Howard Hughes Medical Institute

De Novo Design and Structural Optimization of Mn(salen)‐Based Artificial Metalloenzymes for Asymmetric Sulfoxidation

ABSTRACT Artificial metalloenzymes (ArMs) exhibit exceptional selectivity, yet extending their reactivity beyond native cofactors remains a major challenge. While previous designs using native protein scaffolds to incorporate nonnative cofactors have been reported, de novo protei...

Multi-organelle signatures map cell-state diversity and metabolic adaptation in tissues

Cell-state diversity drives tissue adaptability, repair, and disease resilience, but capturing this complexity is a challenge. Current approaches rely on transcriptional profiling and overlook organelle structure, a key indicator of metabolism and stress. We developed spatial Org...

VIPR RNA-guided DNA recognition by noncontiguous geometric triplex formation

Viral interference programmable repeat (VIPR) systems use a noncontiguous code for RNA-guided transcriptional silencing. How the Vipr protein and a VIPR RNA (vrRNA) comprising alternating GGY and NN segments achieve precise DNA targeting is unknown. Here, we present 21 cryo–elect...

A noncontiguous code for RNA-guided DNA recognition at the origin of CRISPR-Cas

CRISPR-Cas provides RNA-mediated adaptive immunity, but how its first RNA-guided effector arose is unclear. In this study, we report the discovery of Viral Interference Programmable Repeat (VIPR) systems consisting of a Vipr protein ancestral to the earliest CRISPR-Cas effectors...

Adherent-invasive Escherichia coli pduB drives vitamin B 12 -dependent colitis in mice

ABSTRACT Adherent-invasive Escherichia coli (AIEC) are strongly implicated in the pathogenesis of Crohn’s disease, but the virulence factors driving their invasive and pro-inflammatory behavior remain incompletely defined. Here, we demonstrate that vitamin B 12 availability modul...

From silos to synergy: the interdisciplinary discovery potential in redefining polyendocrine metabolic ovarian syndrome

Polyendocrine metabolic ovarian syndrome (PMOS) affects one of every eight women worldwide and is associated with high rates of cardiovascular disease, type 2 diabetes, and infertility. Polycystic ovarian syndrome (PCOS), another term for this condition, reflects a historical foc...

Live dynamics of induced cell-cell fusion between mitotic and interphasic cells

The cell cycle is tightly regulated by checkpoint mechanisms that ensure faithful duplication and segregation of the genome. Here, we induced cell-cell fusion between mitotic and interphase cells to study how nuclei from different cell cycle stages behave in a shared cytoplasm. W...

Neocortical long-range inhibition promotes cortical synchrony and sleep

Abstract Sleep and wakefulness are associated with distinct cortical patterns of rhythmic activity 1 . During low-arousal states such as slow-wave sleep, synchronous low-frequency rhythms dominate activity across widespread cortical regions. Although inhibitory neurons are increa...

The distribution of fitness effects of nonsynonymous mutations varies phylogenetically across animals

The distribution of fitness effects (DFE) describes the selection coefficients of newly arising mutations and fundamentally influences population genetic processes. However, the extent and mechanisms of differences in the DFE for non-synonymous mutations have not been systematica...

Mutation E300 recommended by protein language models gives ChrimsonR amplified photocurrent response

Abstract A central challenge in opsin engineering is identifying mutations that reliably improve desired functional properties, a task made difficult by the enormous mutation space and limited throughput of electrophysiological screening. Improving opsin properties such as photoc...

The YTHDF proteins modulate Alzheimer’s disease-associated brain gene signatures

Abstract Gene signatures of Alzheimer’s disease (AD) brains reflect the output of a complex interplay of genetic, epigenetic, epi-transcriptomic, and post-transcriptional regulations. To nominate candidate factors modulating these signatures, we developed a machine learning model...

Human-inherited RORγT deficiency encompasses genetic heterogeneity, T cell deficiency, and clinical homogeneity

Abstract We previously reported inherited RORγT deficiency in seven patients from three ancestries (Chilean, Palestinian, Saudi Arabian) with mycobacterial disease and chronic mucocutaneous candidiasis (CMC). We report here five additional patients from different ancestries (Afgh...

In extracto cryo-EM reveals eEF2 as a major hibernation factor on 60S and 80S particles

Abstract Cryogenic electron microscopy (cryo-EM) made impressive progress in resolving cellular macromolecules and their detailed interactions. Single-particle cryo-EM traditionally relies on purified macromolecules and lacks the complexity of cellular environments, whereas in si...

Rapidly evolving aphid gall effector proteins exhibit saposin-like folds

Abstract Many insects manipulate plants by injecting effector proteins. In one extreme example of this molecular “hijacking”, Hormaphis cornu aphids inject bicycle proteins into Hamamelis virginiana , contributing to the development of novel organs called galls. Bicycle proteins...

The roles of symmetric and asymmetric parental histone recycling in cell fate, development, and disease

Replication of the epigenome occurs concurrently with DNA replication. A major component of epigenetic memory is contained in histones, and this memory is preserved via recycling of parental histones onto the leading and lagging strands of the replication fork. The histones of on...

Laboratory and wild Drosophila sechellia have conserved niche specialization phenotypes

Abstract Many studies investigating the proximate causes of evolutionary adaptations dissect potentially adaptive phenotypes under laboratory conditions where organisms are more easily experimentally manipulated. For such models, it remains unclear if organisms maintained long-te...

Maternal immune activation disrupts epigenomic and functional maturation of cortical excitatory neurons

Elevated levels of maternal pro-inflammatory cytokines following severe infection during gestation can disrupt offspring neural development and increase the risk of neurodevelopmental disorders. The viral mimetic Poly(I:C) reproduces the effects of gestational influenza exposure,...

Population morphology implies a common developmental blueprint for Drosophila motion detectors

Abstract T4 and T5 neurons are the first direction-selective neurons in the visual pathway. They are the most numerous cell types in the fly brain (∼ 6000 within each optic lobe) and, as a population, their compact dendritic arbours span the entire visual field. They are classifi...

Combined Disruption of Multiple Cytokine Signaling Pathways Enables One-Step Anterograde Tracing with Vesicular Stomatitis Virus

Abstract Defining the direct postsynaptic targets of selected neuronal populations remains a major challenge for neural circuit mapping. Vesicular stomatitis virus (VSV) spreads efficiently in the anterograde direction, but replication-competent VSV undergoes multistep spread and...

Assessing the Validity of the Fixed Tree Topology Assumption in Phylodynamic Inference

Abstract Fixed tree topologies are widely used in phylodynamic analyses to reduce computational burden, yet the consequences of this assumption remain insufficiently understood. Here, we systematically assess the impact of various fixed-topology strategies on phylogenetic and phy...