Analysis of IL2/IL21 Gene Variants in Cholestatic Liver Diseases Reveals an Association with Primary Sclerosing Cholangitis

Background/Aims: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. Methods: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. Results: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). Conclusion: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC. Copyright (C) 2011 S. Karger AG, Base

Coordinated Ionospheric Reconstruction CubeSat Experiment (CIRCE), In situ and Remote Ionospheric Sensing (IRIS) suite

The UK’s Defence Science and Technology Laboratory (Dstl) is partnering with the US Naval Research Laboratory (NRL) on a joint mission to launch miniature sensors that will advance space weather measurement and modelling capabilities. The Coordinated Ionospheric Reconstruction Cubesat Experiment (CIRCE) comprises two 6U cube-satellites that will be launched into a near-polar low earth orbit (LEO), targeting 500 km altitude, in 2021. The UK contribution to CIRCE is the In situ and Remote Ionospheric Sensing (IRIS) suite, complementary to NRL sensors, and comprising three highly miniaturised payloads provided to Dstl by University College London (UCL), University of Bath, and University of Surrey/Surrey Satellite Technology Ltd (SSTL). One IRIS suite will be flown on each satellite, and incorporates an ion/neutral mass spectrometer, a tri-band global positioning system (GPS) receiver for ionospheric remote sensing, and a radiation environment monitor. From the US, NRL have provided two 1U Triple Tiny Ionospheric Photometers (Tri-TIPs) on each satellite (Nicholas et al., 2019), observing the ultraviolet 135.6 nm emission of atomic oxygen at night-time to characterize the two-dimensional distribution of electrons

Meteorological, impact and climate perspectives of the 29 June 2017 heavy precipitation event in the Berlin metropolitan area

Extreme precipitation is a weather phenomenon with tremendous damaging potential for property and human life. As the intensity and frequency of such events is projected to increase in a warming climate, there is an urgent need to advance the existing knowledge on extreme precipitation processes, statistics and impacts across scales. To this end, a working group within the Germany-based project, ClimXtreme, has been established to carry out multidisciplinary analyses of high-impact events. In this work, we provide a comprehensive assessment of the 29 June 2017 heavy precipitation event (HPE) affecting the Berlin metropolitan region (Germany), from the meteorological, impacts and climate perspectives, including climate change attribution. Our analysis showed that this event occurred under the influence of a mid-tropospheric trough over western Europe and two shortwave surface lows over Britain and Poland (Rasmund and Rasmund II), inducing relevant low-level wind convergence along the German–Polish border. Over 11 000 convective cells were triggered, starting early morning 29 June, displacing northwards slowly under the influence of a weak tropospheric flow (10 m s−1 at 500 hPa). The quasi-stationary situation led to totals up to 196 mm d−1, making this event the 29 June most severe in the 1951–2021 climatology, ranked by means of a precipitation-based index. Regarding impacts, it incurred the largest insured losses in the period 2002 to 2017 (EUR 60 million) in the greater Berlin area. We provide further insights on flood attributes (inundation, depth, duration) based on a unique household-level survey data set. The major moisture source for this event was the Alpine–Slovenian region (63 % of identified sources) due to recycling of precipitation falling over that region 1 d earlier. Implementing three different generalised extreme value (GEV) models, we quantified the return periods for this case to be above 100 years for daily aggregated precipitation, and up to 100 and 10 years for 8 and 1 h aggregations, respectively. The conditional attribution demonstrated that warming since the pre-industrial era caused a small but significant increase of 4 % in total precipitation and 10 % for extreme intensities. The possibility that not just greenhouse-gas-induced warming, but also anthropogenic aerosols affected the intensity of precipitation is investigated through aerosol sensitivity experiments. Our multi-disciplinary approach allowed us to relate interconnected aspects of extreme precipitation. For instance, the link between the unique meteorological conditions of this case and its very large return periods, or the extent to which it is attributable to already-observed anthropogenic climate change.</p

Meteorological, impact and climate perspectives of the 29 June 2017 heavy precipitation event in the Berlin metropolitan area

