Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability.

Thrombospondins (Thbs) are a family of five secreted matricellular glycoproteins in vertebrates that broadly affect cell-matrix interaction. While Thbs4 is known to protect striated muscle from disease by enhancing sarcolemmal stability through increased integrin and dystroglycan attachment complexes, here we show that Thbs3 antithetically promotes sarcolemmal destabilization by reducing integrin function, augmenting disease-induced decompensation. Deletion of Thbs3 in mice enhances integrin membrane expression and membrane stability, protecting the heart from disease stimuli. Transgene-mediated overexpression of α7β1D integrin in the heart ameliorates the disease predisposing effects of Thbs3 by augmenting sarcolemmal stability. Mechanistically, we show that mutating Thbs3 to contain the conserved RGD integrin binding domain normally found in Thbs4 and Thbs5 now rescues the defective expression of integrins on the sarcolemma. Thus, Thbs proteins mediate the intracellular processing of integrin plasma membrane attachment complexes to regulate the dynamics of cellular remodeling and membrane stability

Upgrade of the ultracold neutron source at the pulsed reactor TRIGA Mainz

The performance of the upgraded solid deuterium ultracold neutron source at the pulsed reactor TRIGA Mainz is described. The current configuration stage comprises the installation of a He liquefier to run UCN experiments over long-term periods, the use of stainless steel neutron guides with improved transmission as well as sputter-coated non-magnetic $^{58}$NiMo alloy at the inside walls of the thermal bridge and the converter cup. The UCN yield was measured in a `standard' UCN storage bottle (stainless steel) with a volume of 32 litres outside the biological shield at the experimental area yielding UCN densities of 8.5 /cm$^3$; an increase by a factor of 3.5 compared to the former setup. The measured UCN storage curve is in good agreement with the predictions from a Monte Carlo simulation developed to model the source. The growth and formation of the solid deuterium converter during freeze-out are affected by the ortho/para ratio of the H$_2$ premoderator.Comment: 12 pages, 7 figure

Shift work and cognitive impairment in later life - results of a cross-sectional pilot study testing the feasibility of a large-scale epidemiologic investigation

Background: The effect of shift work on impairment of cognition in later life has not yet been sufficiently investigated. Therefore, we aimed at testing the feasibility of a large-scale epidemiologic study examining this putative association in a pilot study. Methods: Between January and April 2017, a cross-sectional study invited a random sample of 425 former and current employees of a German university hospital aged 55 years and older to undergo a cognitive test battery (including the Repeatable Battery for the Assessment of Neuropsychological Status, Trail Making Test, Letter-Number Span, and Vocabulary Test) and to complete a self-administered questionnaire on socio-demographic characteristics, chronotype, sleep, occupational history including shift work, and medical history. Fifty percent of the invitees were registered in the hospital's occupational records as currently working or having worked in a shift system. The feasibility of a large-scale study was evaluated by the response of the study sample and the completeness of data. In addition, we calculated the prevalence of shift work and cognitive impairment in the study population. Results: Seventy five subjects (18%) completed the questionnaire, of whom 47 (11% of the total sample) participated in cognitive testing. In all but four items assessed in the questionnaire, the proportion of missing data was below 10 %, suggesting that the quality of collected data can be considered as high. Eighty percent of the participants reported that they ever worked in a shift system, indicating selective participation by exposure to shift work. With respect to chronotype, the majority of the study subjects rated themselves as rather evening type, while a quarter considered themselves as definite morning type. All cognitive tests could be carried out completely. We observed slight difficulties in at least one of the cognitive tests in 17 participants (36%) while two participants (4%) showed more pronounced signs of cognitive impairment. Conclusion: The present pilot study only partially supported the feasibility of the planned large-scale study. As response rates were low and depended on exposure to shift work, a better way of sampling and recruitment needs to be identified. The questionnaire and the test battery appear to be viable instruments

Cardiovascular risk in patients with alpha-1-antitrypsin deficiency

Background: Alpha-1-antitrypsin deficiency (AATD) is a rare inherited condition caused by mutations of the SERPINA1 gene that is associated with the development of a COPD like lung disease. The comorbidities in patients with AATDrelated lung diseases are not well defined. The aim of this study was to analyze the clinical phenotype of AATD patients within the German COPD cohort study COSYCONET (“COPD and SYstemic consequences-COmorbidities NETwork”) cohort focusing on the distribution of comorbidities. Method and results: The data from 2645 COSYCONET patients, including 139 AATD patients (110 with and 29 without augmentation therapy), were analyzed by descriptive statistics and regression analyses. We found significantly lower prevalence of cardiovascular comorbidities in AATD patients as compared to non-AATD COPD patients. After correction for age, pack years, body mass index, and sex, the differences were still significant for coronary artery disease (p = 0.002) and the prevalence of peripheral artery disease as determined by an ankle-brachial-index <= 0.9 (p = 0.035). Also the distribution of other comorbidities such as bronchiectasis differed between AATD and non-deficient COPD. Conclusion: AATD is associated with a lower prevalence of cardiovascular disease, the underlying mechanisms need further investigation

