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Showing papers by "Michigan State University published in 2021"


Book
17 Sep 2021
TL;DR: This chapter discusses research variables, Validity, and Reliability, and issues related to data Gathering, as well as Analyzing Quantitative Data.
Abstract: Contents: Preface. Introduction to Research. Issues Related to Data Gathering. Common Data Collection Measures. Research Variables, Validity, and Reliability. Designing a Quantitative Study. Qualitative Research. Classroom Research. Coding. Analyzing Quantitative Data. Concluding and Reporting Research. Appendices.

1,574 citations


Journal ArticleDOI
TL;DR: In this article, the authors 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.
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.

1,129 citations


Journal ArticleDOI
10 Mar 2021-Nature
TL;DR: In this article, the authors show that the production of reactive oxygen species by the NADPH oxidase RBOHD is a critical early signalling event connecting pattern-triggered immunity and leucine-rich repeat receptors (NLRs) mediated immunity.
Abstract: The plant immune system is fundamental for plant survival in natural ecosystems and for productivity in crop fields. Substantial evidence supports the prevailing notion that plants possess a two-tiered innate immune system, called pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). PTI is triggered by microbial patterns via cell surface-localized pattern-recognition receptors (PRRs), whereas ETI is activated by pathogen effector proteins via predominantly intracellularly localized receptors called nucleotide-binding, leucine-rich repeat receptors (NLRs)1–4. PTI and ETI are initiated by distinct activation mechanisms and involve different early signalling cascades5,6. Here we show that Arabidopsis PRR and PRR co-receptor mutants—fls2 efr cerk1 and bak1 bkk1 cerk1 triple mutants—are markedly impaired in ETI responses when challenged with incompatible Pseudomonas syrinage bacteria. We further show that the production of reactive oxygen species by the NADPH oxidase RBOHD is a critical early signalling event connecting PRR- and NLR-mediated immunity, and that the receptor-like cytoplasmic kinase BIK1 is necessary for full activation of RBOHD, gene expression and bacterial resistance during ETI. Moreover, NLR signalling rapidly augments the transcript and/or protein levels of key PTI components. Our study supports a revised model in which potentiation of PTI is an indispensable component of ETI during bacterial infection. This revised model conceptually unites two major immune signalling cascades in plants and mechanistically explains some of the long-observed similarities in downstream defence outputs between PTI and ETI. Bacteria elicit two distinct immune responses in Arabidopsis thaliana, mediated by diverse signalling receptors but working in a synergistic manner.

401 citations


Journal ArticleDOI
TL;DR: In this paper, the anti-SARS-CoV-2 antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19 were determined based on a U.S. national registry, and the primary outcome was death within 30 days after plasma transfusion.
Abstract: Background Convalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown. Methods In a retrospective study based on a U.S. national registry, we determined the anti-SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti-SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis. Results Of the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti-SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32). Conclusions Among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti-SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT04338360.).

396 citations


Journal ArticleDOI
TL;DR: In this article, the authors examined the effects of long-term experimental warming on the complexity and stability of molecular ecological networks in grassland soil microbial communities, and found that warming significantly increased network complexity, including network size, connectivity, connectance, average clustering coefficient, relative modularity and number of keystone species.
Abstract: Unravelling the relationships between network complexity and stability under changing climate is a challenging topic in theoretical ecology that remains understudied in the field of microbial ecology. Here, we examined the effects of long-term experimental warming on the complexity and stability of molecular ecological networks in grassland soil microbial communities. Warming significantly increased network complexity, including network size, connectivity, connectance, average clustering coefficient, relative modularity and number of keystone species, as compared with the ambient control. Molecular ecological networks under warming became significantly more robust, with network stability strongly correlated with network complexity, supporting the central ecological belief that complexity begets stability. Furthermore, warming significantly strengthened the relationships of network structure to community functional potentials and key ecosystem functioning. These results indicate that preserving microbial ‘interactions’ is critical for ecosystem management and for projecting ecological consequences of future climate warming. The authors examine the effect of long-term experimental warming on the complexity and stability of molecular ecological networks in grassland soil microbial communities. They find warming increases network complexity, which is strongly correlated with network stability.

