Wie Kochsalz Mitochondrien beeinflusst

Dietary high salt (HS) is a major risk factor for cardio-vascular and chronic inflammatory diseases. Sodium can increase postprandially but can also accumulate in diverse tissues. Immune cells, such as macrophages, sense this salty environment and adapt accordingly, shifting towards a more pro-inflammatory state. Mechanistically, HS inhibits complex II of the electron transport chain and thereby reduces mitochondrial function. In two independent clinical studies, an HS-diet transiently impaired human monocytic mitochondrial function

Centrality scaling in large networks

Betweenness centrality lies at the core of both transport and structural vulnerability properties of complex networks, however, it is computationally costly, and its measurement for networks with millions of nodes is near impossible. By introducing a multiscale decomposition of shortest paths, we show that the contributions to betweenness coming from geodesics not longer than L obey a characteristic scaling vs L, which can be used to predict the distribution of the full centralities. The method is also illustrated on a real-world social network of 5.5*10^6 nodes and 2.7*10^7 links

Tractable Pathfinding for the Stochastic On-Time Arrival Problem

We present a new and more efficient technique for computing the route that maximizes the probability of on-time arrival in stochastic networks, also known as the path-based stochastic on-time arrival (SOTA) problem. Our primary contribution is a pathfinding algorithm that uses the solution to the policy-based SOTA problem---which is of pseudo-polynomial-time complexity in the time budget of the journey---as a search heuristic for the optimal path. In particular, we show that this heuristic can be exceptionally efficient in practice, effectively making it possible to solve the path-based SOTA problem as quickly as the policy-based SOTA problem. Our secondary contribution is the extension of policy-based preprocessing to path-based preprocessing for the SOTA problem. In the process, we also introduce Arc-Potentials, a more efficient generalization of Stochastic Arc-Flags that can be used for both policy- and path-based SOTA. After developing the pathfinding and preprocessing algorithms, we evaluate their performance on two different real-world networks. To the best of our knowledge, these techniques provide the most efficient computation strategy for the path-based SOTA problem for general probability distributions, both with and without preprocessing.Comment: Submission accepted by the International Symposium on Experimental Algorithms 2016 and published by Springer in the Lecture Notes in Computer Science series on June 1, 2016. Includes typographical corrections and modifications to pre-processing made after the initial submission to SODA'15 (July 7, 2014

Investigating the role of GLUL as a survival factor in cellular adaptation to glutamine depletion via targeted stable isotope resolved metabolomics

Cellular glutamine synthesis is thought to be an important resistance factor in protecting cells from nutrient deprivation and may also contribute to drug resistance. The application of ‟targeted stable isotope resolved metabolomics” allowed to directly measure the activity of glutamine synthetase in the cell. With the help of this method, the fate of glutamine derived nitrogen within the biochemical network of the cells was traced. The application of stable isotope labelled substrates and analyses of isotope enrichment in metabolic intermediates allows the determination of metabolic activity and flux in biological systems. In our study we used stable isotope labelled substrates of glutamine synthetase to demonstrate its role in the starvation response of cancer cells. We applied (13)C labelled glutamate and (15)N labelled ammonium and determined the enrichment of both isotopes in glutamine and nucleotide species. Our results show that the metabolic compensatory pathways to overcome glutamine depletion depend on the ability to synthesise glutamine via glutamine synthetase. We demonstrate that the application of dual-isotope tracing can be used to address specific reactions within the biochemical network directly. Our study highlights the potential of concurrent isotope tracing methods in medical research

TIGIT expressing CD4+T cells represent a tumor-supportive T cell subset in chronic lymphocytic leukemia

While research on T cell exhaustion in context of cancer particularly focuses on CD8C cytotoxic T cells, the role of inhibitory receptors on CD4C T-helper cells have remained largely unexplored. TIGIT is a recently identified inhibitory receptor on T cells and natural killer (NK) cells. In this study, we examined TIGIT expression on T cell subsets from CLL patients. While we did not observe any differences in TIGIT expression in CD8C T cells of healthy controls and CLL cells, we found an enrichment of TIGITC T cells in the CD4C T cell compartment in CLL. Intriguingly, CLL patients with an advanced disease stage displayed elevated numbers of CD4C TIGITC T cells compared to low risk patients. Autologous CLL-T cell co-culture assays revealed that depleting CD4C TIGITC expressing T cells from co-cultures significantly decreased CLL viability. Accordingly, a supportive effect of TIGITCCD4C T cells on CLL cells in vitro could be recapitulated by blocking the interaction of TIGIT with its ligands using TIGIT-Fc molecules, which also impeded the T cell specific production of CLL-prosurvival cytokines. Our data reveal that TIGITCCD4CT cells provide a supportive microenvironment for CLL cells, representing a potential therapeutic target for CLL treatment

