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Showing papers by "Kyoto University published in 2020"


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Georges Aad1, E. Abat2, Jalal Abdallah3, Jalal Abdallah4  +3029 moreInstitutions (164)
23 Feb 2020
TL;DR: The ATLAS detector as installed in its experimental cavern at point 1 at CERN is described in this paper, where a brief overview of the expected performance of the detector when the Large Hadron Collider begins operation is also presented.
Abstract: The ATLAS detector as installed in its experimental cavern at point 1 at CERN is described in this paper. A brief overview of the expected performance of the detector when the Large Hadron Collider begins operation is also presented.

3,111 citations


Journal ArticleDOI
TL;DR: On 5 February 2020, in Yokohama, Japan, a cruise ship hosting 3,711 people underwent a 2-week quarantine after a former passenger was found with COVID-19 post-disembarking, and the delay-adjusted asymptomatic proportion of infections, along with the infections’ timeline were derived.
Abstract: On 5 February 2020, in Yokohama, Japan, a cruise ship hosting 3,711 people underwent a 2-week quarantine after a former passenger was found with COVID-19 post-disembarking. As at 20 February, 634 persons on board tested positive for the causative virus. We conducted statistical modelling to derive the delay-adjusted asymptomatic proportion of infections, along with the infections' timeline. The estimated asymptomatic proportion was 17.9% (95% credible interval (CrI): 15.5-20.2%). Most infections occurred before the quarantine start.

2,195 citations


Journal ArticleDOI
TL;DR: This Consensus Statement is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications to reduce misunderstanding and misinterpretation of research data generated in various experimental models.
Abstract: Epithelial-mesenchymal transition (EMT) encompasses dynamic changes in cellular organization from epithelial to mesenchymal phenotypes, which leads to functional changes in cell migration and invasion. EMT occurs in a diverse range of physiological and pathological conditions and is driven by a conserved set of inducing signals, transcriptional regulators and downstream effectors. With over 5,700 publications indexed by Web of Science in 2019 alone, research on EMT is expanding rapidly. This growing interest warrants the need for a consensus among researchers when referring to and undertaking research on EMT. This Consensus Statement, mediated by 'the EMT International Association' (TEMTIA), is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications. We trust that these guidelines will help to reduce misunderstanding and misinterpretation of research data generated in various experimental models and to promote cross-disciplinary collaboration to identify and address key open questions in this research field. While recognizing the importance of maintaining diversity in experimental approaches and conceptual frameworks, we emphasize that lasting contributions of EMT research to increasing our understanding of developmental processes and combatting cancer and other diseases depend on the adoption of a unified terminology to describe EMT.

931 citations


Journal ArticleDOI
17 Jan 2020-eLife
TL;DR: The structural study of the doublets of Chlamydomonas reinhardtii and Tetrahymena thermophila shows that the inner junction serves as an interaction hub that involves tubulin post-translational modifications that contribute to the stability of thedoublet and hence, normal ciliary motility.
Abstract: Microtubules are cytoskeletal structures involved in stability, transport and organization in the cell. The building blocks, the α- and β-tubulin heterodimers, form protofilaments that associate laterally into the hollow microtubule. Microtubule also exists as highly stable doublet microtubules in the cilia where stability is needed for ciliary beating and function. The doublet microtubule maintains its stability through interactions at its inner and outer junctions where its A- and B-tubules meet. Here, using cryo-electron microscopy, bioinformatics and mass spectrometry of the doublets of Chlamydomonas reinhardtii and Tetrahymena thermophila, we identified two new inner junction proteins, FAP276 and FAP106, and an inner junction-associated protein, FAP126, thus presenting the complete answer to the inner junction identity and localization. Our structural study of the doublets shows that the inner junction serves as an interaction hub that involves tubulin post-translational modifications. These interactions contribute to the stability of the doublet and hence, normal ciliary motility.

886 citations


Journal ArticleDOI
Jens Kattge1, Gerhard Bönisch2, Sandra Díaz3, Sandra Lavorel  +751 moreInstitutions (314)
TL;DR: The extent of the trait data compiled in TRY is evaluated and emerging patterns of data coverage and representativeness are analyzed to conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements.
Abstract: Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.