Cardiovascular risk in patients with alpha-1-antitrypsin deficiency

Background: Alpha-1-antitrypsin deficiency (AATD) is a rare inherited condition caused by mutations of the SERPINA1 gene that is associated with the development of a COPD like lung disease. The comorbidities in patients with AATD-related lung diseases are not well defined. The aim of this study was to analyze the clinical phenotype of AATD patients within the German COPD cohort study COSYCONET (“COPD and SYstemic consequences-COmorbidities NETwork”) cohort focusing on the distribution of comorbidities. Method and results: The data from 2645 COSYCONET patients, including 139 AATD patients (110 with and 29 without augmentation therapy), were analyzed by descriptive statistics and regression analyses. We found significantly lower prevalence of cardiovascular comorbidities in AATD patients as compared to non-AATD COPD patients. After correction for age, pack years, body mass index, and sex, the differences were still significant for coronary artery disease (p = 0.002) and the prevalence of peripheral artery disease as determined by an ankle-brachial-index <= 0.9 (p = 0.035). Also the distribution of other comorbidities such as bronchiectasis differed between AATD and non-deficient COPD. Conclusion: AATD is associated with a lower prevalence of cardiovascular disease, the underlying mechanisms need further investigation

Effect of smoking status on neuronal responses to graphic cigarette warning labels

Background Smoking is responsible for a large proportion of cancer, respiratory and cardiovascular deaths. Nevertheless the health risks of smoking are still underestimated in many smokers. The present study aimed to examine neurobiological responses to graphical warnings on cigarette packings in non-smokers and patients with tobacco dependence. Methods Twenty non-smokers and twenty-four patients with tobacco dependence participated in a functional MRI study during that pictures of different categories were presented ((a) EU-warning pictures, (b) text-only warnings, (c) neutral pictures with short information). Patients contributed twice in the experiment (after 10 hours nicotine withdrawal / about 5 minutes after nicotine consumption). Results Smokers during withdrawal demonstrated increased neuronal responses predominantly in subcortical, temporal and frontal brain regions that are associated with emotional and cognitive processes during the presentation of graphical warnings compared to neutral pictures. In smokers after smoking and non-smokers, the differences between graphical warnings and neutral pictures were increased compared to smokers during withdrawal. The comparison of the graphical warnings with text-only labels demonstrated the importance of affective brain regions especially in smokers after smoking and in non-smokers. During withdrawal, the neural responses associated with graphical warnings and text-only labels differed only marginally. Discussion and conclusion The results suggest that emotional and cognitive reactions to graphical warnings are predominantly seen in smokers after smoking and in non-smokers. The impact of these pictures during withdrawal seems to be less pronounced;in this case, more unspecific processes seem to be important, including the projection of sensory signals to the cerebral cortex

Linear square-mass trajectories of radially and orbitally excited hadrons in holographic QCD

We consider a new approach towards constructing approximate holographic duals of QCD from experimental hadron properties. This framework allows us to derive a gravity dual which reproduces the empirically found linear square-mass trajectories of universal slope for radially and orbitally excited hadrons. Conformal symmetry breaking in the bulk is exclusively due to infrared deformations of the anti-de Sitter metric and governed by one free mass scale proportional to Lambda_QCD. The resulting background geometry exhibits dual signatures of confinement and provides the first examples of holographically generated linear trajectories in the baryon sector. The predictions for the light hadron spectrum include new relations between trajectory slopes and ground state masses and are in good overall agreement with experiment.Comment: 33 pages, 5 figures, updated to the extended version published in JHEP, vector meson bulk potential and metric corrected, comments and references added, phenomenology and conclusions unchange

Production plan based recovery of vehicle routing plans within integrated transportnetworks : Forschungsinitiative des BMWi "ProveIT" : Gemeinsamer Abschlussbericht : Projektlaufzeit: 01.11.2013 - 31.10.2016 : Stand: 25.04.2017

