Showing papers by "Centre national de la recherche scientifique published in 2021"

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies.

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.7 and B.1.351 variants were first identified in the United Kingdom and South Africa, respectively, and have since spread to many countries. These variants harboring diverse mutations in the gene encoding the spike protein raise important concerns about their immune evasion potential. Here, we isolated infectious B.1.1.7 and B.1.351 strains from acutely infected individuals. We examined sensitivity of the two variants to SARS-CoV-2 antibodies present in sera and nasal swabs from individuals infected with previously circulating strains or who were recently vaccinated, in comparison with a D614G reference virus. We utilized a new rapid neutralization assay, based on reporter cells that become positive for GFP after overnight infection. Sera from 58 convalescent individuals collected up to 9 months after symptoms, similarly neutralized B.1.1.7 and D614G. In contrast, after 9 months, convalescent sera had a mean sixfold reduction in neutralizing titers, and 40% of the samples lacked any activity against B.1.351. Sera from 19 individuals vaccinated twice with Pfizer Cominarty, longitudinally tested up to 6 weeks after vaccination, were similarly potent against B.1.1.7 but less efficacious against B.1.351, when compared to D614G. Neutralizing titers increased after the second vaccine dose, but remained 14-fold lower against B.1.351. In contrast, sera from convalescent or vaccinated individuals similarly bound the three spike proteins in a flow cytometry-based serological assay. Neutralizing antibodies were rarely detected in nasal swabs from vaccinees. Thus, faster-spreading SARS-CoV-2 variants acquired a partial resistance to neutralizing antibodies generated by natural infection or vaccination, which was most frequently detected in individuals with low antibody levels. Our results indicate that B1.351, but not B.1.1.7, may increase the risk of infection in immunized individuals.

COVID-19 vaccine hesitancy in a representative working-age population in France: a survey experiment based on vaccine characteristics.

Abstract: Summary Background Opinion polls on vaccination intentions suggest that COVID-19 vaccine hesitancy is increasing worldwide; however, the usefulness of opinion polls to prepare mass vaccination campaigns for specific new vaccines and to estimate acceptance in a country's population is limited. We therefore aimed to assess the effects of vaccine characteristics, information on herd immunity, and general practitioner (GP) recommendation on vaccine hesitancy in a representative working-age population in France. Methods In this survey experiment, adults aged 18–64 years residing in France, with no history of SARS-CoV-2 infection, were randomly selected from an online survey research panel in July, 2020, stratified by gender, age, education, household size, and region and area of residence to be representative of the French population. Participants completed an online questionnaire on their background and vaccination behaviour-related variables (including past vaccine compliance, risk factors for severe COVID-19, and COVID-19 perceptions and experience), and were then randomly assigned according to a full factorial design to one of three groups to receive differing information on herd immunity (>50% of adults aged 18–64 years must be immunised [either by vaccination or infection]; >50% of adults must be immunised [either by vaccination or infection]; or no information on herd immunity) and to one of two groups regarding GP recommendation of vaccination (GP recommends vaccination or expresses no opinion). Participants then completed a series of eight discrete choice tasks designed to assess vaccine acceptance or refusal based on hypothetical vaccine characteristics (efficacy [50%, 80%, 90%, or 100%], risk of serious side-effects [1 in 10 000 or 1 in 100 000], location of manufacture [EU, USA, or China], and place of administration [GP practice, local pharmacy, or mass vaccination centre]). Responses were analysed with a two-part model to disentangle outright vaccine refusal (irrespective of vaccine characteristics, defined as opting for no vaccination in all eight tasks) from vaccine hesitancy (acceptance depending on vaccine characteristics). Findings Survey responses were collected from 1942 working-age adults, of whom 560 (28·8%) opted for no vaccination in all eight tasks (outright vaccine refusal) and 1382 (71·2%) did not. In our model, outright vaccine refusal and vaccine hesitancy were both significantly associated with female gender, age (with an inverted U-shaped relationship), lower educational level, poor compliance with recommended vaccinations in the past, and no report of specified chronic conditions (ie, no hypertension [for vaccine hesitancy] or no chronic conditions other than hypertension [for outright vaccine refusal]). Outright vaccine refusal was also associated with a lower perceived severity of COVID-19, whereas vaccine hesitancy was lower when herd immunity benefits were communicated and in working versus non-working individuals, and those with experience of COVID-19 (had symptoms or knew someone with COVID-19). For a mass vaccination campaign involving mass vaccination centres and communication of herd immunity benefits, our model predicted outright vaccine refusal in 29·4% (95% CI 28·6–30·2) of the French working-age population. Predicted hesitancy was highest for vaccines manufactured in China with 50% efficacy and a 1 in 10 000 risk of serious side-effects (vaccine acceptance 27·4% [26·8–28·0]), and lowest for a vaccine manufactured in the EU with 90% efficacy and a 1 in 100 000 risk of serious side-effects (vaccine acceptance 61·3% [60·5–62·1]). Interpretation COVID-19 vaccine acceptance depends on the characteristics of new vaccines and the national vaccination strategy, among various other factors, in the working-age population in France. Funding French Public Health Agency (Sante Publique France).

