. 12i enables imaging and quantification of specific 5-HT2B receptor labelling in live cells by automated fluorescence microscopy as well as quantification by measurements of fluorescence intensity using a fluorescence plate reader.

  15. Effects of nano bamboo charcoal on PAHs-degrading strain Sphingomonas sp. GY2B.

    Science.gov (United States)

    She, Bojia; Tao, Xueqin; Huang, Ting; Lu, Guining; Zhou, Zhili; Guo, Chuling; Dang, Zhi

    2016-03-01

    Nano bamboo charcoal (NBC) has been commonly used in the production of textiles, plastics, paint, etc. However, little is known regarding their effects towards the microorganisms. The effects of NBC on phenanthrene degrading strain Sphingomonas sp. GY2B were investigated in the present study. Results showed that the addition of NBC could improve the phenanthrene removal by Sphingomonas sp. GY2B, with removal efficiencies increased by 10.29-18.56% in comparison to the control at 24h, and phenanthrene was almost completely removed at 48h. With the presence of low dose of NBC (20 and 50mgL(-1)), strain GY2B displayed a better growth at 6h, suggesting that NBC was beneficial to the growth of GY2B and thus resulting in the quick removal of phenanthrene from water. However, the growth of strain GY2B in high dose of NBC (200mgL(-1)) was inhibited at 6h, and the inhibition could be attenuated and eliminated after 12h. NBC-effected phenanthrene solubility experiment suggested that NBC makes a negligible contribution to the solubilization of phenanthrene in water. Results of electronic microscopy analysis (SEM and TEM) indicated NBC may interact with the cell membrane, causing the enhanced membrane permeability and then NBC adsorbed on the membrane would enter into the cells. The findings of this work would provide important information for the future usage and long-term environmental risk assessment of NBC. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. H2B ubiquitylation controls the formation of export-competent mRNP.

    Science.gov (United States)

    Vitaliano-Prunier, Adeline; Babour, Anna; Hérissant, Lucas; Apponi, Luciano; Margaritis, Thanasis; Holstege, Frank C P; Corbett, Anita H; Gwizdek, Carole; Dargemont, Catherine

    2012-01-13

    Histone H2B ubiquitylation is a transcription-dependent modification that not only regulates nucleosome dynamics but also controls the trimethylation of histone H3 on lysine 4 by promoting ubiquitylation of Swd2, a component of both the histone methyltransferase COMPASS complex and the cleavage and polyadenylation factor(CPF). We show that preventing either H2B ubiquitylation or H2B-dependent modification of Swd2 results in nuclear accumulation of poly(A) RNA due to a defect in the integrity and stability of APT, a subcomplex of the CPF. Ubiquitin-regulated APT complex dynamics is required for the correct recruitment of the mRNA export receptor Mex67 to nuclear mRNPs. While H2B ubiquitylation controls the recruitment of the different Mex67 adaptors to mRNPs, the effect of Swd2 ubiquitylation is restricted to Yra1 and Nab2, which, in turn, controls poly(A) tail length. Modification of H2B thus participates in the crosstalk between cotranscriptional events and assembly of mRNPs linking nuclear processing and mRNA export. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Albinterferon alfa-2b, a novel fusion protein of human albumin and human interferon alfa-2b, for chronic hepatitis C.

    Science.gov (United States)

    Rustgi, Vinod K

    2009-04-01

    New treatment options for chronic hepatitis C (CHC) that offer improved efficacy, tolerability, and convenience compared with weekly interferon alfa (IFNalpha)-based regimens are needed. Longer-acting IFNalpha formulations with reduced dosing requirements and improved tolerability have been a focus of drug development efforts. The objective of this report is to review the characteristics, pharmacokinetics, pharmacodynamics, and clinical and virologic outcomes reported in studies of albinterferon alfa-2b (alb-IFN), a novel fusion protein of human albumin and human IFNalpha-2b. This review was based on all published data regarding alb-IFN to date. An unlimited PubMed database search was conducted using the keywords 'albuferon,' 'albinterferon,' and 'albumin AND interferon.' Albinterferon alfa-2b has been developed for the treatment of CHC. This agent exhibits a prolonged half-life and duration of antiviral activity that indicate potential suitability for dosing intervals of 2-4 weeks. Phase 2 trials in prior IFN nonresponders and IFN-naïve patients with genotype 1 or 2/3 CHC have shown antiviral activity and acceptable safety/tolerability of alb-IFN 900-1500 microg every 2 weeks and 1200-1500 microg every 4 weeks. Based on the phase 2 data, alb-IFN 900 microg and 1200 microg every 2 weeks were selected for two ongoing phase 3 trials in IFN-naïve patients with genotype 1 and 2/3 CHC. Albinterferon alfa-2b exhibits high antiviral activity, and appears to offer safety/tolerability comparable to the current standard of care, and health-related quality-of-life benefits in patients with CHC. Its ability to maintain drug concentrations above the 90% effective concentration over prolonged dosing intervals suggests that it may be an ideal partner for combination therapy with direct antiviral agents in CHC. The results of the phase 3 trials are eagerly anticipated as they should greatly clarify the future role of alb-IFN in the treatment of CHC.

  18. Social Media within a B2B context : A qualitative study about how industrial corporations can use social media to maintain B2B relationships

    OpenAIRE

    Andersén, Sophia; Bengtsson, Annie; Gilén, Sandra

    2014-01-01

    The last thirty years there has been a dramatic change in relationship marketing. The use of computers connected to the Internet at work places has increased over time and social media is widely used in marketing strategies. Social media is a new phenomenon to communicate with each other, it enables market information based on individual consumer’s experiences. Therefore managers are seeking a way to incorporate social media into their strategies, but this is more common within B2C than B2B. ...

  19. The adaptor protein SH2B3 (Lnk negatively regulates neurite outgrowth of PC12 cells and cortical neurons.

    Directory of Open Access Journals (Sweden)

    Tien-Cheng Wang

    Full Text Available SH2B adaptor protein family members (SH2B1-3 regulate various physiological responses through affecting signaling, gene expression, and cell adhesion. SH2B1 and SH2B2 were reported to enhance nerve growth factor (NGF-induced neuronal differentiation in PC12 cells, a well-established neuronal model system. In contrast, SH2B3 was reported to inhibit cell proliferation during the development of immune system. No study so far addresses the role of SH2B3 in the nervous system. In this study, we provide evidence suggesting that SH2B3 is expressed in the cortex of embryonic rat brain. Overexpression of SH2B3 not only inhibits NGF-induced differentiation of PC12 cells but also reduces neurite outgrowth of primary cortical neurons. SH2B3 does so by repressing NGF-induced activation of PLCγ, MEK-ERK1/2 and PI3K-AKT pathways and the expression of Egr-1. SH2B3 is capable of binding to phosphorylated NGF receptor, TrkA, as well as SH2B1β. Our data further demonstrate that overexpression of SH2B3 reduces the interaction between SH2B1β and TrkA. Consistent with this finding, overexpressing the SH2 domain of SH2B3 is sufficient to inhibit NGF-induced neurite outgrowth. Together, our data demonstrate that SH2B3, unlike the other two family members, inhibits neuronal differentiation of PC12 cells and primary cortical neurons. Its inhibitory mechanism is likely through the competition of TrkA binding with the positive-acting SH2B1 and SH2B2.

  20. [Antiviral activity of recombinant interferon-alpha-2b in combination with certain antioxidant].

    Science.gov (United States)

    Vasil'ev, A N; Deriabin, P G; Galegov, G A

    2011-01-01

    In vitro activity of interferon-alpha-2b in combination with various antioxidants against the influenza virus and Herpes simplex was studied. The standard strains and a clinical strain of Herpes simplex isolated from a patient with resistance to acyclovir were used. The in vitro studie showed that antioxidants, such as alpho-tocoferol acetate (vitamin E), Unithiol and ascorbic acid had a significant antiinfluenzae and antiherpetic action on the influenza virus A/H5N1 and Herpes simplex variants. They protected up to 100% of the cell monolayer from the virus cytopathic effect. The taurin solutions had no antiviral activity irrespective of the infection dose. Combinations of interferon-alpha-2b with alpha-tocopherol acetate (vitamin E), Unithiol or ascorbic acid showed a significant synergistic effect: the antiviral activity of interferon increased several times. The antiinfluenza activity of interferon-a-2b in the presence of various concentrations of taurin did not change.

  1. IMMUNOMODULATING THERAPY BY RECOMBINANT ALPHA-2B INTERFERON AMONG CHILDREN WITH TIMOMEGALIA

    Directory of Open Access Journals (Sweden)

    L.A. Nikulin

    2007-01-01

    Full Text Available The study of the enlarged thymus gland syndrome is extremely important for understanding of the immune system formation and functioning mechanisms. the purpose of this study is to conduct clinical and immunological analysis of the children, suffering from the syndrome of the enlarged thymus gland II and III degrees, who received recombinant alpha2b interferon (in suppositories. The revealed changes in the immune sys tem during timomegalia are complex and conducive to the development of the infectious and inflammatory diseases among infants, thus, determining the necessity for the adequate immune correction. The application of the recombinant alpha 2b interferon among such children allows one to uncover the immunomodulating effects, normalizing the imbalances in the immune system of children with timomegalia.Key words: timomegalia, alpha 2b interferon, immunity, immune correction, children.

  2. Neuropsychiatric complications associated with interferon - alpha -2b treatment of malignant melanoma.

    LENUS (Irish Health Repository)

    Enudi, W

    2012-02-01

    Several adverse effects have been associated with interferon alpha 2b treatment and neuropsychiatric effects have also been commonly reported. Psychosis and mood disorders have been described in the literature. This case report is of a 30 year old man with malignant melanoma stage 3a who was receiving adjuvant alpha 2b interferon and developed a manic episode two weeks post switching after one month of treatment on a high dose to a low dose. There was no previous psychiatric illness and no known family history of mental illness. This is in keeping with previous reports that mania has been observed in patients undergoing interferon treatment especially after significant dose-reduction or treatment breaks. Mania induced by interferon responds well to antimanic drugs .Since interferon alpha 2b is now commonly used in the treatment of malignant melanoma and other conditions, the need to be aware of its neuropsychiatric complications is essential.

  3. Sustained major molecular response on interferon alpha-2b in two patients with polycythemia vera

    DEFF Research Database (Denmark)

    Larsen, T.S.; Pallisgaard, N.; Andersen, M.T.

    2008-01-01

    chromosome negative chronic myeloproliferative disorders. Reductions in the JAK2 V617F allele burden in patients treated with pegylated interferon alpha-2a (Peg-IFN-2a) have been demonstrated, although follow-up was relatively short. We report here the first profound and sustained molecular responses......Quantitative assessment of the JAK2 V617F allele burden during disease evolution and ongoing myelosuppressive treatment is likely to be implemented in the future clinical setting. Interferon alpha has demonstrated efficacy in treatment of both chronic myeloid leukemia and the Philadelphia...... with a JAK2 V617F allele burden below 1.0% in two patients with polycythemia vera treated with interferon alpha-2b (IFN-2b). Discontinuation of IFN-2b in one of the patients was followed by a sustained long-lasting (12 months of follow-up) major molecular response Udgivelsesdato: 2008/10...

  4. Sustained major molecular response on interferon alpha-2b in two patients with polycythemia vera

    DEFF Research Database (Denmark)

    Larsen, Thomas Stauffer; Bjerrum, O W; Pallisgaard, N

    2008-01-01

    Quantitative assessment of the JAK2 V617F allele burden during disease evolution and ongoing myelosuppressive treatment is likely to be implemented in the future clinical setting. Interferon alpha has demonstrated efficacy in treatment of both chronic myeloid leukemia and the Philadelphia...... chromosome negative chronic myeloproliferative disorders. Reductions in the JAK2 V617F allele burden in patients treated with pegylated interferon alpha-2a (Peg-IFN-2a) have been demonstrated, although follow-up was relatively short. We report here the first profound and sustained molecular responses...... with a JAK2 V617F allele burden below 1.0% in two patients with polycythemia vera treated with interferon alpha-2b (IFN-2b). Discontinuation of IFN-2b in one of the patients was followed by a sustained long-lasting (12 months of follow-up) major molecular response....

  5. Accessory nerve function after level 2b-preserving selective neck dissection.

    Science.gov (United States)

    Celik, Bilge; Coskun, Hakan; Kumas, Ferda F; Irdesel, Jale; Zarifoglu, Mehmet; Erisen, Levent; Onart, Selcuk

    2009-11-01

    The aim of this prospective study was to evaluate the relationship between accessory nerve functions and level 2b-preserving selective neck dissection. Forty-one necks of 30 patients with laryngeal cancer who underwent unilateral or bilateral level 2b-preserving neck dissections, between February 2003 and July 2005, were evaluated. Neck and shoulder movements and muscle strengths were examined and electroneuromyography (ENMG) was performed preoperatively at the postoperative 21st day and 6th month. Pathological anatomical findings at the postoperative 6th month were also evaluated. All shoulder movements and muscle strengths were preserved. Neck extension, rotation movements, and flexion strengths were restricted. ENMG values were affected moderately in the early postoperative period and improved slightly in the late postoperative period. None of the patients developed shoulder syndrome or adhesive capsulitis. Preserving level 2b during selective neck dissection decreases trauma to the accessory nerve and improves functional results. (c) 2009 Wiley Periodicals, Inc. Head Neck, 2009.

  6. Neuropsychiatric complications associated with interferon - alpha -2b treatment of malignant melanoma.

    LENUS (Irish Health Repository)

    Enudi, W

    2009-08-01

    Several adverse effects have been associated with interferon alpha 2b treatment and neuropsychiatric effects have also been commonly reported. Psychosis and mood disorders have been described in the literature. This case report is of a 30 year old man with malignant melanoma stage 3a who was receiving adjuvant alpha 2b interferon and developed a manic episode two weeks post switching after one month of treatment on a high dose to a low dose. There was no previous psychiatric illness and no known family history of mental illness. This is in keeping with previous reports that mania has been observed in patients undergoing interferon treatment especially after significant dose-reduction or treatment breaks. Mania induced by interferon responds well to antimanic drugs .Since interferon alpha 2b is now commonly used in the treatment of malignant melanoma and other conditions, the need to be aware of its neuropsychiatric complications is essential.

  7. Contributions of PHOX2B in the pathogenesis of Hirschsprung disease.

    Directory of Open Access Journals (Sweden)

    Raquel María Fernández

    Full Text Available Hirschsprung disease (HSCR is a congenital malformation of the hindgut resulting from a disruption of neural crest cell migration during embryonic development. It has a complex genetic aetiology with several genes involved in its pathogenesis. PHOX2B plays a key function in the development of neural crest derivatives, and heterozygous mutations cause a complex dysautonomia associating HSCR, Congenital Central Hypoventilation Syndrome (CCHS and neuroblastoma (NB in various combinations. In order to determine the role of PHOX2B in isolated HSCR, we performed a mutational screening in a cohort of 207 Spanish HSCR patients. Our most relevant finding has been the identification of a de novo and novel deletion (c.393_410del18 in a patient with HSCR. Results of in silico and functional assays support its pathogenic effect related to HSCR. Therefore our results support that PHOX2B loss-of-function is a rare cause of HSCR phenotype.

  8. Skp2 and Skp2B team up against Rb and p53.

    Science.gov (United States)

    Germain, Doris

    2011-01-21

    The Skp2 locus encodes two proteins, Skp2 and Skp2B. The role of Skp2 in the ubiquitin-dependent degradation of key regulators of the retinoblastoma protein pathway has been well established. More recent work from the McCormick's group suggested that Skp2 has an ubiquitin-independent function in the regulation of the p53 pathway. Adding to this observation, we reported that Skp2B also regulates the activity of p53 by degrading a distinct substrate, prohibitin. Since prohibitin has been implicated in the regulation of the Rb pathway, collectively, these observations suggest that Skp2 and Skp2B team up against p53 and Rb.

  9. IFN Alfa-2B and BCG Therapy Is An Effective Method In Superficial Bladder Carcinoma

    Directory of Open Access Journals (Sweden)

    Ahmet Ozdemir

    2012-04-01

    Full Text Available Aim: The initial therapy for superficial bladder carcinoma is the transurethral resection of the tumor. In spite of successful resections, there are 60-79% recurrence and 15% progression rates. Additional therapies are suggested for the treatment of superficial bladder carcinoma. We compared the efficacy of interferon alfa-2b monotherapy with interferon alfa-2b plus Bacillus Calmette Guerin (BCG combination therapy with urine interleukin (IL 2, 6 and 10 levels of patients with superficial bladder carcinoma. Material and Method: The patients who underwent TUR-BT for superficial bladder tumor (pathological staging Ta-T1 between 2004 and 2007 at our hospital included in this prospective study. Intravesical immunotherapy was administered once a week for 6 weeks and there after a month for 6 months, starting 4 weeks after TUR-BT. IL levels were measured. Results: IL-2, IL-6 and IL- 10 levels in urine samples were taken at 2nd and 4th hours of intravesical therapy. A statistically significant difference was observed between mean urine IL-2 levels of patients treated with IFN%u03B1-2b monotherapy and IFN%u03B1- 2b plus BCG combination both at 2nd and 4th hours. (p=0.05 In IFN%u03B1-2b plus BCG combination group, there was a statistical significant difference between stages regarding IL-2 and IL-6 levels (p=0.05. Among patients with G3 tumors, IL-2 levels were higher at 2 and 4 hours (p=0.05 but there was no significant difference in IL-6 and IL-10 levels in this group of patients regardless of intravesical therapy received (p=0.05. Discussion: IFN%u03B1-2b and BCG combination therapy is a reliable and effective therapy in the management of superficial bladder tumors.

  10. GRIN2B mediates susceptibility to intelligence quotient and cognitive impairments in developmental dyslexia.

    Science.gov (United States)

    Mascheretti, Sara; Facoetti, Andrea; Giorda, Roberto; Beri, Silvana; Riva, Valentina; Trezzi, Vittoria; Cellino, Maria R; Marino, Cecilia

    2015-02-01

    Developmental dyslexia (DD) is a complex heritable condition associated with impairments in multiple neurocognitive domains. Substantial heritability has been reported for DD and related phenotypes, and candidate genes have been identified. Recently, a candidate gene for human cognitive processes, that is, GRIN2B, has been found to be associated significantly with working memory in a German DD sample. In this study, we explored the contribution of six GRIN2B markers to DD and key DD-related phenotypes by association analyses in a sample of Italian nuclear families. Moreover, we assessed potential gene-by-environment interactions on DD-related phenotypes. We carried out a family-based association study to determine whether the GRIN2B gene influences both DD as a categorical trait and its related cognitive traits in a large cohort of 466 Italian nuclear families ascertained through a proband affected by DD. Moreover, we tested the role of the selected GRIN2B markers and a set of commonly described environmental moderators using a test for G×E interaction in sib pair-based association analysis of quantitative traits in 178 Italian nuclear families. Evidence for a significant association was found with the categorical diagnosis of DD, performance intelligence quotient, phonemic elision, and auditory short-term memory. No significant gene-by-environment effects were found. Our results add further evidence in support of GRIN2B contributing toward DD and deficits in DD. More specifically, our data support the view that GRIN2B influences DD as a categorical trait and its related quantitative phenotypes, thus shedding further light on the etiologic basis and the phenotypic complexity of this disorder.

  11. Chain-network anatase/TiO2 (B) thin film with improved photocatalytic efficiency.

    Science.gov (United States)

    Yen, Yin-Cheng; Chen, Jing-Zhi; Lu, Yu-Jung; Gwo, Shangjr; Lin, Kuan-Jiuh

    2014-06-13

    A 3-dimensional chain-network anatase/TiO2 (B) was obtained via the basic hydrothermal treatment of a sandwich Ti/TiO2/Ti film on a glass substrate that was prepared from 16 nm anatase TiO2 nanoparticles. The Ti film was converted to the TiO2 (B) phase in a Teflon vessel containing a 10 M NaOH aqueous solution that was encapsulated in a stainless-steel autoclave and heated at 130 °C for 2 h. The TiO2 (B) then served as a binder layer that enabled the formation of pearl-necklace chains made of anatase TiO2 nanoparticles, and these chain-like structures thoroughly interpenetrated into the textured layer. Decomposition tests using methylene blue indicated that the chain-network anatase/TiO2 (B) mixed-phase film had a photocatalytic half-life that was 0.84 and 0.69 times shorter than those of as-prepared anatase TiO2 and P25, respectively. In addition, the intensity of the room temperature photoluminescence spectra of anatase TiO2 was 2.55-fold higher than that of the chain-network anatase/TiO2 (B). We thus conclude that the remarkable photocatalytic activity of the chain-network anatase/TiO2 (B) is attributed to the chain-network structural characteristics and a synergistic effect of the matching band gap potentials, which increases the transfer of photogenerated electrons and reduces electron-hole recombination.

