A Pair of Dopamine Neurons Target the D1-Like Dopamine Receptor DopR in the Central Complex to Promote Ethanol-Stimulated Locomotion in Drosophila

Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol

Disparities and risks of sexually transmissible infections among men who have sex with men in China: a meta-analysis and data synthesis.

BACKGROUND: Sexually transmitted infections (STIs), including Hepatitis B and C virus, are emerging public health risks in China, especially among men who have sex with men (MSM). This study aims to assess the magnitude and risks of STIs among Chinese MSM. METHODS: Chinese and English peer-reviewed articles were searched in five electronic databases from January 2000 to February 2013. Pooled prevalence estimates for each STI infection were calculated using meta-analysis. Infection risks of STIs in MSM, HIV-positive MSM and male sex workers (MSW) were obtained. This review followed the PRISMA guidelines and was registered in PROSPERO. RESULTS: Eighty-eight articles (11 in English and 77 in Chinese) investigating 35,203 MSM in 28 provinces were included in this review. The prevalence levels of STIs among MSM were 6.3% (95% CI: 3.5-11.0%) for chlamydia, 1.5% (0.7-2.9%) for genital wart, 1.9% (1.3-2.7%) for gonorrhoea, 8.9% (7.8-10.2%) for hepatitis B (HBV), 1.2% (1.0-1.6%) for hepatitis C (HCV), 66.3% (57.4-74.1%) for human papillomavirus (HPV), 10.6% (6.2-17.6%) for herpes simplex virus (HSV-2) and 4.3% (3.2-5.8%) for Ureaplasma urealyticum. HIV-positive MSM have consistently higher odds of all these infections than the broader MSM population. As a subgroup of MSM, MSW were 2.5 (1.4-4.7), 5.7 (2.7-12.3), and 2.2 (1.4-3.7) times more likely to be infected with chlamydia, gonorrhoea and HCV than the broader MSM population, respectively. CONCLUSION: Prevalence levels of STIs among MSW were significantly higher than the broader MSM population. Co-infection of HIV and STIs were prevalent among Chinese MSM. Integration of HIV and STIs healthcare and surveillance systems is essential in providing effective HIV/STIs preventive measures and treatments. TRIAL REGISTRATION: PROSPERO NO: CRD42013003721

The level of claudin-7 is reduced as an early event in colorectal carcinogenesis

<p>Abstract</p> <p>Background</p> <p>Compromised epithelial barriers are found in dysplastic tissue of the gastrointestinal tract. Claudins are transmembrane proteins important for tight junctions. Claudins regulate the paracellular transport and are crucial for maintaining a functional epithelial barrier. Down-regulation of the oncogenic serine protease, matriptase, induces leakiness in epithelial barriers both <it>in vivo </it>and <it>in vitro</it>. We found in an <it>in-silico </it>search tight co-regulation between <it>matriptase </it>and <it>claudin-7 </it>expression. We have previously shown that the <it>matriptase </it>expression level decreases during colorectal carcinogenesis. In the present study we investigated whether <it>claudin-7 </it>expression is likewise decreased during colorectal carcinogenesis, thereby causing or contributing to the compromised epithelial leakiness of dysplastic tissue.</p> <p>Methods</p> <p>The mRNA level of <it>claudin-7 </it>(CLDN7) was determined in samples from 18 healthy individuals, 100 individuals with dysplasia and 121 colorectal cancer patients using quantitative real time RT-PCR. In addition, immunohistochemical stainings were performed on colorectal adenomas and carcinomas, to confirm the mRNA findings.</p> <p>Results</p> <p>A 2.7-fold reduction in the <it>claudin-7 </it>mRNA level was found when comparing the biopsies from healthy individuals with the biopsies of carcinomas (p < 0.001). Reductions in the <it>claudin-7 </it>mRNA levels were also detected in mild/moderate dysplasia (p < 0.001), severe dysplasia (p < 0.01) and carcinomas (p < 0.01), compared to a control sample from the same individual. The decrease at mRNA level was confirmed at the protein level by immunohistochemical stainings.</p> <p>Conclusions</p> <p>Our results show that the <it>claudin-7 </it>mRNA level is decreased already as an early event in colorectal carcinogenesis, probably contributing to the compromised epithelial barrier in adenomas.</p

Pancreatitis, very early compared with normal start of enteral feeding (PYTHON trial): design and rationale of a randomised controlled multicenter trial