393 citations


Journal ArticleDOI
TL;DR: In this article, the authors examined the mental health implications of the COVID-19 pandemic in low-income and middle-income countries (LMICs) in four parts: the emerging literature on the impact of the pandemic on mental health, which shows high rates of psychological distress and early warning signs of an increase in mental health disorders.

359 citations


Journal ArticleDOI
TL;DR: In this article, the parton distribution functions (PDFs) from the CTEQ-TEA collaboration were obtained using a wide variety of high-precision Large Hadron Collider (LHC) data, in addition to the combined HERA I+II deep-inelastic scattering dataset, along with the datasets present in the CT14 global QCD analysis.
Abstract: We present the new parton distribution functions (PDFs) from the CTEQ-TEA collaboration, obtained using a wide variety of high-precision Large Hadron Collider (LHC) data, in addition to the combined HERA I+II deep-inelastic scattering dataset, along with the datasets present in the CT14 global QCD analysis. New LHC measurements in single-inclusive jet production with the full rapidity coverage, as well as production of Drell-Yan pairs, top-quark pairs, and high-pT Z bosons, are included to achieve the greatest sensitivity to the PDFs. The parton distributions are determined at next-to-leading order and next-to-next-to-leading order, with each of these PDFs accompanied by error sets determined using the Hessian method. Fast PDF survey techniques, based on the Hessian representation and the Lagrange multiplier method, are used to quantify the preference of each data set to quantities such as αs(mZ), and the gluon and strange quark distributions. We designate the main resulting PDF set as CT18. The ATLAS 7 TeV precision W/Z data are not included in CT18, due to their tension with other datasets in the global fit. Alternate PDF sets are generated including the ATLAS precision 7 TeV W/Z data (CT18A), a new scale choice for low-x DIS data (CT18X), or all of the above with a slightly higher choice for the charm mass (CT18Z). Theoretical calculations of standard candle cross sections at the LHC (such as the gg fusion Higgs boson cross section) are presented.

335 citations


Journal ArticleDOI
TL;DR: This Review aims to guide MOF design for novel biomedical applications by reviewing the historical application of MOFs for drug delivery, with a specific focus on the available options for designingMOFs for specific drug delivery applications.
Abstract: The use of metal-organic frameworks (MOFs) in biomedical applications has greatly expanded over the past decade due to the precision tunability, high surface areas, and high loading capacities of MOFs. Specifically, MOFs are being explored for a wide variety of drug delivery applications. Initially, MOFs were used for delivery of small-molecule pharmaceuticals; however, more recent work has focused on macromolecular cargos, such as proteins and nucleic acids. Here, we review the historical application of MOFs for drug delivery, with a specific focus on the available options for designing MOFs for specific drug delivery applications. These options include choices of MOF structure, synthetic method, and drug loading. Further considerations include tuning, modifications, biocompatibility, cellular targeting, and uptake. Altogether, this Review aims to guide MOF design for novel biomedical applications.

257 citations


Journal ArticleDOI
TL;DR: The potential outcomes of this exclusion of older adults from a society based on physical social contact are discussed and recommendations for rectifying the situation are provided, with a particular focus on older adults in long-term care facilities.
Abstract: The COVID-19 pandemic has excluded older adults from a society based on physical social contact. Vulnerable populations like older adults also tend to be excluded from digital services because they opt not to use the internet, lack necessary devices and network connectivity, or inexperience using the technology. Older adults who are frail and are not online, many of whom are in long-term care facilities, struggle with the double burden of social and digital exclusion. This paper discusses the potential outcomes of this exclusion and provides recommendations for rectifying the situation, with a particular focus on older adults in long-term care facilities.

228 citations


Journal ArticleDOI
TL;DR: In this article, using ensemble hydrological simulations, the authors show that climate change could reduce water storage in many regions, especially those in the Southern Hemisphere, and highlight the importance of climate change mitigation to avoid adverse water storage impacts and increased droughts.
Abstract: Terrestrial water storage (TWS) modulates the hydrological cycle and is a key determinant of water availability and an indicator of drought. While historical TWS variations have been increasingly studied, future changes in TWS and the linkages to droughts remain unexamined. Here, using ensemble hydrological simulations, we show that climate change could reduce TWS in many regions, especially those in the Southern Hemisphere. Strong inter-ensemble agreement indicates high confidence in the projected changes that are driven primarily by climate forcing rather than land and water management activities. Declines in TWS translate to increases in future droughts. By the late twenty-first century, the global land area and population in extreme-to-exceptional TWS drought could more than double, each increasing from 3% during 1976–2005 to 7% and 8%, respectively. Our findings highlight the importance of climate change mitigation to avoid adverse TWS impacts and increased droughts, and the need for improved water resource management and adaptation.

