Showing papers by "University of Queensland published in 2021"
Daniel J. Klionsky1, Amal Kamal Abdel-Aziz2, Sara Abdelfatah3, Mahmoud Abdellatif4 +2980 more•Institutions (777)
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
Erola Pairo-Castineira1, Erola Pairo-Castineira2, Sara Clohisey2, Lucija Klaric1 +1446 more•Institutions (27)
TL;DR: The GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2244 critically ill Covid-19 patients from 208 UK intensive care units is reported, finding evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease.
Abstract: Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10−8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice. A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.
941 citations
Memorial Sloan Kettering Cancer Center1, Yonsei University2, Royal Free London NHS Foundation Trust3, University of Duisburg-Essen4, Texas Oncology5, Catholic University of Korea6, McMaster University7, University of Miami8, University of Western Ontario9, Autonomous University of Barcelona10, University of Queensland11, Seoul National University12, Macquarie University13, Rambam Health Care Campus14, Kyushu University15, University of Tübingen16, Medical University of Vienna17, Eisai18, Merck & Co.19, Harvard University20
TL;DR: In this article, Lenvatinib in combination with pembrolizumab or everolimus has been shown to have activity against advanced renal cell carcinoma (RCC).
Abstract: Background Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib ...
722 citations
National Institutes of Health1, Wellcome Trust Sanger Institute2, University of Cambridge3, Rockefeller University4, University of California, Davis5, Leibniz Association6, Seoul National University7, University of Southern California8, European Bioinformatics Institute9, Dresden University of Technology10, Max Planck Society11, Radboud University Nijmegen12, University of St Andrews13, University of Massachusetts Amherst14, University of Adelaide15, University of Missouri16, East Carolina University17, University of Queensland18, Clemson University19, University of Otago20, University of Arizona21, Natural History Museum22, Bangor University23, University of Konstanz24, Harvard University25, Northeastern University26, University of Antwerp27, National Museum of Natural History28, University of Graz29, University of Florida30, University of Basel31, University of California, Santa Cruz32, Zoological Society of San Diego33, Pacific Biosciences34, Pompeu Fabra University35, University of Maryland, College Park36, Harbin Institute of Technology37, University of Chicago38, Oregon Health & Science University39, Monash University Malaysia Campus40, Qatar Airways41, University of Milan42, Goethe University Frankfurt43, Pennsylvania State University44, University of Los Andes45, University of Copenhagen46, Norwegian University of Science and Technology47, Agency for Science, Technology and Research48, Royal Ontario Museum49, Smithsonian Institution50, Howard Hughes Medical Institute51, Walter Reed Army Institute of Research52, University of East Anglia53, University College Dublin54, University of Illinois at Urbana–Champaign55, La Trobe University56, University of California, San Diego57, Nova Southeastern University58
TL;DR: The Vertebrate Genomes Project (VGP) as mentioned in this paper is 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.
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.
647 citations
TL;DR: In this paper, a global prevalence of 25% and is a leading cause of cirrhosis and hepatocellular carcinoma, and the leading causes of death in people with NAFLD are cardiovascular disease and extrahepatic malignancy.
628 citations
Guy's Hospital1, Harvard University2, Tel Aviv University3, University of Milan4, Breast International Group5, University of Pennsylvania6, University of Pittsburgh7, Université libre de Bruxelles8, AstraZeneca9, National Institutes of Health10, Sahlgrenska University Hospital11, Gdańsk Medical University12, Kaiser Permanente13, Fudan University14, Northside Hospital15, Curie Institute16, Pomeranian Medical University17, University of California, Los Angeles18, Goethe University Frankfurt19, Medical University of Vienna20, Merck & Co.21, University of Queensland22
TL;DR: In this paper, a poly(adenosine diphosphate-ribose) polymerase inhibitor was proposed to target cancers with defects in homologous recombination repair by synthetic lethality.
Abstract: Background Poly(adenosine diphosphate–ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduc...
530 citations
528 citations
TL;DR: The Unified Human Gastrointestinal Genome (UHGG) collection, comprising 204,938 nonredundant genomes from 4,644 gut prokaryotes, is presented, providing comprehensive resources for microbiome researchers.
