Showing papers by "Max Planck Society published in 2021"

Detection of a SARS-CoV-2 variant of concern in South Africa.

Abstract: Continued uncontrolled transmission of SARS-CoV-2 in many parts of the world is creating conditions for substantial evolutionary changes to the virus1,2. Here we describe a newly arisen lineage of SARS-CoV-2 (designated 501Y.V2; also known as B.1.351 or 20H) that is defined by eight mutations in the spike protein, including three substitutions (K417N, E484K and N501Y) at residues in its receptor-binding domain that may have functional importance3-5. This lineage was identified in South Africa after the first wave of the epidemic in a severely affected metropolitan area (Nelson Mandela Bay) that is located on the coast of the Eastern Cape province. This lineage spread rapidly, and became dominant in Eastern Cape, Western Cape and KwaZulu-Natal provinces within weeks. Although the full import of the mutations is yet to be determined, the genomic data-which show rapid expansion and displacement of other lineages in several regions-suggest that this lineage is associated with a selection advantage that most plausibly results from increased transmissibility or immune escape6-8.

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.

performance: An R Package for Assessment, Comparison and Testing of Statistical Models

Abstract: A crucial part of statistical analysis is evaluating a model’s quality and fit, or performance. During analysis, especially with regression models, investigating the fit of models to data also often involves selecting the best fitting model amongst many competing models. Upon investigation, fit indices should also be reported both visually and numerically to bring readers in on the investigative effort.

Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant.

Abstract: Background Assessment of the safety and efficacy of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different populations is essential, as is investiga...

Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19.

Abstract: The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.

GWTC-2: Compact Binary Coalescences Observed by LIGO and Virgo During the First Half of the Third Observing Run

Abstract: We report on gravitational wave discoveries from compact binary coalescences detected by Advanced LIGO and Advanced Virgo in the first half of the third observing run (O3a) between 1 April 2019 15:00 UTC and 1 October 2019 15:00. By imposing a false-alarm-rate threshold of two per year in each of the four search pipelines that constitute our search, we present 39 candidate gravitational wave events. At this threshold, we expect a contamination fraction of less than 10%. Of these, 26 candidate events were reported previously in near real-time through GCN Notices and Circulars; 13 are reported here for the first time. The catalog contains events whose sources are black hole binary mergers up to a redshift of ~0.8, as well as events whose components could not be unambiguously identified as black holes or neutron stars. For the latter group, we are unable to determine the nature based on estimates of the component masses and spins from gravitational wave data alone. The range of candidate events which are unambiguously identified as binary black holes (both objects $\geq 3~M_\odot$) is increased compared to GWTC-1, with total masses from $\sim 14~M_\odot$ for GW190924_021846 to $\sim 150~M_\odot$ for GW190521. For the first time, this catalog includes binary systems with significantly asymmetric mass ratios, which had not been observed in data taken before April 2019. We also find that 11 of the 39 events detected since April 2019 have positive effective inspiral spins under our default prior (at 90% credibility), while none exhibit negative effective inspiral spin. Given the increased sensitivity of Advanced LIGO and Advanced Virgo, the detection of 39 candidate events in ~26 weeks of data (~1.5 per week) is consistent with GWTC-1.

Exceptional topology of non-Hermitian systems

Abstract: The current understanding of the role of topology in non-Hermitian (NH) systems and its far-reaching physical consequences observable in a range of dissipative settings are reviewed. In particular, how the paramount and genuinely NH concept of exceptional degeneracies, at which both eigenvalues and eigenvectors coalesce, leads to phenomena drastically distinct from the familiar Hermitian realm is discussed. An immediate consequence is the ubiquitous occurrence of nodal NH topological phases with concomitant open Fermi-Seifert surfaces, where conventional band-touching points are replaced by the aforementioned exceptional degeneracies. Furthermore, new notions of gapped phases including topological phases in single-band systems are detailed, and the manner in which a given physical context may affect the symmetry-based topological classification is clarified. A unique property of NH systems with relevance beyond the field of topological phases consists of the anomalous relation between bulk and boundary physics, stemming from the striking sensitivity of NH matrices to boundary conditions. Unifying several complementary insights recently reported in this context, a picture of intriguing phenomena such as the NH bulk-boundary correspondence and the NH skin effect is put together. Finally, applications of NH topology in both classical systems including optical setups with gain and loss, electric circuits, and mechanical systems and genuine quantum systems such as electronic transport settings at material junctions and dissipative cold-atom setups are reviewed.

