Extended Nitric Oxide Measurements in Exhaled Air of Cystic Fibrosis and Healthy Adults

In cystic fibrosis (CF) lung disease, exhaled nitric oxide (FeNO) is not raised, but rather is normal or even decreased when measured at a single expiratory flow. FeNO measurements at several flow rates allow differentiation between alveolar and bronchial nitric oxide (NO) production. Extended FeNO measurements therefore should be useful to localize the FeNO deficit in CF airways. FeNO was measured in stable CF adults with moderate lung disease and in healthy controls. Bronchial NO fluxes (JNO,Br) and alveolar NO concentrations (CAlv) were calculated from FeNO measurements at flow rates of 100, 150 and 200ml/s using a method previously described. Thirty-two adults were included in the study, 12 of whom had CF. CF adults had significantly lower FeNO values at all flow rates. The median JNO,Br was significantly lower in CF adults than in healthy controls [0.31nl/s (range=0.11-0.63) vs. 0.70nl/s (0.27-3.52); P<0.001], while the median CAlv was similar in both groups [1.7ppb (0.3-3.9) vs. 1.2 (0.1-5.2)]. Pulmonary NO exchange did not differ significantly between subgroups of CF patients with and without chronic Pseudomonas aeruginosa infection. No significant correlation was detectable between FEV1/VC and JNO,Br and CAlv, respectively. Extended FeNO measurements can separate alveolar and bronchial NO outputs in CF adults. The lower FeNO in adults with moderate to severe CF lung disease is likely to be the result of lower bronchial NO outpu

Histologic and Molecular Patterns in Responders and Non-responders With Chronic-Active Antibody-Mediated Rejection in Kidney Transplants

Introduction There is no proven therapy for chronic-active antibody-mediated rejection (caABMR), the major cause of late kidney allograft failure. Histological and molecular patterns associated with possible therapy responsiveness are not known. Methods Based on rigorous selection criteria this single center, retrospective study identified 16 out of 1027 consecutive kidney transplant biopsies taken between 2008 and 2016 with pure, unquestionable caABMR, without other pathologic features. The change in estimated GFR pre- and post-biopsy/treatment were utilized to differentiate subjects into responders and non-responders. Gene sets reflecting active immune processes of caABMR were defined a priori, including endothelial, inflammatory, cellular, interferon gamma (IFNg) and calcineurin inhibitor (CNI) related-genes based on the literature. Transcript measurements were performed in RNA extracted from stored, formalin-fixed, paraffin-embedded (FFPE) samples using NanoString™ technology. Histology and gene expression patterns of responders and non-responders were compared. Results A reductionist approach applying very tight criteria to identify caABMR and treatment response excluded the vast majority of clinical ABMR cases. Only 16 out of 139 cases with a written diagnosis of chronic rejection fulfilled the caABMR criteria. Histological associations with therapy response included a lower peritubular capillaritis score (p = 0.028) along with less glomerulitis. In contrast, no single gene discriminated responders from non-responders. Activated genes associated with NK cells and endothelial cells suggested lack of treatment response. Conclusion In caABMR active microvascular injury, in particular peritubular capillaritis, differentiates treatment responders from non-responders. Transcriptome changes in NK cell and endothelial cell associated genes may further help to identify treatment response. Future prospective studies will be needed which include more subjects, who receive standardized treatment protocols to identify biomarkers for treatment response. Clinical Trial Registration [ClinicalTrials.gov], identifier [NCT03430414]

Moderate altitude but not additional endurance training increases markers of oxidative stress in exhaled breath condensate

