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We found that a significantly higher percentage (an increase of 18.7% to 47.2%) of eQTLs identified by T-GEN are inferred to be functional by ChromHMM and more are deleterious based on their Combined Annotation Dependent Depletion (CADD) scores. Applying T-GEN to 207 complex traits, we were able to identify more trait-associated genes (ranging from 7.7% to 102%) than those from existing methods. Among the identified genes associated with these traits, T-GEN can better identify genes with high (>0.99) pLI scores compared to other methods. When T-GEN was applied to late-onset Alzheimer's disease, we identified 96 genes located at 15 loci, including two novel loci not implicated in previous GWAS. We further replicated 50 genes in an independent GWAS, including one of the two novel loci.The treatment of cancer cells obtained by blocking cellular metabolism has received a lot of attention recently. Previous studies have demonstrated that Kras mutation-mediated abnormal glucose metabolism would lead to an aberrant cell proliferation in human pancreatic ductal adenocarcinoma (PDAC) cells. Previous literature has suggested that consumption of fish oil is associated with lower risk of pancreatic cancer. In this study, we investigated the anti-cancer effects of docosahexaenoic acid (DHA) in human PDAC cells in vitro and in vivo. Omega-3 polyunsaturated fatty acids (PUFAs) such as DHA and eicosapentaenoic acid (EPA) significantly inhibited the proliferation of human PDAC cells. The actions of DHA were evaluated through an induction of cell cycle arrest at G1 phase and noticed a decreased expression of cyclin A, cyclin E and cyclin B proteins in HPAF-II cells. Moreover, it was found that co-treatment of DHA and gemcitabine (GEM) effectively induced oxidative stress and cell death in HPAF-II cells. Ient of GSSG/GSH ratio, an upregulation of xCT and CTH proteins in tumor tissues. In conclusion, DHA significantly inhibited survival of PDAC cells both in vitro and in vivo through its recently identified novel mode of action, including an increment in the ratio of GSSG/GSH and NADP/NADPH respectively, and promoting reduction in the levels of nucleotide synthesis.U2 Small Nuclear RNA Auxiliary Factor 1 (U2AF1) forms a heterodimeric complex with U2AF2 that is primarily responsible for 3' splice site selection. U2AF1 mutations have been identified in most cancers but are prevalent in Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML), and the most common mutation is a missense substitution of serine-34 to phenylalanine (S34F). The U2AF heterodimer also has a noncanonical function as a translational regulator. Here, we report that the U2AF1-S34F mutation results in specific misregulation of the translation initiation and ribosome biogenesis machinery. The net result is an increase in mRNA translation at the single-cell level. Among the translationally up-regulated targets of U2AF1-S34F is Nucleophosmin 1 (NPM1), which is a major driver of myeloid malignancy. Depletion of NPM1 impairs the viability of the U2AF1-S34F mutant cells and causes ribosomal RNA (rRNA) processing defects, thus indicating an unanticipated synthetic interaction between U2AF1, NPM1, and ribosome biogenesis. Our results establish a unique molecular phenotype for the U2AF1 mutation that recapitulates translational misregulation in myeloid disease.Histone acetylation, balanced by histone acetyltransferase (HAT) and histone deacetylase (HDAC) complexes, affects dynamic transitions of chromatin structure to regulate transcriptional accessibility. However, OTX008 order is known about the interplay between HAT and HDAC complexes in Fusarium graminearum, a causal agent of Fusarium Head Blight (FHB) that uniquely contains chromosomal regions enriched for house-keeping or infection-related genes. In this study, we identified the ortholog of the human inhibitor of growth (ING1) gene in F. graminearum (FNG1) and found that it specifically interacts with the FgEsa1 HAT of the NuA4 complex. Deletion of FNG1 led to severe growth defects and blocked conidiation, sexual reproduction, DON production, and plant infection. The fng1 mutant was normal in H3 acetylation but significantly reduced in H4 acetylation. #link# A total of 34 spontaneous suppressors of fng1 with faster growth rate were isolated. link2 Most of them were still defective in sexual reproduction and plant infection. Thimplex and functionally related to the FgRpd3 HDAC complex for transcriptional regulation of genes important for growth, conidiation, sexual reproduction, and plant infection in F. graminearum.Germline mutations in the folliculin (FLCN) tumor suppressor gene are linked to Birt-Hogg-Dubé (BHD) syndrome, a dominantly inherited genetic disease characterized by predisposition to fibrofolliculomas, lung cysts, and renal cancer. Most BHD-linked FLCN variants include large deletions and splice site aberrations predicted to cause loss of function. The mechanisms by which missense variants and short in-frame deletions in FLCN trigger disease are unknown. Here, we present an integrated computational and experimental study that reveals that the majority of such disease-causing FLCN variants cause loss of function due to proteasomal degradation of the encoded FLCN protein, rather than directly ablating FLCN function. Accordingly, several different single-site FLCN variants are present at strongly reduced levels in cells. In line with our finding that FLCN variants are protein quality control targets, several are also highly insoluble and fail to associate with the FLCN-binding partners FNIP1 and FNIP2. The lack of FLCN binding leads to rapid proteasomal degradation of FNIP1 and FNIP2. Half of the tested FLCN variants are mislocalized in cells, and one variant (ΔE510) forms perinuclear protein aggregates. A yeast-based stability screen revealed that the deubiquitylating enzyme Ubp15/USP7 and molecular chaperones regulate the turnover of the FLCN variants. Lowering the temperature led to a stabilization of two FLCN missense proteins, and for one (R362C), function was re-established at low temperature. In conclusion, we propose that most BHD-linked FLCN missense variants and small in-frame deletions operate by causing misfolding and degradation of the FLCN protein, and that stabilization and resulting restoration of function may hold therapeutic potential of certain disease-linked variants. Our computational saturation scan encompassing both missense variants and single site deletions in FLCN may allow classification of rare FLCN variants of uncertain clinical significance.