REG-γ associates with and modulates the abundance of nuclear activation-induced deaminase

REG-γ, a protein involved in protein degradation, binds to nuclear AID, and REG-γ–deficient B cells contain more AID and exhibit increased immunoglobulin class switching

A complex hepatitis B virus (X/C) recombinant is common in Long An county, Guangxi and may have originated in southern China

Recently, a complex (X/C) hepatitis B virus (HBV) recombinant, first reported in 2000, was proposed as a new genotype; although this was refuted immediately because the strains differ by less than 8 % in nucleotide distance from genotype C. Over 13.5 % (38/281) of HBV isolates from the Long An cohort in China were not assigned to a specific genotype, using current genotyping tools to analyse surface ORF sequences, and these have about 98 % similarity to the X/C recombinants. To determine whether this close identity extends to the full-length sequences and to investigate the evolutionary history of the Long An X/C recombinants, 17 complete genome sequences were determined. They are highly similar (96–99 %) to the Vietnamese strains and, although some reach or exceed 8 % nucleotide sequence difference from all known genotypes, they cluster together in the same clade, separating in a phylogenetic tree from the genotype C branch. Analysis of recombination reveals that all but one of the Long An isolates resembles the Vietnamese isolates in that they result from apparent recombination between genotype C and a parent of unknown genotype (X), which shows similarity in part to genotype G. The exception, isolate QL523, has a greater proportion of genotype C parent. Phylogeographic analysis reveals that these recombinants probably arose in southern China and spread later to Vietnam and Laos

Unlocking value from machines: business models and the industrial internet of things

In this article we argue that the Industrial Internet of Things (IIoT) offers new opportunities and harbors threats that companies are not able to address with existing business models. Entrepreneurship and Transaction Cost Theories are used to explore the conditions for designing nonownership business models for the emerging IIoT with its implications for sharing uncertain opportunities and downsides, and for transforming these uncertainties into business opportunities. Nonownership contracts are introduced as the basis for business model design and are proposed as an architecture for the productive sharing of uncertainties in IIoT manufacturing networks. The following three main types of IIoT-enabled business models were identified: (1) Provision of manufacturing assets, maintenance and repair, and their operation, (2) innovative information and analytical services that help manufacturing (e.g., based on artificial intelligence, big data, and analytics), and (3) new services targeted at end-users (e.g., offering efficient customization by integrating end-users into the manufacturing and supply chain ecosystem)

HPK1 Associates with SKAP-HOM to Negatively Regulate Rap1-Mediated B-Lymphocyte Adhesion

BACKGROUND: Hematopoietic progenitor kinase 1 (HPK1) is a Ste20-related serine/threonine kinase activated by a range of environmental stimuli including genotoxic stress, growth factors, inflammatory cytokines and antigen receptor triggering. Being inducibly recruited to membrane-proximal signalling scaffolds to regulate NFAT, AP-1 and NFkappaB-mediated gene transcription in T-cells, the function of HPK1 in B-cells to date remains rather ill-defined. METHODOLOGY/PRINCIPAL FINDINGS: By using two loss of function models, we show that HPK1 displays a novel function in regulating B-cell integrin activity. Wehi 231 lymphoma cells lacking HPK1 after shRNA mediated knockdown exhibit increased basic activation levels of Ras-related protein 1 (Rap1), accompanied by a severe lymphocyte function-associated antigen-1 (LFA-1) dependent homotypic aggregation and increased adhesion to intercellular adhesion molecule 1 (ICAM-1). The observed phenotype of enhanced integrin activity is caused downstream of Src, by a signalling module independent of PI3K and PLC, involving HPK1, SKAP55 homologue (SKAP-HOM) and Rap1-GTP-interacting adaptor molecule (RIAM). This alters actin dynamics and renders focal adhesion kinase (FAK) constitutively phosphorylated. Bone marrow and splenic B-cell development of HPK1(-/-) mice are largely unaffected, except age-related tendencies for increased splenic cellularity and BCR downregulation. In addition, naïve splenic knockout B-cells appear hyperresponsive to a range of stimuli applied ex vivo as recently demonstrated by others for T-cells. CONCLUSIONS/SIGNIFICANCE: We therefore conclude that HPK1 exhibits a dual function in B-cells by negatively regulating integrin activity and controlling cellular activation, which makes it an interesting candidate to study in pathological settings like autoimmunity and cancer