Impact of polymorphisms on gene expression and splicing in response to exercise and diet-induced weight loss in human skeletal muscle tissues.

Weight loss through exercise and diet reduces the risk of type 2 diabetes, but the genetic regulation of gene expression and splicing in response to weight loss remains unclear in humans. We collected clinical data and skeletal muscle biopsies from 54 overweight/obese Asian individuals before and after a 16-week lifestyle intervention, which resulted in an average of ∼10% weight loss, accompanied by an ∼30% increase in insulin-stimulated glucose uptake. Improvements were observed in 118 of 252 clinical traits and six blood lipids.

scPrediXcan integrates deep learning methods and single-cell data into a cell-type-specific transcriptome-wide association study framework.

Transcriptome-wide association studies (TWASs) help identify disease-causing genes but often fail to pinpoint disease mechanisms at the cellular level because of the limited sample sizes and sparsity of cell-type-specific expression data. Here, we propose scPrediXcan, which integrates state-of-the-art deep learning approaches that predict epigenetic features from DNA sequences with the canonical TWAS framework. Our prediction approach, ctPred, predicts cell-type-specific expression with high accuracy and captures complex gene-regulatory grammar that linear models overlook.

Towards a consensus atlas of human and mouse adipose tissue at single-cell resolution.

Adipose tissue (AT) is a complex connective tissue with a high relative proportion of adipocytes, which are specialized cells with the ability to store lipids in large droplets. AT is found in multiple discrete depots throughout the body, where it serves as the primary repository for excess calories. In addition, AT has an important role in functions as diverse as insulation, immunity and regulation of metabolic homeostasis.

Asian diversity in human immune cells.

The relationships of human diversity with biomedical phenotypes are pervasive yet remain understudied, particularly in a single-cell genomics context. Here, we present the Asian Immune Diversity Atlas (AIDA), a multi-national single-cell RNA sequencing (scRNA-seq) healthy reference atlas of human immune cells. AIDA comprises 1,265,624 circulating immune cells from 619 donors, spanning 7 population groups across 5 Asian countries, and 6 controls.

Estimation of heart rate and respiratory rate by fore-background spatiotemporal modeling of videos.

Heart rate (HR) and respiratory rate (RR) are two critical physiological parameters that can be estimated from video recordings. However, the accuracy of remote estimation of HR and RR is affected by fluctuations in ambient illumination. To address this adverse effect, we propose a fore-background spatiotemporal (FBST) method for estimating HR and RR from videos captured by consumer-grade cameras.

The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.

The 40S ribosomal subunit recycling pathway is an integral link in the cellular quality control network, occurring after translational errors have been corrected by the ribosome-associated quality control (RQC) machinery. Despite our understanding of its role, the impact of translation quality control on cellular metabolism remains poorly understood. Here, we reveal a conserved role of the 40S ribosomal subunit recycling (USP10-G3BP1) complex in regulating mitochondrial dynamics and function.

Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases.

Alternative splicing contributes to complex traits, but whether this differs in trait-relevant cell types across diverse genetic ancestries is unclear. Here we describe cell-type-specific, sex-biased and ancestry-biased alternative splicing in ~1 M peripheral blood mononuclear cells from 474 healthy donors from the Asian Immune Diversity Atlas. We identify widespread sex-biased and ancestry-biased differential splicing, most of which is cell-type-specific.

scPrediXcan integrates advances in deep learning and single-cell data into a powerful cell-type-specific transcriptome-wide association study framework.

Transcriptome-wide association studies (TWAS) help identify disease causing genes, but often fail to pinpoint disease mechanisms at the cellular level because of the limited sample sizes and sparsity of cell-type-specific expression data. Here we propose scPrediXcan which integrates state-of-the-art deep learning approaches that predict epigenetic features from DNA sequences with the canonical TWAS framework. Our prediction approach, ctPred, predicts cell-type-specific expression with high accuracy and captures complex gene regulatory grammar that linear models overlook.

siRNADiscovery: a graph neural network for siRNA efficacy prediction via deep RNA sequence analysis.

The clinical adoption of small interfering RNAs (siRNAs) has prompted the development of various computational strategies for siRNA design, from traditional data analysis to advanced machine learning techniques. However, previous studies have inadequately considered the full complexity of the siRNA silencing mechanism, neglecting critical elements such as siRNA positioning on mRNA, RNA base-pairing probabilities, and RNA-AGO2 interactions, thereby limiting the insight and accuracy of existing models. Here, we introduce siRNADiscovery, a Graph Neural Network (GNN) framework that leverages both non-empirical and empirical rule-based features of siRNA and mRNA to effectively capture the complex dynamics of gene silencing.

Fenofibrate Recognition and G Protein Coupling Mechanisms of the Human Cannabinoid Receptor CB1.

The G-protein-coupled human cannabinoid receptor 1 (CB1) is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. The structures of CB1-G complexes in synthetic agonist-bound forms have been resolved to date. However, the commercial drug recognition and G coupling mechanisms of CB1 remain elusive.

Synthesis of -Dienyl Esters Using Acetylene as C2 Synthon.