  12. Cortical GluN2B deletion attenuates punished suppression of food reward-seeking.

    Science.gov (United States)

    Radke, Anna K; Nakazawa, Kazu; Holmes, Andrew

    2015-10-01

    Compulsive behavior, which is a hallmark of psychiatric disorders such as addiction and obsessive-compulsive disorder, engages corticostriatal circuits. Previous studies indicate a role for corticostriatal N-methyl-D-aspartate receptors (NMDARs) in mediating compulsive-like responding for drugs of abuse, but the specific receptor subunits controlling reward-seeking in the face of punishment remain unclear. The current study assessed the involvement of corticostriatal GluN2B-containing NMDARs in measures of persistent and punished food reward-seeking. Mice with genetic deletion of GluN2B in one of three distinct neuronal populations, cortical principal neurons, forebrain interneurons, or striatal medium spiny neurons, were tested for (1) sustained food reward-seeking when reward was absent, (2) reward-seeking under a progressive ratio schedule of reinforcement, and (3) persistent reward-seeking after a footshock punishment. Mutant mice with genetic deletion of GluN2B in cortical principal neurons demonstrated attenuated suppression of reward-seeking during punishment. These mice performed normally on other behavioral measures, including an assay for pain sensitivity. Mutants with interneuronal or striatal GluN2B deletions were normal on all behavioral assays. Current findings offer novel evidence that loss of GluN2B-containing NMDARs expressed on principal neurons in the cortex results in reduced punished food reward-seeking. These data support the involvement of GluN2B subunit in cortical circuits regulating cognitive flexibility in a variety of settings, with implications for understanding the basis of inflexible behavior in neuropsychiatric disorders including obsessive-compulsive disorders (OCD) and addictions.

  13. Results from the photoemission spectroscopy beamline 2B1 at Pohang Light Source

    CERN Document Server

    Chung, Y H; Kim, D Y; Kim, H J; Kim, J M; Kim, T S; Ro, C; Raza, H; Thornton, G; Kim, B S; Kim, K J; Kang, T H

    1999-01-01

    The results of photoemission spectroscopy using molybdenum and tantalum samples have been obtained from the new beamline 2B1 at Pohang Light Source. Beamline 2B1 is based on a spherical grating monochromator (SGM) which is equipped with five gratings. The photon energy range from 184 to 1100 eV was covered in this work using two gratings (Gratings 4 and 5). The photon energy resolution has been deduced from Ta Fermi-level spectra and 3d spectra of Mo.

  14. Extreme ultraviolet spectroscopy of G191-B2B - Direct observation of ionization edges

    Science.gov (United States)

    Wilkinson, Erik; Green, James C.; Cash, Webster

    1992-01-01

    We present the first spectrum of the hot, DA white dwarf G191-B2B (wd 0501 + 527) between 200 and 330 A. The spectrum, which has about 2 A resolution, was obtained with a sounding rocket-borne, grazing incidence spectrograph. The spectrum shows no evidence of He II, the expected primary opacity source in this wavelength region. Three ionization edges and one absorption feature were observed and are suggestive of O III existing in the photosphere of G191-B2B. Also noted is a broad spectral depression that may result from Fe VI in the photosphere.

  15. Ab initio investigation of Al/Mo2B interfacial adhesion

    OpenAIRE

    SI ABDELKADER, H.; Faraoun, H.I.

    2011-01-01

    First-principles calculations were performed to study the adhesion and the interfacial electronic structure of aluminum/molybdenum semi-boride (Al/Mo2B) interface. The work of adhesion (Wad) was calculated for both terminations of the Mo2B surface and it was found that Mo-terminated has larger Wad than the B-terminated one. It was shown that interfacial Al and B atoms form polar covalent bonds, while bonding of interfacial Al and Mo atoms mainly presents metallic character. Computational M...

  16. Discovery of LAS101057: A Potent, Selective, and Orally Efficacious A2B Adenosine Receptor Antagonist.

    Science.gov (United States)

    Eastwood, Paul; Esteve, Cristina; González, Jacob; Fonquerna, Silvia; Aiguadé, Josep; Carranco, Inés; Doménech, Teresa; Aparici, Mònica; Miralpeix, Montserrat; Albertí, Joan; Córdoba, Mónica; Fernández, Raquel; Pont, Mercè; Godessart, Núria; Prats, Neus; Loza, María Isabel; Cadavid, María Isabel; Nueda, Arsenio; Vidal, Bernat

    2011-03-10

    The structure-activity relationships for a series of pyrazine-based A2B adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A2B receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels.

  17. Short syntheses of enantiopure calystegine B-2, B-3, and B-4

    DEFF Research Database (Denmark)

    Skaanderup, Philip Robert; Madsen, Robert

    2001-01-01

    Calystegine B-2 B-3, and B-4 have been prepared in 5 steps from the benzyl protected methyl 6-iodoglycopyranosides of glucose, galactose and mannose, respectively, by using a zinc-mediated domino reaction followed by ring-closing olefin metathesis as the key steps.......Calystegine B-2 B-3, and B-4 have been prepared in 5 steps from the benzyl protected methyl 6-iodoglycopyranosides of glucose, galactose and mannose, respectively, by using a zinc-mediated domino reaction followed by ring-closing olefin metathesis as the key steps....

  18. Glucosylsphingosine Activates Serotonin Receptor 2a and 2b: Implication of a Novel Itch Signaling Pathway

    OpenAIRE

    Afzal, Ramsha; Shim, Won-Sik

    2017-01-01

    Recent reports claimed that glucosylsphingosine (GS) is highly accumulated and specifically evoking itch-scratch responses in the skins of atopic dermatitis (AD) patients. However, it was unclear how GS can trigger itch-scratch responses, since there were no known molecular singling pathways revealed yet. In the present study, it was verified for the first time that GS can activate mouse serotonin receptor 2a (mHtr2a) and 2b (mHtr2b), but not 2c (mHtr2c) that are expressed in HEK293T cells. S...

  19. PHOX2B Mutation in a Taiwanese Newborn with Congenital Central Hypoventilation Syndrome

    Directory of Open Access Journals (Sweden)

    Tzu-Chiang Wang

    2014-02-01

    Full Text Available Congenital central hypoventilation syndrome (CCHS is characterized by defective automatic regulation of breathing, mostly during sleep. The diagnostic criteria of CCHS include persistent sleep hypoventilation without primary cardiac, pulmonary disease or neuromuscular dysfunction, and no arousal response to hypoxemia and hypercapnia. Mutations in the PHOX2B gene have been indentified in 93–100% of patients with CCHS. We report a CCHS case with presentation of hypoventilation during sleep and Hirschsprung disease; moreover, a genetic study of the patient confirmed the PHOX2B gene mutation as polyanaline stretch.

  20. Spectroscopic Observation of G191-B2B Between 200 and 340 Angstroms

    Science.gov (United States)

    Wilkinson, E.; Green, J. C.; Cash, W. C.

    1992-05-01

    We present the first spectrum of the hot, DA white dwarf G191-B2B between 200 and 340 Angstroms . The spectrum was acquired using a sounding rocket borne EUV spectrograph launched from White Sands Missile Range on January 10, 1992 at 3:40 am GMT. The spectrum, which has ~1.5 Angstroms resolution, shows possible absorption features of ionized metals. Absorption features of HeII are remarkably absent. This observation rules out He as being the opacity source for lambda \\ short wavelength opacity source in the case of G191-B2B.

  1. Functional human GRIN2B promoter polymorphism and variation of mental processing speed in older adults

    OpenAIRE

    Jiang, Yang; Kuan Lin, Ming; Jicha, Gregory A.; Ding, Xiuhua; McIlwrath, Sabrina L.; Fardo, David W.; Broster, Lucas S.; Schmitt, Frederick A.; Kryscio, Richard; Lipsky, Robert H.

    2017-01-01

    We investigated the role of a single nucleotide polymorphism rs3764030 (G>A) within the human GRIN2B promoter in mental processing speed in healthy, cognitively intact, older adults. In vitro DNA-binding and reporter gene assays of different allele combinations in transfected cells showed that the A allele was a gain-of-function variant associated with increasing GRIN2B mRNA levels. We tested the hypothesis that individuals with A allele will have better memory performance (i.e. faster reacti...

  2. Association of N-Methyl-D-Aspartate receptor 2B Subunit (GRIN2B) polymorphism with earlier age at onset of withdrawal symptoms in Indian alcohol dependent subjects.

    Science.gov (United States)

    Paul, Pradip; Dahale, Ajit; Kishore, Brij; Chand, Prabhat; Benegal, Vivek; Jain, Sanjeev; Murthy, Pratima; Purushottam, Meera

    2017-01-01

    The associations of GRIN2B polymorphism (rs1806201) with alcohol withdrawal and related clinical parameters in alcohol dependent subjects were investigated. Cases were assessed using a semi-structured clinical pro forma for alcohol abuse and a questionnaire for family history of alcohol dependence and psychiatric disorders after obtaining informed consent. The study included alcohol dependent male cases (n = 220, age at onset of alcohol withdrawal symptoms = 32.4 ± 8.8 y) recruited at the Center for Addiction Medicine, National Institute of Mental Health and Neurosciences, Bangalore, India. The controls comprised of healthy unrelated males (n = 183) who were ethnically matched and selected randomly. The polymorphism rs1806201 was analyzed by polymerase chain reaction and restriction fragment length polymorphism. The presence of T allele at this locus was significantly associated with lower age at onset of alcohol withdrawal symptoms (p = .005) among the cases. Mean age at onset of alcohol withdrawal symptoms in subjects who were T carriers was 31.4 ± 8.5 y (n = 160) and non-T carriers was 35.2 ± 9.0 y (n = 60). The SNP rs1806201 in GRIN2B may play an important role in genetic susceptibility to earlier age of withdrawal in alcohol dependent patients.

  3. 77 FR 24225 - Information Collection Approval; Temporary Non-Agricultural Employment of H-2B Aliens in the...

    Science.gov (United States)

    2012-04-23

    ... of H-2B Aliens in the United States AGENCY: Employment and Training Administration, Department of... Employment of H-2B Aliens in the United States; Final Rule. See 77 FR 10038, Feb. 21, 2012. DATES: On April 8...

  4. The promoter and the 5'-untranslated region of rice metallothionein OsMT2b gene are capable of directing high-level gene expression in germinated rice embryos.

    Science.gov (United States)

    Wu, Chung-Shen; Chen, Dai-Yin; Chang, Chung-Fu; Li, Min-Jeng; Hung, Kuei-Yu; Chen, Liang-Jwu; Chen, Peng-Wen

    2014-05-01

    Critical regions within the rice metallothionein OsMT2b gene promoter are identified and the 5'-untranslated region (5'-UTR) is found essential for the high-level promoter activity in germinated transgenic rice embryos. Many metallothionein (MT) genes are highly expressed in plant tissues. A rice subfamily p2 (type 2) MT gene, OsMT2b, has been shown previously to exhibit the most abundant gene expression in young rice seedling. In the present study, transient expression assays and a transgenic approach were employed to characterize the expression of the OsMT2b gene in rice. We found that the OsMT2b gene is strongly and differentially expressed in germinated rice embryos during seed germination and seedling development. Histochemical staining analysis of transgenic rice carrying OsMT2b::GUS chimeric gene showed that high-level GUS activity was detected in germinated embryos and at the meristematic part of other tissues during germination. Deletion analysis of the OsMT2b promoter revealed that the 5'-flanking region of the OsMT2b between nucleotides -351 and -121 relative to the transcriptional initiation site is important for promoter activity in rice embryos, and this region contains the consensus sequences of G box and TA box. Our study demonstrates that the 5'-untranslated region (5'-UTR) of OsMT2b gene is not only necessary for the OsMT2b promoter activity, but also sufficient to augment the activity of a minimal promoter in both transformed cell cultures and germinated transgenic embryos in rice. We also found that addition of the maize Ubi intron 1 significantly enhanced the OsMT2b promoter activity in rice embryos. Our studies reveal that OsMT2b351-ubi(In) promoter can be applied in plant transformation and represents potential for driving high-level production of foreign proteins in transgenic rice.

  5. Mo{sub 2}B{sub 4}O{sub 9} - connecting borate and metal-cluster chemistry

    Energy Technology Data Exchange (ETDEWEB)

    Schmitt, Martin K.; Huppertz, Hubert [Institut fuer Allgemeine, Anorganische und Theoretische Chemie, Universitaet Innsbruck (Austria); Janka, Oliver; Poettgen, Rainer [Institut fuer Anorganische und Analytische Chemie, Universitaet Muenster (Germany); Benndorf, Christopher [Institut fuer Anorganische und Analytische Chemie, Universitaet Muenster (Germany); Institut fuer Physikalische Chemie, Universitaet Muenster (Germany); Institut fuer Mineralogie, Kristallographie und Materialwissenschaften, Universitaet Leipzig (Germany); Oliveira, Marcos de Jr. [Sao Carlos Institute of Physics, University of Sao Paulo, Sao Carlos (Brazil); Eckert, Hellmut [Institut fuer Physikalische Chemie, Universitaet Muenster (Germany); Sao Carlos Institute of Physics, University of Sao Paulo, Sao Carlos (Brazil); Pielnhofer, Florian; Tragl, Amadeus-Samuel [Institut fuer Anorganische Chemie, Universitaet Regensburg (Germany); Weihrich, Richard [Institut fuer Materials Resource Management, Universitaet Augsburg (Germany); Joachim, Bastian [Institut fuer Mineralogie und Petrographie, Universitaet Innsbruck (Austria); Johrendt, Dirk [Department Chemie, Ludwig-Maximilians-Universitaet Muenchen (Germany)

    2017-06-01

    We report on the first thoroughly characterized molybdenum borate, which was synthesized in a high-pressure/high-temperature experiment at 12.3 GPa/1300 C using a Walker-type multianvil apparatus. Mo{sub 2}B{sub 4}O{sub 9} incorporates tetrahedral molybdenum clusters into an anionic borate crystal structure - a structural motif that has never been observed before in the wide field of borate crystal chemistry. The six bonding molecular orbitals of the [Mo{sub 4}] tetrahedron are completely filled with 12 electrons, which are fully delocalized over the four molybdenum atoms. This finding is in agreement with the results of the magnetic measurements, which confirmed the diamagnetic character of Mo{sub 2}B{sub 4}O{sub 9}. The two four-coordinated boron sites can be differentiated in the {sup 11}B MAS-NMR spectrum because of the strongly different degrees of local distortions. Experimentally obtained IR and Raman bands were assigned to vibrational modes based on DFT calculations. (copyright 2017 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim)

  6. Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation

    DEFF Research Database (Denmark)

    Clayton, Emma L.; Mancuso, Renzo; Nielsen, Troels Tolstrup

    2017-01-01

    Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like c...

  7. A physiological role of AMP-activated protein kinase in phenobarbital-mediated constitutive androstane receptor activation and CYP2B induction.

    Science.gov (United States)

    Shindo, Sawako; Numazawa, Satoshi; Yoshida, Takemi

    2007-02-01

    CAR (constitutive androstane receptor) is a nuclear receptor that regulates the transcription of target genes, including CYP (cytochrome P450) 2B and 3A. The transactivation by CAR is regulated by its subcellular localization; however, the mechanism that governs nuclear translocation has yet to be clarified. It has been reported recently that AMPK (AMP-activated protein kinase) is involved in phenobarbital-mediated CYP2B induction in a particular culture system. We therefore investigated in vivo whether AMPK is involved in the activation of CAR-dependent gene expression. Immunoblot analysis using an antibody which recognizes Thr-172-phosphorylated AMPKalpha1/2 revealed phenobarbital-induced AMPK activation in rat and mouse livers as well. Phenobarbital, however, failed to increase the liver phospho-AMPK level of tumour-bearing rats in which CAR nuclear translocation had been impaired. In in vivo reporter gene assays employing PBREM (phenobarbital-responsive enhancer module) from CYP2B1, an AMPK inhibitor 8-bromo-AMP abolished phenobarbital-induced transactivation. In addition, Cyp2b10 gene expression was attenuated by 8-bromo-AMP. Forced expression of a dominant-negative mutant and the wild-type of AMPKalpha2 in the mouse liver suppressed and further enhanced phenobarbital-induced PBREM-reporter activity respectively. Moreover, the AMPK activator AICAR (5-amino-4-imidazolecarboxamide riboside) induced PBREM transactivation and an accumulation of CAR in the nuclear fraction of the mouse liver. However, AICAR and metformin, another AMPK activator, failed to induce hepatic CYP2B in mice and rats. These observations suggest that AMPK is at least partly involved in phenobarbital-originated signalling, but the kinase activation by itself is not sufficient for CYP2B induction in vivo.

  8. SCFAtPP2-B11 modulates ABA signaling by facilitating SnRK2.3 degradation in Arabidopsis thaliana.

    Science.gov (United States)

    Cheng, Chunhong; Wang, Zhijuan; Ren, Ziyin; Zhi, Liya; Yao, Bin; Su, Chao; Liu, Liu; Li, Xia

    2017-08-01

    The phytohormone abscisic acid (ABA) is an essential part of the plant response to abiotic stressors such as drought. Upon the perception of ABA, pyrabactin resistance (PYR)/PYR1-like (PYL)/regulatory components of ABA receptor (RCAR) proteins interact with co-receptor protein phosphatase type 2Cs to permit activation Snf1-related protein kinase2 (SnRK2) kinases, which switch on ABA signaling by phosphorylating various target proteins. Thus, SnRK2 kinases are central regulators of ABA signaling. However, the mechanisms that regulate SnRK2 degradation remain elusive. Here, we show that SnRK2.3 is degradated by 26S proteasome system and ABA promotes its degradation. We found that SnRK2.3 interacts with AtPP2-B11 directly. AtPP2-B11 is an F-box protein that is part of a SKP1/Cullin/F-box E3 ubiquitin ligase complex that negatively regulates plant responses to ABA by specifically promoting the degradation of SnRK2.3. AtPP2-B11 was induced by ABA, and the knockdown of AtPP2-B11 expression markedly increased the ABA sensitivity of plants during seed germination and postgerminative development. Overexpression of AtPP2-B11 does not affect ABA sensitivity, but inhibits the ABA hypersensitive phenotypes of SnRK2.3 overexpression lines. These results reveal a novel mechanism through which AtPP2-B11 specifically degrades SnRK2.3 to attenuate ABA signaling and the abiotic stress response in Arabidopsis.

  9. B2B SME Management of Antecedents to the Application of Social Media

    DEFF Research Database (Denmark)

    Brink, Tove

    2017-01-01

    This paper elucidates how business-to-business (B2B) small and medium-sized enterprises (SMEs) can manage antecedents to the application of social media for potential contributions to their business. This in-depth qualitative research study was conducted at four plastic-producing SMEs from October...

  10. A Cross-Industry Review of B2B Critical Success Factors.

    Science.gov (United States)

    Eid, Riyad; Trueman, Myfanwy; Ahmed, Abdel Moneim

    2002-01-01

    Presents a comprehensive review of B2B (business-to- business) international Internet marketing and identifies 21 critical success factors in five categories: marketing strategy, including management support, strategic goals, and collaboration; Web site factors, including Web site design; global factors, including multilanguage sites and cultural…

  11. Using the Internet for B2B Activities: A Review and Future Directions for Research.

    Science.gov (United States)

    Gattiker, Urs E.; Perlusz, Stefano; Bohmann, Kristoffer

    2000-01-01

    Illustrates some of the challenges that electronic commerce practitioners and researchers face, focusing on business to business (B2B) transactions. Highlights include a conceptual framework of Web user behavior; purchasing context; socio-demographic characteristics; cultural factors; economic factors; attitudes toward information technology;…

  12. Magnetic properties of ball-milled TbFe2 and TbFe2B

    Indian Academy of Sciences (India)

    Home; Journals; Bulletin of Materials Science; Volume 27; Issue 2. Magnetic properties of ... Amorphous materials; intermetallic compounds; magnetic materials; magnetic properties. Abstract. The magnetic properties of ball-milled TbFe2 and TbFe2B were studied by magnetization measurements. X-ray diffraction studies on ...

  13. Synaptic vesicle protein 2b is expressed temporospatially in (pre)odontoblasts in developing molars.

    Science.gov (United States)

    Yang, So-Young; Jeon, Soo-Kyung; Kang, Jee-Hae; Yoo, Hong-Il; Kim, Yoo-Seong; Moon, Jung-Sun; Kim, Min-Seok; Koh, Jung-Tae; Oh, Won-Mann; Kim, Sun-Hun

    2012-12-01

    The formation of dentin and enamel is initiated by the differentiation of odontogenic precursor cells into odontoblasts and ameloblasts, respectively. This study was performed to identify new molecules involved in the differentiation of odontogenic cells. The genes expressed differentially between the root stage (after the differentiation of odontogenic cells and dental hard-tissue formation) and the cap stage (before the differentiation of odontogenic cells and dental hard-tissue formation) were searched using differential display PCR. For the first time, synaptic vesicle protein (SV) 2b, an important transmembrane transporter of Ca(2+) -stimulated vesicle exocytosis, was identified as a differentially expressed molecule. Real-time PCR and western blotting revealed an increase in the transcriptional and translational levels of SV2b during or after the differentiation of odontogenic cells. Immunofluorescence revealed this molecule to be localized in not only fully differentiated odontoblasts but also in pre-odontoblasts before dentin matrix secretion. The expression pattern of the SV2a isoform was similar to that of the SV2b isoform, whereas the SV2c isoform showed a contrasting pattern of expression. After treatment with alendronate, an inhibitor of protein isoprenylation for the transport of secretory vesicles, the expression of SV2a and SV2b decreased, whereas that of SV2c increased. These results suggest that the SV2 isoforms are functional molecules of (pre)odontoblasts which may be involved in vesicle transport. © 2012 Eur J Oral Sci.

