Oxidative Glucose Metabolism Promotes Senescence in Vascular Endothelial Cells

Vascular aging is based on the development of endothelial dysfunction, which is thought to be promoted by senescent cells accumulating in aged tissues and is possibly affected by their environment via inflammatory mediators and oxidative stress. Senescence appears to be closely interlinked with changes in cell metabolism. Here, we describe an upregulation of both glycolytic and oxidative glucose metabolism in replicative senescent endothelial cells compared to young endothelial cells by employing metabolic profiling and glucose flux measurements and by analyzing the expression of key metabolic enzymes. Senescent cells exhibit higher glycolytic activity and lactate production together with an enhanced expression of lactate dehydrogenase A as well as increases in tricarboxylic acid cycle activity and mitochondrial respiration. The latter is likely due to the reduced expression of pyruvate dehydrogenase kinases (PDHKs) in senescent cells, which may lead to increased activity of the pyruvate dehydrogenase complex. Cellular and mitochondrial ATP production were elevated despite signs of mitochondrial dysfunction, such as an increased production of reactive oxygen species and extended mitochondrial mass. A shift from glycolytic to oxidative glucose metabolism induced by pharmacological inhibition of PDHKs in young endothelial cells resulted in premature senescence, suggesting that alterations in cellular glucose metabolism may act as a driving force for senescence in endothelial cells

NFDI4Culture - Consortium for research data on material and immaterial cultural heritage

Digital data on tangible and intangible cultural assets is an essential part of daily life, communication and experience. It has a lasting influence on the perception of cultural identity as well as on the interactions between research, the cultural economy and society. Throughout the last three decades, many cultural heritage institutions have contributed a wealth of digital representations of cultural assets (2D digital reproductions of paintings, sheet music, 3D digital models of sculptures, monuments, rooms, buildings), audio-visual data (music, film, stage performances), and procedural research data such as encoding and annotation formats. The long-term preservation and FAIR availability of research data from the cultural heritage domain is fundamentally important, not only for future academic success in the humanities but also for the cultural identity of individuals and society as a whole. Up to now, no coordinated effort for professional research data management on a national level exists in Germany. NFDI4Culture aims to fill this gap and create a usercentered, research-driven infrastructure that will cover a broad range of research domains from musicology, art history and architecture to performance, theatre, film, and media studies. The research landscape addressed by the consortium is characterized by strong institutional differentiation. Research units in the consortium's community of interest comprise university institutes, art colleges, academies, galleries, libraries, archives and museums. This diverse landscape is also characterized by an abundance of research objects, methodologies and a great potential for data-driven research. In a unique effort carried out by the applicant and co-applicants of this proposal and ten academic societies, this community is interconnected for the first time through a federated approach that is ideally suited to the needs of the participating researchers. To promote collaboration within the NFDI, to share knowledge and technology and to provide extensive support for its users have been the guiding principles of the consortium from the beginning and will be at the heart of all workflows and decision-making processes. Thanks to these principles, NFDI4Culture has gathered strong support ranging from individual researchers to highlevel cultural heritage organizations such as the UNESCO, the International Council of Museums, the Open Knowledge Foundation and Wikimedia. On this basis, NFDI4Culture will take innovative measures that promote a cultural change towards a more reflective and sustainable handling of research data and at the same time boost qualification and professionalization in data-driven research in the domain of cultural heritage. This will create a long-lasting impact on science, cultural economy and society as a whole

Structure-function analysis of the AMPK activator SC4 and identification of a potent pan AMPK activator

The AMP-activated protein kinase (AMPK) αβγ heterotrimer is a primary cellular energy sensor and central regulator of energy homeostasis. Activating skeletal muscle AMPK with small molecule drugs improves glucose uptake and provides an opportunity for new strategies to treat type 2 diabetes and insulin resistance, with recent genetic and pharmacological studies indicating the α2β2γ1 isoform combination as the heterotrimer complex primarily responsible. With the goal of developing α2β2-specific activators, here we perform structure/function analysis of the 2-hydroxybiphenyl group of SC4, an activator with tendency for α2-selectivity that is also capable of potently activating β2 complexes. Substitution of the LHS 2-hydroxyphenyl group with polar-substituted cyclohexene-based probes resulted in two AMPK agonists, MSG010 and MSG011, which did not display α2-selectivity when screened against a panel of AMPK complexes. By radiolabel kinase assay, MSG010 and MSG011 activated α2β2γ1 AMPK with one order of magnitude greater potency than the pan AMPK activator MK-8722. A crystal structure of MSG011 complexed to AMPK α2β1γ1 revealed a similar binding mode to SC4 and the potential importance of an interaction between the SC4 2-hydroxyl group and α2-Lys31 for directing α2-selectivity. MSG011 induced robust AMPK signalling in mouse primary hepatocytes and commonly used cell lines, and in most cases this occurred in the absence of changes in phosphorylation of the kinase activation loop residue α-Thr172, a classical marker of AMP-induced AMPK activity. These findings will guide future design of α2β2-selective AMPK activators, that we hypothesise may avoid off-target complications associated with indiscriminate activation of AMPK throughout the body