A digital supply chain twin for managing the disruption risks and resilience in the era of Industry 4.0

Abstract: We theorize a notion of a digital supply chain (SC) twin – a computerized model that represents network states for any given moment in real time. We explore the conditions surrounding the design an...

Gaia Early Data Release 3. The astrometric solution

Abstract: Context. Gaia Early Data Release 3 (Gaia EDR3) contains results for 1.812 billion sources in the magnitude range G = 3–21 based on observations collected by the European Space Agency Gaia satellite during the first 34 months of its operational phase.Aims. We describe the input data, the models, and the processing used for the astrometric content of Gaia EDR3, as well as the validation of these results performed within the astrometry task.Methods. The processing broadly followed the same procedures as for Gaia DR2, but with significant improvements to the modelling of observations. For the first time in the Gaia data processing, colour-dependent calibrations of the line- and point-spread functions have been used for sources with well-determined colours from DR2. In the astrometric processing these sources obtained five-parameter solutions, whereas other sources were processed using a special calibration that allowed a pseudocolour to be estimated as the sixth astrometric parameter. Compared with DR2, the astrometric calibration models have been extended, and the spin-related distortion model includes a self-consistent determination of basic-angle variations, improving the global parallax zero point.Results. Gaia EDR3 gives full astrometric data (positions at epoch J2016.0, parallaxes, and proper motions) for 1.468 billion sources (585 millionwith five-parameter solutions, 882 million with six parameters), and mean positions at J2016.0 for an additional 344 million.Solutions with five parameters are generally more accurate than six-parameter solutions, and are available for 93% of the sources brighter than the 17th magnitude. The median uncertainty in parallax and annual proper motion is 0.02–0.03 mas at magnitude G = 9–14, and around 0.5 mas at G = 20. Extensive characterisation of the statistical properties of the solutions is provided, including the estimated angular power spectrum of parallax bias from the quasars.

Hydrogen energy systems: A critical review of technologies, applications, trends and challenges

Abstract: The global energy transition towards a carbon neutral society requires a profound transformation of electricity generation and consumption, as well as of electric power systems. Hydrogen has an important potential to accelerate the process of scaling up clean and renewable energy, however its integration in power systems remains little studied. This paper reviews the current progress and outlook of hydrogen technologies and their application in power systems for hydrogen production, re-electrification and storage. The characteristics of electrolysers and fuel cells are demonstrated with experimental data and the deployments of hydrogen for energy storage, power-to-gas, co- and tri-generation and transportation are investigated using examples from worldwide projects. The current techno-economic status of these technologies and applications is presented, in which cost, efficiency and durability are identified as the main critical aspects. This is also confirmed by the results of a statistical analysis of the literature. Finally, conclusions show that continuous efforts on performance improvements, scale ramp-up, technical prospects and political support are required to enable a cost-competitive hydrogen economy.

Population Properties of Compact Objects from the Second LIGO-Virgo Gravitational-Wave Transient Catalog

Abstract: We report on the population of 47 compact binary mergers detected with a false-alarm rate of 0.01 are dynamically assembled. Third, we estimate merger rates, finding RBBH = 23.9-+8.614.3 Gpc-3 yr-1 for BBHs and RBNS = 320-+240490 Gpc-3 yr-1 for binary neutron stars. We find that the BBH rate likely increases with redshift (85% credibility) but not faster than the star formation rate (86% credibility). Additionally, we examine recent exceptional events in the context of our population models, finding that the asymmetric masses of GW190412 and the high component masses of GW190521 are consistent with our models, but the low secondary mass of GW190814 makes it an outlier.