Sensitive protein alignments at tree-of-life scale using DIAMOND.

Abstract: We are at the beginning of a genomic revolution in which all known species are planned to be sequenced. Accessing such data for comparative analyses is crucial in this new age of data-driven biology. Here, we introduce an improved version of DIAMOND that greatly exceeds previous search performances and harnesses supercomputing to perform tree-of-life scale protein alignments in hours, while matching the sensitivity of the gold standard BLASTP.

Towards complete and error-free genome assemblies of all vertebrate species

Abstract: High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are available for only a few non-microbial species1-4. To address this issue, the international Genome 10K (G10K) consortium5,6 has worked over a five-year period to evaluate and develop cost-effective methods for assembling highly accurate and nearly complete reference genomes. Here we present lessons learned from generating assemblies for 16 species that represent six major vertebrate lineages. We confirm that long-read sequencing technologies are essential for maximizing genome quality, and that unresolved complex repeats and haplotype heterozygosity are major sources of assembly error when not handled correctly. Our assemblies correct substantial errors, add missing sequence in some of the best historical reference genomes, and reveal biological discoveries. These include the identification of many false gene duplications, increases in gene sizes, chromosome rearrangements that are specific to lineages, a repeated independent chromosome breakpoint in bat genomes, and a canonical GC-rich pattern in protein-coding genes and their regulatory regions. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an international effort to generate high-quality, complete reference genomes for all of the roughly 70,000 extant vertebrate species and to help to enable a new era of discovery across the life sciences.

Toward Causal Representation Learning

Abstract: The two fields of machine learning and graphical causality arose and are developed separately. However, there is, now, cross-pollination and increasing interest in both fields to benefit from the advances of the other. In this article, we review fundamental concepts of causal inference and relate them to crucial open problems of machine learning, including transfer and generalization, thereby assaying how causality can contribute to modern machine learning research. This also applies in the opposite direction: we note that most work in causality starts from the premise that the causal variables are given. A central problem for AI and causality is, thus, causal representation learning, that is, the discovery of high-level causal variables from low-level observations. Finally, we delineate some implications of causality for machine learning and propose key research areas at the intersection of both communities.

Completed SDSS-IV extended Baryon Oscillation Spectroscopic Survey: cosmological implications from two decades of spectroscopic surveys at the Apache Point Observatory

