Expressions 1987

https://openspace.dmacc.edu/expressions/1030/thumbnail.jp

Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response

To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated HckF/F “knock-in” mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y499-residue in the Hck protein. Unlike their Hck−/− “loss-of-function” counterparts, HckF/F “gain-of-function” mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways. Lungs from HckF/F mice showed areas of mild emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress in aging mice. When challenged transnasally with lipopolysaccharide (LPS), HckF/F mice displayed an exaggerated pulmonary innate immune response, characterized by excessive release of matrix metalloproteinases and tumor necrosis factor (TNF)α. Similarly, HckF/F mice were highly sensitive to endotoxemia after systemic administration of LPS, and macrophages and neutrophils derived from HckF/F mice exhibited enhanced effector functions in vitro (e.g., nitric oxide and TNFα production, chemotaxis, and degranulation). Based on the demonstrated functional association of Hck with leukocyte integrins, we propose that constitutive activation of Hck may mimic adhesion-dependent priming of leukocytes. Thus, our observations collectively suggest an enhanced innate immune response in HckF/F mice thereby skewing innate immunity from a reversible physiological host defense response to one causing irreversible tissue damage

Coumarin anticoagulants and co-trimoxazole: avoid the combination rather than manage the interaction

OBJECTIVE: The objective of our study was to examine the management of the interaction between acenocoumarol or phenprocoumon and several antibiotics by anticoagulation clinics and to compare the consequences of this interaction on users of co-trimoxazole with those for users of other antibiotics. METHODS: A follow-up study was conducted at four anticoagulation clinics in The Netherlands. Data on measurements of the International Normalised Ratio (INR), application of a preventive dose reduction (PDR) of the coumarin anticoagulant, fever and time within or outside the therapeutic INR range were collected. RESULTS: The study cohort consisted of 326 subjects. A PDR was given more often to users of co-trimoxazole PDR than to users of other antibiotics. The PDR in co-trimoxazole users resulted in a significantly reduced risk of both moderate overanticoagulation (INR >4.5) and severe overanticoagulation (INR >6.0) compared with no PDR, with odds ratios (ORs) of 0.06 [95% confidence interval (CI): 0.01-0.51] and 0.09 (95% CI: 0.01-0.92), respectively. In co-trimoxazole users without PDR, the risk of overanticoagulation was significantly increased compared with users of other antibiotics. All co-trimoxazole users spent significantly more time under the therapeutic INR range during the first 6 weeks after the course than users of other antibiotics. CONCLUSION: PDR is effective in preventing overanticoagulation in co-trimoxazole users, but results in a significantly prolonged period of underanticoagulation after the course. Avoidance of concomitant use of co-trimoxazole with acenocoumarol or phenprocoumon seems to be a safer approach than management of the interaction between these drugs

The cold regions hydrological modelling platform for hydrological diagnosis and prediction based on process understanding

Natural Sciences and Engineering Research Council of Canada, Environment Canada, Indian and Northern Affairs Canada, Yukon Environment, the Forest Resource Improvement Association of Alberta, Alberta Agriculture and Forestry, Alberta Environment, Ducks Unlimited Canada, Water Security Agency of Saskatchewan, Natural Environment Research Council (UK), IPE-CSIC (Spain), Canada Research Chair and Canada Excellence Research Chairs programmes, Canada First Research Excellence Fund’s Global Water Futures programmePeer ReviewedCold regions involve hydrological processes that are not often addressed appropriately in hydrological models. The Cold Regions Hydrological Modelling platform (CRHM) was initially developed in 1998 to assemble and explore the hydrological understanding developed from a series of research basins spanning Canada and international cold regions. Hydrological processes and basin response in cold regions are simulated in a flexible, modular, object-oriented, multiphysics platform. The CRHM platform allows for multiple representations of forcing data interpolation and extrapolation, hydrological model spatial and physical process structures, and parameter values. It is well suited for model falsification, algorithm intercomparison and benchmarking, and has been deployed for basin hydrology diagnosis, prediction, land use change and water quality analysis, climate impact analysis and flood forecasting around the world. This paper describes CRHM’s capabilities, and the insights derived by applying the model in concert with process hydrology research and using the combined information and understanding from research basins to predict hydrological variables, diagnose hydrological change and determine the appropriateness of model structure and parameterisations

