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The most common form of genetic heart disease is hypertrophic cardiomyopathy (HCM), which is caused by variants in cardiac sarcomeric genes and leads to abnormal heart muscle thickening. Complications of HCM include heart failure, arrhythmia and sudden cardiac death. The dominant-negative c.1208G>A (p.R403Q) pathogenic variant (PV) in β-myosin ( MYH7 ) is a common and well-studied PV that leads to increased cardiac contractility and HCM onset. In this study we identify an adenine base editor and single-guide RNA system that can efficiently correct this human PV with minimal bystander editing and off-target editing at selected sites. We show that delivery of base editing components rescues pathological manifestations of HCM in induced pluripotent stem cell cardiomyocytes derived from patients with HCM and in a humanized mouse model of HCM. Our findings demonstrate the potential of base editing to treat inherited cardiac diseases and prompt the further development of adenine base editor-based therapies to correct monogenic variants causing cardiac disease. Adenine base editing successfully corrected a MYH7 pathogenic variant that causes hypertrophic cardiomyopathy in human cardiomyocytes and a mouse model of the disease, highlighting the potential of the approach to correct monogenic variants causing cardiac disease.

Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker (MYMK) and Myomixer (MYMX). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity. Homozygosity of this human variant resulted in a spectrum of abnormalities that mimicked the clinical presentation of Carey-Fineman-Ziter syndrome (CFZS), caused by hypomorphic MYMK variants. Myoblasts generated from patient-derived induced pluripotent stem cells displayed defective fusion, and mice bearing the human MYMX variant died perinatally due to muscle abnormalities. In vitro assays showed that the human MYMX variant conferred minimal cell-cell fusogenicity, which could be restored with CRISPR/Cas9-mediated base editing, thus providing therapeutic potential for this disorder. Our findings identify MYMX as a recessive, monogenic human disease gene involved in CFZS, and provide new insights into the contribution of myoblast fusion to neuromuscular diseases.

The challenge of predicting which patients with breast cancer will develop metastases leads to the overtreatment of patients with benign disease and to the inadequate treatment of aggressive cancers. Here, we report the development and testing of a microfluidic assay that quantifies the abundance and proliferative index of migratory cells in breast cancer specimens, for the assessment of their metastatic propensity and for the rapid screening of potential antimetastatic therapeutics. On the basis of the key roles of cell motility and proliferation in cancer metastasis, the device accurately predicts the metastatic potential of breast cancer cell lines and of patient-derived xenografts. Compared with unsorted cancer cells, highly motile cells isolated by the device exhibited similar tumourigenic potential but markedly increased metastatic propensity in vivo. RNA sequencing of the highly motile cells revealed an enrichment of motility-related and survival-related genes. The approach might be developed into a companion assay for the prediction of metastasis in patients and for the selection of effective therapeutic regimens. A microfluidic assay predicts the metastatic potential of breast cancer specimens by quantifying the abundance and proliferative index of the migratory cells within them.

Background The glycosylphosphatidylinositol-anchored extracellular membrane serine protease prostasin is expressed in normal bladder urothelial cells. Bladder inflammation reduces prostasin expression and a loss of prostasin expression is associated with epithelial-mesenchymal transition (EMT) in human bladder transitional cell carcinomas. Non-steroidal anti-inflammatory drugs (NSAIDs) decrease the incidence of various cancers including bladder cancer, but the molecular mechanisms underlying the anticancer effect of NSAIDs are not fully understood. Methods The normal human bladder urothelial cell line UROtsa, the normal human trophoblast cell line B6Tert-1, human bladder transitional cell carcinoma cell lines UM-UC-5 and UM-UC-9, and the human breast cancer cell line JIMT-1 were used for the study. Expression changes of the serine proteases prostasin and matriptase, and cyclooxygenases (COX-1 and COX-2) in these cells following ibuprofen treatments were analyzed by means of reverse-transcription/quantitative polymerase chain reaction (RT-qPCR) and immunoblotting. The functional role of the ibuprofen-regulated prostasin in epithelial tight junction formation and maintenance was assessed by measuring the transepithelial electrical resistance (TEER) and epithelial permeability in the B6Tert-1 cells. Prostasin’s effects on tight junctions were also evaluated in B6Tert-1 cells over-expressing a recombinant human prostasin, silenced for prostasin expression, or treated with a functionally-blocking prostasin antibody. Matriptase zymogen activation was examined in cells over-expressing prostasin. Results Ibuprofen increased prostasin expression in the UROtsa and the B6Tert-1 cells. Cyclooxygenase-2 (COX-2) expression was up-regulated at both the mRNA and the protein levels in the UROtsa cells by ibuprofen in a dose-dependent manner, but was not a requisite for up-regulating prostasin expression. The ibuprofen-induced prostasin contributed to the formation and maintenance of the epithelial tight junctions in the B6Tert-1 cells. The matriptase zymogen was down-regulated in the UROtsa cells by ibuprofen possibly as a result of the increased prostasin expression because over-expressing prostasin leads to matriptase activation and zymogen down-regulation in the UROtsa, JIMT-1, and B6Tert-1 cells. The expression of prostasin and matriptase was differentially regulated by ibuprofen in the bladder cancer cells. Conclusions Ibuprofen has been suggested for use in treating bladder cancer. Our results bring the epithelial extracellular membrane serine proteases prostasin and matriptase into the potential molecular mechanisms of the anticancer effect of NSAIDs.