Abstract: Comprehensive, high-quality reference genomes are required for functional characterization and taxonomic assignment of the human gut microbiota. We present the Unified Human Gastrointestinal Genome (UHGG) collection, comprising 204,938 nonredundant genomes from 4,644 gut prokaryotes. These genomes encode >170 million protein sequences, which we collated in the Unified Human Gastrointestinal Protein (UHGP) catalog. The UHGP more than doubles the number of gut proteins in comparison to those present in the Integrated Gene Catalog. More than 70% of the UHGG species lack cultured representatives, and 40% of the UHGP lack functional annotations. Intraspecies genomic variation analyses revealed a large reservoir of accessory genes and single-nucleotide variants, many of which are specific to individual human populations. The UHGG and UHGP collections will enable studies linking genotypes to phenotypes in the human gut microbiome.
485 citations
University of California1, Boston University2, University of Ferrara3, McMaster University4, Brigham and Women's Hospital5, HealthPartners6, Harvard University7, University of Alcalá8, Manchester Academic Health Science Centre9, Institute of Chartered Accountants of Nigeria10, University of Otago11, University of Giessen12, Royal Brisbane and Women's Hospital13, University of Queensland14
TL;DR: In this paper, the authors determined factors associated with COVID-19-related death in people with rheumatic diseases, including age, sex, smoking status, comorbidities, diagnosis, disease activity and medications.
Abstract: OBJECTIVES: To determine factors associated with COVID-19-related death in people with rheumatic diseases. METHODS: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. RESULTS: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. CONCLUSION: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.
405 citations
Niamh Mullins1, Andreas J. Forstner2, Andreas J. Forstner3, Andreas J. Forstner4 +396 more•Institutions (119)
TL;DR: The authors 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, including genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics.
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.
378 citations
TL;DR: Wang et al. as discussed by the authors explored what trigger the public's pandemic "travel fear" and how people impose self-protection, coping and resilience related to travel and found that travel fear can evoke different coping strategies, which increases people's psychological resilience and adoption of cautious travel behaviors.
Harvard University1, University of Michigan2, Icahn School of Medicine at Mount Sinai3, Yeshiva University4, Rutgers University5, Seton Hall University6, University of Pennsylvania7, Cornell University8, Rush University Medical Center9, Anschutz Medical Campus10, Northwestern University11, Medical College of Wisconsin12, Rowan University13, Tufts University14, Thomas Jefferson University15, Ochsner Health System16, University of Queensland17, Johns Hopkins University18, New York University19, Indiana University – Purdue University Indianapolis20, ProMedica21, University of Vermont22, University of Miami23, Vanderbilt University24
TL;DR: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilzumab, and the findings may be susceptible to unmeasured confounding.
Abstract: Importance Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness. Objective To test whether tocilizumab decreases mortality in this population. Design, setting, and participants The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding. Exposures Treatment with tocilizumab in the first 2 days of ICU admission. Main outcomes and measures Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences. Results Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of Conclusions and relevance Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.
University Medical Center Groningen1, European Bioinformatics Institute2, Netherlands Cancer Institute3, Georgia Institute of Technology4, Leipzig University5, Johns Hopkins University6, University of Cambridge7, NHS Blood and Transplant8, Garvan Institute of Medical Research9, University of Tartu10, Ontario Institute for Cancer Research11, University of Washington12, Public Health Research Institute13, University of Chicago14, Greifswald University Hospital15, Ludwig Maximilian University of Munich16, University of Bristol17, Erasmus University Rotterdam18, Royal Devon and Exeter Hospital19, Luleå University of Technology20, University of Westminster21, Swiss Institute of Bioinformatics22, University of Lausanne23, University of Dundee24, University of Geneva25, Agency for Science, Technology and Research26, University of Queensland27, Leiden University Medical Center28, Radboud University Nijmegen29, University of Liège30, University of Oxford31, Menzies Research Institute32, Icahn School of Medicine at Mount Sinai33, Ikerbasque34, VU University Amsterdam35, Stanford University36, Turku University Hospital37, University of Turku38, Maastricht University39, Karolinska Institutet40, Utrecht University41, University of Helsinki42, National Institutes of Health43, Technische Universität München44, Wellcome Trust Sanger Institute45, German Cancer Research Center46, Westlake University47, University of New South Wales48
TL;DR: In this article, the authors performed cis-and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium.
