Type 1 diabetes is an autoimmune disease with rising incidence in high-income countries. Genetic and environmental predisposing factors contribute to the etiology of the disease, although their interaction is not sufficiently understood to allow for preventive action. Strongest known associations with genetic variation map to classical HLA class II genes. Because of its genetic complexity, the HLA region has been under-represented in genome-wide association studies, having potentially hindered the identification of relevant associations underlying the etiology of the disease. Here, we performed a comprehensive HLA-wide genetic association analysis of type 1 diabetes including multi-allelic and rare variants. We used high-density whole-exome sequencing data of the HLA region in the large UK Biobank dataset to apply gene-based association tests with a carefully defined type 1 diabetes phenotype (97 cases and 48,700 controls). Exon-based and single-variant association tests were used to complement the analysis. We replicated the known association of type 1 diabetes with the classical HLA-DQ gene. Tailoring the analysis toward rare variants, we additionally identified the lysine methyl transferase EHMT2 as associated. Deeper insight into genetic variation associated with disease as presented and discussed in detail here can help unraveling mechanistic details of the etiology of type 1 diabetes. More specifically, we hypothesize that genetic variation in EHMT2 could impact autoimmunity in type 1 diabetes development.Weniger anzeigen
Membrane-bound proteins that change protonation during function use specific protein groups to bind and transfer protons. Knowledge of the identity of the proton-binding groups is of paramount importance to decipher the reaction mechanism of the protein, and protonation states of prominent are studied extensively using experimental and computational approaches. Analyses of model transporters and receptors from different organisms, and with widely different biological functions, indicate common structure-sequence motifs at internal proton-binding sites. Proton-binding dynamic hydrogen-bond networks that are exposed to the bulk might provide alternative proton-binding sites and proton-binding pathways. In this perspective article I discuss protonation coupling and proton binding at internal and external carboxylate sites of proteins that use proton transfer for function. An inter-helical carboxylate-hydroxyl hydrogen-bond motif is present at functionally important sites of membrane proteins from archaea to the brain. External carboxylate-containing H-bond clusters are observed at putative proton-binding sites of protonation-coupled model proteins, raising the question of similar functionality in spike protein S.Weniger anzeigen
Introduction: Heavy alcohol consumption constitutes a major health risk among University students. Social relationships with peers strongly affect University students' perception of the drinking behavior of others, which in turn plays a crucial role in determining their own alcohol intake. University students tend to overestimate their peers' alcohol consumption – a belief that is associated with an increase in an individual's own consumption. Therefore, we implemented a social norms intervention with personalized normative feedback at a major University in Germany to reduce and prevent excessive drinking among University students.
Methods: Our intervention was part of a regular health monitoring survey. We invited all enrolled University students to take part in this survey on two occasions. A total of 862 University students completed the questionnaire, 563 (65.3%) of which received e-mail-based feedback upon request concerning their peers' and their own alcohol consumption. For the intervention group (n = 190) as well as the control group (no feedback requested; n = 101), we included only University students in the evaluation who overestimated their peers' alcohol use and indicated above average consumption of the peers. We applied analyses of variance to assess intervention effects with regard to the correction of overestimated group norms as well as University students' drinking behavior.