Technik und Gender

Fiktionale Darstellungen von Technik scheinen von Geschlechterstereotypen bevölkert, die Klischees bedienen und auf der Opposition traditioneller, geschlechtlich assoziierter Merkmale basieren. So verkörpert Männlichkeit das technische Prinzip, während das Weibliche der Sphäre der Natur zugeordnet ist. Doch wie stereotyp sind technische Zukunftsvisionen? Der Band nimmt die geschlechtliche Kodiertheit literarischer und filmischer Technikzukünfte in den Fokus. Die Beiträge dieses Sammelbandes betrachten jeweils differenziertere Aspekte, beispielsweise im Hinblick auf stereotype, genderspezifische Rollenzuschreibungen, die Bedeutung geschlechtlicher Identitäten in den von Technik geprägten Räumen und ihre jeweilige mediale Vermittlung, und liefern ein erstes Panoptikum zur Erschließung der Fragestellung von Gender und Technikzukünften unter spezifisch kulturwissenschaftlicher Perspektive

Growing old at home – A randomized controlled trial to investigate the effectiveness and cost-effectiveness of preventive home visits to reduce nursing home admissions: study protocol [NCT00644826]

<p>Abstract</p> <p>Background</p> <p>Regarding demographic changes in Germany it can be assumed that the number of elderly and the resulting need for long term care is increasing in the near future. It is not only an individual's interest but also of public concern to avoid a nursing home admission. Current evidence indicates that preventive home visits can be an effective way to reduce the admission rate in this way making it possible for elderly people to stay longer at home than without home visits. As the effectiveness and cost-effectiveness of preventive home visits strongly depends on existing services in the social and health system existing international results cannot be merely transferred to Germany. Therefore it is necessary to investigate the effectiveness and cost-effectiveness of such an intervention in Germany by a randomized controlled trial.</p> <p>Methods</p> <p>The trial is designed as a prospective multi-center randomized controlled trial in the cities of Halle and Leipzig. The trial includes an intervention and a control group. The control group receives usual care. The intervention group receives three additional home visits by non-physician health professionals (1) geriatric assessment, (2) consultation, (3) booster session.</p> <p>The nursing home admission rate after 18 months will be defined as the primary outcome. An absolute risk reduction from a 20% in the control-group to a 7% admission rate in the intervention group including an assumed drop out rate of 30% resulted in a required sample size of N = 320 (n = 160 vs. n = 160).</p> <p>Parallel to the clinical outcome measurement the intervention will be evaluated economically. The economic evaluation will be performed from a society perspective.</p> <p>Discussion</p> <p>To the authors' knowledge for the first time a trial will investigate the effectiveness and cost-effectiveness of preventive home visits for people aged 80 and over in Germany using the design of a randomized controlled trial. Thus, the trial will contribute to the existing evidence on preventive home visits especially in Germany.</p

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

The GEOTRACES Intermediate Data Product 2014

The GEOTRACES Intermediate Data Product 2014 (IDP2014) is the first publicly available data product of the international GEOTRACES programme, and contains data measured and quality controlled before the end of 2013. It consists of two parts: (1) a compilation of digital data for more than 200 trace elements and isotopes (TEIs) as well as classical hydrographic parameters, and (2) the eGEOTRACES Electronic Atlas providing a strongly inter-linked on-line atlas including more than 300 section plots and 90 animated 3D scenes. The IDP2014 covers the Atlantic, Arctic, and Indian oceans, exhibiting highest data density in the Atlantic. The TEI data in the IDP2014 are quality controlled by careful assessment of intercalibration results and multi-laboratory data comparisons at cross-over stations. The digital data are provided in several formats, including ASCII spreadsheet, Excel spreadsheet, netCDF, and Ocean Data View collection. In addition to the actual data values the IDP2014 also contains data quality flags and 1-? data error values where available. Quality flags and error values are useful for data filtering. Metadata about data originators, analytical methods and original publications related to the data are linked to the data in an easily accessible way. The eGEOTRACES Electronic Atlas is the visual representation of the IDP2014 data providing section plots and a new kind of animated 3D scenes. The basin-wide 3D scenes allow for viewing of data from many cruises at the same time, thereby providing quick overviews of large-scale tracer distributions. In addition, the 3D scenes provide geographical and bathymetric context that is crucial for the interpretation and assessment of observed tracer plumes, as well as for making inferences about controlling processes

Numerische Analyse des Kontaktproblems kugelsymmetrischer Indenter auf Schicht-Substrat-Systemenkugelsymmetrischer Indenter auf Schicht-Substrat-Systemen

Die vorliegende Arbeit beschäftigt sich mit der Beurteilung beschichteter Materalien hinsichtlich ihres Verhaltens im Kontaktzustand. Hierzu werden numerische und analytische Berechnungen durchgeführt und diskutiert. Eine nicht kommerzielle Software, mit der numerische Berechnungen ausgeführt werden können (SPC-PM 2Ad), soll mit bekannterer und mehr erforschter Software verglichen werden. Die Frage, ob sich das SPC-PM 2Ad zur Analyse von Schicht-Substrat-Systemen eignet und welche Vor- bzw. Nachteile gegenüber anderen Programmen zu erwarten sind, soll innerhalb dieser Arbeit beantwortet werden