The stereoselective synthesis of dienyl esters with high atom- and step-economy has been largely unexplored. Herein, we report an efficient approach for the synthesis of -dienyl esters via rhodium catalysis using carboxylic acid and acetylene as C2 synthon through the cascade of cyclometalation and C-O coupling. This protocol features mild conditions, excellent functional group tolerance, and exclusive -stereoselectivity and utility in the late-stage modification of pharmaceuticals and natural products.

Algorithm for optimized mRNA design improves stability and immunogenicity.

Messenger RNA (mRNA) vaccines are being used to combat the spread of COVID-19 (refs. ), but they still exhibit critical limitations caused by mRNA instability and degradation, which are major obstacles for the storage, distribution and efficacy of the vaccine products. Increasing secondary structure lengthens mRNA half-life, which, together with optimal codons, improves protein expression.

Synthesis of vinyl-substituted alcohols using acetylene as a C2 building block.

Vinyl-substituted alcohols represent a highly useful class of molecular skeletons. The current method typically requires either stoichiometric metallic reagents or preformed precursors. Herein, we report a nickel catalysis-enabled synthesis of vinyl-substituted alcohols a 5-membered oxa-metallacycle.

Correction: Synthesis of vinyl-substituted alcohols using acetylene as a C2 building block.

[This corrects the article DOI: 10.1039/D2SC06400F.].

Molecular mechanisms of coronary artery disease risk at the PDGFD locus.

Genome wide association studies for coronary artery disease (CAD) have identified a risk locus at 11q22.3. Here, we verify with mechanistic studies that rs2019090 and PDGFD represent the functional variant and gene at this locus.

Molecular mechanisms of coronary artery disease risk at the locus.

Platelet derived growth factor (PDGF) signaling has been extensively studied in the context of vascular disease, but the genetics of this pathway remain to be established. Genome wide association studies (GWAS) for coronary artery disease (CAD) have identified a risk locus at 11q22.3, and we have verified with fine mapping approaches that the regulatory variant rs2019090 and represent the functional variant and putative functional gene.

Cu-catalyzed carboboration of acetylene with Michael acceptors.

A copper-catalyzed three-component carboboration of acetylene with BPin and Michael acceptors is reported. In this reaction, a cheap and abundant C2 chemical feedstock, acetylene, was used as a starting material to afford -alkenyl boronates bearing a homoallylic carbonyl group. The reaction was robust and could be reliably performed on the molar scale.

Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism.

Human neurodegenerative disorders often exhibit similar pathologies, suggesting a shared aetiology. Key pathological features of Parkinson's disease (PD) are also observed in other neurodegenerative diseases. Pantothenate Kinase-Associated Neurodegeneration (PKAN) is caused by mutations in the human PANK2 gene, which catalyzes the initial step of de novo CoA synthesis.

Migratory insertion of copper-allenylidene from propargyl ester.

The highly efficient copper-catalyzed homo-dimerization and cross-coupling of propargyl esters have been developed. Various 1-en-3,5-diynes, [5]cumulenes and 1,3-diynes were successfully furnished the copper-allenylidene intermediates with moderate to excellent yields. Migratory insertion is proposed as the key step to achieve the selectivity at the carbene carbon of the copper-allenylidene.

Analysis and Visualization of Spatial Transcriptomic Data.

Human and animal tissues consist of heterogeneous cell types that organize and interact in highly structured manners. Bulk and single-cell sequencing technologies remove cells from their original microenvironments, resulting in a loss of spatial information. Spatial transcriptomics is a recent technological innovation that measures transcriptomic information while preserving spatial information.

Acronyms and Opportunities for Improving Deep Nets.

Recently, several studies have reported promising results with BERT-like methods on acronym tasks. In this study, we find an older rule-based program, Ab3P, not only performs better, but error analysis suggests why. There is a well-known spelling convention in acronyms where each letter in the short form (SF) refers to "salient" letters in the long form (LF).

LinearTurboFold: Linear-time global prediction of conserved structures for RNA homologs with applications to SARS-CoV-2.

The constant emergence of COVID-19 variants reduces the effectiveness of existing vaccines and test kits. Therefore, it is critical to identify conserved structures in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes as potential targets for variant-proof diagnostics and therapeutics. However, the algorithms to predict these conserved structures, which simultaneously fold and align multiple RNA homologs, scale at best cubically with sequence length and are thus infeasible for coronaviruses, which possess the longest genomes (∼30,000 nt) among RNA viruses.

LinearTurboFold: Linear-Time Global Prediction of Conserved Structures for RNA Homologs with Applications to SARS-CoV-2.

Unlabelled: The constant emergence of COVID-19 variants reduces the effectiveness of existing vaccines and test kits. Therefore, it is critical to identify conserved structures in SARS-CoV-2 genomes as potential targets for variant-proof diagnostics and therapeutics. However, the algorithms to predict these conserved structures, which simultaneously fold and align multiple RNA homologs, scale at best cubically with sequence length, and are thus infeasible for coronaviruses, which possess the longest genomes (∼30,000 ) among RNA viruses.