226 citations


Journal ArticleDOI
TL;DR: After the ICSP had voted to include the rank of phylum in the rules of the International Code of Nomenclature of Prokaryotes (ICNP), and following publication of the decision in the IJSEM, this paper presented names and formal descriptions of 42 phyla to effect valid publication of their names based on genera as the nomenclatural types.
Abstract: After the International Committee on Systematics of Prokaryotes (ICSP) had voted to include the rank of phylum in the rules of the International Code of Nomenclature of Prokaryotes (ICNP), and following publication of the decision in the IJSEM, we here present names and formal descriptions of 42 phyla to effect valid publication of their names, based on genera as the nomenclatural types.

Journal ArticleDOI
TL;DR: The Big Ten Conference requires comprehensive cardiac testing including cardiac magnetic resonance (CMR) imaging for all athletes with COVID-19, allowing comparison of screening approaches for safe return to play as mentioned in this paper.
Abstract: Importance Myocarditis is a leading cause of sudden death in competitive athletes Myocardial inflammation is known to occur with SARS-CoV-2 Different screening approaches for detection of myocarditis have been reported The Big Ten Conference requires comprehensive cardiac testing including cardiac magnetic resonance (CMR) imaging for all athletes with COVID-19, allowing comparison of screening approaches Objective To determine the prevalence of myocarditis in athletes with COVID-19 and compare screening strategies for safe return to play Design, Setting, and Participants Big Ten COVID-19 Cardiac Registry principal investigators were surveyed for aggregate observational data from March 1, 2020, through December 15, 2020, on athletes with COVID-19 For athletes with myocarditis, presence of cardiac symptoms and details of cardiac testing were recorded Myocarditis was categorized as clinical or subclinical based on the presence of cardiac symptoms and CMR findings Subclinical myocarditis classified as probable or possible myocarditis based on other testing abnormalities Myocarditis prevalence across universities was determined The utility of different screening strategies was evaluated Exposures SARS-CoV-2 by polymerase chain reaction testing Main Outcome and Measure Myocarditis via cardiovascular diagnostic testing Results Representing 13 universities, cardiovascular testing was performed in 1597 athletes (964 men [604%]) Thirty-seven (including 27 men) were diagnosed with COVID-19 myocarditis (overall 23%; range per program, 0%-76%); 9 had clinical myocarditis and 28 had subclinical myocarditis If cardiac testing was based on cardiac symptoms alone, only 5 athletes would have been detected (detected prevalence, 031%) Cardiac magnetic resonance imaging for all athletes yielded a 74-fold increase in detection of myocarditis (clinical and subclinical) Follow-up CMR imaging performed in 27 (730%) demonstrated resolution of T2 elevation in all (100%) and late gadolinium enhancement in 11 (407%) Conclusions and Relevance In this cohort study of 1597 US competitive athletes with CMR screening after COVID-19 infection, 37 athletes (23%) were diagnosed with clinical and subclinical myocarditis Variability was observed in prevalence across universities, and testing protocols were closely tied to the detection of myocarditis Variable ascertainment and unknown implications of CMR findings underscore the need for standardized timing and interpretation of cardiac testing These unique CMR imaging data provide a more complete understanding of the prevalence of clinical and subclinical myocarditis in college athletes after COVID-19 infection The role of CMR in routine screening for athletes safe return to play should be explored further

