Reproductive toxins and alligator abnormalities at Lake Apopka, Florida.

The alligator population at Lake Apopka in central Florida declined dramatically between 1980 and 1987. Endocrine-disrupting chemicals and specifically DDT metabolites have been implicated in the alligators' reproductive failure. The DDT metabolite hypothesis is based largely on the observation of elevated concentrations of p,p-DDE and p,p-DDD in alligator eggs obtained from Lake Apopka in 1984 and 1985. In the following commentary, we draw attention to two nematocides that are established reproductive toxins in humans, dibromochloropropane (DBCP) and ethylene dibromide (EDB), which could also have played a role in the reproductive failure observed in alligators from Lake Apopka in the early 1980s

MicroRNA-22 Regulates Hypoxia Signaling in Colon Cancer Cells

MicroRNAs (MiRNAs) are short, non-coding RNA that regulate a variety of cellular functions by suppressing target protein expression. We hypothesized that a set of microRNA regulate tumor responses to hypoxia by inhibiting components of the hypoxia signaling pathway. We found that miR-22 expression in human colon cancer is lower than in normal colon tissue. We also found that miR-22 controls hypoxia inducible factor 1α (HIF-1α) expression in the HCT116 colon cancer cell line. Over-expression of miR-22 inhibits HIF-1α expression, repressing vascular endothelial growth factor (VEGF) production during hypoxia. Conversely, knockdown of endogenous miR-22 enhances hypoxia induced expression of HIF-1α and VEGF. The conditioned media from cells over-expressing miR-22 contain less VEGF protein than control cells, and also induce less endothelial cell growth and invasion, suggesting miR-22 in adjacent cells influences endothelial cell function. Taken together, our data suggest that miR-22 might have an anti-angiogenic effect in colon cancer

Self-reported access to health care, communicable diseases, violence and perception of legal status among online transgender identifying sex workers in the UK.

OBJECTIVES: Transgender-identifying sex workers (TGISWs) are among the most vulnerable groups but are rarely the focus of health research. Here we evaluated perceived barriers to healthcare access, risky sexual behaviours and exposure to violence in the United Kingdom (UK), based on a survey of all workers on BirchPlace, the main transgender sex commerce website in the UK. STUDY DESIGN: The study design used in the study is an opt-in text-message 12-item questionnaire. METHODS: Telephone contacts were harvested from BirchPlace's website (n = 592 unique and active numbers). The questionnaire was distributed with Qualtrics software, resulting in 53 responses. RESULTS: Our survey revealed significant reported barriers to healthcare access, exposure to risky sexual behaviours and to physical violence. Many transgender sex workers reportedly did not receive a sexual screening, and 28% engaged in condomless penetrative sex within the preceding six months, and 68% engaged in condomless oral sex. 17% responded that they felt unable to access health care they believed medically necessary. Half of the participants suggested their quality of life would be improved by law reform. CONCLUSIONS: TGISWs report experiencing a high level of risky sexual behaviour, physical violence and inadequate healthcare access. Despite a National Health System, additional outreach may be needed to ensure access to services by this population.ECD

Blood and bones: Osteoblastic HIF signaling regulates erythropoiesis

Comment on: Rankin EB, et al. Cell 2012; 149:63-74

Roles of Coactivators in Hypoxic Induction of the Erythropoietin Gene

Hypoxia-inducible expression of the erythropoietin (EPO) gene is mediated principally by hypoxia-inducible factor 2alpha (HIF-2alpha) in Hep3B cells under physiologic conditions. How/whether p300/CBP and the members of p160 coactivator family potentiate hypoxic induction of endogenous EPO and other HIF-2alpha and hypoxia-inducible factor 1alpha (HIF-1alpha) target genes remains unclear.We demonstrate, using chromatin immunoprecipitation (ChIP) analysis, that the histone acetyl transferase (HAT) coactivators p300, SRC-1 and SRC-3 are recruited to the 3' enhancer of the EPO gene upon hypoxic stimulation, and that each associates with the enhancer in a periodic fashion. Hypoxia induced acetylation of the EPO gene 5' promoter at histone 4 and lysine 23 of histone 3. Knocking down SRC-3, but not SRC-1 or SRC-2, using short interfering RNAs (siRNAs), reduced EPO transcriptional activity. Knocking down p300 resulted in dramatic down-regulation of hypoxic stimulation of EPO gene transcription, negated recruitment of RNA polymerase II to the gene's promoter, and eliminated hypoxia-stimulated acetylation at the promoter and recruitments of SRC-1 and SRC-3 to the enhancer. The inhibitory effects of knocking down p300 and the chromatin remodeling coactivator, Brm/Brg-1, on EPO transcription were additive, suggesting that p300 and Brm/Brg-1 act independently. p300 was also required for hypoxia induced transcription of the HIF-1alpha target gene, VEGF, but was dispensable for induction of two other HIF-1alpha target genes, PGK and LDHA. Knocking down CBP, a homolog of p300, augmented hypoxic induction of VEGF, LDHA and PGK. Different HIF target genes also exhibited different requirements for members of the p160 coactivator family.p300 plays a central coactivator role in hypoxic induction of EPO. The coactivators exhibit different specificities for different HIF target genes and each can behave differently in transcriptional regulation of different target genes mediated by the same transcription factor

