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Based on accumulating evidence of a role of lipid signaling in many physiological and pathophysiological processes including psychiatric diseases, the present data driven analysis was designed to gather information needed to develop a prospective biomarker, using a targeted lipidomics approach covering different lipid mediators. Using unsupervised methods of data structure detection, implemented as hierarchal clustering, emergent self-organizing maps of neuronal networks, and principal component analysis, a cluster structure was found in the input data space comprising plasma concentrations of d = 35 different lipid-markers of various classes acquired in n = 94 subjects with the clinical diagnoses depression, bipolar disorder, ADHD, dementia, or in healthy controls. The structure separated patients with dementia from the other clinical groups, indicating that dementia is associated with a distinct lipid mediator plasma concentrations pattern possibly providing a basis for a future biomarker. This hypothesis was subsequently assessed using supervised machine-learning methods, implemented as random forests or principal component analysis followed by computed ABC analysis used for feature selection, and as random forests, k-nearest neighbors, support vector machines, multilayer perceptron, and naïve Bayesian classifiers to estimate whether the selected lipid mediators provide sufficient information that the diagnosis of dementia can be established at a higher accuracy than by guessing. This succeeded using a set of d = 7 markers comprising GluCerC16:0, Cer24:0, Cer20:0, Cer16:0, Cer24:1, C16 sphinganine, and LacCerC16:0, at an accuracy of 77%. By contrast, using random lipid markers reduced the diagnostic accuracy to values of 65% or less, whereas training the algorithms with randomly permuted data was followed by complete failure to diagnose dementia, emphasizing that the selected lipid mediators were display a particular pattern in this disease possibly qualifying as biomarkers.
Compartmentalization of immune response and microbial translocation in decompensated cirrhosis
(2019)
Background: Acquired dysfunctional immunity in cirrhosis predisposes patients to frequent bacterial infections, especially spontaneous bacterial peritonitis (SBP), leading to systemic inflammation that is associated with poor outcome. But systemic inflammation can also be found in the absence of a confirmed infection. Detection of bacterial DNA has been investigated as a marker of SBP and as a predictor of prognosis. Data is, however, contradictory. Here we investigated whether levels of IL-6 and IL-8 putatively produced by myeloid cells in ascites are associated with systemic inflammation and whether inflammation depends on the presence of specific bacterial DNA.
Methods and Materials: We enrolled 33 patients with decompensated liver cirrhosis from whom we collected paired samples of blood and ascites. IL-6 and IL-8 were measured in serum samples of all patients using ELISA. In a subset of 10 representative patients, bacterial DNA was extracted from ascites and whole blood, followed by 16S rRNA gene amplicon sequencing.
Results: There were significantly higher levels of IL-6 in ascites fluid compared to blood samples in all patients. Interestingly, IL-6 levels in blood correlated tightly with disease severity and surrogates of systemic inflammation, while IL-6 levels in ascites did not. Moreover, patients with higher blood CRP levels showed greater SBP prevalence compared to patients with lower levels, despite similar positive culture results. Bacterial richness was also significantly higher in ascites compared to the corresponding patient blood. We identified differences in microbial composition and diversity between ascites and blood, but no tight relationship with surrogates of systemic inflammation could be observed.
Discussion: In decompensated cirrhosis, markers of systemic inflammation and microbiota composition seem to be dysregulated in ascites and blood. While a relationship between systemic inflammation and microbiota composition seems to exist in blood, this is not the case for ascites in our hands. These data may suggest compartmentalization of the immune response and interaction of the latter with the microbiota especially in the blood compartment.
In this article, we explore civil society mobilisation and the impact of organised interests on the energy policies of two post-communist countries—Hungary and Czechia—and specifically nuclear energy. Drawing on numerous hypotheses from the literature on organised interests, we explore how open both political systems are for civil society input and what interest group-specific and socio-economic factors mediate the influence of organised interests. Based on the preference attainment method, our case studies focus on the extent to which organised interests have succeeded bringing nuclear energy legislation in line with their preferences. We find that while both democracies are open to civil society input, policy-making is generally conducted in state-industrial circles, whereby anti-nuclear and renewable energy advocates are at best able to make minor corrections to already pre-determined policies.
From the colour glass condensate to filamentation: systematics of classical Yang–Mills theory
(2019)
The non-equilibrium early time evolution of an ultra-relativistic heavy ion collision is often described by classical lattice Yang–Mills theory, starting from the colour glass condensate (CGC) effective theory with an anisotropic energy momentum tensor as initial condition. In this work we investigate the systematics associated with such studies and their dependence on various model parameters (IR, UV cutoffs and the amplitude of quantum fluctuations) which are not yet fixed by experiment. We perform calculations for SU() and SU(), both in a static box and in an expanding geometry. Generally, the dependence on model parameters is found to be much larger than that on technical parameters like the number of colours, boundary conditions or the lattice spacing. In a static box, all setups lead to isotropisation through chromo-Weibel instabilities, which is illustrated by the accompanying filamentation of the energy density. However, the associated time scale depends strongly on the model parameters and in all cases is longer than the phenomenologically expected one. In the expanding system, no isotropisation is observed for any parameter choice. We show how investigations at fixed initial energy density can be used to better constrain some of the model parameters.