Large-scale sequencing projects, such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), have generated high throughput sequencing and molecular profiling data sets, but it is still challenging to identify potentially causal changes in cellular processes in cancer as well as in other diseases in an automated fashion. We developed the netboxr package written in the R programming language, which makes use of the NetBox algorithm to identify candidate cancer-related functional modules. The algorithm makes use of a data-driven, network-based approach that combines prior knowledge with a network clustering algorithm, obviating the need for and the limitation of independently curated functionally labeled gene sets. The method can combine multiple data types, such as mutations and copy number alterations, leading to more reliable identification of functional modules. We make the tool available in the Bioconductor R ecosystem for applications in cancer research and cell biology.

The netboxr package is free and open-sourced under the GNU GPL-3 license R package available at https//www.bioconductor.org/packages/release/bioc/html/netboxr.html.

The netboxr package is free and open-sourced under the GNU GPL-3 license R package available at https//www.bioconductor.org/packages/release/bioc/html/netboxr.html.

trans-fatty acids (TFAs) are a well-known risk factor of ischemic heart disease (IHD). In Australia, the highest TFA intake is concentrated to the most socioeconomically disadvantaged groups. Elimination of industrial TFA (iTFA) from the Australian food supply could result in reduced IHD mortality and morbidity while improving health equity. However, such legislation could lead to additional costs for both government and food industry. Thus, we assessed the potential cost-effectiveness, health gains, and effects on health equality of an iTFA ban from the Australian food supply.

Markov cohort models were used to estimate the impact on IHD burden and health equity, as well as the cost-effectiveness of a national ban of iTFA in Australia. Intake of TFA was assessed using the 2011-2012 Australian National Nutrition and Physical Activity Survey. The IHD burden attributable to TFA was calculated by comparing the current level of TFA intake to a counterfactual setting where consumption was lowered to a theoreticmination of iTFA can cost-effectively improve health and health equality even in countries with low iTFA intake.

Our model estimates that a ban of iTFAs could avert substantial numbers of IHD events and deaths in Australia and would likely be a highly cost-effective strategy to reduce social-economic and urban-rural inequalities in health. These findings suggest that elimination of iTFA can cost-effectively improve health and health equality even in countries with low iTFA intake.Studies of differential gene expression have identified several molecular signatures and pathways associated with Parkinson's disease (PD). The role of isoform switches and differential transcript usage (DTU) remains, however, unexplored. Here, we report the first genome-wide study of DTU in PD. We performed RNA sequencing following ribosomal RNA depletion in prefrontal cortex samples of 49 individuals from two independent case-control cohorts. DTU was assessed using two transcript-count based approaches, implemented in the DRIMSeq and DEXSeq tools. Multiple PD-associated DTU events were detected in each cohort, of which 23 DTU events in 19 genes replicated across both patient cohorts. For several of these, including THEM5, SLC16A1 and BCHE, DTU was predicted to have substantial functional consequences, such as altered subcellular localization or switching to non-protein coding isoforms. Furthermore, genes with PD-associated DTU were enriched in functional pathways previously linked to PD, including reactive oxygen species generation and protein homeostasis. Importantly, the vast majority of genes exhibiting DTU were not differentially expressed at the gene-level and were therefore not identified by conventional differential gene expression analysis. Our findings provide the first insight into the DTU landscape of PD and identify novel disease-associated genes. Moreover, we show that DTU may have important functional consequences in the PD brain, since it is predicted to alter the functional composition of the proteome. Based on these results, we propose that DTU analysis is an essential complement to differential gene expression studies in order to provide a more accurate and complete picture of disease-associated transcriptomic alterations.Each year in the United States, influenza causes illness in 9.2 to 35.6 million individuals and is responsible for 12,000 to 56,000 deaths. link3 The U.S. Centers for Disease Control and Prevention (CDC) tracks influenza activity through a national surveillance network. These data are only available after a delay of 1 to 2 weeks, and thus influenza epidemiologists and transmission modelers have explored the use of other data sources to produce more timely estimates and predictions of influenza activity. We evaluated whether data collected from a national commercial network of influenza diagnostic machines could produce valid estimates of the current burden and help to predict influenza trends in the United States. Quidel Corporation provided us with de-identified influenza test results transmitted in real-time from a national network of influenza test machines called the Influenza Test System (ITS). We used this ITS dataset to estimate and predict influenza-like illness (ILI) activity in the United States over the 2015-2016 and 2016-2017 influenza seasons.