Abstract: Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
TL;DR: The Genome Taxonomy Database (GTDB) as discussed by the authors provides a phylogenetically consistent and rank normalized genome-based taxonomy for prokaryotic genomes sourced from the NCBI Assembly database.
Abstract: The Genome Taxonomy Database (GTDB; https://gtdb.ecogenomic.org) provides a phylogenetically consistent and rank normalized genome-based taxonomy for prokaryotic genomes sourced from the NCBI Assembly database. GTDB R06-RS202 spans 254 090 bacterial and 4316 archaeal genomes, a 270% increase since the introduction of the GTDB in November, 2017. These genomes are organized into 45 555 bacterial and 2339 archaeal species clusters which is a 200% increase since the integration of species clusters into the GTDB in June, 2019. Here, we explore prokaryotic diversity from the perspective of the GTDB and highlight the importance of metagenome-assembled genomes in expanding available genomic representation. We also discuss improvements to the GTDB website which allow tracking of taxonomic changes, easy assessment of genome assembly quality, and identification of genomes assembled from type material or used as species representatives. Methodological updates and policy changes made since the inception of the GTDB are then described along with the procedure used to update species clusters in the GTDB. We conclude with a discussion on the use of average nucleotide identities as a pragmatic approach for delineating prokaryotic species.
TL;DR: The efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections in 95 hospitals in 16 countries in North America, South America, Europe, and Asia is assessed.
Abstract: Summary Background New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections. Methods We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7–14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov ( NCT02714595 ) and EudraCT (2015-004703-23). Findings Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8–66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9–75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2–65·5) of 23 patients in the cefiderocol group and six (43%, 17·7–71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8–77·0) of 17 patients in the cefiderocol group and one (20%, 0·5–71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug. Interpretation Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options. Funding Shionogi.
University of New South Wales1, Garvan Institute of Medical Research2, Royal Institute of Technology3, University of North Carolina at Chapel Hill4, Harvard University5, French Institute of Health and Medical Research6, Institut Gustave Roussy7, St. Vincent's Health System8, Royal Prince Alfred Hospital9, Princess Alexandra Hospital10, University of Queensland11, University of Sydney12, National University of Singapore13, Agency for Science, Technology and Research14, Shanghai Jiao Tong University15, St George's Hospital16
TL;DR: In this paper, a single-cell and spatially resolved transcriptomics analysis of human breast cancers is presented, which reveals recurrent neoplastic cell heterogeneity and heterotypic interactions play central roles in disease progression.
Abstract: Breast cancers are complex cellular ecosystems where heterotypic interactions play central roles in disease progression and response to therapy. However, our knowledge of their cellular composition and organization is limited. Here we present a single-cell and spatially resolved transcriptomics analysis of human breast cancers. We developed a single-cell method of intrinsic subtype classification (SCSubtype) to reveal recurrent neoplastic cell heterogeneity. Immunophenotyping using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) provides high-resolution immune profiles, including new PD-L1/PD-L2+ macrophage populations associated with clinical outcome. Mesenchymal cells displayed diverse functions and cell-surface protein expression through differentiation within three major lineages. Stromal-immune niches were spatially organized in tumors, offering insights into antitumor immune regulation. Using single-cell signatures, we deconvoluted large breast cancer cohorts to stratify them into nine clusters, termed 'ecotypes', with unique cellular compositions and clinical outcomes. This study provides a comprehensive transcriptional atlas of the cellular architecture of breast cancer.
TL;DR: In this article, the authors summarize the latest insights into cellular uptake mechanisms and pathways and highlight limitations of current systems to study endocytosis, particularly problems with non-specific inhibitors.
Abstract: Endocytosis is a critical step in the process by which many therapeutic nanomedicines reach their intracellular targets. Our understanding of cellular uptake mechanisms has developed substantially in the past five years. However, these advances in cell biology have not fully translated to the nanoscience and therapeutics literature. Misconceptions surrounding the role of different endocytic pathways and how to study these pathways are hindering progress in developing improved nanoparticle therapies. Here, we summarize the latest insights into cellular uptake mechanisms and pathways. We highlight limitations of current systems to study endocytosis, particularly problems with non-specific inhibitors. We also summarize alternative genetic approaches to robustly probe these pathways and discuss the need to understand how cells endocytose particles in vivo. We hope that this critical assessment of the current methods used in studying nanoparticle uptake will guide future studies at the interface of cell biology and nanomedicine.