Results: Within the intervention group, we observed a significantly larger reduction of the previously overestimated behavioral norms compared to the control group (p < 0.001; η2p = 0.06). With regard to behavioral outcomes the intervention group showed a significantly larger reduction in the AUDIT-C score (p = 0.020; η2p
Discussion: Our study confirms previous research whereupon personalized, gender-specific and selective normative feedback is effective for alcohol prevention among University students. However, University students still overestimated their peers' alcohol intake after the intervention. Furthermore, we did not reach high-risk groups (University students with the highest alcohol intake) since no feedback was requested. Future studies should address factors influencing the impact of the intervention and reachability of selective groups.Weniger anzeigen
Personality changes throughout the life course and change is often caused by environmental influences, such as critical life events. In the present study, we investigate personality trait development in emerging adulthood as a result of experiencing two major life events: graduating from school and moving away from home. Thereby, we examined the occurrence of the two life events per se and the subjective perception of the critical life event in terms of valence. In addition, we postulate a moderation effect of the construct of mindset, which emphasizes that beliefs over the malleability of global attributes can be seen as predictors of resilience to challenges. This suggests that mindset acts as a buffer for these two distinct events. In a large longitudinal sample of 1,243 people entering adulthood, we applied latent structural equation modeling to assess mean-level changes in the Big Five, the influence of life events per se, the subjective perception of life events, and a moderating role of mindset. In line with maturity processes, results showed significant mean-level changes in all Big Five traits. While no changes in the Big Five dimensions were noted when the mere occurrence of an event is assessed, results indicated a greater increase in extraversion and diminished increase in emotional stability when we accounted for the individual's (positive/negative) perception of the critical life event. In case of extraversion, this also holds true for the moderator mindset. Our findings contribute valuable insights into the relevance of subjective appraisals to life events and the importance of underlying processes to these events.Weniger anzeigen
Cytochrome P450s (CYPs) are an essential family of enzymes in the human body. They play a crucial role in metabolism, especially in human steroid biosynthesis. Reactions catalyzed by these enzymes are highly stereo- and regio-specific. Lack or severe malfunctions of CYPs can cause severe diseases and even shorten life. Hence, investigations on metabolic reactions and structural requirements of substrates are crucial to gain further knowledge on the relevance of different enzymes in the human body functions and the origin of diseases. One key enzyme in the biosynthesis of gluco- and mineralocorticoids is CYP21A2, also known as steroid 21-hydroxylase. To investigate the steric and regional requirements of substrates for this enzyme, we performed whole-cell biotransformation assays using a strain of fission yeast Schizosaccharomyces pombe recombinantly expressing CYP21A2. The progestogens progesterone, pregnenolone, and their 17α-hydroxy-derivatives were used as substrates. After incubation, samples were analyzed using gas chromatography coupled to mass spectrometry. For progesterone and 17α-hydroxyprogesterone, their corresponding 21-hydroxylated metabolites 11-deoxycorticosterone and 11-deoxycortisol were detected, while after incubation of pregnenolone and 17α-hydroxypregnenolone, no hydroxylated product was observed. Findings were confirmed with authentic reference material. Molecular docking experiments agree with these results and suggest that interaction between the 3-oxo group and arginine-234 of the enzyme is a strict requirement. The presented results demonstrate once more that the presence of an oxo-group in position 3 of the steroid is indispensable, while a 3-hydroxy group prevents hydroxylation in position C-21 by CYP21A2. This knowledge may be transferred to other CYP21A2 substrates and hence help to gain essential insights into steroid metabolism.Weniger anzeigen
Trust is regarded as one of the main predictors for adopting automated buses (ABs). However, theories about trust (development) in technology generally vary and an in-depths study about trust in ABs specifically is still outstanding. The present study fills this gap by presenting results from focus group interviews to trust (development) in shared automated buses prior to exposure. The objectives of this study are to contrast participants’ naïve concepts of trust with theory and to identify underlying factors influencing a-priori trust in ABs. Results show that the N = 21 focus group participants use different strategies to familiarise themselves with the new technology of ABs, e.g., comparisons with familiar technologies, fundamental tendencies to approach or avoid, additional information seeking, or anthropomorphisation. These strategies largely support existing theories on trust (development) in technology. Differences between naïve interpretations of trust and its theoretical assumptions were found in focus group debates where more control over technology limited uncertainty and led to more trust. While theories suggest control and trust to be incompatible opposites, participants see control as a way to enhance trust. We provide starting points for further theory development and expansion and stress the importance of explanations in emerging technologies for trust and acceptance building.Weniger anzeigen
While mental health treatments have proven to be effective for a range of mental health problems, there is comparably little research on its effects on personality disorders or difficulty (PD). New dimensional conceptualizations of PD such as the ICD-11 PD model enable the cost- and time-effective dimensional assessment of severity and style of PD. Furthermore, they constitute a promising tool to investigate PD, not only as a treatment endpoint but also as a predictive or influencing factor for mental health treatments. In this study, we investigated the effects in two different mental health treatment settings [online (N = 38); face-to-face and blended [FTF/blended] (N = 35)] on the reduction of maladaptive personality traits as well as the interaction between maladaptive personality patterns and the response on primary endpoints (i.e., mental distress). Results indicate that both treatment settings have comparable within-group effects on the reduction of distress symptoms, while the treatment in the FTF/blended setting seems to have a stronger impact on the reduction of maladaptive traits. Further, reduction of maladaptive trait expressions was a reliable predictor of treatment response in the FTF/blended setting while explaining less variance in the online setting. Beyond the promising findings on the utility of maladaptive trait change as an outcome measure, we discuss possible applications as an information source for treatment decisions.Weniger anzeigen
Background Compensatory lameness is common in horses and evaluation can be challenging.