Extreme precipitation is a weather phenomenon with tremendous damaging potential for property and human life. As the intensity and frequency of such events is projected to increase in a warming climate, there is an urgent need to advance the existing knowledge on extreme precipitation processes, statistics and impacts across scales. To this end, a working group within the Germany-based project, ClimXtreme, has been established to carry out multidisciplinary analyses of high-impact events. In this work, we provide a comprehensive assessment of the 29 June 2017 heavy precipitation event (HPE) affecting the Berlin metropolitan region (Germany), from the meteorological, impacts and climate perspectives, including climate change attribution. Our analysis showed that this event occurred under the influence of a mid-tropospheric trough over western Europe and two shortwave surface lows over Britain and Poland (Rasmund and Rasmund II), inducing relevant low-level wind convergence along the German–Polish border. Over 11 000 convective cells were triggered, starting early morning 29 June, displacing northwards slowly under the influence of a weak tropospheric flow (10 m s$^{−1}$ at 500 hPa). The quasi-stationary situation led to totals up to 196 mm d$^{−1}$, making this event the 29 June most severe in the 1951–2021 climatology, ranked by means of a precipitation-based index. Regarding impacts, it incurred the largest insured losses in the period 2002 to 2017 (EUR 60 million) in the greater Berlin area. We provide further insights on flood attributes (inundation, depth, duration) based on a unique household-level survey data set. The major moisture source for this event was the Alpine–Slovenian region (63 % of identified sources) due to recycling of precipitation falling over that region 1 d earlier. Implementing three different generalised extreme value (GEV) models, we quantified the return periods for this case to be above 100 years for daily aggregated precipitation, and up to 100 and 10 years for 8 and 1 h aggregations, respectively. The conditional attribution demonstrated that warming since the pre-industrial era caused a small but significant increase of 4 % in total precipitation and 10 % for extreme intensities. The possibility that not just greenhouse-gas-induced warming, but also anthropogenic aerosols affected the intensity of precipitation is investigated through aerosol sensitivity experiments. Our multi-disciplinary approach allowed us to relate interconnected aspects of extreme precipitation. For instance, the link between the unique meteorological conditions of this case and its very large return periods, or the extent to which it is attributable to already-observed anthropogenic climate change

A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease

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Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Uridine Treatment of the First Known Case of SLC25A36 Deficiency

SLC25A36 is a pyrimidine nucleotide carrier playing an important role in maintaining mitochondrial biogenesis. Deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction. In human beings, diseases triggered by 'SLC25A36' mutations have not been described yet. We report the first known case of SLC25A36 deficiency in a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. Whole exome analysis identified the homozygous mutation c.803dupT, p.Ser269llefs*35 in the 'SLC25A36' gene. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with oral uridine led to an improvement of thyroid function and obstipation, increase of growth and developmental progress. Our findings suggest an important role of SLC25A36 in hormonal regulations and oral uridine as a safe and effective treatment

Severe Form of ßIV-Spectrin Deficiency With Mitochondrial Dysfunction and Cardiomyopathy—A Case Report

ßIV-spectrin is a protein of the spectrin family which is involved in the organization of the cytoskeleton structure and is found in high quantity in the axon initial segment and the nodes of Ranvier. Together with ankyrin G, ßIV-spectrin is responsible for the clustering of KCNQ2/3-potassium channels and NaV-sodium channels. Loss or reduction of ßIV-spectrin causes a destabilization of the cytoskeleton and an impairment in the generation of the action potential, which leads to neuronal degeneration. Furthermore, ßIV-spectrin has been described to play an important role in the maintenance of the neuronal polarity and of the diffusion barrier. ßIV-spectrin is also located in the heart where it takes an important part in the structural organization of ion channels and has also been described to participate in cell signaling pathways through binding of transcription factors. We describe two patients with a severe form of ßIV-spectrin deficiency. Whole-exome sequencing revealed the homozygous stop mutation c.6016C>T (p.R2006*) in the SPTBN4 gene. The phenotype of these patients is characterized by profound psychomotor developmental arrest, respiratory insufficiency and deafness. Additionally one of the patients presents with cardiomyopathy, optical nerve atrophy, and mitochondrial dysfunction. This is the first report of a severe form of ßIV-spectrin deficiency with hypertrophic cardiomyopathy and mitochondrial dysfunction

Plasmodium induces swelling-activated ClC-2 anion channels in the host erythrocyte

Intraerythrocytic growth of the human malaria parasite Plasmodium falciparum depends on delivery of nutrients. Moreover, infection challenges cell volume constancy of the host erythrocyte requiring enhanced activity of cell volume regulatory mechanisms. Patch clamp recording demonstrated inwardly and outwardly rectifying anion channels in infected but not in control erythrocytes. The molecular identity of those channels remained elusive. We show here for one channel type that voltage dependence, cell volume sensitivity, and activation by oxidation are identical to ClC-2. Moreover, Western blots and FACS analysis showed protein and functional ClC-2 expression in human erythrocytes and erythrocytes from wild type (Clcn2(+/+)) but not from Clcn2(-/-) mice. Finally, patch clamp recording revealed activation of volume-sensitive inwardly rectifying channels in Plasmodium berghei-infected Clcn2(+/+) but not Clcn2(-/-) erythrocytes. Erythrocytes from infected mice of both genotypes differed in cell volume and inhibition of ClC-2 by ZnCl(2) (1 mm) induced an increase of cell volume only in parasitized Clcn2(+/+) erythrocytes. Lack of ClC-2 did not inhibit P. berghei development in vivo nor substantially affect the mortality of infected mice. In conclusion, activation of host ClC-2 channels participates in the altered permeability of Plasmodium-infected erythrocytes but is not required for intraerythrocytic parasite survival