Oxidative stress occurs at altitude, and physical exertion might enhance this stress. In the present study, we investigated the combined effects of exercise and moderate altitude on redox balance in ten endurance exercising biathletes, and five sedentary volunteers during a 6-week-stay at 2,800m. As a marker for oxidative stress, hydrogen peroxide (H2O2) was analyzed by the biosensor measuring system Ecocheck™, and 8-iso prostaglandin F2α (8-iso PGF2α) was determined by enzyme immunoassay in exhaled breath condensate (EBC). To determine the whole blood antioxidative capacity, we measured reduced glutathione (GSH) enzymatically using Ellman's reagent. Exercising athletes and sedentary volunteers showed increased levels of oxidative markers at moderate altitude, contrary to our expectations; there was no difference between both groups. Therefore, all subjects' data were pooled to examine the oxidative stress response exclusively due to altitude exposure. H2O2 levels increased at altitude and remained elevated for 3days after returning to sea level (p≤0.05). On the other hand, 8-iso PGF2α levels showed a tendency to increase at altitude, but declined immediately after returning to sea level (p≤0.001). Hypoxic exposure during the first day at altitude resulted in elevated GSH levels (p≤0.05), that decreased during prolonged sojourn at altitude (p≤0.001). In conclusion, a stay at moderate altitude for up to 6weeks increases markers of oxidative stress in EBC independent of additional endurance training. Notably, this oxidative stress is still detectable 3days upon return to sea leve

p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans

Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours

Gephyrin phosphorylation in the functional organization and plasticity of GABAergic synapses

Gephyrin is a multifunctional scaffold protein essential for accumulation of inhibitory glycine and GABAA receptors at post-synaptic sites. The molecular events involved in gephyrin-dependent GABAA receptor clustering are still unclear. Evidence has been recently provided that gephyrin phosphorylation plays a key role in these processes. Gephyrin post-translational modifications have been shown to influence the structural remodeling of GABAergic synapses and synaptic plasticity by acting on post-synaptic scaffolding properties as well as stability. In addition, gephyrin phosphorylation and the subsequent phosphorylation-dependent recruitment of the chaperone molecule Pin1 provide a mechanism for the regulation of GABAergic signaling. Extensively characterized as pivotal enzyme controlling cell proliferation and differentiation, the prolyl-isomerase activity of Pin1 has been shown to regulate protein synthesis necessary to sustain the late phase of long-term potentiation at excitatory synapses, which suggests its involvement at synaptic sites. In this review we summarize the current state of knowledge of the signaling pathways responsible for gephyrin post-translational modifications. We will also outline future lines of research that might contribute to a better understanding of molecular mechanisms by which gephyrin regulates synaptic plasticity at GABAergic synapses. \ua9 2014 Zacchi, Antonelli and Cherubini

Jahrbuch Wirtschaftsrecht Schweiz – EU - Überblick und Kommentar 2023/24

Der vorliegende 19. Band der Jahrbuchreihe „Wirtschaftsrecht Schweiz – EU“ dokumentiert die aktuellen Entwicklungen in zentralen Bereichen des EU-Wirtschaftsrechts und deren Bedeutung für die Schweiz. Berücksichtigt werden diverse wirtschaftsrelevante Rechtsgebiete, u.a. Kapitalmarktrecht, Immaterialgüterrecht, Arbeitsrecht, Steuerrecht und Wettbewerbsrecht. Das Jahrbuch richtet sich an Unternehmens‑, Wirtschafts- und VerwaltungsjuristInnen sowie an RichterInnen und RechtsanwältInnen und bietet ihnen einen kompakten Überblick über die wichtigsten Gesetzgebungsvorstösse, neue Rechtsakte und ergangene Urteile im vergangenen Jahr 2023. Auch diese Ausgabe des Jahrbuchs erscheint wiederum im Verlag EIZ Publishing, und zwar als frei verfügbares E-Book (open access) sowie in gedruckter Form (print on demand)