Abstract: We present the cosmological implications from final measurements of clustering using galaxies, quasars, and Lyα forests from the completed Sloan Digital Sky Survey (SDSS) lineage of experiments in large-scale structure. These experiments, composed of data from SDSS, SDSS-II, BOSS, and eBOSS, offer independent measurements of baryon acoustic oscillation (BAO) measurements of angular-diameter distances and Hubble distances relative to the sound horizon, rd, from eight different samples and six measurements of the growth rate parameter, fσ8, from redshift-space distortions (RSD). This composite sample is the most constraining of its kind and allows us to perform a comprehensive assessment of the cosmological model after two decades of dedicated spectroscopic observation. We show that the BAO data alone are able to rule out dark-energy-free models at more than eight standard deviations in an extension to the flat, ΛCDM model that allows for curvature. When combined with Planck Cosmic Microwave Background (CMB) measurements of temperature and polarization, under the same model, the BAO data provide nearly an order of magnitude improvement on curvature constraints relative to primary CMB constraints alone. Independent of distance measurements, the SDSS RSD data complement weak lensing measurements from the Dark Energy Survey (DES) in demonstrating a preference for a flat ΛCDM cosmological model when combined with Planck measurements. The combined BAO and RSD measurements indicate σ8=0.85±0.03, implying a growth rate that is consistent with predictions from Planck temperature and polarization data and with General Relativity. When combining the results of SDSS BAO and RSD, Planck, Pantheon Type Ia supernovae (SNe Ia), and DES weak lensing and clustering measurements, all multiple-parameter extensions remain consistent with a ΛCDM model. Regardless of cosmological model, the precision on each of the three parameters, ωΛ, H0, and σ8, remains at roughly 1%, showing changes of less than 0.6% in the central values between models. In a model that allows for free curvature and a time-evolving equation of state for dark energy, the combined samples produce a constraint ωk=-0.0022±0.0022. The dark energy constraints lead to w0=-0.909±0.081 and wa=-0.49-0.30+0.35, corresponding to an equation of state of wp=-1.018±0.032 at a pivot redshift zp=0.29 and a Dark Energy Task Force Figure of Merit of 94. The inverse distance ladder measurement under this model yields H0=68.18±0.79 km s-1 Mpc-1, remaining in tension with several direct determination methods; the BAO data allow Hubble constant estimates that are robust against the assumption of the cosmological model. In addition, the BAO data allow estimates of H0 that are independent of the CMB data, with similar central values and precision under a ΛCDM model. Our most constraining combination of data gives the upper limit on the sum of neutrino masses at mν<0.115 eV (95% confidence). Finally, we consider the improvements in cosmology constraints over the last decade by comparing our results to a sample representative of the period 2000-2010. We compute the relative gain across the five dimensions spanned by w, ωk, mν, H0, and σ8 and find that the SDSS BAO and RSD data reduce the total posterior volume by a factor of 40 relative to the previous generation. Adding again the Planck, DES, and Pantheon SN Ia samples leads to an overall contraction in the five-dimensional posterior volume of 3 orders of magnitude.

NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Abstract: Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma.

Abstract: SARS-CoV-2 variants of concern (VOC) have arisen independently at multiple locations1,2 and may reduce the efficacy of current vaccines that target the spike glycoprotein of SARS-CoV-23. Here, using a live-virus neutralization assay, we compared the neutralization of a non-VOC variant with the 501Y.V2 VOC (also known as B.1.351) using plasma collected from adults who were hospitalized with COVID-19 during the two waves of infection in South Africa, the second wave of which was dominated by infections with the 501Y.V2 variant. Sequencing demonstrated that infections of plasma donors from the first wave were with viruses that did not contain the mutations associated with 501Y.V2, except for one infection that contained the E484K substitution in the receptor-binding domain. The 501Y.V2 virus variant was effectively neutralized by plasma from individuals who were infected during the second wave. The first-wave virus variant was effectively neutralized by plasma from first-wave infections. However, the 501Y.V2 variant was poorly cross-neutralized by plasma from individuals with first-wave infections; the efficacy was reduced by 15.1-fold relative to neutralization of 501Y.V2 by plasma from individuals infected in the second wave. By contrast, cross-neutralization of first-wave virus variants using plasma from individuals with second-wave infections was more effective, showing only a 2.3-fold decrease relative to neutralization of first-wave virus variants by plasma from individuals infected in the first wave. Although we tested only one plasma sample from an individual infected with a SARS-CoV-2 variant with only the E484K substitution, this plasma sample potently neutralized both variants. The observed effective neutralization of first-wave virus by plasma from individuals infected with 501Y.V2 provides preliminary evidence that vaccines based on VOC sequences could retain activity against other circulating SARS-CoV-2 lineages.

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.

State of the Art and Prospects for Halide Perovskite Nanocrystals.

