PROFET Predicts Continuous Gene Expression Dynamics from scRNA-seq Data to Elucidate Heterogeneity of Cancer Treatment Responses.

Single-cell RNA sequencing captures static snapshots of gene expression but lacks the ability to track continuous gene expression dynamics over time. To overcome this limitation, we developed PROFET (Particle-based Reconstruction Of generative Force-matched Expression Trajectories), a computational framework that reconstructs continuous, nonlinear single-cell gene expression trajectories from sparsely sampled scRNA-seq data. PROFET first generates particle flows between time-stamped samples using a novel Lipschitz-regularized gradient flow approach and then learns a global vector field for trajectory reconstruction using neural force-matching.

Ox-LDL induces a non-inflammatory response enriched for coronary artery disease risk in human endothelial cells.

Oxidised low-density lipoprotein cholesterol (ox-LDL) is critical in the initiation and progression of atherosclerosis. While excessive atherogenic lipids in the arterial intima can trigger endothelial dysfunction in advanced lesions, the response of endothelial cells to ox-LDL in the early stages of atherogenesis remains unclear. Here, we conducted a comprehensive, genome-wide multi-omics characterisation of the cellular response to ox-LDL in primary human aortic endothelial cells (HAECs).

Lifestyle factors, genetic susceptibility and risk of incident diverticulitis: an integrated analysis of four prospective cohort studies and electronic health records-linked biobank.

Background: Both lifestyle factors and genetic predisposition contribute to the development of diverticulitis.

Objective: To examine whether lifestyle modification can reduce the genetic risk of diverticulitis.

Design: We derived an overall healthy lifestyle score for diverticulitis based on smoking, body mass index (BMI), physical activity, fibre and red meat among 179 564 participants in three prospective cohorts-the Nurses' Health Study (NHS), NHSII and the Health Professionals Follow-Up Study.

Disease-specific U1 spliceosomal RNA mutations in mature B-cell neoplasms.

Recurrent mutations in the third base of U1 spliceosomal RNA responsible for marked splicing and expression abnormalities have been described in chronic lymphocytic leukemia (CLL) and some solid tumors. However, the clinical significance of these mutations in large and independent CLL cohorts as well as their presence in other B-cell neoplasms is unknown. Here we characterized U1 mutations in 1670 CLL and 363 mature B-cell lymphomas.

Synthetic Mucins as Glycan-Defined Prebiotics.

The human microbiome contains at least as many bacterial cells as human cells. Some bacteria offer benefits, like improving gut barrier function, suppressing pathobiont growth, and modulating immunity. These benefits have popularized probiotics, but probiotic retention is often hindered by low colonization efficiency in the mucosal layer that lines all epithelial cells.

Mapping MAVE data for use in human genomics applications.

Background: Experimental data from functional assays have a critical role in interpreting the impact of genetic variants. Assay data must be unambiguously mapped to a reference genome to make it accessible, but it is often reported relative to assay-specific sequences, complicating downstream use and integration of variant data across resources. To make multiplexed assays of variant effect (MAVE) data more broadly available to the research and clinical communities, the Atlas of Variant Effects Alliance mapped MAVE data from the MaveDB community database to human reference sequences, creating an extensive set of machine-readable homology mappings that are incorporated into widely used human genomics applications.

Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy.

Healthy blood vessels supply neurons to preserve metabolic function. In blinding proliferative retinopathies (PRs), pathological neovascular tufts often emerge in lieu of needed physiological revascularization. Here we show that metabolic shifts in the neovascular niche define angiogenic fate.

CellMemory: hierarchical interpretation of out-of-distribution cells using bottlenecked transformer.

Machine learning methods, especially Transformer architectures, have been widely employed in single-cell omics studies. However, interpretability and accurate representation of out-of-distribution (OOD) cells remains challenging. Inspired by the global workspace theory in cognitive neuroscience, we introduce CellMemory, a bottlenecked Transformer with improved generalizability designed for the hierarchical interpretation of OOD cells.

ZNF280A links DNA double-strand break repair to human 22q11.2 distal deletion syndrome.

DNA double-strand breaks (DSB) are among the most deleterious forms of DNA damage and, if unresolved, result in DNA mutations and chromosomal aberrations that can cause disease, including cancer. Repair of DSBs by homologous recombination requires extensive nucleolytic digestion of DNA ends in a process known as DNA-end resection. In recent years, progress has been made in understanding how this process is initiated, but the later stages of this process-long-range DNA-end resection-are not well understood.

CH-π interactions confer orientational flexibility in protein-carbohydrate binding sites.

Protein-carbohydrate binding plays an essential role in biological processes including cellular recognition and immune signaling. However, glycans are hydrophilic with limited hydrophobic surfaces, a challenge for selective recognition by proteins. CH-π stacking interactions are pervasive in protein-carbohydrate binding sites and have emerged as critical drivers of protein-carbohydrate recognition.

Pleiotropic Effects of Metformin on the Chemotherapy Response of HPV-Positive Cancer Cells.

Improved treatment strategies for HPV-positive cancers are urgently required. The viral E6/E7 oncoproteins are essential for the proliferation of HPV-positive cancer cells and considered attractive therapeutic targets. Metformin is proposed to be repurposed for cancer therapy, but this is under controversial debate.

Optimizing participant and community engagement in cancer genomic sequencing research.

Purpose: We describe strategies implemented across research centers of the Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network to optimize engagement of participants and communities in cancer genomics research. We also present consensus definitions of engagement and engagement optimization, informed by our shared experiences in the Network.