TL;DR: In this paper, an open-label, parallel-group, phase 2, randomised controlled trial (Steroids in COVID-19; STOIC) of inhaled budesonide, compared with usual care, in adults within 7 days of the onset of mild COPD symptoms was performed in the community in Oxfordshire, UK.
University of California, Santa Barbara1, Utah State University2, IFREMER3, University of British Columbia4, Virginia Tech5, Leibniz Institute of Marine Sciences6, University of Freiburg7, University of Montpellier8, The Nature Conservancy9, Marine Conservation Institute10, University of Queensland11, Dalhousie University12, Oregon State University13
TL;DR: In this paper, a conservation planning framework is developed to prioritize highly protected marine protected areas in places that would result in multiple benefits today and in the future, by protecting biodiversity, boosting the yield of fisheries and securing marine carbon stocks that are at risk from human activities.
Abstract: The ocean contains unique biodiversity, provides valuable food resources and is a major sink for anthropogenic carbon. Marine protected areas (MPAs) are an effective tool for restoring ocean biodiversity and ecosystem services1,2, but at present only 2.7% of the ocean is highly protected3. This low level of ocean protection is due largely to conflicts with fisheries and other extractive uses. To address this issue, here we developed a conservation planning framework to prioritize highly protected MPAs in places that would result in multiple benefits today and in the future. We find that a substantial increase in ocean protection could have triple benefits, by protecting biodiversity, boosting the yield of fisheries and securing marine carbon stocks that are at risk from human activities. Our results show that most coastal nations contain priority areas that can contribute substantially to achieving these three objectives of biodiversity protection, food provision and carbon storage. A globally coordinated effort could be nearly twice as efficient as uncoordinated, national-level conservation planning. Our flexible prioritization framework could help to inform both national marine spatial plans4 and global targets for marine conservation, food security and climate action. Using a globally coordinated strategic conservation framework to plan an increase in ocean protection through marine protected areas can yield benefits for biodiversity, food provisioning and carbon storage.
University of Washington1, University of Modena and Reggio Emilia2, Extracorporeal Life Support Organization3, Baylor College of Medicine4, University of Texas Southwestern Medical Center5, Emory University6, NewYork–Presbyterian Hospital7, Columbia University8, University of Michigan9, Guy's and St Thomas' NHS Foundation Trust10, King's College London11, Pierre-and-Marie-Curie University12, Maastricht University13, University of Regensburg14, Alfred I. duPont Hospital for Children15, University of Florida16, University of Queensland17
TL;DR: The role of extracorporeal membrane oxygenation (ECMO) for patients with severe cardiopulmonary failure due to coronavirus disease 2019 (COVID-19) is discussed in this paper.
Abstract: This is an updated guideline from the Extracorporeal Life Support Organization (ELSO) for the role of extracorporeal membrane oxygenation (ECMO) for patients with severe cardiopulmonary failure due to coronavirus disease 2019 (COVID-19). The great majority of COVID-19 patients (>90%) requiring ECMO have been supported using venovenous (V-V) ECMO for acute respiratory distress syndrome (ARDS). While COVID-19 ECMO run duration may be longer than in non-COVID-19 ECMO patients, published mortality appears to be similar between the two groups. However, data collection is ongoing, and there is a signal that overall mortality may be increasing. Conventional selection criteria for COVID-19-related ECMO should be used; however, when resources become more constrained during a pandemic, more stringent contraindications should be implemented. Formation of regional ECMO referral networks may facilitate communication, resource sharing, expedited patient referral, and mobile ECMO retrieval. There are no data to suggest deviation from conventional ECMO device or patient management when applying ECMO for COVID-19 patients. Rarely, children may require ECMO support for COVID-19-related ARDS, myocarditis or multisystem inflammatory syndrome in children (MIS-C); conventional selection criteria and management practices should be the standard. We strongly encourage participation in data submission to investigate the optimal use of ECMO for COVID-19.