The cold regions hydrological modelling platform for hydrological diagnosis and prediction based on process understanding

© 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Cold regions involve hydrological processes that are not often addressed appropriately in hydrological models. The Cold Regions Hydrological Modelling platform (CRHM) was initially developed in 1998 to assemble and explore the hydrological understanding developed from a series of research basins spanning Canada and international cold regions. Hydrological processes and basin response in cold regions are simulated in a flexible, modular, object-oriented, multiphysics platform. The CRHM platform allows for multiple representations of forcing data interpolation and extrapolation, hydrological model spatial and physical process structures, and parameter values. It is well suited for model falsification, algorithm intercomparison and benchmarking, and has been deployed for basin hydrology diagnosis, prediction, land use change and water quality analysis, climate impact analysis and flood forecasting around the world. This paper describes CRHM’s capabilities, and the insights derived by applying the model in concert with process hydrology research and using the combined information and understanding from research basins to predict hydrological variables, diagnose hydrological change and determine the appropriateness of model structure and parameterisations.Peer reviewe

Antimicrobial proteins and polypeptides in pulmonary innate defence

Inspired air contains a myriad of potential pathogens, pollutants and inflammatory stimuli. In the normal lung, these pathogens are rarely problematic. This is because the epithelial lining fluid in the lung is rich in many innate immunity proteins and peptides that provide a powerful anti-microbial screen. These defensive proteins have anti-bacterial, anti- viral and in some cases, even anti-fungal properties. Their antimicrobial effects are as diverse as inhibition of biofilm formation and prevention of viral replication. The innate immunity proteins and peptides also play key immunomodulatory roles. They are involved in many key processes such as opsonisation facilitating phagocytosis of bacteria and viruses by macrophages and monocytes. They act as important mediators in inflammatory pathways and are capable of binding bacterial endotoxins and CPG motifs. They can also influence expression of adhesion molecules as well as acting as powerful anti-oxidants and anti-proteases. Exciting new antimicrobial and immunomodulatory functions are being elucidated for existing proteins that were previously thought to be of lesser importance. The potential therapeutic applications of these proteins and peptides in combating infection and preventing inflammation are the subject of ongoing research that holds much promise for the future

Transcriptional Activation of c3 and hsp70 as Part of the Immune Response of Acropora millepora to Bacterial Challenges

The impact of disease outbreaks on coral physiology represents an increasing concern for the fitness and resilience of reef ecosystems. Predicting the tolerance of corals to disease relies on an understanding of the coral immune response to pathogenic interactions. This study explored the transcriptional response of two putative immune genes (c3 and c-type lectin) and one stress response gene (hsp70) in the reef building coral, Acropora millepora challenged for 48 hours with bacterial strains, Vibrio coralliilyticus and Alteromonas sp. at concentrations of 106 cells ml-1. Coral fragments challenged with V. coralliilyticus appeared healthy while fragments challenged with Alteromonas sp. showed signs of tissue lesions after 48 hr. Coral-associated bacterial community profiles assessed using denaturing gradient gel electrophoresis changed after challenge by both bacterial strains with the Alteromonas sp. treatment demonstrating the greatest community shift. Transcriptional profiles of c3 and hsp70 increased at 24 hours and correlated with disease signs in the Alteromonas sp. treatment. The expression of hsp70 also showed a significant increase in V. coralliilyticus inoculated corals at 24 h suggesting that even in the absence of disease signs, the microbial inoculum activated a stress response in the coral. C-type lectin did not show a response to any of the bacterial treatments. Increase in gene expression of c3 and hsp70 in corals showing signs of disease indicates their potential involvement in immune and stress response to microbial challenges

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio