Nitric oxide modulates expression of extracellular matrix genes linked to fibrosis in kidney mesangial cells

Mesangial cells are thought to be important mediators of glomerular inflammation and fibrosis. Studies have established a direct role for nitric oxide (NO) in the regulation of gene expression in mesangial cells. Representational difference analysis was used to investigate changes in gene expression elicited by the treatment of S-nitroso-L-glutathione in rat mesangial cells. Seven upregulated and 11 downregulated genes were identified. Four out of 11 downregulated genes (connective tissue growth factor, thrombospondin-1, collagen type I all and collagen type I alpha 2) are known to be linked to inflammation and fibrosis. Results were verified across species in mesangial cells treated with a series of NO donors using Northern blot analysis, quantitative real-time PCR and protein analysis methods. Induction of endogenous NO production by cytokine stimulation also triggered regulation of the genes. One example gene, connective tissue growth factor, was studied at the promoter level. Promoter-reporter gene studies in mesangial cells demonstrated that NO acts at the transcriptional level to suppress gene expression. Our results reveal a complex role of NO in regulating gene expression in mesangial cells and suggest an antifibrotic potential for NO

Copepod life strategy and population viability in response to prey timing and temperature : testing a new model across latitude, time, and the size spectrum

A new model ("Coltrane": Copepod Life-history Traits and Adaptation to Novel Environments) describes environmental controls on copepod populations via (1) phenology and life history and (2) temperature and energy budgets in a unified framework. The model tracks a cohort of copepods spawned on a given date using a set of coupled equations for structural and reserve biomass, developmental stage, and survivorship, similar to many other individual-based models. It then analyzes a family of cases varying spawning date over the year to produce population-level results, and families of cases varying one or more traits to produce community-level results. In an idealized global-scale testbed, the model correctly predicts life strategies in large Calanus spp. ranging from multiple generations per year to multiple years per generation. In a Bering Sea testbed, the model replicates the dramatic variability in the abundance of Calanus glacialis/marshallae observed between warm and cold years of the 2000s, and indicates that prey phenology linked to sea ice is a more important driver than temperature per se. In a Disko Bay, West Greenland testbed, the model predicts the viability of a spectrum of large-copepod strategies from income breeders with a adult size ~100 μgC reproducing once per year through capital breeders with an adult size > 1000 μgC with a multiple-year life cycle. This spectrum corresponds closely to the observed life histories and physiology of local populations of Calanus finmarchicus, C. glacialis, and Calanus hyperboreus. Together, these complementary initial experiments demonstrate that many patterns in copepod community composition and productivity can be predicted from only a few key constraints on the individual energy budget: the total energy available in a given environment per year; the energy and time required to build an adult body; the metabolic and predation penalties for taking too long to reproduce; and the size and temperature dependence of the vital rates involved

Exogenously added GPI-anchored tissue inhibitor of matrix metal loproteinase-1 (TIMP-1) displays enhanced and novel biological activities

The family of tissue inhibitors of metalloproteinases (TIMPs) exhibits diverse physiological/biological functions including the inhibition of active matrix metalloproteinases, regulation of proMMP activation, cell growth, and the modulation of angiogenesis. TIMP-1 is a secreted protein that can be detected on the cell surface through its interaction with surface proteins. The diverse biological functions of TIMP-1 are thought to lie, in part, in the kinetics of TIMP-1/MMP/surface protein interactions. Proteins anchored by glycoinositol phospholipids (GPIs), when purified and added to cells in vitro, are incorporated into their surface membranes. A GPI anchor was fused to TIMP-1 to generate a reagent that could be added directly to cell membranes and thus focus defined concentrations of TIMP-1 protein on any cell surface independent of protein-protein interaction. Unlike native TIMP-1, exogenously added GPI-anchored TIMP-1 protein effectively blocked release of MMP-2 and MMP-9 from osteosarcoma cells. TIMP-1-GP1 was a more effective modulator of migration and proliferation than TIMP-1. While control hTIMP-1 protein did not significantly affect migration of primary microvascular endothelial cells at the concentrations tested, the GPI-anchored TIMP-1 protein showed a pronounced suppression of endothelial cell migration in response to bFGF. In addition, TIMP-1-GPI was more effective at inducing microvascular endothelial proliferation. In contrast, fibroblast proliferation was suppressed by the agent. Reagents based on this method should assist in the dissection of the protease cascades and activities involved in TIMP biology. Membrane-fixed TIMP-1 may represent a more effective version of the protein for use in therapeutic expression

