Induction of endothelial PAS domain protein-1 by hypoxia: Characterization and comparison with hypoxia-inducible factor-1 alpha

Hypoxia results in adaptive changes in the transcription of a range of genes including erythropoietin. An important mediator is hypoxia-inducible factor-1 (HIF-1), a DNA binding complex shown to contain at least two basic helix-loop-helix PAS-domain (bHLH-PAS) proteins, HIF-1 alpha and aryl hydrocarbon nuclear receptor translocator (ARNT), In response to hypoxia, HIF-1 alpha is activated and accumulates rapidly in the cell. Endothelial PAS domain protein 1 (EPAS-1) is a recently identified bHLH-PAS protein with 48% identity to HIF-1 alpha, raising the question of its role in responses to hypoxia. We developed specific antibodies and studied expression and regulation of EPAS-1 mRNA and protein across a range of human cell lines. EPAS-1 was widely expressed, and strongly induced by hypoxia at the level of protein but not mRNA. Comparison of the effect of a range of activating and inhibitory stimuli showed striking similarities in the EPAS-1 and HIF-1 alpha responses. Although major differences were observed in the abundance of EPAS-1 and HIF-1 alpha in different cell types, differences in the inducible response were subtle with EPAS-1 protein being slightly more evident in normoxic and mildly hypoxic cells. Functional studies in a mutant cell line (Ka13) expressing neither HIF-1 alpha nor EPAS-1 confirmed that both proteins interact with hypoxically responsive targets, but suggest target specificity with greater EPAS-1 transactivation (relative to HIF-1 alpha transactivation) of the VEGF promoter than the LDH-A promoter. (C) 1998 by The American Society of Hematology.

Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus

Purpose. Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease. Methods. Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype. Results. The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 × 10 ). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 × 10 ) and rs17501108 (P = 9.9 × 10 ). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036). Conclusions. Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

Gingival fibroblast response to cyclosporin A and transforming growth factor beta(1)

This study investigates a potential role for TGF beta(1), in the pathogenesis of cyclosporin A-induced gingival overgrowth (CsA-OG). TGF beta(1) was localized immunohistochemically in the connective tissue of both normal gingiva and CsA-OG. Intense staining for TGF beta(1) was detected at the tips of the dermal papillae of the overgrown gingiva. In addition, fibroblasts derived from healthy gingiva and fibroblasts derived from CsA-OG were cultured both as monolayers or embedded in a 3D-collagen gel. Fibroblast activity was monitored in terms of protein and collagen production in the presence of (i) 1 ng/ml TGF beta(1), (ii) 500 ng/ml CsA, or (iii) 500 ng/ml CsA and 1 ng/ml TGF beta(1). In monolayer culture TGF beta(1) significantly increased protein and collagen production in all cell strains (p

Trauma typology as a risk factor for aggression and self-harm in a complex PTSD population: The mediating role of alterations in self-perception

This study examined the role of prolonged, repeated traumatic experiences such as childhood and sectarian trauma in the development of posttraumatic aggression and self-harm. Forty-four adult participants attending therapy for complex trauma in Northern Ireland were obtained via convenience sampling. When social desirability was controlled, childhood emotional and physical neglect were significant correlates of posttraumatic hostility and history of self-harm. These relationships were mediated by alterations in self-perception (e.g., shame, guilt). Severity of sectarian-related experiences was not related to self-destructive behaviors. Moreover, none of the trauma factors were related to overt aggressive behavior. The findings have implications for understanding risk factors for posttraumatic aggression and self-harm, as well as their treatment. © 2013 Copyright Taylor & Francis Group, LLC.

The association between complement component 2/complement factor B polymorphisms and age-related macular degeneration: A HuGE review and meta-analysis

The authors performed a systematic review of the association of complement component 2(C2)/complement factor B (CFB) gene polymorphisms with age-related macular degeneration (AMD). In total, data from 19 studies published between 2006 and 2011 were pooled for 4 polymorphisms: rs9332739 and rs547154 in the C2 gene and rs4151667 and rs641153 in the CFB gene. Data extraction and assessments for risk of bias were independently performed by 2 reviewers. Allele frequencies and allele and genotypic effects were pooled. Heterogeneity and publication bias were explored. Pooled minor allele frequencies for all 4 SNPs were between 4.7% and 9.6% for all polymorphisms, except for an Indian population in which the C allele at rs9332739 was the major allele. For the C2 polymorphisms, the minor C allele at rs9332739 and the minor T allele at rs547154 carried estimated relative risks (odds ratios) of 0.55 (95% confidence interval (CI): 0.46, 0.65) and 0.47 (95% CI: 0.39, 0.57), respectively. For the CFB polymorphisms, the minor A alleles at rs4151667 and rs614153 carried estimated risks of 0.54 (95% CI: 0.45, 0.64) and 0.41 (95% CI: 0.34, 0.51), respectively. These allele effects contributed to an absolute lowering of the risk of all AMD in Caucasian populations by 2.0%-6.0%. This meta-analysis provides a robust estimate of the protective association of C2/CFB with AMD.

“An Examination of the Key Factor of Influence In the Development Process of Credit Union Industries,”

The aim of this paper is to analyse credit union industries within a development framework. Explicit consideration is given to credit union industries in four countries – Great Britain, Ireland, New Zealand and the United States. It is argued that in terms of a developmental typology the credit union industry in Great Britain is at a nascent stage of development, the industries in Ireland and New Zealand are at a transition stage while the US credit union industry is mature in nature. In progression between stages the analysis considers the influence of factors such as situational leadership, the complexion of trade associations, professionalisation, regulatory and legislative initiatives and technology. The analysis concluded that while there was a substantial commonality of experience, there were also significant differences in the impact of these factors. This consequently encouraged the recognition of the existence of ‘a variety of the species’ in respect of credit union development.

Genomic instability in human lymphocytes irradiated with individual charged particles: Involvement of tumor necrosis factor a in irradiated cells but not bystander cells

Exposure to ionizing radiation can increase the risk of cancer, which is often characterized by genomic instability. In environmental exposures to high-LET radiation (e.g. Ra-222), it is unlikely that many cells will be traversed or that any cell will be traversed by more than one alpha particle, resulting in an in vivo bystander situation, potentially involving inflammation. Here primary human lymphocytes were irradiated with precise numbers of He-3(2+) ions delivered to defined cell population fractions, to as low as a single cell being traversed, resembling in vivo conditions. Also, we assessed the contribution to genomic instability of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFA). Genomic instability was significantly elevated in irradiated groups ( greater than or equal totwofold over controls) and was comparable whether cells were traversed by one or two He-3(2+) ions. Interestingly, substantial heterogeneity in genomic instability between experiments was observed when only one cell was traversed. Genomic instability was significantly reduced (60%) in cultures in which all cells were irradiated in the presence of TNFA antibody, but not when fractions were irradiated under the same conditions, suggesting that TNFA may have a role in the initiation of genomic instability in irradiated cells but not bystander cells. These results have implications for low-dose exposure risks and cancer. (C) 2005 by Radiation Research Society.