COMMD1-deficient dogs accumulate copper in hepatocytes and provide a good model for chronic hepatitis and fibrosis

New therapeutic concepts developed in rodent models should ideally be evaluated in large animal models prior to human clinical application. COMMD1-deficiency in dogs leads to hepatic copper accumulation and chronic hepatitis representing a Wilson's disease like phenotype. Detailed understanding of the pathogenesis and time course of this animal model is required to test its feasibility as a large animal model for chronic hepatitis. In addition to mouse models, true longitudinal studies are possible due to the size of these dogs permitting detailed analysis of the sequence of events from initial insult to final cirrhosis. Therefore, liver biopsies were taken each half year from five new born COMMD1-deficient dogs over a period of 42 months. Biopsies were used for H&E, reticulin, and rubeanic acid (copper) staining. Immunohistochemistry was performed on hepatic stellate cell (HSC) activation marker (alpha-smooth muscle actin, α-SMA), proliferation (Ki67), apoptosis (caspase-3), and bile duct and liver progenitor cell (LPC) markers keratin (K) 19 and 7. Quantitative RT-PCR and Western Blots were performed on gene products involved in the regenerative and fibrotic pathways. Maximum copper accumulation was reached at 12 months of age, which coincided with the first signs of hepatitis. HSCs were activated (α-SMA) from 18 months onwards, with increasing reticulin deposition and hepatocytic proliferation in later stages. Hepatitis and caspase-3 activity (first noticed at 18 months) increased over time. Both HGF and TGF-β1 gene expression peaked at 24 months, and thereafter decreased gradually. Both STAT3 and c-MET showed an increased time-dependent activation. Smad2/3 phosphorylation, indicative for fibrogenesis, was present at all time-points. COMMD1-deficient dogs develop chronic liver disease and cirrhosis comparable to human chronic hepatitis, although at much higher pace. Therefore they represent a genetically-defined large animal model to test clinical applicability of new therapeutics developed in rodent models

Molecular Characterization of the Gastrula in the Turtle Emys orbicularis: An Evolutionary Perspective on Gastrulation

Due to the presence of a blastopore as in amphibians, the turtle has been suggested to exemplify a transition form from an amphibian- to an avian-type gastrulation pattern. In order to test this hypothesis and gain insight into the emergence of the unique characteristics of amniotes during gastrulation, we have performed the first molecular characterization of the gastrula in a reptile, the turtle Emys orbicularis. The study of Brachyury, Lim1, Otx2 and Otx5 expression patterns points to a highly conserved dynamic of expression with amniote model organisms and makes it possible to identify the site of mesoderm internalization, which is a long-standing issue in reptiles. Analysis of Brachyury expression also highlights the presence of two distinct phases, less easily recognizable in model organisms and respectively characterized by an early ring-shaped and a later bilateral symmetrical territory. Systematic comparisons with tetrapod model organisms lead to new insights into the relationships of the blastopore/blastoporal plate system shared by all reptiles, with the blastopore of amphibians and the primitive streak of birds and mammals. The biphasic Brachyury expression pattern is also consistent with recent models of emergence of bilateral symmetry, which raises the question of its evolutionary significance

Detecting the Collapse of Cooperation in Evolving Networks

The sustainability of biological, social, economic and ecological communities is often determined by the outcome of social conflicts between cooperative and selfish individuals (cheaters). Cheaters avoid the cost of contributing to the community and can occasionally spread in the population leading to the complete collapse of cooperation. Although such collapse often unfolds unexpectedly, it is unclear whether one can detect the risk of cheater’s invasions and loss of cooperation in an evolving community. Here, we combine dynamical networks and evolutionary game theory to study the abrupt loss of cooperation with tools for studying critical transitions. We estimate the risk of cooperation collapse following the introduction of a single cheater under gradually changing conditions. We observe an increase in the average time it takes for cheaters to be eliminated from the community as the risk of collapse increases. We argue that such slow system response resembles slowing down in recovery rates prior to a critical transition. In addition, we show how changes in community structure reflect the risk of cooperation collapse. We find that these changes strongly depend on the mechanism that governs how cheaters evolve in the community. Our results highlight novel directions for detecting abrupt transitions in evolving networks