882 citations


Journal ArticleDOI
Gilberto Pastorello1, Carlo Trotta2, E. Canfora2, Housen Chu1  +300 moreInstitutions (119)
TL;DR: The FLUXNET2015 dataset provides ecosystem-scale data on CO 2 , water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe, and is detailed in this paper.
Abstract: The FLUXNET2015 dataset provides ecosystem-scale data on CO2, water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible.

681 citations


Journal ArticleDOI
TL;DR: This review comprehensively covering the studies on electrochemical materials for KIBs, including electrode and electrolyte materials and a discussion on recent achievements and remaining/emerging issues includes insights into electrode reactions and solid-state ionics and nonaqueous solution chemistry.
Abstract: Li-ion batteries (LIBs), commercialized in 1991, have the highest energy density among practical secondary batteries and are widely utilized in electronics, electric vehicles, and even stationary energy storage systems. Along with the expansion of their demand and application, concern about the resources of Li and Co is growing. Therefore, secondary batteries composed of earth-abundant elements are desired to complement LIBs. In recent years, K-ion batteries (KIBs) have attracted significant attention as potential alternatives to LIBs. Previous studies have developed positive and negative electrode materials for KIBs and demonstrated several unique advantages of KIBs over LIBs and Na-ion batteries (NIBs). Thus, besides being free from any scarce/toxic elements, the low standard electrode potentials of K/K+ electrodes lead to high operation voltages competitive to those observed in LIBs. Moreover, K+ ions exhibit faster ionic diffusion in electrolytes due to weaker interaction with solvents and anions than that of Li+ ions; this is essential to realize high-power KIBs. This review comprehensively covers the studies on electrochemical materials for KIBs, including electrode and electrolyte materials and a discussion on recent achievements and remaining/emerging issues. The review also includes insights into electrode reactions and solid-state ionics and nonaqueous solution chemistry as well as perspectives on the research-based development of KIBs compared to those of LIBs and NIBs.

651 citations


Journal ArticleDOI
TL;DR: A new version of K EGG Mapper is reported, a suite of KEGG mapping tools available at the KEGg website, together with the KOALA family tools for automatic assignment of KO (KEGG Orthology) identifiers used in the mapping.
Abstract: KEGG is a reference knowledge base for biological interpretation of large-scale molecular datasets, such as genome and metagenome sequences. It accumulates experimental knowledge about high-level functions of the cell and the organism represented in terms of KEGG molecular networks, including KEGG pathway maps, BRITE hierarchies, and KEGG modules. By the process called KEGG mapping, a set of protein coding genes in the genome, for example, can be converted to KEGG molecular networks enabling interpretation of cellular functions and other high-level features. Here we report a new version of KEGG Mapper, a suite of KEGG mapping tools available at the KEGG website (https://www.kegg.jp/ or https://www.genome.jp/kegg/), together with the KOALA family tools for automatic assignment of KO (KEGG Orthology) identifiers used in the mapping.

646 citations


Journal ArticleDOI
TL;DR: KofamKOALA is a web server to assign KEGG Orthologs (KOs) to protein sequences by homology search against a database of profile hidden Markov models (KOfam) with pre-computed adaptive score thresholds.
Abstract: SUMMARY KofamKOALA is a web server to assign KEGG Orthologs (KOs) to protein sequences by homology search against a database of profile hidden Markov models (KOfam) with pre-computed adaptive score thresholds. KofamKOALA is faster than existing KO assignment tools with its accuracy being comparable to the best performing tools. Function annotation by KofamKOALA helps linking genes to KEGG resources such as the KEGG pathway maps and facilitates molecular network reconstruction. AVAILABILITY AND IMPLEMENTATION KofamKOALA, KofamScan and KOfam are freely available from GenomeNet (https://www.genome.jp/tools/kofamkoala/). SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