High and rising economic costs of biological invasions worldwide

Abstract: Biological invasions are responsible for substantial biodiversity declines as well as high economic losses to society and monetary expenditures associated with the management of these invasions1,2 The InvaCost database has enabled the generation of a reliable, comprehensive, standardized and easily updatable synthesis of the monetary costs of biological invasions worldwide3 Here we found that the total reported costs of invasions reached a minimum of US$1288 trillion (2017 US dollars) over the past few decades (1970-2017), with an annual mean cost of US$268 billion Moreover, we estimate that the annual mean cost could reach US$1627 billion in 2017 These costs remain strongly underestimated and do not show any sign of slowing down, exhibiting a consistent threefold increase per decade We show that the documented costs are widely distributed and have strong gaps at regional and taxonomic scales, with damage costs being an order of magnitude higher than management expenditures Research approaches that document the costs of biological invasions need to be further improved Nonetheless, our findings call for the implementation of consistent management actions and international policy agreements that aim to reduce the burden of invasive alien species

Observation of Gravitational Waves from Two Neutron Star–Black Hole Coalescences

Abstract: We report the observation of gravitational waves from two compact binary coalescences in LIGO’s and Virgo’s third observing run with properties consistent with neutron star–black hole (NSBH) binaries. The two events are named GW200105_162426 and GW200115_042309, abbreviated as GW200105 and GW200115; the first was observed by LIGO Livingston and Virgo and the second by all three LIGO–Virgo detectors. The source of GW200105 has component masses 8.9−1.5+1.2 and 1.9−0.2+0.3M⊙ , whereas the source of GW200115 has component masses 5.7−2.1+1.8 and 1.5−0.3+0.7M⊙ (all measurements quoted at the 90% credible level). The probability that the secondary’s mass is below the maximal mass of a neutron star is 89%–96% and 87%–98%, respectively, for GW200105 and GW200115, with the ranges arising from different astrophysical assumptions. The source luminosity distances are 280−110+110 and 300−100+150Mpc , respectively. The magnitude of the primary spin of GW200105 is less than 0.23 at the 90% credible level, and its orientation is unconstrained. For GW200115, the primary spin has a negative spin projection onto the orbital angular momentum at 88% probability. We are unable to constrain the spin or tidal deformation of the secondary component for either event. We infer an NSBH merger rate density of 45−33+75Gpc−3yr−1 when assuming that GW200105 and GW200115 are representative of the NSBH population or 130−69+112Gpc−3yr−1 under the assumption of a broader distribution of component masses.

The Radius of PSR J0740+6620 from NICER and XMM-Newton Data

Abstract: PSR J0740$+$6620 has a gravitational mass of $2.08\pm 0.07~M_\odot$, which is the highest reliably determined mass of any neutron star. As a result, a measurement of its radius will provide unique insight into the properties of neutron star core matter at high densities. Here we report a radius measurement based on fits of rotating hot spot patterns to Neutron Star Interior Composition Explorer (NICER) and X-ray Multi-Mirror (XMM-Newton) X-ray observations. We find that the equatorial circumferential radius of PSR J0740$+$6620 is $13.7^{+2.6}_{-1.5}$ km (68%). We apply our measurement, combined with the previous NICER mass and radius measurement of PSR J0030$+$0451, the masses of two other $\sim 2~M_\odot$ pulsars, and the tidal deformability constraints from two gravitational wave events, to three different frameworks for equation of state modeling, and find consistent results at $\sim 1.5-3$ times nuclear saturation density. For a given framework, when all measurements are included the radius of a $1.4~M_\odot$ neutron star is known to $\pm 4$% (68% credibility) and the radius of a $2.08~M_\odot$ neutron star is known to $\pm 5$%. The full radius range that spans the $\pm 1\sigma$ credible intervals of all the radius estimates in the three frameworks is $12.45\pm 0.65$ km for a $1.4~M_\odot$ neutron star and $12.35\pm 0.75$ km for a $2.08~M_\odot$ neutron star.