Entanglement is a costly life-history stage in large whales

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Ecology and Evolution 7 (2017): 92–106, doi:10.1002/ece3.2615.Individuals store energy to balance deficits in natural cycles; however, unnatural events can also lead to unbalanced energy budgets. Entanglement in fishing gear is one example of an unnatural but relatively common circumstance that imposes energetic demands of a similar order of magnitude and duration of life-history events such as migration and pregnancy in large whales. We present two complementary bioenergetic approaches to estimate the energy associated with entanglement in North Atlantic right whales, and compare these estimates to the natural energetic life history of individual whales. Differences in measured blubber thicknesses and estimated blubber volumes between normal and entangled, emaciated whales indicate between 7.4 × 1010 J and 1.2 × 1011 J of energy are consumed during the course to death of a lethal entanglement. Increased thrust power requirements to overcome drag forces suggest that when entangled, whales require 3.95 × 109 to 4.08 × 1010 J more energy to swim. Individuals who died from their entanglements performed significantly more work (energy expenditure × time) than those that survived; entanglement duration is therefore critical in determining whales’ survival. Significant sublethal energetic impacts also occur, especially in reproductive females. Drag from fishing gear contributes up to 8% of the 4-year female reproductive energy budget, delaying time of energetic equilibrium (to restore energy lost by a particular entanglement) for reproduction by months to years. In certain populations, chronic entanglement in fishing gear can be viewed as a costly unnatural life-history stage, rather than a rare or short-term incident.Cooperative Institute for the North Atlantic Region (CINAR) Grant Number: NA14OAR4320158; Herrington-Fitch Family Foundation; M.S. Worthington Foundation; North Pond Foundation; Natural Sciences and Engineering Research Council of Canada; MIT Martin Family for Sustainability Fellowshi

Jahrbuch Wirtschaftsrecht Schweiz - EU - Überblick und Kommentar 2022/23

Der vorliegende 18. Band der Jahrbuchreihe „Wirtschaftsrecht Schweiz – EU“ dokumentiert die aktuellen Entwicklungen in zentralen Bereichen des EU-Wirtschaftsrechts und deren Bedeutung für die Schweiz. Berücksichtigt werden diverse wirtschaftsrelevante Rechtsgebiete, u.a. Kapitalmarktrecht, Immaterialgüterrecht, Arbeitsrecht, Steuerrecht und Wettbewerbsrecht. Das Jahrbuch richtet sich an Unternehmens-, Wirtschafts- und VerwaltungsjuristInnen sowie an RichterInnen und RechtsanwältInnen und bietet ihnen einen kompakten Überblick über die wichtigsten Gesetzgebungsvorstösse, neue Rechtsakte und ergangene Urteile im vergangenen Jahr 2022

Global maps of soil temperature

Research in global change ecology relies heavily on global climatic grids derived from estimates of air temperature in open areas at around 2 m above the ground. These climatic grids do not reflect conditions below vegetation canopies and near the ground surface, where critical ecosystem functions occur and most terrestrial species reside. Here, we provide global maps of soil temperature and bioclimatic variables at a 1-km² resolution for 0–5 and 5–15 cm soil depth. These maps were created by calculating the difference (i.e., offset) between in-situ soil temperature measurements, based on time series from over 1200 1-km² pixels (summarized from 8500 unique temperature sensors) across all the world’s major terrestrial biomes, and coarse-grained air temperature estimates from ERA5-Land (an atmospheric reanalysis by the European Centre for Medium-Range Weather Forecasts). We show that mean annual soil temperature differs markedly from the corresponding gridded air temperature, by up to 10°C (mean = 3.0 ± 2.1°C), with substantial variation across biomes and seasons. Over the year, soils in cold and/or dry biomes are substantially warmer (+3.6 ± 2.3°C) than gridded air temperature, whereas soils in warm and humid environments are on average slightly cooler (-0.7 ± 2.3°C). The observed substantial and biome-specific offsets emphasize that the projected impacts of climate and climate change on near-surface biodiversity and ecosystem functioning are inaccurately assessed when air rather than soil temperature is used, especially in cold environments. The global soil-related bioclimatic variables provided here are an important step forward for any application in ecology and related disciplines. Nevertheless, we highlight the need to fill remaining geographic gaps by collecting more in-situ measurements of microclimate conditions to further enhance the spatiotemporal resolution of global soil temperature products for ecological applications.publishedVersio