276 research outputs found

    microPIR: An Integrated Database of MicroRNA Target Sites within Human Promoter Sequences

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    Background: microRNAs are generally understood to regulate gene expression through binding to target sequences within 39-UTRs of mRNAs. Therefore, computational prediction of target sites is usually restricted to these gene regions. Recent experimental studies though have suggested that microRNAs may alternatively modulate gene expression by interacting with promoters. A database of potential microRNA target sites in promoters would stimulate research in this field leading to more understanding of complex microRNA regulatory mechanism. Methodology: We developed a database hosting predicted microRNA target sites located within human promoter sequences and their associated genomic features, called microPIR (microRNA-Promoter Interaction Resource). microRNA seed sequences were used to identify perfect complementary matching sequences in the human promoters and the potential target sites were predicted using the RNAhybrid program..15 million target sites were identified which are located within 5000 bp upstream of all human genes, on both sense and antisense strands. The experimentally confirmed argonaute (AGO) binding sites and EST expression data including the sequence conservation across vertebrate species of each predicted target are presented for researchers to appraise the quality of predicted target sites. The microPIR database integrates various annotated genomic sequence databases, e.g. repetitive elements, transcription factor binding sites, CpG islands, and SNPs, offering users the facility to extensively explore relationships among target sites and other genomi

    Constraining Galactic cosmic-ray parameters with Z<=2 nuclei

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    The secondary-to-primary B/C ratio is widely used to study Galactic cosmic-ray propagation processes. The 2H/4He and 3He/4He ratios probe a different Z/A regime, therefore testing the `universality' of propagation. We revisit the constraints on diffusion-model parameters set by the quartet (1H, 2H, 3He, 4He), using the most recent data as well as updated formulae for the inelastic and production cross-sections. The analysis relies on the USINE propagation package and a Markov Chain Monte Carlo technique to estimate the probability density functions of the parameters. Simulated data are also used to validate analysis strategies. The fragmentation of CNO cosmic rays (resp. NeMgSiFe) on the ISM during their propagation contributes to 20% (resp. 20%) of the 2H and 15% (resp. 10%) of the 3He flux at high energy. The C to Fe elements are also responsible for up to 10% of the 4He flux measured at 1 GeV/n. The analysis of 3He/4He (and to a less extent 2H/4He) data shows that the transport parameters are consistent with those from the B/C analysis: the diffusion model with delta~0.7 (diffusion slope), Vc~20 km/s (galactic wind), Va~40 km/s (reacceleration) is favoured, but the combination delta~0.2, Vc~0, and Va~80 km/s is a close second. The confidence intervals on the parameters show that the constraints set by the quartet data are competitive with those brought by the B/C data. These constraints are tighter when adding the 3He (or 2H) flux measurements, and the tightest when further adding the He flux. For the latter, the analysis of simulated and real data show an increased sensitivity to biases. Using secondary-to-primary ratio along with a loose prior on the source parameters is recommended to get the most robust constraints on the transport parameters.Comment: 17 pages, 7 tables, 20 figures (submitted to A&A

    A Systematic Proteomic Study of Irradiated DNA Repair Deficient Nbn-Mice

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    BACKGROUND: The NBN gene codes for the protein nibrin, which is involved in the detection and repair of DNA double strand breaks (DSBs). The NBN gene is essential in mammals. METHODOLOGY/PRINCIPAL FINDINGS: We have used a conditional null mutant mouse model in a proteomics approach to identify proteins with modified expression levels after 4 Gy ionizing irradiation in the absence of nibrin in vivo. Altogether, amongst approximately 8,000 resolved proteins, 209 were differentially expressed in homozygous null mutant mice in comparison to control animals. One group of proteins significantly altered in null mutant mice were those involved in oxidative stress and cellular redox homeostasis (p<0.0001). In substantiation of this finding, analysis of Nbn null mutant fibroblasts indicated an increased production of reactive oxygen species following induction of DSBs. CONCLUSIONS/SIGNIFICANCE: In humans, biallelic hypomorphic mutations in NBN lead to Nijmegen breakage syndrome (NBS), an autosomal recessive genetic disease characterised by extreme radiosensitivity coupled with growth retardation, immunoinsufficiency and a very high risk of malignancy. This particularly high cancer risk in NBS may be attributable to the compound effect of a DSB repair defect and oxidative stress

    Genetic Evidence for a Mitochondriate Ancestry in the ‘Amitochondriate’ Flagellate Trimastix pyriformis

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    Most modern eukaryotes diverged from a common ancestor that contained the α-proteobacterial endosymbiont that gave rise to mitochondria. The ‘amitochondriate’ anaerobic protist parasites that have been studied to date, such as Giardia and Trichomonas harbor mitochondrion-related organelles, such as mitosomes or hydrogenosomes. Yet there is one remaining group of mitochondrion-lacking flagellates known as the Preaxostyla that could represent a primitive ‘pre-mitochondrial’ lineage of eukaryotes. To test this hypothesis, we conducted an expressed sequence tag (EST) survey on the preaxostylid flagellate Trimastix pyriformis, a poorly-studied free-living anaerobe. Among the ESTs we detected 19 proteins that, in other eukaryotes, typically function in mitochondria, hydrogenosomes or mitosomes, 12 of which are found exclusively within these organelles. Interestingly, one of the proteins, aconitase, functions in the tricarboxylic acid cycle typical of aerobic mitochondria, whereas others, such as pyruvate:ferredoxin oxidoreductase and [FeFe] hydrogenase, are characteristic of anaerobic hydrogenosomes. Since Trimastix retains genetic evidence of a mitochondriate ancestry, we can now say definitively that all known living eukaryote lineages descend from a common ancestor that had mitochondria