Bedingt durch die stochastische Natur des Verkehrsgeschehens, menschliche Fehler oder technisches Versagen kommt es in Logistiksystemen fortwährend zu Abweichungen von einem geplanten Sollzustand. Um das System wieder zurück in den gewünschten Sollzustand zu überführen, sind oftmals aufwändige Eingriffe erforderlich. Die zunehmende Verbreitung von Konzepten wie der Just-in-Time Anlieferung sowie das Senken von Sicherheitsbeständen aus Gründen der Verschlankung der Supply Chain führen dazu, dass die Vulnerabilität von Logistiksystemen für derartige Störungen zunimmt. Ohne angemessenen Eingriff kann eine Störung im Transport sogar zum Bandstillstand führen. Ob ein Eingriff sinnvoll oder angemessen ist, wird heutzutage von einem menschlichen Disponenten beurteilt. Diese Entscheidung ist jedoch sehr komplex: Selbst wenn dem menschlichen Planer alle notwendigen Informationen zur Verfügung stehen, ist nicht sichergestellt, dass die Qualität der getroffenen Entscheidung ausreichend gut ist. Das Konsortium von ProveIT hatte sich daher zum Ziel gesetzt, den Planer in die Lage zu versetzen, objektiv richtige, rechtzeitige und automatisierte Eingriffe in vernetzte Logistiksysteme zu ermöglichen, um so wirtschaftliche und stabile Lieferketten zu gestalten

Immune Status in Children Before Liver Transplantation—A Cross-Sectional Analysis Within the ChilsSFree Multicentre Cohort Study

Background: Both, markers of cellular immunity and serum cytokines have been proposed as potential biomarkers for graft rejection after liver transplantation. However, no good prognostic model is available for the prediction of acute cellular rejection. The impact of underlying disease and demographic factors on immune status before pediatric liver transplantation (pLTx) is still poorly understood. We investigated expression of immune markers before pLTx, in order to better understand the pre-transplant immune status. Improved knowledge of the impact of pre-transplant variables may enhance our understanding of immunological changes post pLTx in the future.Methods: This is a cross-sectional analysis of data from the ChilSFree study, a European multicentre cohort study investigating the longitudinal patterns of immune response before and after pLTx. Immune cell counts and soluble immune markers were measured in 155 children 1–30 days before pLTx by TruCount analysis and BioPlex assays. Results were logarithmised due to skewed distributions and then compared according to age, sex, and diagnosis using t-tests, ANOVAs, and Tukey post-hoc tests. The association between immune markers at time of pLTx and patients' age was assessed using a fractional polynomial approach. Multivariable regression models were used to assess the relative contribution of each factor.Results: Sex had no effect on immune status. We found strong evidence for age-specific differences in the immune status. The majority of immune markers decreased in a log-linear way with increasing age. T and B cells showed a sharp increase within the first months of life followed by a log-linear decline in older age groups. Several immune markers were strongly associated with underlying diagnoses. The effects of age and underlying disease remained virtually unchanged when adjusting for each other in multivariable models.Discussion: We show for the first time that age and diagnosis are major independent determinants of cellular and soluble immune marker levels in children with end-stage liver disease. These results need to be considered for future research on predictive immune monitoring after pLTx

Birth Order, Caesarean Section, or Daycare Attendance in Relation to Child- and Adult-Onset Type 1 Diabetes: Results from the German National Cohort

Background: Global incidence of type 1 diabetes (T1D) is rising and nearly half occurred in adults. However, it is unclear if certain early-life childhood T1D risk factors were also associated with adult-onset T1D. This study aimed to assess associations between birth order, delivery mode or daycare attendance and type 1 diabetes (T1D) risk in a population-based cohort and whether these were similar for childhood- and adult-onset T1D (cut-off age 15); (2) Methods: Data were obtained from the German National Cohort (NAKO Gesundheitsstudie) baseline assessment. Self-reported diabetes was classified as T1D if: diagnosis age ≤ 40 years and has been receiving insulin treatment since less than one year after diagnosis. Cox regression was applied for T1D risk analysis; (3) Results: Analyses included 101,411 participants (100 childhood- and 271 adult-onset T1D cases). Compared to “only-children”, HRs for second- or later-born individuals were 0.70 (95% CI = 0.50–0.96) and 0.65 (95% CI = 0.45–0.94), respectively, regardless of parental diabetes, migration background, birth year and perinatal factors. In further analyses, higher birth order reduced T1D risk in children and adults born in recent decades. Caesarean section and daycare attendance showed no clear associations with T1D risk; (4) Conclusions: Birth order should be considered in both children and adults’ T1D risk assessment for early detection