A human-mouse atlas of intrarenal myeloid cells identifies conserved disease-associated macrophages in lupus nephritis.

Monocytes and macrophages in patients with lupus nephritis exhibit altered behavior compared with healthy kidneys. How to optimally use mouse models to develop treatments targeting these cells is poorly understood. This study compared intrarenal myeloid cells in four mouse models and 155 lupus nephritis patients using single-cell profiling, spatial transcriptomics, and functional studies.

Coagulation factor XII haploinsufficiency is protective against venous thromboembolism in a population-scale multidimensional analysis.

Coagulation factor XII has been identified as a potential drug target that could prevent thrombosis without increasing the risk of bleeding. However, human data to support the development of factor XII-directed therapeutics are lacking. To assess the role of factor XII in venous thromboembolism, we examine genetic variation in the coding region of the F12 locus across 703,745 participants in the UK Biobank and NIH All of Us biorepositories.

Longitudinal Antibody Responses to SARS-CoV-2 Infection in Children: Impact of Age, Vaccines and Symptoms.

The majority of children experience severe acute respiratory syndrome coronavirus-2 infection as a mild infection. In this longitudinal single-center study of children infected early in the pandemic and managed as outpatients, we assess the impact of age, vaccination, recurrent infection and initial symptoms on severe acute respiratory syndrome coronavirus-2-specific antibody responses over time.

The mitotic STAG3-cohesin complex shapes male germline nucleome.

Germ cells are unique in that they tailor chromatin toward generating totipotency. Accordingly, mammalian spermatogonia, including spermatogonial stem cells that constitute the source for male gametes, acquire distinctive chromatin organization with weak insulation, but the underlying mechanism remains unknown. Here we show that STAG3, so far known to exclusively form meiotic cohesins, generates a mitotic cohesin for male germline nucleome programming in mice.

Exogenous estrogen enhances T cell activation in male primates.

Estrogen influences T cell development and enhances infection resistance in females, but its immunological effects during gender-affirming hormone therapy (GAHT) remain poorly understood. Here, we characterize immune adaptations in male rhesus macaques (RMs) treated with 17β-estradiol (E2) or placebo over 7 months. E2 therapy suppressed endogenous testosterone production, induced female physical traits, and altered blood cell counts and chemistry profiles.

Genome-wide association study of borderline personality disorder identifies 11 loci and highlights shared risk with mental and somatic disorders.

We conducted the largest genome-wide meta-analysis of borderline personality disorder (BPD) to date, with a discovery sample of 12,339 cases and 1,041,717 controls, and a replication study of 685 cases and 107,750 controls (all participants of European ancestry). We identified 11 independent associated genomic loci, and nine risk genes in the gene-based analysis. We observed a single-nucleotide polymorphism (SNP) heritability of 17.

Alpha-synuclein abundance and localization are regulated by the RNA-binding protein PUMILIO1.

The protein α-synuclein, encoded by SNCA, accumulates in Parkinson's disease (PD) and other synucleinopathies for reasons that remain unclear. Here, we investigated whether SNCA is regulated in vivo by the RNA-binding protein PUM1. We establish that PUM1 binds to SNCA's 3' UTR in mouse and human cells.

Clonotype-enriched somatic hypermutations drive affinity maturation of a public human antibody targeting an occluded sarbecovirus epitope.

Investigating public antibodies that recognize conserved epitopes is critical for vaccine development. Identifying somatic hypermutations (SHMs) that enhance antigen affinity in these public antibodies is key to guiding vaccine design for better protection against pathogens. We propose that affinity-enhancing SHMs are selectively enriched in public antibody clonotypes, surpassing the background frequency seen in antibodies carrying the same V genes but with different epitope specificities.

Compartment-Specific Metabolic Alterations to Insulin Reflect Adiposity-Driven Variation and Predict Type 2 Diabetes.

Context: The metabolic mechanisms underlying insulin resistance (IR) are not fully understood. Metabolomic profiling can reveal compartment-specific variations and identify individuals at risk for type 2 diabetes (T2D).

Objective: To characterize insulin-induced metabolomic changes during a hyperinsulinemic-euglycemic clamp and evaluate a derived risk score's predictive value for T2D.

CDK8 Inhibition Releases the Muscle Differentiation Block in Fusion-driven Alveolar Rhabdomyosarcoma.

Alveolar rhabdomyosarcoma (aRMS) is a fusion-driven pediatric cancer with poor survival and limited therapeutic options. To uncover novel vulnerabilities, we employed complex-based analysis of the DepMap functional genomic data, identifying CDK8 as a dependency in aRMS. Both knockout and pharmacologic inhibition impaired tumor cell growth and induced myogenic differentiation and .

Integrative proteogenomics and forward genetics reveals a novel mitotic vulnerability in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with few effective targeted therapies. Taxanes and other microtubule-targeting agents (MTAs) are frontline chemotherapies for TNBC; however, the molecular pathways that cause TNBC taxane sensitivity are largely unknown, preventing selection of taxane-responsive patients and development of more selective therapeutic strategies. In this study, we identified tumor-selective vulnerabilities in TNBC harboring inactivation of the tumor suppressor PTPN12 by integrating proteogenomic characterization and synthetic lethality screening.

Real-time, multi-pathogen wastewater genomic surveillance with Freyja 2.