A NICER View of the Massive Pulsar PSR J0740+6620 Informed by Radio Timing and XMM-Newton Spectroscopy

Abstract: We report on Bayesian estimation of the radius, mass, and hot surface regions of the massive millisecond pulsar PSR J0740$+$6620, conditional on pulse-profile modeling of Neutron Star Interior Composition Explorer X-ray Timing Instrument (NICER XTI) event data. We condition on informative pulsar mass, distance, and orbital inclination priors derived from the joint NANOGrav and CHIME/Pulsar wideband radio timing measurements of arXiv:2104.00880. We use XMM European Photon Imaging Camera spectroscopic event data to inform our X-ray likelihood function. The prior support of the pulsar radius is truncated at 16 km to ensure coverage of current dense matter models. We assume conservative priors on instrument calibration uncertainty. We constrain the equatorial radius and mass of PSR J0740$+$6620 to be $12.39_{-0.98}^{+1.30}$ km and $2.072_{-0.066}^{+0.067}$ M$_{\odot}$ respectively, each reported as the posterior credible interval bounded by the 16% and 84% quantiles, conditional on surface hot regions that are non-overlapping spherical caps of fully-ionized hydrogen atmosphere with uniform effective temperature; a posteriori, the temperature is $\log_{10}(T$ [K]$)=5.99_{-0.06}^{+0.05}$ for each hot region. All software for the X-ray modeling framework is open-source and all data, model, and sample information is publicly available, including analysis notebooks and model modules in the Python language. Our marginal likelihood function of mass and equatorial radius is proportional to the marginal joint posterior density of those parameters (within the prior support) and can thus be computed from the posterior samples.

Autoantibodies neutralizing type I IFNs are present in ~ 4% of uninfected individuals over 70 years old and account for ~ 20% of COVID-19 deaths.

Abstract: Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.

Single-molecule localization microscopy

Abstract: Single-molecule localization microscopy (SMLM) describes a family of powerful imaging techniques that dramatically improve spatial resolution over standard, diffraction-limited microscopy techniques and can image biological structures at the molecular scale. In SMLM, individual fluorescent molecules are computationally localized from diffraction-limited image sequences and the localizations are used to generate a super-resolution image or a time course of super-resolution images, or to define molecular trajectories. In this Primer, we introduce the basic principles of SMLM techniques before describing the main experimental considerations when performing SMLM, including fluorescent labelling, sample preparation, hardware requirements and image acquisition in fixed and live cells. We then explain how low-resolution image sequences are computationally processed to reconstruct super-resolution images and/or extract quantitative information, and highlight a selection of biological discoveries enabled by SMLM and closely related methods. We discuss some of the main limitations and potential artefacts of SMLM, as well as ways to alleviate them. Finally, we present an outlook on advanced techniques and promising new developments in the fast-evolving field of SMLM. We hope that this Primer will be a useful reference for both newcomers and practitioners of SMLM. This Primer explains the central concepts of single-molecule localization microscopy (SMLM) before discussing experimental considerations regarding fluorophores, optics and data acquisition, processing and analysis. The Primer further describes recent high-impact discoveries made by SMLM techniques and concludes by discussing emerging methodologies.

Hydrogen storage technologies for stationary and mobile applications: Review, analysis and perspectives

Abstract: Hydrogen storage systems (HSSs), are the backbone of feasible hydrogen economy. To provide a reliable renewable energy system, safe, cost effective and compact HSS is due. Physical storage systems involve the compressed gas, liquid and cryo-compressed techniques while material based one involves adsorptive materials, metal hydrides and chemical storage materials. In this paper, the features of a variety of HSSs are impartially discussed. The technical comparative analysis of the different physical and material based types of HSSs illustrates the paradoxical inherent features, including gravimetric and volumetric storage densities and parameters associated with storage and release processes, among these systems. Accordingly, no ideal hydrogen storage technique can be considered the best-fit for all stationary and automotive applications. Therefore, not only a unique HSS solution can properly provide the needs, but a set of complementary HSS solutions which may offer the system designer several options. This set of options can be hardly interpretable in case of the unclear definition of the application needs which may be time variant. Inside this review, the critical insights and recommendations about suitable applications for storage systems are provided. Different standards and codes alongside the corresponding tests are demonstrated for the different storage technologies. Moreover, storage vessels research work is overviewed for the different hydrogen storage technologies. In addition, the failure behaviour, criteria and prediction models are investigated for composite vessels subjected to high pressures and extreme temperatures degrading their mechanical behaviour and failure resistance.

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors

Abstract: The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

The default mode network in cognition: a topographical perspective.

