Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming ...growth factor β1 (TGFβ1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.
Cancer survivors constitute 3.5% of the United States population, but second primary malignancies among this high-risk group now account for 16% of all cancer incidence. Although few data currently ...exist regarding the molecular mechanisms for second primary cancers and other late outcomes after cancer treatment, the careful measurement and documentation of potentially carcinogenic treatments (chemotherapy and radiotherapy) provide a unique platform for in vivo research on gene–environment interactions in human carcinogenesis. We review research priorities identified during a National Cancer Institute (NCI)–sponsored workshop entitled “Cancer Survivorship—Genetic Susceptibility and Second Primary Cancers.” These priorities include 1) development of a national research infrastructure for studies of cancer survivorship; 2) creation of a coordinated system for biospecimen collection; 3) development of new technology, bioinformatics, and biomarkers; 4) design of new epidemiologic methods; and 5) development of evidence-based clinical practice guidelines. Many of the infrastructure resources and design strategies that would facilitate research in this area also provide a foundation for the study of other important nonneoplastic late effects of treatment and psychosocial concerns among cancer survivors. These research areas warrant high priority to promote NCI's goal of eliminating pain and suffering related to cancer.
Novel avian H7N9 virus emerged in China in 2013 resulting in a case fatality rate of around 39% and continues to pose zoonotic and pandemic risk. Amino acid substitutions in PB2 protein were shown to ...influence the pathogenicity and transmissibility of H7N9 following experimental infection of ferrets and mice. In this study, we evaluated the role of amino acid substitution PB2-627K or compensatory changes at PB2-591K and PB2-701N, on the tropism and replication competence of H7N9 viruses for human and swine respiratory tracts using ex vivo organ explant cultures. Recombinant viruses of A/Shanghai/2/2013 (rgH7N9) and its mutants with PB2-K627E, PB2-K627E + Q591K and PB2-K627E + D701N were generated by plasmid-based reverse genetics. PB2-E627K was essential for efficient replication of rgH7N9 in ex vivo cultures of human and swine respiratory tracts. Mutant rgPB2-K627E + D701N replicated better than rgPB2-K627E in human lung but not as well as rgH7N9 virus. The rgPB2-K627E mutant failed to replicate in human type I-like pneumocytes (ATI) and peripheral blood monocyte-derived macrophages (PMϕ) at 37 °C while the compensatory mutant rgPB2-K627E + Q591K and rgPB2-K627E + D701N had partly restored replication competence in PMϕ. Our results demonstrate that PB2-E627K was important for efficient replication of influenza H7N9 in both human and swine respiratory tracts.
We report the discovery of 29 promising (and 59 total) new lens candidates from the Canada–France–Hawaii Telescope Legacy Survey (CFHTLS) based on about 11 million classifications performed by ...citizen scientists as part of the first Space Warps lens search. The goal of the blind lens search was to identify lens candidates missed by robots (the ringfinder on galaxy scales and arcfinder on group/cluster scales) which had been previously used to mine the CFHTLS for lenses. We compare some properties of the samples detected by these algorithms to the Space Warps sample and find them to be broadly similar. The image separation distribution calculated from the Space Warps sample shows that previous constraints on the average density profile of lens galaxies are robust. Space Warps recovers about 65 per cent of known lenses, while the new candidates show a richer variety compared to those found by the two robots. This detection rate could be increased to 80 per cent by only using classifications performed by expert volunteers (albeit at the cost of a lower purity), indicating that the training and performance calibration of the citizen scientists is very important for the success of Space Warps. In this work we present the SIMCT pipeline, used for generating in situ a sample of realistic simulated lensed images. This training sample, along with the false positives identified during the search, has a legacy value for testing future lens-finding algorithms. We make the pipeline and the training set publicly available.
