The rockefeller university

The origin and fixation of evolutionarily young genes is a fundamental question in evolutionary biology. However, understanding the origins of newly evolved genes arising de novo from noncoding genomic sequences is challenging. This is partly due to the low likelihood that several neutral or nearly neutral mutations fix prior to the appearance of an important novel molecular function. This issue is particularly exacerbated in large effective population sizes where the effect of drift is small. To address this problem, we propose a regulation-focused, cultivator model for de novo gene evolution. This cultivator-focused model posits that each step in a novel variant's evolutionary trajectory is driven by well-defined, selectively advantageous functions for the cultivator genes, rather than solely by the de novo genes, emphasizing the critical role of genome organization in the evolution of new genes.

Our ability to fight pathogens relies on major histocompatibility complex class I (MHC - I) molecules presenting diverse antigens on the surface of diseased cells. The transporter associated with antigen processing (TAP) transports nearly the entire repertoire of antigenic peptides into the endoplasmic reticulum for MHC - I loading. How TAP transports peptides specific for MHC - I is unclear. In this study, we used cryo - EM to determine a series of structures of human TAP, both in the absence and presence of peptides with various sequences and lengths. The structures revealed that peptides of eight or nine residues in length bind in a similarly extended conformation, despite having little sequence overlap. We also identified two peptide - anchoring pockets on either side of the transmembrane cavity, each engaging one end of a peptide with primarily main chain atoms. Occupation of both pockets results in a global conformational change in TAP, bringing the two halves of the transporter closer together to prime it for isomerization and ATP hydrolysis. Shorter peptides are able to bind to each pocket separately but are not long enough to bridge the cavity to bind to both simultaneously. Mutations that disrupt hydrogen bonds with the N and C termini of peptides almost abolish MHC - I surface expression. Our findings reveal that TAP functions as a molecular caliper that selects peptides according to length rather than sequence, providing antigen diversity for MHC - I presentation.

AlphaFold2 (AF2) models have had wide impact but mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 models of the sigma(2) and serotonin 2A (5-HT2A) receptors, testing hundreds of new molecules and comparing results with those obtained from docking against the experimental structures. Hit rates were high and similar for the experimental and AF2 structures, as were affinities. Success in docking against the AF2 models was achieved despite differences between orthosteric residue conformations in the AF2 models and the experimental structures. Determination of the cryo-electron microscopy structure for one of the more potent 5-HT2A ligands from the AF2 docking revealed residue accommodations that resembled the AF2 prediction. AF2 models may sample conformations that differ from experimental structures but remain low energy and relevant for ligand discovery, extending the domain of structure-based drug design.

A combination of the results of several searches for the electroweak production of the supersymmetric partners of standard model bosons, and of charged leptons, is presented. All searches use proton-proton collision data at root s = 13 TeV recorded with the CMS detector at the LHC in 2016-2018. The analyzed data correspond to an integrated luminosity of up to 137 fb(-1). The results are interpreted in terms of simplified models of supersymmetry. Two new interpretations are added with this combination: a model spectrum with the bino as the lightest supersymmetric particle together with mass-degenerate Higgsinos decaying to the bino and a standard model boson, and the compressed-spectrum region of a previously studied model of slepton pair production. Improved analysis techniques are employed to optimize sensitivity for the compressed spectra in the wino and slepton pair production models. The results are consistent with expectations from the standard model. The combination provides a more comprehensive coverage of the model parameter space than the individual searches, extending the exclusion by up to 125 GeV, and also targets some of the intermediate gaps in the mass coverage.

JGP study shows that hydrophobic residues in the S1 transmembrane domain modulate the voltage-sensor movements and enzymatic activity of voltage-sensing phosphatase.

A combination of fifteen top quark mass measurements performed by the ATLAS and CMS experiments at the LHC is presented. The datasets used correspond to an integrated luminosity of up to 5 and 20 fb(-1) of proton-proton collisions at center-of-mass energies of 7 and 8 TeV, respectively. The combination includes measurements in top quark pair events that exploit both the semileptonic and hadronic decays of the top quark, and a measurement using events enriched in single top quark production via the electroweak t channel. The combination accounts for the correlations between measurements and achieves an improvement in the total uncertainty of 31% relative to the most precise input measurement. The result is m(t) = 172.52 +/- 0.14(stat) +/- 0.30(stat) GeV, with a total uncertainty of 0.33 GeV.

