Genetic variants that modulate gene expression levels play an important role in the etiology of human diseases and complex traits. Although large-scale eQTL mapping studies routinely identify many ...local eQTLs, the molecular mechanisms by which genetic variants regulate expression remain unclear, particularly for distal eQTLs, which these studies are not well powered to detect. Here, we leveraged all variants (not just those that pass stringent significance thresholds) to analyze the functional architecture of local and distal regulation of gene expression in 15 human tissues by employing an extension of stratified LD-score regression that produces robust results in simulations. The top enriched functional categories in local regulation of peripheral-blood gene expression included coding regions (11.41×), conserved regions (4.67×), and four histone marks (p < 5 × 10−5 for all enrichments); local enrichments were similar across the 15 tissues. We also observed substantial enrichments for distal regulation of peripheral-blood gene expression: coding regions (4.47×), conserved regions (4.51×), and two histone marks (p < 3 × 10−7 for all enrichments). Analyses of the genetic correlation of gene expression across tissues confirmed that local regulation of gene expression is largely shared across tissues but that distal regulation is highly tissue specific. Our results elucidate the functional components of the genetic architecture of local and distal regulation of gene expression.
Graphene nanoribbons are a type of graphene characterized by remarkable electrical and mechanical properties. This review considers the prospects for the application of graphene ribbons in ...biomedicine, taking into account safety aspects. According to the analysis of the recent studies, the topical areas of using graphene nanoribbons include mechanical, chemical, photo- and acoustic sensors, devices for the direct sequencing of biological macromolecules, including DNA, gene and drug delivery vehicles, and tissue engineering. There is evidence of good biocompatibility of graphene nanoribbons with human cell lines, but a number of researchers have revealed toxic effects, including cytotoxicity and genotoxicity. Moreover, the damaging effects of nanoribbons are often higher than those of chemical analogs, for instance, graphene oxide nanoplates. The possible mechanism of toxicity is the ability of graphene nanoribbons to damage the cell membrane mechanically, stimulate reactive oxidative stress (ROS) production, autophagy, and inhibition of proliferation, as well as apoptosis induction, DNA fragmentation, and the formation of chromosomal aberrations. At the same time, the biodegradability of graphene nanoribbons under the environmental factors has been proven. In general, this review allows us to conclude that graphene nanoribbons, as components of high-precision nanodevices and therapeutic agents, have significant potential for biomedical applications; however, additional studies of their safety are needed. Particular emphasis should be placed on the lack of information about the effect of graphene nanoribbons on the organism as a whole obtained from in vivo experiments, as well as about their ecological toxicity, accumulation, migration, and destruction within ecosystems.
Nanoparticles (NPs) have various applications in medicine, cosmetics, optics, catalysis, environmental purification, and other areas nowadays. With an increasing annual production of NPs, the risks ...of their harmful influence to the environment and human health is rising. Currently, our knowledge about the mechanisms of interaction between NPs and living organisms is limited. Additionally, poor understanding of how physical and chemical characteristic and different conditions influence the toxicity of NPs restrict our attempts to develop the standards and regulations which might allow us to maintain safe living conditions. The marine species and their habitat environment are under continuous stress due to anthropogenic activities which result in the appearance of NPs in the aquatic environment. Our study aimed to evaluate and compare biochemical effects caused by the influence of different types of carbon nanotubes, carbon nanofibers, and silica nanotubes on four marine microalgae species. We evaluated the changes in growth-rate, esterase activity, membrane polarization, and size changes of microalgae cells using flow cytometry method. Our results demonstrated that toxic effects caused by the carbon nanotubes strongly correlated with the content of heavy metal impurities in the NPs. More hydrophobic carbon NPs with less ordered structure had a higher impact on the red microalgae
because of higher adherence between the particles and mucous covering of the algae. Silica NPs caused significant inhibition of microalgae growth-rate predominantly produced by mechanical influence.
This paper describes an experimental study of the relationships between thermal diffusivity and mechanical characteristics including Brinell hardness, microhardness, and Young's modulus of common ...pine (
L.), pedunculate oak (
L.), and small-leaf lime (
Mill.) wood. A dependence of Brinell hardness and thermal diffusivity tensor components upon humidity for common pine wood is found. The results of the measurement of Brinell hardness, microhardness, Young's modulus, and main components of thermal diffusivity tensor for three perpendicular cuts are found to be correlated. It is shown that the mechanical properties correlate better with the ratio of longitude to transversal thermal diffusivity coefficients than with the respective individual absolute values. The mechanical characteristics with the highest correlation with the abovementioned ratio are found to be the ratio of Young's moduli in longitude and transversal directions. Our technique allows a comparative express assessment of wood mechanical properties by means of a contactless non-destructive measurement of its thermal properties using dynamic thermal imaging instead of laborious and material-consuming destructive mechanical tests.
Considerable effort has gone into understanding the mechanisms underlying high-frequency 'bursting' of thalamocortical impulses, their sensory information content and their involvement in perception. ...However, little is known about the influence of such impulses on their cortical targets. Here we follow bursting thalamic impulses to their terminus at the thalamocortical synapse of the awake rabbit, and examine their influence on a class of somatosensory cortical neurons. We show that thalamic bursts potently activate cortical circuits. Initial impulses of each burst have a greatly enhanced ability to elicit cortical action potentials, and later impulses in the burst further raise the probability of eliciting spikes. In some cases, multiple cortical spikes result from a single burst. Moreover, we show that the interval preceding each burst is crucial for generating the enhanced cortical response. The powerful activation of neocortex by thalamocortical bursts is fully consistent with an involvement of these impulses in perceptual/attentional processes.