Journal ArticleDOI
M. G. Aartsen1, Rasha Abbasi2, Markus Ackermann, Jenni Adams1  +440 moreInstitutions (60)
TL;DR: In this article, the authors present an overview of a next-generation instrument, IceCube-Gen2, which will sharpen our understanding of the processes and environments that govern the Universe at the highest energies.
Abstract: The observation of electromagnetic radiation from radio to γ-ray wavelengths has provided a wealth of information about the Universe. However, at PeV (1015 eV) energies and above, most of the Universe is impenetrable to photons. New messengers, namely cosmic neutrinos, are needed to explore the most extreme environments of the Universe where black holes, neutron stars, and stellar explosions transform gravitational energy into non-thermal cosmic rays. These energetic particles havemillions of times higher energies than those produced in the most powerful particle accelerators on Earth. As neutrinos can escape from regions otherwise opaque to radiation, they allow an unique view deep into exploding stars and the vicinity of the event horizons of black holes. The discovery of cosmic neutrinos with IceCube has opened this new window on the Universe. IceCube has been successful in finding first evidence for cosmic particle acceleration in the jet of an active galactic nucleus. Yet, ultimately, its sensitivity is too limited to detect even the brightest neutrino sources with high significance, or to detect populations of less luminous sources. In thiswhite paper, we present an overview of a next-generation instrument, IceCube-Gen2, which will sharpen our understanding of the processes and environments that govern the Universe at the highest energies. IceCube-Gen2 is designed to: (a) Resolve the high-energy neutrino sky from TeV to EeV energies (b) Investigate cosmic particle acceleration through multi-messenger observations (c) Reveal the sources and propagation of the highest energy particles in the Universe (d) Probe fundamental physics with high-energy neutrinos IceCube-Gen2 will enhance the existing IceCube detector at the South Pole. It will increase the annual rate of observed cosmic neutrinos by a factor of ten compared to IceCube, and will be able to detect sources five times fainter than its predecessor. Furthermore, through the addition of a radio array, IceCube- Gen2 will extend the energy range by several orders of magnitude compared to IceCube. Construction will take 8 years and cost about $350M. The goal is to have IceCube-Gen2 fully operational by 2033. IceCube-Gen2 will play an essential role in shaping the new era of multimessenger astronomy, fundamentally advancing our knowledge of the highenergy Universe. This challenging mission can be fully addressed only through the combination of the information from the neutrino, electromagnetic, and gravitational wave emission of high-energy sources, in concert with the new survey instruments across the electromagnetic spectrum and gravitational wave detectors which will be available in the coming years.

Journal ArticleDOI
TL;DR: In this paper, the authors review innovative technologies that offer solutions achieving carbon neutrality and sustainable development, including those for renewable energy production, food system transformation, waste valorization, C sink conservation, and C-negative manufacturing.
Abstract: Global development has been heavily reliant on the overexploitation of natural resources since the Industrial Revolution. With the extensive use of fossil fuels, deforestation, and other forms of land-use change, anthropogenic activities have contributed to the ever-increasing concentrations of greenhouse gases (GHGs) in the atmosphere, causing global climate change. In response to the worsening global climate change, achieving carbon neutrality by 2050 is the most pressing task on the planet. To this end, it is of utmost importance and a significant challenge to reform the current production systems to reduce GHG emissions and promote the capture of CO2 from the atmosphere. Herein, we review innovative technologies that offer solutions achieving carbon (C) neutrality and sustainable development, including those for renewable energy production, food system transformation, waste valorization, C sink conservation, and C-negative manufacturing. The wealth of knowledge disseminated in this review could inspire the global community and drive the further development of innovative technologies to mitigate climate change and sustainably support human activities.


Journal ArticleDOI
TL;DR: A review of recent discoveries investigating microbial mechanisms of human bile acids and explores the chemical diversity that may exist in bile acid structures in light of the new discovery of microbial conjugations is provided in this paper.
Abstract: Bile acids play key roles in gut metabolism, cell signaling, and microbiome composition. While the liver is responsible for the production of primary bile acids, microbes in the gut modify these compounds into myriad forms that greatly increase their diversity and biological function. Since the early 1960s, microbes have been known to transform human bile acids in four distinct ways: deconjugation of the amino acids glycine or taurine, and dehydroxylation, dehydrogenation, and epimerization of the cholesterol core. Alterations in the chemistry of these secondary bile acids have been linked to several diseases, such as cirrhosis, inflammatory bowel disease, and cancer. In addition to the previously known transformations, a recent study has shown that members of our gut microbiota are also able to conjugate amino acids to bile acids, representing a new set of "microbially conjugated bile acids." This new finding greatly influences the diversity of bile acids in the mammalian gut, but the effects on host physiology and microbial dynamics are mostly unknown. This review focuses on recent discoveries investigating microbial mechanisms of human bile acids and explores the chemical diversity that may exist in bile acid structures in light of the new discovery of microbial conjugations. Video Abstract.

