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Re-exposure to an antigen generates abundant antibody responses and drives the formation of secondary germinal centers (GCs). Recall GCs in mice consist almost entirely of na & imath;ve B cells, whereas recall antibodies derive overwhelmingly from memory B cells. Here, we examine this division between cellular and serum compartments. After repeated immunization with the same antigen, tetramer analyses of recall GCs revealed a marked decrease in the ability of B cells in these structures to bind the antigen. Boosting with viral variant proteins restored antigen binding in recall GCs, as did genetic ablation of primary-derived antibody-secreting cells through conditional deletion of Prdm1, demonstrating suppression of GC recall responses by pre-existing antibodies. In hapten-carrier experiments in which B and T cell specificities were uncoupled, memory T cell help allowed B cells with undetectable antigen binding to access GCs. Thus, antibody-mediated feedback steers recall GC B cells away from previously targeted epitopes and enables specific targeting of variant epitopes, with implications for vaccination protocols.

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.

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.

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.

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 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.

Regardless of microbial virulence (i.e., the global infection-fatality ratio), age generally drives the prevalence of death from infection in unvaccinated humans. Four mortality patterns are recognized: the common U- and L-shaped curves of endemic infections and the unique W- and J-shaped curves of pandemic infections. We suggest that these patterns result from different sets of human genetic and immunological determinants. In this model, it is the interplay between (1) monogenic genotypes affecting immunity to primary infection that preferentially manifest early in life and related genotypes or their phenocopies, including auto-antibodies, which manifest later in life and (2) the occurrence and persistence of adaptive, acquired immunity to primary or cross-reactive infections, which shapes the age-dependent pattern of human deaths from infection.

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful nodules, abscesses and purulent secretions in intertriginous regions. Intense pruritus frequently accompanies HS lesions, adding further discomfort for patients. While Th17 pathway activation is implicated in HS pathogenesis, disease mechanisms are still not fully understood, and therapeutics are lacking. Previous reports raise a potential role for eosinophils in HS, showing a strong association of eosinophil levels with disease severity. To investigate eosinophils in HS, we recruited patients and matched healthy controls and then performed flow-cytometry studies, eosinophil stimulation assays, and lesional skin staining for eosinophils. We found that HS patients reported similar levels of pain and itch. Compared to matched controls, HS blood exhibited decreased mature eosinophils and increased numbers of immature eosinophils, coupled with a significant increase in dermal eosinophilic infiltrates. Additionally, IL-17RA+ eosinophils were highly and significantly correlated with multiple HS-related clinical scores. In both stimulated and unstimulated conditions, HS eosinophils showed an inflammatory phenotype versus controls, including an increase in costimulatory T- and B-cell markers (e.g. CD5 and CD40) following all stimulations (TNF alpha/IL-17A/IL-17F). These findings highlight the significance of pruritus in HS and suggest a higher turnover of eosinophils in HS blood, potentially due to the consumption of eosinophils in skin lesions. Our data delineate the features and functions of eosinophils in HS and suggest that eosinophils participate in disease pathogenesis, advancing Th17-related inflammation. Further studies are needed to investigate eosinophils' response to current HS treatments and their potential as a therapeutic target in the disease.

Editor's note: This is the 22nd 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.