Abstract
Atherothrombosis is a frequent cause of cardiovascular mortality. It is mostly triggered by plaque rupture and exposure of the thrombogenic subendothelial matrix, which initiates platelet ...aggregation and clot formation. Current antithrombotic strategies, however, target both thrombosis and physiological hemostasis and thereby increase bleeding risk. Thus, there is an unmet clinical need for optimized therapies. Neutrophil activation and consecutive interactions of neutrophils and platelets contribute mechanistically to thromboinflammation and arterial thrombosis, and thus present a potential therapeutic target. Platelet–neutrophil interactions are mediated through adhesion molecules such as P-selectin and P-selectin glycoprotein ligand 1 as well as glycoprotein Ib and macrophage-1 antigen, which mediate physical cell interactions and intracellular signaling. Release of soluble mediators as well as direct signaling between platelets and neutrophils lead to their reciprocal activation and neutrophil release of extracellular traps, scaffolds of condensed chromatin that play a prothrombotic role in atherothrombosis. In this article, we review the role of neutrophils and neutrophil-derived prothrombotic molecules in platelet activation and atherothrombosis, and highlight potential therapeutic targets.
Constraint-based modeling is a widely used and powerful methodology to assess the metabolic phenotypes and capabilities of an organism. The starting point and cornerstone of all such modeling is a ...genome-scale metabolic network reconstruction. The creation, further development, and application of such networks is a growing field of research thanks to a plethora of readily accessible computational tools. While the majority of studies are focused on single-species analyses, typically of a microbe, the computational study of communities of organisms is gaining attention. Similarly, reconstructions that are unified for a multi-cellular organism have gained in popularity. Consequently, the rapid generation of genome-scale metabolic reconstructed networks is crucial. While multiple web-based or stand-alone tools are available for automated network reconstruction, there is, however, currently no publicly available tool that allows the swift assembly of draft reconstructions of community metabolic networks and consolidated metabolic networks for a specified list of organisms.
Here, we present AutoKEGGRec, an automated tool that creates first draft metabolic network reconstructions of single organisms, community reconstructions based on a list of organisms, and finally a consolidated reconstruction for a list of organisms or strains. AutoKEGGRec is developed in Matlab and works seamlessly with the COBRA Toolbox v3, and it is based on only using the KEGG database as external input. The generated first draft reconstructions are stored in SBML files and consist of all reactions for a KEGG organism ID and corresponding linked genes. This provides a comprehensive starting point for further refinement and curation using the host of COBRA toolbox functions or other preferred tools. Through the data structures created, the tool also facilitates a comparative analysis of metabolic content in any given number of organisms present in the KEGG database.
AutoKEGGRec provides a first step in a metabolic network reconstruction process, filling a gap for tools creating community and consolidated metabolic networks. Based only on KEGG data as external input, the generated reconstructions consist of data with a directly traceable foundation and pedigree. With AutoKEGGRec, this kind of modeling is made accessible to a wider part of the genome-scale metabolic analysis community.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Approaches for systematizing information of relatedness between organisms is important in biology. Phylogenetic analyses based on sets of highly conserved genes are currently the basis for the Tree ...of Life. Genome-scale metabolic reconstructions contain high-quality information regarding the metabolic capability of an organism and are typically restricted to metabolically active enzyme-encoding genes. While there are many tools available to generate draft reconstructions, expert-level knowledge is still required to generate and manually curate high-quality genome-scale metabolic models and to fill gaps in their reaction networks. Here, we use the tool AutoKEGGRec to construct 975 genome-scale metabolic draft reconstructions encoded in the KEGG database without further curation. The organisms are selected across all three domains, and their metabolic networks serve as basis for generating phylogenetic trees. We find that using all reactions encoded, these metabolism-based comparisons give rise to a phylogenetic tree with close similarity to the Tree of Life. While this tree is quite robust to reasonable levels of noise in the metabolic reaction content of an organism, we find a significant heterogeneity in how much noise an organism may tolerate before it is incorrectly placed in the tree. Furthermore, by using the protein sequences for particular metabolic functions and pathway sets, such as central carbon-, nitrogen-, and sulfur-metabolism, as basis for the organism comparisons, we generate highly specific phylogenetic trees. We believe the generation of phylogenetic trees based on metabolic reaction content, in particular when focused on specific functions and pathways, could aid the identification of functionally important metabolic enzymes and be of value for genome-scale metabolic modellers and enzyme-engineers.
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Excessive workload may impair patient safety. However, little is known about emergency care providers' workload during the treatment of life-threatening cases including cardiopulmonary resuscitation ...(CPR). Therefore, we tested the hypothesis that subjective and physiological indicators of workload are associated with the patient's initial NACA score and that workload is particularly high during CPR.