  14. Enabling low cost biopharmaceuticals: high level interferon alpha-2b production in Trichoderma reesei.

    Science.gov (United States)

    Landowski, Christopher P; Mustalahti, Eero; Wahl, Ramon; Croute, Laurence; Sivasiddarthan, Dhinakaran; Westerholm-Parvinen, Ann; Sommer, Benjamin; Ostermeier, Christian; Helk, Bernhard; Saarinen, Juhani; Saloheimo, Markku

    2016-06-10

    The filamentous fungus Trichoderma reesei has tremendous capability to secrete over 100 g/L of proteins and therefore it would make an excellent host system for production of high levels of therapeutic proteins at low cost. We have developed T. reesei strains suitable for production of therapeutic proteins by reducing the secreted protease activity. Protease activity has been the major hindrance to achieving high production levels. We have constructed a series of interferon alpha-2b (IFNα-2b) production strains with 9 protease deletions to gain knowledge for further strain development. We have identified two protease deletions that dramatically improved the production levels. Deletion of the subtilisin protease slp7 and the metalloprotease amp2 has enabled production levels of IFNα-2b up to 2.1 and 2.4 g/L, respectively. With addition of soybean trypsin protease inhibitor the level of production improved to 4.5 g/L, with an additional 1.8 g/L still bound to the secretion carrier protein. High levels of IFNα-2b were produced using T. reesei strains with reduced protease secretion. Further strain development can be done to improve the production system by reducing protease activity and improving carrier protein cleavage.

  15. Information Transparency in B2B Auction Markets: The Role of Winner Identity Disclosure

    NARCIS (Netherlands)

    Y. Lu (Yixin); A. Gupta (Alok); W. Ketter (Wolfgang); H.W.G.M. van Heck (Eric)

    2017-01-01

    textabstractWe study the impact of information transparency in B2B auctions. Specifically, we measure the effect of concealing winners’ identities on auction outcomes using a large-scale, quasi-natural field experiment. Contrary to the conventional wisdom that “the more information, the better,” we

  16. Do self-service technologies affect interfirm relationships? A B2B perspective

    Directory of Open Access Journals (Sweden)

    Raechel Johns

    2014-11-01

    Full Text Available While considerable literature examines business-to business (B2B relationships, the impact of technology on these relationships has lacked attention. IT has impacted the way businesses operate in a B2B context as well as influencing services by altering the way services are delivered. To understand the way in which Internet technology has impacted these B2B services, it is essential to examine its impact not only on business processes but on business relationships too. One technology, enabled by modern Internet technologies, which is changing the nature of business relationships is the increased use of self-service technologies (SSTs or technology-enabled services, however, there is a shortage of research in the area in a B2B context. The discussion in this paper provides an overview of the impact of IT on business relationships, using Relationship Marketing theory to provide a theoretical framework. A qualitative study in the Australian banking industry provides findings relating to the theory. The findings of this study provide evidence that while traditional Relationship Marketing theory is still applicable for some business customers, new theory is required for business customers who do not seek relationships. With both practical and theoretical implications, the research detailed in this paper makes a useful contribution to the literature and indicates the necessity for further research to be developed which explores business customers who prefer to remain transaction-oriented, rather than develop interpersonal relationships.

  17. Johnston Atoll Site 2B-P 6/30/2000 24-25M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at Johnston Atoll, site 2B-P (16 45.606N, 169 30.705W), between 24 and 25 meters along a permanent transect.

  18. Designing the marketing-sales interface in B2B firms

    NARCIS (Netherlands)

    Biemans, W.G.; Makovec Brencic, M.

    2007-01-01

    Purpose - This paper explores the marketing-sales interface in Dutch and Slovenian B2B firms. Design/methodology/approach - The study included 11 Dutch firms and ten Slovenian firms, with both samples as closely matched as possible. The firms were all manufacturers of physical products that operate

  19. 21 A Srinivasa Rao1, V Sarath2, B Mrudhula3 1Corresponding ...

    African Journals Online (AJOL)

    IMTU Medical Journal Volume 6- July, 2015. 21. A Srinivasa Rao1, V Sarath2, B Mrudhula3. 1Corresponding Author, , Professor, Department of Orthopaedics, Katuri Medical College &. Hospital, Guntur 522 019, Andhra Pradesh, India,. Phone: 9490115156, e mail drsriortho@yahoo. co.in. 2Associate Professor, Department ...

  20. Improved serodiagnosis of cystic echinococcosis using the new recombinant 2B2t antigen.

    Directory of Open Access Journals (Sweden)

    Ana Hernández-González

    Full Text Available A standardized test for the serodiagnosis of human cystic echinococcosis (CE is still needed, because of the low specificity and sensitivity of the currently available commercial tools and the lack of proper evaluation of the existing recombinant antigens. In a previous work, we defined the new ELISA-B2t diagnostic tool for the detection of specific IgGs in CE patients, which showed high sensitivity and specificity, and was useful in monitoring the clinical evolution of surgically treated CE patients. Nevertheless, this recombinant antigen gave rise to false-negative results in a percentage of CE patients. Therefore, in an attempt to improve its sensitivity, we constructed B2t-derived recombinant antigens with two, four and eight tandem repeat of B2t units, and tested them by ELISA on serum samples of CE patients and patients with related parasites. The best diagnostic values were obtained with the two tandem repeat 2B2t antigen. The influence of several clinical variables on the performance of the tests was also evaluated. Finally, the diagnostic performance of the 2B2t-ELISA was compared with that of an indirect haemagglutination commercial test. The 2B2t recombinant antigen performed better than the HF and B2t antigens, and the IHA commercial kit. Therefore, this new 2B2t-ELISA is a promising candidate test for the serodiagnosis of CE in clinical settings.

  1. Data of evolutionary structure change: 3EK2B-3FNFC [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 90479 3.110795021057129 EVID> 4 3FNF...3EK2B-3FNFC 3EK2 3FNF B C MGFLDGKRILLTGLLSNRSIAYGIAKACKREGAELAFTY...VGDRFKDRITEFAAEFGSE-LVFPCDVADDAQIDALFASLKTHWD---SLDGLVHSIGFAPREAIAG-DFLDGLTRENFRIAHDISAYSFPALAKAALPMLSDDASLL...HHHHHH EEEEE GGG -- EVID> 0 3...line>LEU CA 564 3FNF C 3FNF

  2. Water‐Data Report 413721083124001 Pool 2B at Ottawa NWR-2014

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Water levels and water quality parameters recorded on Crane Creek. Water-Data Report 2014 413721083124001 Pool 2B at Ottawa NWR LOCATION: Lat. 41°37'21.08"N, long...

  3. Water‐Data Report 413721083124001 Pool 2B at Ottawa NWR-2013

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Water levels and water quality parameters recorded on Crane Creek. Water-Data Report 2013 413721083124001 Pool 2B at Ottawa NWR LOCATION: Lat. 41°37'21.08"N, long...

  4. On the critical success factors for B2B e-marketplace

    Directory of Open Access Journals (Sweden)

    Sareh Ahmad Khan Beige

    2015-01-01

    Full Text Available Advancement of network technology, quick growth of Internet and Internet based solutions lead many firms to apply online processes as well as electronic businesses. Internet based B2B E-C requires applying Internet and affiliated technologies for exchanging products, services and information. Implementation of business to business (B2B requires long-term commitment of organizations. Carrying out research in this field is regarded as very important issue for recognizing effective factors on successful implementation and execution of B2B and determining current status of organization. This research deals with studying effective critical factors on successful implementation and execution of B2B. Factors are recognized through studying literature review and IT experts. Then, through case study (studying a vehicle manufacturing firm and by using analytical network process (ANP, the importance of factor and their rank are determined. The factors that are regarded at this research are including: culture, commitment and support of senior management, government support, purposes, organizational strategies, trust, partial advantage and technical infrastructure. Results of research show that support and commitment of senior management are the highest priority factors.

  5. Determining the frequencies of B1, B2, B3 and E alleles of the ...

    African Journals Online (AJOL)

    The aim of the study was to determine the frequencies of B1, B2, B3 and E alleles of the CSN1S1 gene and their effects on milk yield and composition in the Saanen goat breed. Milk samples were collected to identify milk composition with Fourier transform ınfrared (FTIR) spectroscopy. The polymerase chain ...

  6. Magnetism and superconductivity in ErNi 2 B 2 C

    Indian Academy of Sciences (India)

    We have performed a series of neutron diffraction experiments from the magnetic order and the vortex lattice in single crystal ErNi2B2C. The incommensurate magnetic structure develops additional even harmonics below the `ferromagnetic' ordering temperature, F of 2.3 K. This feature and the existence of rods of diffuse ...

  7. A carbon-coated TiO(2)(B) nanosheet composite for lithium ion batteries.

    Science.gov (United States)

    Sun, Zhenyu; Huang, Xing; Muhler, Martin; Schuhmann, Wolfgang; Ventosa, Edgar

    2014-05-28

    The carbon-coated TiO2(B) nanosheet composite synthesized by one-step hydrolysis of TiCl3 followed by vacuum annealing and air annealing delivers outstanding electrochemical performance as a negative electrode for Li-ion batteries, i.e. reversible capacity above 150 mA h g(-1) at 30 C (10 A g(-1)).

  8. Molecular dynamic simulation of complex NS2B-NS3 DENV2 ...

    African Journals Online (AJOL)

    In many researches, several models of peptides inhibitor were generated in complexes with the NS2B-NS3 DENV2 protease by performing molecular docking. The goal of this research was to study the interaction of ligands as inhibitors for protein (enzyme) in solvent explicit condition by performing molecular dynamics ...

  9. Molecular dynamic simulation of complex NS2B-NS3 DENV2 ...

    African Journals Online (AJOL)

    Nissia

    2013-07-10

    Jul 10, 2013 ... many researches, several models of peptides inhibitor were generated in complexes with the NS2B-NS3. DENV2 protease by performing molecular docking. The goal of this research was to study the interaction of ligands as inhibitors for protein (enzyme) in solvent explicit condition by performing molecular ...

  10. Polymorphisms in sh2b1 and spns1 loci are associated with ...

    Indian Academy of Sciences (India)

    Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden. [Västermark Å., Jacobsson J. A., Johansson Å., Fredriksson R., Gyllensten U. and Schiöth H. B. 2012 Polymorphisms in sh2b1 and spns1 loci are associated with triglyceride levels in a healthy population in northern Sweden. J. Genet. 91, 237–240]. Introduction.

  11. CDKN2B Loss Promotes Progression from Benign Melanocytic Nevus to Melanoma.

    Science.gov (United States)

    McNeal, Andrew S; Liu, Kevin; Nakhate, Vihang; Natale, Christopher A; Duperret, Elizabeth K; Capell, Brian C; Dentchev, Tzvete; Berger, Shelley L; Herlyn, Meenhard; Seykora, John T; Ridky, Todd W

    2015-10-01

    Deletion of the entire CDKN2B-CDKN2A gene cluster is among the most common genetic events in cancer. The tumor-promoting effects are generally attributed to loss of CDKN2A-encoded p16 and p14ARF tumor suppressors. The degree to which the associated CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here, we show that CDKN2B is highly upregulated in benign melanocytic nevi, contributes to maintaining nevus melanocytes in a growth-arrested premalignant state, and is commonly lost in melanoma. Using primary melanocytes isolated directly from freshly excised human nevi naturally expressing the common BRAF(V600E)-activating mutation, nevi progressing to melanoma, and normal melanocytes engineered to inducibly express BRAF(V600E), we show that BRAF activation results in reversible, TGFβ-dependent, p15 induction that halts proliferation. Furthermore, we engineer human skin grafts containing nevus-derived melanocytes to establish a new, architecturally faithful, in vivo melanoma model, and demonstrate that p15 loss promotes the transition from benign nevus to melanoma. Although BRAF(V600E) mutations cause melanocytes to initially proliferate into benign moles, mechanisms responsible for their eventual growth arrest are unknown. Using melanocytes from human moles, we show that BRAF activation leads to a CDKN2B induction that is critical for restraining BRAF oncogenic effects, and when lost, contributes to melanoma. ©2015 American Association for Cancer Research.

  12. Data of evolutionary structure change: 1EE2B-2EERA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1EE2B-2EERA 1EE2 2EER B A STAGKVIKCKAAVLWEQKKPFSIEEVEVAPPKAHEVRIK...dbID>2EER A 2EERA VVIGAGGGLGT...A 2EERA PLITLNEVQFI 2EER A 2EERA YLYKL-R...pdbID>2EER A 2EERA INASS--QDPVS

  13. Adhesive and Cohesive Strength in FeB/Fe2B Systems

    Science.gov (United States)

    Meneses-Amador, A.; Blancas-Pérez, D.; Corpus-Mejía, R.; Rodríguez-Castro, G. A.; Martínez-Trinidad, J.; Jiménez-Tinoco, L. F.

    2018-01-01

    In this work, FeB/Fe2B systems were evaluated by the scratch test. The powder-pack boriding process was performed on the surface of AISI M2 steel. The mechanical parameters, such as yield stress and Young's modulus of the boride layer, were obtained by the instrumented indentation technique. Residual stresses produced on the boride layer were estimated by using the x-ray diffraction (XRD) technique. The scratch test was performed in order to evaluate the cohesive/adhesive strength of the FeB/Fe2B coating. In addition, a numerical evaluation of the scratch test on boride layers was performed by the finite element method. Maximum principal stresses were related to the failure mechanisms observed by the experimental scratch test. Shear stresses at the interfaces of the FeB/Fe2B/substrate system were also evaluated. Finally, the results obtained provide essential information about the effect of the layer thickness, the residual stresses, and the resilience modulus on the cohesive/adhesive strength in FeB/Fe2B systems.

  14. A process-stakeholder analysis of B2B industry standardisation

    NARCIS (Netherlands)

    Rodon, J.; Ramis-Pujol, J.; Christiaanse, E.

    2007-01-01

    Purpose - Interoperability standards are a crucial aspect in the development of B2B e-business. The aim of this paper is to understand how standardisation evolves by analysing the interplay between activities and stakeholders within the process. Unlike most of the IS research that focuses on the

  15. Effect of Quercetin flavonoid on structural changes of recombinant human FGFR2b kinase domain

    Directory of Open Access Journals (Sweden)

    Benyamin Alimohammadi

    2017-08-01

    Conclusion: The tertiary structural change of FGFR2b kinase domain represents a conformational change that may have a critical role in signal transduction cascade. Thus, this molecular transduction inconsistency can lead to cellular transduction complication; and as a result, inhibit the development and multiplication of  cancerous cells.

  16. Copy number variations in the amylase gene (AMY2B) in Japanese native dog breeds.

    Science.gov (United States)

    Tonoike, A; Hori, Y; Inoue-Murayama, M; Konno, A; Fujita, K; Miyado, M; Fukami, M; Nagasawa, M; Mogi, K; Kikusui, T

    2015-10-01

    A recent study suggested that increased copy numbers of the AMY2B gene might be a crucial genetic change that occurred during the domestication of dogs. To investigate AMY2B expansion in ancient breeds, which are highly divergent from modern breeds of presumed European origins, we analysed copy numbers in native Japanese dog breeds. Copy numbers in the Akita and Shiba, two ancient breeds in Japan, were higher than those in wolves. However, compared to a group of various modern breeds, Akitas had fewer copy numbers, whereas Shibas exhibited the same level of expansion as modern breeds. Interestingly, average AMY2B copy numbers in the Jomon-Shiba, a unique line of the Shiba that has been bred to maintain their appearance resembling ancestors of native Japanese dogs and that originated in the same region as the Akita, were lower than those in the Shiba. These differences may have arisen from the earlier introduction of rice farming to the region in which the Shiba originated compared to the region in which the Akita and the Jomon-Shiba originated. Thus, our data provide insights into the relationship between the introduction of agriculture and AMY2B expansion in dogs. © 2015 Stichting International Foundation for Animal Genetics.

  17. Flexibility in crosstalk between H2B ubiquitination and H3 methylation in vivo (Corrigendum)

    NARCIS (Netherlands)

    Vlaming, Hanneke; van Welsem, Tibor; de Graaf, Erik L; Ontoso, David; Altelaar, A F Maarten; San-Segundo, Pedro A; Heck, Albert J R; van Leeuwen, Fred

    2014-01-01

    Histone H2B ubiquitination is a dynamic modification that promotes methylation of histone H3K79 and H3K4. This crosstalk is important for the DNA damage response and has been implicated in cancer. Here, we show that in engineered yeast strains, ubiquitins tethered to every nucleosome promote H3K79

  18. Flexibility in crosstalk between H2B ubiquitination and H3 methylation in vivo

    NARCIS (Netherlands)

    Vlaming, Hanneke; van Welsem, Tibor; de Graaf, Erik L; Ontoso, David; Altelaar, A F Maarten; San-Segundo, Pedro A; Heck, Albert J R; van Leeuwen, Fred

    2014-01-01

    Histone H2B ubiquitination is a dynamic modification that promotes methylation of histone H3K79 and H3K4. This crosstalk is important for the DNA damage response and has been implicated in cancer. Here, we show that in engineered yeast strains, ubiquitins tethered to every nucleosome promote H3K79

  19. Graft-derived anti-HPA-2b production after allogeneic bone-marrow transplantation

    DEFF Research Database (Denmark)

    Taaning, E; Jacobsen, N; Morling, N

    1994-01-01

    We report on a male who received a bone-marrow allograft from his HLA identical sister for acute myelogenous leukaemia. After transplantation, the patient suffered from refractoriness to the transfusions of HLA-matched platelets and a strong platelet-specific antibody, anti-HPA-2b, of IgG1 subclass...

  20. 76 FR 3451 - Wage Methodology for the Temporary Non-agricultural Employment H-2B Program

    Science.gov (United States)

    2011-01-19

    ... unemployment rates among specific groups of vulnerable low-wage workers: Youth, Hispanics, and African..., unemployment-related issues, the incorporation or continuation of special procedures in the H-2B program... conditions below the established minimum levels, citing examples of high unemployment rates in industries in...

  1. Equine cytochrome P450 2B6 — Genomic identification, expression and functional characterization with ketamine

    Energy Technology Data Exchange (ETDEWEB)

    Peters, L.M.; Demmel, S. [Division Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University Bern, Laenggassstr. 124, 3012 Bern (Switzerland); Pusch, G.; Buters, J.T.M. [ZAUM — Center of Allergy and Environment, Helmholtz Zentrum München/Technische Universität München, Biedersteiner Str. 29, 80802 München (Germany); Thormann, W. [Clinical Pharmacology Laboratory, Institute for Infectious Diseases, University of Bern, Murtenstrasse 35, 3010 Bern (Switzerland); Zielinski, J. [Division Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University Bern, Laenggassstr. 124, 3012 Bern (Switzerland); Leeb, T. [Institute of Genetics, Vetsuisse Faculty, University Bern, Bremgartenstr. 109, 3012 Bern (Switzerland); Mevissen, M. [Division Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University Bern, Laenggassstr. 124, 3012 Bern (Switzerland); Schmitz, A., E-mail: andrea.schmitz@vetsuisse.unibe.ch [Division Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University Bern, Laenggassstr. 124, 3012 Bern (Switzerland)

    2013-01-01

    Ketamine is an anesthetic and analgesic regularly used in veterinary patients. As ketamine is almost always administered in combination with other drugs, interactions between ketamine and other drugs bear the risk of either adverse effects or diminished efficacy. Since cytochrome P450 enzymes (CYPs) play a pivotal role in the phase I metabolism of the majority of all marketed drugs, drug–drug interactions often occur at the active site of these enzymes. CYPs have been thoroughly examined in humans and laboratory animals, but little is known about equine CYPs. The characterization of equine CYPs is essential for a better understanding of drug metabolism in horses. We report annotation, cloning and heterologous expression of the equine CYP2B6 in V79 Chinese hamster fibroblasts. After computational annotation of all CYP2B genes, the coding sequence (CDS) of equine CYP2B6 was amplified by RT-PCR from horse liver total RNA and revealed an amino acid sequence identity of 77% and a similarity of 93.7% to its human ortholog. A non-synonymous variant c.226G>A in exon 2 of the equine CYP2B6 was detected in 97 horses. The mutant A-allele showed an allele frequency of 82%. Two further variants in exon 3 were detected in one and two horses of this group, respectively. Transfected V79 cells were incubated with racemic ketamine and norketamine as probe substrates to determine metabolic activity. The recombinant equine CYP2B6 N-demethylated ketamine to norketamine and produced metabolites of norketamine, such as hydroxylated norketamines and 5,6-dehydronorketamine. V{sub max} for S-/and R-norketamine formation was 0.49 and 0.45 nmol/h/mg cellular protein and K{sub m} was 3.41 and 2.66 μM, respectively. The N-demethylation of S-/R-ketamine was inhibited concentration-dependently with clopidogrel showing an IC{sub 50} of 5.63 and 6.26 μM, respectively. The functional importance of the recorded genetic variants remains to be explored. Equine CYP2B6 was determined to be a CYP

  2. Using msa-2b as a molecular marker for genotyping Mexican isolates of Babesia bovis.

    Science.gov (United States)

    Genis, Alma D; Perez, Jocelin; Mosqueda, Juan J; Alvarez, Antonio; Camacho, Minerva; Muñoz, Maria de Lourdes; Rojas, Carmen; Figueroa, Julio V

    2009-12-01

    Variable merozoite surface antigens of Babesia bovis are exposed glycoproteins having a role in erythrocyte invasion. Members of this gene family include msa-1 and msa-2 (msa-2c, msa-2a(1), msa-2a(2) and msa-2b). To determine the sequence variation among B. bovis Mexican isolates using msa-2b as a genetic marker, PCR amplicons corresponding to msa-2b were cloned and plasmids carrying the corresponding inserts were purified and sequenced. Comparative analysis of nucleotide and deduced amino acid sequences revealed distinct degrees of variability and identity among the coding gene sequences obtained from 16 geographically different Mexican B. bovis isolates and a reference strain. Clustal-W multiple alignments of the MSA-2b deduced amino acid sequences performed with the 17 B. bovis Mexican isolates, revealed the identification of three genotypes with a distinct set each of amino acid residues present at the variable region: Genotype I represented by the MO7 strain (in vitro culture-derived from the Mexico isolate) as well as RAD, Chiapas-1, Tabasco and Veracruz-3 isolates; Genotype II, represented by the Jalisco, Mexico and Veracruz-2 isolates; and Genotype III comprising the sequences from most of the isolates studied, Tamaulipas-1, Chiapas-2, Guerrero-1, Nayarit, Quintana Roo, Nuevo Leon, Tamaulipas-2, Yucatan and Guerrero-2. Moreover, these three genotypes could be discriminated against each other by using a PCR-RFLP approach. The results suggest that occurrence of indels within the variable region of msa-2b sequences can be useful markers for identifying a particular genotype present in field populations of B. bovis isolated from infected cattle in Mexico.

