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STAT3 haploinsufficiency is associated with autosomal dominant hyper-IgE syndrome
No full textThe autosomal dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency, which originates from heterozygous missense mutations in the signal transducer and activator of transcription 3 (STAT3) gene. It is accepted that most STAT3 variants causing AD-HIES are dominant negative. Whether haploinsufficient mutations cause a phenotype in humans is still debated. We report on a family with a heterozygous STAT3 nonsense mutation that led to rapid decay of the mutant mRNA and protein, leading to haploinsufficiency. To explore STAT3 heterozygosity, we created a Stat3 haploinsufficient (Stat3+/−) mouse model in which we found that Stat3+/− mice had increased IgE serum levels, reduced TH17 cell differentiation, and were susceptible to a cutaneous Staphylococcus aureus infection. Together, our findings provide mechanistic evidence for the impact of haploinsufficiency in STAT3 with residual protein expression as an important cause for immune deficiency. The implications extend to the diagnosis of immunodeficiency disorders and to the design of gene therapy in situations where gene dosage matters
Entwicklung und Evaluation einer innovativen Gruppentherapie zur Behandlung depressiver Erkrankungen im Jugendalter : Verknüpfung von Sport- und Bewegungstherapie, einschließlich Surftherapie, und kognitiver Verhaltenstherapie
No full textDepressive Erkrankungen zählen zu den häufigsten und schwerwiegendsten psychischen Störungen im Jugendalter. Mit den bestehenden Behandlungsansätzen werden nicht immer die gewünschten Ergebnisse erzielt, was die Entwicklung und Untersuchung alternativer oder ergänzender Interventionen erforderlich macht. Die Sport- und Bewegungstherapie kann eine solche Möglichkeit sein, deren potenzieller Nutzen zur Reduktion depressiverSymptome bereits in Übersichtsarbeiten aufgezeigt wurde. Eine innovativeBehandlungsmethode innerhalb dieses Ansatzes stellt die Surftherapie dar. Erste Studien zur Wirkung der Surftherapie deuten auf eine Reduktion depressiver Symptome bei Erwachsenen und eine Verbesserung allgemeiner Aspekte der psychischen Gesundheit (z. B. Wohlbefinden) bei Kindern und Jugendlichen hin. Die Forschung in diesem Bereich ist jedoch noch begrenzt. Bisher wird die Surftherapie zudem nicht bei Jugendlichen mit psychischen Erkrankungen angewandt und beschränkt sich auf an der Küste gelegene Standorte.Die vorliegende Dissertation adressiert diese Forschungslücke mit zwei zentralen Zielen:Erstens wurde eine neuartige Gruppentherapie zur Behandlung depressiver Erkrankungen für 13- bis 18-jährige Jugendliche entwickelt, die Elemente der Sport- und Bewegungstherapie, einschließlich der Surftherapie, mit Aspekten der kognitiven Verhaltenstherapie verknüpft. Dies ermöglicht eine Aufteilung der Therapie in zwei Phasen, wobei die erste im Landesinneren durchgeführt werden kann, gefolgt von einer einwöchigen Intensivphase der Surftherapie am Meer. Zur standardisierten Durchführung wurden die Inhalte der Therapie in einem Manual verschriftlicht. Ergänzend dazu wurde ein Arbeitsbuch für die Jugendlichen erstellt.Als zweites Ziel der Dissertation wurde die entwickelte Gruppentherapie in einer Studie mit einer Stichprobe von 32 Patient_innen im Alter von 13 bis 18 Jahren evaluiert. Die Ergebnisse zeigten eine geringe Abbruchrate von 9.38 % (n = 3). Depressive Symptome wurden signifikant über die Zeit reduziert und blieben drei Monate nach Therapieende konstant. Die Studie liefert somit Hinweise auf die Durchführbarkeit und Wirksamkeit der Intervention für Jugendliche mit depressiven Störungen. Weitere Studien, die insbesondere Kontrollgruppen einschließen, sind jedoch nötig. Mögliche klinische Implikationen der Dissertation werden erörtert
Building to last : strategic approaches to a sustainably funded institutional research data management
No full textAt research institutions, an array of infrastructures for institutional RDM is emerging which includes both highly specialized applications and standard services.[3] They are developed in response to specific needs, and their implementation fosters not only technical expertise but also valuable knowledge about processes.[7] These efforts often rely on local resources or third-party funding.[6] However, when such resources are depleted or discontinued, these services may be left behind as "zombies" or shut down. In these early phases, those operating such services often face legal risks they may not be aware. Not every initiative, tool or service deserves to be institutionalized. It would be more beneficial for the scientific community and host institutions if users—or even paying customers—could determine the value of start-up-like initiatives, rather than leaving it to bureaucratic chance. Effective operational models for sustainable RDM rely on transparent divisions of labor, legal certainty, and clearly defined responsibilities.[4] Proven models lead to more efficient resource use—both within individual services and across the landscape of academically used services. Transparent accounting of resources is essential for a legally sustainable operational model. Conceptual platforms are required[2] that could serve as hosts for operational model templates, which include initiatives like the NFDI,[5] state initiatives or, as a subsidiary option, central IT services at universities.[8] Research institutions must actively shape their RDM strategies and integrate the diverse landscape of local, regional, and (inter-)national services into a coherent overall offering.[3][9] Both the bottom-up-driven NFDI and the European Open Science Cloud, as well as state-level initiatives, play an increasingly important role in this. There are multiple examples of bottom-up initiatives showing potential for integration into a distributed service landscape. Popular services with longer development histories, such as Galaxy, OMERO, InvenioRDM, or Chemotion, coexist alongside approaches like DataPLANT's GitLab-based DataHUB.[3] Service operations span from foundational infrastructure like servers and storage, ideally provided by computing centers, to research-proximate activities closely aligned with domain-specific communities.