Abstract: Metal-halide perovskites have rapidly emerged as one of the most promising materials of the 21st century, with many exciting properties and great potential for a broad range of applications, from photovoltaics to optoelectronics and photocatalysis. The ease with which metal-halide perovskites can be synthesized in the form of brightly luminescent colloidal nanocrystals, as well as their tunable and intriguing optical and electronic properties, has attracted researchers from different disciplines of science and technology. In the last few years, there has been a significant progress in the shape-controlled synthesis of perovskite nanocrystals and understanding of their properties and applications. In this comprehensive review, researchers having expertise in different fields (chemistry, physics, and device engineering) of metal-halide perovskite nanocrystals have joined together to provide a state of the art overview and future prospects of metal-halide perovskite nanocrystal research.

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Abstract: Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing.

Abstract: Biomolecular condensates are membraneless intracellular assemblies that often form via liquid-liquid phase separation and have the ability to concentrate biopolymers. Research over the past 10 years has revealed that condensates play fundamental roles in cellular organization and physiology, and our understanding of the molecular principles, components and forces underlying their formation has substantially increased. Condensate assembly is tightly regulated in the intracellular environment, and failure to control condensate properties, formation and dissolution can lead to protein misfolding and aggregation, which are often the cause of ageing-associated diseases. In this Review, we describe the mechanisms and regulation of condensate assembly and dissolution, highlight recent advances in understanding the role of biomolecular condensates in ageing and disease, and discuss how cellular stress, ageing-related loss of homeostasis and a decline in protein quality control may contribute to the formation of aberrant, disease-causing condensates. Our improved understanding of condensate pathology provides a promising path for the treatment of protein aggregation diseases.

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.

Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV.

Abstract: The emergence and global spread of SARS-CoV-2 has resulted in the urgent need for an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology1-10. Integration of such datasets to obtain a holistic view of virus-host interactions and to define the pathogenic properties of SARS-CoV-2 is limited by the heterogeneity of the experimental systems. Here we report a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactomes of both viruses, as well as their influence on the transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon infection with SARS-CoV-2 and SARS-CoV at different levels and enabled identification of distinct and common molecular mechanisms of these closely related coronaviruses. The TGF-β pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy was specifically dysregulated by SARS-CoV-2 ORF3. The extensive dataset (available at https://covinet.innatelab.org ) highlights many hotspots that could be targeted by existing drugs and may be used to guide rational design of virus- and host-directed therapies, which we exemplify by identifying inhibitors of kinases and matrix metalloproteases with potent antiviral effects against SARS-CoV-2.

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.

Planck 2018 results - VI. Cosmological parameters (Corrigendum)

Abstract: Author(s): Aghanim, N; Akrami, Y; Ashdown, M; Aumont, J; Baccigalupi, C; Ballardini, M; Banday, AJ; Barreiro, RB; Bartolo, N; Basak, S; Battye, R; Benabed, K; Bernard, JP; Bersanelli, M; Bielewicz, P; Bock, JJ; Bond, JR; Borrill, J; Bouchet, FR; Boulanger, F; Bucher, M; Burigana, C; Butler, RC; Calabrese, E; Cardoso, JF; Carron, J; Challinor, A; Chiang, HC; Chluba, J; Colombo, LPL; Combet, C; Contreras, D; Crill, BP; Cuttaia, F; De Bernardis, P; De Zotti, G; Delabrouille, J; Delouis, JM; DI Valentino, E; DIego, JM; Dore, O; Douspis, M; Ducout, A; Dupac, X; Dusini, S; Efstathiou, G; Elsner, F; Enslin, TA; Eriksen, HK; Fantaye, Y; Farhang, M; Fergusson, J; Fernandez-Cobos, R; Finelli, F; Forastieri, F; Frailis, M; Fraisse, AA; Franceschi, E; Frolov, A; Galeotta, S; Galli, S; Ganga, K; Genova-Santos, RT; Gerbino, M; Ghosh, T; Gonzalez-Nuevo, J; Gorski, KM; Gratton, S; Gruppuso, A; Gudmundsson, JE; Hamann, J; Handley, W; Hansen, FK; Herranz, D; Hildebrandt, SR; Hivon, E; Huang, Z; Jaffe, AH; Jones, WC; Karakci, A; Keihanen, E; Keskitalo, R; Kiiveri, K; Kim, J; Kisner, TS | Abstract: In the original version, the bounds given in Eqs. (87a) and (87b) on the contribution to the early-time optical depth, (15,30), contained a numerical error in deriving the 95th percentile from the Monte Carlo samples. The corrected 95% upper bounds are: τ(15,30) l 0:018 (lowE, flat τ(15, 30), FlexKnot), (1) τ(15, 30) l 0:023 (lowE, flat knot, FlexKnot): (2) These bounds are a factor of 3 larger than the originally reported results. Consequently, the new bounds do not significantly improve upon previous results from Planck data presented in Millea a Bouchet (2018) as was stated, but are instead comparable. Equations (1) and (2) give results that are now similar to those of Heinrich a Hu (2021), who used the same Planck 2018 data to derive a 95% upper bound of 0.020 using the principal component analysis (PCA) model and uniform priors on the PCA mode amplitudes.

