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The first search for singly produced narrow resonances decaying to three well-separated hadronic jets is presented. The search uses proton-proton collision data corresponding to an integrated luminosity of 138 fb(-1) at root s = 13 TeV, collected at the CERN LHC. No significant deviations from the background predictions are observed between 1.75 and 9.00 TeV. The results provide the first mass limits on a right-handed boson Z(R) decaying to three gluons and on an excited quark decaying via a vector boson to three quarks, as well as updated limits on a Kaluza-Klein gluon decaying via a radion to three gluons.

Receptor activity-modifying proteins (RAMPs) form complexes with G protein-coupled receptors (GPCRs) and may regulate their cellular trafficking and pharmacology. RAMP interactions have been identified for about 50 GPCRs, but only a few GPCR-RAMP complexes have been studied in detail. To elucidate a comprehensive GPCR-RAMP interactome, we created a library of 215 dual epitope-tagged (DuET) GPCRs representing all GPCR subfamilies and coexpressed each GPCR with each of the three RAMPs. Screening the GPCR-RAMP pairs with customized multiplexed suspension bead array (SBA) immunoassays, we identified 122 GPCRs that showed strong evidence for interaction with at least one RAMP. We screened for interactions in three cell lines and found 23 endogenously expressed GPCRs that formed complexes with RAMPs. Mapping the GPCR-RAMP interactome expands the current system-wide functional characterization of RAMP-interacting GPCRs to inform the design of selective therapeutics targeting GPCR-RAMP complexes.

T follicular regulatory (T-fr) cells can counteract the B cell helper activity of T follicular helper (T-fh) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (T-reg) cells into T-fr cells is still missing. Herein, we report that low doses of the pro-T-fh cytokine interleukin-12 (IL-12) drive the induction of a T-fr cell program on activated human T-reg cells while also preserving their regulatory function. Mechanistically, we found that IL-12 led to STAT4 (signal transducer and activator of transcription 4) phosphorylation and binding to IL-12-driven follicular signature genes. Patients with inborn errors of immunity in the IL12RB1 gene presented with a strong decrease in circulating T-fr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of T-fr cell differentiation in vivo and provides an approach for the in vitro generation of human T-fr-like cells.

To the Editor: In their study investigating the presence of autoantibodies against interleukin-23 in patients with various types of infection, Cheng et al. (March 21 issue)(1) found interleukin-23 neutralizing antibodies in 34 of 249 patients. These included 27 patients who had one or more types of infection: 1 with parasitic infection, 10 with fungal infections, and 11 with bacterial infections; 7 of these patients were asymptomatic. However, the authors' data do not support a connection between these infections and interleukin-23 neutralizing antibodies. Causality between the presence of cytokine neutralizing antibodies and an infectious disease can be established if the same . . .

The production of gamma(2S) and gamma(3S) mesons in lead-lead (Pb-Pb) and proton-proton (pp) collisions is studied in their dimuon decay channel using the CMS detector at the LHC. The gamma(3S) meson is observed for the first time in Pb-Pb collisions, with a significance above 5 standard deviations. The ratios of yields measured in Pb-Pb and pp collisions are reported for both the gamma(2S) and gamma(3S) mesons, as functions of transverse momentum and Pb-Pb collision centrality. These ratios, when appropriately scaled, are significantly less than unity, indicating a suppression of gamma yields in Pb-Pb collisions. This suppression increases from peripheral to central Pb-Pb collisions. Furthermore, the suppression is stronger for gamma(3S) mesons compared to gamma(2S) mesons, extending the pattern of sequential suppression of quarkonium states in nuclear collisions previously seen for the J/psi, psi(2S), gamma(1S), and gamma(2S) mesons.

A search for Higgs boson pair (HH) production with one Higgs boson decaying to two bottom quarks and the other to two W bosons are presented. The search is done using proton-proton collisions data at a centre-of-mass energy of 13TeV, corresponding to an integrated luminosity of 138 fb(-1) recorded by the CMS detector at the LHC from 2016 to 2018. The final states considered include at least one leptonically decaying W boson. No evidence for the presence of a signal is observed and corresponding upper limits on the HH production cross section are derived. The limit on the inclusive cross section of the nonresonant HH production, assuming that the distributions of kinematic observables are as expected in the standard model (SM), is observed (expected) to be 14 (18) times the value predicted by the SM, at 95% confidence level. The limits on the cross section are also presented as functions of various Higgs boson coupling modifiers, and anomalous Higgs boson coupling scenarios. In addition, limits are set on the resonant HH production via spin-0 and spin-2 resonances within the mass range 250-900 GeV.