607 citations


Journal ArticleDOI
TL;DR: In this article, a review of lattice results related to pion, kaon, D-meson, neutral kaon mixing, B-meon, and nucleon physics with the aim of making them easily accessible to the nuclear and particle physics communities is presented.
Abstract: We review lattice results related to pion, kaon, D-meson, B-meson, and nucleon physics with the aim of making them easily accessible to the nuclear and particle physics communities. More specifically, we report on the determination of the light-quark masses, the form factor $f_+(0)$ arising in the semileptonic $K \rightarrow \pi $ transition at zero momentum transfer, as well as the decay constant ratio $f_K/f_\pi $ and its consequences for the CKM matrix elements $V_{us}$ and $V_{ud}$. Furthermore, we describe the results obtained on the lattice for some of the low-energy constants of $SU(2)_L\times SU(2)_R$ and $SU(3)_L\times SU(3)_R$ Chiral Perturbation Theory. We review the determination of the $B_K$ parameter of neutral kaon mixing as well as the additional four B parameters that arise in theories of physics beyond the Standard Model. For the heavy-quark sector, we provide results for $m_c$ and $m_b$ as well as those for D- and B-meson decay constants, form factors, and mixing parameters. These are the heavy-quark quantities most relevant for the determination of CKM matrix elements and the global CKM unitarity-triangle fit. We review the status of lattice determinations of the strong coupling constant $\alpha _s$. Finally, in this review we have added a new section reviewing results for nucleon matrix elements of the axial, scalar and tensor bilinears, both isovector and flavor diagonal.

607 citations


Journal ArticleDOI
TL;DR: The addition of abemaciclib to fulvestrant provided a clinically meaningful median OS benefit of 9.4 months for patients with HR-positive, ERBB2-negative advanced breast cancer that had progressed on endocrine therapy.
Abstract: Importance Statistically significant overall survival (OS) benefits of CDK4 and CDK6 inhibitors in combination with fulvestrant for hormone receptor (HR)–positive, ERBB2 (formerly HER2)-negative advanced breast cancer (ABC) in patients regardless of menopausal status after prior endocrine therapy (ET) has not yet been demonstrated. Objective To compare the effect of abemaciclib plus fulvestrant vs placebo plus fulvestrant on OS at the prespecified interim of MONARCH 2 (338 events) in patients with HR-positive, ERBB2-negative advanced breast cancer that progressed during prior ET. Design, Setting, and Participants MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib plus fulvestrant vs placebo plus fulvestrant for treatment of premenopausal or perimenopausal women (with ovarian suppression) and postmenopausal women with HR-positive, ERBB2-negative ABC that progressed during ET. Patients were enrolled between August 7, 2014, and December 29, 2015. Analyses for this report were conducted at the time of database lock on June 20, 2019. Interventions Patients were randomized 2:1 to receive abemaciclib or placebo, 150 mg, every 12 hours on a continuous schedule plus fulvestrant, 500 mg, per label. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary vs secondary). Main Outcomes and Measures The primary end point was investigator-assessed progression-free survival. Overall survival was a gated key secondary end point. The boundaryPvalue for the interim analysis was .02. Results Of 669 women enrolled, 446 (median [range] age, 59 [32-91] years) were randomized to the abemaciclib plus fulvestrant arm and 223 (median [range] age, 62 [32-87] years) were randomized to the placebo plus fulvestrant arm. At the prespecified interim, 338 deaths (77% of the planned 441 at the final analysis) were observed in the intent-to-treat population, with a median OS of 46.7 months for abemaciclib plus fulvestrant and 37.3 months for placebo plus fulvestrant (hazard ratio [HR], 0.757; 95% CI, 0.606-0.945;P = .01). Improvement in OS was consistent across all stratification factors. Among stratification factors, more pronounced effects were observed in patients with visceral disease (HR, 0.675; 95% CI, 0.511-0.891) and primary resistance to prior ET (HR, 0.686; 95% CI, 0.451-1.043). Time to second disease progression (median, 23.1 months vs 20.6 months), time to chemotherapy (median, 50.2 months vs 22.1 months), and chemotherapy-free survival (median, 25.5 months vs 18.2 months) were also statistically significantly improved in the abemaciclib arm vs placebo arm. No new safety signals were observed for abemaciclib. Conclusions and Relevance Treatment with abemaciclib plus fulvestrant resulted in a statistically significant and clinically meaningful median OS improvement of 9.4 months for patients with HR-positive, ERBB2-negative ABC who progressed after prior ET regardless of menopausal status. Abemaciclib substantially delayed the receipt of subsequent chemotherapy. Trial Registration ClinicalTrials.gov identifier:NCT02107703

