Howard Hughes Medical Institute

Gene-rich fungus gnat germline-restricted chromosomes are largely transcriptionally quiescent

Germline-restricted chromosomes (GRCs) constitute a unique class of chromosomes confined to germ cells. Arising in multiple evolutionarily distant lineages, GRCs have been identified in three insect families (non-biting midges, gall midges, and fungus gnats), each within the orde...

Prediction of cardiovascular outcomes using electrocardiography from overnight polysomnography.

STUDY OBJECTIVES: Polysomnography (PSG) is the gold standard for diagnosing sleep disorders, which are recognized as cardiovascular risk factors. Single-lead electrocardiograms (ECGs) are recorded during PSG but rarely analyzed, presenting an opportunity to leverage overnight ECG...

Tree Rearrangement Graphs Admit Paths of Decreasing Robinson-Foulds Distance

Tree rearrangements such as Nearest Neighbor Interchange (NNI) and Subtree Prune and Regraft (SPR) are commonly used to explore phylogenetic treespace. Computing distances based on them, however, is often intractable, so the efficiently computable Robinson-Foulds (RF) distance is...

Dystrophic changes of nigrostriatal axons harboring a SYNJ1 Parkinson’s mutation suggest catastrophic failure of endocytic mechanisms

Synaptojanin 1 is a brain enriched phosphoinositide phosphatase implicated in endocytosis at the synapse. A mutation (R258Q) that selectively impairs its Sac1 phosphatase domain causes early onset familial Parkinsonism. Neurons of mice with this mutation display synaptic vesicle...

A DNA Typewriter records the cell lineage history of a mouse, from zygote to late organogenesis

Mammalian biology unfolds over time, within tissues and organs opaque to our eyes and instruments. We applied DNA Typewriter, a sequential molecular recorder, to record the cell lineage of a mouse over nearly two weeks of development. From one embryo, we reconstruct a time-calibr...

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...

Structural basis for regulating lipopolysaccharide transmembrane transport

Gram-negative bacteria are surrounded by a multilayered cell envelope with a mostly impermeable outer membrane that provides intrinsic resistance to many antibiotics1–5. The outer membrane is an asymmetrical bilayer with phospholipids in the inner leaflet and lipopolysaccharide (...

Recurrent hypermotif regulatory circuits in developmental programs

During development, cells self-organize into complex spatial and temporal patterns driven by regulatory circuits of transcription factors and morphogen signaling. However, the principles that govern these regulatory interactions remain poorly understood. Here, we introduce a fram...

Autoantibodies neutralizing type I IFNs underlie ~5% of herpes simplex encephalitis in adults.

Inborn errors of type I interferon (IFN-I) immunity account for ∼7-8% of herpes simplex encephalitis (HSE) cases in young children, but the pathogenesis of HSE in adults is largely unknown. We report that IFN-I autoantibodies (auto-Abs) in serum/plasma samples drawn before, durin...

Near-atomistic simulations reveal the molecular principles that control chromatin structure and phase separation

Abstract Understanding how chromatin’s physicochemical properties shape its emergent organization is central to deciphering genome function. To address this, we present OpenCGChromatin, a high-performance coarse-grained model that achieves near-atomistic simulations of chromatin...

Acanthamoeba ATP synthase structure reveals the TCA cycle is tethered to OXPHOS

Oxidative phosphorylation (OXPHOS) is a key metabolic process that couples redox energy to ATP production. While some core OXPHOS complex subunits are found across all domains of life, many have diverged or expanded across evolution—as seen in the protozoan pathogen Acanthamoeba...

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...

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...

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...

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...

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...

Structural basis of stepwise G protein activation by the viral chemokine receptor US28

Abstract G protein-coupled receptors (GPCRs) govern diverse cellular responses and are crucial drug targets. However, the sequence of structural events from G protein recognition to GDP release has remained elusive. Here, we leveraged the viral chemokine GPCR US28 to capture mult...

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...

Self‐Supervised Internal Learning Enhances Isotropic Resolution for Three‐Dimensional Fluorescence Microscopy

ABSTRACT Three‐dimensional fluorescence microscopy often exhibits anisotropic resolution because axial information is poorly sampled and more blurred than lateral information, which complicates quantitative interpretation of fine 3D structures. Although optical remedies and compu...

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...