The role of soluble guanylate cyclase in metabolism

Obesity is a worldwide health problem characterized by a chronic positive energy balance. The excess energy is stored primarily as lipids (TGs) in white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) utilizes energy to produce heat in response to cold exposure. BAT is a promising target for developing anti-obesity therapies. This thesis focusses on the role of soluble guanylate cyclase (sGC) in metabolism and identifies BATcentered therapies. Analysis of sGCβ1 knockout mice revealed reduced BAT mass and less UCP1 expression in comparison to WT mice. Furthermore, differentiation and function of brown adipocytes was impaired in mice lacking the β1 subunit of sGC. Congruently, chronic stimulation of sGC with 3 μM BAY 41-8543 during differentiation of brown adipocytes (BAs) resulted in improved adipogenic (PPARg and aP2) and thermogenic marker (PGC-1a and UCP1) expression. Functionally, lipolysis, was also enhanced in BAs treated with BAY 41-8543. Pharmacological stimulation of sGC during a high fat diet regime protects against weight gain. Stimulation of sGC increases function of BAs and energy consumption by UCP1 mediated thermogenesis. Importantly, BAY 41-8543 counteracts comorbidities of obesity, such as fatty liver and diabetes, even in already established obesity via increased energy expenditure. Notably, mice treated with the sGC stimulator exhibited reduced "whitening" of BAT and enhanced "browning" of WAT. In addition, sGC stimulation leads to increased expression of mitochondrial markers in muscle, which shows the overall effect of sGC stimulation. Stimulation of sGC results in increased lipid uptake and utilization by BAT, WATi, liver and muscle. Overall, sGC stimulation leads to reduced body weight gain, even in obese mice. Moreover, sGC stimulation improves metabolic phenotype in mice with diet-induced obesity (DIO), as well as on control diet (CD). Therefore, sGC stimulators represent a novel pharmacological approach for the treatment of obesity and its comorbidities

Time to make a change:A call for more experimental research on key mechanisms in anorexia nervosa

Anorexia nervosa (AN) is a life‐threatening eating disorder, characterised by persistent pathological weight loss behaviours and an intense fear of weight gain and food consumption. Although there is an abundance of scientific theories on the neurobiological, psychological and sociocultural factors thought to be involved in the maintenance of AN, there is little experimental research testing these ideas. The need for theory firmly grounded in empirical evidence becomes strikingly clear when we consider that current treatments for patients with AN are limited in their effectiveness, and relapse after treatment is common

Understanding how the V(D)J recombinase catalyzes transesterification: distinctions between DNA cleavage and transposition

The Rag1 and Rag2 proteins initiate V(D)J recombination by introducing site-specific DNA double-strand breaks. Cleavage occurs by nicking one DNA strand, followed by a one-step transesterification reaction that forms a DNA hairpin structure. A similar reaction allows Rag transposition, in which the 3′-OH groups produced by Rag cleavage are joined to target DNA. The Rag1 active site DDE triad clearly plays a catalytic role in both cleavage and transposition, but no other residues in Rag1 responsible for transesterification have been identified. Furthermore, although Rag2 is essential for both cleavage and transposition, the nature of its involvement is unknown. Here, we identify basic amino acids in the catalytic core of Rag1 specifically important for transesterification. We also show that some Rag1 mutants with severe defects in hairpin formation nonetheless catalyze substantial levels of transposition. Lastly, we show that a catalytically defective Rag2 mutant is impaired in target capture and displays a novel form of coding flank sensitivity. These findings provide the first identification of components of Rag1 that are specifically required for transesterification and suggest an unexpected role for Rag2 in DNA cleavage and transposition

Submarine volcanic morphology of the western Galapagos based on EM300 bathymetry and MR1 side-scan sonar