Journal ArticleDOI
Shinya Yamanaka1
TL;DR: Two decades of research aimed at overcoming practical issues that limit ESCs and iPSCs use, including their inherent properties of tumorigenicity, immunogenicity, and heterogeneity are reviewed.

Journal ArticleDOI
TL;DR: This review discusses the current understanding of T Reg immunobiology in normal and disease states, with the perspective on the realization of Treg-targeting therapies in the clinic.
Abstract: Naturally occurring CD4+ regulatory T cells (Tregs), which specifically express the transcription factor FoxP3 in the nucleus and CD25 and CTLA-4 on the cell surface, are a functionally distinct T cell subpopulation actively engaged in the maintenance of immunological self-tolerance and homeostasis. Recent studies have facilitated our understanding of the cellular and molecular basis of their generation, function, phenotypic and functional stability, and adaptability. It is under investigation in humans how functional or numerical Treg anomalies, whether genetically determined or environmentally induced, contribute to immunological diseases such as autoimmune diseases. Also being addressed is how Tregs can be targeted to control physiological and pathological immune responses, for example, by depleting them to enhance tumor immunity or by expanding them to treat immunological diseases. This review discusses our current understanding of Treg immunobiology in normal and disease states, with a perspective on the realization of Treg-targeting therapies in the clinic.

Journal ArticleDOI
Sean Walkowiak1, Sean Walkowiak2, Liangliang Gao3, Cécile Monat4, Georg Haberer, Mulualem T. Kassa5, Jemima Brinton6, Ricardo H. Ramirez-Gonzalez6, Markus C. Kolodziej7, Emily Delorean3, Dinushika Thambugala8, Valentyna Klymiuk2, Brook Byrns2, Heidrun Gundlach, Venkat Bandi2, Jorge Nunez Siri2, Kirby T. Nilsen2, Catharine Aquino, Axel Himmelbach4, Dario Copetti9, Dario Copetti7, Tomohiro Ban10, Luca Venturini11, Michael W. Bevan6, Bernardo J. Clavijo6, Dal-Hoe Koo3, Jennifer Ens2, Krystalee Wiebe2, Amidou N’Diaye2, Allen K. Fritz3, Carl Gutwin2, Anne Fiebig4, Christine Fosker6, Bin Xiao Fu1, Gonzalo Garcia Accinelli6, Keith A. Gardner, Nick Fradgley, Juan J. Gutierrez-Gonzalez12, Gwyneth Halstead-Nussloch7, Masaomi Hatakeyama7, Chu Shin Koh2, Jasline Deek13, Alejandro C. Costamagna14, Pierre R. Fobert5, Darren Heavens6, Hiroyuki Kanamori, Kanako Kawaura10, Fuminori Kobayashi, Ksenia V. Krasileva6, Tony Kuo15, Tony Kuo16, Neil McKenzie6, Kazuki Murata17, Yusuke Nabeka17, Timothy Paape7, Sudharsan Padmarasu4, Lawrence Percival-Alwyn, Sateesh Kagale5, Uwe Scholz4, Jun Sese15, Philomin Juliana18, Ravi P. Singh18, Rie Shimizu-Inatsugi7, David Swarbreck6, James Cockram, Hikmet Budak, Toshiaki Tameshige10, Tsuyoshi Tanaka, Hiroyuki Tsuji10, Jonathan M. Wright6, Jianzhong Wu, Burkhard Steuernagel6, Ian Small19, Sylvie Cloutier8, Gabriel Keeble-Gagnère, Gary J. Muehlbauer12, Josquin Tibbets, Shuhei Nasuda17, Joanna Melonek19, Pierre Hucl2, Andrew G. Sharpe2, Matthew D. Clark11, Erik Legg20, Arvind K. Bharti20, Peter Langridge21, Anthony Hall6, Cristobal Uauy6, Martin Mascher4, Simon G. Krattinger22, Simon G. Krattinger7, Hirokazu Handa23, Kentaro Shimizu10, Kentaro Shimizu7, Assaf Distelfeld24, Kenneth J. Chalmers21, Beat Keller7, Klaus F. X. Mayer25, Jesse Poland3, Nils Stein4, Nils Stein26, Curt A. McCartney8, Manuel Spannagl, Thomas Wicker7, Curtis J. Pozniak2 
25 Nov 2020-Nature
TL;DR: Comparative analysis of multiple genome assemblies from wheat reveals extensive diversity that results from the complex breeding history of wheat and provides a basis for further potential improvements to this important food crop.
Abstract: Advances in genomics have expedited the improvement of several agriculturally important crops but similar efforts in wheat (Triticum spp.) have been more challenging. This is largely owing to the size and complexity of the wheat genome1, and the lack of genome-assembly data for multiple wheat lines2,3. Here we generated ten chromosome pseudomolecule and five scaffold assemblies of hexaploid wheat to explore the genomic diversity among wheat lines from global breeding programs. Comparative analysis revealed extensive structural rearrangements, introgressions from wild relatives and differences in gene content resulting from complex breeding histories aimed at improving adaptation to diverse environments, grain yield and quality, and resistance to stresses4,5. We provide examples outlining the utility of these genomes, including a detailed multi-genome-derived nucleotide-binding leucine-rich repeat protein repertoire involved in disease resistance and the characterization of Sm16, a gene associated with insect resistance. These genome assemblies will provide a basis for functional gene discovery and breeding to deliver the next generation of modern wheat cultivars.

