Unspecific CTL Killing Is Enhanced by High Glucose via TNF-Related Apoptosis-Inducing Ligand

TNF-related apoptosis inducing ligand (TRAIL) is expressed on cytotoxic T lymphocytes (CTLs) and TRAIL is linked to progression of diabetes. However, the impact of high glucose on TRAIL expression and its related killing function in CTLs still remains largely elusive. Here, we report that TRAIL is substantially up-regulated in CTLs in environments with high glucose (HG) both in vitro and in vivo. Non-mitochondrial reactive oxygen species, NFκB and PI3K/Akt are essential in HG-induced TRAIL upregulation in CTLs. TRAILhigh CTLs induce apoptosis of pancreatic beta cell line 1.4E7. Treatment with metformin and vitamin D reduces HG-enhanced expression of TRAIL in CTLs and coherently protects 1.4E7 cells from TRAIL-mediated apoptosis. Our work suggests that HG-induced TRAILhigh CTLs might contribute to the destruction of pancreatic beta cells in a hyperglycemia condition

B-cell receptor reactivity against Rothia mucilaginosa in nodular lymphocyte-predominant Hodgkin lymphoma

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a Hodgkin lymphoma expressing functional B-cell receptors (BCR). Recently, we described a dual stimulation model of IgD+ lymphocyte-predominant cells by Moraxella catarrhalis antigen RpoC and its superantigen MID/hag, associated with extralong CDR3 and HLA-DRB1*04 or HLADRB1*07 haplotype. The aim of the present study was to extend the antigen screening to further bacteria and viruses. The fragment antibody-binding (Fab) regions of seven new and 15 previously reported cases were analyzed. The reactivity of non-Moraxella spp.-reactive Fab regions against lysates of Rothia mucilaginosa was observed in 5/22 (22.7%) cases. Galactofuranosyl transferase (Gltf) and 2,3-butanediol dehydrogenase (Bdh) of R. mucilaginosa were identified by comparative silver- and immuno-staining in two-dimensional gels, with subsequent mass spectrometry and validation by western blots and enzyme-linked immunosorbent assay. Both R. mucilaginosa Gltf and Bdh induced BCR pathway activation and proliferation in vitro. Apoptosis was induced by recombinant Gltf/ETA’-immunotoxin conjugates in DEV cells expressing recombinant R. mucilaginosa-reactive BCR. Reactivity against M. catarrhalis RpoC was confirmed in 3/7 newly expressed BCR (total 10/22 reactive to Moraxella spp.), resulting in 15/22 (68.2%) cases with BCR reactivity against defined bacterial antigens. These findings strengthen the hypothesis of bacterial trigger contributing to subsets of NLPHL

Nanoindenting the Chelyabinsk meteorite to learn about impact deflection effects in asteroids

The Chelyabinsk meteorite is a highly shocked, low porosity, ordinary chondrite, probably similar to S- or Q-type asteroids. Therefore, nanoindentation experiments on this meteorite allow us to obtain key data to understand the physical properties of near-Earth asteroids (NEAs). Tests at different length scales provide information about the local mechanical properties of the minerals forming this meteorite: reduced Young's modulus, hardness, elastic recovery, and fracture toughness. Those tests are also useful to understand the potential to deflect threatening asteroids using a kinetic projectile. We found that the differences in mechanical properties between regions of the meteorite, which increase or reduce the efficiency of impacts, are not a result of compositional differences. A low mean particle size, attributed to repetitive shock, can increase hardness, while low porosity promotes a higher momentum multiplication. Momentum multiplication is the ratio between the change in momentum of a target due to an impact, and the momentum of the projectile, and therefore higher values imply more efficient impacts. In the Chelyabinsk meteorite the properties of the light-colored lithology materials facilitate obtaining higher momentum multiplication values, compared to the other regions described for this meteorite. Also, we found a low value of fracture toughness in the shock-melt veins of Chelyabinsk, which would promote the ejection of material after an impact and therefore increase the momentum multiplication. These results are relevant in the context of a future mission to test asteroid deflection, currently being studied by ESA and NASA: the Asteroid Impact and Deflection Assessment (AIDA) mission

The Nachtlichter app: a citizen science tool for documenting outdoor light sources in public space

The relationship between satellite based measurements of city radiance at night and the numbers and types of physical lights installed on the ground is not well understood. Here we present the "Nachtlichter app", which was developed to enable citizen scientists to classify and count light sources along street segments over large spatial scales. The project and app were co-designed: citizen scientists played key roles in the app development, testing, and recruitment, as well as in analysis of the data. In addition to describing the app itself and the data format, we provide a general overview of the project, including training materials, data cleaning, and the result of some basic data consistency checks

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Time-dependend behaviour of non-stimulated arterial and venous vessels of the retina in primary open-angle glaucoma patients

