Broad Institute

Efficient and accurate steering of large language models through attention-guided feature learning

Activation steering, or direct manipulation of internal activations to guide large language model (LLM) responses toward specific semantic concepts, is emerging as a promising avenue for both understanding how semantic concepts are stored within LLMs and advancing LLM capabilitie...

Poison exon splicing in the human brain provides a new paradigm for understanding and targeting neurological disorders

Poison exons are highly conserved exons whose inclusion creates premature termination codons and triggers nonsense-mediated decay (NMD) of the mature transcript. Despite their important role in post-transcriptional regulation, poison exons remain poorly annotated due to the lack...

Cohesin Mutations in Cancer and Development

Cohesin is a ring-shaped protein complex that wraps around DNA and is crucial for sister chromatid cohesion, chromatin organization, gene regulation, replication, and DNA damage repair. In somatic cells, it consists of the core ring subunits SMC1A, SMC3, and RAD21 and one of two...

Svep1 orchestrates distal airway patterning and alveolar differentiation in murine lung development

Abstract Disruptions in airway branching or alveolar differentiation during lung development can lead to severe respiratory deficiencies and neonatal death. The molecular mechanisms governing branching patterning and early alveolar formation remain elusive. Loss of Svep1 function...

Exploring transcriptomic and genomic latent variable correction approaches in differential expression analysis

Abstract Background Differential expression analysis is a central tool for studying the biological processes altered in human diseases via transcriptomic signatures. However, transcriptomic datasets are systematically confounded by latent variables from two distinct sources: unme...

Advancing Heart Failure Classification Beyond Left Ventricular Ejection Fraction: Unsupervised Machine Learning Insights From the Japanese Nationwide Acute Decompensated Heart Failure Cohort: JROADHF

Background Heart failure (HF) classification based on left ventricular ejection fraction (LVEF) inadequately captures HF heterogeneity, limiting phenotype‐specific therapies. While machine learning (ML) has been applied to HF with preserved ejection fraction, comprehensive approa...

Lymph node contraction links sex-biased naive CD8+ T cell decline to compromised antigen recognition during middle age

Abstract The abundance of diverse naive CD8 + T cell clones is essential for broad protection against infection and cancer, but how sex and aging jointly shape this compartment remains poorly understood. Here, using mouse models with supporting human data, we uncover a sex-biased...

Latent causal diffusions for single-cell perturbation modeling

Perturbation screens hold the potential to systematically map regulatory processes at single-cell resolution, yet modeling and predicting transcriptome-wide responses to perturbations remains a major computational challenge. Existing methods often underperform simple baselines, f...

Human trilayer engineered blood vessel reveals influence of fibroblasts on disease progression in model of Hutchinson-Gilford progeria

In vitro models of vascular disease have focused primarily on the pathophysiology of smooth muscle cell (SMC) or endothelial cell (EC). Adventitial fibroblasts can contribute to disease progression, but their specific influence is not well understood in different disease contexts...

A multiomic atlas reveals distinct immune landscapes in preterm and term chronic placental inflammation

Chronic placental inflammation (CPI), an umbrella term encompassing chronic chorioamnionitis, chronic villitis, and chronic deciduitis, is associated with preterm birth (PTB), yet its cellular and molecular determinants across gestation remain poorly defined. Here, we constructed...

Neuropsychiatry genetics in Africa

Across Africa, rising mental health needs coincide with rapid advances in genomics, digital health and continental policy reform. Yet research into the genetic, environmental and social determinants of neuropsychiatric illness remains sparse and underfunded. This review argues th...

Alzheimer’s disease neuropathological characterization of the dog brain and relationship to biofluid biomarkers and cognitive function

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting more than 55 million people worldwide and is characterized by cognitive decline, amyloid-beta (Aβ) plaques, and neurofibrillary tangles. Although transgenic rodent models have advanced understanding of...

The landscape of allele-specific expression in human kidneys

Allele-specific expression (ASE), the preferential expression of one gene copy, is a key mechanism of genomic regulation. However, its role in human kidney disease remains poorly understood. In this study, we generated a high-quality, genome-wide ASE map using paired whole-genome...

Leptin-sensitive hypothalamic Lepr+/Glp1r+ neurons limit hyperphagia and weight gain in diet-induced obesity

Abstract Despite loss of responsiveness to exogenous leptin in obesity, endogenous leptin continues to restrain feeding, although the neural substrates that remain sensitive and mediate this effect remain unknown. Combining spatial transcriptomics with single-nucleus RNA sequenci...

A rapid, inexpensive diagnostic for bacterial pathogen and resistance detection in resource-limited settings

Antimicrobial resistance is a major global health threat, with disproportionate impact in regions with limited diagnostic infrastructure. To address this challenge, we developed BADLOCK (Bacterial and AMR Detection by SHERLOCK), a rapid, low-cost molecular diagnostic platform for...

Interpretable and Calibrated Classification of Clinical Data Using Supervised Feature Binarization

Black-box models limit the adoption of artificial intelligence in medicine because their predictions are difficult to interpret and reproduce. We present a statistically grounded framework for interpretable, rule-based clinical classification using the Bernoulli Naïve Bayes (BNB)...

A high-confidence plant mitochondrial proteome via protein correlation profiling

Plant mitochondria share many features with animal mitochondria but also possess unique traits, including presence of both circular and linear mitochondrial DNA, RNA editing, a branched electron transport chain, and metabolic pathways supporting photosynthesis. An accurate mitoch...

Mitochondrial proteome of Acanthamoeba delineates aerobic and anaerobic pathways dynamically regulated by oxygen

Acanthamoeba castellanii causes infectious blindness and resides in a key evolutionary outgroup to humans and fungi. Its divergent mitochondria are of outstanding interest due to their predicted aerobic and anaerobic functions with potential for drug targeting. However, a detaile...

Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling

Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature, but how these diverse signals are molecularly integrated remains unknown. We showed that these cues converge on the orphan mitochondrial transporter SLC25A34 to orchestrate lipid...

Comparative analysis of mitochondrial proteomes across the tree of life

Mitochondria arose from the endosymbiosis of a bacterium with an archaea-related host cell about 2 billion years ago. To understand their origins and evolution, we compared experimentally defined mitoproteomes from the MitoCarta Tree of Life project. Across eight organisms, we id...