60 research outputs found
The Impact of Various Reactive Oxygen Species on the Formation of Neutrophil Extracellular Traps
The formation of neutrophil extracellular traps (NETs) depends on the generation of reactive oxygen species (ROS). Previous studies revealed that both NADPH oxidase and myeloperoxidase (MPO) are required for NET release. However, the contribution of various ROS as well as the role of mitochondria-derived ROS has not been addressed so far. In the present study we aimed to investigate in a systematic and comprehensive manner the contribution of various ROS and ROS-generating pathways to the PMA-induced NET release. By using specific inhibitors, the role of both NADPH oxidase- and mitochondria-derived ROS as well as the contribution of superoxide dismutase (SOD) and MPO on the NET release was assessed. We could demonstrate that NADPH oxidase function is crucial for the formation of NETs. In addition, we could clearly show the involvement of MPO-derived ROS in NET release. Our results, however, did not provide evidence for the role of SOD- or mitochondria-derived ROS in NET formation
Low daily dose of 3 mg monacolin K from RYR reduces the concentration of LDL-C in a randomized, placebo-controlled intervention
AbstractHypercholesterolemia and elevated homocysteine concentrations are associated with cardiovascular risk. Previous studies have demonstrated a cholesterol-lowering effect of red yeast rice (RYR) supplements which contained 5 to 10 mg of monacolin K. We hypothesized that the intake of a low monacolin K dose may likewise reduce low-density lipoproteinâcholesterol (LDL-C) and other plasma lipids. In secondary analyses, we tested the homocysteine lowering effect of folic acid, which was also included in the study preparation. Therefore, we conducted a randomized, double-blind, and placebo-controlled intervention study. One hundred forty-two nonstatin-treated participants with hypercholesterolemia (LDL-C â„ 4.14 †5.69 mmol/L) were randomized to the supplement group with RYR or the placebo group. Participants of the supplement group consumed 3 mg monacolin K and 200 ÎŒg folic acid per day. A significant (P < .001) reduction of LDL-C (â14.8%), total cholesterol (â11.2%), and homocysteine (â12.5%) was determined in the supplement group after 12 weeks. A total of 51% of the participants treated with RYR achieved the limit of LDL-C <4.14 mmol/L advised and 26% reached the threshold level of homocysteine <10 ÎŒmol/L. No significant changes were exhibited within the placebo group. Other parameters remained unchanged and no intolerances or serious adverse events were observed. In conclusion, we demonstrated that a low dose of daily 3 mg monacolin K from RYR reduces the concentration of LDL-C; a risk factor for cardiovascular diseases
Initiation of Pancreatic Cancer: The Interplay of Hyperglycemia and Macrophages Promotes the Acquisition of Malignancy-Associated Properties in Pancreatic Ductal Epithelial Cells
Pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive solid malignancies with a poor prognosis. Obesity and type 2 diabetes mellitus (T2DM) are two major risk factors linked to the development and progression of PDAC, both often characterized by high blood glucose levels. Macrophages represent the main immune cell population in PDAC contributing to PDAC development. It has already been shown that pancreatic ductal epithelial cells (PDEC) undergo epithelial-mesenchymal transition (EMT) when exposed to hyperglycemia or macrophages. Thus, this study aimed to investigate whether concomitant exposure to hyperglycemia and macrophages aggravates EMT-associated alterations in PDEC. Exposure to macrophages and elevated glucose levels (25 mM glucose) impacted gene expression of EMT inducers such as IL-6 and TNF-α as well as EMT transcription factors in benign (H6c7-pBp) and premalignant (H6c7-kras) PDEC. Most strikingly, exposure to hyperglycemic coculture with macrophages promoted downregulation of the epithelial marker E-cadherin, which was associated with an elevated migratory potential of PDEC. While blocking IL-6 activity by tocilizumab only partially reverted the EMT phenotype in H6c7-kras cells, neutralization of TNF-α by etanercept was able to clearly impair EMT-associated properties in premalignant PDEC. Altogether, the current study attributes a role to a T2DM-related hyperglycemic, inflammatory micromilieu in the acquisition of malignancy-associated alterations in premalignant PDEC, thus providing new insights on how metabolic diseases might promote PDAC initiation
Simulation-based model selection for dynamical systems in systems and population biology
Computer simulations have become an important tool across the biomedical
sciences and beyond. For many important problems several different models or
hypotheses exist and choosing which one best describes reality or observed data
is not straightforward. We therefore require suitable statistical tools that
allow us to choose rationally between different mechanistic models of e.g.
signal transduction or gene regulation networks. This is particularly
challenging in systems biology where only a small number of molecular species
can be assayed at any given time and all measurements are subject to
measurement uncertainty. Here we develop such a model selection framework based
on approximate Bayesian computation and employing sequential Monte Carlo
sampling. We show that our approach can be applied across a wide range of
biological scenarios, and we illustrate its use on real data describing
influenza dynamics and the JAK-STAT signalling pathway. Bayesian model
selection strikes a balance between the complexity of the simulation models and
their ability to describe observed data. The present approach enables us to
employ the whole formal apparatus to any system that can be (efficiently)
simulated, even when exact likelihoods are computationally intractable.Comment: This article is in press in Bioinformatics, 2009. Advance Access is
available on Bioinformatics webpag
Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (âMISEVâ) guidelines for the field in 2014. We now update these âMISEV2014â guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points
Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study
Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008â11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003â13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 Ă 10â10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 Ă 10â8 DHFR p=8·37 Ă 10â7 MTRNR2L2 p=2·15 Ă 10â9) and to a lesser extent in REGISTRY (MSH3 p=9·36 Ă 10â4 DHFR p=8·45 Ă 10â4 MTRNR2L2 p=1·20 Ă 10â3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 Ă 10â8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16â0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06â0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation
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
"Bara vi andas sÄ pÄverkar vi" : En kvalitativ studie om pedagogers upplevelser av utanförskap i förskolan
Syftet med den genomförda studien Àr att synliggöra pedagogers uppfattningar och erfarenheter samt olika metoder, i arbetet med att motverka och förebygga utanförskap i förskolan. En kvalitativ studie har genomförts dÀr Ätta stycken intervjuer med barnskötare och förskollÀrare Àr utgÄngspunkten. UtifrÄn genomförda intervjuer och tidigare forskning gÄr det att dra slutsatsen att pedagogers förhÄllningssÀtt och metoder har stor pÄverkan pÄ hur utanförskap uppstÄr, motverkas och förebyggs. I samtliga intervjuer berÀttar pedagogerna om deras uppfattningar av vad ett utanförskap kan vara, och vad som kan vara anledningar till ett utanförskap. Det framgÄr att ett utanförskap kan förstÄs som situationer dÄ ett barn blir aktivt avvisat, och situationer dÄ ett barn frivilligt distanserar sig frÄn resten av gruppen. Anledningar till att ett utanförskap uppkommer förstÄs vara dÄ det finns spÀnningar mellan barns sociala resurser och kontext, samt bero pÄ försummande frÄn pedagogernas sida. Pedagogerna berÀttar Àven om olika metoder som gÄr att anvÀnda i arbetet med att förebygga och motverka utanförskap. De olika metoderna har i studien sammanstÀllts i kategorierna; övningar och kartlÀggningar, temaarbeten och gruppstÀrkande material, sprÄkutvecklande aktiviteter, stödjande och rollstÀrkande metoder, och normkritiskt tÀnkande och samsyn. I studiens diskussionskapitel relateras resultatet till tidigare forskning, och eventuella didaktiska konsekvenser som kan uppstÄ för yrkesutövningen belyses
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