Mechanism of SARS-CoV-2 polymerase stalling by remdesivir.

Abstract: Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3'-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3'-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3'-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication.

The eROSITA X-ray telescope on SRG

Abstract: eROSITA (extended ROentgen Survey with an Imaging Telescope Array) is the primary instrument on the Spectrum-Roentgen-Gamma (SRG) mission, which was successfully launched on July 13, 2019, from the Baikonour cosmodrome. After the commissioning of the instrument and a subsequent calibration and performance verification phase, eROSITA started a survey of the entire sky on December 13, 2019. By the end of 2023, eight complete scans of the celestial sphere will have been performed, each lasting six months. At the end of this program, the eROSITA all-sky survey in the soft X-ray band (0.2–2.3 keV) will be about 25 times more sensitive than the ROSAT All-Sky Survey, while in the hard band (2.3–8 keV) it will provide the first ever true imaging survey of the sky. The eROSITA design driving science is the detection of large samples of galaxy clusters up to redshifts z > 1 in order to study the large-scale structure of the universe and test cosmological models including Dark Energy. In addition, eROSITA is expected to yield a sample of a few million AGNs, including obscured objects, revolutionizing our view of the evolution of supermassive black holes. The survey will also provide new insights into a wide range of astrophysical phenomena, including X-ray binaries, active stars, and diffuse emission within the Galaxy. Results from early observations, some of which are presented here, confirm that the performance of the instrument is able to fulfil its scientific promise. With this paper, we aim to give a concise description of the instrument, its performance as measured on ground, its operation in space, and also the first results from in-orbit measurements.

Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis.

Abstract: Molnupiravir is an orally available antiviral drug candidate currently in phase III trials for the treatment of patients with COVID-19. Molnupiravir increases the frequency of viral RNA mutations and impairs SARS-CoV-2 replication in animal models and in humans. Here, we establish the molecular mechanisms underlying molnupiravir-induced RNA mutagenesis by the viral RNA-dependent RNA polymerase (RdRp). Biochemical assays show that the RdRp uses the active form of molnupiravir, β-D-N4-hydroxycytidine (NHC) triphosphate, as a substrate instead of cytidine triphosphate or uridine triphosphate. When the RdRp uses the resulting RNA as a template, NHC directs incorporation of either G or A, leading to mutated RNA products. Structural analysis of RdRp-RNA complexes that contain mutagenesis products shows that NHC can form stable base pairs with either G or A in the RdRp active center, explaining how the polymerase escapes proofreading and synthesizes mutated RNA. This two-step mutagenesis mechanism probably applies to various viral polymerases and can explain the broad-spectrum antiviral activity of molnupiravir.

