The Burden of Motor Neuron Diseases in the United States, 1990-2021: A Systematic Analysis of the Global Burden of Disease Study 2021.

Introduction/aims: There is a lack of up-to-date information on the burden of motor neuron diseases (MNDs) in the United States (US). This study aimed to estimate trends in the prevalence, incidence, mortality, and disability-adjusted life years (DALYs) for MNDs in the US from 1990 to 2021.

Methods: We performed a secondary analysis of MNDs in the US using estimates of prevalence, incidence, and mortality obtained from analyses of the Global Burden of Disease 2021 dataset.

Ensuring Biosecurity and Research Agility for Outbreak Response: A Researcher's Perspective on the Federal Nucleic Acid Screening Framework.

The Framework for Nucleic Acid Synthesis Screening (FNASS), introduced by the U.S. White House Office of Science and Technology Policy, establishes new biosecurity measures to address emerging concerns about the potential misuse of synthetic nucleic acid sequences.

User journeys in cross-European secondary use of health data: insights ahead of the European Health Data Space.

The European Health Data Space (EHDS) regulation aims to facilitate cross-border sharing of health data across Europe. However, practical challenges related to data access, interoperability, quality, and interpretive competence remain, particularly when working with health systems across countries. This study aimed to evaluate and report the user journey of researchers accessing and utilizing health data across four European countries for secondary research purposes prior to implementation of EHDS.

Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals.

Background: Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability.

Learning ecosystem-scale dynamics from microbiome data with MDSINE2.

Although dynamical systems models are a powerful tool for analysing microbial ecosystems, challenges in learning these models from complex microbiome datasets and interpreting their outputs limit use. We introduce the Microbial Dynamical Systems Inference Engine 2 (MDSINE2), a Bayesian method that learns compact and interpretable ecosystems-scale dynamical systems models from microbiome timeseries data. Microbial dynamics are modelled as stochastic processes driven by interaction modules, or groups of microbes with similar interaction structure and responses to perturbations, and additionally, noise characteristics of data are modelled.

Antibody-bottlebrush prodrug conjugates for targeted cancer therapy.

Antibody-drug conjugates (ADCs) are effective targeted therapeutics but are limited in their ability to incorporate less-potent payloads, varied drug mechanisms of action, different drug release mechanisms and tunable drug-to-antibody ratios. Here we introduce a technology to overcome these limitations called 'antibody-bottlebrush prodrug conjugates' (ABCs). An ABC consists of an IgG1 monoclonal antibody covalently conjugated to the terminus of a compact bivalent bottlebrush prodrug that has payloads bound through cleavable linkers and polyethylene glycol branches.

Combinatorial prediction of therapeutic perturbations using causally inspired neural networks.

Phenotype-driven approaches identify disease-counteracting compounds by analysing the phenotypic signatures that distinguish diseased from healthy states. Here we introduce PDGrapher, a causally inspired graph neural network model that predicts combinatorial perturbagens (sets of therapeutic targets) capable of reversing disease phenotypes. Unlike methods that learn how perturbations alter phenotypes, PDGrapher solves the inverse problem and predicts the perturbagens needed to achieve a desired response by embedding disease cell states into networks, learning a latent representation of these states, and identifying optimal combinatorial perturbations.

Circulating tumor human papillomavirus DNA whole genome sequencing enables human papillomavirus-associated oropharynx cancer early detection.

Purpose: Early detection of HPV-associated oropharyngeal cancer (HPV+OPSCC), the most common HPV cancer in the United States, could reduce disease-related morbidity and mortality, yet currently, there are no early detection tests. Circulating tumor HPV DNA (ctHPVDNA) is a sensitive and specific biomarker for HPV+OPSCC at diagnosis. It is unknown if ctHPVDNA is detectable prior to diagnosis, and thus it's potential as an early detection test.

TissueMosaic: Self-supervised learning of tissue representations enables differential spatial transcriptomics across samples.

Spatial transcriptomics allows for the measurement of gene expression within the native tissue context. However, despite technological advancements, computational methods to link cell states with their microenvironment and compare these relationships across samples and conditions remain limited. To address this, we introduce Tissue Motif-Based Spatial Inference across Conditions (TissueMosaic), a self-supervised convolutional neural network designed to discover and represent tissue architectural motifs from multi-sample spatial transcriptomic datasets.

Warp Analysis Research Pipelines: Cloud-optimized workflows for biological data processing and reproducible analysis.

Summary: In the era of large data, the cloud is increasingly used as a computing environment, necessitating the development of cloud-compatible pipelines that can provide uniform analysis across disparate biological datasets. The Warp Analysis Research Pipelines (WARP) repository is a GitHub repository of open-source, cloud-optimized workflows for biological data processing that are semantically versioned, tested, and documented. A companion repository, WARP-Tools, hosts Docker containers and custom tools used in WARP workflows.

Adverse Outcome Pathways Applied to Space Radiation Research.

Long-duration spaceflight exposes astronauts to various stressors that can alter human physiology, potentially causing immediate and long-term health effects. These stressors can damage biomolecules, cells, tissues, and organs, leading to adverse outcomes. Developing adverse outcome pathways (AOPs) relevant to radiation exposure can guide research priorities and inform risk assessments of future space exploration activities.

A Multimodal Imaging Framework to Advance Phenotyping of Living Label-free Breast Cancer Cells.

We present multimodal confocal Raman micro-spectroscopy (RS) and tomographic phase microscopy (TPM) for quick morpho-chemical phenotyping of human breast cancer cells (MDA-MB-231). Leveraging the non-perturbative nature of these advanced microscopy techniques, we captured detailed morpho-molecular data from living, label-free cells in their native physiological environment. Human bias-free data processing pipelines were developed to analyze hyperspectral Raman images (spanning Raman modes from 600 cm to 1800 cm, which uniquely characterize a wide range of molecular bonds and subcellular structures), as well as morphological data from three-dimensional refractive index tomograms (providing measurements of cell volume, surface area, footprint, and sphericity at nanometer resolution, alongside dry mass and density).

