Broad Institute

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...

Conserved and divergent mitochondrial assemblies in kinetoplastid parasites

The mitochondrial proteomes of Leishmania tarentolae and Trypanosoma brucei contain ∼1,700 proteins, most of which lack homologs in higher eukaryotes. Here, we integrate complexome profiling and cryo-electron microscopy to define conserved and lineage-specific macromolecular asse...

Single-cell profiling and genetic regulation of alternative polyadenylation in the human brain

Abstract Alternative polyadenylation (APA) has a central role in regulation of the fate of mRNA and exhibits high variability in the brain and in neurons. However, brain APA regulation has not been mapped at cell type resolution, and the genetic control of APA in brain cell types...

REDISCOVERING THE DEAD: REANALYSIS OF A LOST IRON AGE CEMETERY AT HIGHSTED, KENT

Summary Highsted, near Sittingbourne in Kent, was the location of a large cemetery, thought to date to the Late Iron Age. The site was excavated under rescue conditions in 1955, but due to the apparent theft of the archive and finds, was never published. As part of a wider projec...

Multivariate genetic analyses test for the presence of a general ‘ n ’ factor underlying neurodevelopmental conditions

Abstract Background Neurodevelopmental conditions often emerge early in life and have substantial genetic influences. There are significant genetic correlations between neurodevelopmental conditions, such as between autism spectrum disorder (Autism) and attention deficit‐hyperact...

A Versatile DNA‐Encoded Library Platform for the Discovery of Highly Cooperative Chemical Inducers of Proximity

ABSTRACT Chemical‐induced proximity, particularly via molecular glues, represents a rapidly advancing therapeutic paradigm. Expanding the scope of proximity‐based therapeutics requires generalizable discovery platforms that can be easily tailored to diverse presenter proteins. He...

mRNA Therapeutics for Skin Rejuvenation: From Aging Atlases to Clinical Translation

ABSTRACT Skin aging is a multifactorial process characterized by the progressive decline of tissue structure, function and regenerative capacity. Although numerous interventions have been developed to improve the clinical manifestations of aging, most primarily alleviate downstre...

An rRNA hybridization-based approach for rapid and accurate identification of diverse fungal pathogens

species, to identify diverse fungal pathogens. We created a set of 91 probes targeting 86 medically relevant fungal species, designed to recognize regions of differential conservation across taxonomic groupings, from class- to species-specific probes. We assessed assay performanc...

Tumor microbial biodiversity and microsatellite instability in colorectal cancer

Background Growing evidence links the gut microbiome to colorectal cancer (CRC) progression, with certain bacterial species enriched in specific molecular tumor subtypes. DNA mismatch repair deficiency in CRC, evidenced by the presence of microsatellite instability (MSI), has bee...

Positive selection screen identifies natural product β-catenin inactivators

Many genetically validated targets in cancer, including the transcription factor β-catenin (β-cat), have historically been viewed as undruggable. Cell-based phenotypic screening of chemical compounds can reveal unanticipated biological and pharmacological principles. Natural prod...

Divergent medulloblastoma chromatin states disclose KDM2B as a selective dependency

Abstract Medulloblastoma is a biologically heterogeneous childhood cerebellar tumor harboring frequent chromatin-modifying gene alterations. How these alterations promote transcriptional programs governing malignancy remains poorly defined. To address this knowledge gap, we evalu...

A design approach for bitopic kinase inhibitors

Abstract Traditional kinase inhibitors face a trade-off between potency and selectivity because their affinity depends on limited molecular interactions in a single highly conserved binding site. Bitopic inhibitors overcome this limitation by engaging multiple sites on the same t...

Actionable genetic landscape and dynamics in circulating DNA from 12,827 patients with metastatic breast cancer

Abstract Plasma cell-free DNA (cfDNA) is a sensitive, noninvasive tool for monitoring the genomic landscape, heterogeneity, and evolution of cancer, aggregating genetic information from multiple metastatic sites. Here, we study 15,564 cfDNA samples from 12,827 patients with metas...

Gut microbiome maturation in early childhood interacts with host genetics to predict type 1 diabetes risk

Prospective evidence linking early-life microbiome development and host genetics with type 1 diabetes (T1D) risk is limited. Here, we describe how gut microbiome maturation and host genetics influence T1D risk in the TEDDY study. We analysed 12,151 longitudinal metagenomes and ho...

RamanOmics decodes the spatial vibrational–molecular architecture of senescence in aging and repair

Aging and tissue repair involve heterogeneous remodeling across transcriptional, biochemical and cellular dimensions, yet prevailing definitions rely on isolated molecular markers that obscure how these states co-evolve. Here we present RamanOmics, a multimodal framework integrat...

1. CONTRIBUTION OF COMMON AND RARE VARIANTS TO SCHIZOPHRENIA RISK IN EAST AND SOUTH ASIAN ANCESTRIES

Background Genetic studies of patients with schizophrenia have primarily focused on European ancestries, leaving other populations, including East Asian and South Asian ancestries, underrepresented, potentially increasing health disparities. Methods Here, we report findings from...

Bioresorbable batteries for transient ingestible bioelectronics

Abstract Ingestible and implantable electronic devices are transforming personalized healthcare by enabling real-time sensing, targeted therapy and diagnostic capabilities. However, powering these systems remains a major challenge owing to biocompatibility concerns and the enviro...

T9. BRAIN–BONE CROSSTALK IN SCHIZOPHRENIA-ASSOCIATED OSTEOPOROSIS: FROM BRAIN-CENTERED THERAPY TO BRAIN–BONE CO-TREATMENT

Background Schizophrenia is increasingly recognized as a systemic disorder rather than a purely brain-centered psychiatric disease. Osteoporosis and fragility fractures are underrecognized but clinically important comorbidities in patients with schizophrenia, who often show reduc...

Tumor Vascular Features and Colorectal Cancer–Specific Mortality

Importance The phenotypic and morphologic heterogeneity of tumor vasculature in colorectal cancer (CRC) has been increasingly recognized; however, its clinical importance remains unclear. Objective To examine whether specific tumor vascular features are associated with CRC-specif...

Cross-platform Bayesian deconvolution of MeDIP-seq reveals tissue-specific and cancer-associated methylation signatures

Abstract DNA methylation profiling of cell-free DNA is increasingly used for tissue-of-origin analysis and cancer detection, but quantitative interpretation of enrichment-based sequencing data remains a major challenge. MeDIP-seq provides scalable, cost-effective profiling of low...