Journal ArticleDOI
24 Jun 2021-Cell
TL;DR: In this paper, a pan-genome-scale genomic resources including a graph-based genome, providing access to rice genomic variations, were developed to facilitate rice breeding as well as plant functional genomics and evolutionary biology research.

Journal ArticleDOI
Daniele Paolo Anderle1, V. Bertone2, Xu Cao3, Lei Chang4, Ningbo Chang5, Gu Chen6, Xurong Chen3, Zhuojun Chen7, Zhu-Fang Cui8, Ling-Yun Dai7, Weitian Deng9, Minghui Ding10, Xu Feng11, Chang Gong11, Long-Cheng Gui12, Feng-Kun Guo3, Chengdong Han3, J. J. He13, Tie-Jiun Hou14, Hongxia Huang13, Yin Huang15, Krešimir Kumerički16, L. P. Kaptari3, L. P. Kaptari17, Demin Li18, Hengne Li1, Minxiang Li3, Minxiang Li19, Xue-Qian Li4, Y. T. Liang3, Zuotang Liang20, Chen Liu20, Chuan Liu11, Guoming Liu1, Jie Liu3, Liuming Liu3, X. Liu19, Tiehui Liu20, Xiaofeng Luo21, Zhun Lyu22, Bo-Qiang Ma11, Fu Ma3, Jian-Ping Ma3, Yu-Gang Ma3, Yu-Gang Ma23, Lijun Mao3, C. Mezrag2, Hervé Moutarde2, Jialun Ping13, Si-Xue Qin24, Hang Ren3, Craig D. Roberts8, Juan Rojo25, Guodong Shen3, Chao Shi26, Qintao Song18, Hao Sun27, Paweł Sznajder, Enke Wang1, Fan Wang8, Qian Wang1, Rong Wang3, Ruiru Wang3, Taofeng Wang28, Wei Wang29, Xiaoyu Wang18, Xiaoyun Wang30, Jia-Jun Wu3, Xing-Gang Wu24, Lei Xia31, Bo-Wen Xiao21, Bo-Wen Xiao32, Guoqing Xiao3, Ju Jun Xie3, Ya-Ping Xie3, Hongxi Xing1, Hu-Shan Xu3, Nu Xu21, Nu Xu3, Shu-Sheng Xu33, Mengshi Yan11, Wenbiao Yan31, Wencheng Yan18, Xinhu Yan34, Jiancheng Yang3, Yi Bo Yang3, Zhi Yang35, De-Liang Yao7, Z. Ye36, Pei-Lin Yin33, C.-P. Yuan37, Wenlong Zhan3, Jianhui Zhang38, Jinlong Zhang20, Pengming Zhang39, Yifei Zhang31, Chao Hsi Chang3, Zhenyu Zhang40, Hongwei Zhao3, Kuang Ta Chao11, Qiang Zhao3, Yuxiang Zhao3, Zhengguo Zhao31, Liang Zheng41, Jian Zhou20, Xiang Zhou40, Xiaorong Zhou31, Bing-Song Zou3, Liping Zou3 
TL;DR: In this article, an Electron-ion collider in China (EicC) has been proposed, which will be constructed based on an upgraded heavy-ion accelerator, High Intensity heavy ion Accelerator Facility (HIAF), together with a new electron ring.
Abstract: Lepton scattering is an established ideal tool for studying inner structure of small particles such as nucleons as well as nuclei. As a future high energy nuclear physics project, an Electron-ion collider in China (EicC) has been proposed. It will be constructed based on an upgraded heavy-ion accelerator, High Intensity heavy-ion Accelerator Facility (HIAF) which is currently under construction, together with a new electron ring. The proposed collider will provide highly polarized electrons (with a polarization of ∼80%) and protons (with a polarization of ∼70%) with variable center of mass energies from 15 to 20 GeV and the luminosity of (2–3) × 10$^{33}$ cm$^{−2}$ · s$^{−1}$. Polarized deuterons and Helium-3, as well as unpolarized ion beams from Carbon to Uranium, will be also available at the EicC.The main foci of the EicC will be precision measurements of the structure of the nucleon in the sea quark region, including 3D tomography of nucleon; the partonic structure of nuclei and the parton interaction with the nuclear environment; the exotic states, especially those with heavy flavor quark contents. In addition, issues fundamental to understanding the origin of mass could be addressed by measurements of heavy quarkonia near-threshold production at the EicC. In order to achieve the above-mentioned physics goals, a hermetical detector system will be constructed with cutting-edge technologies.This document is the result of collective contributions and valuable inputs from experts across the globe. The EicC physics program complements the ongoing scientific programs at the Jefferson Laboratory and the future EIC project in the United States. The success of this project will also advance both nuclear and particle physics as well as accelerator and detector technology in China.[graphic not available: see fulltext]