  3. Uso de una conantokina y anticuerpos policlonales para identificar la subunidad NR2B del receptor

    Directory of Open Access Journals (Sweden)

    Leonardo Lareo,†

    2010-12-01

    Full Text Available Objetivo. Proponer una metodología de identificación de la subunidad NR2B, mediante el uso de conantokina G, así como una adecuada extracción de la subunidad NR2B. Materiales y métodos. Se ensayaron dos metodologías para la extracción de la subunidad NR2B de cerebro de rata adulta, la primera buscó la extracción de la subunidad a partir de la membrana mediante la utilización del detergente deoxicolato de sodio y la segunda, garantizó primero la solubilización y eliminación de proteínas citoplasmáticas para luego realizar la extracción de la subunidad mediante el uso del mismo detergente, a partir del pellet generado en la centrifugación del extracto obtenido. Adicionalmente se biotiniló la conantokina G para evaluar su eficiencia en la identificación de la subunidad y comparar los resultados con los obtenidos por metodologías tradicionales como DOT-BLOT, WESTERN-BLOT, ELISA e Inmunohistoquímica. Resultados. La segunda metodología mostró mayor extracción de NR2B por lo que se seleccionó para la realización de los extractos posteriores. Los ensayos de identificación con la conantokina biotinilada evidenciaron interferencia en el reconocimiento, haciéndose necesaria la identificación de la presencia de la subunidad NR2B mediante el uso de anticuerpos policlonales en los ensayos mencionados. Conclusiones. Se propone que hay un impedimento de tipo estérico en el marcaje de la conantokina con la biotina lo que no favorece la interacción de este péptido con la subunidad.

  4. Camk2b protects neurons from homocysteine-induced apoptosis with the involvement of HIF-1α signal pathway

    OpenAIRE

    Fang, Min; Feng, Chao; Zhao, Yan-Xin; Liu, Xue-Yuan

    2014-01-01

    In our previous study using iTRAQ technique we found that the level of calmodulin-dependent protein kinase 2b (Camk2b) was lower in rats with hyperhomocysteinemia. We presumed that Camk2b might be involved in homocysteine-induced apoptosis and tried to explore its role in this study through the transfection with Camk2b gene. Results showed that neurons of HHcy group had lower activity measured by MTT, higher percentage of apoptotic neurons, lower expression levels of Camk2b mRNA and protein t...

  5. Successful unintentional ABO-incompatible renal transplantation: Blood group A1B donor into an A2B recipient.

    Science.gov (United States)

    Fadeyi, Emmanuel A; Stratta, Robert J; Farney, Alan C; Pomper, Gregory J

    2014-05-01

    To report a successful unintentional transplantation of a deceased donor kidney from an "incompatible" A1B donor into a recipient who was blood group A2B with unsuspected preformed anti-A1 antibodies. The donor and recipient were both typed for ABO antigens. The recipient was tested for ABO and non-ABO antibodies. The recipient was typed for HLA class I and class II antigens, including HLA antibody screen. The T-and B-flow cytometry crossmatch test was performed using standard protocol. The donor-recipient pair was a complete six-antigen human leukocyte antigen mismatch, but final T- and B-flow cytometry cross-match tests were compatible. The recipient was a 65-year-old woman with a medical history of end-stage renal disease secondary to diabetic nephropathy who underwent kidney transplantation from a 46-year-old brain-dead standard criteria donor. The recipient's RBCs were negative with A1 lectin, and the recipient was thus typed as an A2 subgroup. Anti-A1 could be demonstrated in the recipient's plasma. The donor's RBCs were positive with A1 lectin, thereby conferring an A1 blood type. It is safe to transplant across the A1/A2 blood group barrier provided that the preformed antibodies are not reactive at 37°C and with anti-human globulin.

  6. An investigation on effects of perceived value on brand popularity and brand loyalty: A B2B case study

    Directory of Open Access Journals (Sweden)

    Zakaria Karimi Rad

    2014-03-01

    Full Text Available This research evaluates the effect of perceived value on brand popularity and brand loyalty for some organizations in business-to-business (B2B domain under the effect of risk and e-service quality. The practical relationships among six different kinds of risks including performance, social, financial, time, psychological and safety with consideration of quality in e-commerce business on customer’s perceived value are evaluated and the effects of this perception of value on consequences of perceived value are measured. In this study, using the partial least square method as well as gathering the information of some Iranian firms that use electronic services, the study finds that there was a significant relationship between various types of risks and perceived value. There is also considerable influence of perceived value on satisfaction, brand popularity, and brand loyalty.

  7. Reaction and reorientation of electronically excited H[sub 2](B)

    Energy Technology Data Exchange (ETDEWEB)

    Pibel, C.D.

    1992-09-01

    The room temperature rate (TR) constants for fluorescence quenching fluorescence of H[sub 2], HD, and D[sub 2] B [sup 1][Sigma][sub u][sup +] by [sup 4]He were measured as a function of the initially excited rotational and vibrational level of the hydrogen molecule, and the RT rate constants for molecular angular momentum reorientation of H[sub 2], HD and D[sub 2] (B [sup 1][Sigma][sub u][sup +]. v[prime]=0, J[prime]=1, M[sub J]=0) in collisions with He, Ne, Ar and H[sub 2](X [sup 1][Sigma][sub g][sup +]) were also measured. Vibrational state dependence of the quenching cross sections fits a vibrationally adiabatic model of the quenching process. From the vibrational state dependence of the quenching cross section, the barrier height for the quenching reaction is found to be 250[plus minus]40 cm[sup [minus]1], and the difference in the H-H stretching frequencies between H[sub 2](B) and the H[sub 2]-He complex at the barrier to reaction is 140[plus minus]80 cm[sup [minus]1]. The effective cross sections for angular momentum reorientation in collisions of H[sub 2], HD, D[sub 2] with He and Ne were found to be about 30 [Angstrom][sup 2] and were nearly the same for each isotope and with He and Ne as collision partners. Cross sections forreorientation of HD and D[sub 2] in collisions with Ar were 10.6[plus minus]2.0 and 13.9[plus minus]3.0 [Angstrom][sup 2], respectively. Reorientation of D[sub 2](B) in collisions with room temperature H[sub 2](X) occurs with a 7.6[plus minus]3.4 [Angstrom][sup 2] cross section. Calculated cross sections using semiclassical and quantum close coupled methods give cross sections for reorientation of H[sub 2](B) and D[sub 2](B) in collisions with He that agree quantitatively with experiment. Discrepancy between the calculated and experimental cross sections for HD(B)-HE are likely due to rotational relaxation in HD a Turbo PASCAL version of the data-taking program is included.

  8. Photoelectron Spectroscopy Study of [Ta2B6]-: a Hexagonal Bipyramdial Cluster

    Science.gov (United States)

    Jian, Tian; Li, Weili; Romanescu, Constantin; Wang, Lai-Sheng

    2014-06-01

    It has been a long-sought goal in cluster science to discover stable atomic clusters as building blocks for cluster-assembled nanomaterials, as exemplified by the fullerenes and their subsequent bulk syntheses.[1,2] Clusters have also been considered as models to understand bulk properties, providing a bridge between molecular and solid-state chemistry.[3] Herein we report a joint photoelectron spectroscopy and theoretical study on the [Ta2B6]- and [Ta2B6] clusters.[4] The photoelectron spectrum of [Ta2B6]- displays a simple spectral pattern and a large HOMO-LUMO gap, suggesting its high symmetry. Theoretical calculations show that both the neutral and anion are D6h pyramidal. The chemical bonding analyses for [Ta2B6] revealed the nature of the B6 and Ta interactions and uncovered strong covalent bonding between B6 and Ta. The D6h-[TaB6Ta] gaseous cluster is reminiscent of the structural pattern in the ReB6X6Re core in the [(Cp*Re)2B6H4Cl2] and the TiB6Ti motif in the newly synthesized Ti7Rh4Ir2B8 solid-state compound.[5,6] The current work provides an intrinsic link between a gaseous cluster and motifs for solid materials. Continued investigations of the transition-metal boron clusters may lead to the discovery of new structural motifs involving pure boron clusters for the design of novel boride materials. Reference [1] H.W. Kroto, J. R. Heath, S. C. OBrien, R. F. Curl, R. E. Smalley, Nature 1985, 318, 162 - 163. [2] W. Krtschmer, L. D. Lamb, K. Fostiropoulos, D. R. Huffman, Nature 1990, 347, 354 - 358. [3] T. P. Fehlner, J.-F. Halet, J.-Y. Saillard, Molecular Clusters: A Bridge to Solid-State Chemitry, Cambridge University Press, UK, 2007. [4] W. L. Li, L. Xie, T. Jian, C. Romanescu, X. Huang, L.-S. Wang, Angew. Chem. Int. Ed. 2014, 126, 1312 - 1316. [5] B. Le Guennic, H. Jiao, S. Kahlal, J.-Y. Saillard, J.-F. Halet, S. Ghosh, M. Shang, A. M. Beatty, A. L. Rheingold, T. P. Fehlner, J. Am. Chem. Soc. 2004, 126, 3203 - 3217. [6] B. P. T. Fokwa, M. Hermus, Angew

  9. Changes in the Adult GluN2B Associated Proteome following Adolescent Intermittent Ethanol Exposure.

    Directory of Open Access Journals (Sweden)

    H Scott Swartzwelder

    Full Text Available Adolescent alcohol use is the strongest predictor for alcohol use disorders. In rodents, adolescents have distinct responses to acute ethanol, and prolonged alcohol exposure during adolescence can maintain these phenotypes into adulthood. One brain region that is particularly sensitive to the effects of both acute and chronic ethanol exposure is the hippocampus. Adolescent intermittent ethanol exposure (AIE produces long lasting changes in hippocampal synaptic plasticity and dendritic morphology, as well as in the susceptibility to acute ethanol-induced spatial memory impairment. Given the pattern of changes in hippocampal structure and function, one potential target for these effects is the ethanol sensitive GluN2B subunit of the NMDA receptor, which is known to be involved in synaptic plasticity and dendritic morphology. Thus we sought to determine if there were persistent changes in hippocampal GluN2B signaling cascades following AIE. We employed a previously validated GluN2B-targeted proteomic strategy that was used to identify novel signaling mechanisms altered by chronic ethanol exposure in the adult hippocampus. We collected adult hippocampal tissue (P70 from rats that had been given 2 weeks of AIE from P30-45. Tissue extracts were fractionated into synaptic and non-synaptic pools, immuno-precipitated for GluN2B, and then analyzed using proteomic methods. We detected a large number of proteins associated with GluN2B. AIE produced significant changes in the association of many proteins with GluN2B in both synaptic and non-synaptic fractions. Intriguingly the number of proteins changed in the non-synaptic fraction was double that found in the synaptic fraction. Some of these proteins include those involved in glutamate signaling cytoskeleton rearrangement, calcium signaling, and plasticity. Disruptions in these pathways may contribute to the persistent cellular and behavioral changes found in the adult hippocampus following AIE. Further

  10. MAT2B promotes adipogenesis by modulating SAMe levels and activating AKT/ERK pathway during porcine intramuscular preadipocyte differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Cunzhen; Chen, Xiaochang; Wu, Wenjing; Wang, Wusu; Pang, Weijun; Yang, Gongshe, E-mail: gsyang999@hotmail.com

    2016-05-15

    Intramuscular fat (IMF) has been demonstrated as one of the crucial factors of livestock meat quality. The MAT2B protein with MAT2α catalyzes the formation of methyl donor S- adenosylmethionine (SAMe) to mediate cell metabolism including proliferation and apoptosis. However, the regulatory effect of MAT2B on IMF deposition is still unclear. In this study, the effect of MAT2B on adipogenesis and its potential mechanism during porcine intramuscular preadipocyte differentiation was studied. The results showed that overexpression of MAT2B promoted adipogenesis and significantly up-regulated the mRNA and protein levels of adipogenic marker genes including FASN, PPARγ and aP2, consistently, knockdown of MAT2B inhibited lipid accumulation and down-regulated the mRNA and protein levels of the above genes. Furthermore, flow cytometry and EdU-labeling assay indicated that MAT2B regulate adipogenesis was partly due to influence intracellular SAMe levels and further affect cell clonal expansion. Also, increased expression of MAT2B activated the phosphorylations of AKT and ERK1/2, whereas knockdown of MAT2B blocked AKT signaling and repressed the phosphorylation of ERK1/2. Moreover, the inhibitory effect of LY294002 (a specific PI3K inhibitor) on the activities of AKT and ERK1/2 was partially recovered by overexpression of MAT2B in porcine intramuscular adipocytes. Finally, Co-IP experiments showed that MAT2B can directly interact with AKT. Taken together, our findings suggested that MAT2B acted as a positive regulator through modifying SAMe levels as well as activating AKT/ERK signaling pathway to promote porcine intramuscular adipocyte differentiation. - Highlights: • MAT2B up-regulates the expression of adipogenic marker genes and promotes porcine intramuscular preadipocyte differentiation. • MAT2B influences intracellular SAMe levels and further affects cell clonal expansion. • MAT2B interacts with AKT and activates AKT/ERK signaling pathway.

  11. Influence of various polymorphic variants of cytochrome P450 oxidoreductase (POR on drug metabolic activity of CYP3A4 and CYP2B6.

    Directory of Open Access Journals (Sweden)

    Xuan Chen

    Full Text Available Cytochrome P450 oxidoreductase (POR is known as the sole electron donor in the metabolism of drugs by cytochrome P450 (CYP enzymes in human. However, little is known about the effect of polymorphic variants of POR on drug metabolic activities of CYP3A4 and CYP2B6. In order to better understand the mechanism of the activity of CYPs affected by polymorphic variants of POR, six full-length mutants of POR (e.g., Y181D, A287P, K49N, A115V, S244C and G413S were designed and then co-expressed with CYP3A4 and CYP2B6 in the baculovirus-Sf9 insect cells to determine their kinetic parameters. Surprisingly, both mutants, Y181D and A287P in POR completely inhibited the CYP3A4 activity with testosterone, while the catalytic activity of CYP2B6 with bupropion was reduced to approximately ~70% of wild-type activity by Y181D and A287P mutations. In addition, the mutant K49N of POR increased the CLint (Vmax/Km of CYP3A4 up to more than 31% of wild-type, while it reduced the catalytic efficiency of CYP2B6 to 74% of wild-type. Moreover, CLint values of CYP3A4-POR (A115V, G413S were increased up to 36% and 65% of wild-type respectively. However, there were no appreciable effects observed by the remaining two mutants of POR (i.e., A115V and G413S on activities of CYP2B6. In conclusion, the extent to which the catalytic activities of CYP were altered did not only depend on the specific POR mutations but also on the isoforms of different CYP redox partners. Thereby, we proposed that the POR-mutant patients should be carefully monitored for the activity of CYP3A4 and CYP2B6 on the prescribed medication.

  12. Canine Parvovirus (CPV) Vaccination: Comparison of Neutralizing Antibody Responses in Pups after Inoculation with CPV2 or CPV2b Modified Live Virus Vaccine

    Science.gov (United States)

    Pratelli, Annamaria; Cavalli, Alessandra; Martella, Vito; Tempesta, Maria; Decaro, Nicola; Carmichael, Leland Eugene; Buonavoglia, Canio

    2001-01-01

    Canine parvovirus type 2 (CPV2) emerged in 1978 as causative agent of a new disease of dogs. New antigenic variants (biotypes), designated CPV2a and CPV2b, became widespread during 1979 to 1980 and 1984, respectively. At the present time the original CPV2 has disappeared in the dog population and has been replaced by the two new viruses. In the present study the comparison of neutralizing antibody titers in two groups of pups (18 pups in each group) inoculated with CPV2 and CPV2b modified live virus vaccines is reported. Using the hemagglutination inhibition (HI) test, relevant differences between antibody titers, against either the homologous or the heterologous virus, were not constantly observed. Using the neutralization (Nt) test, however, the pups inoculated with CPV2 had antibody titers which were approximately 30 times higher to the homologous virus (mean, 4,732) than to the heterologous virus (CPV2b) (mean, 162). The results of these experiments support two conclusions: (i) the HI test may not always accurately evaluate the true immune status of dogs with respect to CPV, and (ii) dogs inoculated with CPV2 vaccine develop relatively low Nt antibody titers against the heterologous virus (CPV2b). These data may suggest an advantage for new vaccines, considering that most presently licensed vaccines are produced with CPV2, which no longer exists in the dog population. PMID:11329467

  13. Cognitive impairment in the preclinical stage of dementia in FTD-3 CHMP2B mutation carriers

    DEFF Research Database (Denmark)

    Stokholm, Jette; Teasdale, Thomas W; Johannsen, Peter

    2013-01-01

    OBJECTIVE AND METHODS: A longitudinal study spanning over 8 years and including 17 asymptomatic individuals with CHMP2B mutations was conducted to assess the earliest neuropsychological changes in autosomal dominant neurodegenerative disease frontotemporal dementia (FTD) linked to chromosome 3 (FTD...... members and spouses. Longitudinal analyses showed a gradual decline in psychomotor speed, working memory capacity and global executive measures in the group of non-demented mutation carriers that was not found in the control group. In contrast, there were no significant group differences in domain scores...... on memory or visuospatial functions. On an individual level the cognitive changes over time varied considerably. CONCLUSION: Subjects with CHMP2B mutation show cognitive changes dominated by executive dysfunctions, years before they fulfil diagnostic criteria of FTD. However, there is great heterogeneity...

  14. Graphene nanoscrolls encapsulated TiO2 (B) nanowires for lithium storage

    Science.gov (United States)

    Li, Xinlu; Zhang, Yonglai; Li, Tongtao; Zhong, Qineng; Li, Hongyi; Huang, Jiamu

    2014-12-01

    Graphene nanoscrolls encapsulated TiO2 (B) nanowires have been fabricated through a self-scrolling and template-free process for the first time. Transmission electron microscope images reveal that graphene tightly encompassed TiO2 (B) nanowires to construct nanoscrolled architectures. Cyclic voltammetry demonstrates that pseudocapacitive behavior dominates fast lithium storage rather than diffusion-controlled insertion in the hybrids. Galvanostatic cycling tests show that the reversible specific capacity of the hybrids remains 153 mAh g-1 after 300 cycles at 10 C with capacity retention of 94%. The excellent lithium storage performance can be attributed to the unique nanoscrolled structure, which provides abundant channels for lithium ions transport, as well as accommodates volume variation during fast lithiation and delithiation.

  15. Discovery of Potent and Highly Selective A2B Adenosine Receptor Antagonist Chemotypes.

    Science.gov (United States)

    El Maatougui, Abdelaziz; Azuaje, Jhonny; González-Gómez, Manuel; Miguez, Gabriel; Crespo, Abel; Carbajales, Carlos; Escalante, Luz; García-Mera, Xerardo; Gutiérrez-de-Terán, Hugo; Sotelo, Eddy

    2016-03-10

    Three novel families of A2B adenosine receptor antagonists were identified in the context of the structural exploration of the 3,4-dihydropyrimidin-2(1H)-one chemotype. The most appealing series contain imidazole, 1,2,4-triazole, or benzimidazole rings fused to the 2,3-positions of the parent diazinone core. The optimization process enabled identification of a highly potent (3.49 nM) A2B ligand that exhibits complete selectivity toward A1, A2A, and A3 receptors. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The main SAR trends identified within the series were substantiated by a molecular modeling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human A2A receptor.

