TGF-ß induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression.

Abstract TGF-ß/Activin induces epithelial-to-mesenchymal transition (EMT) and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-ß transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-ß also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-ß-mediated response indicating that these miRNAs are important TGF-ß effectors. We integrated AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell-cell junctions’ pathways. Together, we uncover that TGF-ß induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b, play opposing roles in controlling PDAC tumourigenesis

Mutation increasing β-carotene concentrations does not adversely affect concentrations of essential mineral elements in pepper fruit

<div><p>Vitamin and mineral deficiencies are prevalent in human populations throughout the world. Vitamin A deficiency affects hundreds of millions of pre-school age children in low income countries. Fruits of pepper (<i>Capsicum annuum</i> L.) can be a major dietary source of precursors to Vitamin A biosynthesis, such as β-carotene. Recently, pepper breeding programs have introduced the orange-fruited (<i>of</i>) trait of the mutant variety Oranzheva kapiya, which is associated with high fruit β-carotene concentrations, to the mutant variety Albena. In this manuscript, concentrations of β-carotene and mineral elements (magnesium, phosphorus, sulphur, potassium, zinc, calcium, manganese, iron and copper) were compared in fruit from P31, a red-fruited genotype derived from the variety Albena, and M38, a genotype developed by transferring the orange-fruited mutation (<i>of</i>) into Albena. It was observed that fruit from M38 plants had greater β-carotene concentration at both commercial and botanical maturity (4.9 and 52.7 mg / kg fresh weight, respectively) than fruit from P31 plants (2.3 and 30.1 mg / kg fresh weight, respectively). The mutation producing high β-carotene concentrations in pepper fruits had no detrimental effect on the concentrations of mineral elements required for human nutrition.</p></div

MCM-test: a fuzzy-set-theory-based approach to differential analysis of gene pathways

Abstract Background Gene pathway can be defined as a group of genes that interact with each other to perform some biological processes. Along with the efforts to identify the individual genes that play vital roles in a particular disease, there is a growing interest in identifying the roles of gene pathways in such diseases. Results This paper proposes an innovative fuzzy-set-theory-based approach, Multi-dimensional Cluster Misclassification test (MCM-test), to measure the significance of gene pathways in a particular disease. Experiments have been conducted on both synthetic data and real world data. Results on published diabetes gene expression dataset and a list of predefined pathways from KEGG identified OXPHOS pathway involved in oxidative phosphorylation in mitochondria and other mitochondrial related pathways to be deregulated in diabetes patients. Our results support the previously supported notion that mitochondrial dysfunction is an important event in insulin resistance and type-2 diabetes. Conclusion Our experiments results suggest that MCM-test can be successfully used in pathway level differential analysis of gene expression datasets. This approach also provides a new solution to the general problem of measuring the difference between two groups of data, which is one of the most essential problems in most areas of research

Predicting change in quality of life from age 79 to 90 in the Lothian Birth Cohort 1921

Purpose: Quality of life (QoL) decreases in very old age, and is strongly related to health outcomes and mortality. Understanding the predictors of QoL and change in QoL amongst the oldest old may suggest potential targets for intervention. This study investigated change in QoL from age 79 to 90 years in a group of older adults in Scotland, and identified potential predictors of that change. Method: Participants were members of the Lothian Birth Cohort 1921 who attended clinic visits at age 79 (n = 554) and 90 (n = 129). Measures at both time points included QoL (WHOQOL-BREF: four domains and two single items), anxiety and depression, objective health, functional ability, self-rated health, loneliness, and personality. Results: Mean QoL declined from age 79 to 90. Participants returning at 90 had scored significantly higher at 79 on most QoL measures, and exhibited better objective health and functional ability, and lower anxiety and depression than non-returners. Hierarchical multiple regression models accounted for 20.3–56.3% of the variance in QoL at age 90. Baseline QoL was the strongest predictor of domain scores (20.3–35.6% variance explained), suggesting that individual differences in QoL judgements remain largely stable. Additional predictors varied by the QoL domain and included self-rated health, loneliness, and functional and mood decline between age 79 and 90 years. Conclusions: This study has identified potential targets for interventions to improve QoL in the oldest old. Further research should address causal pathways between QoL and functional and mood decline, perceived health and loneliness

The Wnt Receptor Ryk Reduces Neuronal and Cell Survival Capacity by Repressing FOXO Activity During the Early Phases of Mutant Huntingtin Pathogenicity

The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including γ-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD). Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that Ryk is up-regulated in neurons expressing mutant huntingtin (HTT) in several models of Huntington's disease (HD). Further investigation in Caenorhabditis elegans and mouse striatal cell models of HD provided a model in which the early-stage increase of Ryk promotes neuronal dysfunction by repressing the neuroprotective activity of the longevity-promoting factor FOXO through a noncanonical mechanism that implicates the Ryk-ICD fragment and its binding to the FOXO co-factor β-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished β-catenin protection of mutant htt striatal cells against cell death vulnerability. Additionally, Ryk-ICD was increased in the nucleus of mutant htt cells, and reducing γ-secretase PS1 levels compensated for the cytotoxicity of full-length Ryk in these cells. These findings reveal that the Ryk-ICD pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting that neurons are unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in HD. © 2014 Tourette et al