Objectives To investigate patterns of compensatory movements in clinical cases with fore- or hindlimb lameness before and after diagnostic analgesia.
Study design Retrospective clinical study.
Methods Multiple limb lameness of 367 horses was characterised by type (push-off, impact or mixed), limb (fore- or hindlimb in predominant lameness) and side (ipsi- or contralateral in concurrent lameness) using a body-mounted inertial sensor (BMIS). Diagnostic analgesia was performed until the percentage improvement of the vector sum in forelimb lameness and the mean difference of the maximum or minimum pelvic height (PDmax or PDmin) in hindlimb lameness was >= 50%. Linear mixed model and post-estimation of effects were performed by contrast command with multiple comparisons adjusted by Bonferroni method. Correlation of pre- and post-analgesia of all head and pelvis asymmetry parameters was tested with Spearman's rank correlation.
Results Improvement in vector sum per mm after diagnostic analgesia in forelimb impact lameness positively correlated with decrease in PDmax in contralateral mixed lameness (0.187 mm, r = .58, P < .05). Improvement in PDmin per mm after diagnostic analgesia in hindlimb mixed and PDmax in hindlimb push-off lameness decreased vector sum in ipsilateral forelimb impact lameness by 0.570 and 0.696 mm, respectively (P < .05), with no positive correlation.
Main limitations A variety of cases with inhomogeneous distribution of lameness patterns was investigated retrospectively, therefore, it is impossible to distinguish between true multiple limb lameness and compensatory lameness in this clinical material.
Conclusions Various asymmetry patterns of concurrent lameness were seen in horses with naturally occurring primary forelimb impact lameness with contralateral compensatory hindlimb lameness with a mixed component being the most common. In horses with hindlimb lameness, compensatory movements were seen in ipsilateral forelimbs, mostly as an ipsilateral impact lameness during straight line trot.Weniger anzeigen
Las instituciones de educación superior (IES) desempeñan un papel estratégicamente importante en las transformaciones multidimensionales necesarias para lograr formas de vida más sostenibles en este mundo. Aplicando un enfoque holístico centrado en todas las áreas de la universidad, pueden promover e implementar la sostenibilidad en la investigación, docencia y gestión del campus, y generar conocimiento transdisciplinar útil para la sociedad, como una misión "tercera misión" de las universidades.
Esta publicación presenta diversos proyectos e iniciativas desarrollados por universidades de Alemania, Canadá, Chile, China, Colombia, Israel, México, Perú y Rusia para promover el tema de la sostenibilidad en la gobernanza, docencia, investigación y gestión del campus.
Al presentar los temas clave, las recomendaciones y las lecciones aprendidas de estas iniciativas, se esbozan enfoques innovadores y diversos que contribuyen a fomentar la sostenibilidad en las IES. Estos casos ponen de relieve experiencias de todo el mundo que pueden ser adoptadas por las IES interesadas en cualquier lugar del planeta, en particular aquellas universidades que se ven obligadas a operar en condiciones de grave escasez de recursos y en contextos en los que la sostenibilidad aún no es una parte importante de las actividades académicas. También esperamos que esta publicación sea el inicio de un mayor intercambio de iniciativas de sostenibilidad entre las universidades de todo el mundo.Weniger anzeigen
Background: Social support plays an important role for health outcomes. Support for those living with chronic conditions may be particularly important for their health, and even for their survival. The role of support for the survival of cancer patients after receiving an allogeneic hematopoietic cell transplant (alloHCT) is understudied. To better understand the link between survival and support, as well as different sources and functions of support, we conducted two studies in alloHCT patients. First, we examined whether social support is related to survival (Study 1). Second, we examined who provides which support and which specific support-related functions and tasks are fulfilled by lay caregivers and healthcare professionals (Study 2).