Moiré heterostructures as a condensed-matter quantum simulator

Abstract: Twisted van der Waals heterostructures have latterly received prominent attention for their many remarkable experimental properties and the promise that they hold for realizing elusive states of matter in the laboratory We propose that these systems can, in fact, be used as a robust quantum simulation platform that enables the study of strongly correlated physics and topology in quantum materials Among the features that make these materials a versatile toolbox are the tunability of their properties through readily accessible external parameters such as gating, straining, packing and twist angle; the feasibility to realize and control a large number of fundamental many-body quantum models relevant in the field of condensed-matter physics; and finally, the availability of experimental readout protocols that directly map their rich phase diagrams in and out of equilibrium This general framework makes it possible to robustly realize and functionalize new phases of matter in a modular fashion, thus broadening the landscape of accessible physics and holding promise for future technological applications Moire heterostructures have latterly captured the attention of condensed-matter physicists This Review Article explores the idea of adopting them as a quantum simulation platform that enables the study of strongly correlated physics and topology in quantum materials

KiDS-1000 Cosmology: Multi-probe weak gravitational lensing and spectroscopic galaxy clustering constraints

Abstract: We present a joint cosmological analysis of weak gravitational lensing observations from the Kilo-Degree Survey (KiDS-1000), with redshift-space galaxy clustering observations from the Baryon Oscillation Spectroscopic Survey (BOSS) and galaxy-galaxy lensing observations from the overlap between KiDS-1000, BOSS, and the spectroscopic 2-degree Field Lensing Survey (2dFLenS). This combination of large-scale structure probes breaks the degeneracies between cosmological parameters for individual observables, resulting in a constraint on the structure growth parameter S 8 = σ8 √ Ωm/0.3 = 0.766+0.020 −0.014, which has the same overall precision as that reported by the full-sky cosmic microwave background observations from Planck. The recovered S 8 amplitude is low, however, by 8.3 ± 2.6% relative to Planck. This result builds from a series of KiDS-1000 analyses where we validate our methodology with variable depth mock galaxy surveys, our lensing calibration with image simulations and null-tests, and our optical-to-near-infrared redshift calibration with multi-band mock catalogues and a spectroscopic-photometric clustering analysis. The systematic uncertainties identified by these analyses are folded through as nuisance parameters in our cosmological analysis. Inspecting the offset between the marginalised posterior distributions, we find that the S 8-difference with Planck is driven by a tension in the matter fluctuation amplitude parameter, σ8. We quantify the level of agreement between the cosmic microwave background and our large-scale structure constraints using a series of different metrics, finding differences with a significance ranging between ∼ 3σ, when considering the offset in S 8, and ∼2σ, when considering the full multi-dimensional parameter space.

Sixteen novel lineages of SARS-CoV-2 in South Africa.

Abstract: The first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in South Africa was identified on 5 March 2020, and by 26 March the country was in full lockdown (Oxford stringency index of 90)1. Despite the early response, by November 2020, over 785,000 people in South Africa were infected, which accounted for approximately 50% of all known African infections2. In this study, we analyzed 1,365 near whole genomes and report the identification of 16 new lineages of SARS-CoV-2 isolated between 6 March and 26 August 2020. Most of these lineages have unique mutations that have not been identified elsewhere. We also show that three lineages (B.1.1.54, B.1.1.56 and C.1) spread widely in South Africa during the first wave, comprising ~42% of all infections in the country at the time. The newly identified C lineage of SARS-CoV-2, C.1, which has 16 nucleotide mutations as compared with the original Wuhan sequence, including one amino acid change on the spike protein, D614G (ref. 3), was the most geographically widespread lineage in South Africa by the end of August 2020. An early South African-specific lineage, B.1.106, which was identified in April 2020 (ref. 4), became extinct after nosocomial outbreaks were controlled in KwaZulu-Natal Province. Our findings show that genomic surveillance can be implemented on a large scale in Africa to identify new lineages and inform measures to control the spread of SARS-CoV-2. Such genomic surveillance presented in this study has been shown to be crucial in the identification of the 501Y.V2 variant in South Africa in December 2020 (ref. 5).