Polygenic risk scores (PRS) have shown promise in predicting human complex traits and diseases. Here, we present PRS-CS, a polygenic prediction method that infers posterior effect sizes of single ...nucleotide polymorphisms (SNPs) using genome-wide association summary statistics and an external linkage disequilibrium (LD) reference panel. PRS-CS utilizes a high-dimensional Bayesian regression framework, and is distinct from previous work by placing a continuous shrinkage (CS) prior on SNP effect sizes, which is robust to varying genetic architectures, provides substantial computational advantages, and enables multivariate modeling of local LD patterns. Simulation studies using data from the UK Biobank show that PRS-CS outperforms existing methods across a wide range of genetic architectures, especially when the training sample size is large. We apply PRS-CS to predict six common complex diseases and six quantitative traits in the Partners HealthCare Biobank, and further demonstrate the improvement of PRS-CS in prediction accuracy over alternative methods.
Horizontal pleiotropy occurs when the variant has an effect on disease outside of its effect on the exposure in Mendelian randomization (MR). Violation of the 'no horizontal pleiotropy' assumption ...can cause severe bias in MR. We developed the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test to identify horizontal pleiotropic outliers in multi-instrument summary-level MR testing. We showed using simulations that the MR-PRESSO test is best suited when horizontal pleiotropy occurs in <50% of instruments. Next we applied the MR-PRESSO test, along with several other MR tests, to complex traits and diseases and found that horizontal pleiotropy (i) was detectable in over 48% of significant causal relationships in MR; (ii) introduced distortions in the causal estimates in MR that ranged on average from -131% to 201%; (iii) induced false-positive causal relationships in up to 10% of relationships; and (iv) could be corrected in some but not all instances.
Background & Aims
Differentiation antagonizing non‐protein coding RNA is associated with various types of neoplasms. Hepatitis C virus‐related hepatocellular carcinoma has a high risk of recurrence. ...Here we determined the role of differentiation antagonizing non‐protein coding RNA in hepatitis C virus‐related hepatocarcinogenesis and identified potential therapeutic targets and non‐invasive prognostic markers for long‐term outcome of hepatitis C virus‐related hepatocellular carcinoma after surgical resection.
Methods
Differentiation antagonizing non‐protein coding RNAs relevant to hepatitis C virus‐related hepatocellular carcinoma were identified through comparative RNA‐sequencing of tumour and adjacent non‐tumour (ANT) tissues in a screening set, and were validated using real‐time polymerase chain reaction. Target long non‐coding RNAs (lncRNAs) in tissues and serum exosomes were used to predict the recurrence of hepatitis C virus‐related hepatocellular carcinoma after curative surgical resection in a large application cohort from 2005 to 2012.
Results
We confirmed that differentiation antagonizing non‐protein coding RNA was upregulated following hepatitis C virus infection and identified as the lncRNA most relevant to hepatitis C virus‐related hepatocellular carcinoma in tumour tissues as compared to that in ANT tissues. In 183 hepatitis C virus‐related hepatocellular carcinoma patients followed for 10 years after curative HCC resection, the expression level of circulating exosomal differentiation antagonizing non‐protein coding RNA was positively associated with HCC recurrence and was the most predictive factor associated with HCC recurrence and mortality (hazard ratio/95% confidence intervals: 7.0/4.3‐11.6 and 2.7/1.5‐5.1 respectively).
Conclusions
Differentiation antagonizing non‐protein coding RNA is highly relevant to disease progression of hepatitis C virus‐related hepatocellular carcinoma. Our finding indicated that circulating exosomal differentiation antagonizing non‐protein coding RNA might serve as a non‐invasive prognostic biomarker for hepatitis C virus‐related hepatocellular carcinoma.
Heritability estimation provides important information about the relative contribution of genetic and environmental factors to phenotypic variation, and provides an upper bound for the utility of ...genetic risk prediction models. Recent technological and statistical advances have enabled the estimation of additive heritability attributable to common genetic variants (SNP heritability) across a broad phenotypic spectrum. Here, we present a computationally and memory efficient heritability estimation method that can handle large sample sizes, and report the SNP heritability for 551 complex traits derived from the interim data release (152,736 subjects) of the large-scale, population-based UK Biobank, comprising both quantitative phenotypes and disease codes. We demonstrate that common genetic variation contributes to a broad array of quantitative traits and human diseases in the UK population, and identify phenotypes whose heritability is moderated by age (e.g., a majority of physical measures including height and body mass index), sex (e.g., blood pressure related traits) and socioeconomic status (education). Our study represents the first comprehensive phenome-wide heritability analysis in the UK Biobank, and underscores the importance of considering population characteristics in interpreting heritability.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genome-wide association studies (GWAS) have identified thousands of genetic variants linked to the risk of human disease. However, GWAS have so far remained largely underpowered in relation to ...identifying associations in the rare and low-frequency allelic spectrum and have lacked the resolution to trace causal mechanisms to underlying genes
. Here we combined whole-exome sequencing in 392,814 UK Biobank participants with imputed genotypes from 260,405 FinnGen participants (653,219 total individuals) to conduct association meta-analyses for 744 disease endpoints across the protein-coding allelic frequency spectrum, bridging the gap between common and rare variant studies. We identified 975 associations, with more than one-third being previously unreported. We demonstrate population-level relevance for mutations previously ascribed to causing single-gene disorders, map GWAS associations to likely causal genes, explain disease mechanisms, and systematically relate disease associations to levels of 117 biomarkers and clinical-stage drug targets. Combining sequencing and genotyping in two population biobanks enabled us to benefit from increased power to detect and explain disease associations, validate findings through replication and propose medical actionability for rare genetic variants. Our study provides a compendium of protein-coding variant associations for future insights into disease biology and drug discovery.
