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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.

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 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.

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.

Background: The role of anticoagulation in ovarian vein thrombosis (OVT) is uncertain. Objectives: We aimed to evaluate safety and efficacy of anticoagulant treatment in OVT patients. Methods: A systematic search was conducted in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases up to April 2024. Eligible studies included randomized controlled trials and observational studies enrolling at least 10 adult patients with objectively diagnosed OVT and treated with any anticoagulants. The protocol was prospectively registered in the International Prospective Register of Systematic Reviews (CRD42021270883). Results: We included 17 observational studies (621 anticoagulated and 376 nonanticoagulated OVT patients); 9 studies enrolled mainly pregnancy/puerperiumrelated OVT. Most patients received heparins alone (45.7%) or proceeded to vitamin K antagonists (39.2%). The average treatment duration was <= 3 months in 8 studies (47.1%), >3 to <= 6 months in 6 studies (35.3%), and >6 months in 3 studies (17.6%). In treated patients, mortality rate was 2.43% (95% CI, 0.54%-5.41%; I2 2 = 53.8%; 12/406 patients; 13 studies), major bleeding was 1.27% (95% CI, 0.48%2.38%; I2 2 = 2.5%; 7/583 patients; 15 studies), recurrent venous thromboembolism (VTE) was 3.49% (95% CI, 1.12%-6.95%; I2 2 = 63.5%; 22/482 patients; 15 studies), and vessel recanalization was 89.4% (95% CI, 74.6%-98.6%; I2 2 = 80.6%; 163/184 patients; 8 studies). The rate of recurrent VTE in untreated patients was 8.65% (95% CI, 2.61%-17.35%); however, the difference compared with treated patients was not statistically significant (risk ratio, 0.70; 95% CI, 0.36-1.37). At subgroup analyses, the rates of major bleeding and recurrent VTE were 0.80% (95% CI, 0.0-2%.17%) and 3.81% (95% CI, 0.42%-9.63%) in pregnancy/puerperium-related OVT, respectively, and 1.12% (95% CI, 0.32%-2.34%) and 1.78% (95% CI, 0.62%-3.46%), respectively, when analyzing only full-text studies. Conclusion: There is paucity of literature regarding OVT. Our results suggest that anticoagulation is associated with low rates of major bleeding and recurrent VTE. [Gaphics]

Telomere maintenance requires the extension of the G-rich telomeric repeat strand by telomerase and the fillin synthesis of the C-rich strand by Pola/primase. At telomeres, Pola/primase is bound to Ctc1/Stn1/Ten1 (CST), a single-stranded DNA-binding complex. Like mutations in telomerase, mutations affecting CSTPola/primase result in pathological telomere shortening and cause a telomere biology disorder, Coats plus (CP). We determined cryogenic electron microscopy structures of human CST bound to the shelterin heterodimer POT1/TPP1 that reveal how CST is recruited to telomeres by POT1. Our findings suggest that POT1 hinge phosphorylation is required for CST recruitment, and the complex is formed through conserved interactions involving several residues mutated in CP. Our structural and biochemical data suggest that phosphorylated POT1 holds CST-Pola/primase in an inactive, autoinhibited state until telomerase has extended the telomere ends. We propose that dephosphorylation of POT1 releases CST-Pola/primase into an active state that completes telomere replication through fill-in synthesis.

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.

Ervin Bauer (1890-1938) outlined the paradigm of theoretical biology from the perspective of biophysics and bioenergetics. His molecular-based biological theory is centered on the principle of sustainable non-equilibrium, which is continuously produced and maintained by all biological systems throughout their life. Ervin Bauer became the victim of Stalin's Great Terror. Here we present two of the fundamental works of Ervin Bauer in English translation: the paper "The definition of living beings on the basis of their thermodynamic properties, and the fundamental biological principles that follow from it" published in Naturwissenschaften (1920) and the excerpts from his magnum opus "Theoretical Biology" (1935). These works became a bibliographical rarity. A complete English translation of "Theoretical Biology" is an important task for the future.

BackgroundThe meticulous selection of appropriate vaccine adjuvants is crucial for optimizing immune responses. Traditionally, pemphigus vulgaris (PV), an autoimmune disorder, has been modelled using complete Freund's adjuvant (CFA). In this study, we aimed to discern potential variations in immune responses elicited by Toll-like receptor (TLR) ligands as compared to CFA.MethodsA comprehensive investigation was conducted, comparing the effects of these adjuvants in conjunction with ovalbumin or desmoglein-3. Flow cytometry was employed to analyse distinct cell subsets, while enzyme-linked immunosorbent assay quantified antigen-specific antibodies and cytokine levels. Histological examination of harvested skin tissues and transcriptome analysis of skin lesions were performed to identify differentially expressed genes.ResultsTLR ligands demonstrated efficacy in inducing PV-like symptoms in wild-type mice, in contrast to CFA. This underscored the substantial impact of the adjuvant on self-antigen tolerance. Furthermore, we proposed an enhanced method for establishing a PV model through adoptive transfer, substituting CFA with TLR ligands. Our results revealed that in contrast to the perception that CFA being the most potent immunopotentiator reported, CFA promoted regulatory T cells (Treg), follicular regulatory T cells and IL-10-producing neutrophils, whereas TLR ligands downregulated CCL17 and IL-10. This suggested potential implications for the recruitment and activation of Treg subsets. While B cell and CD8+ T cell responses exhibited similarity, CFA induced less activation in dendritic cell subsets. A novel mouse model of PV and systemic comparison of immunostimulatory effects of adjuvants were provided by this study.ConclusionsThe systematic comparison of CFA and TLR ligands shed light on the distinctive properties of these adjuvants, presenting innovative mouse models for the investigation of pemphigus. This study significantly contributes to adjuvant research and advances our understanding of PV pathogenesis.Key points/highlights Immunization with desmoglein 3 and Toll-like receptor (TLR) ligands effectively induces pemphigus symptoms in wild-type mice, whereas complete Freund's adjuvant (CFA) fails. TLR ligands heightened the autoreactivity of donor cells in the adoptive transfer pemphigus model. CFA promoted regulatory T cells and IL-10-producing neutrophils, whereas TLR ligands downregulated CCL17 and IL-10, leading to more effective immune responses. Immunization with desmoglein 3 and Toll-like receptor (TLR) ligands effectively induces pemphigus symptoms in wild-type mice, whereas complete Freund's adjuvant (CFA) fails. TLR ligands heightened the autoreactivity of donor cells in the adoptive transfer pemphigus model. CFA promoted regulatory T cells and IL-10-producing neutrophils, whereas TLR ligands downregulated CCL17 and IL-10, leading to more effective immune responses. image