Abstract: The default mode network (DMN) is a set of widely distributed brain regions in the parietal, temporal and frontal cortex. These regions often show reductions in activity during attention-demanding tasks but increase their activity across multiple forms of complex cognition, many of which are linked to memory or abstract thought. Within the cortex, the DMN has been shown to be located in regions furthest away from those contributing to sensory and motor systems. Here, we consider how our knowledge of the topographic characteristics of the DMN can be leveraged to better understand how this network contributes to cognition and behaviour. Regions of the default mode network (DMN) are distributed across the brain and show patterns of activity that have linked them to various different functional domains. In this Perspective, Smallwood and colleagues consider how an examination of the topographic characteristics of the DMN can shed light on its contribution to cognition.

Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics.

Abstract: Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

Bacteriocins as a new generation of antimicrobials: toxicity aspects and regulations

Abstract: In recent decades, bacteriocins have received substantial attention as antimicrobial compounds. Although bacteriocins have been predominantly exploited as food preservatives, they are now receiving increased attention as potential clinical antimicrobials and as possible immune-modulating agents. Infections caused by antibiotic-resistant bacteria have been declared as a global threat to public health. Bacteriocins represent a potential solution to this worldwide threat due to their broad- or narrow-spectrum activity against antibiotic-resistant bacteria. Notably, despite their role in food safety as natural alternatives to chemical preservatives, nisin remains the only bacteriocin legally approved by regulatory agencies as a food preservative. Moreover, insufficient data on the safety and toxicity of bacteriocins represent a barrier against the more widespread use of bacteriocins by the food and medical industry. Here, we focus on the most recent trends relating to the application of bacteriocins, their toxicity and impacts.

Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial

Abstract: Summary Background Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer. Methods KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS ClinicalTrials.gov , number NCT02555657 . Findings From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8–34·4) for the pembrolizumab group and 31·5 months (27·8–34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9–16·3) for the pembrolizumab group and 11·6 months (8·3–13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57–1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3–12·5) for the pembrolizumab group and 10·2 months (7·9–12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69–1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3–11·4) for the pembrolizumab group and 10·8 months (9·1–12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82–1·15]). The most common grade 3–4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [ Interpretation Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer. Funding Merck Sharp & Dohme.

Root traits as drivers of plant and ecosystem functioning: current understanding, pitfalls and future research needs

Abstract: The effects of plants on the biosphere, atmosphere and geosphere are key determinants of terrestrial ecosystem functioning. However, despite substantial progress made regarding plant belowground components, we are still only beginning to explore the complex relationships between root traits and functions. Drawing on the literature in plant physiology, ecophysiology, ecology, agronomy and soil science, we reviewed 24 aspects of plant and ecosystem functioning and their relationships with a number of root system traits, including aspects of architecture, physiology, morphology, anatomy, chemistry, biomechanics and biotic interactions. Based on this assessment, we critically evaluated the current strengths and gaps in our knowledge, and identify future research challenges in the field of root ecology. Most importantly, we found that belowground traits with the broadest importance in plant and ecosystem functioning are not those most commonly measured. Also, the estimation of trait relative importance for functioning requires us to consider a more comprehensive range of functionally relevant traits from a diverse range of species, across environments and over time series. We also advocate that establishing causal hierarchical links among root traits will provide a hypothesis-based framework to identify the most parsimonious sets of traits with the strongest links on functions, and to link genotypes to plant and ecosystem functioning.

Toward a hierarchical model of social cognition: A neuroimaging meta-analysis and integrative review of empathy and theory of mind.

Abstract: Along with the increased interest in and volume of social cognition research, there has been higher awareness of a lack of agreement on the concepts and taxonomy used to study social processes. Two central concepts in the field, empathy and Theory of Mind (ToM), have been identified as overlapping umbrella terms for different processes of limited convergence. Here, we review and integrate evidence of brain activation, brain organization, and behavior into a coherent model of social-cognitive processes. We start with a meta-analytic clustering of neuroimaging data across different social-cognitive tasks. Results show that understanding others' mental states can be described by a multilevel model of hierarchical structure, similar to models in intelligence and personality research. A higher level describes more broad and abstract classes of functioning, whereas a lower one explains how functions are applied to concrete contexts given by particular stimulus and task formats. Specifically, the higher level of our model suggests 3 groups of neurocognitive processes: (a) predominantly cognitive processes, which are engaged when mentalizing requires self-generated cognition decoupled from the physical world; (b) more affective processes, which are engaged when we witness emotions in others based on shared emotional, motor, and somatosensory representations; (c) combined processes, which engage cognitive and affective functions in parallel. We discuss how these processes are explained by an underlying principal gradient of structural brain organization. Finally, we validate the model by a review of empathy and ToM task interrelations found in behavioral studies. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Machine learning and applications in ultrafast photonics