Observing the intricate chemical transformation of an individual molecule as it undergoes a complex reaction is a long-standing challenge in molecular imaging. Advances in scanning probe microscopy ...now provide the tools to visualize not only the frontier orbitals of chemical reaction partners and products, but their internal covalent bond configurations as well. We used noncontact atomic force microscopy to investigate reaction-induced changes in the detailed internal bond structure of individual oligo-(phenylene-1, 2-ethynylenes) on a (100) oriented silver surface as they underwent a series of cyclization processes. Our images reveal the complex surface reaction mechanisms underlying thermally induced cyclization cascades of enediynes. Calculations using ab initio density functional theory provide additional support for the proposed reaction pathways.
In recent decades, chemotherapies targeting apoptosis have emerged and demonstrated remarkable achievements. However, emerging evidence has shown that chemoresistance is mediated by impairing or ...bypassing apoptotic cell death. Several novel types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, have recently been reported to play significant roles in the modulation of cancer progression and are considered a promising strategy for cancer treatment. Thus, the switch between apoptosis and pyroptosis is also discussed. Cancer immunotherapy has gained increasing attention due to breakthroughs in immune checkpoint inhibitors; moreover, ferroptosis, necroptosis, and pyroptosis are highly correlated with the modulation of immunity in the tumor microenvironment. Compared with necroptosis and ferroptosis, pyroptosis is the primary mechanism for host defense and is crucial for bridging innate and adaptive immunity. Furthermore, recent evidence has demonstrated that pyroptosis exerts benefits on cancer immunotherapies, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell therapy (CAR-T). Hence, in this review, we elucidate the role of pyroptosis in cancer progression and the modulation of immunity. We also summarize the potential small molecules and nanomaterials that target pyroptotic cell death mechanisms and their therapeutic effects on cancer.
Vitamin D has been associated with a variety of human complex traits and diseases in observational studies, but a causal relationship remains unclear. To examine a putative causal effect of vitamin D ...across phenotypic domains and disease categories, we conducted Mendelian randomization (MR) analyses using genetic instruments associated with circulating 25-hydroxyvitamin D 25(OH)D concentrations. We leveraged genome-wide significant 25(OH)D-associated SNPs (N = 138) from a meta-analysis combining a vitamin D GWAS conducted in 401,460 white British UK Biobank (UKBB) participants and an independent vitamin D GWAS including 42,274 samples of European ancestry, and examined 190 large-scale health-related GWAS spanning a broad spectrum of complex traits, diseases and biomarkers. We applied multiple MR methods to estimate the causal effect of vitamin D while testing and controlling for potential biases from horizontal pleiotropy. Consistent with previous findings, genetically predicted increased 25(OH)D levels significantly decreased the risk of multiple sclerosis (OR = 0.824; 95% CI 0.689-0.986). The protective effect estimate was consistent across different MR methods and four different multiple sclerosis GWAS with varying sample sizes and genotyping platforms. On the contrary, we found limited evidence in support of a causal effect of 25(OH)D on anthropometric traits, obesity, cognitive function, sleep behavior, breast and prostate cancer, and autoimmune, cardiovascular, metabolic, neurological and psychiatric traits and diseases, and blood biomarkers. Our results may inform ongoing and future randomized clinical trials of vitamin D supplementation.
Bandgap engineering is used to create semiconductor heterostructure devices that perform processes such as resonant tunnelling and solar energy conversion. However, the performance of such devices ...degrades as their size is reduced. Graphene-based molecular electronics has emerged as a candidate to enable high performance down to the single-molecule scale. Graphene nanoribbons, for example, can have widths of less than 2 nm and bandgaps that are tunable via their width and symmetry. It has been predicted that bandgap engineering within a single graphene nanoribbon may be achieved by varying the width of covalently bonded segments within the nanoribbon. Here, we demonstrate the bottom-up synthesis of such width-modulated armchair graphene nanoribbon heterostructures, obtained by fusing segments made from two different molecular building blocks. We study these heterojunctions at subnanometre length scales with scanning tunnelling microscopy and spectroscopy, and identify their spatially modulated electronic structure, demonstrating molecular-scale bandgap engineering, including type I heterojunction behaviour. First-principles calculations support these findings and provide insight into the microscopic electronic structure of bandgap-engineered graphene nanoribbon heterojunctions.
Potato common scab, which is caused by soil-borne Streptomyces species, is a severe plant disease that results in a significant reduction in the economic value of potatoes worldwide. Due to the lack ...of efficacious pesticides, crop rotations, and resistant potato cultivars against the disease, we investigated whether biological control can serve as an alternative approach. In this study, multiple Bacillus species were isolated from healthy potato tubers, and Bacillus amyloliquefaciens Ba01 was chosen for further analyses based on its potency against the potato common scab pathogen Streptomyces scabies. Ba01 inhibited the growth and sporulation of S. scabies and secreted secondary metabolites such as surfactin, iturin A, and fengycin with potential activity against S. scabies as determined by imaging mass spectrometry. In pot assays, the disease severity of potato common scab decreased from 55.6 ± 11.1% (inoculated with S. scabies only) to 4.2 ± 1.4% (inoculated with S. scabies and Ba01). In the field trial, the disease severity of potato common scab was reduced from 14.4 ± 2.9% (naturally occurring) to 5.6 ± 1.1% after Ba01 treatment, representing evidence that Bacillus species control potato common scab in nature.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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