Vaskuläre Mechanismen und Durchblutungsstörungen spielen bei der Pathogenese des primären Offenwinkelglaukoms eine Rolle. Ein besseres Verständnis hierüber könnte genauere prognostische Einschätzungen ermöglichen und die Therapieansätze des primären Offenwinkelglaukoms zukünftig erweitern und verbessern. Verglichen worden sind die Messergebnisse von 38 Patienten mit primärem Offenwinkelglaukom unter Therapie mit normalem Augeninnendruck mit den Messergebnissen von 38 gesunden Probanden. Das Gefäßverhalten wurde mit dem Retinal Vessel Analyzer erfasst und die so gewonnenen Rohdaten mittels der Fourier-Analyse, der Autokorrelationsanalyse und der Kreuzkorrelationsanalyse weiterberechnet. Die Patientengruppe wurde mit der Probandengruppe hinsichtlich Gefäßdurchmesser, Pulsamplitude, Oszillationsfrequenzen sowie den Quotienten zwischen myogenem und kardialem Gefäßverhalten verglichen. In der Gruppe der Glaukom-Patienten fanden sich signifikant größere Gefäßdurchmesser der gemessenen venösen Gefäßabschnitte (p<0,05). Die Frequenzen, die das Schwingungsverhalten von Arterien und Venen miteinander beschreiben, sind bei den Glaukom-Patienten signifikant niedriger als bei den Gesunden (p<0,01). Die Frequenzbereiche myogenen Ursprungs zeigen bei den Venen der Patientengruppe eine Störung des myogenen regulatorischen Gefäßverhaltens (p<0,05; p<0,01). Der Vergleich der Gefäßreaktionen kardialen Ursprungs mit den myogenen Gefäßreaktionen, zeigt eine Unterlegenheit der myogenen Gefäßreaktion gegenüber der kardialen Gefäßreaktion bei den venösen Gefäßen (p< 0,01; p<0,05). Die Pulsamplitude der Venen und der Arterien ist bei Glaukom-Patienten signifikant größer als bei den Gesunden. In dieser Arbeit wurde nachgewiesen, dass bei Glaukom-Patienten unter Therapie eine gestörte Regulation des myogenen Gefäßverhaltens retinaler Venen besteht. Weitere Studien sind notwendig um diese Pathomechanismen besser differenzieren zu können und um besser beurteilen zu können, ob das retinale Gefäßverhalten die mögliche Ursache oder die Folge eines primären Offenwinkelglaukoms ist bzw. in wie weit die Antiglaukomtherapie für die erhobenen Messergebnisse verantwortlich ist.Alterations of retinal vessels might affect the course of patients with primary open-angle glaucoma. However, there is a paucity of data investigating the relation between glaucoma and the prevalence of retinal vessels alterations. We relied on 38 primary open-angle glaucoma patients sufficiently treated for intraocular pressure, and 38 non-glaucoma patients. Retinal vessel alterations were assessed using the retinal vessel analyzer. The raw data has been calculated with Fourier-analysis, autocorrelation-analysis and cross-correlation-analysis. Differences according to vessel diameter, puls amplitude, frequences of oscillation behaviour, and the quotient of frequences according to myogenic vs. cardiac genisis in retinal vessels alterations were compared between primary open-angle glaucoma and non-glaucoma patients, respectively. The median venous vessel diameter was higher in primary open-angle glaucoma patients (p<0.05). Similarly, the median puls amplitude was significantly higer in primary open-angle glaucoma than in non-glaucoma patients (p<0.01). Additionally, the quotient of frequences according to myogenic vs. cardiac genisis in venous vessels was higher in primary open-angle glaucoma patients (p<0.01). Finally, primary open-angle glaucoma patients had significantly lower freuqences of oscillation behavior of venous retinal vessels than non-glaucoma patients (p<0.05). There was no diffrerence in the arterial retinal vessels between primary open-angle glaucoma patients and non-glaucoma patiens Primary open-angle glaucoma patients harboured significant alterations of retinal venous vessels compared to non-glaucoma patients. Further research is warranted to ascertain whether retinal vessel alterations are reason or result of primary open angle glaucoma resp. whether therapy of glaucoma is responsible for the current data

Functional alterations of the nigrostriatal dopamine system in estrogen receptor-α knockout (ERKO) mice

International audienceEstrogen represents an important factor for the development and function of the nigrostriatal dopamine system. Estrogen also controls sex-specific differentiation and activity of the nigrostriatal dopaminergic system. We used an estrogen receptor-alpha knockout (-/-) model (ERKO) to study the influence of this particular receptor subtype on the regulation of functional characteristics of the male and female nigrostriatal dopamine system. On the striatal level, we found a sex-specific regulation of dopamine D1 receptors (D1) and dopamine receptor-interacting protein 78 (Drip78). In female (-/-) mice D1 receptor expression levels were increased compared to wild type (wt) animals, whereas in male (-/-) mice Drip78 mRNA levels were decreased compared to wt. In the midbrain, expression of tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF) was reduced in (-/-) mice of both sexes. Glial cell line-derived neurotrophic factor (GDNF) expression was not affected. These data demonstrate that the integrity of estrogen receptor-alpha (ERalpha) signalling is necessary for the regulation of gene expression of proteins known to be important for the function of the nigrostriatal system at the postsynaptic striatal and presynaptic midbrain level