Multifaceted Activities of Seven Nanobodies against Complement C4b

Cleavage of the mammalian plasma protein C4 into C4b initiates opsonization, lysis, and clearance of microbes and damaged host cells by the classical and lectin pathways of the complement system. Dysregulated activation of C4 and other initial components of the classical pathway may cause or aggravate pathologies, such as systemic lupus erythematosus, Alzheimer disease, and schizophrenia. Modulating the activity of C4b by small-molecule or protein-based inhibitors may represent a promising therapeutic approach for preventing excessive inflammation and damage to host cells and tissue. Here, we present seven nanobodies, derived from llama (Lama glama) immunization, that bind to human C4b (Homo sapiens) with high affinities ranging from 3.2 nM to 14 pM. The activity of the nanobodies varies from no to complete inhibition of the classical pathway. The inhibiting nanobodies affect different steps in complement activation, in line with blocking sites for proconvertase formation, C3 substrate binding to the convertase, and regulator-mediated inactivation of C4b. For four nanobodies, we determined singleparticle cryo-electron microscopy structures in complex with C4b at 3.4-4 Å resolution. The structures rationalize the observed functional effects of the nanobodies and define their mode of action during complement activation. Thus, we characterized seven anti-C4b nanobodies with diverse effects on the classical pathway of complement activation that may be explored for imaging, diagnostic, or therapeutic applications

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Multifaceted Activities of Seven Nanobodies against Complement C4b

Cleavage of the mammalian plasma protein C4 into C4b initiates opsonization, lysis, and clearance of microbes and damaged host cells by the classical and lectin pathways of the complement system. Dysregulated activation of C4 and other initial components of the classical pathway may cause or aggravate pathologies, such as systemic lupus erythematosus, Alzheimer disease, and schizophrenia. Modulating the activity of C4b by small-molecule or protein-based inhibitors may represent a promising therapeutic approach for preventing excessive inflammation and damage to host cells and tissue. Here, we present seven nanobodies, derived from llama (Lama glama) immunization, that bind to human C4b (Homo sapiens) with high affinities ranging from 3.2 nM to 14 pM. The activity of the nanobodies varies from no to complete inhibition of the classical pathway. The inhibiting nanobodies affect different steps in complement activation, in line with blocking sites for proconvertase formation, C3 substrate binding to the convertase, and regulator-mediated inactivation of C4b. For four nanobodies, we determined singleparticle cryo-electron microscopy structures in complex with C4b at 3.4-4 Å resolution. The structures rationalize the observed functional effects of the nanobodies and define their mode of action during complement activation. Thus, we characterized seven anti-C4b nanobodies with diverse effects on the classical pathway of complement activation that may be explored for imaging, diagnostic, or therapeutic applications

Risk of COVID-19 after natural infection or vaccinationResearch in context

Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health

Search for light Higgs bosons from supersymmetric cascade decays in pp\text {pp} collisions at s=13 TeV\sqrt{s}=13\,\textrm{TeV}

A search is reported for pairs of light Higgs bosons (${\textrm{H}} _1$) produced in supersymmetric cascade decays in final states with small missing transverse momentum. A data set of LHC $\hbox {pp}$ collisions collected with the CMS detector at $\sqrt{s}=13\,\text {TeV}$ and corresponding to an integrated luminosity of 138$\,\text {fb}^{-1}$ is used. The search targets events where both ${\textrm{H}} _1$ bosons decay into pairs that are reconstructed as large-radius jets using substructure techniques. No evidence is found for an excess of events beyond the background expectations of the standard model (SM). Results from the search are interpreted in the next-to-minimal supersymmetric extension of the SM, where a “singlino” of small mass leads to squark and gluino cascade decays that can predominantly end in a highly Lorentz-boosted singlet-like ${\textrm{H}} _1$ and a singlino-like neutralino of small transverse momentum. Upper limits are set on the product of the squark or gluino pair production cross section and the square of the branching fraction of the ${\textrm{H}} _1$ in a benchmark model containing almost mass-degenerate gluinos and light-flavour squarks. Under the assumption of an SM-like branching fraction, ${\textrm{H}} _1$ bosons with masses in the range 40–120$\,\text {GeV}$ arising from the decays of squarks or gluinos with a mass of 1200–2500$\,\text {GeV}$ are excluded at 95% confidence level

Azimuthal correlations in Z +jets events in proton–proton collisions at s=13 TeV\sqrt{s} = 13\,\text {Te}\hspace{-.08em}\text {V}

The production of Z bosons associated with jets is measured in $\text {p}\text {p}$ collisions at $\sqrt{s}=13\,\text {Te}\hspace{-.08em}\text {V}$ with data recorded with the CMS experiment at the LHC corresponding to an integrated luminosity of 36.3$\,\text {fb}^{-1}$. The multiplicity of jets with transverse momentum $p_{\textrm{T}} > 30\,\text {Ge}\hspace{-.08em}\text {V}$ is measured for different regions of the Z boson’s $p_{\textrm{T}} (\text {Z })$, from lower than 10$\,\text {Ge}\hspace{-.08em}\text {V}$ to higher than 100$\,\text {Ge}\hspace{-.08em}\text {V}$. The azimuthal correlation $\varDelta \phi$ between the Z boson and the leading jet, as well as the correlations between the two leading jets are measured in three regions of $p_{\textrm{T}} (\text {Z })$. The measurements are compared with several predictions at leading and next-to-leading orders, interfaced with parton showers. Predictions based on transverse-momentum dependent parton distributions and corresponding parton showers give a good description of the measurement in the regions where multiple parton interactions and higher jet multiplicities are not important. The effects of multiple parton interactions are shown to be important to correctly describe the measured spectra in the low $p_{\textrm{T}} (\text {Z })$ regions