Methods: Key informant interviews and a document review identified engagement and optimization strategies across PE-CGS research centers.

Omic Risk Scores are Associated with COPD-related Traits Across Three Cohorts.

Background: Chronic obstructive pulmonary disease (COPD) exhibits marked heterogeneity in lung function decline, mortality, exacerbations, and other disease-related outcomes. Omic risk scores (ORS) estimate the cumulative contribution of omics, such as the transcriptome, proteome, and metabolome, to a particular trait. This study evaluates the predictive value of ORS for COPD-related traits in both smoking-enriched and general population cohorts.

Increased Complement C4 in a Sparse Neuronal Subset Induces Network-Wide Transcriptomic Alterations in the Prefrontal Cortex.

The complement (C) pathway, a vital part of innate immunity, defends against pathogens and supports tissue surveillance. While local activation in the periphery enhances immune protection, dysregulation can trigger a self-amplifying cascade that spreads beyond the initial site, resulting in tissue injury. In the brain, complement proteins regulate synaptic plasticity and connectivity, raising the possibility that similar mechanisms of maladaptive propagation may disrupt neural circuits under pathological conditions.

Clinical validity of congenital myopathy genes determined by the ClinGen Congenital Myopathies Expert Panel.

Background: Congenital myopathies are a group of neuromuscular disorders that typically present at birth or early childhood with hypotonia and non-progressive or slowly progressive muscle weakness. They are classically subclassified by characteristic structural changes and histopathological findings in skeletal muscle. Variants in over 40 genes have been described to date in patients with various forms of congenital myopathy with overlapping phenotypic and histological features, which poses a challenge for laboratories and clinicians in interpreting genetic findings.

Chromatin Dynamics are Highly Subdiffusive Across Seven Orders of Magnitude.

Chromatin dynamics control the timescales of essential biological processes including DNA damage repair and activation of gene promoters by distal enhancers. Prior chromatin dynamics studies have reported widely varying degrees of subdiffusion, likely due to technical limitations. Here, we integrate MINFLUX-a recently developed single particle tracking method capable of achieving microsecond time resolution-with traditional tracking methodologies.

Socio-medical factors associated with neurodevelopmental disorders on the Kenyan coast.

Neurodevelopmental disorders (NDDs) are a group of conditions with their onset during the early developmental period and include conditions such as autism and intellectual disability. Occurrence of NDDs is thought to be determined by both genetic and environmental factors, but data on the role of environmental factors for NDD in Africa is limited. This study investigates environmental influences on NDDs in children from Kenya.

Realizing the promise of genome-wide association studies for effector gene prediction.

Genome-wide association studies (GWAS) identify regions of the genome in which genetic variation is associated with the risk of complex diseases, such as diabetes, or the magnitude of traits, such as blood pressure. Determining which 'effector genes' mediate the effects of GWAS associations is essential to using GWAS to understand disease mechanisms and develop new therapies. In recent years, GWAS authors have increasingly included effector gene predictions as part of their study results.

Determinants and clinical impact of time to plasma exchange in patients with immune thrombotic thrombocytopenic purpura.

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a hematologic disorder characterized by severe acquired deficiency in ADAMTS13, resulting in thrombotic microangiopathy and death if untreated. Plasma exchange (PLEX) is the backbone of iTTP management and has improved survival in this disorder. Guidelines suggest initiation of PLEX within 4-8 h of presentation; however, there is little evidence to guide the precise timing of PLEX, and barriers exist to its timely deployment.

Comprehensive evaluation of phosphoproteomic-based kinase activity inference.

Kinases regulate cellular processes and are essential for understanding cellular function and disease. To investigate the regulatory state of a kinase, numerous methods have been developed to infer kinase activities from phosphoproteomics data using kinase-substrate libraries. However, few phosphorylation sites can be attributed to an upstream kinase in these libraries, limiting the scope of kinase activity inference.

Type 1 Diabetes Polygenic Scores Improve Diagnostic Accuracy in Pediatric Diabetes Care.

Introduction: Accurately classifying pediatric diabetes can be challenging for providers, and misclassification can result in suboptimal care. In recent years, type 1 diabetes (T1D) polygenic scores, which quantify one's genetic risk for T1D based on T1D risk allele burden, have been developed with good discriminating capacity between T1D and not-T1D. These tools have the potential to improve significantly diagnostic provider accuracy if used in clinic.

Genomics reveals zoonotic and sustained human mpox spread in West Africa.

Five years before the 2022 multi-country mpox outbreak, Nigeria and Cameroon reported their first cases in more than three decades. Whereas the outbreak in Nigeria is recognized as an ongoing human epidemic, the drivers of the resurgence in Cameroon remain unclear. The rate of zoonoses remains uncertain in both countries, and gaps in genomic data obscure the timing and zoonotic and geographic origin of monkeypox virus (MPXV) emergence in humans.

Human Plasma Proteomics Links Modifiable Lifestyle Exposome to Disease Risk.

Environmental exposures influence disease risk, yet their underlying biological mechanisms remain poorly understood. We present the Human Exposomic Architecture of the Proteome (HEAP), a framework and resource integrating genetic, exposomic, and proteomic data to uncover how lifestyle influences disease through plasma proteins. Applying HEAP to 2,686 proteins in 53,014 UK Biobank participants, we identified over 11,000 exposure-protein associations across 135 lifestyle exposures.