The rockefeller university

Examples of long-range gene regulation in bacteria are rare and generally thought to involve DNA looping. Here, using a combination of biophysical approaches including X-ray crystallography and single-molecule analysis for the KorB-KorA system in Escherichia coli, we show that long-range gene silencing on the plasmid RK2, a source of multi-drug resistance across diverse Gram-negative bacteria, is achieved cooperatively by a DNA-sliding clamp, KorB, and a clamp-locking protein, KorA. We show that KorB is a CTPase clamp that can entrap and slide along DNA to reach distal target promoters up to 1.5 kb away. We resolved the tripartite crystal structure of a KorB-KorA-DNA co-complex, revealing that KorA latches KorB into a closed clamp state. DNA-bound KorA thus stimulates repression by stalling KorB sliding at target promoters to occlude RNA polymerase holoenzymes. Together, our findings explain the mechanistic basis for KorB role switching from a DNA-sliding clamp to a co-repressor and provide an alternative mechanism for long-range regulation of gene expression in bacteria.

Signaling from the T cell antigen receptor (TCR) on CD4+ T cells plays a critical role in adaptive immune responses by inducing T cell activation, proliferation, and differentiation. Here we demonstrate that WNK1, a kinase implicated in osmoregulation in the kidney, is required in T cells to support T-dependent antibody responses. We show that the canonical WNK1-OXSR1-STK39 kinase signaling pathway is required for TCR signaling in CD4+ T cells, their subsequent entry into the cell cycle, and suppression of the ATR-mediated G2/M cell cycle checkpoint. We show that the WNK1 pathway regulates ion influx leading to water influx, potentially through AQP3, and that water influx is required for TCR-induced signaling and cell cycle entry. Thus, TCR signaling via WNK1, OXSR1, STK39 and AQP3 leads to water entry that is essential for CD4+ T cell proliferation and hence T cell-dependent antibody responses.

The Mayaro virus (MAYV), Togaviridae family, genus Alphavirus, has caused several sporadic outbreaks, affecting countries in the Americas. Currently, there are no licensed drugs against MAYV, requiring the search for effective antiviral compounds. Thus, this study aimed to evaluate the antiviral potential of polyphenol (-)-epigallocatechin-3-gallate (EGCG) against MAYV infection, in vitro. Antiviral assays against MAYV were performed in BHK-21 and Vero E6 cells. In addition, molecular docking was performed with EGCG and the MAYV non-structural and structural proteins. EGCG showed a significant protective effect against MAYV infection in both cell lines. The virucidal assay showed an effect on extracellular viral particles at the entry stage into BHK-21 cells. Finally, it also showed significant inhibition in the post-entry stages of the MAYV replication cycle, acting on the replication of the genetic material and late stages, such as assembly and release. In addition, the MAYV proteins E1 and nsP1 were significantly inhibited by the EGCG treatment in BHK-21 cells. Molecular docking analysis also showed that EGCG could interact with MAYV Capsid and Envelope proteins (E1 and E2). Therefore, this study shows the potential of EGCG as a promising antiviral against MAYV, as it acts on different stages of the MAYV replication cycle.

The E-cadherin-beta-catenin-alpha E-catenin (cadherin-catenin) complex couples the cytoskeletons of neighboring cells at adherens junctions (AJs) to mediate force transmission across epithelia. Mechanical force and auxiliary binding partners converge to stabilize the cadherin-catenin complex's inherently weak binding to actin filaments (F-actin) through unclear mechanisms. Here, we show that afadin's coiled-coil (CC) domain and vinculin synergistically enhance the cadherin-catenin complex's F-actin engagement. The cryo-electron microscopy (cryo-EM) structure of an E-cadherin-beta-catenin-alpha E-catenin-vinculin-afadin-CC supra-complex bound to F-actin reveals that afadin-CC bridges adjacent alpha E-catenin actin-binding domains along the filament, stabilizing flexible alpha E-catenin segments implicated in mechanical regulation. These cooperative binding contacts promote the formation of supra-complex clusters along F-actin. Additionally, cryo-EM variability analysis links supra-complex binding along individual F-actin strands to nanoscale filament curvature, a deformation mode associated with cytoskeletal forces. Collectively, this work elucidates a mechanistic framework by which vinculin and afadin tune cadherin-catenin complex-cytoskeleton coupling to support AJ function across varying mechanical regimes.