Retrophylogenomics in rorquals indicate large ancestral population sizes and a rapid radiation
(2019)
Background: Baleen whales (Mysticeti) are the largest animals on earth and their evolutionary history has been studied in detail, but some relationships still remain contentious. In particular, reconstructing the phylogenetic position of the gray whales (Eschrichtiidae) has been complicated by evolutionary processes such as gene flow and incomplete lineage sorting (ILS). Here, whole-genome sequencing data of the extant baleen whale radiation allowed us to identify transposable element (TE) insertions in order to perform phylogenomic analyses and measure germline insertion rates of TEs. Baleen whales exhibit the slowest nucleotide substitution rate among mammals, hence we additionally examined the evolutionary insertion rates of TE insertions across the genomes.
Results: In eleven whole-genome sequences representing the extant radiation of baleen whales, we identified 91,859 CHR-SINE insertions that were used to reconstruct the phylogeny with different approaches as well as perform evolutionary network analyses and a quantification of conflicting phylogenetic signals. Our results indicate that the radiation of rorquals and gray whales might not be bifurcating. The morphologically derived gray whales are placed inside the rorqual group, as the sister-species to humpback and fin whales. Detailed investigation of TE insertion rates confirm that a mutational slow down in the whale lineage is present but less pronounced for TEs than for nucleotide substitutions.
Conclusions: Whole genome sequencing based detection of TE insertions showed that the speciation processes in baleen whales represent a rapid radiation. Large genome-scale TE data sets in addition allow to understand retrotransposition rates in non-model organisms and show the potential for TE calling methods to study the evolutionary history of species.
Background: Approximately 90% of German surface waters do not meet the objectives of the European Water Framework Directive (EU-WFD). This is primarily due to deficits in water body structure and biological quality components, which in turn are negatively affected by chemical pollution. In this context, hydromorphological restoration measures have often been conducted to improve habitat and species diversity and, therefore, the ecological status of water bodies. However, habitat improvement is not necessarily accompanied by biota enhancement and thus by the improvement of the ecological status of rivers. To prioritize water management measures, decision criteria for the water management practice are necessary, which enable the prognosis, whether chemical pollution and its resulting effects or other factors, such as structural deficits of the water bodies, are the main cause for the failure to meet the objective of a good ecological status.
Results: To address this need, we applied the freshwater mudsnail Potamopyrgus antipodarum and the amphipod Gammarus fossarum in active monitoring campaigns and in laboratory experiments with combined water/sediment samples and analyzed water and sediment samples with in vitro assays quarterly over the course of 1 year to provide evidence and guideline to assess if chemical contamination is a relevant stress factor for the aquatic biodiversity in rivers of the Nidda catchment (Hessen, Germany). On the basis of these results, an ecotoxicological, WFD–compliant assessment system was developed which, in comparison with the ecological status classes of the EU-WFD, permits the identification of the probable causes for the failure to meet the objectives of the EU-WFD. From these findings, recommendations for action were derived for the implementation of priority measures in water management practice. For the rivers Nidda, Usa, and Horloff, we identified a need for action to improve water and sediment quality at all investigated sampling sites except for the reference sites in the headwaters. The ecotoxicological assessment system also highlighted that hydromorphological restoration measures on their own will not lead to a good ecological status of rivers, as long as water and sediment quality are deficient.
Conclusion: Hydromorphological restoration measures should be performed in conjunction with measures to reduce chemical contamination to achieve a good ecological status of the rivers Nidda, Usa, and Horloff.
Background: By performing case management, general practitioners and health care assistants can provide additional benefits to their chronically ill patients. However, the economic effects of such case management interventions often remain unclear although how to manage the burden of chronic disease is a key question for policy-makers. This analysis aimed to compare the cost-effectiveness of 24 months of primary care case management for patients with a long-term indication for oral anticoagulation therapy with usual care.
Methods: This analysis is part of the cluster-randomized controlled Primary Care Management for Optimized Antithrombotic Treatment (PICANT) trial. A sample of 680 patients with German statutory health insurance was initially considered for the cost analysis (92% of all participants at baseline). Costs included all disease-related direct health care costs from the payer’s perspective (German statutory health insurers) plus case management costs for the intervention group. A-Quality Adjusted Life Year (QALY) measurement (EQ-5D-3 L instrument) was used to evaluate utility, and incremental cost-effectiveness ratio (ICER) to assess cost-effectiveness. Mean differences were calculated and displayed with 95%-confidence intervals (CI) from non-parametric bootstrapping (1000 replicates).
Results: N = 505 patients (505/680, 74%) were included in the cost analysis (complete case analysis with a follow-up after 12 and 24 months as well as information on cost and QALY). After two years, the mean difference of direct health care costs per patient (€115, 95% CI [− 201; 406]) and QALYs (0.03, 95% CI [− 0.04; 0.11]) in the two groups was small and not significant. The costs of case management in the intervention group caused mean total costs per patient in this group to rise significantly (mean difference €503, 95% CI [188; 794]). The ICER was €16,767 per QALY. Regardless of the willingness of insurers to pay per QALY, the probability of the intervention being cost-effective never rose above 70%.
