Translational Therapeutics (United States)

Edited HSPCs rescue frataxin deficiency and inflammation-driven multisystemic pathology in Friedreich’s ataxia mice

Friedreich’s ataxia (FRDA) is a multisystemic neurodegenerative disorder caused by GAA repeat expansion in intron 1 of frataxin ( FXN ), resulting in FXN deficiency and mitochondrial dysfunction. Current therapies do not correct the underlying genetic defect. Here, we demonstrate...

Circadian Rhythms in Drug Response: From Molecular Clocks to Precision Dosing

Circadian rhythms organize mammalian physiology across the 24-h day through molecular clocks coordinated by the central clock in the suprachiasmatic nucleus and distributed to peripheral oscillators. These clocks regulate processes central to pharmacology, including drug absorpti...

Epigenome-Wide Association Study of Abdominal Aortic Aneurysm Identifies Central Role for Inflammatory Pathways

BACKGROUND: Epigenetic mechanisms underlying susceptibility to abdominal aortic aneurysm (AAA) remain poorly understood. Identifying causal DNA methylation markers for AAA can elucidate the regulatory processes that drive aneurysm formation and accelerate translational applicatio...

Single-nucleus transcriptome-wide association study of human brain disorders

Abstract Common brain disorders impose a substantial health burden, but localizing their genetic risk in the brain remains challenging 1 . Although genome-wide association studies have identified numerous loci associated with neuropsychiatric and neurodegenerative disorders, many...

Personalized single-cell transcriptomics reveals molecular diversity in Alzheimer’s disease

Alzheimer’s disease (AD) is highly heterogeneous and driven by diverse molecular and cellular mechanisms. Functional genomics investigates these mechanisms from genetic variants to gene expression and regulation. We performed personalized functional genomics analysis on populatio...

AI-based characterization of Alzheimer’s disease phenotypes from population-scale single-cell data

The complexity of Alzheimer’s disease (AD) manifests in diverse clinical phenotypes, including cognitive impairment and neuropsychiatric symptoms. However, the etiology of these phenotypes remains elusive. To address this, the PsychAD project generated a population-level single-n...

Management of non-survivable head trauma: Opportunities for improvement

Background Managing patients with non-survivable head trauma who do not meet brain death criteria presents significant ethical and clinical challenges. Decisions frequently fall to surrogates with limited guidance, particularly when organ donation status is unknown. This study as...

Repositioning of polyubiquitin alters the pathologic tau filament structure

Abstract Structurally diverse tau filaments form proteinaceous aggregates in a heterogeneous group of neurodegenerative diseases called tauopathies 1 . The factors extrinsic to the highly ordered core structure that influence tau filament stability are not well understood. Here,...

Assessing the need for reproductive genetic counseling among adults with cystic fibrosis

Abstract Background Reproductive health has become an increasingly important focus for people with cystic fibrosis (CF), and guidelines have recommended routine inclusion of genetic counselors on care teams to address questions regarding infertility, pregnancy planning, prenatal...

Potent type-specific de novo antibodies complement broadly reactive imprinted antibodies in immune responses to SARS-CoV-2 variants

Abstract For rapidly mutating viruses such as influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), immune memory recalled by antigenically drifted variants primarily comprises antibodies that cross-react to the priming strain rather than de novo eli...

Genome folding and nuclear speckles converge to orchestrate fibroblast activation

Fibroblasts adopt diverse cell states in response to inductive cues to maintain tissue homeostasis. We leveraged this cell-state plasticity to define how genome organization contributes to changes in cellular identity. We show that TGF-β reconfigures topologically associating dom...