The super-relaxed state of myosin (SRX) plays a fundamental role in maintaining the low resting metabolic rate of skeletal muscle. Our previous work on this state has been in animal models. Piperine is a small molecule that has been shown to destabilize the SRX in rabbit fast twitch fibers.

Here we extend this work to human muscle obtained from biopsies of the vastus lateralis of both lean and obese subjects. The slow release of nucleotides by myosin in the SRX was measured by incubating permeable fibers in a fluorescent analog of ATP and chasing with ATP.

The fraction of myosin heads in the SRX was 0.48±0.04 with a lifetime of 148±5s in lean subjects and a fraction of 0.41±0.05 and a lifetime of 176±7s in obese subjects. Addition of 100μM piperine decreased the SRX population by 43±7% in lean subjects and 36±7% in obese subjects, with little change in lifetimes. Addition of piperine to human cardiac cells had no effect on the SRX, a requirement for a drug to treat metabolic diseases.

In human muscle the SRX and its responses to piperine are similar to those seen previously, with no significant differences between muscles from lean and obese subjects. Thus analogs of piperine that have greater specificity could provide effective treatment for metabolic diseases. The SRX provides a potential mechanism contributing to the large dynamic range of metabolic rate.

In human muscle the SRX and its responses to piperine are similar to those seen previously, with no significant differences between muscles from lean and obese subjects. Thus analogs of piperine that have greater specificity could provide effective treatment for metabolic diseases. The SRX provides a potential mechanism contributing to the large dynamic range of metabolic rate.Drinking water is frequently recontaminated during transport and storage when water is poured into jerrycans. To address this issue, three strategies aiming at reducing these recontamination risks were implemented at water kiosks in Eastern Uganda. In all three strategies, water at the kiosks was chlorinated to a free residual chlorine (FRC) concentration of 2 mg/L at the tap of the kiosk. this website In addition, water was collected in different containers for drinking water transport a) uncleaned jerrycans, b) cleaned jerrycans, and c) cleaned improved containers with a wide mouth and a spigot. Water quality in the containers was compared to that of a control group collecting unchlorinated water in uncleaned jerrycans. Water samples were collected at the tap of the kiosk, from the containers of 135 households after they were filled at the tap, and from the same containers in the households after 24 h of water storage. The samples were analysed for counts of E. coli, total coliforms, and FRC. Household interviews and st Improved containers with a larger opening allowed for cleaning with a brush and showed the lowest levels of recontamination for both E. coli and total coliforms. In addition to the intervention strategies, households receiving a higher number of WASH education visits within the previous year had lower recontamination levels of E. coli in stored water (OR = 0.54, p = 0.003).Cell type annotation is a fundamental task in the analysis of single-cell RNA-sequencing data. In this work, we present CellO, a machine learning-based tool for annotating human RNA-seq data with the Cell Ontology. CellO enables accurate and standardized cell type classification of cell clusters by considering the rich hierarchical structure of known cell types. Furthermore, CellO comes pre-trained on a comprehensive data set of human, healthy, untreated primary samples in the Sequence Read Archive. CellO’s comprehensive training set enables it to run out of the box on diverse cell types and achieves competitive or even superior performance when compared to existing state-of-the-art methods. Lastly, CellO’s linear models are easily interpreted, thereby enabling exploration of cell-type-specific expression signatures across the ontology. To this end, we also present the CellO Viewer a web application for exploring CellO’s models across the ontology.One of the outstanding problems in complexity science and engineering is the study of high-dimensional networked systems and of their susceptibility to transitions to undesired states as a result of changes in external drivers or in the structural properties. Because of the incredibly large number of parameters controlling the state of such complex systems and the heterogeneity of its components, the study of their dynamics is extremely difficult. Here we propose an analytical framework for collapsing complex N-dimensional networked systems into an S+1-dimensional manifold as a function of S effective control parameters with S less then N. We test our approach on a variety of real-world complex problems showing how this new framework can approximate the system’s response to changes and correctly identify the regions in the parameter space corresponding to the system’s transitions. Our work offers an analytical method to evaluate optimal strategies in the design or management of networked systems.The Japanese or Honshū wolf was one the most distinct gray wolf subspecies due to its small stature and endemicity to the islands of Honshū, Shikoku, and Kyūshū. Long revered as a guardian of farmers and travellers, it was persecuted from the 17th century following a rabies epidemic, which led to its extinction in the early 20th century. To better understand its evolutionary history, we sequenced the nuclear genome of a 19th century Honshū wolf specimen to an average depth of coverage of 3.7✕. We find Honshū wolves were closely related to a lineage of Siberian wolves that were previously believed to have gone extinct in the Late Pleistocene, thereby extending the survival of this ancient lineage until the early 20th century. We also detected significant gene flow between Japanese dogs and the Honshū wolf, corroborating previous reports on Honshū wolf dog interbreeding.Cancers are the result of eco-evolutionary processes fueled by heritable phenotypic diversification and driven by environmentally dependent selection. Space represents a key growth-limiting ecological resource, the ability to explore this resource is likely under strong selection. Using agent-based modeling, we explored the interplay between phenotypic strategies centered on gaining access to new space through cell-extrinsic degradation of extracellular matrix barriers and the exploitation of this resource through maximizing cell proliferation. While cell proliferation is a cell-intrinsic property, newly accessed space represents a public good, which can benefit both producers and non-producers. We found that this interplay results in ecological succession, enabling emergence of large, heterogeneous, and highly proliferative populations. Even though in our simulations both remodeling and proliferation strategies were under strong positive selection, their interplay led to sub-clonal architecture that could be interpreted as evidence for neutral evolution, warranting cautious interpretation of inferences from sequencing of cancer genomes.