NASA task load index (NASA-tlx) and alarm codes were obtained for 216 sorties of pre-hospital emergency medical care. Furthermore, initial NACA scores of 140 patients were extracted from the physicians' protocols. The physiological workload indicators mean heart rate (HR) and permutation entropy (PeEn) were calculated for 51 sorties of primary care. General linear mixed models were used to analyze the association of NACA scores with subjective (NASA-tlx) and physiological (mean HR, PeEn) measures of workload.
In contrast to the physiological variables PeEn (p = 0.10) and HR (p = 0.19), the mental (p<0.001) and temporal demands (p<0.001) as well as the effort (p<0.001) and frustration (p = 0.04) subscale of the NASA-tlx were significantly associated with initial NACA scores. Compared to NACA = I, an initial NACA score of VI (representing CPR) increased workload by a mean of 389.5% (p = 0.001) in the mental and 345.9% (p<0.001) in the temporal demands, effort by a mean of 446,8% (p = 0.002) and frustration by 190.0% (p = 0.03). In line with the increase in NASA-tlx, PeEn increased by 20.6% (p = 0.01) and HR by 6.4% (p = 0.57).
Patients' initial NACA scores are associated with subjective workload. Workload was highest during CPR.
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Cities around the world have launched greening initiatives to reduce their carbon footprint and to become more sustainable. At the same time, they have also sought to use these initiatives to ...position themselves as climate change leaders and green champions. This paper focuses on the City of Vancouver's Greenest City 2020 Action Plan as urban policy strategy to reduce carbon emissions. Based on interviews with actors and experts involved in the development and implementation of the plan, the paper evaluates the role green leadership aspirations play in shaping urban climate change policy and how policy makers and stakeholders use policy to position the city and its greening initiatives locally and globally. In particular, it analyzes the role of competitive positioning and green leadership in sustainability initiatives and change within and beyond urban boundaries. While leadership suggests increased buy-in of residents and those involved in the implementation of the strategy and multiplication effects through learning within the region and between (peer) cities, it can also pose challenges as the interest in meeting leadership claims can impede more radical change through specific targets and implementation strategies and challenge other sustainability objectives.
•Some cities seek to position themselves as climate change leaders and green champions.•Vancouver is peculiarly positioned for greening.•Green leadership aspirations play an increasing role in shaping urban climate change policy and outcomes.•Policy makers and stakeholders use this policy to position the city and its greening initiatives locally and globally.•The competitive positioning and green leadership shows both benefits and limitations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The microbiome varies along the human gastrointestinal (GI) tract with exposure to luminal and mucosal factors. We analyzed active bacterial communities at 8 locations along the GI tract using ...high-throughput sequencing techniques.
We collected saliva, mucosal, and fecal samples from healthy adults (10 men and 11 women; mean age, 59 ± 12.3 years) who underwent upper and lower GI tract endoscopy in Germany from December 2015 through September 2016. Biopsies were taken from stomach, antrum, corpus, duodenum, terminal ileum, ascending colon, and descending colon. RNA was extracted from all samples and reverse transcribed into complementary DNA; V1–V2 regions of 16S ribosomal RNA genes were amplified and sequenced on an Illumina MiSeq platform. Abundances of the taxa in all taxonomic ranks in each sample type were used to construct sample-similarity matrices with the Bray-Curtis algorithm. Significant differences between a priori–defined groups were evaluated using analysis of similarity.
After taxonomic annotation, 4045 phylotypes, belonging to 169 genera and 14 different phyla, were identified. Each subject had a different bacterial community. We identified distinct microbial consortia in saliva, upper GI tract, lower GI tract, and fecal samples. The predominant genera in the upper GI tract (Gemella, Veillonella, Neisseria, Fusobacterium, Streptococcus, Prevotella, Pseudomonas, and Actinomyces) were almost absent from the lower GI tract, where the microbial communities mainly comprised Faecalibacterium, Ruminococcus, and Bacteroides. The bacterial communities in the upper GI tract were characterized by greater richness and heterogeneity (measured by the Shannon index) than those in the lower GI tract. We detected Helicobacter pylori in only the upper GI tract.
In an analysis of saliva, mucosal, and fecal samples from 21 healthy adults, we found each individual, and each GI region, to have a different bacterial community. The fecal microbiome is not representative of the mucosal microbiome. We propose a systematic method to analyze the bacterial communities of the GI tract.
Abstract
Background
Assessment of the disease activity in inflammatory bowel disease (IBD) is essential for adequate treatment management and reliable noninvasive biomarkers for verification of ...mucosal healing are still needed. MicroRNAs (miRNAs) are differentially expressed in IBD and cancer. We aimed to evaluate the potential of circulating and fecal miRNAs as diagnostic biomarkers for IBD.