Case-based infectious disease surveillance is fundamental to public health, but is resource-intensive, logistically complex, and prone to sampling bias. Wastewater testing and sequencing have increasingly been used for population-scale monitoring of pathogen dynamics, including in low-resource settings. Broader adoption of wastewater genomic surveillance, however, is limited by a lack of flexibility across sequencing platforms and approaches, and adaptability to additional pathogens.

TGF-β Coordinates Alanine Synthesis and Import for Myofibroblast Differentiation in Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease marked by aberrant fibroblast-to-myofibroblast differentiation, a process that requires metabolic reprogramming. We identify alanine as a critical metabolite that confers metabolic flexibility to support differentiation. TGF-β increases alanine by activating both its synthesis and import in normal and IPF lung fibroblasts.

Chromatin Perturbation Promotes Susceptibility to Hypomethylating Agents.

Cancer-directed drugs are often clinically deployed without definitive understanding of their molecular mechanisms of action (MOA). Hypomethylating agents (HMAs), which result in the degradation of the DNA methyltransferase 1 (DNMT1), have been deployed for decades in the treatment of haematological malignancies. The precise mechanism of action of these drugs, however, has been debated, rendering the design of rational combination therapies challenging.

Role of the gut microbiome in frequent gut colonization with extended-spectrum β lactamase-producing Enterobacterales among Peruvian children.

Gut colonization with extended-spectrum beta lactamase-producing Enterobacterales (ESBL-E) is increasingly common among children in low- and middle-income countries. Some children nevertheless remain never or rarely colonized during early life. Understanding how this protection is conferred could be helpful for designing future interventions to protect children's health.

Supporting Participant Engagement in Cancer Genomics Research in Rare Cancers: A Qualitative Study of Patients, Caregivers, and Advocates.

IntroductionThe purpose of this study was to identify patterns and themes that support participant engagement in patient-partnered cancer genomics research.MethodsThe Osteosarcoma (OS) and Leiomyosarcoma (LMS) Projects of Count Me In allow any patient with OS and LMS in the US and Canada to contribute their health information, tumor samples, and lived experience to an aggregated, public research database. We conducted in-depth interviews with research partners, including patients, caregivers, and advocates, who were purposefully sampled to ensure inclusion of racial and ethnic minorities, those with less than college education, and adolescents (age 12-17).

Improved Allele Frequencies in gnomAD through Local Ancestry Inference.

The Genome Aggregation Database (gnomAD) is a foundational resource for allele frequency data, widely used in genomic research and clinical interpretation. However, traditional estimates rely on individual-level genetic ancestry groupings that may obscure variation in recently admixed populations. To improve resolution, we applied local ancestry inference (LAI) to over 27 million variants in two admixed groups: Admixed American (n = 7,612) and African/African American (n = 20,250), deriving ancestry-specific allele frequencies.

Intelectin-2 is a broad-spectrum antimicrobial lectin.

Mammals regulate the localization, composition, and activity of their native microbiota at colonization sites. Lectins residing at these sites influence microbial populations, but their individual functions are often unclear. Intelectins are found in chordates at mucosal barriers, but their functions are not well characterized.

Uncovering methylation-dependent genetic effects on regulatory element function in diverse genomes.

A major goal in evolutionary biology and biomedicine is to understand the complex interactions between genetic variants, the epigenome, and gene expression. However, the causal relationships between these factors remain poorly understood. mSTARR-seq, a methylation-sensitive massively parallel reporter assay, is capable of identifying methylation-dependent regulatory activity at many thousands of genomic regions simultaneously and allows for the testing of causal relationships between DNA methylation and gene expression on a region-by-region basis.

Genome structure mapping with high-resolution 3D genomics and deep learning.

Gene expression is often regulated by distal enhancers through cell-type-specific 3D looping interactions, but comprehensive mapping of these interactions across cell types is experimentally intractable. To address this gap, we introduce an integrated approach where we generate ultra-deep Region Capture Micro-C (RCMC) and Micro-C data specifically designed for state-of-the-art deep learning architectures. We developed Cleopatra, an attention-based deep learning model that takes epigenomic inputs and is pre-trained on genome-wide Micro-C data followed by fine-tuning with high-resolution RCMC data.

Cell type-specific contributions to impaired blood-brain barrier and cerebral metabolism in presymptomatic 5XFAD mice.

Altered cerebral metabolism and blood-brain barrier (BBB) dysfunction are emerging as critical contributors to the preclinical phase of Alzheimer's disease (AD), underscoring their role in early pathogenesis. To identify sensitive biomarkers before irreversible neuronal loss and cognitive decline, we examined 5XFAD mice at 3 months of age by applying multiple advanced MRI techniques. Arterial spin tagging based MRI revealed increased BBB permeability and water extraction fraction, indicating compromised BBB integrity at the early stage of pathogenesis in 5×FAD mice.

Cross-omics risk scores of inflammation markers are associated with all-cause mortality: The Canadian Longitudinal Study on Aging.

Inflammation is a critical component of chronic diseases, aging progression, and lifespan. Omics signatures may characterize inflammation status beyond blood biomarkers. We leveraged genetics (polygenic risk score [PRS]), metabolomics (metabolomic risk score [MRS]), and epigenetics (epigenetic risk score [ERS]) to build multi-omics-multi-marker risk scores for inflammation status represented by the level of circulating C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α).

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.