Inhibition of Plasmodium falciparum Field Isolates-Mediated Endothelial Cell Apoptosis by Fasudil: Therapeutic Implications for Severe Malaria

Plasmodium falciparum infection can abruptly progress to severe malaria, a life-threatening complication resulting from sequestration of parasitized red blood cells (PRBC) in the microvasculature of various organs such as the brain and lungs. PRBC adhesion can induce endothelial cell (EC) activation and apoptosis, thereby disrupting the blood-brain barrier. Moreover, hemozoin, the malarial pigment, induces the erythroid precursor apoptosis. Despite the current efficiency of antimalarial drugs in killing parasites, severe malaria still causes up to one million deaths every year. A new strategy targeting both parasite elimination and EC protection is urgently needed in the field. Recently, a rho-kinase inhibitior Fasudil, a drug already in clinical use in humans for cardio- and neuro-vascular diseases, was successfully tested on laboratory strains of P. falciparum to protect and to reverse damages of the endothelium. We therefore assessed herein whether Fasudil would have a similar efficiency on P. falciparum taken directly from malaria patients using contact and non-contact experiments. Seven (23.3%) of 30 PRBC preparations from different patients were apoptogenic, four (13.3%) acting by cytoadherence and three (10%) via soluble factors. None of the apoptogenic PRBC preparations used both mechanisms indicating a possible mutual exclusion of signal transduction ligand. Three PRBC preparations (42.9%) induced EC apoptosis by cytoadherence after 4 h of coculture (“rapid transducers”), and four (57.1%) after a minimum of 24 h (“slow transducers”). The intensity of apoptosis increased with time. Interestingly, Fasudil inhibited EC apoptosis mediated both by cell-cell contact and by soluble factors but did not affect PRBC cytoadherence. Fasudil was found to be able to prevent endothelium apoptosis from all the P. falciparum isolates tested. Our data provide evidence of the strong anti-apoptogenic effect of Fasudil and show that endothelial cell-P. falciparum interactions are more complicated than previously thought. These findings may warrant clinical trials of Fasudil in severe malaria management

Sex-specific effects of the local social environment on juvenile post-fledging dispersal in great tits

An individual’s decision to disperse from the natal habitat can affect its future fitness prospects. Especially in species with sex-biased dispersal, we expect the cost–benefit balance for dispersal to vary according to the social environment (e.g., local sex ratio and density). However, little is known about the social factors affecting dispersal decisions and about the temporal and spatial patterns of the dispersal process. In our study, we investigated experimentally the effects of the social environment on post-fledging dispersal of juvenile great tits by simultaneously manipulating the density and sex ratio of fledglings within forest plots. We expected young females in the post-fledging period mainly to compete for resources related to food and, as they are subordinate to males, we predicted higher female dispersal from male-biased plots. Juvenile males compete for vacant territories already in late summer and autumn; thus, we predicted increased male dispersal from high density and male-biased plots. We found that juvenile females had a higher probability to leave male-biased plots and had dispersed further from male-biased plots in the later post-fledging phase when juvenile males start to become territorial and more aggressive. Juvenile males were least likely to leave male-biased plots and had smallest dispersal distances from female-biased plots early after fledging. The results suggest that the social environment differentially affected the costs and benefits of philopatry for male and female juveniles. The local sex ratio of individuals is thus an important social trait to be considered for understanding sex-specific dispersal processes

Twelve-month observational study of children with cancer in 41 countries during the COVID-19 pandemic

Introduction Childhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality. Methods Prospective cohort study in 109 institutions in 41 countries. Inclusion criteria: children <18 years who were newly diagnosed with or undergoing active treatment for acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, retinoblastoma, Wilms tumour, glioma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, medulloblastoma and neuroblastoma. Of 2327 cases, 2118 patients were included in the study. The primary outcome measure was all-cause mortality at 30 days, 90 days and 12 months. Results All-cause mortality was 3.4% (n=71/2084) at 30-day follow-up, 5.7% (n=113/1969) at 90-day follow-up and 13.0% (n=206/1581) at 12-month follow-up. The median time from diagnosis to multidisciplinary team (MDT) plan was longest in low-income countries (7 days, IQR 3-11). Multivariable analysis revealed several factors associated with 12-month mortality, including low-income (OR 6.99 (95% CI 2.49 to 19.68); p<0.001), lower middle income (OR 3.32 (95% CI 1.96 to 5.61); p<0.001) and upper middle income (OR 3.49 (95% CI 2.02 to 6.03); p<0.001) country status and chemotherapy (OR 0.55 (95% CI 0.36 to 0.86); p=0.008) and immunotherapy (OR 0.27 (95% CI 0.08 to 0.91); p=0.035) within 30 days from MDT plan. Multivariable analysis revealed laboratory-confirmed SARS-CoV-2 infection (OR 5.33 (95% CI 1.19 to 23.84); p=0.029) was associated with 30-day mortality. Conclusions Children with cancer are more likely to die within 30 days if infected with SARS-CoV-2. However, timely treatment reduced odds of death. This report provides crucial information to balance the benefits of providing anticancer therapy against the risks of SARS-CoV-2 infection in children with cancer