Journal ArticleDOI
TL;DR: In this article, an omics-based framework was developed to evaluate ARG risk considering human-associated-enrichment, gene mobility, and host pathogenicity, and the authors classified humanassociated, mobile ARGs (3.6% of all ARGs) as the highest risk.
Abstract: Antibiotic resistance genes (ARGs) are widespread among bacteria. However, not all ARGs pose serious threats to public health, highlighting the importance of identifying those that are high-risk. Here, we developed an ‘omics-based’ framework to evaluate ARG risk considering human-associated-enrichment, gene mobility, and host pathogenicity. Our framework classifies human-associated, mobile ARGs (3.6% of all ARGs) as the highest risk, which we further differentiate as ‘current threats’ (Rank I; 3%) - already present among pathogens - and ‘future threats’ (Rank II; 0.6%) - novel resistance emerging from non-pathogens. Our framework identified 73 ‘current threat’ ARG families. Of these, 35 were among the 37 high-risk ARGs proposed by the World Health Organization and other literature; the remaining 38 were significantly enriched in hospital plasmids. By evaluating all pathogen genomes released since framework construction, we confirmed that ARGs that recently transferred into pathogens were significantly enriched in Rank II (‘future threats’). Lastly, we applied the framework to gut microbiome genomes from fecal microbiota transplantation donors. We found that although ARGs were widespread (73% of genomes), only 8.9% of genomes contained high-risk ARGs. Our framework provides an easy-to-implement approach to identify current and future antimicrobial resistance threats, with potential clinical applications including reducing risk of microbiome-based interventions. Antibiotic resistance genes are common but not all are of high risk to human health. Here, the authors develop an omics-based framework for ranking genes by risk that incorporates level of enrichment in human associated environments, gene mobility, and host pathogenicity.

Journal ArticleDOI
TL;DR: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer, and represents a novel treatment option in a therapeutically challenging disease state.
Abstract: Summary Background BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. Methods In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov , NCT02773849 . Findings Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3–4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. Interpretation Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. Funding FKD Therapies Oy.

Journal ArticleDOI
12 Mar 2021-Science
TL;DR: This article analyzed time series of low, mean, and high river flows from 7250 observatories around the world covering the years 1971 to 2010 and identified spatially complex trend patterns, where some regions are drying and others are wetting consistently across low and high flows.
Abstract: Anthropogenic climate change is expected to affect global river flow Here, we analyze time series of low, mean, and high river flows from 7250 observatories around the world covering the years 1971 to 2010 We identify spatially complex trend patterns, where some regions are drying and others are wetting consistently across low, mean, and high flows Trends computed from state-of-the-art model simulations are consistent with the observations only if radiative forcing that accounts for anthropogenic climate change is considered Simulated effects of water and land management do not suffice to reproduce the observed trend pattern Thus, the analysis provides clear evidence for the role of externally forced climate change as a causal driver of recent trends in mean and extreme river flow at the global scale

Journal ArticleDOI
TL;DR: It is shown that algorithmic ‘sorting out’ of users has consequences for who is exposed to news and politics on Facebook, including people who are algorithmically categorized as interested in news or politics.
Abstract: The visibility of news and politics in a Facebook newsfeed depends on the actions of a diverse set of actors: users, their friends, content publishers such as news organizations, advertisers, and a...

