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The Compact Linear Collider (CLIC) is an option for a future e + e - collider operating at centre-of-mass energies up to 3 TeV , providing sensitivity to a wide range of new physics phenomena and precision physics measurements at the energy frontier. This paper is the first comprehensive presentation of the Higgs physics reach of CLIC operating at three energy stages: s = 350 GeV , 1.4 and 3 TeV . The initial stage of operation allows the study of Higgs boson production in Higgsstrahlung ( e + e - → Z H ) and W W -fusion ( e + e - → H ν e ν ¯ e ), resulting in precise measurements of the production cross sections, the Higgs total decay width Γ H , and model-independent determinations of the Higgs couplings. Operation at s > 1 TeV provides high-statistics samples of Higgs bosons produced through W W -fusion, enabling tight constraints on the Higgs boson couplings. Studies of the rarer processes e + e - → t t ¯ H and e + e - → H H ν e ν ¯ e allow measurements of the top Yukawa coupling and the Higgs boson self-coupling. This paper presents detailed studies of the precision achievable with Higgs measurements at CLIC and describes the interpretation of these measurements in a global fit.

The Compact Linear Collider (CLIC) is an option for a future e+e- collider operating at centre-of-mass energies up to 3 TeV, providing sensitivity to a wide range of new physics phenomena and precision physics measurements at the energy frontier. This paper is the first comprehensive presentation of the Higgs physics reach of CLIC operating at three energy stages: sqrt(s) = 350 GeV, 1.4 TeV and 3 TeV. The initial stage of operation allows the study of Higgs boson production in Higgsstrahlung (e+e- -> ZH) and WW-fusion (e+e- -> Hnunu), resulting in precise measurements of the production cross sections, the Higgs total decay width Gamma_H, and model-independent determinations of the Higgs couplings. Operation at sqrt(s) > 1 TeV provides high-statistics samples of Higgs bosons produced through WW-fusion, enabling tight constraints on the Higgs boson couplings. Studies of the rarer processes e+e- -> ttH and e+e- -> HHnunu allow measurements of the top Yukawa coupling and the Higgs boson self-coupling. This paper presents detailed studies of the precision achievable with Higgs measurements at CLIC and describes the interpretation of these measurements in a global fit.

The Compact Linear Collider (CLIC) is an option for a future ${\\mathrm{e}^{+}}{\\mathrm{e}^{-}} $ collider operating at centre-of-mass energies up to $3\\,\\text {TeV} $ , providing sensitivity to a wide range of new physics phenomena and precision physics measurements at the energy frontier. This paper is the first comprehensive presentation of the Higgs physics reach of CLIC operating at three energy stages: $\\sqrt{s} = 350\\,\\text {GeV} $ , 1.4 and $3\\,\\text {TeV} $ . The initial stage of operation allows the study of Higgs boson production in Higgsstrahlung ( ${\\mathrm{e}^{+}}{\\mathrm{e}^{-}} \\rightarrow {\\mathrm{Z}} {\\mathrm{H}} $ ) and ${\\mathrm{W}} {\\mathrm{W}} $ -fusion ( ${\\mathrm{e}^{+}}{\\mathrm{e}^{-}} \\rightarrow {\\mathrm{H}} {{\\nu }}_{\\!\\mathrm{e}} {\\bar{{\\nu }}}_{\\!\\mathrm{e}} $ ), resulting in precise measurements of the production cross sections, the Higgs total decay width $\\varGamma _{{\\mathrm{H}}}$ , and model-independent determinations of the Higgs couplings. Operation at $\\sqrt{s} > 1\\,\\text {TeV} $ provides high-statistics samples of Higgs bosons produced through ${\\mathrm{W}} {\\mathrm{W}} $ -fusion, enabling tight constraints on the Higgs boson couplings. Studies of the rarer processes ${\\mathrm{e}^{+}}{\\mathrm{e}^{-}} \\rightarrow \\mathrm{t} {\\bar{\\mathrm{t}}} {\\mathrm{H}} $ and ${\\mathrm{e}^{+}}{\\mathrm{e}^{-}} \\rightarrow {\\mathrm{H}} {\\mathrm{H}} {{\\nu }}_{\\!\\mathrm{e}} {\\bar{{\\nu }}}_{\\!\\mathrm{e}} $ allow measurements of the top Yukawa coupling and the Higgs boson self-coupling. This paper presents detailed studies of the precision achievable with Higgs measurements at CLIC and describes the interpretation of these measurements in a global fit.