Conclusions: A primary care case management for patients with a long-term indication for oral anticoagulation therapy improved QALYs compared to usual care, but was more costly. However, the results may help professionals and policy-makers allocate scarce health care resources in such a way that the overall quality of care is improved at moderate costs, particularly for chronically ill patients.
Trial registration: Current Controlled Trials ISRCTN41847489.
Change ahead—emerging life-course transitions as practical accomplishments of growing old(er)
(2019)
With the aging of the "Baby Boomer" cohort, more and more adults are transiting from work into retirement. In public discourse, this development is framed as one of the major challenges of today's welfare societies. To develop social innovations that consider the everyday lives of older people requires a deeper theoretical understanding of the retiring process. In age studies, retiring has been approached from various theoretical perspectives, most prominently disengagement perspectives (retirement as the withdrawal from social roles and responsibilities) and rational choice perspectives (retiring as a rational decision based on incentives and penalties). Whereas, the former have been accused of promoting a deficient image of aging, the latter are criticized for concealing the socially stratified constraints older people experience. This paper proposes a practice-theoretical perspective on retiring, understanding it as a processual, practical accomplishment that involves various social practices, sites, and human, as well as non-human, actors. To exemplify this approach, I draw upon data from the project "Doing Retiring" that follows 30 older adults in Germany from 1 year before to 3 years after retirement. Results depict retiring as a complex process of change, assembled by social practices that are scattered across time, space, and carriers. Practice sequences and constellations differ significantly between older adults who retire expectedly and unexpectedly, for example through sudden job loss or illness. However, even among those who envisaged retiring "on their own terms," the agency to retire was distributed across the network of employers, retirement schemes, colleagues, laws, families, workplaces, bodies and health, and the future retiree themselves. Results identified a distinct set of sequentially organized practices that were temporally and spatially configured. Many study participants expressed an idea about a "right time to retire" embedded in the imagination of a chrononormative life-course, and they often experienced spatio-temporal withdrawal from the workplace (e.g., reduction of working hours) which entailed affective disengagement from work as well. In conclusion, a practice-theoretical perspective supports social innovations that target more than just the retiring individual.
In this paper, we investigate whether timing in monolingual acquisition interacts with age of onset and input effects in child bilingualism. Six different morpho-syntactic and semantic phenomena acquired early, late or very late are considered, with their timing in L1 acquisition varying between age 3 (subject-verb agreement) and after age 6 (case marking). Data from simultaneous bilingual children (2L1) whose mean age of onset to German was 3 months are compared with data from early second language learners of German (eL2) whose mean age of onset to German was 35 months as well as with data from monolingual children. To explore change over time, children were tested twice at the ages of 4;4 and 5;8 years. The main findings were that 2L1 children had an advantage over their eL2 peers in early acquired phenomena, which disappeared with time, whereas in late acquired phenomena 2L1 and eL2 children did not differ. Moreover, 2L1 children performed like monolingual children in early acquired phenomena but had a disadvantage in the late acquired phenomena with the amount of delay decreasing with time. We conclude that age of onset effects are modulated by effects of timing in monolingual acquisition. Contrary to expectation, input in terms of language dominance, measured as the dominant language used at home, did not affect simultaneous bilingual children’s performance in any of the phenomena. We discuss the implications of our findings for the hypothesis that acquisition of late phenomena is determined by input alone and suggest an alternative concept: the learner’s internal need for time to master a phenomenon, which is determined by its complexity and cross-linguistic robustness.
Orthologs document the evolution of genes and metabolic capacities encoded in extant and ancient genomes. However, the similarity between orthologs decays with time, and ultimately it becomes insufficient to infer common ancestry. This leaves ancient gene set reconstructions incomplete and distorted to an unknown extent. Here we introduce the "evolutionary traceability" as a measure that quantifies, for each protein, the evolutionary distance beyond which the sensitivity of the ortholog search becomes limiting. Using yeast, we show that genes that were thought to date back to the last universal common ancestor are of high traceability. Their functions mostly involve catalysis, ion transport, and ribonucleoprotein complex assembly. In turn, the fraction of yeast genes whose traceability is not sufficient to infer their presence in last universal common ancestor is enriched for regulatory functions. Computing the traceabilities of genes that have been experimentally characterized as being essential for a self-replicating cell reveals that many of the genes that lack orthologs outside bacteria have low traceability. This leaves open whether their orthologs in the eukaryotic and archaeal domains have been overlooked. Looking at the example of REC8, a protein essential for chromosome cohesion, we demonstrate how a traceability-informed adjustment of the search sensitivity identifies hitherto missed orthologs in the fast-evolving microsporidia. Taken together, the evolutionary traceability helps to differentiate between true absence and nondetection of orthologs, and thus improves our understanding about the evolutionary conservation of functional protein networks. "protTrace," a software tool for computing evolutionary traceability, is freely available at https://github.com/BIONF/protTrace.git; last accessed February 10, 2019.