  16. Characteristics of the brand building on the business (B2B market

    Directory of Open Access Journals (Sweden)

    Gligorijević Mirjana

    2011-01-01

    Full Text Available This paper analyzes the characteristics of the brand building in the business (B2B market. Branding strategy at the business market is complex and difficult to implement because of the many limiting factors. Building a brand in the business market is marked by very specific characteristics of industrial products. The value of B2B brands is built through functional characteristics and performances of the product (functional values and emotional value, which together guarantee the delivery a unique experience of business customers. All marketing mix tools can be considered to be branding instruments. The purpose of this paper is to emphasize the importance of applying a branding strategy on business market.

  17. Fabrication of VO2 (B Nanobelts and Their Application in Lithium Ion Batteries

    Directory of Open Access Journals (Sweden)

    Shibing Ni

    2011-01-01

    Full Text Available VO2 (B nanobelts have been successfully synthesized via a simple hydrothermal route. The products were characterized by X-ray diffraction (XRD, field emission scanning electron microscopy (FE-SEM, and Raman spectrum. These nanobelts are of rectangular cross-section with mean length about 1 μm, mean width about 80 nm, and mean thickness about 50 nm. The as-synthesized VO2 nanobelts were assembled as the cathode electrodes of lithium ion batteries. Their electrochemical properties were studied by conventional charge/discharge tests, which show an initial discharge capacity of 321 mAh g−1 with voltage plateau near 2.5 V. These results indicated that such hydrothermally synthesized VO2 (B nanobelts could be an ideal candidate of cathode material for lithium ion battery.

  18. The Histone H2B Monoubiquitination Regulatory Pathway Is Required for Differentiation of Multipotent Stem Cells

    DEFF Research Database (Denmark)

    Karpiuk, Oleksandra; Najafova, Zeynab; Kramer, Frank

    2012-01-01

    understood. We show that histone H2B monoubiquitination (H2Bub1) significantly increases during differentiation of human mesenchymal stem cells (hMSCs) and various lineage-committed precursor cells and in diverse organisms. Furthermore, the H2B ubiquitin ligase RNF40 is required for the induction......Extensive changes in posttranslational histone modifications accompany the rewiring of the transcriptional program during stem cell differentiation. However, the mechanisms controlling the changes in specific chromatin modifications and their function during differentiation remain only poorly...... during the transition from an inactive to an active chromatin conformation. Thus, these data indicate that H2Bub1 is required for maintaining multipotency of hMSCs and plays a central role in controlling stem cell differentiation....

  19. Immobilized Ionic Liquid-Catalyzed Synthesis of Pyrano[3,2-b]indole Derivatives

    Directory of Open Access Journals (Sweden)

    Saman Damavandi

    2012-01-01

    Full Text Available An ionic liquid-catalyzed synthesis of 2-amino-4,5-dihydro-4-arylpyrano[3,2-b]indole-3-carbonitrile derivatives through a novel three-component condensation of 3-hydroxyindole, aromatic aldehydes and malononitrile in the presence of silica supported ionic liquid of [pmim]HSO4SiO2 (silica supported 1-methyl-3-(triethoxysilylpropylimidazolium hydrogensulfate as an efficient catalyst is described.

  20. Mesoporous TiO2-B Microspheres with Superior Rate Performance for Lithium Ion Batteries

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Hansan [ORNL; Bi, Zhonghe [ORNL; Sun, Xiao-Guang [ORNL; Unocic, Raymond R [ORNL; Paranthaman, Mariappan Parans [ORNL; Dai, Sheng [ORNL; Brown, Gilbert M [ORNL

    2011-01-01

    Mesoporous TiO2-B microsperes with a favorable material architecture are designed and synthesized for high power lithium ion batteries. This material, combining the advantages of fast lithium transport with a pseudocapacitive mechanism, adequate electrode-electrolyte contact and compact particle packing in electrode layer, shows superior high-rate charge-discharge capability and long-time cyclability for lithium ion batteries.

  1. Mesoporous TiO{sub 2}-B microspheres with superior rate performance for lithium ion batteries

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Hansan; Bi, Zhonghe; Sun, Xiao-Guang; Paranthaman, M.Parans; Dai, Sheng; Brown, Gilbert M. [Chemical Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831 (United States); Unocic, Raymond R. [Material Sciences and Technology Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831 (United States)

    2011-08-09

    Mesoporous TiO{sub 2}-B microspheres with a favorable material architecture are designed and synthesized for highpower lithium ion batteries. This material, which combines the advantages of fast lithium transport with a pseudocapacitive mechanism, adequate electrode-electrolyte contact, and compact particle packing in the electrode layer, shows superior high-rate charge-discharge capability and long-time cyclability for lithium ion batteries. (Copyright copyright 2011 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  2. Granulin exacerbates lupus nephritis via enhancing macrophage M2b polarization.

    Directory of Open Access Journals (Sweden)

    Xi Chen

    Full Text Available BACKGROUND AND AIMS: Lupus nephritis (LN, with considerable morbidity and mortality, is one of the most severe manifestations of systemic lupus erythematosus (SLE. Yet, the pathogenic mechanisms of LN have not been clearly elucidated, and efficient therapies are still in great need. Granulin (GRN, a multifunctional protein linked to inflammatory diseases, has recently been reported to correlate with the disease activity of autoimmune diseases. However, the role of GRN in the pathogenic process of LN still remains obscure. In this study, we explored its potential role and underlying mechanism in the pathogenesis of LN. METHODOLOGY/PRINCIPAL FINDINGS: We found that serum GRN levels were significantly up-regulated and were positively correlated with the severity of LN. Overexpression of GRN in vivo by transgenic injection remarkably exacerbated LN, whereas down-regulation of GRN with shRNA ameliorated LN, firmly demonstrating the critical role of GRN in the pathogenesis of LN. Notably, macrophage phenotype analysis revealed that overexpression of GRN could enhance macrophage polarization to M2b, a key mediator of the initiation and progression of LN. On the contrary, down-regulation of GRN resulted in impaired M2b differentiation, thus ameliorating LN. Moreover, we found that MAPK signals were necessary for the effect of GRN on macrophage M2b polarization. CONCLUSION/SIGNIFICANCE: We first demonstrated that GRN could aggravate lupus nephritis (LN via promoting macrophage M2b polarization, which might provide insights into the pathogenesis of LN as well as potential therapeutic strategies against LN.

  3. Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk.

    Directory of Open Access Journals (Sweden)

    Cathy Slack

    2010-03-01

    Full Text Available Drosophila Lnk is the single ancestral orthologue of a highly conserved family of structurally-related intracellular adaptor proteins, the SH2B proteins. As adaptors, they lack catalytic activity but contain several protein-protein interaction domains, thus playing a critical role in signal transduction from receptor tyrosine kinases to form protein networks. Physiological studies of SH2B function in mammals have produced conflicting data. However, a recent study in Drosophila has shown that Lnk is an important regulator of the insulin/insulin-like growth factor (IGF-1 signaling (IIS pathway during growth, functioning in parallel to the insulin receptor substrate, Chico. As this pathway also has an evolutionary conserved role in the determination of organism lifespan, we investigated whether Lnk is required for normal lifespan in Drosophila. Phenotypic analysis of mutants for Lnk revealed that loss of Lnk function results in increased lifespan and improved survival under conditions of oxidative stress and starvation. Starvation resistance was found to be associated with increased metabolic stores of carbohydrates and lipids indicative of impaired metabolism. Biochemical and genetic data suggest that Lnk functions in both the IIS and Ras/Mitogen activated protein Kinase (MapK signaling pathways. Microarray studies support this model, showing transcriptional feedback onto genes in both pathways as well as indicating global changes in both lipid and carbohydrate metabolism. Finally, our data also suggest that Lnk itself may be a direct target of the IIS responsive transcription factor, dFoxo, and that dFoxo may repress Lnk expression. We therefore describe novel functions for a member of the SH2B protein family and provide the first evidence for potential mechanisms of SH2B regulation. Our findings suggest that IIS signaling in Drosophila may require the activity of a second intracellular adaptor, thereby yielding fundamental new insights into the

  4. Orosomucoid 1 drives opportunistic infections through the polarization of monocytes to the M2b phenotype.

    Science.gov (United States)

    Nakamura, Kiwamu; Ito, Ichiaki; Kobayashi, Makiko; Herndon, David N; Suzuki, Fujio

    2015-05-01

    Orosomucoid (ORM, composed of two isoforms, ORM1 and ORM2) has been described as an inducer of M2 macrophages, which are cells that decrease host antibacterial innate immunities. However, it is unknown which phenotypes of M2 macrophages are induced by ORM. In this study, healthy donor monocytes stimulated with ORM (ORM-monocytes) were characterized phenotypically and biologically. CCL1 (a biomarker of M2b macrophages) and IL-10 were detected in monocyte cultures supplemented with ORM1; however, CCL17 (a biomarker of M2a macrophages) and CXCL13 (a biomarker of M2c macrophages) were not produced in these cultures. All of these soluble factors were not detected in the culture fluids of monocytes stimulated with ORM2. Monocytes stimulated with ORM1 were characterized as CD64(-)CD209(-)CD163(+)CCL1(+) cells. MRSA and Enterococcus faecalis infections were accelerated in chimeras (NOD/scid IL-2Rγ(null) mice reconstituted with white blood cells) after inoculation with monocytes stimulated with ORM1 or treatment with ORM1; however, the infections were greatly mitigated in both chimeras inoculated with ORM1-stimulated monocytes and treated with ORM1, after an additional treatment with an inhibitor of M2b macrophages (CCL1 antisense ODN). These results indicate that ORM1 stimulates quiescent monocytes to polarize to M2b monocytes. The regulation of M2b macrophages may be beneficial in controlling opportunistic infections in patients with a large amount of plasma ORM1. Copyright © 2015. Published by Elsevier Ltd.

  5. Orosomucoid 1 drives opportunistic infections through the polarization of monocytes to the M2b phenotype

    OpenAIRE

    Nakamura, Kiwamu; Ito, Ichiaki; Kobayashi, Makiko; Herndon, David N.; Suzuki, Fujio

    2015-01-01

    Orosomucoid (ORM, composed of two isoforms, ORM1 and ORM2) has been described as an inducer of M2 macrophages, which are cells that decrease host antibacterial innate immunities. However, it is unknown which phenotypes of M2 macrophages are induced by ORM. In this study, healthy donor monocytes stimulated with ORM (ORM-monocytes) were characterized phenotypically and biologically. CCL1 (a biomarker of M2b macrophages) and IL-10 were detected in monocyte cultures supplemented with ORM1; howeve...

  6. Customer intimacy strategy in B2B technology businesses in Colombia

    OpenAIRE

    Gomez Andres, Jorge

    2015-01-01

    The main objective of this Thesis is to analyze Customer Intimacy Strategy in B2B technology businesses in Colombia and the variables that have a direct relationship with it like perception, trust and networking. And how a Customer Intimacy Strategy can affect a company to achieve positive or negative results in an operation, in terms of business opportunities, relations and profitable and sustainable sales if properly managed or mismanaged. With a population of almost 50 mi...

  7. Everolimus Stabilizes Podocyte Microtubules via Enhancing TUBB2B and DCDC2 Expression.

    Directory of Open Access Journals (Sweden)

    Stefanie Jeruschke

    Full Text Available Glomerular podocytes are highly differentiated cells that are key components of the kidney filtration units. The podocyte cytoskeleton builds the basis for the dynamic podocyte cytoarchitecture and plays a central role for proper podocyte function. Recent studies implicate that immunosuppressive agents including the mTOR-inhibitor everolimus have a protective role directly on the stability of the podocyte actin cytoskeleton. In contrast, a potential stabilization of microtubules by everolimus has not been studied so far.To elucidate mechanisms underlying mTOR-inhibitor mediated cytoskeletal rearrangements, we carried out microarray gene expression studies to identify target genes and corresponding pathways in response to everolimus. We analyzed the effect of everolimus in a puromycin aminonucleoside experimental in vitro model of podocyte injury.Upon treatment with puromycin aminonucleoside, microarray analysis revealed gene clusters involved in cytoskeletal reorganization, cell adhesion, migration and extracellular matrix composition to be affected. Everolimus was capable of protecting podocytes from injury, both on transcriptional and protein level. Rescued genes included tubulin beta 2B class IIb (TUBB2B and doublecortin domain containing 2 (DCDC2, both involved in microtubule structure formation in neuronal cells but not identified in podocytes so far. Validating gene expression data, Western-blot analysis in cultured podocytes demonstrated an increase of TUBB2B and DCDC2 protein after everolimus treatment, and immunohistochemistry in healthy control kidneys confirmed a podocyte-specific expression. Interestingly, Tubb2bbrdp/brdp mice revealed a delay in glomerular podocyte development as showed by podocyte-specific markers Wilm's tumour 1, Podocin, Nephrin and Synaptopodin.Taken together, our study suggests that off-target, non-immune mediated effects of the mTOR-inhibitor everolimus on the podocyte cytoskeleton might involve regulation of

  8. Community annotation experiment for ground truth generation for the i2b2 medication challenge.

    Science.gov (United States)

    Uzuner, Ozlem; Solti, Imre; Xia, Fei; Cadag, Eithon

    2010-01-01

    Within the context of the Third i2b2 Workshop on Natural Language Processing Challenges for Clinical Records, the authors (also referred to as 'the i2b2 medication challenge team' or 'the i2b2 team' for short) organized a community annotation experiment. For this experiment, the authors released annotation guidelines and a small set of annotated discharge summaries. They asked the participants of the Third i2b2 Workshop to annotate 10 discharge summaries per person; each discharge summary was annotated by two annotators from two different teams, and a third annotator from a third team resolved disagreements. In order to evaluate the reliability of the annotations thus produced, the authors measured community inter-annotator agreement and compared it with the inter-annotator agreement of expert annotators when both the community and the expert annotators generated ground truth based on pooled system outputs. For this purpose, the pool consisted of the three most densely populated automatic annotations of each record. The authors also compared the community inter-annotator agreement with expert inter-annotator agreement when the experts annotated raw records without using the pool. Finally, they measured the quality of the community ground truth by comparing it with the expert ground truth. The authors found that the community annotators achieved comparable inter-annotator agreement to expert annotators, regardless of whether the experts annotated from the pool. Furthermore, the ground truth generated by the community obtained F-measures above 0.90 against the ground truth of the experts, indicating the value of the community as a source of high-quality ground truth even on intricate and domain-specific annotation tasks.

  9. Interdependence of magnetism and superconductivity in the borocarbide TmNi2B2C

    DEFF Research Database (Denmark)

    Nørgaard, K.; Eskildsen, M.R.; Andersen, N.H.

    2000-01-01

    We have discovered anew antiferromagnetic phase in TmNi2B2C by neutron diffraction. The ordering vector is Q(A) = (0.48,0,0) and the phase appears shove a critical in-plans magnetic field of 0.9 T. The field was applied in order to test the assumption that the zero-field magnetic structure at Q...

  10. An Empirical Examination of Reverse Auction Appropriateness in B2B Source Selection

    Science.gov (United States)

    2006-01-01

    U.S. GOVERNMENT. An Empirical Examination of Reverse Auction Appropriateness in B2B Source Selection Abstract Electronic reverse auctions (e-RA) are...of business-to-business electronic markets . Joo and Kim’s (2004) study revealed that external pressure, such as competition and firm size, directly...competitive market structure, the greater the appropriateness of an e- RA as a sourcing strategy . Specifiability In the sourcing strategy development

  11. Customer journey in B2B SaaS business models

    OpenAIRE

    Opanasenko, Mariia

    2017-01-01

    In this paper customer journey for B2B SaaS business models was analyzed to study customer experience, customer success and its key performance indicators. The research method is the case study of Supplier Relationship Management SaaS solution provider. In recent years, the research in customer journey management identified the tendency of acknowledge customer journey as a differentiator and a competitive advantage. Customer journey is a complex process that entails structured customer experi...

  12. Glucosylsphingosine Activates Serotonin Receptor 2a and 2b: Implication of a Novel Itch Signaling Pathway.

    Science.gov (United States)

    Afzal, Ramsha; Shim, Won-Sik

    2017-09-01

    Recent reports claimed that glucosylsphingosine (GS) is highly accumulated and specifically evoking itch-scratch responses in the skins of atopic dermatitis (AD) patients. However, it was unclear how GS can trigger itch-scratch responses, since there were no known molecular singling pathways revealed yet. In the present study, it was verified for the first time that GS can activate mouse serotonin receptor 2a (mHtr2a) and 2b (mHtr2b), but not 2c (mHtr2c) that are expressed in HEK293T cells. Specifically, effects of GS on all mouse serotonin receptor 2 subfamily were evaluated by calcium imaging techniques. The GS-induced intracellular calcium increase was dose-dependent, and antagonists such as ketanserin (Htr2a antagonist) and RS-127445 (Htr2b antagonist) significantly blocked the GS-induced responses. Moreover, the proposed GS-induced responses appear to be mediated by phospholipase C (PLC), since pretreatment of a PLC inhibitor U-73122 abolished the GS-induced responses. Additionally, the GS-induced calcium influx is probably mediated by endogenous TRPC ion channels in HEK293T cells, since pretreatment of SKF-96365, an inhibitor for TRPC, significantly suppressed GS-induced response. In conclusion, the present study revealed for the first time that GS can stimulate mHtr2a and mHtr2b to induce calcium influx, by utilizing PLC-dependent pathway afterwards. Considering that GS is regarded as a pruritogen in AD, the present study implicates a novel GS-induced itch signaling pathway.

  13. Multiple endocrine neoplasia 2B: Differential increase in enteric nerve subgroups in muscle and mucosa

    Science.gov (United States)

    Hutson, John M; Farmer, Pam J; Peck, Cristal J; Chow, Chung W; Southwell, Bridget R

    2017-01-01

    Multiple endocrine neoplasia 2B (MEN2B) is a rare syndrome caused by an activating mutation of the RET gene, leading to enteric gangliomatosis. This child presented with constipation at 1-mo old, was diagnosed with MEN2B by rectal biopsy at 4 mo, had thyroidectomy at 9 mo and a colectomy at 4 years. We studied the extent of neuronal and nerve fibre proliferation and which classes of enteric nerves are affected by examining the colon with multiple neuronal antibodies. Resected transverse colon was fixed, frozen, sectioned and processed for fluorescence immunohistochemistry labelling with antibodies against TUJ1, Hu, ChAT, NOS, VIP, SP and CGRP and cKit. Control transverse colon was from the normal margin of Hirschsprung (HSCR) colon (4-year-old) and a child with familial adenomatous polyposis (FAP, 12 year). Myenteric ganglia were increased in size to as wide as the circular muscle. There was a large increase in nerve cells and nerve fibres. ChAT-, NOS-, VIP- and SP-immunoreactive nerve fibres all increased in the myenteric ganglia. NOS-IR nerves preferentially increased in the muscle, while VIP and SP increased in submucosal ganglia and mucosal nerve fibres. The density of ICC was normal. RET overactivation in MEN2B lead to a large increase in intrinsic nerve fibres in the myenteric and submucosal ganglia, with a relative increase in NOS-IR nerve fibres in the circular muscle and VIP and SP in the submucosal ganglia and mucosa. The changes were associated with severe constipation resulting in colectomy at 4 years. PMID:28868184

  14. Lithiation Thermodynamics and Kinetics of the TiO2(B) Nanoparticles.

    Science.gov (United States)

    Hua, Xiao; Liu, Zheng; Fischer, Michael G; Borkiewicz, Olaf; Chupas, Peter J; Chapman, Karena W; Steiner, Ullrich; Bruce, Peter G; Grey, Clare P

    2017-09-27

    TiO 2 (B) has attracted considerable attention in recent years because it exhibits the largest capacity among all studied titania polymorphs, with high rate performance for Li intercalation being achieved when this material is nanostructured. However, due to the complex nature of its lithiation mechanism and practical challenges in probing Li structure in nanostructured materials, a definitive understanding of the lithiation thermodynamics has yet to be established. A comprehensive mechanistic investigation of the TiO 2 (B) nanoparticles is therefore presented using a combination of in situ/operando X-ray pair distribution function (PDF) and electrochemical techniques. The discharge begins with surface reactions in parallel with Li insertion into the subsurface of the nanoparticles. The Li bulk insertion starts with a single-phase reaction into the A2 site, a position adjacent to the b-channel. A change of the Li diffusion pathway from that along this open channel to that along the c-direction is likely to occur at the composition of Li 0.25 TiO 2 until Li 0.5 TiO 2 is attained, leading to a two-step A2-site incorporation with one step kinetically distinct from the other. Subsequent Li insertion involves the C' site, a position situated inside the channel, and follows a rapid two-phase reaction to form Li 0.75 TiO 2 . Due to the high diffusion barrier associated with the further lithiation, Li insertion into the A1 site, another position adjacent to the channel neighboring the A2 sites, is kinetically restricted. This study not only explores the lithiation reaction thermodynamics and mechanisms of nanoparticulate TiO 2 (B) but also serves as a strong reference for future studies of the bulk phase, and for future calculations to study the Li transport properties of TiO 2 (B).