Hematopoiesis is a multistage process involving the differentiation of stem and progenitor cells into distinct mature cell lineages. Here we present Haemopedia, an atlas of murine gene-expression ...data containing 54 hematopoietic cell types, covering all the mature lineages in hematopoiesis. We include rare cell populations such as eosinophils, mast cells, basophils, and megakaryocytes, and a broad collection of progenitor and stem cells. We show that lineage branching and maturation during hematopoiesis can be reconstructed using the expression patterns of small sets of genes. We also have identified genes with enriched expression in each of the mature blood cell lineages, many of which show conserved lineage-enriched expression in human hematopoiesis. We have created an online web portal called Haemosphere to make analyses of Haemopedia and other blood cell transcriptional datasets easier. This resource provides simple tools to interrogate gene-expression-based relationships between hematopoietic cell types and genes of interest.
Display omitted
•Haemopedia is an expression dataset covering 54 murine hematopoietic cell types•Relationship of cells recreated with the expression pattern of small sets of genes•Many murine lineage-specific genes still lineage specific in humans•Data can be accessed via online portal for ease of analysis
De Graaf and colleagues transcriptionally profile 54 murine blood cell types from stem to mature cells. Lineage relationship of cells can be reconstructed from the expression patterns of small sets of genes. Lineage-specific genes are identified, many of which show conserved expression patterns in humans. An online web portal to this dataset is provided for ease of analysis.
Complex tumor microenvironmental (TME) features influence the outcome of cancer immunotherapy (IO). Here we perform immunogenomic analyses on 67 intratumor sub-regions of a PD-1 inhibitor-resistant ...melanoma tumor and 2 additional metastases arising over 8 years, to characterize TME interactions. We identify spatially distinct evolution of copy number alterations influencing local immune composition. Sub-regions with chromosome 7 gain display a relative lack of leukocyte infiltrate but evidence of neutrophil activation, recapitulated in The Cancer Genome Atlas (TCGA) samples, and associated with lack of response to IO across three clinical cohorts. Whether neutrophil activation represents cause or consequence of local tumor necrosis requires further study. Analyses of T-cell clonotypes reveal the presence of recurrent priming events manifesting in a dominant T-cell clonotype over many years. Our findings highlight the links between marked levels of genomic and immune heterogeneity within the physical space of a tumor, with implications for biomarker evaluation and immunotherapy response.
Triaging and prioritising patients for RT-PCR test had been essential in the management of COVID-19 in resource-scarce countries. In this study, we applied machine learning (ML) to the task of ...detection of SARS-CoV-2 infection using basic laboratory markers. We performed the statistical analysis and trained an ML model on a retrospective cohort of 5148 patients from 24 hospitals in Hong Kong to classify COVID-19 and other aetiology of pneumonia. We validated the model on three temporal validation sets from different waves of infection in Hong Kong. For predicting SARS-CoV-2 infection, the ML model achieved high AUCs and specificity but low sensitivity in all three validation sets (AUC: 89.9-95.8%; Sensitivity: 55.5-77.8%; Specificity: 91.5-98.3%). When used in adjunction with radiologist interpretations of chest radiographs, the sensitivity was over 90% while keeping moderate specificity. Our study showed that machine learning model based on readily available laboratory markers could achieve high accuracy in predicting SARS-CoV-2 infection.
•Simvastatin inhibited virus replication and cytokine production by H5N1 virus.•Zometa and FPT inhibitor III inhibited both H5N1 and H1N1 replication.•FPT inhibitor III is a strong immuno-regulator ...during H5N1 infection.•Protein farnesylation plays a role in cytokine induction by H5N1 virus.