Journal ArticleDOI
TL;DR: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD, and a reduced-dose regimen of glucocorticoids was noninferior to a standard- dose regimen with respect to death orESKD.
Abstract: Background More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. Methods We conducted a randomized trial with a 2-by-2 factor...

Journal ArticleDOI
TL;DR: Recent reports on the key physiological functions of the FFAR-mediated signaling transduction pathways in the regulation of metabolism and immune responses are discussed and future research opportunities for developing therapeutics for metabolic and immune disorders are revealed.
Abstract: Fatty acids are metabolized and synthesized as energy substrates during biological responses. Long- and medium-chain fatty acids derived mainly from dietary triglycerides, and short-chain fatty aci...

Journal ArticleDOI
TL;DR: It is shown that chimpanzees exhibit greater behavioural diversity in environments with more variability — in both recent and historical timescales, suggesting that environmental variability was a critical evolutionary force promoting the behavioural, as well as cultural diversification of great apes.
Abstract: Large brains and behavioural innovation are positively correlated, species-specific traits, associated with the behavioural flexibility animals need for adapting to seasonal and unpredictable habitats. Similar ecological challenges would have been important drivers throughout human evolution. However, studies examining the influence of environmental variability on within-species behavioural diversity are lacking despite the critical assumption that population diversification precedes genetic divergence and speciation. Here, using a dataset of 144 wild chimpanzee (Pan troglodytes) communities, we show that chimpanzees exhibit greater behavioural diversity in environments with more variability — in both recent and historical timescales. Notably, distance from Pleistocene forest refugia is associated with the presence of a larger number of behavioural traits, including both tool and non-tool use behaviours. Since more than half of the behaviours investigated are also likely to be cultural, we suggest that environmental variability was a critical evolutionary force promoting the behavioural, as well as cultural diversification of great apes. Environmental variability is one potential driver of behavioural and cultural diversity in humans and other animals. Here, the authors show that chimpanzee behavioural diversity is higher in habitats that are more seasonal and historically unstable, and in savannah woodland relative to forested sites.

Journal ArticleDOI
TL;DR: YAKE!, a light-weight unsupervised automatic keyword extraction method which rests on statistical text features extracted from single documents to select the most relevant keywords of a text, is described.