Measurements of differential cross-sections in top-quark pair events with a high transverse momentum top quark and limits on beyond the Standard Model contributions to top-quark pair production with the ATLAS detector at √s = 13 TeV

Cross-section measurements of top-quark pair production where the hadronically decaying top quark has transverse momentum greater than 355 GeV and the other top quark decays into ℓνb are presented using 139 fb−1 of data collected by the ATLAS experiment during proton-proton collisions at the LHC. The fiducial cross-section at s = 13 TeV is measured to be σ = 1.267 ± 0.005 ± 0.053 pb, where the uncertainties reflect the limited number of data events and the systematic uncertainties, giving a total uncertainty of 4.2%. The cross-section is measured differentially as a function of variables characterising the tt¯ system and additional radiation in the events. The results are compared with various Monte Carlo generators, including comparisons where the generators are reweighted to match a parton-level calculation at next-to-next-to-leading order. The reweighting improves the agreement between data and theory. The measured distribution of the top-quark transverse momentum is used to search for new physics in the context of the effective field theory framework. No significant deviation from the Standard Model is observed and limits are set on the Wilson coefficients of the dimension-six operators OtG and Otq(8), where the limits on the latter are the most stringent to date. [Figure not available: see fulltext.]

Search for bottom-squark pair production in pp collision events at √s=13 TeV with hadronically decaying τ-leptons, b-jets, and missing transverse momentum using the ATLAS detector

A search for pair production of bottom squarks in events with hadronically decaying τ -leptons, b -tagged jets, and large missing transverse momentum is presented. The analyzed dataset is based on proton-proton collisions at √ s = 13     TeV delivered by the Large Hadron Collider and recorded by the ATLAS detector from 2015 to 2018, and corresponds to an integrated luminosity of 139     fb − 1 . The observed data are compatible with the expected Standard Model background. Results are interpreted in a simplified model where each bottom squark is assumed to decay into the second-lightest neutralino ˜ χ 0 2 and a bottom quark, with ˜ χ 0 2 decaying into a Higgs boson and the lightest neutralino ˜ χ 0 1 . The search focuses on final states where at least one Higgs boson decays into a pair of hadronically decaying τ -leptons. This allows the acceptance and thus the sensitivity to be significantly improved relative to the previous results at low masses of the ˜ χ 0 2 , where bottom-squark masses up to 850 GeV are excluded at the 95% confidence level, assuming a mass difference of 130 GeV between ˜ χ 0 2 and ˜ χ 0 1 . Model-independent upper limits are also set on the cross section of processes beyond the Standard Model

Measurements of differential cross-sections in four-lepton events in 13 TeV proton-proton collisions with the ATLAS detector

Measurements of four-lepton differential and integrated fiducial cross-sections in events with two same-flavour, opposite-charge electron or muon pairs are presented. The data correspond to 139 fb−1 of s√ = 13 TeV proton-proton collisions, collected by the ATLAS detector during Run 2 of the Large Hadron Collider (2015–2018). The final state has contributions from a number of interesting Standard Model processes that dominate in different four-lepton invariant mass regions, including single Z boson production, Higgs boson production and on-shell ZZ production, with a complex mix of interference terms, and possible contributions from physics beyond the Standard Model. The differential cross-sections include the four-lepton invariant mass inclusively, in slices of other kinematic variables, and in different lepton flavour categories. Also measured are dilepton invariant masses, transverse momenta, and angular correlation variables, in four regions of four-lepton invariant mass, each dominated by different processes. The measurements are corrected for detector effects and are compared with state-of-the-art Standard Model calculations, which are found to be consistent with the data. The Z → 4ℓ branching fraction is extracted, giving a value of (4.41 ± 0.30) × 10−6. Constraints on effective field theory parameters and a model based on a spontaneously broken B − L gauge symmetry are also evaluated. Further reinterpretations can be performed with the provided information