Computational solutions for omics data

High-throughput experimental technologies are generating increasingly massive and complex genomic data sets. The sheer enormity and heterogeneity of these data threaten to make the arising problems computationally infeasible. Fortunately, powerful algorithmic techniques lead to software that can answer important biomedical questions in practice. In this Review, we sample the algorithmic landscape, focusing on state-of-the-art techniques, the understanding of which will aid the bench biologist in analysing omics data. We spotlight specific examples that have facilitated and enriched analyses of sequence, transcriptomic and network data sets.National Institutes of Health (U.S.) (Grant GM081871

Experience of sexual coercion and risky sexual behavior among Ugandan university students

<p>Abstract</p> <p>Background</p> <p>Growing worldwide evidence shows that the experience of sexual coercion is fairly prevalent among young people and is associated with risky sexual behavior thereafter. The causal mechanisms behind this are unclear but may be dependent on specific contextual determinants. Little is known about factors that could buffer the negative effects of coercion. The aim of this study was to assess the association between the experience of sexual coercion and risky sexual behavior among university students of both sexes in Uganda.</p> <p>Methods</p> <p>In 2005, 980 (80%) out of a total of 1,220 students enrolled in Mbarara University of Science and Technology in Uganda participated in a self-administered questionnaire covering socio-demographic and religious factors, social capital, mental health, alcohol use, and sexual behavior. A validated scale of six items was used to assess the experience of sexual coercion. Logistic regression analyses were applied to control for confounders. Potential buffering factors were analyzed by testing for effect modification.</p> <p>Results</p> <p>Fifty-nine percent of those who responded had previously had sexual intercourse. Among the male students 29.0%, and among the female students 33.1% reported having had some experience of sexual coercion. After controlling for age, gender, and educational level of household of origin, role of religion and trust in others sexual coercion was found to be statistically significantly associated with previously had sex (OR 1.6, 95% CI; 1.1-2.3), early sexual debut (OR 2.4, 95% CI; 1.5-3.7), as well as with having had a great number of sexual partners (OR 1.9, 95% CI; 1.2-3.0), but not with inconsistent condom use.</p> <p>Scoring low on an assessment of mental health problems, reporting high trust in others, or stating that religion played a major role in one's family of origin seemed to buffer the negative effect that the experience of sexual coercion had on the likelihood of having many sexual partners.</p> <p>Conclusion</p> <p>The findings of this study suggest that the experience of sexual coercion is common among youth/young adults in Uganda and is subsequently associated with risky sexual behavior in both sexes. The existence of individual and contextual factors that buffer the effects mentioned was also demonstrated. In the Ugandan context, this has implications for policy formulation and the implementation of preventive strategies for combating HIV/AIDS.</p

Manufacturing Epidemics: The Role of Global Producers in Increased Consumption of Unhealthy Commodities Including Processed Foods, Alcohol, and Tobacco

In an article that forms part of the PLoS Medicine series on Big Food, David Stuckler and colleagues report that unhealthy packaged foods are being consumed rapidly in low- and middle-income countries, consistent with rapid expansion of multinational food companies into emerging markets and fueling obesity and chronic disease epidemics

Synergistic Association of PTGS2 and CYP2E1 Genetic Polymorphisms with Lung Cancer Risk in Northeastern Chinese

BACKGROUND: Lung cancer is the most common cause of cancer-related deaths worldwide. The aim of this study was to investigate the association of five extensively-studied polymorphisms in PTGS2 (rs689466, rs5275, rs20417) and CYP2E1 (rs2031920, rs6413432) genes with lung cancer risk in a large northeastern Chinese population. METHODOLOGY/PRINCIPAL FINDINGS: This is a hospital-based case-control study involving 684 patients with lung cancer and 604 cancer-free controls. Genotyping was performed using the PCR-LDR method. Data were analyzed using Haplo.stats and MDR programs. There were significant differences between patients and controls in allele/genotype distributions of rs5275 (P = 0.002/0.003) and rs6413432 (P = 0.037/0.044), as well as in genotype distributions of rs689466 (P = 0.02). The risk for lung cancer associated with the rs5275-C mutant allele was decreased by 60% (95% CI [confidence interval]: 0.21-0.74; P = 0.004) under the recessive model. Carriers of rs689466-G mutant allele had a 28% (95% CI: 0.57-0.92; P = 0.008) reduced risk of developing lung cancer relative to the AA genotype carriers. In haplotype analysis, haplotype G-C-C-T (in order of rs689466, rs5275, rs2031920 and rs6413432) decreased the odds of lung cancer by 28% (95% CI: 0.51-0.93; P = 0.019) after adjusting for confounding factors, whereas haplotype A-T-T-T had 1.49-fold (95% CI: 1.21-1.79; P = 0.012) increased risk for lung cancer. Using MDR method, the overall best model including rs5275, rs689466 and rs6413432 polymorphisms was identified with a maximal testing accuracy of 66.1% and a maximal cross-validation consistency of 10 out of 10 (P = 0.003). CONCLUSIONS/SIGNIFICANCE: Our findings demonstrated a potentially synergistic association of PTGS2 and CYP2E1 polymorphisms with the underlying cause of lung cancer in northeastern Chinese