Journal ArticleDOI
TL;DR: These findings not only help to explain the poor interferon response in COVID-19 patients, but also describe the emergence of natural SARS-CoV-2 quasispecies with an extended ORF3b gene that may potentially affect CO VID-19 pathogenesis.

Journal ArticleDOI
TL;DR: The steps taken to provide better guidance on structuring complex ODDs and an ODD summary for inclusion in a journal article are documented and the need for standard descriptions of simulation experiments is advocated.
Abstract: The Overview, Design concepts and Details (ODD) protocol for describing Individual-and Agent-Based Models (ABMs) is now widely accepted and used to document such models in journal articles. As a standardized document for providing a consistent, logical and readable account of the structure and dynamics of ABMs, some research groups also find it useful as a workflow for model design. Even so, there are still limitations to ODD that obstruct its more widespread adoption. Such limitations are discussed and addressed in this paper: the limited availability of guidance on how to use ODD; the length of ODD documents; limitations of ODD for highly complex models; lack of sufficient details of many ODDs to enable reimplementation without access to the model code; and the lack of provision for sections in the document structure covering model design ratio-nale, the model’s underlying narrative, and the means by which the model’s fitness for purpose is evaluated. We document the steps we have taken to provide better guidance on: structuring complex ODDs and an ODD summary for inclusion in a journal article (with full details in supplementary material; Table 1); using ODD to point readers to relevant sections of the model code; update the document structure to include sections on model rationale and evaluation. We also further advocate the need for standard descriptions of simulation experiments and argue that ODD can in principle be used for any type of simulation model. Thereby ODD would provide a lingua franca for simulation modelling.

Journal ArticleDOI
10 Sep 2020-Nature
TL;DR: In this paper, the authors used an ensemble of land-use and biodiversity models to assess whether and how humans can reverse the declines in terrestrial biodiversity caused by habitat conversion, which is a major threat to biodiversity.
Abstract: Increased efforts are required to prevent further losses to terrestrial biodiversity and the ecosystem services that it provides1,2. Ambitious targets have been proposed, such as reversing the declining trends in biodiversity3; however, just feeding the growing human population will make this a challenge4. Here we use an ensemble of land-use and biodiversity models to assess whether—and how—humanity can reverse the declines in terrestrial biodiversity caused by habitat conversion, which is a major threat to biodiversity5. We show that immediate efforts, consistent with the broader sustainability agenda but of unprecedented ambition and coordination, could enable the provision of food for the growing human population while reversing the global terrestrial biodiversity trends caused by habitat conversion. If we decide to increase the extent of land under conservation management, restore degraded land and generalize landscape-level conservation planning, biodiversity trends from habitat conversion could become positive by the mid-twenty-first century on average across models (confidence interval, 2042–2061), but this was not the case for all models. Food prices could increase and, on average across models, almost half (confidence interval, 34–50%) of the future biodiversity losses could not be avoided. However, additionally tackling the drivers of land-use change could avoid conflict with affordable food provision and reduces the environmental effects of the food-provision system. Through further sustainable intensification and trade, reduced food waste and more plant-based human diets, more than two thirds of future biodiversity losses are avoided and the biodiversity trends from habitat conversion are reversed by 2050 for almost all of the models. Although limiting further loss will remain challenging in several biodiversity-rich regions, and other threats—such as climate change—must be addressed to truly reverse the declines in biodiversity, our results show that ambitious conservation efforts and food system transformation are central to an effective post-2020 biodiversity strategy. To promote the recovery of the currently declining global trends in terrestrial biodiversity, increases in both the extent of land under conservation management and the sustainability of the global food system from farm to fork are required.

Journal ArticleDOI
TL;DR: This Review aims to summarize and provide a comprehensive understanding of proton transport in MOFs and discusses the fundamental principles and various design strategies and implementations aimed at enhancing proton conductivity with representative examples.
Abstract: Solid-state proton conductors (SSPCs), which are a key component for the safety and efficiency of fuel cells, have received much attention due to their broad application in electrochemical devices....