Candida species are the predominant cause of fungal infections in patients treated in hospital, contributing substantially to morbidity and mortality. Candidaemia and other forms of invasive candidiasis primarily affect patients who are immunocompromised or critically ill. In contrast, mucocutaneous forms of candidiasis, such as oral thrush and vulvovaginal candidiasis, can occur in otherwise healthy individuals. Although mucocutaneous candidiasis is generally not life-threatening, it can cause considerable discomfort, recurrent infections, and complications, particularly in patients with underlying conditions such as diabetes or in those taking immunosuppressive therapies. The rise of difficult-to-treat Candida infections is driven by new host factors and antifungal resistance. Pathogens, such as Candida auris (Candidozyma auris) and fluconazole-resistant Candida parapsilosis, pose serious global health risks. Recent taxonomic revisions have reclassified several Candida spp, potentially causing confusion in clinical practice. Current management guidelines are limited in scope, with poor coverage of emerging pathogens and new treatment options. In this Review, we provide updated recommendations for managing Candida infections, with detailed evidence summaries available in the appendix.

The Argo Program has been implemented and sustained for almost two decades, as a global array of about 4000 profiling floats. Argo provides continuous observations of ocean temperature and salinity versus pressure, from the sea surface to 2000 dbar. The successful installation of the Argo array and its innovative data management system arose opportunistically from the combination of great scientific need and technological innovation. Through the data system, Argo provides fundamental physical observations with broad societally-valuable applications, built on the cost-efficient and robust technologies of autonomous profiling floats. Following recent advances in platform and sensor technologies, even greater opportunity exists now than 20 years ago to (i) improve Argo’s global coverage and value beyond the original design, (ii) extend Argo to span the full ocean depth, (iii) add biogeochemical sensors for improved understanding of oceanic cycles of carbon, nutrients, and ecosystems, and (iv) consider experimental sensors that might be included in the future, for example to document the spatial and temporal patterns of ocean mixing. For Core Argo and each of these enhancements, the past, present, and future progression along a path from experimental deployments to regional pilot arrays to global implementation is described. The objective is to create a fully global, top-to-bottom, dynamically complete, and multidisciplinary Argo Program that will integrate seamlessly with satellite and with other in situ elements of the Global Ocean Observing System (Legler et al., 2015). The integrated system will deliver operational reanalysis and forecasting capability, and assessment of the state and variability of the climate system with respect to physical, biogeochemical, and ecosystems parameters. It will enable basic research of unprecedented breadth and magnitude, and a wealth of ocean-education and outreach opportunities.

In this paper, we outline the need for a coordinated international effort toward the building of an open-access Global Ocean Oxygen Database and ATlas (GO2DAT) complying with the FAIR principles (Findable, Accessible, Interoperable, and Reusable). GO2DAT will combine data from the coastal and open ocean, as measured by the chemical Winkler titration method or by sensors (e.g., optodes, electrodes) from Eulerian and Lagrangian platforms (e.g., ships, moorings, profiling floats, gliders, ships of opportunities, marine mammals, cabled observatories). GO2DAT will further adopt a community-agreed, fully documented metadata format and a consistent quality control (QC) procedure and quality flagging (QF) system. GO2DAT will serve to support the development of advanced data analysis and biogeochemical models for improving our mapping, understanding and forecasting capabilities for ocean O2 changes and deoxygenation trends. It will offer the opportunity to develop quality-controlled data synthesis products with unprecedented spatial (vertical and horizontal) and temporal (sub-seasonal to multi-decadal) resolution. These products will support model assessment, improvement and evaluation as well as the development of climate and ocean health indicators. They will further support the decision-making processes associated with the emerging blue economy, the conservation of marine resources and their associated ecosystem services and the development of management tools required by a diverse community of users (e.g., environmental agencies, aquaculture, and fishing sectors). A better knowledge base of the spatial and temporal variations of marine O2 will improve our understanding of the ocean O2 budget, and allow better quantification of the Earth’s carbon and heat budgets. With the ever-increasing need to protect and sustainably manage ocean services, GO2DAT will allow scientists to fully harness the increasing volumes of O2 data already delivered by the expanding global ocean observing system and enable smooth incorporation of much higher quantities of data from autonomous platforms in the open ocean and coastal areas into comprehensive data products in the years to come. This paper aims at engaging the community (e.g., scientists, data managers, policy makers, service users) toward the development of GO2DAT within the framework of the UN Global Ocean Oxygen Decade (GOOD) program recently endorsed by IOC-UNESCO. A roadmap toward GO2DAT is proposed highlighting the efforts needed (e.g., in terms of human resources).