Highly pathogenic H5N1 viruses continue to transmit zoonotically, with mortality higher than 60%, and pose a pandemic threat. Antivirals remain the primary choice for treating H5N1 diseases and have their limitations. Encouraging findings highlight the beneficial effects of combined treatment of host targeting agents with immune-modulatory activities. This study evaluated the undefined roles of sterol metabolic pathway in viral replication and cytokine induction by H5N1 virus in human alveolar epithelial cells. The suppression of the sterol biosynthesis by Simvastatin in human alveolar epithelial cells led to reduction of virus replication and cytokine production by H5N1 virus. We further dissected the antiviral role of different regulators of the sterol metabolism, we showed that Zometa, FPT inhibitor III, but not GGTI-2133 had anti-viral activities against both H5N1 and H1N1 viruses. More importantly, FPT inhibitor III treatment significantly suppressed cytokine production by H5N1 virus infected alveolar epithelial cells. Since both viral replication itself and the effects of viral hyper-induction of cytokines contribute to the immunopathology of severe H5N1 disease, our findings highlights the therapeutic potential of FPT inhibitor III for severe human H5N1 diseases. Furthermore, our study is the first to dissect the roles of different steps in the sterol metabolic pathway in H5N1 virus replication and cytokine production.
We describe Space Warps, a novel gravitational lens discovery service that yields samples of high purity and completeness through crowdsourced visual inspection. Carefully produced colour composite ...images are displayed to volunteers via a web-based classification interface, which records their estimates of the positions of candidate lensed features. Images of simulated lenses, as well as real images which lack lenses, are inserted into the image stream at random intervals; this training set is used to give the volunteers instantaneous feedback on their performance, as well as to calibrate a model of the system that provides dynamical updates to the probability that a classified image contains a lens. Low-probability systems are retired from the site periodically, concentrating the sample towards a set of lens candidates. Having divided 160 deg2 of Canada–France–Hawaii Telescope Legacy Survey imaging into some 430 000 overlapping 82 by 82 arcsec tiles and displaying them on the site, we were joined by around 37 000 volunteers who contributed 11 million image classifications over the course of eight months. This stage 1 search reduced the sample to 3381 images containing candidates; these were then refined in stage 2 to yield a sample that we expect to be over 90 per cent complete and 30 per cent pure, based on our analysis of the volunteers performance on training images. We comment on the scalability of the Space Warps system to the wide field survey era, based on our projection that searches of 105 images could be performed by a crowd of 105 volunteers in 6 d.
Objectives The majority of patients with respiratory illness are seen in primary care settings. Given COVID-19 is predominantly a respiratory illness, the INTernational ConsoRtium of Primary Care BIg ...Data Researchers (INTRePID), assessed the pandemic impact on primary care visits for respiratory illnesses. Design Definitions for respiratory illness types were agreed on collectively. Monthly visit counts with diagnosis were shared centrally for analysis. Setting Primary care settings in Argentina, Australia, Canada, China, Norway, Peru, Singapore, Sweden and the United States. Participants Over 38 million patients seen in primary care settings in INTRePID countries before and during the pandemic, from January 1st, 2018, to December 31st, 2021. Main outcome measures Relative change in the monthly mean number of visits before and after the onset of the pandemic for acute infectious respiratory disease visits including influenza, upper and lower respiratory tract infections and chronic respiratory disease visits including asthma, chronic obstructive pulmonary disease, respiratory allergies, and other respiratory diseases. Results INTRePID countries reported a marked decrease in the average monthly visits for respiratory illness. Changes in visits varied from −10.9% 95% confidence interval (CI): −33.1 to +11.3% in Norway to −79.9% (95% CI: −86.4% to −73.4%) in China for acute infectious respiratory disease visits and − 2.1% (95% CI: −12.1 to +7.8%) in Peru to −59.9% (95% CI: −68.6% to −51.3%) in China for chronic respiratory illness visits. While seasonal variation in allergic respiratory illness continued during the pandemic, there was essentially no spike in influenza illness during the first 2 years of the pandemic. Conclusion The COVID-19 pandemic had a major impact on primary care visits for respiratory presentations. Primary care continued to provide services for respiratory illness, although there was a decrease in infectious illness during the COVID pandemic. Understanding the role of primary care may provide valuable information for COVID-19 recovery efforts and planning for future global emergencies.
PDF