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight 1 . Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories 2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones 3 , showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes. MRI data from more than 100 studies have been aggregated to yield new insights about brain development and ageing, and create an interactive open resource for comparison of brain structures throughout the human lifespan, including those associated with neurological and psychiatric disorders.

BackgroundAvailability of flavours and potential modified risk tobacco product (MRTP) claims may influence young adults’ (YAs’) perceptions of and intentions to use nicotine pouches (‘pouches’).MethodsYAs aged 21–34 years (N=47, M age=24.5, SD=3.1) with past-month nicotine/tobacco use (10.6% cigarette-only, 51.1% e-cigarette-only, 38.3% dual use) and no intention to quit were randomised to self-administer four Zyn 3 mg nicotine pouches in a 4 (flavour; within-subjects: smooth, mint, menthol, citrus) × 2 (MRTP claim on packaging; between subjects: present or absent) mixed-factorial design. After self-administering each pouch, participants reported appeal, use intentions and perceived harm compared with cigarettes and e-cigarettes. Three mixed-factorial analysis of variances (ANOVAs) examined main and interactive effects of flavour and MRTP claim on appeal, use intentions and comparative harm perceptions.ResultsMint (M=55.9, SD=26.4), menthol (M=49.7, SD=26.8) and citrus (M=46.6, SD=24.8) flavours were significantly more appealing than smooth (M=37.6, SD=25.4; p<0.001). MRTP claim did not significantly affect product appeal (p=0.376). Use intentions were greater for mint (M=2.6, SD=1.3) and menthol (M=2.0, SD=1.1) flavours than smooth (M=1.8, SD=1.0; p=0.002). Flavour did not affect comparative harm perceptions (p values>0.418). MRTP claims increased use intention (p=0.032) and perceptions of pouches as less harmful than cigarettes (p=0.011), but did not affect perceived harm relative to e-cigarettes (p=0.142). Flavour × MRTP claim interactions were not significant.ConclusionsFlavoured (vs smooth) pouches were more appealing to YAs. MRTP claims reduced perceived harm of pouches compared with cigarettes; however, intentions to switch were low. To protect YAs’ health, regulatory restrictions could target flavours and MRTP claims.

A comprehensive analysis of both the molecular genetic and phenotypic responses of any organism to the space flight environment has never been accomplished because of significant technological and logistical hurdles. Moreover, the effects of space flight on microbial pathogenicity and associated infectious disease risks have not been studied. The bacterial pathogen Salmonella typhimurium was grown aboard Space Shuttle mission STS-115 and compared with identical ground control cultures. Global microarray and proteomic analyses revealed that 167 transcripts and 73 proteins changed expression with the conserved RNA-binding protein Hfq identified as a likely global regulator involved in the response to this environment. Hfq involvement was confirmed with a ground-based microgravity culture model. Space flight samples exhibited enhanced virulence in a murine infection model and extracellular matrix accumulation consistent with a biofilm. Strategies to target Hfq and related regulators could potentially decrease infectious disease risks during space flight missions and provide novel therapeutic options on Earth.

Actin polymerization and assembly into stress fibers (SFs) is central to many cellular processes. However, how SFs form in response to the mechanical interaction of cells with their environment is not fully understood. Here we have identified Piezo2 mechanosensitive cationic channel as a transducer of environmental physical cues into mechanobiological responses. Piezo2 is needed by brain metastatic cells from breast cancer (MDA-MB-231-BrM2) to probe their physical environment as they anchor and pull on their surroundings or when confronted with confined migration through narrow pores. Piezo2-mediated Ca2+ influx activates RhoA to control the formation and orientation of SFs and focal adhesions (FAs). A possible mechanism for the Piezo2-mediated activation of RhoA involves the recruitment of the Fyn kinase to the cell leading edge as well as calpain activation. Knockdown of Piezo2 in BrM2 cells alters SFs, FAs, and nuclear translocation of YAP; a phenotype rescued by overexpression of dominant-positive RhoA or its downstream effector, mDia1. Consequently, hallmarks of cancer invasion and metastasis related to RhoA, actin cytoskeleton, and/or force transmission, such as migration, extracellular matrix degradation, and Serpin B2 secretion, were reduced in cells lacking Piezo2.

