Pathogenic Cardiomyopathy-Associated Gene Variants and Prognosis in Atrial Fibrillation: Results in 18,000 Clinical Trial Participants.

Background: Genetic variants in cardiomyopathy genes are associated with risk of atrial fibrillation (AF), although data on clinical outcomes for AF patients with such variants remain sparse.

Objectives: We aimed to study the prognostic implication of rare cardiomyopathy-associated pathogenic variants (CMP-PLP) in AF patients from large, well-phenotyped clinical trials.

Methods: CMP-PLP carriers were identified using exome sequencing in 5 multinational trials from the Thrombolysis in Myocardial Infarction study group (ENGAGE AF, FOURIER, SAVOR, PEGASUS, and DECLARE), with replication in the EAST-AFNET-4 trial.

An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer.

is among the most frequently mutated oncogenes in cancer, and for decades, efforts at pharmacological blockade of its function in solid cancers have been unsuccessful. A notable advance in this endeavor is the recent development of small-molecule KRAS inhibitors, which enable direct targeting of the mutant oncoprotein. Here, we comprehensively evaluated the preclinical efficacy of BI-2493, a first-in-class allele-agnostic mutant-KRAS inhibitor (panKRASi), in pancreatic ductal adenocarcinoma (PDAC).

Polygenic Contributions to Lithium Augmentation Outcomes in Unipolar Depression.

Importance: Lithium augmentation is an effective treatment for patients with major depression after inadequate antidepressant response, but therapeutic outcomes vary considerably between individuals. Molecular studies may provide novel insights into treatment prediction and guide personalized therapy.

Objective: To investigate the association of polygenic risk scores (PRS) for schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) with clinical outcomes after lithium augmentation.

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.

DNA methylation insulates genic regions from CTCF loops near nuclear speckles.

The insulator protein CTCF is essential for mediating chromatin loops and regulating gene expression. While it is established that DNA methylation hinders CTCF binding, the impacts of this methylation-sensitive CTCF binding on chromatin architecture and transcription are poorly defined. Here, we used a selective DNMT1 inhibitor (DNMT1i) to investigate the characteristics and functions of 'DNMT1i-specific' CTCF peaks resulting from global DNA demethylation.

Navigating the life stage after stroke: From Life 2.0 to stroke prevention models of care - A qualitative exploration of younger and middle-aged adult stroke patients' experiences and recommendations.

Background: Global stroke incidence has been rising among adults 65 years of age or younger. A dearth of research exists exploring and understanding younger and middle-aged adults' lifestyle-related knowledge and habits along with associated facilitators and/or barriers with the adoption, maintenance, and support needs for development of new brain health interventions, which this study sought to address.

Methods: A qualitative study was conducted, followed by virtual, semi-structured focus groups.

Improving the FAIRness and Sustainability of the NHGRI Resources Ecosystem.

In 2024, individuals funded by NHGRI to support genomic community resources completed a Self-Assessment Tool (SAT) to evaluate their application of the FAIR (Findable, Accessible, Interoperable, and Reusable) principles and assess their sustainability. By collecting insights from the self-administered questionnaires and conducting personal interviews, a valuable perspective was gained on the FAIRness and sustainability of the NHGRI resources. The results highlighted several challenges and key areas the NHGRI resource community could improve by working together to form recommendations to address these challenges.

TCR germline diversity reveals evidence of natural selection on variable and joining alpha chain genes.

T cell receptors (TCRs) orchestrate adaptive immunity, yet the complex, repetitive architecture of the TCR loci has impeded systematic characterization of human genetic variation in the genes encoding the TCR. Using public long-read sequencing data from 2,668 donors, we build a near-complete map of common alleles in TCR V, D, and J genes, revealing amino acid variation at almost every position within V genes. We discover pervasive evidence of natural selection on TCR genes, including balancing selection on a TRAJ gene recognizing an immunodominant influenza epitope and positive selection on a TRAV gene.

Pre-training Genomic Language Model with Variants for Better Modeling Functional Genomics.

Sequence-to-function models can predict gene expression from sequence data and be used to link genetic information with transcriptomics data to understand regulatory processes and their effects on complex phenotypes. The genomic language models are pre-trained with large-scale DNA sequences and can generate robust representations of these sequences by learning the genomic context. However, few studies can estimate the predictability of gene expression levels and bridge these two classes of models together to explore individualized gene expression prediction.

Development of Degraders and 2-pyridinecarboxyaldehyde (2-PCA) as a recruitment Ligand for FBXO22.

Targeted protein degradation (TPD) is a promising therapeutic strategy that requires the discovery of small molecules that induce proximity between E3 ubiquitin ligases and proteins of interest. FBXO22 is an E3 ligase that is overexpressed in many cancers and implicated in tumorigenesis. While FBXO22 was previously identified as capable of recognizing ligands bearing a primary amine degron, further investigation and development of recruitment ligands is required to enable its broader utility for TPD.

Defensive tolerance drives the reprogramming and dysfunction of infiltrating pathogenic B cells assuring the maintenance of tolerance.

We previously showed that infiltrating cytotoxic immune cells are reprogrammed to regulatory-like/exhausted cells within accepted kidney allografts through a 'defensive tolerance' mechanism. We observed a regulatory B cell (Breg) signature within the accepted kidney. Here we show that despite a Breg phenotype, neither B cell depletion nor the use of μMT recipients which lack B cells, resulted in kidney allograft rejection.

A novel and evolutionarily conserved inhibitory circuit selectively regulates dentate gyrus mossy cell function.