Abstract: Recent years have seen the rapid growth and development of the field of smart photonics, where machine-learning algorithms are being matched to optical systems to add new functionalities and to enhance performance. An area where machine learning shows particular potential to accelerate technology is the field of ultrafast photonics — the generation and characterization of light pulses, the study of light–matter interactions on short timescales, and high-speed optical measurements. Our aim here is to highlight a number of specific areas where the promise of machine learning in ultrafast photonics has already been realized, including the design and operation of pulsed lasers, and the characterization and control of ultrafast propagation dynamics. We also consider challenges and future areas of research. The potential of machine-learning application to the field of ultrafast photonics is reviewed, with key examples including pulsed lasers, and control and characterization of ultrafast propagation dynamics.

Climate model projections from the Scenario Model Intercomparison Project (ScenarioMIP) of CMIP6

Abstract: . The Scenario Model Intercomparison Project (ScenarioMIP) defines and coordinates the primary future climate projections within the Coupled Model Intercomparison Project Phase 6 (CMIP6). This paper presents a range of its outcomes by synthesizing results from the participating global coupled Earth system models for concentration driven simulations. We limit our scope to the analysis of strictly geophysical outcomes: mainly global averages and spatial patterns of change for surface air temperature and precipitation. We also compare CMIP6 projections to CMIP5 results, especially for those scenarios that were designed to provide continuity across the CMIP phases, at the same time highlighting important differences in forcing composition, as well as in results. The range of future temperature and precipitation changes by the end of the century encompassing the Tier 1 experiments (SSP1-2.6, SSP2-4.5, SSP3-7.0 and SSP5-8.5) and SSP1-1.9 spans a larger range of outcomes compared to CMIP5, due to higher warming (by 1.15 °C) reached at the upper end of the 5–95 % envelope of the highest scenario, SSP5-8.5. This is due to both the wider range of radiative forcing that the new scenarios cover and to higher climate sensitivities in some of the new models compared to their CMIP5 predecessors. Spatial patterns of change for temperature and precipitation averaged over models and scenarios have familiar features, and an analysis of their variations confirms model structural differences to be the dominant source of uncertainty. Models also differ with respect to the size and evolution of internal variability as measured by individual models' initial condition ensembles' spread, according to a set of initial condition ensemble simulations available under SSP3-7.0. The same experiments suggest a tendency for internal variability to decrease along the course of the century, a new result that will benefit from further analysis over a larger set of models. Benefits of mitigation, all else being equal in terms of societal drivers, appear clearly when comparing scenarios developed under the same SSP, but to which different degrees of mitigation have been applied. It is also found that a mild overshoot in temperature of a few decades in mid-century, as represented in SSP5-3.4OS, does not affect the end outcome in terms of temperature and precipitation changes by 2100, which return to the same level as those reached by the gradually increasing SSP4-3.4. Central estimates of the time at which the ensemble means of the different scenarios reach a given warming level show all scenarios reaching 1.5 °C of warming compared to the 1850–1900 baseline in the second half of the current decade, with the time span between slow and fast warming covering 20–28 years from present. 2 °C of warming is reached as early as the late '30s by the ensemble mean under SSP5-8.5, but as late as the late '50s under SSP1-2.6. The highest warming level considered, 5 °C, is reached only by the ensemble mean under SSP5-8.5, and not until the mid-90s.