Smoking is the leading risk factor for chronic obstructive pulmonary disease (COPD) worldwide, yet many people who never smoke develop COPD. We perform a longitudinal analysis of COPD in the UK ...Biobank to derive and validate the Socioeconomic and Environmental Risk Score which captures additive and cumulative environmental, behavioral, and socioeconomic exposure risks beyond tobacco smoking. The Socioeconomic and Environmental Risk Score is more predictive of COPD than smoking status and pack-years. Individuals in the highest decile of the risk score have a greater risk for incident COPD compared to the remaining population. Never smokers in the highest decile of exposure risk are more likely to develop COPD than previous and current smokers in the lowest decile. In general, the prediction accuracy of the Social and Environmental Risk Score is lower in non-European populations. While smoking status is often considered in screening COPD, our finding highlights the importance of other non-smoking environmental and socioeconomic variables.
Abstract Coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. Current methods lack the ability to ...incorporate new information throughout the life course or to combine innate genetic risk factors with acquired lifetime risk. We designed a general multistate model (MSGene) to estimate age-specific transitions across 10 cardiometabolic states, dependent on clinical covariates and a CAD polygenic risk score. This model is designed to handle longitudinal data over the lifetime to address this unmet need and support clinical decision-making. We analyze longitudinal data from 480,638 UK Biobank participants and compared predicted lifetime risk with the 30-year Framingham risk score. MSGene improves discrimination (C-index 0.71 vs 0.66), age of high-risk detection (C-index 0.73 vs 0.52), and overall prediction (RMSE 1.1% vs 10.9%), in held-out data. We also use MSGene to refine estimates of lifetime absolute risk reduction from statin initiation. Our findings underscore our multistate model’s potential public health value for accurate lifetime CAD risk estimation using clinical factors and increasingly available genetics toward earlier more effective prevention.
The purpose of our study was to assess the individual variability of the response to climatic conditions of the radial increment of
L. trees aged 100-140 years. The studied pine stand grows in the ...conditions of a site with a heterogeneous microrelief in the Voronezh Reserve. The calculated coefficients of synchronicity and correlation of radial increment of a sample of individual Scots pine trees (wood cores). It has been established that in the radial increment of pine trees in the Voronezh Reserve, there is a significant diversity in the reflection of the climatic signal, which, as a rule, manifests itself in certain years that are not extreme in terms of climatic conditions. The reasons for the differentiated reaction of trees to climate are the differentiated conditions of the microrelief, and also, probably, the genetic diversity of forest stands. In natural stands there are individual trees showing very low values of synchronicity coefficients (GLK, %) or correlation coefficients (CC, %) with stand average values. Intrapopulation differences in the response of pine forest stands to fluctuations in climatic factors are one of the forms of protective mechanisms for the survival of a species that have developed as a result of evolutionary development. As our study showed, intrapopulation differences are large in stands of natural origin and not subject to anthropogenic impacts.
The immune composition of the tumor microenvironment influences response and resistance to immunotherapies. While numerous studies have identified somatic correlates of immune infiltration, germline ...features that associate with immune infiltrates in cancers remain incompletely characterized. We analyze seven million autosomal germline variants in the TCGA cohort and test for association with established immune-related phenotypes that describe the tumor immune microenvironment. We identify one SNP associated with the amount of infiltrating follicular helper T cells; 23 candidate genes, some of which are involved in cytokine-mediated signaling and others containing cancer-risk SNPs; and networks with genes that are part of the DNA repair and transcription elongation pathways. In addition, we find a positive association between polygenic risk for rheumatoid arthritis and amount of infiltrating CD8+ T cells. Overall, we identify multiple germline genetic features associated with tumor-immune phenotypes and develop a framework for probing inherited features that contribute to differences in immune infiltration.
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•Tumor immune infiltration impacts response to immunotherapy•GWAS identifies inherited genetic variants associated with immune infiltration•Aggregating variants into genes and networks increases power to find associations•Germline associations may offer insight into predictors of response to immunotherapy
The role of inherited variants in influencing the immune composition of the tumor microenvironment is not fully characterized. Shahamatdar et al. identify germline variants, genes, and pathways associated with immune infiltration phenotypes in cancer, which may offer insights into determinants of response to immunotherapy.
The functional consequences of somatic non-coding mutations in ovarian cancer (OC) are unknown. To identify regulatory elements (RE) and genes perturbed by acquired non-coding variants, here we ...establish epigenomic and transcriptomic landscapes of primary OCs using H3K27ac ChIP-seq and RNA-seq, and then integrate these with whole genome sequencing data from 232 OCs. We identify 25 frequently mutated regulatory elements, including an enhancer at 6p22.1 which associates with differential expression of ZSCAN16 (P = 6.6 × 10-4) and ZSCAN12 (P = 0.02). CRISPR/Cas9 knockout of this enhancer induces downregulation of both genes. Globally, there is an enrichment of single nucleotide variants in active binding sites for TEAD4 (P = 6 × 10-11) and its binding partner PAX8 (P = 2×10-10), a known lineage-specific transcription factor in OC. In addition, the collection of cis REs associated with PAX8 comprise the most frequently mutated set of enhancers in OC (P = 0.003). These data indicate that non-coding somatic mutations disrupt the PAX8 transcriptional network during OC development.
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