Methods: In Study 1, we conducted a retrospective chart review of alloHCT patients (N = 173, 42.8% female, age: M = 49.88) and registered availability of a dedicated lay caregiver and survival. In Study 2, we prospectively followed patients after alloHCT (N = 28, 46.4% female, age: M = 53.97, 46.4% ethnic minority) from the same hospital, partly overlapping from Study 1, who shared their experiences of support from lay caregivers and healthcare providers in semi-structured in-depth interviews 3 to 6 months after their first hospital discharge.
Results: Patients with a dedicated caregiver had a higher probability of surviving to 100 days (86.7%) than patients without a caregiver (69.6%), OR = 2.84, p = 0.042. Study 2 demonstrated the importance of post-transplant support due to patients' emotional needs and complex self-care regimen. The role of lay caregivers extended to many areas of patients' daily lives, including support for attending doctor's appointments, managing medications and financial tasks, physical distancing, and maintaining strict dietary requirements. Healthcare providers mainly fulfilled medical needs and provided informational support, while lay caregivers were the main source of emotional and practical support.
Conclusion: The findings highlight the importance of studying support from lay caregivers as well as healthcare providers, to better understand how they work together to support patients' adherence to recommended self-care and survival.Weniger anzeigen
Retinol binding protein 4 (RBP4) is a member of the lipocalin family and the major transport protein of the hydrophobic molecule retinol, also known as vitamin A, in the circulation. Expression of RBP4 is highest in the liver, where most of the body's vitamin A reserves are stored as retinyl esters. For the mobilization of vitamin A from the liver, retinyl esters are hydrolyzed to retinol, which then binds to RBP4 in the hepatocyte. After associating with transthyretin (TTR), the retinol/RBP4/TTR complex is released into the bloodstream and delivers retinol to tissues via binding to specific membrane receptors. So far, two distinct RBP4 receptors have been identified that mediate the uptake of retinol across the cell membrane and, under specific conditions, bi-directional retinol transport. Although most of RBP4's actions depend on its role in retinoid homeostasis, functions independent of retinol transport have been described. In this review, we summarize and discuss the recent findings on the structure, regulation, and functions of RBP4 and lay out the biological relevance of this lipocalin for human diseases.Weniger anzeigen
Background: Neuromyelitis optica spectrum disorder (NMOSD) is a clinically defined, inflammatory central nervous system (CNS) disease of unknown cause, associated with humoral autoimmune findings such as anti-aquaporin 4 (AQP4)-IgG. Recent clinical trials showed a benefit of anti-B cell and anti-complement-antibodies in NMOSD, suggesting relevance of anti-AQP4-IgG in disease pathogenesis.
Objective: AQP4-IgG in NMOSD is clearly defined, yet up to 40% of the patients are negative for AQP4-IgG. This may indicate that AQP4-IgG is not disease-driving in NMOSD or defines a distinct patient endotype.
Methods: We established a biobank of 63 clinically well-characterized NMOSD patients with an extensive annotation of 351 symptoms, patient characteristics, laboratory results and clinical scores. We used phylogenetic clustering, heatmaps, principal component and longitudinal causal interference analyses to test for the relevance of anti-AQP4-IgG.
Results: Anti-AQP4-IgG was undetectable in 29 (46%) of the 63 NMOSD patients. Within anti-AQP4-IgG-positive patients, anti-AQP4-IgG titers did not correlate with clinical disease activity. Comparing anti-AQP4-IgG-positive vs. -negative patients did not delineate any clinically defined subgroup. However, anti-AQP4-IgG positive patients had a significantly (p = 0.022) higher rate of additional autoimmune diagnoses.
Conclusion: Our results challenge the assumption that anti-AQP4-IgG alone plays a disease-driving role in NMOSD. Anti-AQP4-IgG might represent an epiphenomenon associated with NMOSD, may represent one of several immune mechanisms that collectively contribute to the pathogenesis of this disease or indeed, anti-AQP4-IgG might be the relevant factor in only a subgroup of patients.Weniger anzeigen
Background: Measurement of tinnitus-related distress and treatment responsiveness is key in understanding, conceptualizing and addressing this often-disabling symptom. Whilst several self-report measures exist, the heterogeneity of patient populations, available translations, and treatment contexts requires ongoing psychometric replication and validation efforts.
