297 research outputs found
The Cyprinodon variegatus genome reveals gene expression changes underlying differences in skull morphology among closely related species
Genes in durophage intersection set at 15 dpf. This is a comma separated table of the genes in the 15 dpf durophage intersection set. Given are edgeR results for each pairwise comparison. Columns indicating whether a gene is included in the intersection set at a threshold of 1.5 or 2 fold are provided. (CSV 13Â kb
RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord
ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned \u3e50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG’s). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network “hub” gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF’s involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful in ALS patients
IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysing In Silico performance across different compound classes
Modality- and task-specific brain regions involved in Chinese lexical processing
fMRI was used to examine lexical processing in native adult Chinese speakers. A 2 task (semantics and phonology) x 2 modality (visual and auditory) within-subject design was adopted. The semantic task involved a meaning association judgment and the phonological task involved a rhyming judgment to two sequentially presented words. The overall effect across tasks and modalities was used to identify seven ROIs, including the left fusiform gyrus (FG), the left superior temporal gyrus (STG), the left ventral inferior frontal gyrus (VIFG), the left middle temporal gyrus (MTG), the left dorsal inferior frontal gyrus (DIFG), the left inferior parietal lobule (IPL), and the left middle frontal gyrus (MFG). ROI analyses revealed two modality-specific areas, FG for visual and STG for auditory, and three task-specific areas, IPL and DIFG for phonology and VIFG for semantics. Greater DIFG activation was associated with conflicting tonal information between words for the auditory rhyming task, suggesting this region's role in strategic phonological processing, and greater VIFG activation was correlated with lower association between words for both the auditory and the visual meaning task, suggesting this region's role in retrieval and selection of semantic representations. The modality- and task-specific effects in Chinese revealed by this study are similar to those found in alphabetical languages. Unlike English, we found that MFG was both modality- and task-specific, suggesting that MFG may be responsible for the visuospatial analysis of Chinese characters and orthography-to-phonology integration at a syllabic level
Children with Reading Disability Show Brain Differences in Effective Connectivity for Visual, but Not Auditory Word Comprehension
Background: Previous literature suggests that those with reading disability (RD) have more pronounced deficits during semantic processing in reading as compared to listening comprehension. This discrepancy has been supported by recent neuroimaging studies showing abnormal activity in RD during semantic processing in the visual but not in the auditory modality. Whether effective connectivity between brain regions in RD could also show this pattern of discrepancy has not been investigated. Methodology/Principal Findings: Children (8- to 14-year-olds) were given a semantic task in the visual and auditory modality that required an association judgment as to whether two sequentially presented words were associated. Effective connectivity was investigated using Dynamic Causal Modeling (DCM) on functional magnetic resonance imaging (fMRI) data. Bayesian Model Selection (BMS) was used separately for each modality to find a winning family of DCM models separately for typically developing (TD) and RD children. BMS yielded the same winning family with modulatory effects on bottom-up connections from the input regions to middle temporal gyrus (MTG) and inferior frontal gyrus(IFG) with inconclusive evidence regarding top-down modulations. Bayesian Model Averaging (BMA) was thus conducted across models in this winning family and compared across groups. The bottom-up effect from the fusiform gyrus (FG) to MTG rather than the top-down effect from IFG to MTG was stronger in TD compared to RD for the visual modality. The stronge
Effectiveness of IT-based diabetes management interventions: a review of the literature
Background : Information technology (IT) is increasingly being used in general practice to manage health care including type 2 diabetes. However, there is conflicting evidence about whether IT improves diabetes outcomes. This review of the literature about IT-based diabetes management interventions explores whether methodological issues such as sample characteristics, outcome measures, and mechanisms causing change in the outcome measures could explain some of the inconsistent findings evident in IT-based diabetes management studies.Methods : Databases were searched using terms related to IT and diabetes management. Articles eligible for review evaluated an IT-based diabetes management intervention in general practice and were published between 1999 and 2009 inclusive in English. Studies that did not include outcome measures were excluded.Results : Four hundred and twenty-five articles were identified, sixteen met the inclusion criteria: eleven GP focussed and five patient focused interventions were evaluated. Nine were RCTs, five non-randomised control trials, and two single-sample before and after designs. Important sample characteristics such as diabetes type, familiarity with IT, and baseline diabetes knowledge were not addressed in any of the studies reviewed. All studies used HbA1c as a primary outcome measure, and nine reported a significant improvement in mean HbA1c over the study period; only two studies reported the HbA1c assay method. Five studies measured diabetes medications and two measured psychological outcomes. Patient lifestyle variables were not included in any of the studies reviewed. IT was the intervention method considered to effect changes in the outcome measures. Only two studies mentioned alternative possible causal mechanisms.Conclusion : Several limitations could affect the outcomes of IT-based diabetes management interventions to an unknown degree. These limitations make it difficult to attribute changes solely to such interventions.<br /
Identifying lineage effects when controlling for population structure improves power in bacterial association studies
Bacteria pose unique challenges for genome-wide association studies because of strong structuring into distinct strains and substantial linkage disequilibrium across the genome1,2. Although methods developed for human studies can correct for strain structure3,4, this risks considerable loss-of-power because genetic differences between strains often contribute substantial phenotypic variability5. Here, we propose a new method that captures lineage-level associations even when locus-specific associations cannot be fine-mapped. We demonstrate its ability to detect genes and genetic variants underlying resistance to 17 antimicrobials in 3,144 isolates from four taxonomically diverse clonal and recombining bacteria: Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae. Strong selection, recombination and penetrance confer high power to recover known antimicrobial resistance mechanisms and reveal a candidate association between the outer membrane porin nmpC and cefazolin resistance in E. coli. Hence, our method pinpoints locus-specific effects where possible and boosts power by detecting lineage-level differences when fine-mapping is intractable
Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk
Coding variants represent many of the strongest associations between genotype and phenotype; however, they exhibit interindividual differences in effect, termed 'variable penetrance'. Here, we study how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx), we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease-implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. Finally, we experimentally validated this model by editing a Mendelian single-nucleotide polymorphism (SNP) using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.Peer reviewe
Introduction to “Binary Binds”: Deconstructing Sex and Gender Dichotomies in Archaeological Practice
YesGender archaeology has made significant strides toward deconstructing the hegemony of binary categorizations. Challenging dichotomies such as man/woman, sex/gender, and biology/culture, approaches informed by poststructuralist, feminist, and queer theories have moved beyond essentialist and universalist identity constructs to more nuanced configurations. Despite the theoretical emphasis on context, multiplicity, and fluidity, binary starting points continue to streamline the spectrum of variability that is recognized, often reproducing normative assumptions in the evidence. The contributors to this special issue confront how sex, gender, and sexuality categories condition analytical visibility, aiming to develop approaches that respond to the complexity of theory in archaeological practice. The papers push the ontological and epistemological boundaries of bodies, personhood, and archaeological possibility, challenging a priori assumptions that contain how sex, gender, and sexuality categories are constituted and related to each other. Foregrounding intersectional approaches that engage with ambiguity, variability, and difference, this special issue seeks to “de-contain” categories, assumptions, and practices from “binding” our analytical gaze toward only certain kinds of persons and knowledges, in interpretations of the past and practices in the present
IMI – Oral Biopharmaceutics Tools project – Evaluation of Bottom-up PBPK Prediction Success Part 2: An Introduction to the Simulation Exercise and Overview of Results
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