University of Maryland, Baltimore County1, University of Arizona2, Utrecht University3, Pennsylvania State University4, Max Planck Society5, University of Queensland6, National University of Cordoba7, University College London8, Northwest University (China)9, University of Maine10, University of Hong Kong11, United Nations Environment Programme12, University of Amsterdam13, Smithsonian Institution14, World Wide Fund for Nature15, Duke University16, Aarhus University17, Wildlife Conservation Society18
TL;DR: In this paper, the authors use the most up-to-date, spatially explicit global reconstruction of historical human populations and land use to show that this paradigm is likely wrong.
Abstract: Archaeological and paleoecological evidence shows that by 10,000 BCE, all human societies employed varying degrees of ecologically transformative land use practices, including burning, hunting, species propagation, domestication, cultivation, and others that have left long-term legacies across the terrestrial biosphere. Yet, a lingering paradigm among natural scientists, conservationists, and policymakers is that human transformation of terrestrial nature is mostly recent and inherently destructive. Here, we use the most up-to-date, spatially explicit global reconstruction of historical human populations and land use to show that this paradigm is likely wrong. Even 12,000 y ago, nearly three quarters of Earth’s land was inhabited and therefore shaped by human societies, including more than 95% of temperate and 90% of tropical woodlands. Lands now characterized as “natural,” “intact,” and “wild” generally exhibit long histories of use, as do protected areas and Indigenous lands, and current global patterns of vertebrate species richness and key biodiversity areas are more strongly associated with past patterns of land use than with present ones in regional landscapes now characterized as natural. The current biodiversity crisis can seldom be explained by the loss of uninhabited wildlands, resulting instead from the appropriation, colonization, and intensifying use of the biodiverse cultural landscapes long shaped and sustained by prior societies. Recognizing this deep cultural connection with biodiversity will therefore be essential to resolve the crisis.
TL;DR: A comprehensive overview of recent advances in the P1P energy system and an insightful discussion of the challenges that need to be addressed in order to establish P2P sharing as a viable energy management option in today’s electricity market are focused on.
Stephen P.H. Alexander1, Arthur Christopoulos2, Anthony P. Davenport3, Eamonn Kelly4 +151 more•Institutions (85)
TL;DR: The Concise Guide to PHARMACOLOGY 2021/22 as mentioned in this paper provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands.
Abstract: The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
TL;DR: In this article, the authors provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of the endothelial dysfunction, and identify pathways to effective targeted therapies.
Abstract: The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1β monoclonal antibodies, counter endothelial dysfunction as part of their clinical benefits. The regulation of endothelial dysfunction by noncoding RNAs has provided novel insights into these newly described regulators of endothelial dysfunction, thus yielding potential new therapeutic approaches. Altogether, a better understanding of the versatile (dys)functions of endothelial cells will not only deepen our comprehension of human diseases but also accelerate effective therapeutic drug discovery. In this review, we provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of endothelial dysfunction, and identify pathways to effective targeted therapies. SIGNIFICANCE STATEMENT: The endothelium was initially considered to be a semipermeable biomechanical barrier and gatekeeper of vascular health. In recent decades, a deepened understanding of the biological functions of the endothelium has led to its recognition as a ubiquitous tissue regulating vascular tone, cell behavior, innate immunity, cell-cell interactions, and cell metabolism in the vessel wall. Endothelial dysfunction is the hallmark of cardiovascular, metabolic, and emerging infectious diseases. Pharmacotherapies targeting endothelial dysfunction have potential for treatment of cardiovascular and many other diseases.
TL;DR: In this paper, the authors examined the impact of technological innovation and fiscal decentralization on carbon dioxide (CO2) emissions in the presence of gross domestic product (GDP) and globalization in the case of China for the period 2005Q1 to 2018Q4.
TL;DR: A review of the role of testing during the COVID-19 pandemic can be found in this article, where the authors describe the changing role of the testing during this pandemic, including the use of genomic surveillance to track SARS-CoV-2 transmission, contact tracing to contain disease outbreaks and testing for the presence of the virus circulating in the environment.