Effect of magnesium and vitamin B6 supplementation on mental health and quality of life in stressed healthy adults: Post‐hoc analysis of a randomised controlled trial

Magnesium status and vitamin B6 intake have been linked to mental health and/or quality of life (QoL). In an 8‐week Phase IV randomised controlled study in individuals with low magnesemia and severe/extremely severe stress but who were otherwise healthy, greater stress reduction was achieved with magnesium combined with vitamin B6 than with magnesium alone. We present a previously unreported secondary analysis of the effect of magnesium, with and without vitamin B6, on depression, anxiety, and QoL. Adults with Depression Anxiety Stress Scales (DASS‐42) stress subscale score >18 were randomised 1:1 to magnesium + vitamin B6 combination (Magne B6®; daily dose 300 and 30 mg, respectively) or magnesium alone (Magnespasmyl®; daily dose 300 mg). Outcomes included changes from baseline in DASS‐42 depression and anxiety scores, and QoL (Short Form‐36 Health Survey). DASS‐42 anxiety and depression scores significantly improved from baseline to week 8 with both treatments, particularly during the first 4 weeks. Improvement in QoL continued over 8 weeks. Participants' perceived capacity for physical activity in daily life showed greater improvement with magnesium + vitamin B6 than magnesium alone (Week 4). In conclusion, magnesium supplementation, with or without vitamin B6, could provide a meaningful clinical benefit in daily life for individuals with stress and low magnesemia

Meta-study on energy scenarios

The energy sector today accounts for about 10% to 15% of global freshwater withdrawal. Most water in the energy sector is used for generating electricity, especially for cooling processes in thermal power plants. At the same time the demand for electricity is expected to increase significantly due to population growth and economic development in emerging and developing economies. Growing demand is also driven by electrification strategies pursued by industrialized countries to decarbonize their economies. With the global demand for electricity expected to increase significantly in the coming decades also the water demand in the power sector is expected to rise. However, due to the on-going global energy transition, the future structure of the power supply - and hence future water demand for power generation - is subject to high levels of uncertainty because the volume of water required for electricity generation varies significantly depending on both the generation technology and cooling system. In light of these challenges the objective of this analysis is to provide more systematic and robust answers in terms of the impacts of different decarbonization strategies in the electricity sector on water demand at global and regional level. The focus is on operational water use for electricity generation

Standing Eddies in the Meridional Overturning Circulation

The role of standing eddies for the meridional overturning circulation (MOC) is discussed. The time-mean isopycnal meridional streamfunction is decomposed into a time- and zonal-mean part, a standing-eddy part, and a transient-eddy part. It turns out that the construction of an isopycnal MOC with an exactly vanishing standing-eddy part has to be performed by zonal integration along depth-dependent horizontal isolines of time-mean density. In contrast, zonal integration along time-mean geostrophic streamlines generally only leads to an isopycnal MOC with a reduced standing-eddy part. A generalized approach of constructing meridional transport streamfunctions by two tracer fields and the generalized way to neutralize the corresponding standing-eddy part is given to summarize the discussion. Using the results of an idealized Southern Ocean model, it is demonstrated that neglecting the depth dependence of the zonal integration paths by integrating along density contours or geostrophic streamlines of a fixed depth ("contour depth") may represent an acceptable approximation: although the standing-eddy part then exactly vanishes only at the contour depth (except for the ageostrophic surface layer using geostrophic streamlines), the overall standing-eddy part is significantly reduced for adequate contour depths. In the idealized Southern Ocean model, density contours at middepth and surface geostrophic streamlines represent the most adequate approximations. Moreover, it is found that the effect of changing the zonal integration paths from latitude circles to curvilinear paths on the zonally averaged density is of the same order as changing from Eulerian to isopycnal averaging