Differential cross sections for top quark pair (t (t) over bar) production are measured in proton-proton collisions at a center-of-mass energy of 13 TeV using a sample of events containing two oppositely charged leptons. The data were recorded with the CMS detector at the CERN Large Hadron Collider and correspond to an integrated luminosity of 138 fb(-1). The differential cross sections are measured as functions of kinematic observables of the t (t) over bar system, the top quark and antiquark and their decay products, as well as of the number of additional jets in the event. The results are presented as functions of up to three variables and are corrected to the parton and particle levels. When compared to standard model predictions based on quantum chromodynamics at different levels of accuracy, it is found that the calculations do not always describe the observed data. The deviations are found to be largest for the multi-differential cross sections.

The macaque cerebral cortex contains concentrations of neurons that prefer faces over inanimate objects. Although these so-called face patches are thought to be specialized for the analysis of facial signals, their exact tuning properties remain unclear. For example, what happens when an object by chance resembles a face? Everyday objects can sometimes, through the accidental positioning of their internal components, appear as faces. This phenomenon is known as face pareidolia. Behavioral experiments have suggested that macaques, like humans, perceive illusory faces in such objects. However, it is an open question whether such stimuli would naturally stimulate neurons residing in cortical face patches. To address this question, we recorded single unit activity from four fMRI-defined face-selective regions: the anterior medial (AM), anterior fundus (AF), prefrontal orbital (PO), and perirhinal cortex (PRh) face patches. We compared neural responses elicited by images of real macaque faces, pareidolia-evoking objects, and matched control objects. Contrary to expectations, we found no evidence of a general preference for pareidolia-evoking objects over control objects. Although a subset of neurons exhibited stronger responses to pareidolia-evoking objects, the population responses to both categories of objects were similar, and collectively much less than to real macaque faces. These results suggest that neural responses in the four regions we tested are principally concerned with the analysis of realistic facial characteristics, whereas the special attention afforded to face-like pareidolia stimuli is supported by activity elsewhere in the brain.

Evidence suggests that bats are important hosts of filoviruses, yet the specific species involved remain largely unidentified. Niemann-Pick C1 (NPC1) is an essential entry receptor, with amino acid variations influencing viral susceptibility and species-specific tropism. Herein, we conducted combinatorial binding studies with seven filovirus glycoproteins (GPs) and NPC1 orthologs from 81 bat species. We found that GP-NPC1 binding correlated poorly with phylogeny. By integrating binding assays with machine learning, we identified genetic factors influencing virus-receptor-binding and predicted GP-NPC1-binding avidity for additional filoviruses and bats. Moreover, combining receptor-binding avidities with bat geographic distribution and the locations of previous Ebola outbreaks allowed us to rank bats by their potential as Ebola virus hosts. This study represents a comprehensive investigation of filovirus-receptor binding in bats (1,484 GP-NPC1 pairs, 11 filoviruses, and 135 bats) and describes a multidisciplinary approach to predict susceptible species and guide filovirus host surveillance.

Background: Lichenification, common in moderate to severe atopic dermatitis (AD) at any age, is often difficult to treat. This analysis assessed dupilumab vs placebo in AD lichenification by age and race-defined groups. Methods: This post hoc analysis included pooled data from 5 clinical trials of dupilumab (NCT03054428, NCT03345914, NCT02277743, NCT02277769, NCT02395133), including 1,997 patients aged 6 to 88 years of all races with moderate to severe AD. Results: Placebo/dupilumab randomized groups analyzed by age (n=1,535) included 123/244 children, 85/166 adolescents, and 460/457 adults; groups analyzed by self-reported racial background (n=1,902) included 132/234 Asian, 74/112 Black/African American, and 427/923 White patients. Dupilumab treatment resulted in nominally significant reductions vs placebo in Global Individual Signs Score lichenification from week 1 (adults/adolescents) or week 2 (children) through week 16. Lichenification measured by SCORing Atopic Dermatitis and Eczema Area and Severity Index improved similarly. By week 16, dupilumab significantly improved lichenification, with nominal significance vs placebo across all racial groups. Conclusion: Dupilumab treatment resulted in rapid and sustained improvement in lichenification across anatomic regions in all ages. Lichenification improved to a similar extent across racial groups.