Ongoing, early-stage clinical trials illustrate the translational potential of human pluripotent stem cell (hPSC)based cell therapies in Parkinson's disease (PD). However, an unresolved challenge is the extensive cell death following transplantation. Here, we performed a pooled CRISPR-Cas9 screen to enhance postmitotic dopamine neuron survival in vivo . We identified p53-mediated apoptotic cell death as a major contributor to dopamine neuron loss and uncovered a causal link of tumor necrosis factor alpha (TNF-a)-nuclear factor kB (NF-kB) signaling in limiting cell survival. As a translationally relevant strategy to purify postmitotic dopamine neurons, we identified cell surface markers that enable purification without the need for genetic reporters. Combining cell sorting and treatment with adalimumab, a clinically approved TNF-a inhibitor, enabled efficient engraftment of postmitotic dopamine neurons with extensive reinnervation and functional recovery in a preclinical PD mouse model. Thus, transient TNF-a inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic hPSC-derived dopamine neurons in PD.

A test of lepton flavor universality in B-+/- -> K +/- mu(+) mu(-) and B-+/- -> (K)+/- e(+) e(-) decays, as well as a measurement of differential and integrated branching fractions of a nonresonant B-+/- -> K-+/- mu(+)mu(-) decay are presented. The analysis is made possible by a dedicated data set of proton-proton collisions at root s = 13 TeV recorded in 2018, by the CMS experiment at the LHC, using a special high-rate data stream designed for collecting about 10 billion unbiased b hadron decays. The ratio of the branching fractions B(B-+/- -> K-+/- mu(+) mu(-)) to B(B-+/- -> K-+/- e(+) e(-)) is determined from the measured double ratio R(K) of these decays to the respective branching fractions of the B-+/- -> J/psi K-+/- with J/psi -> mu(+)mu(-) and e(+) e(-) decays, which allow for significant cancellation of systematic uncertainties. The ratio R(K) is measured in the range 1.1 < q(2) < 6.0 GeV2, where q is the invariant mass of the lepton pair, and is found to be R(K) = 0.78(-0.23)(+0.47), in agreement with the standard model expectation R(K) approximate to 1. This measurement is limited by the statistical precision of the electron channel. The integrated branching fraction in the same q(2) range, B(B-+/- -> K-+/- mu(+) mu(-)) = (12.42 +/- 0.68) x 10(-8), is consistent with the present world-average value and has a comparable precision.

The brain is organized hierarchically to process sensory signals. But, how do functional connections within and across areas contribute to this hierarchical order? We addressed this problem in the thalamocortical network, while monkeys detected vibrotactile stimulus. During this task, we quantified neural variability and directed functional connectivity in simultaneously recorded neurons sharing the cutaneous receptive field within and across VPL and areas 3b and 1. Before stimulus onset, VPL and area 3b exhibited similar fast dynamics while area 1 showed slower timescales. During the stimulus presence, inter-trial neural variability increased along the network VPL-3b-1 while VPL established two main feedforward pathways with areas 3b and 1 to process the stimulus. This lower variability of VPL and area 3b was found to regulate feedforward thalamocortical pathways. Instead, intra-cortical interactions were only anticipated by higher intrinsic timescales in area 1. Overall, our results provide evidence of hierarchical functional roles along the thalamocortical network.

The essential Mediator (MED) coactivator complex plays a well-understood role in regulation of basal transcription in all eukaryotes, but the mechanism underlying its role in activator-dependent transcription remains unknown. We investigated modulation of metazoan MED interaction with RNA polymerase II (RNA Pol II) by antagonistic effects of the MED26 subunit and the CDK8 kinase module (CKM). Biochemical analysis of CKM-MED showed that the CKM blocks binding of the RNA Pol II carboxy-terminal domain (CTD), preventing RNA Pol II interaction. This restriction is eliminated by nuclear receptor (NR) binding to CKM-MED, which enables CTD binding in a MED26-dependent manner. Cryoelectron microscopy (cryo-EM) and cross- linking-mass spectrometry (XL-MS) revealed that the structural basis for modulation of CTD interaction with MED relates to a large intrinsically disordered region (IDR) in CKM subunit MED13 that blocks MED26 and CTD interaction with MED but is repositioned upon NR binding. Hence, NRs can control transcription initiation by priming CKM-MED for MED26-dependent RNA Pol II interaction.