The mammalian dentate gyrus contributes to mnemonic function by parsing similar events and places. The disparate activity patterns of mossy cells and granule cells are believed to enable this function yet the mechanisms that drive this circuit dynamic remain elusive. We identified a novel inhibitory interneuron subtype, characterized by VGluT3 expression, with overwhelming target selectivity for mossy cells while also revealing that CCK, PV, SST and VIP interneurons preferentially innervate granule cells.

Deep Learning with Disc Photos or OCT Scans in Glaucoma Detection.

Objective: To determine whether a deep learning (DL) model using retinal nerve fiber layer thickness (RNFLT) maps from OCT scans can detect glaucoma, defined by functional visual field (VF) impairment, more accurately than a DL model using disc photos (DPs). A secondary objective was to assess the diagnostic performance of these DL models across demographic groups (race, sex, and ethnicity).

Design: Retrospective cohort study at a tertiary glaucoma center utilizing OCT and DP datasets collected between 2011 and 2022.

Risk factors for dementia and cognitive impairment within 5 years after stroke: a prospective multicentre cohort study.

Background: Stroke survivors frequently experience subsequent cognitive impairment or dementia. We aimed to identify risk factors for post-stroke dementia (PSD) and cognitive impairment (PSCI) within 5 years after stroke.

Methods: The DEMDAS (German Center for Neurological Diseases (DZNE) mechanisms of dementia after stroke) study is a prospective cohort of stroke patients admitted to six German tertiary stroke centres between May 1, 2011 and January 31, 2019.

Colchicine and Longitudinal Dynamics of Clonal Hematopoiesis: An Exploratory Substudy of the LoDoCo2 Trial.

Background: Clonal hematopoiesis (CH) is an aging-related hematologic condition associated with increased risk for cardiovascular events. Larger CH clones associate more strongly with cardiovascular risk. Preclinical data indicate that inflammatory signaling drives expansion of CH clones and CH-associated cardiovascular disease.

Defining the antitumor mechanism of action of a clinical-stage compound as a selective degrader of the nuclear pore complex.

Cancer cells are acutely dependent on nuclear transport due to elevated transcriptional activity, suggesting an unrealized opportunity for selective therapeutic inhibition of the nuclear pore complex. Through large-scale phenotypic profiling of cancer cell lines, genome-scale functional genomic modifier screens, and mass spectrometry-based proteomics, we discovered that the clinical drug PRLX-93936 is a molecular glue that binds and reprograms the TRIM21 ubiquitin ligase to degrade the nuclear pore complex. Upon compound-induced TRIM21 recruitment, the nuclear pore is ubiquitylated and degraded, resulting in the loss of short-lived cytoplasmic mRNA transcripts and induction of cancer cell apoptosis.

Mitigating antimicrobial resistance by innovative solutions in AI (MARISA): a modified James Lind Alliance analysis.

Antimicrobial resistance (AMR) is a critical global health threat and artificial intelligence (AI) presents new opportunities for our response. However, research priorities at the AI-AMR intersection remain undefined. This study aimed to identify and prioritise key areas for future investigation.

Mature and migratory dendritic cells promote immune infiltration and response to anti-PD-1 checkpoint blockade in metastatic melanoma.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, yet most patients fail to achieve durable responses. To better understand the tumor microenvironment (TME), we analyze single-cell RNA-seq (~189 K cells) from 36 metastatic melanoma samples, defining 14 cell types, 55 subtypes, and 15 transcriptional hallmarks of malignant cells. Correlations between cell subtype proportions reveal six distinct clusters, with a mature dendritic cell subtype enriched in immunoregulatory molecules (mregDC) linked to naive T and B cells.

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.

Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia.

In studies of individuals of primarily European genetic ancestry, common and low- frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole genome sequencing (∼27X) of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study).

Alternate dyes for image-based profiling assays.

Background: Cell Painting, the leading image-based profiling assay, involves staining plated cells with six dyes that mark the different compartments in a cell. Such profiles can then be used to discover connections between samples (whether different cell lines, different genetic treatments, or different compound treatments) as well as to assess particular features impacted by each treatment. Researchers may wish to vary the standard dye panel to assess particular phenotypes, or image cells live while maintaining the ability to cluster profiles overall.

Tamoxifen induces PI3K activation in uterine cancer.

Mutagenic processes and clonal selection contribute to the development of therapy-associated secondary neoplasms, a known complication of cancer treatment. The association between tamoxifen therapy and secondary uterine cancers is uncommon but well established; however, the genetic mechanisms underlying tamoxifen-driven tumorigenesis remain unclear. We find that oncogenic PIK3CA mutations, common in spontaneously arising estrogen-associated de novo uterine cancer, are significantly less frequent in tamoxifen-associated tumors.

Objectively and Subjectively Measured Physical Activity and Their Associations With Cardiometabolic Risk in the UK Biobank: Retrospective Cohort Study.

Background: The association between physical activity (PA) behavior and cardiometabolic risk factors has depended largely on questionnaire-based reporting. More studies are turning to mobile health (mHealth) device solutions to measure PA. While there are differences between self-reported activity levels and objectively measured accelerometer-based activity, how these differences manifest in disease risk is unknown.

Assocation Between a Brain Care Score Derived from Participant Responses and Incident Stroke from the COSMOS Study.

Objective: The Brain Care Score (BCS), previously validated to predict the risk of age-related brain diseases, incorporates 12 modifiable risk factors, including blood pressure and laboratory measurements. In the U.S.