School life expectancy and risk for tuberculosis in Europe.

OBJECTIVE: This study aims to investigate the effect of country-level school life expectancy on Tuberculosis (TB) incidence to gain further understanding of substantial variation in TB incidence across Europe. METHODS: An ecological study examined the prospective association between baseline country-level education in 2000 measured by school life expectancy and TB incidence in 2000-2010 in 40 countries of the WHO European region using quantile regression. Subsequently, to validate the ecological associations between education and TB incidence, an individual-level analysis was performed using case-based data in 29 EU/EEA countries from the European Surveillance System (TESSy) and simulating a theoretical control group. RESULTS: The ecological analysis showed that baseline school life expectancy had a negative prospective association with TB incidence. We observed consistent negative effects of school life expectancy on individuals' TB infections prospectively. CONCLUSIONS: These findings suggests that country-level education is an important determinant of individual-level TB infection in the region, and in the absence of a social determinants indicator that is routinely collected for reportable infectious diseases, the adoption of country-level education for reportable infectious diseases would significantly advance the field

GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation

Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic ß-cells in a glucose dependent manner. Several pathways mediate this action by rapid, kinase phosphorylation-dependent, but gene expression-independent mechanisms. Since GLP-1-induced insulin secretion requires glucose metabolism, we aimed to address the hypothesis that GLP-1 receptor (GLP-1R) signalling can modulate glucose uptake and utilization in ß-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 ß-cells and rodent islets to the GLP-1R agonist Exendin-4 (50 nM). Here we report for the first time that prolonged stimulation of the GLP-1R for 18 hours promotes metabolic reprogramming of ß-cells. This is evidenced by up-regulation of glycolytic enzyme expression, increased rates of glucose uptake and consumption, as well as augmented ATP content, insulin secretion and glycolytic flux after removal of Exendin-4. In our model, depletion of Hypoxia-Inducible Factor 1 alpha (HIF-1a) impaired the effects of Exendin-4 on glucose metabolism, while pharmacological inhibition of Phosphoinositide 3-kinase (PI3K) or mTOR completely abolished such effects. Considering the central role of glucose catabolism for stimulus-secretion coupling in ß-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated ß-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression

Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von hippel-lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities

E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities

Exploring Campylobacter seasonality across Europe (2008-2016) using The European Surveillance System TESSy

Background: Campylobacteriosis is the most commonly reported food-borne infection in the European Union, with an annual number of cases estimated at around 9 million. In many countries, campylobacteriosis has a striking seasonal peak during early/ mid-summer. In the early 2000s, several publications reported on campylobacteriosis seasonality across Europe and associations with temperature and precipitation. Subsequently, many European countries have introduced new measures against this foodborne disease. Aim: To examine how the seasonality of campylobacteriosis varied across Europe from 2008–16, to explore associations with temperature and precipitation, and to compare these results with previous studies. We also sought to assess the utility of the European Surveillance System TESSy for cross-European seasonal analysis of campylobacteriosis. Methods: Ward’s Minimum Variance Clustering was used to group countries with similar seasonal patterns of campylobacteriosis. A two-stage multivariate meta-analysis methodology was used to explore associations with temperature and precipitation. Results: Nordic countries had a pronounced seasonal campylobacteriosis peak in mid-to late summer (weeks 29–32), while most other European countries had a less pronounced peak earlier in the year. The United Kingdom, Ireland, Hungary and Slovakia had a slightly earlier peak (week 24). Campylobacteriosis cases were positively associated with temperature and, to a lesser degree, precipitation. Conclusion: Across Europe, the strength and timing of campylobacteriosis peaks have remained similar to those observed previously. In addition, TESSy is a useful resource for cross-Euro-pean seasonal analysis of infectious diseases such as campylobacteriosis, but its utility depends upon each country’s reporting infrastructure