  15. Optimizing social media channels for B2B startups : Case of Odd Expert Oy

    OpenAIRE

    Nguyen, Thi Ngoc Anh

    2016-01-01

    In recent years, the dramatic development of social media and its huge advances on global businesses cannot be deniable. With a large user base and useful analytics support, it helps many companies, especially startups, to reach their target audiences. Additionally, it requires low budget on advertising which stimulates all kinds of businesses to utilize social media channels. This thesis analyzes the effectiveness of social media marketing from perspectives of business-to-business (B2B) ...

  16. Interactive Cohort Identification of Sleep Disorder Patients Using Natural Language Processing and i2b2.

    Science.gov (United States)

    Chen, W; Kowatch, R; Lin, S; Splaingard, M; Huang, Y

    2015-01-01

    Nationwide Children's Hospital established an i2b2 (Informatics for Integrating Biology & the Bedside) application for sleep disorder cohort identification. Discrete data were gleaned from semistructured sleep study reports. The system showed to work more efficiently than the traditional manual chart review method, and it also enabled searching capabilities that were previously not possible. We report on the development and implementation of the sleep disorder i2b2 cohort identification system using natural language processing of semi-structured documents. We developed a natural language processing approach to automatically parse concepts and their values from semi-structured sleep study documents. Two parsers were developed: a regular expression parser for extracting numeric concepts and a NLP based tree parser for extracting textual concepts. Concepts were further organized into i2b2 ontologies based on document structures and in-domain knowledge. 26,550 concepts were extracted with 99% being textual concepts. 1.01 million facts were extracted from sleep study documents such as demographic information, sleep study lab results, medications, procedures, diagnoses, among others. The average accuracy of terminology parsing was over 83% when comparing against those by experts. The system is capable of capturing both standard and non-standard terminologies. The time for cohort identification has been reduced significantly from a few weeks to a few seconds. Natural language processing was shown to be powerful for quickly converting large amount of semi-structured or unstructured clinical data into discrete concepts, which in combination of intuitive domain specific ontologies, allows fast and effective interactive cohort identification through the i2b2 platform for research and clinical use.

  17. The FRCR 2B examination: a survey of candidate perceptions and experiences

    Energy Technology Data Exchange (ETDEWEB)

    Yeung, A., E-mail: andrewyeung@hotmail.co [Department of Radiology, Freeman Hospital, Newcastle upon Tyne (United Kingdom); Booth, T.C. [Department of Radiology, Royal Free Hospital, London (United Kingdom); Jacob, K. [Department of Radiology, Weston General Hospital, Weston-super-Mare (United Kingdom); McCoubrie, P. [Department of Radiology, Southmead Hospital, Bristol (United Kingdom); McKnight, L. [Department of Radiology, Morriston Hospital, Swansea (United Kingdom)

    2011-05-15

    Aim: To survey the views of recent candidates of the Fellowship of the Royal College of Radiologists (FRCR) 2B examination with reference to assessment validity, reliability, and acceptability. Materials and methods: One thousand, two hundred and four UK radiology trainees and consultants were invited to complete an automated internet questionnaire regarding their experiences and perceptions of the FRCR 2B examination. The questionnaire was informed by a review of the literature. Eligible participants were candidates who had taken the examination within the previous 3 years. Results: Four hundred and ninety-seven out of 1204 (41%) responses were received; of which 258/497 (52% of respondents) were eligible for inclusion into the study. The rapid reporting component is perceived to be significantly fairer than the oral section (82 versus 70% agree; p < 0.001). The oral component fared poorly in perceived performance-reducing anxiety levels but well in questions relating to validity and reliability. Female candidates are more likely to find the FRCR 2B unfair (p = 0.01) and experience performance-reducing anxiety (p < 0.001) than males. No gender differences were observed in first-time pass rates (p = 0.6). Candidate first language did not affect anxiety levels (p = 0.9) or first-time pass rates (p = 0.06). Only 12% of candidates agreed that the oral examination should move to an objective structured clinical format. Conclusion: Candidates score the FRCR 2B examination well in test validity with little desire for change to the oral examination format. Efforts to help reduce anxiety levels in the oral component would improve perceived fairness.

  18. Tell-Tale SNPs: The Role of CYP2B6 in Methadone Fatalities.

    Science.gov (United States)

    Ahmad, Taha; Sabet, Samie; Primerano, Donald A; Richards-Waugh, Lauren L; Rankin, Gary O

    2017-05-01

    Cytochrome P450 (CYP) enzyme 2B6 plays a significant role in the stereo-selective metabolism of (S)-methadone to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine, an inactive methadone metabolite. Elevated (S)-methadone can cause cardiotoxicity by prolonging the QT interval of the heart's electrical cycle. Large inter-individual variability of methadone pharmacokinetics causes discordance in the relationship between dose, plasma concentrations and side effects. The purpose of this study was to determine if one or more single nucleotide polymorphisms (SNPs) located within the CYP2B6 gene contributes to a poor metabolizer phenotype for methadone in these fatal cases. The genetic analysis was conducted on 125 Caucasian methadone-only fatalities obtained from the West Virginia and Kentucky Offices of the Chief Medical Examiner. The frequency of eight exonic and intronic SNPs (rs2279344, rs3211371, rs3745274, rs4803419, rs8192709, rs8192719, rs12721655 and rs35979566) was determined. The frequencies of SNPs rs3745274 (*9, c516G > T, Q172H), and rs8192719 (21563 C > T) were enhanced in the methadone-only group. Higher blood methadone concentrations were observed in individuals who were genotyped homozygous for SNP rs3211371 (*5, c1459C > T, R487C). These results indicate that these three CYP2B6 SNPs are associated with methadone fatalities. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. CYP2B6 and bupropion’s smoking cessation pharmacology: the role of hydroxybupropion

    Science.gov (United States)

    Zhu, Andy Z.X.; Cox, Lisa Sanderson; Nollen, Nikki; Faseru, Babalola; Okuyemi, Kolawole S.; Ahluwalia, Jasjit S; Benowitz, Neal L; Tyndale, Rachel F.

    2013-01-01

    Bupropion is indicated to promote smoking cessation. Animal studies suggest that bupropion’s major metabolite hydroxybupropion can mediate bupropion’s pharmacologic activity. We measured plasma bupropion and metabolite levels in a double-blind, placebo controlled, randomized smoking cessation trial. Among the treatment adherent individuals, higher hydroxybupropion concentrations (per µg/mL) resulted in better smoking cessation outcomes (Week 3, 7 and 26 OR=2.82, 2.96 and 2.37, P=0.005–0.040), this was not observed with bupropion levels (OR=1.00–1.03, P=0.59–0.90). Genetic variation in CYP2B6, the enzyme that metabolizes bupropion to hydroxybupropion, was identified as a significant source of variability in hydroxybupropion formation. Our data indicate that hydroxybupropion contributes to the pharmacologic effects of bupropion for smoking cessation, and that variability in response to bupropion treatment is related to variability in CYP2B6-mediated hydroxybupropion formation. These findings suggest dosing bupropion to achieve a hydroxybupropion level of 0.7 µg/ml or increasing bupropion dose for CYP2B6 slow metabolizers, could improve bupropion’s cessation outcomes. PMID:23149928

  20. Magnetic structure of the magnetocaloric compound AlFe{sub 2}B{sub 2}

    Energy Technology Data Exchange (ETDEWEB)

    Cedervall, Johan, E-mail: johan.cedervall@kemi.uu.se [Department of Chemistry – Ångström Laboratory, Uppsala University, Box 538, 751 21 Uppsala (Sweden); Andersson, Mikael Svante; Sarkar, Tapati [Department of Engineering Sciences, Uppsala University, Box 534, 751 21 Uppsala (Sweden); Delczeg-Czirjak, Erna K. [Department of Physics and Astronomy, Uppsala University, Box 516, 751 20 Uppsala (Sweden); Bergqvist, Lars [Department of Materials and Nano Physics and Swedish e-Science Research Centre (SeRC), Royal Institute of Technology (KTH), Electrum 229, SE-164 40 Kista (Sweden); Hansen, Thomas C. [Institut Laue-Langevin, B.P. 156, Grenoble Cedex 9, 38042 France (France); Beran, Premysl [Nuclear Physics Institute, Academy of Sciences of the Czech Republic, Rez, 25068 Czech Republic (Czech Republic); Nordblad, Per [Department of Engineering Sciences, Uppsala University, Box 534, 751 21 Uppsala (Sweden); Sahlberg, Martin [Department of Chemistry – Ångström Laboratory, Uppsala University, Box 538, 751 21 Uppsala (Sweden)

    2016-04-15

    The crystal and magnetic structures of AlFe{sub 2}B{sub 2} have been studied with a combination of X-ray and neutron diffraction and electronic structure calculations. The magnetic and magnetocaloric properties have been investigated by magnetisation measurements. The samples have been produced using high temperature synthesis and subsequent heat treatments. The compound crystallises in the orthorhombic crystal system Cmmm and it orders ferromagnetically at 285 K through a second order phase transition. At temperatures below the magnetic transition the magnetic moments align along the crystallographic a-axis. The magnetic entropy change from 0 to 800 kA/m was found to be −1.3 J/K kg at the magnetic transition temperature. - Graphical abstract: The magnetic structure of AlFe{sub 2}B{sub 2} has been investigated using neutron diffraction and the magnetic spins have been found to align ferromagnetically along the crystallographic a-axis. - Highlights: • The crystal and magnetic structures of AlFe{sub 2}B{sub 2} have been studied. • Orders ferromagnetically at 285 K via a second order phase transition. • The magnetic moments are found to be aligned along the crystallographic a-axis. • The magnetic entropy change from 0 to 800 kA/m was found to be −1.3 J/K kg.

  1. Do starspots inflate the exoplanet CoRoT-2b?

    Science.gov (United States)

    Huber, Klaus

    2014-10-01

    We propose to use SOFIA's combination of HIPO and FLITECAM to obtain simultaneous optical and infrared transit photometry of the CoRoT-2 system. This system consists of the highly active planet host-star CoRoT-2A and the unusually inflated hot Jupiter CoRoT-2b. CoRoT-2A's surface is densely covered with starspots, which influence the transit lightcurves and, thus, complicate the determination of accurate planetary parameters. In particular, this can lead to an overestimation of the planetary radius, which could, at least partially, account for the unusually large radius inferred for CoRoT-2b. Using SOFIA, the weaker starspot contrast at longer wavelengths will allow us to derive an accurate planetary radius from infrared photometry and, thereby, pin down CoRoT-2b's radius anomaly. Because of SOFIA's unique capability to simultaneously obtain optical photometry, we will also be able to determine starspot temperatures and estimate the total spot-coverage of CoRoT-2A's surface by comparing the deformation and depth of the infrared and visual-band transit lightcurves. Only SOFIA's combination of HIPO and FLITECAM provides the quasi space-based high-precision multi-band photometry required to address these open questions on the young planetary system CoRoT-2.

  2. Imported Genotype 2B Rubella Virus Caused the 2012 Outbreak in Anqing City, China.

    Directory of Open Access Journals (Sweden)

    Zhen Zhu

    Full Text Available A rubella outbreak occurred in Anqing city of Anhui province, China, from February to July of 2012, and a total of 241 clinically diagnosed or lab-confirmed patients were reported. The highest number of rubella cases during this outbreak was recorded in teenagers between 10 and 19 years of age who had not previously received the rubella vaccine. Genotyping results indicated that the genotype 2B rubella virus (RV was responsible for the outbreak. However, a phylogenetic analysis showed that the genotype 2B RVs isolated in Anqing City were not related to 2B RVs found in other cities of Anhui province and in other provinces of China, thus providing evidence for importation. After importation, the transmission of Anqing RVs was interrupted owing to an effective immunization campaign against rubella, suggesting the timeliness and effectiveness of contingency vaccination. Strengthening rubella surveillance, including the integration of epidemiologic information and laboratory data, is a vital strategy for rubella control and elimination. In addition, except for routine immunization, targeted supplementary immunization activities aimed at susceptible groups according to sero-epidemiological surveillance data also play a key role in stopping the continuous transmission of rubella viruses and in preventing further congenital rubella syndrome cases.

  3. Imported Genotype 2B Rubella Virus Caused the 2012 Outbreak in Anqing City, China.

    Science.gov (United States)

    Zhu, Zhen; Pan, Guixia; Zhou, Shujie; Dai, Jingjing; Chen, Xia; Tang, Jihai; Chen, Shuping; Zheng, Yilun; Song, Jie; Xu, Wenbo

    2015-01-01

    A rubella outbreak occurred in Anqing city of Anhui province, China, from February to July of 2012, and a total of 241 clinically diagnosed or lab-confirmed patients were reported. The highest number of rubella cases during this outbreak was recorded in teenagers between 10 and 19 years of age who had not previously received the rubella vaccine. Genotyping results indicated that the genotype 2B rubella virus (RV) was responsible for the outbreak. However, a phylogenetic analysis showed that the genotype 2B RVs isolated in Anqing City were not related to 2B RVs found in other cities of Anhui province and in other provinces of China, thus providing evidence for importation. After importation, the transmission of Anqing RVs was interrupted owing to an effective immunization campaign against rubella, suggesting the timeliness and effectiveness of contingency vaccination. Strengthening rubella surveillance, including the integration of epidemiologic information and laboratory data, is a vital strategy for rubella control and elimination. In addition, except for routine immunization, targeted supplementary immunization activities aimed at susceptible groups according to sero-epidemiological surveillance data also play a key role in stopping the continuous transmission of rubella viruses and in preventing further congenital rubella syndrome cases.

  4. Information management: The adoption of order processing for B2B e-commerce

    Directory of Open Access Journals (Sweden)

    F. W. Voges

    2007-11-01

    Full Text Available The management of information flow in the order processing activities of small enterprises is not always understood. An inefficient supply chain is often the result of the lack of timely and accessible inter-firm information and data exchange. Small suppliers often do not have the technology infrastructure and capable resources available for proper integration with supply chains. This research investigated suppliers and fast moving consumer goods (FMCG retailers, adopting business-to-business (B2B e-commerce. Small businesses are the focus of this research, as they contribute to a large portion of the South African economy and play an important role in the supply chains of retailers. Case study research using evidence obtained from nine small, medium and micro enterprises (SMMEs and suppliers located in the Western Cape, South Africa, was used. It was found that small suppliers have different processes for conducting business with various retailers. Literature revealed little evidence of using the Internet as an enabling technology in on-line order processing. From the analysis, nine improvement areas were identified to enhance the conduct of efficient B2B order processing and associated information flow. These improvement areas were merged with four factors that were identified in a framework when adopting e-supply chains. This resulted in the proposition of guidelines for small suppliers when adopting B2B e-commerce for order processing.

  5. Painful Hip Leading to the Diagnosis of MEN 2B Syndrome

    Directory of Open Access Journals (Sweden)

    Mehtab Ahmad

    2012-01-01

    Full Text Available Context. MEN 2B syndrome is characterized by the presence of medullary thyroid cancer, pheochromocytoma, mucosal neuromas, marfanoid features, and skeletal abnormalities like kyphoscoliosis, joint laxity, pes cavus, and slipped capital femoral epiphysis (SCFE in a minority; we present the case of a young female who was brought to medical attention due to painful hip because of SCFE. Case Report. A 16-year-old female presented to orthopedics out-patient department (OPD with complaints of pain around the left hip and walking with a limp for the last two months. MRI of hip confirmed the presence of SCFE of the left hip. General examination detected thyroid swelling which was found to be a medullary thyroid cancer and imaging of abdomen confirmed the presence of bilateral pheochromocytoma, also present were neuromas of tongue and lips. Thus, a diagnosis of MEN 2B syndrome was made. Conclusion. SCFE can sometimes be the presenting feature of MEN 2B syndrome. Physicians should keep this in mind as it can lead to early diagnosis of a potentially lethal illness.

  6. Lentivirus mediated shRNA interference targeting MAT2B induces growth-inhibition and apoptosis in hepatocelluar carcinoma.

    Science.gov (United States)

    Wang, Qun; Liu, Quan-Yan; Liu, Zhi-Su; Qian, Qun; Sun, Quan; Pan, Ding-Yu

    2008-08-07

    To investigate the effects of lentivirus vector mediated short hairpin RNA interference targeting methionine adenosyltransferase 2beta gene (LV-shMAT2B) on hepatocelluar carcinoma (HCC) cells. We constructed four plasmids of RNA interference targeting the MAT2B gene. After LV-shMAT2B was transfected with L-02 cells and two kinds of HCC cells, cell viability and proliferation were measured with MTT and [3H]thymidine assays respectively. Flow cytometry was used to assess cell apoptosis. The level of S-adenosyl methionine (SAMe) in HepG2 cells was evaluated. The expressions of cyclin D1, cyclin D2, bcl-x(L) and bcl-x(S) were detected with western blot. We constructed LV-shMAT2B successfully. LV-shMAT2B was safe for human normal liver cells. LV-shMAT2B caused dramatic reduction in proliferation compared with controls in HCC cells Bel-7402 (P = 0.054) and HepG2 (P = 0.031). Flow cytometry analysis showed that cell apoptosis caused by LV-shMAT2B was greater in HCC cells Bel-7402 and HepG2 than in control induced by scrambled siRNA (P = 0.047), but apoptosis rates in L-02 induced by LV-shMAT2B and scrambled siRNA respectively had no significant difference. Moreover, LV-shMAT2B significantly suppressed expression of MAT2B leading to growth-inhibition effect on HCC cells by down-regulating cyclin D1. Apoptosis induced by LV-shMAT2B was involved in down-regulating bcl-x(L) and up- regulating bcl-x(S). LV-shMAT2B can induce cell apoptosis and growth-inhibition in HCC cells. MAT2B may be a therapy target in HCC in the future.

  7. The evidence for association of ATP2B2 polymorphisms with autism in Chinese Han population.

    Directory of Open Access Journals (Sweden)

    Wen Yang

    Full Text Available BACKGROUND: Autism is a neurodevelopmental disorder with a high estimated heritability. ATP2B2, located on human chromosome 3p25.3, encodes the plasma membrane calcium-transporting ATPase 2 which extrudes Ca(2+ from cytosol into extracellular space. Recent studies reported association between ATP2B2 and autism in samples from Autism Genetic Resource Exchange (AGRE and Italy. In this study, we investigated whether ATP2B2 polymorphisms were associated with autism in Chinese Han population. METHODS: We performed a family based association study between five SNPs (rs35678 in exon, rs241509, rs3774180, rs3774179, and rs2278556 in introns in ATP2B2 and autism in 427 autism trios of Han Chinese descent. All SNPs were genotyped using the Sequenom genotyping platform. The family-based association test (FBAT program was used to perform association test for SNPs and haplotype analyses. RESULTS: This study demonstrated a preferential transmission of T allele of rs3774179 to affected offsprings under an additive model (T>C, Z = 2.482, p = 0.013. While C allele of rs3774179 showed an undertransmission from parents to affected children under an additive and a dominant model, respectively (Z = -2.482, p = 0.013; Z = -2.591, p = 0.0096. Haplotype analyses revealed that three haplotypes were significantly associated with autism. The haplotype C-C (rs3774180-rs3774179 showed a significant undertransmission from parents to affected offsprings both in specific and global haplotype FBAT (Z = -2.037, p = 0.042; Global p = 0.03. As for the haplotype constructed by rs3774179 and rs2278556, C-A might be a protective haplotype (Z = -2.206, p = 0.027; Global p = 0.04, while T-A demonstrated an excess transmission from parents to affected offsprings (Z = 2.143, p = 0.032. These results were still significant after using the permutation method to obtain empirical p values. CONCLUSIONS: Our research suggested that ATP2B2

  8. Red wine and component flavonoids inhibit UGT2B17 in vitro

    Directory of Open Access Journals (Sweden)

    Jenkinson Carl

    2012-09-01

    Full Text Available Abstract Background The metabolism and excretion of the anabolic steroid testosterone occurs by glucuronidation to the conjugate testosterone glucuronide which is then excreted in urine. Alterations in UGT glucuronidation enzyme activity could alter the rate of testosterone excretion and thus its bioavailability. The aim of this study is to investigate if red wine, a common dietary substance, has an inhibitory effect on UGT2B17. Methods Testosterone glucuronidation was assayed using human UGT2B17 supersomes with quantification of unglucuronidated testosterone over time using HPLC with DAD detection. The selected red wine was analyzed using HPLC; and the inhibitory effects of the wine and phenolic components were tested independently in a screening assay. Further analyses were conducted for the strongest inhibitors at physiologically relevant concentrations. Control experiments were conducted to determine the effects of the ethanol on UGT2B17. Results Over the concentration range of 2 to 8%, the red wine sample inhibited the glucuronidation of testosterone by up to 70% over 2 hours. The ethanol content had no significant effect. Three red wine phenolics, identified by HPLC analyses, also inhibited the enzyme by varying amounts in the order of quercetin (72%, caffeic acid (22% and gallic acid (9%; using a ratio of phenolic:testosterone of 1:2.5. In contrast p-coumaric acid and chlorogenic acid had no effect on the UGT2B17. The most active phenolic was selected for a detailed study at physiologically relevant concentrations, and quercetin maintained inhibitory activity of 20% at 2 μM despite a ten-fold excess of testosterone. Conclusion This study reports that in an in vitro supersome-based assay, the key steroid-metabolizing enzyme UGT2B17 is inhibited by a number of phenolic dietary substances and therefore may reduce the rate of testosterone glucuronidation in vivo. These results highlight the potential interactions of a number of common