Search for direct pair production of supersymmetric partners of τ\tau leptons in the final state with two hadronically decaying τ\tau leptons and missing transverse momentum in proton-proton collisions at s\sqrt{s} = 13 TeV

A search for the direct production of a pair of $τ$ sleptons, the supersymmetric partners of $τ$ leptons, is presented. Each $τ$ slepton is assumed to decay to a $τ$ lepton and the lightest supersymmetric particle (LSP), which is assumed to be stable and to not interact in the detector, leading to an imbalance in the total reconstructed transverse momentum. The search is carried out in events identified as containing two $τ$ leptons, each decaying to one or more hadrons and a neutrino, and significant transverse momentum imbalance. In addition to scenarios in which the $τ$ sleptons decay promptly, the search also addresses scenarios in which the $τ$ sleptons have sufficiently long lifetimes to give rise to nonprompt $τ$ leptons. The data were collected in proton-proton collisions at a center-of-mass energy of 13 TeV at the CERN LHC with the CMS detector in 2016–2018, and correspond to an integrated luminosity of 138 fb$^{-1}$. No significant excess is seen with respect to standard model expectations. Upper limits on cross sections for the pair production of $τ$ sleptons are obtained in the framework of simplified models. In a scenario in which the $τ$ sleptons are superpartners of left-handed $τ$ leptons, and each undergoes a prompt decay to a $τ$ lepton and a nearly massless LSP, $τ$ slepton masses between 115 and 340 GeV are excluded. In a scenario in which the lifetime of the $τ$ sleptons corresponds to $cτ_0$ = 0.1 mm, where $τ_0$ represents the mean proper lifetime of the $τ$ slepton, masses between 150 and 220 GeV are excluded

Search for CP violating top quark couplings in pp collisions at s \sqrt{s} = 13 TeV

International audienceResults are presented from a search for CP violation in top quark pair production, using proton-proton collisions at a center-of-mass energy of 13 TeV. The data used for this analysis consist of final states with two charged leptons collected by the CMS experiment, and correspond to an integrated luminosity of 35.9 fb$^{−1}$. The search uses two observables, $\mathcal{O} _{1}$ and $\mathcal{O} _{3}$, which are Lorentz scalars. The observable $\mathcal{O} _{1}$ is constructed from the four-momenta of the charged leptons and the reconstructed top quarks, while $\mathcal{O} _{3}$ consists of the four-momenta of the charged leptons and the b quarks originating from the top quarks. Asymmetries in these observables are sensitive to CP violation, and their measurement is used to determine the chromoelectric dipole moment of the top quark. The results are consistent with the expectation from the standard model.[graphic not available: see fulltext

Search for CP violation using tt‾ \textrm{t}\overline{\textrm{t}} events in the lepton+jets channel in pp collisions at s \sqrt{s} = 13 TeV

Results are presented on a search for CP violation in the production and decay of top quark-antiquark pairs in the lepton+jets channel. The search is based on data from proton-proton collisions at $\sqrt{s}$ = 13 TeV, collected with the CMS detector, corresponding to an integrated luminosity of 138 fb$^{−1}$. Possible CP violation effects are evaluated by measuring asymmetries in observables constructed from linearly independent four-momentum vectors of the final-state particles. The dimensionless chromoelectric dipole moment of the top quark obtained from the observed asymmetries is measured to be 0.04 ± 0.10 (stat) ± 0.07(syst), and the asymmetries exhibit no evidence for CP-violating effects, consistent with expectations from the standard model.[graphic not available: see fulltext

Search for Higgs boson decays to a Z boson and a photon in proton-proton collisions at s \sqrt{s} = 13 TeV

Results are presented from a search for the Higgs boson decay H$\to$Z$\gamma$, where Z$\to\ell^+\ell^-$ with $\ell$ = e or $\mu$. The search is performed using a sample of proton-proton (pp) collision data at a center-of-mass energy of 13 TeV, recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 138 fb$^{-1}$. Events are assigned to mutually exclusive categories, which exploit differences in both event topology and kinematics of distinct Higgs production mechanisms to enhance signal sensitivity. The signal strength $\mu$, defined as the product of the cross section and the branching fraction [$\sigma($pp$\to$H$)\mathcal{B}($H$\to$Z$\gamma)$] relative to the standard model prediction, is extracted from a simultaneous fit to the $\ell^+\ell^-\gamma$ invariant mass distributions in all categories and is found to be $\mu$=2.4$\pm$0.9 for a Higgs boson mass of 125.38 GeV. The statistical significance of the observed excess of events is 2.7 standard deviations. This measurement corresponds to $\sigma($pp$\to$H$)\mathcal{B}($H$\to$Z$\gamma)$ = 0.21$\pm$0.08 pb. The observed (expected) upper limit at 95% confidence level on $\mu$ is 4.1 (1.8). The ratio of branching fractions $\mathcal{B}($H$\to$Z$\gamma)/\mathcal{B}($H$\to\gamma\gamma)$ is measured to be 1.5$^{+0.7}_{-0.6}$, which agrees with the standard model prediction of 0.69 $\pm$ 0.04 at the 1.5 standard deviation level