The airway-brain axis: Connecting breath, brain, and behavior.

The neural control of breathing is both dynamic and essential, ensuring life-sustaining gas exchange while protecting the respiratory system from harm. Peripheral neurons innervating the respiratory tract exhibit remarkable diversity, continuously relaying sensory feedback to the brain to regulate breathing, trigger protective reflexes such as coughing and sickness behaviors, and even influence emotional states. Understanding this airway-brain axis is especially critical given the increasing global burden of respiratory diseases, as it holds implications for both human health and broader brain-body interactions.

Portal vein-enriched metabolites as intermediate regulators of the gut microbiome in insulin resistance.

Diet and obesity contribute to insulin resistance and type 2 diabetes, in part via the gut microbiome. To explore the role of gut-derived metabolites in this process, we assessed portal/peripheral blood metabolites in mice with different risks of obesity/diabetes, challenged with a high-fat diet (HFD) + antibiotics. In diabetes/obesity-prone C57BL/6J mice, 111 metabolites were portally enriched and 74 were peripherally enriched, many of which differed in metabolic-syndrome-resistant 129S1/129S6 mice.

LRP2 Expression in Melanoma Is Associated With a Transitory Cell State, Increased T Cell Infiltration, and Is Upregulated by IFNy Signaling.

Low density lipoprotein receptor-related protein 2 (LRP2) is a 600 kilodalton multi-ligand endocytic membrane receptor expressed in several cell types during fetal development, including neuroepithelial cells, and in select absorptive epithelial cells in the adult. In epithelial cancers, LRP2 expression is associated with a differentiated tumor cell state and better prognosis. In previous work, we found that while LRP2 is not expressed in benign naevi, it is frequently acquired in melanoma.

Combining evidence from human genetic and functional screens to identify pathways altering obesity and fat distribution.

Overall adiposity and body fat distribution are heritable traits associated with altered risk of cardiometabolic disease and mortality. Performing rare-variant (minor allele frequency <1%) association testing using exome-sequencing data from 402,375 participants of European ancestry in the UK Biobank for nine overall and tissue-specific fat distribution traits, we identified 19 genes where putatively damaging rare variation associated with at least one trait (Bonferroni-adjusted p < 1.58 × 10) and 50 additional genes at false discovery rate (FDR) ≤1% (p ≤ 4.

Genetic and Cellular Architecture of Breast Cancer Risk in Multi-Ancestry Studies of 159,297 Cases and 212,102 Controls.

Breast cancer genome-wide association studies (GWAS) have identified over 200 independent genome-wide significant susceptibility markers. However, most studies have focused on one or two ancestral groups. We examined breast cancer genetic architecture using GWAS summary statistics from African (AFR), East Asian (EAS), European (EUR) and Hispanic/Latina (H/L) samples, totaling 159,297 cases and 212,102 controls, comprising the largest multi-ancestry study of breast cancer to date.

Phenotypic screening converges on CDK9 inhibition as a therapeutic strategy in translocation renal cell carcinoma.

Translocation renal cell carcinoma (tRCC) is an aggressive kidney cancer driven by gene fusions of the transcription factor. is essential in tRCC but dispensable in normal cells, presenting an attractive but pharmacologically challenging therapeutic target. We show that the basic helix-loop-helix (bHLH) domain of TFE3 is crucial for chromatin binding and transcriptional function.

Prospective study of circulating metabolomic profiles and breast cancer incidence among predominantly premenopausal women.

Background: Associations between premenopausal plasma metabolites and breast cancer incidence are largely unknown.

Methods: We conducted a prospective, matched case-control study in which we measured pre-diagnostic metabolomic profiles among predominantly premenopausal women in the Nurses' Health Study II (n = 2010). Lipids, carbohydrates, and organic acid-related metabolites (n = 218) were profiled via liquid chromatography-tandem mass spectrometry.

Decidual/placental and first trimester plasma levels of hsa-miR-199a-3p|hsa-miR-199b-3p and hsa-miR-3150b-3p are associated with insulin secretion in pregnancy.

Background/aims: The placenta expresses and releases specific microRNAs (miRNAs) into the maternal circulation that may influence insulin secretion during pregnancy. We hypothesized that specific decidual/placental miRNAs are associated with maternal insulin secretion during pregnancy.

Methods: In the Genetics of Glucose regulation in Gestation and Growth (Gen3G) prospective cohort, we estimated maternal insulin secretion using the Stumvoll first phase index derived from an oral glucose tolerance test at ~26 weeks of gestation.

Genetic Adaptation to Brackish Water and Spawning Season in European Cisco.

How species adapt to diverse environmental conditions is essential for understanding evolution and the maintenance of biodiversity. The European cisco (Coregonus albula) is a salmonid that occurs in both fresh and brackish water, and this together with the presence of sympatric spring- and autumn-spawning lacustrine populations provides an opportunity for studying the genetics of adaptation in relation to salinity and timing of reproduction. Here, we present a high-quality reference genome of the European cisco based on PacBio HiFi long read sequencing and HiC-directed scaffolding.

Reproducible single-cell annotation of programs underlying T cell subsets, activation states and functions.

T cells recognize antigens and induce specialized gene expression programs (GEPs), enabling functions like proliferation, cytotoxicity and cytokine production. Traditionally, different T cell classes are thought to exhibit mutually exclusive responses, including T1, T2 and T17 programs. However, single-cell RNA sequencing has revealed a continuum of T cell states without clearly distinct subsets, necessitating new analytical frameworks.

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).