The loss of function of AAA (ATPases associated with diverse cellular activities) mechanoenzymes has been linked to diseases, and small molecules that activate these proteins can be powerful tools to probe mechanisms and test therapeutic hypotheses. Unlike chemical inhibitors that can bind a single conformational state to block enzyme function, activator binding must be permissive to different conformational states needed for mechanochemistry. However, we do not know how AAA proteins can be activated by small molecules. Here, we focus on valosin-containing protein (VCP)/p97, an AAA unfoldase whose loss of function has been linked to protein aggregation-based disorders, to identify druggable sites for chemical activators. We identified VCP ATPase Activator 1 (VAA1), a compound that dose-dependently stimulates VCP ATPase activity up to similar to threefold. Our cryo-EM studies resulted in structures (ranging from similar to 2.9 to 3.7 angstrom-resolution) of VCP in apo and ADP-bound states and revealed that VAA1 binds an allosteric pocket near the C-terminus in both states. Engineered mutations in the VAA1-binding site confer resistance to VAA1, and furthermore, modulate VCP activity. Mutation of a phenylalanine residue in the VCP C-terminal tail that can occupy the VAA1 binding site also stimulates ATPase activity, suggesting that VAA1 acts by mimicking this interaction. Together, our findings uncover a druggable allosteric site and a mechanism of enzyme regulation that can be tuned through small molecule mimicry.

Editor's note: This is the 21st article in a series on clinical research by nurses. The series is designed to be used as a resource for nurses to understand the concepts and principles essential to research. Each column will present the concepts that underpin evidence-based practice-from research design to data interpretation. To see all the articles in the series, go to https://links.lww.com/AJN/A204.

Following tissue damage, epithelial stem cells (SCs) are mobilized to enter the wound, where they confront harsh inflammatory environments that can impede their ability to repair the injury. Here, we investigated the mechanisms that protect skin SCs within this inflammatory environment. Characterization of gene expression profiles of hair follicle SCs (HFSCs) that migrated into the wound site revealed activation of an immune -modulatory program, including expression of CD80, major histocompatibility complex class II (MHCII), and CXC motif chemokine ligand 5 (CXCL5). Deletion of CD80 in HFSCs impaired re-epithelialization, reduced accumulation of peripherally generated Treg (pTreg) cells, and increased infiltration of neutrophils in wounded skin. Importantly, similar wound healing defects were also observed in mice lacking pTreg cells. Our findings suggest that upon skin injury, HFSCs establish a temporary protective network by promoting local expansion of Treg cells, thereby enabling re-epithelialization while still kindling inflammation outside this niche until the barrier is restored.

Background: Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare clinical syndrome characterized by vulnerability to weakly virulent mycobacterial species, including Bacillus Calmette-Guerin (BCG) vaccines and environmental mycobacteria. Objective: We sought to perform a systematic review of the genetic, immunologic, and clinical findings for reported patients with MSMD. Methods: We searched PubMed, Web of Science, and Scopus databases for publications in English relating to MSMD. All full texts were evaluated for eligibility for inclusion. Two reviewers independently selected the publications, with a third reviewer consulted in cases of disagreement. Results: A primary systematic search and searches of other resources identified 16,155 articles. In total, 158 articles from 63 countries were included in qualitative and quantitative analyses. In total, 830 patients-436 males (52.5%), 369 females (44.5%), and 25 patients of unknown sex (3.0%)-from 581 families were evaluated. A positive family history was reported in 347 patients (45.5%). The patients had a mean age of 10.41 6 0.42 (SEM) years. The frequency of MSMD was highest in Iran, Turkey, and Saudi Arabia. Lymphadenopathy was the most common clinical manifestation of MSMD, reported in 378 (45.5%) cases and multifocal in 35.1%. Fever, organomegaly, and sepsis were the next most frequent findings, reported in 251 (30.2%), 206 (24.8%), and 171 (20.8%) cases, respectively. In total, 299 unique mutations in 21 genes known to be involved in MSMD were reported: 100 missense (34%), 80 indel-frameshift (insertion or deletion, 27%), 53 nonsense (18%), 35 splice site (12%), 10 indel-in frame (2.7%), 6 indel (2%), and 15 large deletion/duplication mutations. Finally, 61% of the reported patients with MSMD had mutations of IL12RB1 (41%) or IFNGR1 (20%). At the time of the report, 177 of the patients (21.3%) were dead and 597 (71.9%) were still alive. Conclusions: MSMD is associated with a high mortality rate, mostly due to impaired control of infection. Preexposure strategies, such as changes in vaccination policy in endemic areas, the establishment of a worldwide registry of patients with MSMD, and precise follow-up over generations in affected families, appear to be vital to decrease MSMD-related mortality.