Contains fulltext : 97199.pdf (publisher's version ) (Open Access)BACKGROUND: In predicted severe acute pancreatitis, infections have a negative effect on clinical outcome. A start of enteral nutrition (EN) within 24 hours of onset may reduce the number of infections as compared to the current practice of starting an oral diet and EN if necessary at 3-4 days after admission. METHODS/DESIGN: The PYTHON trial is a randomised controlled, parallel-group, superiority multicenter trial. Patients with predicted severe acute pancreatitis (Imrie-score >/= 3 or APACHE-II score >/= 8 or CRP > 150 mg/L) will be randomised to EN within 24 hours or an oral diet and EN if necessary, after 72 hours after hospital admission.During a 3-year period, 208 patients will be enrolled from 20 hospitals of the Dutch Pancreatitis Study Group. The primary endpoint is a composite of mortality or infections (bacteraemia, infected pancreatic or peripancreatic necrosis, pneumonia) during hospital stay or within 6 months following randomisation. Secondary endpoints include other major morbidity (e.g. new onset organ failure, need for intervention), intolerance of enteral feeding and total costs from a societal perspective. DISCUSSION: The PYTHON trial is designed to show that a very early (< 24 h) start of EN reduces the combined endpoint of mortality or infections as compared to the current practice of an oral diet and EN if necessary at around 72 hours after admission for predicted severe acute pancreatitis. TRIAL REGISTRATION: ISRCTN: ISRCTN18170985

Cytotoxic and Pathogenic Properties of Klebsiella oxytoca Isolated from Laboratory Animals

Klebsiella oxytoca is an opportunistic pathogen implicated in various clinical diseases in animals and humans. Studies suggest that in humans K. oxytoca exerts its pathogenicity in part through a cytotoxin. However, cytotoxin production in animal isolates of K. oxytoca and its pathogenic properties have not been characterized. Furthermore, neither the identity of the toxin nor a complete repertoire of genes involved in K. oxytoca pathogenesis have been fully elucidated. Here, we showed that several animal isolates of K. oxytoca, including the clinical isolates, produced secreted products in bacterial culture supernatant that display cytotoxicity on HEp-2 and HeLa cells, indicating the ability to produce cytotoxin. Cytotoxin production appears to be regulated by the environment, and soy based product was found to have a strong toxin induction property. The toxin was identified, by liquid chromatography-mass spectrometry and NMR spectroscopy, as low molecular weight heat labile benzodiazepine, tilivalline, previously shown to cause cytotoxicity in several cell lines, including mouse L1210 leukemic cells. Genome sequencing and analyses of a cytotoxin positive K. oxytoca strain isolated from an abscess of a mouse, identified genes previously shown to promote pathogenesis in other enteric bacterial pathogens including ecotin, several genes encoding for type IV and type VI secretion systems, and proteins that show sequence similarity to known bacterial toxins including cholera toxin. To our knowledge, these results demonstrate for the first time, that animal isolates of K. oxytoca, produces a cytotoxin, and that cytotoxin production is under strict environmental regulation. We also confirmed tilivalline as the cytotoxin present in animal K. oxytoca strains. These findings, along with the discovery of a repertoire of genes with virulence potential, provide important insights into the pathogenesis of K. oxytoca. As a novel diagnostic tool, tilivalline may serve as a biomarker for K oxytoca-induced cytotoxicity in humans and animals through detection in various samples from food to diseased samples using LC-MS/MS. Induction of K. oxytoca cytotoxin by consumption of soy may be in part involved in the pathogenesis of gastrointestinal disease

Reproducibility of preclinical animal research improves with heterogeneity of study samples

Single-laboratory studies conducted under highly standardized conditions are the gold standard in preclinical animal research. Using simulations based on 440 preclinical studies across 13 different interventions in animal models of stroke, myocardial infarction, and breast cancer, we compared the accuracy of effect size estimates between single-laboratory and multi-laboratory study designs. Single-laboratory studies generally failed to predict effect size accurately, and larger sample sizes rendered effect size estimates even less accurate. By contrast, multi-laboratory designs including as few as 2 to 4 laboratories increased coverage probability by up to 42 percentage points without a need for larger sample sizes. These findings demonstrate that within-study standardization is a major cause of poor reproducibility. More representative study samples are required to improve the external validity and reproducibility of preclinical animal research and to prevent wasting animals and resources for inconclusive research

Children’s Postdisaster Trajectories of PTS Symptoms: Predicting Chronic Distress