Global greenhouse gas emissions from animal-based foods are twice those of plant-based foods

Abstract: Agriculture and land use are major sources of greenhouse gas (GHG) emissions but previous estimates were either highly aggregate or provided spatial details for subsectors obtained via different methodologies. Using a model–data integration approach that ensures full consistency between subsectors, we provide spatially explicit estimates of production- and consumption-based GHG emissions worldwide from plant- and animal-based human food in circa 2010. Global GHG emissions from the production of food were found to be 17,318 ± 1,675 TgCO2eq yr−1, of which 57% corresponds to the production of animal-based food (including livestock feed), 29% to plant-based foods and 14% to other utilizations. Farmland management and land-use change represented major shares of total emissions (38% and 29%, respectively), whereas rice and beef were the largest contributing plant- and animal-based commodities (12% and 25%, respectively), and South and Southeast Asia and South America were the largest emitters of production-based GHGs. The quantification of greenhouse gas emissions related to food production and consumption is still largely hindered by the availability of spatial data consistent across sectors. This study provides a detailed account of emissions from land-use change, farmland, livestock and activities beyond the farm gate associated with plant- and animal-based foods/diets—culminating in local-, country- and global-level emissions from each major agricultural commodity.

COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study.

Abstract: Summary Background Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases Methods In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19 The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group) Severe disease was defined as that requiring admission to an intensive care unit or leading to death Secondary objectives were to analyse deaths and duration of hospital stay The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]) Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD This study is registered with ClinicalTrialsgov, NCT04353609 Findings Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66–6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46–0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55–3·19, p=0·53) Interpretation Rituximab therapy is associated with more severe COVID-19 Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases Funding None

An update of the Worldwide Integrated Assessment (WIA) on systemic insecticides. Part 2: impacts on organisms and ecosystems.

Abstract: New information on the lethal and sublethal effects of neonicotinoids and fipronil on organisms is presented in this review, complementing the previous Worldwide Integrated Assessment (WIA) in 2015. The high toxicity of these systemic insecticides to invertebrates has been confirmed and expanded to include more species and compounds. Most of the recent research has focused on bees and the sublethal and ecological impacts these insecticides have on pollinators. Toxic effects on other invertebrate taxa also covered predatory and parasitoid natural enemies and aquatic arthropods. Little new information has been gathered on soil organisms. The impact on marine and coastal ecosystems is still largely uncharted. The chronic lethality of neonicotinoids to insects and crustaceans, and the strengthened evidence that these chemicals also impair the immune system and reproduction, highlights the dangers of this particular insecticidal class (neonicotinoids and fipronil), with the potential to greatly decrease populations of arthropods in both terrestrial and aquatic environments. Sublethal effects on fish, reptiles, frogs, birds, and mammals are also reported, showing a better understanding of the mechanisms of toxicity of these insecticides in vertebrates and their deleterious impacts on growth, reproduction, and neurobehaviour of most of the species tested. This review concludes with a summary of impacts on the ecosystem services and functioning, particularly on pollination, soil biota, and aquatic invertebrate communities, thus reinforcing the previous WIA conclusions (van der Sluijs et al. 2015).

A gravitational-wave measurement of the Hubble constant following the second observing run of Advanced LIGO and Virgo

Abstract: This paper presents the gravitational-wave measurement of the Hubble constant (H 0) using the detections from the first and second observing runs of the Advanced LIGO and Virgo detector network. The presence of the transient electromagnetic counterpart of the binary neutron star GW170817 led to the first standard-siren measurement of H 0. Here we additionally use binary black hole detections in conjunction with galaxy catalogs and report a joint measurement. Our updated measurement is H 0 = km s−1 Mpc−1 (68.3% of the highest density posterior interval with a flat-in-log prior) which is an improvement by a factor of 1.04 (about 4%) over the GW170817-only value of km s−1 Mpc−1. A significant additional contribution currently comes from GW170814, a loud and well-localized detection from a part of the sky thoroughly covered by the Dark Energy Survey. With numerous detections anticipated over the upcoming years, an exhaustive understanding of other systematic effects are also going to become increasingly important. These results establish the path to cosmology using gravitational-wave observations with and without transient electromagnetic counterparts.

Detection of two interstellar polycyclic aromatic hydrocarbons via spectral matched filtering.

Abstract: Unidentified infrared emission bands are ubiquitous in many astronomical sources. These bands are widely, if not unanimously, attributed to collective emissions from polycyclic aromatic hydrocarbon (PAH) molecules, yet no single species of this class has been identified in space. Using spectral matched filtering of radio data from the Green Bank Telescope, we detected two nitrile-group-functionalized PAHs, 1- and 2-cyanonaphthalene, in the interstellar medium. Both bicyclic ring molecules were observed in the TMC-1 molecular cloud. In this paper, we discuss potential in situ gas-phase PAH formation pathways from smaller organic precursor molecules.