Author Posting. © American Geophysical Union, 2007. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 8 (2007): Q03010, doi:10.1029/2006GC001464.A compilation of high-resolution EM300 multibeam bathymetric and existing MR1 side-scan sonar data was used to investigate the volcanic morphology of the flanks of the western Galápagos Islands. The data portray an assortment of constructional volcanic features on the shallow to deep submarine flanks of Fernandina, Isabela, and Santiago Islands, including rift zones and groups of cones that are considered to be the primary elements in constructing the archipelagic apron. Ten submarine rift zones were mapped, ranging in length from 5 to 20 km, comparable in length to western Canary Island rift zones but significantly shorter than Hawaiian submarine rift zones. A detailed analysis of the northwestern Fernandina submarine rift, including calculated magnetization from a surface-towed magnetic study, suggests that the most recent volcanism has focused at the shallow end of the rift. Small submarine volcanic cones with various morphologies (e.g., pointed, cratered, and occasionally breached) are common in the submarine western Galápagos both on rift zones and on the island flanks where no rifts are present. At depths greater than ∼3000 m, large lava flow fields in regions of low bathymetric relief have been previously identified as a common seafloor feature in the western Galápagos by Geist et al. (2006); however, their source(s) remained enigmatic. The new EM300 data show that a number of the deep lava flows originate from small cones along the mid-lower portion of the NW submarine rift of Fernandina, suggesting that the deep flows owe their origin, at least in part, to submarine rift zone volcanism.Data collected on TN188 was funded by NSF grant OCE0326148 and NOAA grant NA04OAR460009 to S.M.W. Support for data collected on previous multibeam and MR1 cruises was provided by NSF grants OCE9811504 and OCE0002461 (D.J.F.)

Transgenic Mice for a Tamoxifen-Induced, Conditional Expression of the Cre Recombinase in Osteoclasts

Background: Studies on osteoclasts, the bone resorbing cells, have remained limited due to the lack of transgenic mice allowing the conditional knockout of genes in osteoclasts at any time during development or adulthood. Methodology/Principal Finding: We report here on the generation of transgenic mice which specifically express a tamoxifen-inducible Cre recombinase in osteoclasts. These mice, generated on C57BL/6 and FVB background, express a fusion Cre recombinase-ERT2 protein whose expression is driven by the promoter of cathepsin K (CtsK), a gene highly expressed in osteoclasts. We tested the cellular specificity of Cre activity in CtsKCreERT2 strains by breeding with Rosa26LacZ reporter mice. PCR and histological analyses of the CtsKCreERT2LacZ positive adult mice and E17.5 embryos show that Cre activity is restricted largely to bone tissue. In vitro, primary osteoclasts derived from the bone marrow of CtsKCreERT2+/2LacZ+/2 adult mice show a Cre-dependent b-galactosidase activity after tamoxifen stimulation

Adenosine/A2B receptor signaling ameliorates the effects of ageing and counteracts obesity

The combination of aging populations with the obesity pandemic results in an alarming rise in non-communicable diseases. Here, we show that the enigmatic adenosine A2B receptor (A2B) is abundantly expressed in skeletal muscle (SKM) as well as brown adipose tissue (BAT) and might be targeted to counteract age-related muscle atrophy (sarcopenia) as well as obesity. Mice with SKM-specific deletion of A2B exhibited sarcopenia, diminished muscle strength, and reduced energy expenditure (EE), whereas pharmacological A2B activation counteracted these processes. Adipose tissue-specific ablation of A2B exacerbated age-related processes and reduced BAT EE, whereas A2B stimulation ameliorated obesity. In humans, A2B expression correlated with EE in SKM, BAT activity, and abundance of thermogenic adipocytes in white fat. Moreover, A2B agonist treatment increased EE from human adipocytes, myocytes, and muscle explants. Mechanistically, A2B forms heterodimers required for adenosine signaling. Overall, adenosine/A2B signaling links muscle and BAT and has both anti-aging and anti-obesity potential

The German National Registry of Primary Immunodeficiencies (2012-2017)

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment

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