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD–foldon). BNT162b2 encodes the full-length transmembrane S glycoprotein, locked in its prefusion conformation by the substitution of two residues with proline (S(K986P/V987P); hereafter, S(P2) (also known as P2 S)). The flexibly tethered RBDs of the RBD–foldon bind to human ACE2 with high avidity. Approximately 20% of the S(P2) trimers are in the two-RBD ‘down’, one-RBD ‘up’ state. In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong T-helper-1 CD4 + and IFNγ + CD8 + T cell responses. Prime–boost vaccination of rhesus macaques ( Macaca mulatta ) with the BNT162b candidates elicits SARS-CoV-2-neutralizing geometric mean titres that are 8.2–18.2× that of a panel of SARS-CoV-2-convalescent human sera. The vaccine candidates protect macaques against challenge with SARS-CoV-2; in particular, BNT162b2 protects the lower respiratory tract against the presence of viral RNA and shows no evidence of disease enhancement. Both candidates are being evaluated in phase I trials in Germany and the USA 1 – 3 , and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728). BNT162b1 and BNT162b2 are two candidate mRNA vaccines against COVID-19 that elicit high virus-entry inhibition titres in mice, elicit high virus-neutralizing titres in rhesus macaques and protect macaques from SARS-CoV-2 challenge.

The rapidly expanding and energy-intensive production from the Canadian oil sands, one of the largest oil reserves globally, accounts for almost 12 % of Canada's greenhouse gas emissions according to inventories. Developing approaches for evaluating reported methane (CH4) emission is crucial for developing effective mitigation policies, but only one study has characterized CH4 sources in the Athabasca oil sands region (AOSR). We tested the use of 14C and 13C carbon isotope measurements in ambient CH4 from the AOSR to estimate source contributions from key regional CH4 sources: (1) tailings ponds, (2) surface mines and processing facilities, and (3) wetlands. The isotopic signatures of ambient CH4 indicate that the CH4 enrichments measured at the site were mainly influenced by fossil CH4 emissions from surface mining and processing facilities (56 ± 18 %), followed by fossil CH4 emissions from tailings ponds (34 ± 18 %) and to a lesser extent modern CH4 emissions from wetlands (10 ± <1 %). Our results confirm the importance of tailings ponds in regional CH4 emissions and show that this method can successfully distinguish wetland CH4 emissions. In the future, the isotopic characterization of CH4 sources and measurements from different seasons and wind directions are needed to provide a better source attribution in the AOSR.

Carnivores such as cats and minks are highly susceptible to SARS-CoV-2. Brazil is a global COVID-19 hot spot and several cases of human-to-cat transmission have been documented. We investigated the spread of SARS-CoV-2 by testing 547 domestic cats sampled between July-November 2020 from seven states in southern, southeastern, and northeastern Brazil. Moreover, we investigated whether immune responses elicited by enzootic coronaviruses affect SARS-CoV-2 infection in cats. We found infection with significantly higher neutralizing antibody titers against the Gamma variant of concern, endemic in Brazil during 2020, than against an early SARS-CoV-2 B.1 isolate (p<0.0001), validating the use of Gamma for further testing. The overall SARS-CoV-2 seroprevalence in Brazilian cats during late 2020 validated by plaque reduction neutralization test (PRNT 90 ) was 7.3% (95% CI, 5.3-9.8). There was no significant difference in SARS-CoV-2 seroprevalence in cats between Brazilian states, suggesting homogeneous infection levels ranging from 4.6% (95% CI, 2.2-8.4) to 11.4% (95% CI, 6.7-17.4; p=0.4438). Seroprevalence of the prototypic cat coronavirus Feline coronavirus (FCoV) in a PRNT 90 was high at 33.3% (95% CI, 24.9-42.5) and seroprevalence of Bovine coronavirus (BCoV) was low at 1.7% (95% CI, 0.2-5.9) in a PRNT 90 . Neutralizing antibody titers were significantly lower for FCoV than for SARS-CoV-2 (p=0.0001), consistent with relatively more recent infection of cats with SARS-CoV-2. Neither the magnitude of SARS-CoV-2 antibody titers (p=0.6390), nor SARS-CoV-2 infection status were affected by FCoV serostatus (p=0.8863). Our data suggest that pre-existing immunity against enzootic coronaviruses neither prevents, nor enhances SARS-CoV-2 infection in cats. High SARS-CoV-2 seroprevalence already during the first year of the pandemic substantiates frequent infection of domestic cats and raises concerns on potential SARS-CoV-2 mutations escaping human immunity upon spillback.