In this paper, we outline the need for a coordinated international effort toward the building of an open-access Global Ocean Oxygen Database and ATlas (GO2DAT) complying with the FAIR principles (Findable, Accessible, Interoperable, and Reusable). GO2DAT will combine data from the coastal and open ocean, as measured by the chemical Winkler titration method or by sensors (e.g., optodes, electrodes) from Eulerian and Lagrangian platforms (e.g., ships, moorings, profiling floats, gliders, ships of opportunities, marine mammals, cabled observatories). GO2DAT will further adopt a community-agreed, fully documented metadata format and a consistent quality control (QC) procedure and quality flagging (QF) system. GO2DAT will serve to support the development of advanced data analysis and biogeochemical models for improving our mapping, understanding and forecasting capabilities for ocean O2 changes and deoxygenation trends. It will offer the opportunity to develop quality-controlled data synthesis products with unprecedented spatial (vertical and horizontal) and temporal (sub-seasonal to multi-decadal) resolution. These products will support model assessment, improvement and evaluation as well as the development of climate and ocean health indicators. They will further support the decision-making processes associated with the emerging blue economy, the conservation of marine resources and their associated ecosystem services and the development of management tools required by a diverse community of users (e.g., environmental agencies, aquaculture, and fishing sectors). A better knowledge base of the spatial and temporal variations of marine O2 will improve our understanding of the ocean O2 budget, and allow better quantification of the Earth’s carbon and heat budgets. With the ever-increasing need to protect and sustainably manage ocean services, GO2DAT will allow scientists to fully harness the increasing volumes of O2 data already delivered by the expanding global ocean observing system and enable smooth incorporation of much higher quantities of data from autonomous platforms in the open ocean and coastal areas into comprehensive data products in the years to come. This paper aims at engaging the community (e.g., scientists, data managers, policy makers, service users) toward the development of GO2DAT within the framework of the UN Global Ocean Oxygen Decade (GOOD) program recently endorsed by IOC-UNESCO. A roadmap toward GO2DAT is proposed highlighting the efforts needed (e.g., in terms of human resources).

In this paper, we outline the need for a coordinated international effort toward the building of an open-access Global Ocean Oxygen Database and ATlas (GO(2)DAT) complying with the FAIR principles (Findable, Accessible, Interoperable, and Reusable). GO(2)DAT will combine data from the coastal and open ocean, as measured by the chemical Winkler titration method or by sensors (e.g., optodes, electrodes) from Eulerian and Lagrangian platforms (e.g., ships, moorings, profiling floats, gliders, ships of opportunities, marine mammals, cabled observatories). GO(2)DAT will further adopt a community-agreed, fully documented metadata format and a consistent quality control (QC) procedure and quality flagging (QF) system. GO(2)DAT will serve to support the development of advanced data analysis and biogeochemical models for improving our mapping, understanding and forecasting capabilities for ocean O-2 changes and deoxygenation trends. It will offer the opportunity to develop quality-controlled data synthesis products with unprecedented spatial (vertical and horizontal) and temporal (sub-seasonal to multi-decadal) resolution. These products will support model assessment, improvement and evaluation as well as the development of climate and ocean health indicators. They will further support the decision-making processes associated with the emerging blue economy, the conservation of marine resources and their associated ecosystem services and the development of management tools required by a diverse community of users (e.g., environmental agencies, aquaculture, and fishing sectors). A better knowledge base of the spatial and temporal variations of marine O-2 will improve our understanding of the ocean O-2 budget, and allow better quantification of the Earth's carbon and heat budgets. With the ever-increasing need to protect and sustainably manage ocean services, GO(2)DAT will allow scientists to fully harness the increasing volumes of O-2 data already delivered by the expanding global ocean observing system and enable smooth incorporation of much higher quantities of data from autonomous platforms in the open ocean and coastal areas into comprehensive data products in the years to come. This paper aims at engaging the community (e.g., scientists, data managers, policy makers, service users) toward the development of GO(2)DAT within the framework of the UN Global Ocean Oxygen Decade (GOOD) program recently endorsed by IOC-UNESCO. A roadmap toward GO(2)DAT is proposed highlighting the efforts needed (e.g., in terms of human resources).