56 The impact of statin therapy on the efficacy of eplerenone

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106735/1/ehfs80021-9.pd

Cytomegalovirus Management in Solid Organ Transplant Recipients: A Pre-COVID-19 Survey From the Working Group of the European Society for Organ Transplantation

Infections are leading causes of morbidity/mortality following solid organ transplantation (SOT) and cytomegalovirus (CMV) is among the most frequent pathogens, causing a considerable threat to SOT recipients. A survey was conducted 19 July–31 October 2019 to capture clinical practices about CMV in SOT recipients (e.g., how practices aligned with guidelines, how adequately treatments met patients’ needs, and respondents’ expectations for future developments). Transplant professionals completed a ∼30-minute online questionnaire: 224 responses were included, representing 160 hospitals and 197 SOT programs (41 countries; 167[83%] European programs). Findings revealed a heterogenous approach to CMV diagnosis and management and, sometimes, significant divergence from international guidelines. Valganciclovir prophylaxis (of variable duration) was administered by 201/224 (90%) respondents in D+/R− SOT and by 40% in R+ cases, with pre-emptive strategies generally reserved for R+ cases: DNA thresholds to initiate treatment ranged across 10–10,000 copies/ml. Ganciclovir-resistant CMV strains were still perceived as major challenges, and tailored treatment was one of the most important unmet needs for CMV management. These findings may help to design studies to evaluate safety and efficacy of new strategies to prevent CMV disease in SOT recipients, and target specific educational activities to harmonize CMV management in this challenging population

Distributed low voltage power supply system for front end electronics of the TRT detector in ATLAS experiment

We present a low voltage power supply system which has to deliver to the front end electronics of the ATLAS TRT detector [1] ca. 23 kW of electrical power over the distance of 55 -106 m (which adds another 24 kW). The system has to operate in magnetic field and under radiation environment of the LHC experimental cavern. The system has ~ 3000 individual channels which are all monitored and controlled (voltage and current measurement). The hardware solutions are described as well as the system control software

In a comfort zone and beyond—Ecological plasticity of key marine mediators

Copepods of the genus Calanus are the key components of zooplankton. Understanding their response to a changing climate is crucial to predict the functioning of future warmer high‐latitude ecosystems. Although specific Calanus species are morphologically very similar, they have different life strategies and roles in ecosystems. In this study, C. finmarchicus and C. glacialis were thoroughly studied with regard to their plasticity in morphology and ecology both in their preferred original water mass (Atlantic vs. Arctic side of the Polar Front) and in suboptimal conditions (due to, e.g., temperature, turbidity, and competition in Hornsund fjord). Our observations show that “at the same place and time,” both species can reach different sizes, take on different pigmentation, be in different states of population development, utilize different reproductive versus lipid accumulation strategies, and thrive on different foods. Size was proven to be a very mutable morphological trait, especially with regard to reduced length of C. glacialis. Both species exhibited pronounced red pigmentation when inhabiting their preferred water mass. In other domains, C. finmarchicus individuals tended to be paler than C. glacialis individuals. Gonad maturation and population development indicated mixed reproductive strategies, although a surprisingly similar population age structure of the two co‐occurring species in the fjord was observed. Lipid accumulation was high and not species‐specific, and its variability was due to diet differences of the populations. According to the stable isotope composition, both species had a more herbivorous diatom‐based diet in their original water masses. While the diet of C. glacialis was rather consistent among the domains studied, C. finmarchicus exhibited much higher variability in its feeding history (based on lipid composition). Our results show that the plasticity of both Calanus species is indeed impressive and may be regulated differently, depending on whether they live in their “comfort zone” or beyond it.publishedVersionUnit Licence Agreemen