  9. Disruption of chromosome 11 in canine fibrosarcomas highlights an unusual variability of CDKN2B in dogs.

    Science.gov (United States)

    Aguirre-Hernández, Jesús; Milne, Bruce S; Queen, Chris; O'Brien, Patricia C M; Hoather, Tess; Haugland, Sean; Ferguson-Smith, Malcolm A; Dobson, Jane M; Sargan, David R

    2009-07-31

    In dogs in the western world neoplasia constitutes the most frequently diagnosed cause of death. Although there appear to be similarities between canine and human cancers, rather little is known about the cytogenetic and molecular alterations in canine tumours. Different dog breeds are susceptible to different types of cancer, but the genetic basis of the great majority of these predispositions has yet to be discovered. In some retriever breeds there is a high incidence of soft tissue sarcomas and we have previously reported alterations of chromosomes 11 and 30 in two poorly differentiated fibrosarcomas. Here we extend our observations and present a case report on detail rearrangements on chromosome 11 as well as genetic variations in a tumour suppressor gene in normal dogs. BAC hybridisations on metaphases of two fibrosarcomas showed complex rearrangements on chromosome 11, and loss of parts of this chromosome. Microsatellite markers on a paired tumour and blood DNA pointed to loss of heterozygosity on chromosome 11 in the CDKN2B-CDKN2A tumour suppressor gene cluster region. PCR and sequencing revealed the homozygous loss of coding sequences for these genes, except for exon 1beta of CDKN2A, which codes for the N-terminus of p14ARF. For CDKN2B exon 1, two alleles were observed in DNA from blood; one of them identical to the sequence in the dog reference genome and containing 4 copies of a 12 bp repeat found only in the canine gene amongst all species so far sequenced; the other allele was shorter due to a missing copy of the repeat. Sequencing of this exon in 141 dogs from 18 different breeds revealed a polymorphic region involving a GGC triplet repeat and a GGGGACGGCGGC repeat. Seven alleles were recorded and sixteen of the eighteen breeds showed heterozygosity. Complex chromosome rearrangements were observed on chromosome 11 in two Labrador retriever fibrosarcomas. The chromosome alterations were reflected in the loss of sequences corresponding to two tumour

  10. Disruption of chromosome 11 in canine fibrosarcomas highlights an unusual variability of CDKN2B in dogs

    Directory of Open Access Journals (Sweden)

    Haugland Sean

    2009-07-01

    Full Text Available Abstract Background In dogs in the western world neoplasia constitutes the most frequently diagnosed cause of death. Although there appear to be similarities between canine and human cancers, rather little is known about the cytogenetic and molecular alterations in canine tumours. Different dog breeds are susceptible to different types of cancer, but the genetic basis of the great majority of these predispositions has yet to be discovered. In some retriever breeds there is a high incidence of soft tissue sarcomas and we have previously reported alterations of chromosomes 11 and 30 in two poorly differentiated fibrosarcomas. Here we extend our observations and present a case report on detail rearrangements on chromosome 11 as well as genetic variations in a tumour suppressor gene in normal dogs. Results BAC hybridisations on metaphases of two fibrosarcomas showed complex rearrangements on chromosome 11, and loss of parts of this chromosome. Microsatellite markers on a paired tumour and blood DNA pointed to loss of heterozygosity on chromosome 11 in the CDKN2B-CDKN2A tumour suppressor gene cluster region. PCR and sequencing revealed the homozygous loss of coding sequences for these genes, except for exon 1β of CDKN2A, which codes for the N-terminus of p14ARF. For CDKN2B exon 1, two alleles were observed in DNA from blood; one of them identical to the sequence in the dog reference genome and containing 4 copies of a 12 bp repeat found only in the canine gene amongst all species so far sequenced; the other allele was shorter due to a missing copy of the repeat. Sequencing of this exon in 141 dogs from 18 different breeds revealed a polymorphic region involving a GGC triplet repeat and a GGGGACGGCGGC repeat. Seven alleles were recorded and sixteen of the eighteen breeds showed heterozygosity. Conclusion Complex chromosome rearrangements were observed on chromosome 11 in two Labrador retriever fibrosarcomas. The chromosome alterations were reflected

  11. A loss-of-function and H2B-Venus transcriptional reporter allele for Gata6 in mice.

    Science.gov (United States)

    Freyer, Laina; Schröter, Christian; Saiz, Néstor; Schrode, Nadine; Nowotschin, Sonja; Martinez-Arias, Alfonso; Hadjantonakis, Anna-Katerina

    2015-10-24

    The GATA-binding factor 6 (Gata6) gene encodes a zinc finger transcription factor that often functions as a key regulator of lineage specification during development. It is the earliest known marker of the primitive endoderm lineage in the mammalian blastocyst. During gastrulation, GATA6 is expressed in early cardiac mesoderm and definitive endoderm progenitors, and is necessary for development of specific mesoderm and endoderm-derived organs including the heart, liver, and pancreas. Furthermore, reactivation or silencing of the Gata6 locus has been associated with certain types of cancer affecting endodermal organs. We have generated a Gata6(H2B-Venus) knock-in reporter mouse allele for the purpose of labeling GATA6-expressing cells with a bright nuclear-localized fluorescent marker that is suitable for live imaging at single-cell resolution. Expression of the Venus reporter was characterized starting from embryonic stem (ES) cells, through mouse embryos and adult animals. The Venus reporter was not expressed in ES cells, but was activated upon endoderm differentiation. Gata6(H2B-Venus/H2B-Venus) homozygous embryos did not express GATA6 protein and failed to specify the primitive endoderm in the blastocyst. However, null blastocysts continued to express high levels of Venus in the absence of GATA6 protein, suggesting that early Gata6 transcription is independent of GATA6 protein expression. At early post-implantation stages of embryonic development, there was a strong correlation of Venus with endogenous GATA6 protein in endoderm and mesoderm progenitors, then later in the heart, midgut, and hindgut. However, there were discrepancies in reporter versus endogenous protein expression in certain cells, such as the body wall and endocardium. During organogenesis, detection of Venus in specific organs recapitulated known sites of endogenous GATA6 expression, such as in the lung bud epithelium, liver, pancreas, gall bladder, stomach epithelium, and vascular endothelium

  12. A preliminary study on the use of corporate website in B2B marketing : Focusing on the survey of the person who is working in B2B company

    OpenAIRE

    北見, 幸一

    2011-01-01

    This paper aims to discuss the optimal nature of corporate websites for B2B (Business to Business) marketing. One of the purposes of this study is to suggest further opportunities for research from an internet survey of people working in B2B companies. This study shows that B2B corporate websites are to be valued not only at the awareness stage, but also at the exploration stage. Moreover, it is necessary for B2B corporate websites to have not only detailed information on products and service...

  13. Effect of NIMA-related kinase 2B on the sensitivity of breast cancer to paclitaxel in vitro and vivo.

    Science.gov (United States)

    Wang, Yahong; Shen, Honghong; Yin, Quangui; Zhang, Tongxian; Liu, Ziyu; Zhang, Wei; Niu, Yun

    2017-05-01

    NIMA-related kinase 2B has been known to be an important centrosome regulatory factor. The aim of this study was to investigate the effect of NIMA-related kinase 2B on the sensitivity of breast cancer to paclitaxel. We detected the expression of NIMA-related kinase 2B messenger RNA in MCF-10 cells, including MCF-10A, MCF-10AT, MCF-10DCIS.com , and MCF-10CA1a. The influence of NIMA-related kinase 2B in nude mouse was also detected. The association between NIMA-related kinase 2B and clinicopathological factors was explored in invasive ductal carcinoma tissues. NIMA-related kinase 2B was lowly expressed in the precancerous cells, MCF-10A and MCF-10AT, and it was highly expressed in carcinomatous cells, MCF-10DCIS.com and MCF-10CA1a. The upregulation of NIMA-related kinase 2B can introduce the growth of MCF-10AT cells, knockdown of NIMA-related kinase 2B could remarkably inhibit cell proliferation in MCF-10DCIS.com and MCF-10 CA1a cells. Comparing the volume of the xenografts in nude mouse, we found that the tumors treated by NIMA-related kinase 2B small interfering RNA associated with paclitaxel were the smallest among all the groups. Expression of NIMA-related kinase 2B messenger RNA was associated with higher histological grades, positive lymph node, and high Ki67 index (>20%). The partial response rates were 75.0% in NIMA-related kinase 2B negative (NIMA-related kinase 2B-) patients and 15.8% in NIMA-related kinase 2B++ patients. The progressive disease rates were 10.0% in NIMA-related kinase 2B- patients and 52.6% in NIMA-related kinase 2B++ patients ( p = 0.002). Our findings suggested that NIMA-related kinase 2B could play a role in the development and progression of breast cancer. Combination treatment using NIMA-related kinase 2B small interfering RNA and paclitaxel might be a novel potential therapy method for breast cancer.

  14. Regulation of emotional memory by hydrogen sulfide: role of GluN2B-containing NMDA receptor in the amygdala.

    Science.gov (United States)

    Wang, Can-Ming; Yang, Yuan-Jian; Zhang, Jie-Ting; Liu, Jue; Guan, Xin-Lei; Li, Ming-Xing; Lu, Hai-Feng; Wu, Peng-Fei; Chen, Jian-Guo; Wang, Fang

    2015-01-01

    As an endogenous gaseous molecule, hydrogen sulfide (H2 S) has attracted extensive attention because of its multiple biological effects. However, the effect of H2 S on amygdala-mediated emotional memory has not been elucidated. Here, by employing Pavlovian fear conditioning, an animal model widely used to explore the neural substrates of emotion, we determined whether H2 S could regulate emotional memory. It was shown that the H2 S levels in the amygdala of rats were significantly elevated after cued fear conditioning. Both intraamygdala and systemic administrations of H2 S markedly enhanced amygdala-dependent cued fear memory in rats. Moreover, it was found that H2 S selectively increased the surface expression and currents of NMDA-type glutamate receptor subunit 2B (GluN2B)-containing NMDA receptors (NMDARs) in lateral amygdala of rats, whereas blockade of GluN2B-containing NMDARs in lateral amygdala eliminated the effects of H2 S to enhance amygdalar long-term potentiation and cued fear memory. These results demonstrate that H2 S can regulate amygdala-dependent emotional memory by promoting the function of GluN2B-containing NMDARs in amygdala, suggesting that H2 S-associated signaling may hold potential as a new target for the treatment of emotional disorders. In our study, the effect of hydrogen sulfide (H2 S) on amygdala-mediated emotional memory was investigated. It was found that H2 S could enhance amygdala-dependent emotional memory and long-term potentiation (LTP) in rats by selectively increasing the function of GluN2B-containing NMDA receptors in the amygdala. These results suggest that H2 S-associated signaling may be a new target for the treatment of emotional disorders. © 2014 International Society for Neurochemistry.

  15. Hydroxysteroid sulfotransferase SULT2B1b promotes hepatocellular carcinoma cells proliferation in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Xiaoming Yang

    Full Text Available Hydroxysteroid sulfotransferase 2B1b (SULT2B1b is highly selective for the addition of sulfate groups to 3β-hydroxysteroids. Although previous reports have suggested that SULT2B1b is correlated with cell proliferation of hepatocytes, the relationship between SULT2B1b and the malignant phenotype of hepatocarcinoma cells was not clear. In the present study, we found that SULT2B1 was comparatively higher in the human hepatocarcinoma tumorous tissues than their adjacent tissues. Besides, SULT2B1b overexpression promoted the growth of the mouse hepatocarcinoma cell line Hepa1-6, while Lentivirus-mediated SULT2B1b interference inhibited growth as assessed by the CCK-8 assay. Likewise, inhibition of SULT2B1b expression induced cell-cycle arrest and apoptosis in Hepa1-6 cells by upregulating the expression of FAS, downregulating the expression of cyclinB1, BCL2 and MYC in vitro and in vivo at both the transcript and protein levels. Knock-down of SULT2B1b expression significantly suppressed tumor growth in nude mouse xenografts. Moreover, proliferation rates and SULT2B1b expression were highly correlated in the human hepatocarcinoma cell lines Huh-7, Hep3B, SMMC-7721 and BEL-7402 cells. Knock-down of SULT2B1b inhibited cell growth and cyclinB1 levels in human hepatocarcinoma cells and suppressed xenograft growth in vivo. In conclusion, SULT2B1b expression promotes proliferation of hepatocellular carcinoma cells in vitro and in vivo, which may contribute to the progression of HCC.

  16. Histone demethylase JMJD2B is required for tumor cell proliferation and survival and is overexpressed in gastric cancer

    Energy Technology Data Exchange (ETDEWEB)

    Li, Wenjuan; Zhao, Li; Zang, Wen; Liu, Zhifang; Chen, Long; Liu, Tiantian [Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan 250012 (China); Xu, Dawei, E-mail: Dawei.Xu@ki.se [Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan 250012 (China); Department of Medicine, Division of Hematology, Karolinska University Hospital, Solna and Karolinska Institutet, Stockholm (Sweden); Jia, Jihui, E-mail: jiajihui@sdu.edu.cn [Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan 250012 (China)

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer JMJD2B is required for cell proliferation and in vivo tumorigenesis. Black-Right-Pointing-Pointer JMJD2B depletion induces apoptosis and/or cell cycle arrest. Black-Right-Pointing-Pointer JMJD2B depletion activates DNA damage response and enhances p53 stabilization. Black-Right-Pointing-Pointer JMJD2B is overexpressed in human primary gastric cancer. -- Abstract: Epigenetic alterations such as aberrant expression of histone-modifying enzymes have been implicated in tumorigenesis. Jumonji domain containing 2B (JMJD2B) is a newly identified histone demethylase that regulates chromatin structure or gene expression by removing methyl residues from trimethylated lysine 9 on histone H3. Recent observations have shown oncogenic activity of JMJD2B. We explored the functional role of JMJD2B in cancer cell proliferation, survival and tumorigenesis, and determined its expression profile in gastric cancer. Knocking down JMJD2B expression by small interfering RNA (siRNA) in gastric and other cancer cells inhibited cell proliferation and/or induced apoptosis and elevated the expression of p53 and p21{sup CIP1} proteins. The enhanced p53 expression resulted from activation of the DNA damage response pathway. JMJD2B knockdown markedly suppressed xenograft tumor growth in vivo in mice. Moreover, JMJD2B expression was increased in primary gastric-cancer tissues of humans. Thus, JMJD2B is required for sustained proliferation and survival of tumor cells in vitro and in vivo, and its aberrant expression may contribute to the pathogenesis of gastric cancer.

  17. CDKN2B expression and subcutaneous adipose tissue expandability: Possible influence of the 9p21 atherosclerosis locus

    Energy Technology Data Exchange (ETDEWEB)

    Svensson, Per-Arne; Wahlstrand, Björn; Olsson, Maja [Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg (Sweden); Froguel, Philippe; Falchi, Mario [Department of Genomics of Common Disease, School of Public Health, Imperial College London (United Kingdom); Bergman, Richard N. [Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA (United States); McTernan, Philip G. [Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry (United Kingdom); Hedner, Thomas; Carlsson, Lena M.S. [Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg (Sweden); Jacobson, Peter, E-mail: peter.jacobson@medfak.gu.se [Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg (Sweden)

    2014-04-18

    Highlights: • The tumor suppressor gene CDKN2B is highly expressed in human adipose tissue. • Risk alleles at the 9p21 locus modify CDKN2B expression in a BMI-dependent fashion. • There is an inverse relationship between expression of CDKN2B and adipogenic genes. • CDKN2B expression influences to postprandial triacylglycerol clearance. • CDKN2B expression in adipose tissue is linked to markers of hepatic steatosis. - Abstract: Risk alleles within a gene desert at the 9p21 locus constitute the most prevalent genetic determinant of cardiovascular disease. Previous research has demonstrated that 9p21 risk variants influence gene expression in vascular tissues, yet the biological mechanisms by which this would mediate atherosclerosis merits further investigation. To investigate possible influences of this locus on other tissues, we explored expression patterns of 9p21-regulated genes in a panel of multiple human tissues and found that the tumor suppressor CDKN2B was highly expressed in subcutaneous adipose tissue (SAT). CDKN2B expression was regulated by obesity status, and this effect was stronger in carriers of 9p21 risk alleles. Covariation between expression of CDKN2B and genes implemented in adipogenesis was consistent with an inhibitory effect of CDKN2B on SAT proliferation. Moreover, studies of postprandial triacylglycerol clearance indicated that CDKN2B is involved in down-regulation of SAT fatty acid trafficking. CDKN2B expression in SAT correlated with indicators of ectopic fat accumulation, including markers of hepatic steatosis. Among genes regulated by 9p21 risk variants, CDKN2B appears to play a significant role in the regulation of SAT expandability, which is a strong determinant of lipotoxicity and therefore might contribute to the development of atherosclerosis.

  18. Effects of Hypothyroidism on Expression of CRMP2B and ARPC5 during Development of the Rat Frontal Cortex

    Science.gov (United States)

    Liu, Chun-rong; Miao, Jun; Zhang, Yong-liang; Liu, Ya-min; Yu, Bao-guo

    2013-01-01

    Congenital hypothyroidism (CH) can lead to irreversible central nervous system (CNS) damage. However, the pathogenesis of the developmental brain disorders caused by CH has not been completely elucidated. ARPC5 and CRMP2 are closely associated with neurite outgrowth in brain development. Thus, the aim of the present study was to determine whether CRMP2B and ARPC5 expression is altered in the developing cerebral cortex of rats with CH. Control rats and rats with hypothyroidism were sacrificed at birth and at 15 days postpartum. We performed qRT-PCR to detect differences in the crmp2B and arpc5 mRNA expression in the right half of the frontal cortex of these rats. Western blotting was then used to detect differences in CRMP2B and ARPC5 protein expression. Furthermore, immunohistochemical analysis was performed on the left half of the frontal cortex to detect abnormal localization of CRMP2B and ARPC5. Results showed increased expression of the nuclear short isoform of CRMP2B and decreased expression of full-length CRMP2B and ARPC5 in cortical neurons of rats with hypothyroidism. These findings demonstrate that reduced levels of thyroid hormones can inhibit the expression of full-length CRMP2B and ARPC5 and promote nuclear transformation of the short isoform of CRMP2B. CRMP2B and ARPC5 may participate in CNS injury mediated by hypothyroidism by inducing neurite outgrowth inhibition and cytoskeletal protein disorganization. PMID:23459330

  19. Evolving role of 2B4/CD244 in T and NK cell responses during virus infection

    Directory of Open Access Journals (Sweden)

    Stephen Noel Waggoner

    2012-12-01

    Full Text Available The signaling lymphocyte activation molecule (SLAM family receptor, 2B4/CD244, was first implicated in anti-viral immunity by the discovery that mutations of the SLAM-associated protein, SAP/SH2D1A, impaired 2B4-dependent stimulation of T and natural killer (NK cell anti-viral functions in X-linked lymphoproliferative (XLP syndrome patients with uncontrolled Epstein-Barr virus (EBV infections. Engagement of 2B4 has been variably shown to either activate or inhibit lymphocytes which express this receptor. While SAP expression is required for stimulatory functions of 2B4 on lymphocytes, it remains unclear whether inhibitory signals derived from 2B4 can predominate even in the presence of SAP. Regardless, mounting evidence suggests that 2B4 expression by NK and CD8 T cells is altered by virus infection in mice as well as in humans, and 2B4-mediated signaling may be an important determinant of effective immune control of chronic virus infections. In this review, recent findings regarding the expression and function of 2B4 as well as SAP on T and NK cells during virus infection is discussed, with a focus on the role of 2B4-CD48 interactions in crosstalk between innate and adaptive immunity.

  20. Electronic structure and magnetism of layered compounds SrBO2 (B = Ni, Co, Mn): A theoretical investigation

    Science.gov (United States)

    Rahman, Mavlanjan; Zhou, Ke-Chao; Nie, Yao-Zhuang; Guo, Guang-Hua

    2017-10-01

    We investigate the electronic structure and magnetic properties of layered compounds SrBO2 (B = Co, Ni, Mn) based on first principles calculations in the framework of density functional theory with GGA+U method. We compute the phonon dispersion of these compounds to probe the dynamical stability and find that all the compounds are dynamically stable. SrCoO2 and SrNiO2 are G-type antiferromagnetic insulators, and SrMnO2 is an A-type antiferromagnetic conductor. The electronic configurations of 3d orbitals are (dxz)2(dz2)2(dyz)1(dxy)1(dx2-y2)1 and (dxz)2(dyz)2(dz2)2(dxy)1(dx2-y2)1 in SrCoO2 and SrNiO2, respectively. SrCoO2 shows a Jahn-Teller distortion (a>b) because the down-spin Co 3d electron occupies the degenerate (dxz, dyz) levels. Using Monte Carlo simulations based on the Heisenberg model with exchange parameters obtained from first principles calculations, we obtain the Néel temperatures (TN) of SrCoO2 and SrNiO2, which are 249 K and 85 K, respectively.

  1. Histone H2A and H2B are monoubiquitinated at AID-targeted loci.

    Directory of Open Access Journals (Sweden)

    Glen M Borchert

    Full Text Available BACKGROUND: Somatic hypermutation introduces base substitutions into the rearranged and expressed immunoglobulin (Ig variable regions to promote immunity. This pathway requires and is initiated by the Activation Induced Deaminase (AID protein, which deaminates cytidine to produce uracils and UG mismatches at the Ig genes. Subsequent processing of uracil by mismatch repair and base excision repair factors contributes to mutagenesis. While selective for certain genomic targets, the chromatin modifications which distinguish hypermutating from non-hypermutating loci are not defined. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that AID-targeted loci in mammalian B cells contain ubiquitinated chromatin. Chromatin immunoprecipitation (ChIP analysis of a constitutively hypermutating Burkitt's B cell line, Ramos, revealed the presence of monoubiquitinated forms of both histone H2A and H2B at two AID-associated loci, but not at control loci which are expressed but not hypermutated. Similar analysis using LPS activated primary murine splenocytes showed enrichment of the expressed V(H and Sgamma3 switch regions upon ChIP with antibody specific to AID and to monoubiquitinated H2A and H2B. In the mechanism of mammalian hypermutation, AID may interact with ubiquitinated chromatin because confocal immunofluorescence microscopy visualized AID colocalized with monoubiquitinated H2B within discrete nuclear foci. CONCLUSIONS/SIGNIFICANCE: Our results indicate that monoubiquitinated histones accompany active somatic hypermutation, revealing part of the histone code marking AID-targeted loci. This expands the current view of the chromatin state during hypermutation by identifying a specific nucleosome architecture associated with somatic hypermutation.

  2. The Preparation and Characterization of INTEC Phase 2b Composition Variation Study Glasses

    Energy Technology Data Exchange (ETDEWEB)

    B. A. Staples; B. A. Scholes; L. L. Torres; C. A. Musick; B. R. Boyle (INEEL); D. K. Peeler (SRTC); J. D. Vienna (PNNL)

    2000-02-01

    The second phase of the composition variation study (CVS) for the development of glass compositions to immobilize Idaho Nuclear Technology and Engineering Center (INTEC) high level wastes (HLW) is complete. This phase of the CVS addressed waste composition of high activity waste fractions (HAW) from the initial separations flowsheet. Updated estimates if INTEC calcined HLW compositions and of high activity waste fractions proposed to be separated from dissolved calcine were used as the waste component for this CVS phase. These wastes are of particular interest because high aluminum, calcium, zirconium, fluorine, potassium, and low iron and sodium content places them outside the vitrification experience in the Department of Energy complex. Because of the presence of calcium and fluorine, two major zirconia calcine components not addressed in Phase I, a series of scooping tests, designated Phase 2a, were performed. The results of these tests provided information on the effects of calcium and fluoride solubility and their impacts on product properties and composition boundary information for Phase 2b. Details and results of Phase 2a are reported separately. Through application of statistical techniques and the results of Phase 2a, a test matrix was defined for Phase 2b of the CVS. From this matrix, formulations were systematically selected for preparation and characterization with respect to visual and optical homogeneity, viscosity as a function of melt temperature, liquidus temperature (TL), and leaching properties based on response to the product consistency test. The results of preparing and characterizing the Phase 2b glasses are presented in this document. Based on the results, several formulations investigated have suitable properties for further development. A full analysis of the composition-product characteristic relationship of glasses being developed for immobilizing INTEC wastes will be performed at the completion of composition-property relationship

  3. Propofol inhibits LPS-induced apoptosis in lung epithelial cell line, BEAS-2B.

    Science.gov (United States)

    Lv, Xiang; Zhou, Xuhui; Yan, Jia; Jiang, Jue; Jiang, Hong

    2017-03-01

    Lipopolysaccharide (LPS) plays an important role in lung endothelial apoptosis which is crucial for lung fibrogenesis in ARDS progression. Reactive oxygen species (ROS) has been reported to be involved in LPS-induced lung epithelial cell apoptosis. Propofol is a commonly used intravenous anesthetic agent in clinic and it could attenuate LPS-induced epithelial cells oxidation and apoptosis. However, the mechanisms are still obscure. In this study, we examined whether and how propofol attenuates LPS-induced oxidation and apoptosis in BEAS-2B cells. Compared with control group, LPS up-regulated Pin-1, phosphatase A2 (PP2A) expression, induced p66Shc-Ser36 phosphorylation, and facilitated p66Shc mitochondrial translocation, thus leading to superoxide anion (O2-) generation, mitochondrial cytochrome c release, active caspase 3 over-expression and cell viability inhibition. Importantly, propofol was shown to down-regulate LPS-induced PP2A expression, limit p66Shc mitochondrial translocation, decrease O2- generation, inhibit mitochondrial cytochrome c release, reduce active caspase 3 expression, and recover cells viability, while propofol had no effects on LPS-induced Pin-1 expression and p66Shc-Ser36 phosphorylation. Moreover, the protective effects of propofol on LPS-induced BEAS-2B cells apoptosis were similar to that of calyculin A, which is an inhibitor of PP2A. We also found that FTY720, which is an activator of PP2A, can effectively reverse the protective function of propofol. Our data illustrated that propofol could alleviate LPS-induced BEAS-2B cells oxidation and apoptosis through down-regulating PP2A expression, limiting p66Shc-Ser36 dephosphorylation and p66Shc mitochondrial translocation, decreasing O2- generation, mitochondrial cytochrome c release, activating caspase 3 expression. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  4. B2B inter-organisational digitalisation strategies - towards an interaction based approach

    DEFF Research Database (Denmark)

    Ivang, Reimer; Rask, Morten; Hinson, Robert

    2009-01-01

    utilising the digital technology successfully mostly organised their strategic work as described in the interaction approach to digitalisation strategy. Practical value: Study demonstrates a pragmatic route to deepening digitalization success in large firm with considerable e-business investments...... and implemented. Lastly this is one of the few studies utilizing degree of freedom analysis to understand digitalization strategy.......Purpose: Digital technology is increasingly important for businesses as it has the capability to enable, support and sometimes influence the overall strategic direction of the corporation. This paper investigates b2b inter-organisational digitalisation strategies in one of Denmark's biggest...

  5. INACTIVITY OF RECOMBINANT ELA2B PROVIDES A NEW EXAMPLE OF EVOLUTIONARY ELASTASE SILENCING IN HUMANS

    OpenAIRE

    Szepessy, Edit; Sahin-Tóth, Miklós

    2005-01-01

    BACKGROUND. The archetypal mammalian elastase (ELA1) is not expressed in the human pancreas, because evolutionary mutations suppressed transcription of the ELA1 gene. AIMS. In this study we tested the theory that the unique duplication of the ELA2 gene in humans might compensate for the loss of ELA1. METHODS. Recombinant ELA2A and ELA2B were expressed in Escherichia coli, and their activity was tested on Glt-Ala-Ala-Pro-Leu-p-nitroanilide, DQ elastin and bovine milk protein. RESULTS. Surprisi...

  6. Markkinointihyödyn saavuttaminen B2B-sisältömarkkinoinnilla asiantuntijaorganisaatiossa

    OpenAIRE

    Hokkanen, Ossi

    2017-01-01

    Tämän opinnäytetyön aiheena oli sisältömarkkinointi ja pienen yrityksen tunnettuuden lisääminen tuottamalla sisältöjä sosiaalisen median kanaviin. Työn tarkoituksena oli selvittää B2B-asiantuntijayrityksen näkökulmasta katsottuna, minkälaista sisältöä eri sosiaalisen median kanaville tulisi tuottaa, jotta niillä saavutettaisiin mahdollisimman suuri markkinointihyöty. Tämän perusteella luotiin suunnitelmat eri kanavia varten, sekä niihin liittyen konkreettiset toteutusaskeleet. Opinnäytety...

  7. Anomalous vortex dynamics in YNi{sub 2}B{sub 2}C

    Energy Technology Data Exchange (ETDEWEB)

    Okuma, S., E-mail: sokuma@o.cc.titech.ac.j [Research Center for Low Temperature Physics, Tokyo Institute of Technology, 2-12-1, Ohokayama, Meguro-ku, Tokyo 152-8551 (Japan); Ichimura, T. [Research Center for Low Temperature Physics, Tokyo Institute of Technology, 2-12-1, Ohokayama, Meguro-ku, Tokyo 152-8551 (Japan); Takeya, H.; Hirata, K. [National Institute for Materials Science, 1-2-1, Sengen, Tsukuba, Ibaraki 305-0047 (Japan)

    2009-10-15

    We report on measurements of current-voltage (I-V) characteristics for YNi{sub 2}B{sub 2}C single crystals with weak pinning in various fields at 7.6 K. We find nonmonotonic, N-shaped I-V curves in a certain field region deep in the vortex solid phase. This behavior is anomalous, since there exists an intermediate I region where flow voltage V shows a decrease with increasing I (a driving force). While the exact nature remains unknown, this phenomenon suggests vortex motion (driving I) induced pinning.

  8. Unusual pinning induced by vortex motion in YNi{sub 2}B{sub 2}C

    Energy Technology Data Exchange (ETDEWEB)

    Okuma, S., E-mail: sokuma@o.cc.titech.ac.j [Research Center for Low Temperature Physics, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8551 (Japan); Ichimura, T. [Research Center for Low Temperature Physics, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8551 (Japan); Takeya, H.; Hirata, K. [National Institute for Materials Science, 1-2-1, Sengen, Tsukuba, Ibaraki 305-0047 (Japan)

    2010-12-15

    We present measurements of current-voltage (I-V) characteristics and voltage noise S{sub V} generated by current-driven vortices for a YNi{sub 2}B{sub 2}C single crystal with weak-pinning. Nonmonotonic, N-shaped I-V curves are observed deep in the vortex-solid phase. In the intermediate I region where the unusual negative dV/dI is observed, S{sub V} exhibits a sharp peak. The result suggests vortex-motion-induced dynamic pinning.

  9. Peginterferon alpha-2a versus peginterferon alpha-2b for chronic hepatitis C

    DEFF Research Database (Denmark)

    Hauser, Goran; Awad, Tahany; Thorlund, Kristian

    2014-01-01

    : We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and LILACS until October 2013. We also searched conference abstracts, journals, and grey...... literature. SELECTION CRITERIA: We included randomised clinical trials comparing peginterferon alpha-2a versus peginterferon alpha-2b given with or without co-intervention(s) (for example, ribavirin) for chronic hepatitis C. Quasi-randomised studies and observational studies as identified by the searches...

  10. Sociala Medier som kommunikationskanal för B2B-företag

    OpenAIRE

    Kaddura, Layla; Olsson, Karin

    2010-01-01

    The purpose of this thesis is to show what advantages and opportunities social media offer for B2B-companies (business-to-business), and how they can be used for marketing communications. We have studied how companies can use social media, for example evolving the organization, developing products/services, staying up-to-date, building relations, creating customer loyalty and engagement, building the company’s identity and image, and affecting the buying decisions. We have also studied how B2...

  11. DC motors and servo-motors controlled by Raspberry Pi 2B

    Directory of Open Access Journals (Sweden)

    Šustek Michal

    2017-01-01

    Full Text Available The expanding capabilities of today’s microcontrollers and other devices lead to an increased utilization of these technologies in diverse fields. The automation and issue of remote control of moving objects belong to these fields. In this project, a microcontroller Raspberry Pi 2B was chosen for controlling DC motors and servo-motors. This paper provides basic insight into issue of controlling DC motors and servo-motors, connection between Raspberry and other components on breadboard and programming syntaxes for controlling motors in Python programming language.

  12. Theoretical study of the 2A 2 2B 2 separation of the alkali superoxides

    Science.gov (United States)

    Bauschlicher, Charles W., Jr.; Sodupe, Mariona; Partridge, Harry; Langhoff, Stephen R.

    1992-09-01

    The computed 2A 2 2B 2 separations of the alkali superoxides are in good agreement with those deduced from electron-spin resonance spectra. The calculations definitively show that the ground state of CsO 2 is 2A 2. The larger than expected separation for CsO 2, based on the trend from LiO 2 to RbO 2, is attributed primarily to the differential effects of core relaxation. The CsO 2 dissociation energy is computed to be 42.7 kcal/mol, with an uncertainty conservatively estimated as ±4 kcal/mol.

  13. Synthesis and fluorosolvatochromism of 3-arylnaphtho[1,2-b]quinolizinium derivatives

    Directory of Open Access Journals (Sweden)

    Phil M. Pithan

    2016-05-01

    Full Text Available Cationic biaryl derivatives were synthesized by Suzuki–Miyaura coupling of 3-bromonaphtho[1,2-b]quinolizinium bromide with arylboronic acids. The resulting cationic biaryl derivatives exhibit pronounced fluorosolvatochromic properties. First photophysical studies in different solvents showed that the emission energy of the biaryl derivatives decreases with increasing solvent polarity. This red-shifted emission in polar solvents is explained by a charge shift (CS in the excited state and subsequent solvent relaxation. Furthermore, the polarity of protic polar and aprotic polar solvents affects the emission energy to different extent, which indicates a major influence of hydrogen bonding on the stabilization of the ground and excited states.

  14. Pauli paramagnetic effects on vortices in superconducting TmNi2B2C

    DEFF Research Database (Denmark)

    DeBeer-Schmitt, L.; Eskildsen, Morten Ring; Ichioka, M.

    2007-01-01

    The magnetic field distribution around the vortices in TmNi2B2C in the paramagnetic phase was studied experimentally as well as theoretically. The vortex form factor, measured by small-angle neutron scattering, is found to be field independent up to 0.6H(c2) followed by a sharp decrease at higher...... fields. The data are fitted well by solutions to the Eilenberger equations when paramagnetic effects due to the exchange interaction with the localized 4f Tm moments are included. The induced paramagnetic moments around the vortex cores act to maintain the field contrast probed by the form factor....

  15. Common Variants in the ATP2B1 Gene Are Associated With Susceptibility to Hypertension

    Science.gov (United States)

    Tabara, Yasuharu; Kohara, Katsuhiko; Kita, Yoshikuni; Hirawa, Nobuhito; Katsuya, Tomohiro; Ohkubo, Takayoshi; Hiura, Yumiko; Tajima, Atsushi; Morisaki, Takayuki; Miyata, Toshiyuki; Nakayama, Tomohiro; Takashima, Naoyuki; Nakura, Jun; Kawamoto, Ryuichi; Takahashi, Norio; Hata, Akira; Soma, Masayoshi; Imai, Yutaka; Kokubo, Yoshihiro; Okamura, Tomonori; Tomoike, Hitonobu; Iwai, Naoharu; Ogihara, Toshio; Inoue, Itsuro; Tokunaga, Katsushi; Johnson, Toby; Caulfield, Mark; Munroe, Patricia; Umemura, Satoshi; Ueshima, Hirotsugu; Miki, Tetsuro

    2016-01-01

    Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3×10−5; allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1×10−11). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9×10−4). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4×10−18). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6×10−7) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension. PMID:20921432

  16. Advanced complex analysis a comprehensive course in analysis, part 2b

    CERN Document Server

    Simon, Barry

    2015-01-01

    A Comprehensive Course in Analysis by Poincaré Prize winner Barry Simon is a five-volume set that can serve as a graduate-level analysis textbook with a lot of additional bonus information, including hundreds of problems and numerous notes that extend the text and provide important historical background. Depth and breadth of exposition make this set a valuable reference source for almost all areas of classical analysis. Part 2B provides a comprehensive look at a number of subjects of complex analysis not included in Part 2A. Presented in this volume are the theory of conformal metrics (includ

  17. Targeting Sulfotransferase (SULT) 2B1b as a Regulator of Cholesterol Metabolism in Prostate Cancer

    Science.gov (United States)

    2015-10-01

    designing a tet- inducible CRISPR /CAS9-based method to directly edit the genome by inserting LoxP sites flanking critical exon(s) in the SULT2b1b gene and...suppressed growth and greatly enhanced cell death, we performed further analysis to Figure 3. LNCaP cells were transfected with indicated siRNA...until we can generate the stable inducible cell lines using the CRISPR /CAS9 method described above in subtask 2. Major Task 4: Development  of

  18. Finanssialan B2B-demoasiakastietokannan luominen opetuskäyttöön

    OpenAIRE

    Nevalainen, Vilma; Hyrkäs, Suvi

    2013-01-01

    Asiakkuudenhallinnasta on tullut merkittävä osa yritysten liiketoimintaa ja myyntiprosessia. Asiakkuudenhallinnan avuksi on kehitetty erilaisia CRM-ohjelmia, joihin voidaan tallentaa runsaasti tietoja asiakkaista. Pankeissa asiakkuudenhallinta on ollut läsnä useita vuosia, ja pankeilla on käytössään räätälöityjä CRM-ohjelmaratkaisuja. Tämä produktityyppinen opinnäytetyö on tehty toimeksiantona HAAGA-HELIA ammattikorkeakoululle. Tavoitteena on ollut luoda realistinen finanssialan B2B-demoa...

  19. ScRu2B3 and Sc2RuB6: Borides Featuring a 2D Infinite Boron Clustering.

    Science.gov (United States)

    Salamakha, Leonid P; Sologub, Oksana; Stöger, Berthold; Rogl, Peter Franz; Waas, Monika; Kapustianyk, Volodymyr B; Bauer, Ernst

    2017-09-05

    Two borides, ScRu2B3 and Sc2RuB6, were obtained by argon-arc melting of the elements followed by annealing at 800 °C. ScRu2B3 exhibits a new structure type with the space group Cmcm (a = 3.0195(2) Å, b = 15.4056(8) Å, c = 5.4492(3) Å; single crystal X-ray data; RF(2) = 0.0105). Sc2RuB6 adopts the Y2ReB6-type structure (space group Pbam; a = 8.8545(2) Å, b = 11.1620(3) Å, c = 3.4760(1) Å; single crystal X-ray data; RF(2) = 0.0185). ScRu2B3 displays an unusual intergrowth of CeCo3B2- and AlB2-related slabs; a striking feature is a boat configuration of puckered boron hexagons within infinite graphite like boron layers (6(3) nets). Sc2RuB6 presents two-dimensional planar nets of condensed boron pentagons, hexagons, and heptagons sandwiched between metal layers. In Sc/Y substituted Y2ReB6-type, Y atoms are distributed exclusively inside the boron heptagons. Exploration of the Sc-Ru-B system at 800 °C including binary boundaries employing EPMA and powder X-ray diffraction technique furthermore rules out the existence of previously reported "ScRuB4" but confirms the formation and crystal structure of Sc2Ru5B4. ScRu4B4 forms in cast alloys (LuRu4B4-type structure; space group I41/acd (No. 142), a = 7.3543(2) Å, c = 14.92137(8) Å). Cell parameters and atomic coordinates have been refined for ScRu2B3, Sc2RuB6, and ScRu4B4 in the scope of the generalized gradient approximation. Ab initio electronic structure calculations indicate a moderate electronic density of states at the Fermi level situated near the upper edge of essentially filled d-bands. Electrical resistivity measurements characterize ScRu2B3 and Sc2RuB6 as metals in concord with electronic band structure calculations.

  20. Mutation of SH2B3 (LNK), a GWAS candidate for hypertension, attenuates Dahl SS hypertension via inflammatory modulation

    Science.gov (United States)

    Rudemiller, Nathan P.; Lund, Hayley; Priestley, Jessica R. C.; Endres, Bradley T.; Prokop, Jeremy W.; Jacob, Howard J.; Geurts, Aron M.; Cohen, Eric P.; Mattson, David L.

    2015-01-01

    Human genome wide association studies (GWAS) have linked SH2B3 (LNK) to hypertension and renal disease, though little experimental investigation has been done to verify a role for SH2B3 in these pathologies. SH2B3, a member of the SH2B adaptor protein family, is an intracellular adaptor protein that functions as a negative regulator in many signaling pathways, including inflammatory signaling processes. To explore a mechanistic link between SH2B3 and hypertension, we targeted the SH2B3 gene for mutation on the Dahl salt-sensitive (SS) rat genetic background with zinc-finger nucleases (ZFN). The resulting mutation was a 6 base-pair, in-frame deletion within a highly-conserved region of the Src Homology 2 (SH2) domain of SH2B3. This mutation significantly attenuated Dahl salt-sensitive (SS) hypertension and renal disease. Also, infiltration of leukocytes into the kidneys, a key mediator of Dahl SS pathology, was significantly blunted in the Sh2b3em1Mcwi mutant rats. To determine if this was due to differences in immune signaling, bone marrow transplant studies were performed in which Dahl SS and Sh2b3em1Mcwi mutants underwent total body irradiation and were then transplanted with Dahl SS or Sh2b3em1Mcwi mutant bone marrow. Rats that received Sh2b3em1Mcwi mutant bone marrow had a significant reduction in mean arterial pressure and kidney injury when placed on a high salt diet (4% NaCl). These data further support a role for the immune system as a modulator of disease severity in the pathogenesis of hypertension and provide insight into inflammatory mechanisms at play in human hypertension and renal disease. PMID:25776069