Methods
In this proof-of-principle study we used 2 independent patient cohorts. Testing cohort (n = 96) included serum and fecal samples from controls (n = 35) and IBD patients (n = 61) including 43 patients with Crohn′s disease (CD), 18 with ulcerative colitis (UC) with an active disease (n = 38), or in remission (n = 23). Validation cohort included fecal samples from patients with calprotectin/endoscopy-confirmed active disease (n = 30) or in remission (n = 15). Target-based approach (miR-16, miR-21, miR-155, and miR-223) has been used to evaluate miRNA expression.
Results
Sera samples from IBD patients showed higher level of miR-16, miR-21, and miR-223, but not miR-155, compared to controls and was higher in CD than in UC patients. Much stronger miRNA expression changes were observed in feces from IBD patients for all studied miRNAs with highest expression of miR-155 and miR-223 in testing and validation cohorts. MiRNA expression correlated with clinical remission, however, only fecal but not circulating miRNAs, correlated with surrogate parameters such as fecal calprotectin or C-reactive protein.
Conclusions
Our data provide a novel evidence for differential expression level of fecal miRNAs in IBD. We demonstrate that miRNAs in feces correlate with disease activity and may be considered as potential tool for the further biomarker research in IBD.
10.1093/ibd/izy046_video1
izy046.video1
5794822319001
High-Quality Shared-Memory Graph Partitioning Akhremtsev, Yaroslav; Sanders, Peter; Schulz, Christian
IEEE transactions on parallel and distributed systems,
11/2020, Volume:
31, Issue:
11
Journal Article
Peer reviewed
Open access
Partitioning graphs into blocks of roughly equal size such that few edges run between blocks is a frequently needed operation in processing graphs. Recently, size, variety, and structural complexity ...of these networks has grown dramatically. Unfortunately, previous approaches to parallel graph partitioning have problems in this context since they often show a negative trade-off between speed and quality. We present an approach to multi-level shared-memory parallel graph partitioning that produces balanced solutions, shows high speedups for a variety of large graphs and yields very good quality independently of the number of cores used. For example, in an extensive experimental study, at 79 cores, one of our closest competitors is faster but fails to meet the balance criterion in the majority of cases and another is mostly slower and incurs about 13 percent larger cut size. Important ingredients include parallel label propagation for both coarsening and refinement, parallel initial partitioning, a simple yet effective approach to parallel localized local search, and fast locality preserving hash tables.
Testicular macrophages (TM) comprise the largest immune cell population in the mammalian testis. They are characterized by a subdued proinflammatory response upon adequate stimulation, and a ...polarization toward the immunoregulatory and immunotolerant M2 phenotype. This enables them to play a relevant role in supporting the archetypical functions of the testis, namely spermatogenesis and steroidogenesis. During infection, the characteristic blunted immune response of TM reflects the need for a delicate balance between a sufficiently strong reaction to counteract invading pathogens, and the prevention of excessive proinflammatory cytokine levels with the potential to disturb or destroy spermatogenesis. Local microenvironmental factors that determine the special phenotype of TM have just begun to be unraveled, and are discussed in this review.
The immunosuppressive M2 macrophage phenotype of testicular macrophages is determined by the testicular microenvironment to maintain the immune privilege of the testis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Flux balance analysis (FBA) remains one of the most used methods for modeling the entirety of cellular metabolism, and a range of applications and extensions based on the FBA framework have been ...generated. Dynamic flux balance analysis (dFBA), the expansion of FBA into the time domain, still has issues regarding accessibility limiting its widespread adoption and application, such as a lack of a consistently rigid formalism and tools that can be applied without expert knowledge. Recent work has combined dFBA with enzyme-constrained flux balance analysis (decFBA), which has been shown to greatly improve accuracy in the comparison of computational simulations and experimental data, but such approaches generally do not take into account the fact that altering the enzyme composition of a cell is not an instantaneous process. Here, we have developed a decFBA method that explicitly takes enzyme change constraints (ecc) into account, decFBAecc. The resulting software is a simple yet flexible framework for using genome-scale metabolic modeling for simulations in the time domain that has full interoperability with the COBRA Toolbox 3.0. To assess the quality of the computational predictions of decFBAecc, we conducted a diauxic growth fermentation experiment with Escherichia coli BW25113 in glucose minimal M9 medium. The comparison of experimental data with dFBA, decFBA and decFBAecc predictions demonstrates how systematic analyses within a fixed constraint-based framework can aid the study of model parameters. Finally, in explaining experimentally observed phenotypes, our computational analysis demonstrates the importance of non-linear dependence of exchange fluxes on medium metabolite concentrations and the non-instantaneous change in enzyme composition, effects of which have not previously been accounted for in constraint-based analysis.
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