The rockefeller university

Carbapenem-resistant Klebsiella pneumoniae (CR-KP) are a public health concern, causing infections with a high mortality rate, limited therapeutic options and challenging infection control strategies. In Portugal, the CR-KP rate has increased sharply, but the factors associated with this increase are poorly explored. In order to address this question, phylogenetic and resistome analysis were used to compare the draft genomes of 200 CR-KP isolates collected in 2017-2019 from five hospitals in the Lisbon region, Portugal. Most CR-KP belonged to sequence type (ST) 13 (29%), ST17 (15%), ST348 (13%), ST231 (12%) and ST147 (7%). Carbapenem resistance was conferred mostly by the presence of KPC-3 (74%) or OXA-181 (18%), which were associated with IncF/IncN and IncX plasmids, respectively. Almost all isolates were multi -drug resistant, harbouring resistance determinants to aminoglycosides, beta-lactams, trimethoprim, fosfomycin, quinolones and sulphonamides. In addition, 11% of isolates were resistant to colistin. Colonizing and infecting isolates were highly related, and most colonized patients (89%) reported a previous hospitalization. Moreover, among the 171 events of cross -dissemination identified by core genome multilocus sequence typing data analysis (fewer than five allelic differences), 41 occurred between different hospitals and 130 occurred within the same hospital. The results suggest that CR-KP dissemination in the Lisbon region results from acquisition of carbapenemases in mobile genetic elements, influx of CR-KP into the hospitals by colonized ambulatory patients, and transmission of CR-KP within and between hospitals. Prudent use of carbapenems, patient screening at hospital entry, and improvement of infection control are needed to decrease the burden of CR-KP infection in Portugal. 2024 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants is exclusively observed on the minor fraction of histone tails harboring the mutations, the same mutants recurrently disrupt broad H3K27me3 domains in the chromatin context, including near developmentally regulated promoters. H3K27me3 loss leads to de-repression of differentiation pathways, with concordant effects between H3R2 and H3R26 mutants despite different proximity to the PRC2 substrate, H3K27. Functionally, H3R26C-expressing mesenchymal progenitor cells and murine embryonic stem cell-derived teratomas demonstrate impaired differentiation. Collectively, these data show that cancer-associated H3 N-terminal arginine mutations reduce PRC2 activity and disrupt chromatin-dependent developmental functions, a cancer-relevant phenotype. Missense mutations in histones can drive oncogenesis and disrupt chromatin, but the associated mechanisms for many such mutations remain poorly understood. Here, the authors show that cancer-associated histone mutations at arginines in the H3 N-terminal tail disrupt repressive chromatin domains, alter gene expression, and in one case impair differentiation via reduction of PRC2 function.

A search for pair production of scalar and vector leptoquarks (LQs) each decaying to a muon and a bottom quark is performed using proton-proton collision data collected at root s = 13 TeV with the CMS detector at the CERN LHC, corresponding to an integrated luminosity of 138 fb(-1). No excess above standard model expectation is observed. Scalar (vector) LQs with masses less than 1810 (2120) GeV are excluded at 95% confidence level, assuming a 100% branching fraction of the LQ decaying to a muon and a bottom quark. These limits represent the most stringent to date.

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.

A search for the production of long-lived particles in proton- proton collisions at a center-of-mass energy of 13 TeVat the CERN LHC is presented. The search is based on data collected by the CMS experiment in 2016-2018, corresponding to a total integrated luminosity of 137 fb(-1). This search is designed to be sensitive to long-lived particles with mean proper decay lengths between 0.1 and 1000 mm, whose decay products produce a final state with at least one displaced vertex and missing transverse momentum. A machine learning algorithm, which improves the background rejection power by more than an order of magnitude, is applied to improve the sensitivity. The observation is consistent with the standard model background prediction, and the results are used to constrain split supersymmetry (SUSY) and gaugemediated SUSY breaking models with different gluino mean proper decay lengths and masses. This search is the first CMS search that shows sensitivity to hadronically decaying long-lived particles from signals with mass differences between the gluino and neutralino below 100 GeV. It sets the most stringent limits to date for split-SUSY models and gauge-mediated SUSY breaking models with gluino proper decay length less than 6 mm.

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.

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.