Objective: To investigate the convergent validity and responsiveness of the German versions of the Tinnitus Questionnaire [TQ], Tinnitus Handicap Inventory [THI], and Tinnitus Functional Index [TFI] in a large German-speaking sample of patients with chronic tinnitus who completed a psychologically anchored 7-day Intensive Multimodal Treatment Programme.
Methods: Two-hundred-and-ten patients with chronic tinnitus completed all three questionnaires at baseline and post-treatment. Intraclass correlation coefficients determined the convergent validity of each questionnaire's total and subscale scores. Treatment responsiveness was investigated by [a] comparing treatment-related change in responders vs. non-responders as classified by each questionnaire's minimal clinically important difference-threshold, and [b] comparing agreement between the questionnaires' responder classifications.
Results: The total scores of all three questionnaires showed high agreement before and after therapy (TQ | THI: 0.80 [Pre], 0.83 [Post], TQ | TFI: 0.72 [Pre], 0.78 [Post], THI | TFI: 0.76 [Pre] 0.80 [Post]). All total scores changed significantly with treatment yielding small effect sizes. The TQ and TFI yielded comparable (19.65 and 18.64%) and the THI higher responder rates (38.15%). The TQ | THI and TQ | TFI showed fair, and the THI | TFI moderate agreement of responder classifications. Independent of classification, responders showed significantly higher change rates than non-responders across most scores. Each questionnaire's total change score distinguished between responders and non-responders as classified by the remaining two questionnaires.
Conclusion: The total scores of all three questionnaires show high convergent validity and thus, comparability across clinical and research contexts. By contrast, subscale scores show high inconsistency. Whilst the TFI appears well suited for research purposes, the THI may be better suited to measure psychological aspects of tinnitus-related distress and their changes with accordingly focused treatment approaches.Weniger anzeigen
Background: The Cognitive Behavioral Analysis System of Psychotherapy (CBASP) has been tailored specifically to the demands of patients with persistent depressive disorder (PDD). According to the CBASP model, PDD patients are supposed to live perceptually disconnected from their social environment, which consequently maintains depression. While initially developed as an individual treatment modality, the adaptation for group therapy yields an important interpersonal space. However, little is known about the specific factors that contribute to patients' benefit from the CBASP group modality.
Methods: The analyzed sample comprised N = 87 PDD patients who completed a 12 week multimodal inpatient treatment including 2 weekly CBASP-specific individual and group sessions, respectively, as well as CBASP-unspecific medical contacts, pharmacotherapy and complementary therapies. Group sessions included trainings in situational analysis and interpersonal skills. Interpersonal change over therapy was examined based on the patients' self-perceived interpersonal problems (IIP) and the impact messages as perceived by their individual therapists (IMI). Pre and post-treatment data were compared using within-sample t-tests. Additionally, patients evaluated CBASP group therapy on a feedback form. They were invited to reflect on individual benefits and its helpful and unhelpful aspects. Qualitative content analysis with inductive category development was used to analyze feedback. Inter-rater reliability was computed to confirm categories before summarizing the frequencies of reported factors.
Results: Self-perceived interpersonal distress significantly decreased over therapy. Patients reported reduced interpersonal problems and therapists reported more friendly and dominant impact messages. Interestingly, patients who showed a significant depressive symptom reduction described higher change scores. Regarding qualitative data, patients reported five main benefits from group therapy: Gain in social competence, self-confidence, self-reflection, interpersonal dynamics, and optimism/universality. Patients responding to CBASP identified significantly more factors than non-responders.