BACKGROUND: There are no studies of the distinct trajectories of children’s psychological distress over the first year after a destructive natural disaster and the determinants of these trajectories. OBJECTIVE: We examined these issues using an existing dataset of children exposed to Hurricane Andrew, one of the most devastating natural disasters in US history. METHODS: At 3-months postdisaster, 568 children (55 % girls; grades 3–5) residing in areas most directly affected by the hurricane completed measures of hurricane exposure and stressors, social support, coping, and general anxiety. Children also reported major life events occurring since the hurricane (at 7-months) and posttraumatic stress (PTS) symptoms at 3-, 7-, and 10-months postdisaster. RESULTS: Latent growth mixture modeling identified three trajectories of PTS reactions: resilient (37 %), recovering (43 %), and chronic distress (20 %). Predictors of the trajectories were examined. Odds ratios indicated that, compared to the resilient trajectory, girls were more likely to be in the recovering and chronically distressed trajectories, as were children reporting higher anxiety and greater use of coping strategies that reflected poor emotion regulation. Compared to the recovering trajectory, children in the chronically distressed trajectory had greater odds of reporting high anxiety, less social support, more intervening life events, and greater use of poor emotion regulation strategies. CONCLUSIONS: Hurricane exposure may be less effective in identifying children who develop chronic postdisaster distress than other child (anxiety, coping) and contextual variables (social support, life events). Effective screening after disasters is critical for identifying youth most in need of limited clinical resources

SUMOylation by Pias1 Regulates the Activity of the Hedgehog Dependent Gli Transcription Factors

Hedgehog (Hh) signaling, a vital signaling pathway for the development and homeostasis of vertebrate tissues, is mediated by members of the Gli family of zinc finger transcription factors. Hh signaling increases the transcriptional activity of Gli proteins, at least in part, by inhibiting their proteolytic processing. Conversely, phosphorylation by cAMP-dependent protein kinase (PKA) inhibits Gli transcriptional activity by promoting their ubiquitination and proteolysis. Whether other post-translational modifications contribute to the regulation of Gli protein activity has been unclear.Here we provide evidence that all three Gli proteins are targets of small ubiquitin-related modifier (SUMO)-1 conjugation. Expression of SUMO-1 or the SUMO E3 ligase, Pias1, increased Gli transcriptional activity in cultured cells. Moreover, PKA activity reduced Gli protein SUMOylation. Strikingly, in the embryonic neural tube, the forced expression of Pias1 increased Gli activity and induced the ectopic expression of the Gli dependent gene Nkx2.2. Conversely, a point mutant of Pias1, that lacks ligase activity, blocked the endogenous expression of Nkx2.2.Together, these findings provide evidence that Pias1-dependent SUMOylation influences Gli protein activity and thereby identifies SUMOylation as a post-translational mechanism that regulates the hedgehog signaling pathway

MicroRNA—implications for cancer

MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression post-transcriptionally. After the discovery of the first miRNA in the roundworm Caenorhabditis elegans, these short regulatory RNAs have been found to be an abundant class of RNAs in plants, animals, and DNA viruses. About 3% of human genes encode for miRNAs, and up to 30% of human protein coding genes may be regulated by miRNAs. MicroRNAs play a key role in diverse biological processes, including development, cell proliferation, differentiation, and apoptosis. Accordingly, altered miRNA expression is likely to contribute to human disease, including cancer. This review will summarize the emerging knowledge of the connections between human miRNA biology and different aspects of carcinogenesis. Various techniques available to investigate miRNAs will also be discussed

Transcriptomic epidemiology of smoking: the effect of smoking on gene expression in lymphocytes

<p>Abstract</p> <p>Background</p> <p>This investigation offers insights into system-wide pathological processes induced in response to cigarette smoke exposure by determining its influences at the gene expression level.</p> <p>Methods</p> <p>We obtained genome-wide quantitative transcriptional profiles from 1,240 individuals from the San Antonio Family Heart Study, including 297 current smokers. Using lymphocyte samples, we identified 20,413 transcripts with significantly detectable expression levels, including both known and predicted genes. Correlation between smoking and gene expression levels was determined using a regression model that allows for residual genetic effects.</p> <p>Results</p> <p>With a conservative false-discovery rate of 5% we identified 323 unique genes (342 transcripts) whose expression levels were significantly correlated with smoking behavior. These genes showed significant over-representation within a range of functional categories that correspond well with known smoking-related pathologies, including immune response, cell death, cancer, natural killer cell signaling and xenobiotic metabolism.</p> <p>Conclusions</p> <p>Our results indicate that not only individual genes but entire networks of gene interaction are influenced by cigarette smoking. This is the largest <it>in vivo </it>transcriptomic epidemiological study of smoking to date and reveals the significant and comprehensive influence of cigarette smoke, as an environmental variable, on the expression of genes. The central importance of this manuscript is to provide a summary of the relationships between gene expression and smoking in this exceptionally large cross-sectional data set.</p