Abstract: Assembly and publication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome in January 2020 enabled the immediate development of tests to detect the new virus. This began the largest global testing programme in history, in which hundreds of millions of individuals have been tested to date. The unprecedented scale of testing has driven innovation in the strategies, technologies and concepts that govern testing in public health. This Review describes the changing role of testing during the COVID-19 pandemic, including the use of genomic surveillance to track SARS-CoV-2 transmission around the world, the use of contact tracing to contain disease outbreaks and testing for the presence of the virus circulating in the environment. Despite these efforts, widespread community transmission has become entrenched in many countries and has required the testing of populations to identify and isolate infected individuals, many of whom are asymptomatic. The diagnostic and epidemiological principles that underpin such population-scale testing are also considered, as are the high-throughput and point-of-care technologies that make testing feasible on a massive scale.
TL;DR: The positive SARS-CoV-2 RNA detection in wastewater while there were limited clinical reported cases demonstrates the potential of WBE as an early warning system.
TL;DR: In this article, the authors provide the current state and future perspectives on the spatial technologies expected to drive the next generation of research and diagnostic and therapeutic strategies for cancer, and provide a more comprehensive understanding of cell-to-cell variation within and between individual tumors.
Abstract: Understanding intratumoral heterogeneity-the molecular variation among cells within a tumor-promises to address outstanding questions in cancer biology and improve the diagnosis and treatment of specific cancer subtypes. Single-cell analyses, especially RNA sequencing and other genomics modalities, have been transformative in revealing novel biomarkers and molecular regulators associated with tumor growth, metastasis and drug resistance. However, these approaches fail to provide a complete picture of tumor biology, as information on cellular location within the tumor microenvironment is lost. New technologies leveraging multiplexed fluorescence, DNA, RNA and isotope labeling enable the detection of tens to thousands of cancer subclones or molecular biomarkers within their native spatial context. The expeditious growth in these techniques, along with methods for multiomics data integration, promises to yield a more comprehensive understanding of cell-to-cell variation within and between individual tumors. Here we provide the current state and future perspectives on the spatial technologies expected to drive the next generation of research and diagnostic and therapeutic strategies for cancer.
New South Wales Department of Primary Industries1, University of New England (Australia)2, Cooperative Research Centre3, University of Western Australia4, Australian National University5, Spanish National Research Council6, Agricultural Research Organization, Volcani Center7, Colorado State University8, Kazan Federal University9, University of Göttingen10, Zhejiang University11, Korea University12, University of Edinburgh13, University of Queensland14, Cornell University15
TL;DR: In this paper, the authors synthesized 20 years of research to explain the interrelated processes that determine soil and plant responses to biochar and found that biochar can catalyze biotic and abiotic reactions, particularly in the rhizosphere, that increase nutrient supply and uptake by plants.
Abstract: We synthesized 20 years of research to explain the interrelated processes that determine soil and plant responses to biochar. The properties of biochar and its effects within agricultural ecosystems largely depend on feedstock and pyrolysis conditions. We describe three stages of reactions of biochar in soil: dissolution (1–3 weeks); reactive surface development (1–6 months); and aging (beyond 6 months). As biochar ages, it is incorporated into soil aggregates, protecting the biochar carbon and promoting the stabilization of rhizodeposits and microbial products. Biochar carbon persists in soil for hundreds to thousands of years. By increasing pH, porosity, and water availability, biochars can create favorable conditions for root development and microbial functions. Biochars can catalyze biotic and abiotic reactions, particularly in the rhizosphere, that increase nutrient supply and uptake by plants, reduce phytotoxins, stimulate plant development, and increase resilience to disease and environmental stressors. Meta-analyses found that, on average, biochars increase P availability by a factor of 4.6; decrease plant tissue concentration of heavy metals by 17%–39%; build soil organic carbon through negative priming by 3.8% (range −21% to +20%); and reduce non-CO2 greenhouse gas emissions from soil by 12%–50%. Meta-analyses show average crop yield increases of 10%–42% with biochar addition, with greatest increases in low-nutrient P-sorbing acidic soils (common in the tropics), and in sandy soils in drylands due to increase in nutrient retention and water holding capacity. Studies report a wide range of plant responses to biochars due to the diversity of biochars and contexts in which biochars have been applied. Crop yields increase strongly if site-specific soil constraints and nutrient and water limitations are mitigated by appropriate biochar formulations. Biochars can be tailored to address site constraints through feedstock selection, by modifying pyrolysis conditions, through pre- or post-production treatments, or co-application with organic or mineral fertilizers. We demonstrate how, when used wisely, biochar mitigates climate change and supports food security and the circular economy.