The rockefeller university

The central exclusive production of charged-hadron pairs in pp collisions at a center-of-mass energy of 13 TeV is examined, based on data collected in a special high-beta* run of the LHC. The nonresonant continuum processes are studied with the invariant mass of the centrally produced twopion system in the resonance-free region, m(pi+pi-) < 0.7 or m(pi+pi-) > 1.8 GeV. Differential cross sections as functions of the azimuthal angle between the surviving protons, squared exchanged four- momenta, and m(pi+pi-) are measured in a wide region of scattered proton transverse momenta, between 0.2 and 0.8 GeV, and for pion rapidities |y| < 2. A rich structure of interactions related to double-pomeron exchange is observed. A parabolic minimum in the distribution of the two-proton azimuthal angle is observed for the first time. It can be interpreted as an effect of additional pomeron exchanges between the protons from the interference between the bare and the rescattered amplitudes. After model tuning, various physical quantities are determined that are related to the pomeron cross section, protonpomeron and meson-pomeron form factors, pomeron trajectory and intercept, and coefficients of diffractive eigenstates of the proton.

Flaviviruses such as dengue virus (DENV), Zika virus (ZIKV), and yellow fever virus (YFV) are spread by mosquitoes and cause human disease and mortality in tropical areas. In contrast, Powassan virus (POWV), which causes severe neurologic illness, is a flavivirus transmitted by ticks in temperate regions of the Northern hemisphere. We find serologic neutralizing activity against POWV in individuals living in Mexico and Brazil. Monoclonal antibodies P002 and P003, which were derived from a resident of Mexico (where POWV is not reported), neutralize POWV lineage I by recognizing an epitope on the virus envelope domain III (EDIII) that is shared with a broad range of tick- and mosquito -borne flaviviruses. Our findings raise the possibility that POWV, or a flavivirus closely related to it, infects humans in the tropics.

A search for long-lived heavy neutrinos (N) in the decays of B mesons produced in proton-proton collisions at root s = 13 TeV is presented. The data sample corresponds to an integrated luminosity of 41.6 fb(-1) collected in 2018 by the CMS experiment at the CERN LHC, using a dedicated data stream that enhances the number of recorded events containing B mesons. The search probes heavy neutrinos with masses in the range 1 < m(N) < 3 GeV and decay lengths in the range 10(-2) < c tau(N) < 10(4) mm, where tau(N) is the N proper mean lifetime. Signal events are defined by the signature B -> l(B)NX; N -> l(+/-)pi(-/+), where the leptons l(B) and l can be either a muon or an electron, provided that at least one of them is a muon. The hadronic recoil system, X, is treated inclusively and is not reconstructed. No significant excess of events over the standard model background is observed in any of the l(+/-)pi(-/+) invariant mass distributions. Limits at 95% confidence level on the sum of the squares of the mixing amplitudes between heavy and light neutrinos, vertical bar V-N vertical bar(2), and on c tau(N) are obtained in different mixing scenarios for both Majorana and Dirac-like N particles. The most stringent upper limit vertical bar V-N vertical bar(2) < 2.0 x 10(-5) is obtained at m(N) = 1.95 GeV for the Majorana case where N mixes exclusively with muon neutrinos. The limits on vertical bar V-N vertical bar(2) for masses 1 < m(N) < 1.7 GeV are the most stringent from a collider experiment to date.

The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers. We show through transcriptomic analysis a shared IFN-rich environment in non-lesional skin across human lupus and three murine models: MRL/lpr, B6.Sle1yaa, and imiquimod (IMQ) mice. IFN-I inhibits LC ADAM17 sheddase activity in murine and human LCs, and IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity, all without consistent effects on LC ADAM17 protein expression or LC numbers. Anti-IFNAR-mediated LC ADAM17 sheddase function restoration is associated with reduced photosensitive responses that are dependent on EGFR signaling and LC ADAM17. Reactive oxygen species (ROS) is a known mediator of ADAM17 activity; we show that UVR-induced LC ROS production is reduced in lupus model mice, restored by anti-IFNAR, and is cytoplasmic in origin. Our findings suggest that IFN-I promotes photosensitivity at least in part by inhibiting UVR-induced LC ADAM17 sheddase function and raise the possibility that anifrolumab ameliorates lupus skin disease in part by restoring this function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a potential mechanism of action for anifrolumab in lupus.

A search for heavy neutral leptons (HNLs) of Majorana or Dirac type using proton-proton collision data at root s = 13TeV= 13 TeV is presented. The data were collected by the CMS experiment at the CERN LHC and correspond to an integrated luminosity of 138 fb(-1). Events with three charged leptons (electrons, muons, and hadronically decaying tau leptons) are selected, corresponding to HNL production in association with a charged lepton and decay of the HNL to two charged leptons and a standard model (SM) neutrino. The search is performed for HNL masses between 10 GeV and 1.5 TeV. No evidence for an HNL signal is observed in data. Upper limits at 95% confidence level are found for the squared coupling strength of the HNL to SM neutrinos, considering exclusive coupling of the HNL to a single SM neutrino generation, for both Majorana and Dirac HNLs. The limits exceed previously achieved experimental constraints for a wide range of HNL masses, and the limits on tau neutrino coupling scenarios with HNL masses above the W boson mass are presented for the first time.

Optical projection tomography (OPT) is a three-dimensional mesoscopic imaging modality that can use absorption or fluorescence contrast, and is widely applied to fixed and live samples in the mm-cm scale. For fluorescence OPT, we present OPT implemented for accessibility and low cost, an open-source research-grade implementation of modular OPT hardware and software that has been designed to be widely accessible by using low-cost components, including light-emitting diode (LED) excitation and cooled complementary metal-oxide-semiconductor (CMOS) cameras. Both the hardware and software are modular and flexible in their implementation, enabling rapid switching between sample size scales and supporting compressive sensing to reconstruct images from undersampled sparse OPT data, e.g. to facilitate rapid imaging with low photobleaching/phototoxicity. We also explore a simple implementation of focal scanning OPT to achieve higher resolution, which entails the use of a fan-beam geometry reconstruction method to account for variation in magnification. This article is part of the Theo Murphy meeting issue 'Open, reproducible hardware for microscopy'.

The concept of race is prevalent in medical, nursing, and public health literature. Clinicians often incorporate race into diagnostics, prognostic tools, and treatment guidelines. An example is the recently heavily debated use of race and ethnicity in the Vaginal Birth After Cesarean (VBAC) calculator. In this case, the critics argued that the use of race in this calculator implied that race confers immutable characteristics that affect the ability of women to give birth vaginally after a c-section. This debate is co-occurring as research continues to highlight the racial disparities in health outcomes, such as high maternal mortality among Black women compared to other racial groups in the United States. As the healthcare system contemplates the necessity of utilizing race-a social and political construct, to monitor health outcomes, it has sparked more questions about incorporating race into clinical algorithms, including pulmonary tests, kidney function tests, pharmacotherapies, and genetic testing. This paper critically examines the argument against the race-based Vaginal Birth After Cesarean (VBAC) calculator, shedding light on its implications. Moreover, it delves into the detrimental effects of normalizing race as a biological variable, which hinders progress in improving health outcomes and equity.

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.