Journal ArticleDOI
04 Feb 2020-JAMA
TL;DR: Treatment with intravenous vitamin C, hydrocortisone, and thiamine did not significantly improve the duration of time alive and free of vasopressor administration in patients with septic shock, suggesting that treatment with the combination does not lead to a more rapid resolution of septicshock.
Abstract: Importance It is unclear whether vitamin C, hydrocortisone, and thiamine are more effective than hydrocortisone alone in expediting resolution of septic shock. Objective To determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock. Design, Setting, and Participants Multicenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. The first patient was enrolled on May 8, 2018, and the last on July 9, 2019. The final date of follow-up was October 6, 2019. Interventions Patients were randomized to the intervention group (n = 109), consisting of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or to the control group (n = 107), consisting of intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days. Main Outcomes and Measures The primary trial outcome was duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were prespecified, including 90-day mortality. Results Among 216 patients who were randomized, 211 provided consent and completed the primary outcome measurement (mean age, 61.7 years [SD, 15.0]; 133 men [63%]). Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was –0.6 hours (95% CI, –8.3 to 7.2 hours;P = .83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported. Conclusions and Relevance In patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone. Trial Registration ClinicalTrials.gov Identifier:NCT03333278

Posted ContentDOI
18 Feb 2020-medRxiv
TL;DR: The incubation period falls within the range of 2-14 days with 95% confidence and has a mean of around 5 days when approximated using the best-fit lognormal distribution and it is recommended that the length of quarantine should be at least 14 days.
Abstract: The geographic spread of 2019 novel coronavirus (COVID-19) infections from the epicenter of Wuhan, China, has provided an opportunity to study the natural history of the recently emerged virus. Using publicly available event-date data from the ongoing epidemic, the present study investigated the incubation period and other time intervals that govern the epidemiological dynamics of COVID-19 infections. Our results show that the incubation period falls within the range of 2–14 days with 95% confidence and has a mean of around 5 days when approximated using the best-fit lognormal distribution. The mean time from illness onset to hospital admission (for treatment and/or isolation) was estimated at 3–4 days without truncation and at 5–9 days when right truncated. Based on the 95th percentile estimate of the incubation period, we recommend that the length of quarantine should be at least 14 days. The median time delay of 13 days from illness onset to death (17 days with right truncation) should be considered when estimating the COVID-19 case fatality risk.

Journal ArticleDOI
Elsa Bernard1, Yasuhito Nannya2, Robert P. Hasserjian3, Sean M. Devlin1, Heinz Tuechler, Juan S. Medina-Martinez1, Tetsuichi Yoshizato2, Yusuke Shiozawa2, Ryunosuke Saiki2, Luca Malcovati4, Max Levine1, Juan E. Arango1, Yangyu Zhou1, Francesc Solé, Catherine Cargo5, Detlef Haase6, Maria Creignou7, Ulrich Germing8, Yanming Zhang1, Gunes Gundem1, Araxe Sarian1, Arjan A. van de Loosdrecht, Martin Jädersten7, Magnus Tobiasson7, Olivier Kosmider9, Matilde Y. Follo10, Felicitas Thol11, Ronald Feitosa Pinheiro12, Valeria Santini13, Ioannis Kotsianidis14, Jacqueline Boultwood15, Fabio P.S. Santos, Julie Schanz6, Senji Kasahara, Takayuki Ishikawa, Hisashi Tsurumi16, Akifumi Takaori-Kondo2, Toru Kiguchi, Chantana Polprasert17, John M. Bennett18, Virginia M. Klimek1, Michael R. Savona19, Monika Belickova, Christina Ganster6, Laura Palomo, Guillermo Sanz20, Lionel Ades21, Matteo G. Della Porta, Alexandra Smith22, Yesenia Werner1, Minal Patel1, Agnes Viale1, Katelynd Vanness1, Donna Neuberg3, Kristen E. Stevenson3, Kamal Menghrajani1, Kelly L. Bolton1, Pierre Fenaux21, Andrea Pellagatti15, Uwe Platzbecker23, Michael Heuser11, Peter Valent24, Shigeru Chiba25, Yasushi Miyazaki26, Carlo Finelli10, Maria Teresa Voso27, Lee Yung Shih28, Michaela Fontenay9, Joop H. Jansen29, José Cervera, Yoshiko Atsuta, Norbert Gattermann8, Benjamin L. Ebert30, Rafael Bejar31, Peter L. Greenberg32, Mario Cazzola4, Eva Hellström-Lindberg7, Seishi Ogawa2, Elli Papaemmanuil1 
TL;DR: Clinical sequencing across a large prospective cohort of patients with myelodysplasic syndrome uncovers distinct associations between the mono- and biallelic states of TP53 and clinical presentation.
Abstract: Tumor protein p53 (TP53) is the most frequently mutated gene in cancer1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional therapies6–8 and dismal outcomes9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations10. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)11. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response. Clinical sequencing across a large prospective cohort of patients with myelodysplasic syndrome uncovers distinct associations between the mono- and biallelic states of TP53 and clinical presentation