Conclusions: Compared to studies with individual CBASP only, the present findings suggest that CBASP group therapy may contribute to the improvement of interpersonal behavior. Group therapy is discussed as a potential boosting effect for individual CBASP. However, as the present data were collected in a multimodal inpatient setting without competitor, randomized controlled trials are warranted that investigate the specific benefits of the group modality or the combined individual and group therapy over individual CBASP only.Weniger anzeigen
Beschlossen vom Akademischen Senat am 23. Juli 2008
The investigation of vascular calcification and its underlying cellular and molecular pathways is of great interest in current research efforts. Therefore, suitable assays are needed to allow examination of the complex calcification process under controlled conditions. The current study describes a new ex vivo model of isolated-perfused rat aortic tissue with subsequent quantification and vessel staining to analyze the calcium content of the aortic wall. A rat aorta was perfused ex vivo with control and calcification media for 14 days, respectively. The calcification medium was luminally perfused and induced a significant increase in calcium deposition within the media of the vessel wall detected alongside the elastic laminae. Perfusion with control medium induced no calcification. In addition, the mRNA expression of the osteogenic marker bone morphogenetic protein 2 (BMP-2) increased in aortic tissue after perfusion, while SM22α as smooth muscle marker decreased. This newly developed ex vivo model of isolated-perfused rat aorta is suitable for vascular calcification studies testing inducers and inhibitors of vessel calcification and studying signaling pathways within calcification progression.Weniger anzeigen
One key hypothesis explaining the fate of exotic species introductions posits that the establishment of a self-sustaining population in the invaded range can only succeed within conditions matching the native climatic niche. Yet, this hypothesis remains untested for individual release events. Using a dataset of 979 introductions of 173 mammal species worldwide, we show that climate-matching to the realized native climatic niche, measured by a new Niche Margin Index (NMI), is a stronger predictor of establishment success than most previously tested life-history attributes and historical factors. Contrary to traditional climatic suitability metrics derived from species distribution models, NMI is based on niche margins and provides a measure of how distant a site is inside or, importantly, outside the niche. Besides many applications in research in ecology and evolution, NMI as a measure of native climatic niche-matching in risk assessments could improve efforts to prevent invasions and avoid costly eradications.Weniger anzeigen
Listeria (L.) monocytogenes as the cause of human listeriosis is widespread in the environment and a hazard considering food safety. Almost all animal species as well as humans can be asymptomatic carriers of this bacterium. In pigs, the tonsils are identified as the organ with the highest detection rate compared to other sample matrices. We sampled 430 pigs in total in two slaughterhouses in Northwest and East Germany, two structurally different and important regions in pig production, to re-examine pigs as a possible source of Listeria-contamination of pork products. We detected a low prevalence of L. monocytogenes in tonsil samples of 1.6% (7/430) on single animal level and of 11.6% (5/43) on herd level with no significant difference between the two German regions. Apart from L. monocytogenes, the usually non-pathogenic L. innocua had a prevalence of 1.2% (5/430) on single animal level. From 200 pigs from Northwest Germany, intestinal content samples were analysed in addition to tonsil samples from the same animals, but no positive sample was found for L. monocytogenes (0.0%, 0/200), while four pigs were positive for L. innocua (2.0%, 4/200). Although the prevalence of L. monocytogenes in tonsils is low, the risk of cross-contaminating meat with the pathogen is still given.Weniger anzeigen
Using synchrotron radiation in the tender X-ray regime, a photoelectron spectrum showing the formation of single site double-core-hole pre-edge states, involving the K shell of the O atom in CO, has been recorded by means of high-resolution electron spectroscopy. The experimentally observed structures have been simulated, interpreted and assigned, employing state-of-the-art ab initio quantum chemical calculations, on the basis of a theoretical model, accounting for their so-called direct or conjugate character. Features appearing above the double ionization threshold have been reproduced by taking into account the strong mixing between multi-excited and continuum states. The shift of the σ* resonance below the double ionization threshold, in combination with the non-negligible contributions of multi-excited configurations in the final states reached, gives rise to a series of avoided crossings between the different potential energy curvesWeniger anzeigen
Mass activity and long-term stability are two major issues in current fuel cell catalyst designs. While supported catalysts normally suffer from poor long-term stability but show high mass activity, unsupported catalysts tend to perform better in the first point while showing deficits in the latter one. In this study, a facile synthesis route towards self-supported metallic electrocatalyst nanoarchitectures with both aspects in mind is outlined. This procedure consists of a palladium seeding step of ion track-etched polymer templates followed by a nickel electrodeposition and template dissolution. With this strategy, free-standing nickel nanowire networks which contain palladium nanoparticles only in their outer surface are obtained. These networks are tested in anodic half-cell measurements for demonstrating their capability of oxidising methanol in alkaline electrolytes. The results from the electrochemical experiments show that this new catalyst is more tolerant towards high methanol concentrations (up to 5molL−1) than a commercial carbon supported palladium nanoparticle catalyst and provides a much better long-term stability during potential cycling.Weniger anzeigen