Journal ArticleDOI
Lawrence Berkeley National Laboratory1, National University of Singapore2, Stanford University3, University of Wisconsin-Madison4, National Ecological Observatory Network5, Oak Ridge National Laboratory6, McMaster University7, University of Nebraska–Lincoln8, University of California, Berkeley9, Agricultural Research Service10, University of British Columbia11, University of Colorado Boulder12, Ohio State University13, University of Florida14, University of Guelph15, University of Kansas16, Michigan State University17, Pacific Northwest National Laboratory18, United States Department of Agriculture19, University of New Mexico20, National Research Council21, Marine Biological Laboratory22, University of Alberta23, Virginia Commonwealth University24, University of Minnesota25, Dalhousie University26, Université de Montréal27, Carleton University28, Shinshu University29, Japan Agency for Marine-Earth Science and Technology30, Northern Arizona University31, Oregon State University32, Yale University33, Washington State University34, Harvard University35, Texas A&M University36, Indiana University37, Florida International University38, San Diego State University39, California State University, East Bay40, Wayne State University41, University of Sydney42, Wilfrid Laurier University43, University of Alabama44, Environment Canada45, United States Geological Survey46, Argonne National Laboratory47, Osaka Prefecture University48, University of Delaware49, University of Missouri50, University of Sheffield51
TL;DR: In this article, the authors evaluate the representativeness of flux footprints and evaluate potential biases as a consequence of the footprint-to-target-area mismatch, which can be used as a guide to identify site-periods suitable for specific applications.

Journal ArticleDOI
15 May 2021-Genomics
TL;DR: Wang et al. as mentioned in this paper carried out a large-scale study of 506,768 SARS-CoV-2 genome isolates from patients to identify many other rapidly growing mutations on the spike (S) protein receptor-binding domain (RBD).

Journal ArticleDOI
Georges Aad1, Brad Abbott2, Dale Charles Abbott3, A. Abed Abud4  +3008 moreInstitutions (221)
TL;DR: In this article, the ATLAS particle-flow reconstruction method is used to reconstruct the topo-clusters of the proton-proton collision data with a center-of-mass energy of 13$ TeV collected by the LHC.
Abstract: Jet energy scale and resolution measurements with their associated uncertainties are reported for jets using 36-81 fb$^{-1}$ of proton-proton collision data with a centre-of-mass energy of $\sqrt{s}=13$ TeV collected by the ATLAS detector at the LHC. Jets are reconstructed using two different input types: topo-clusters formed from energy deposits in calorimeter cells, as well as an algorithmic combination of charged-particle tracks with those topo-clusters, referred to as the ATLAS particle-flow reconstruction method. The anti-$k_t$ jet algorithm with radius parameter $R=0.4$ is the primary jet definition used for both jet types. Jets are initially calibrated using a sequence of simulation-based corrections. Next, several $\textit{in situ}$ techniques are employed to correct for differences between data and simulation and to measure the resolution of jets. The systematic uncertainties in the jet energy scale for central jets ($|\eta| 2.5$ TeV). The relative jet energy resolution is measured and ranges from ($24 \pm 1.5$)% at 20 GeV to ($6 \pm 0.5$)% at 300 GeV.

Journal ArticleDOI
T. Albahri1, A. Anastasi, Alexey Anisenkov2, Alexey Anisenkov3  +195 moreInstitutions (40)
TL;DR: The Muon g-2 Experiment at Fermi National Accelerator Laboratory (FNAL) has measured the muon anomalous precession frequency to an uncertainty of 434 parts per billion (ppb), statistical, and 56 ppb, systematic, with data collected in four storage ring configurations during its first physics run in 2018.
Abstract: The Muon g-2 Experiment at Fermi National Accelerator Laboratory (FNAL) has measured the muon anomalous precession frequency $\omega_a$ to an uncertainty of 434 parts per billion (ppb), statistical, and 56 ppb, systematic, with data collected in four storage ring configurations during its first physics run in 2018. When combined with a precision measurement of the magnetic field of the experiment's muon storage ring, the precession frequency measurement determines a muon magnetic anomaly of $a_{\mu}({\rm FNAL}) = 116\,592\,040(54) \times 10^{-11}$ (0.46 ppm). This article describes the multiple techniques employed in the reconstruction, analysis and fitting of the data to measure the precession frequency. It also presents the averaging of the results from the eleven separate determinations of \omega_a, and the systematic uncertainties on the result.