Journal ArticleDOI
TL;DR: Abemaciclib when combined with ET is the first CDK4/6 inhibitor to demonstrate a significant improvement in IDFS in patients with HR+, HER2− node-positive EBC at high risk of early recurrence.
Abstract: PURPOSEMany patients with HR+, HER2− early breast cancer (EBC) will not experience recurrence or have distant recurrence with currently available standard therapies. However, up to 30% of patients ...

Journal ArticleDOI
TL;DR: Compared with gefitinib alone, gefithinib combined with carboplatin plus pemetrexed improved PFS in patients with untreated advanced NSCLC with EGFR mutations with an acceptable toxicity profile, although its OS benefit requires further validation.
Abstract: PURPOSEEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitor combined with cytotoxic chemotherapy is highly effective for the treatment of advanced non–small-cell lung cancer (NSCLC) wi...

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TL;DR: The overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab ( a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma was assessed.
Abstract: Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma. Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice–web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24. Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9–43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4–17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4–15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71–1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1–18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9–14·0) in the chemotherapy group (0·85, 95% CI 0·72–1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (<1%) patient in the chemotherapy group (acute kidney injury). Interpretation: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted. Funding: AstraZeneca.

Journal ArticleDOI
Georges Aad1, Brad Abbott2, Dale Charles Abbott3, Ovsat Abdinov4  +2934 moreInstitutions (199)
TL;DR: In this article, a search for the electroweak production of charginos and sleptons decaying into final states with two electrons or muons is presented, based on 139.fb$^{-1}$ of proton-proton collisions recorded by the ATLAS detector at the Large Hadron Collider at
Abstract: A search for the electroweak production of charginos and sleptons decaying into final states with two electrons or muons is presented. The analysis is based on 139 fb$^{-1}$ of proton–proton collisions recorded by the ATLAS detector at the Large Hadron Collider at $\sqrt{s}=13$ $\text {TeV}$. Three R-parity-conserving scenarios where the lightest neutralino is the lightest supersymmetric particle are considered: the production of chargino pairs with decays via either W bosons or sleptons, and the direct production of slepton pairs. The analysis is optimised for the first of these scenarios, but the results are also interpreted in the others. No significant deviations from the Standard Model expectations are observed and limits at 95% confidence level are set on the masses of relevant supersymmetric particles in each of the scenarios. For a massless lightest neutralino, masses up to 420 $\text {Ge}\text {V}$ are excluded for the production of the lightest-chargino pairs assuming W-boson-mediated decays and up to 1 $\text {TeV}$ for slepton-mediated decays, whereas for slepton-pair production masses up to 700 $\text {Ge}\text {V}$ are excluded assuming three generations of mass-degenerate sleptons.

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TL;DR: The discovery and development of catalysts and catalytic processes are essential components to maintaining an ecological balance in the future as mentioned in this paper, and recent revolutions made in data science could have a...
Abstract: The discovery and development of catalysts and catalytic processes are essential components to maintaining an ecological balance in the future. Recent revolutions made in data science could have a ...