    Adaptive molecular evolution of the Major Histocompatibility Complex genes, DRA and DQA, in the genus Equus

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    <p>Abstract</p> <p>Background</p> <p>Major Histocompatibility Complex (MHC) genes are central to vertebrate immune response and are believed to be under balancing selection by pathogens. This hypothesis has been supported by observations of extremely high polymorphism, elevated nonsynonymous to synonymous base pair substitution rates and trans-species polymorphisms at these loci. In equids, the organization and variability of this gene family has been described, however the full extent of diversity and selection is unknown. As selection is not expected to act uniformly on a functional gene, maximum likelihood codon-based models of selection that allow heterogeneity in selection across codon positions can be valuable for examining MHC gene evolution and the molecular basis for species adaptations.</p> <p>Results</p> <p>We investigated the evolution of two class II MHC genes of the Equine Lymphocyte Antigen (ELA), <it>DRA </it>and <it>DQA</it>, in the genus <it>Equus </it>with the addition of novel alleles identified in plains zebra (<it>E. quagga</it>, formerly <it>E. burchelli</it>). We found that both genes exhibited a high degree of polymorphism and inter-specific sharing of allele lineages. To our knowledge, <it>DRA </it>allelic diversity was discovered to be higher than has ever been observed in vertebrates. Evidence was also found to support a duplication of the <it>DQA </it>locus. Selection analyses, evaluated in terms of relative rates of nonsynonymous to synonymous mutations (<it>d</it><sub>N</sub><it>/d</it><sub>S</sub>) averaged over the gene region, indicated that the majority of codon sites were conserved and under purifying selection (<it>d</it><sub>N </sub><<it>d</it><sub>S</sub>). However, the most likely evolutionary codon models allowed for variable rates of selection across codon sites at both loci and, at the <it>DQA</it>, supported the hypothesis of positive selection acting on specific sites.</p> <p>Conclusions</p> <p>Observations of elevated genetic diversity and trans-species polymorphisms supported the conclusion that balancing selection may be acting on these loci. Furthermore, at the <it>DQA</it>, positive selection was occurring at antigen binding sites, suggesting that a few selected residues may play a significant role in equid immune function. Future studies in natural equid populations will be valuable for understanding the functional significance of the uniquely diverse <it>DRA </it>locus and for elucidating the mechanism maintaining diversity at these MHC loci.</p

    Children's and adolescents' rising animal-source food intakes in 1990-2018 were impacted by age, region, parental education and urbanicity

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    Animal-source foods (ASF) provide nutrition for children and adolescents physical and cognitive development. Here, we use data from the Global Dietary Database and Bayesian hierarchical models to quantify global, regional and national ASF intakes between 1990 and 2018 by age group across 185 countries, representing 93% of the worlds child population. Mean ASF intake was 1.9 servings per day, representing 16% of children consuming at least three daily servings. Intake was similar between boys and girls, but higher among urban children with educated parents. Consumption varied by age from 0.6 at <1 year to 2.5 servings per day at 1519 years. Between 1990 and 2018, mean ASF intake increased by 0.5 servings per week, with increases in all regions except sub-Saharan Africa. In 2018, total ASF consumption was highest in Russia, Brazil, Mexico and Turkey, and lowest in Uganda, India, Kenya and Bangladesh. These findings can inform policy to address malnutrition through targeted ASF consumption programmes. (c) 2023, The Author(s)

    Incident type 2 diabetes attributable to suboptimal diet in 184 countries

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    The global burden of diet-attributable type 2 diabetes (T2D) is not well established. This risk assessment model estimated T2D incidence among adults attributable to direct and body weight-mediated effects of 11 dietary factors in 184 countries in 1990 and 2018. In 2018, suboptimal intake of these dietary factors was estimated to be attributable to 14.1 million (95% uncertainty interval (UI), 13.814.4 million) incident T2D cases, representing 70.3% (68.871.8%) of new cases globally. Largest T2D burdens were attributable to insufficient whole-grain intake (26.1% (25.027.1%)), excess refined rice and wheat intake (24.6% (22.327.2%)) and excess processed meat intake (20.3% (18.323.5%)). Across regions, highest proportional burdens were in central and eastern Europe and central Asia (85.6% (83.487.7%)) and Latin America and the Caribbean (81.8% (80.183.4%)); and lowest proportional burdens were in South Asia (55.4% (52.160.7%)). Proportions of diet-attributable T2D were generally larger in men than in women and were inversely correlated with age. Diet-attributable T2D was generally larger among urban versus rural residents and higher versus lower educated individuals, except in high-income countries, central and eastern Europe and central Asia, where burdens were larger in rural residents and in lower educated individuals. Compared with 1990, global diet-attributable T2D increased by 2.6 absolute percentage points (8.6 million more cases) in 2018, with variation in these trends by world region and dietary factor. These findings inform nutritional priorities and clinical and public health planning to improve dietary quality and reduce T2D globally. (c) 2023, The Author(s)
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