Posted ContentDOI
TL;DR: In this paper, the authors evaluate the feasibility and likely benefits of this approach in conservation and find that conserving genome-wide genetic variation is generally the best approach to prevent inbreeding depression and loss of adaptive potential from driving populations toward extinction.
Abstract: The unprecedented rate of extinction calls for efficient use of genetics to help conserve biodiversity. Several recent genomic and simulation-based studies have argued that the field of conservation biology has placed too much focus on conserving genome-wide genetic variation, and that the field should instead focus on managing the subset of functional genetic variation that is thought to affect fitness. Here, we critically evaluate the feasibility and likely benefits of this approach in conservation. We find that population genetics theory and empirical results show that conserving genome-wide genetic variation is generally the best approach to prevent inbreeding depression and loss of adaptive potential from driving populations toward extinction. Focusing conservation efforts on presumably functional genetic variation will only be feasible occasionally, often misleading, and counterproductive when prioritized over genome-wide genetic variation. Given the increasing rate of habitat loss and other environmental changes, failure to recognize the detrimental effects of lost genome-wide genetic variation on long-term population viability will only worsen the biodiversity crisis.

Journal ArticleDOI
TL;DR: Severe acute respiratory syndrome coronavirus 2 pandemic capacity is derived from the unique structural features on its spike protein: fast viral surfing over the epithelium with flat N‐terminal domain, tight binding to ACE2 entry receptor, and furin protease utilization.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic coronavirus disease 2019 (COVID-19) that exhibits an overwhelming contagious capacity over other human coronaviruses (HCoVs). This structural snapshot describes the structural bases underlying the pandemic capacity of SARS-CoV-2 and explains its fast motion over respiratory epithelia that allow its rapid cellular entry. Based on notable viral spike (S) protein features, we propose that the flat sialic acid-binding domain at the N-terminal domain (NTD) of the S1 subunit leads to more effective first contact and interaction with the sialic acid layer over the epithelium, and this, in turn, allows faster viral 'surfing' of the epithelium and receptor scanning by SARS-CoV-2. Angiotensin-converting enzyme 2 (ACE-2) protein on the epithelial surface is the primary entry receptor for SARS-CoV-2, and protein-protein interaction assays demonstrate high-affinity binding of the spike protein (S protein) to ACE-2. To date, no high-frequency mutations were detected at the C-terminal domain of the S1 subunit in the S protein, where the receptor-binding domain (RBD) is located. Tight binding to ACE-2 by a conserved viral RBD suggests the ACE2-RBD interaction is likely optimal. Moreover, the viral S subunit contains a cleavage site for furin and other proteases, which accelerates cell entry by SARS-CoV-2. The model proposed here describes a structural basis for the accelerated host cell entry by SARS-CoV-2 relative to other HCoVs and also discusses emerging hypotheses that are likely to contribute to the development of antiviral strategies to combat the pandemic capacity of SARS-CoV-2.


Journal ArticleDOI
TL;DR: In this article, the authors report a dense Li deposition (99.49% electrode density) with an ideal columnar structure that is achieved by controlling the uniaxial stack pressure during battery operation.
Abstract: Unregulated lithium (Li) growth is the major cause of low Coulombic efficiency, short cycle life and safety hazards for rechargeable Li metal batteries. Strategies that aim to achieve large granular Li deposits have been extensively explored, and yet it remains a challenge to achieve the ideal Li deposits, which consist of large Li particles that are seamlessly packed on the electrode and can be reversibly deposited and stripped. Here we report a dense Li deposition (99.49% electrode density) with an ideal columnar structure that is achieved by controlling the uniaxial stack pressure during battery operation. Using multiscale characterization and simulation, we elucidate the critical role of stack pressure on Li nucleation, growth and dissolution processes and propose a Li-reservoir-testing protocol to maintain the ideal Li morphology during extended cycling. The precise manipulation of Li deposition and dissolution is a critical step to enable fast charging and a low-temperature operation for Li metal batteries. Li electrodeposition is a fundamental process in Li metal batteries and its reversibility is crucial for battery operation. The authors investigate the effects of stack pressure on Li deposition and associated processes and discuss strategies for achieving dense Li deposits and practical Li metal batteries.