[8][10] Funding models must account for these different actors and should aim for a balance of fairness, simplicity, and practicality. When designing them, a mix of low-threshold access for general use and effort-based billing for high-demand users should be considered (i.e., Basic Service, Paid Extra).[9] This necessitates service governance and coordination mechanisms—currently being tested through NFDI—that bring together stakeholders from various domains and align their activities to create synergies. To build trust in the long-term operation of services, their entire lifecycle—from conception and development to operation, scaling, and eventual decommissioning—should be actively supported. Sustainable, cooperative and federated RDM requires not only mutual trust but also external service integration, the ability to extend one's own services to third parties, and more flexible staffing models. The considerations laid out in this paper go back to discussions in the "Arbeitskreis Forschungsdatenmanagement" (AK FDM)[3] embedded in the permanent state-wide exchange on how to foster a vibrant landscape of research data management initiatives
Do fermented foods modify the human gut microbiota in healthy individuals and improve systemic health? Results from a crossover intervention study with fresh and pasteurized Sauerkraut and in vitro growth experiments with single bacterial species and prebiotics
No full textSauerkraut is a fermented food that has been suggested to have a beneficial effect on the gut microbiome and to exhibit anti-inflammatory, and anti-diabetic properties, but there is little scientific evidence to support its health-promoting capabilities. In addition, pasteurization is widely used on foods including sauerkraut, which inactivates the contained microorganisms. This does not necessarily mitigate but potentially alters the physiological properties of sauerkraut. Besides microbial cells, their fermentation products have been identified as important bioactive components with the potential to affect host physiology.To comprehensively investigate the impact of sauerkraut on the bacterial composition of the human gut microbiota, a randomized crossover intervention trial with 87 healthy participants was conducted as part of this dissertation. Using shotgun metagenomic sequencing and mixed regression model analysis, the impact of fresh and pasteurized sauerkraut on the intestinal bacterial community was profiled down to the species level. A functional analysis focused on short-chain fatty acid (SCFA) metabolism was combined with the assessment of SCFA levels in serum and feces to evaluate changes in these bacterial fermentation products. Furthermore, changes in blood pressure, serum inflammatory markers, leaky gut markers, and markers of glycemic control – which an altered microbiota may influence – were assessed. Following the daily consumption of starter-culture-produced fresh and spontaneously fermented pasteurized sauerkraut for four weeks, changes in the relative abundance of single bacterial species could be associated with either sauerkraut variant. However, bacterial α- and β-diversity were unaffected. The pasteurized sauerkraut appeared to induce more pronounced changes in species' relative abundances and was related to an increase in serum SCFAs. Both interventions marginally decreased systolic blood pressure. Changes in serum markers were not significant in the entire study population.No general sauerkraut-specific modulation of the gut microbiome in healthy individuals could be observed. The individual baseline microbiota and the specific composition of the consumed sauerkraut may be important determinants of the food-microbiome-host interaction.During an additional in vitro experiment, the growth of selected bacterial species with the prebiotics inulin and xylooligosaccharides was compared. This approach reinforces the highly individual growth behavior of bacteria, even under controlled conditions
The effect of psychotherapy on the multivariate association between insomnia and depressive symptoms in late-life depression
No full textBackgroundLate-life depression (LLD) is prevalent in older adults and linked to increased disability, mortality, and suicide risk. Insomnia symptoms are considered common remaining symptoms of LLD following treatment. However, the multivariate relationship between insomnia and depressive symptoms and the impact of psychotherapy on their interrelationship is insufficiently assessed.MethodsWe conducted a secondary analysis of data from 185 patients with LLD, recruited from seven university hospitals in Germany as part of a larger original cohort study. Participants had undergone eight-week psychotherapy interventions (cognitive behavioral therapy or supportive unspecific intervention). Three regularized canonical correlation analyses (rCCA) assessed the multivariate association between insomnia and depressive symptoms at baseline, post-treatment, and six-month follow-up. rCCA was conducted within a machine learning framework with 100 repeated hold-out splits and permutation tests to ensure robust findings. Canonical loadings and cross-loading difference scores were calculated to examine symptom changes before/after psychotherapy (Holm-Bonferroni corrected p-value ResultsAt baseline, a moderate association was observed between insomnia and depressive symptoms (r = 0.24). Interestingly, this association slightly increased after the eight-week treatment period (r = 0.42, pcorrected = 0.064) and remained significantly elevated at the follow-up session (r = 0.48, pcorrected = 0.018). At baseline, anxiety-related depressive symptoms were mainly associated with insomnia, while at post-treatment and follow-up sessions, somatic and negative affective symptoms showed the strongest correlation with insomnia symptoms. While the relative relationship of depressive symptoms with insomnia altered after psychotherapy, the pattern of insomnia symptoms remained stable.ConclusionsThe observed changes in the association between insomnia and depressive symptoms after psychotherapy highlight the necessity to consider targeting insomnia for effective LLD treatment
Slow wave activity during non-rapid eye movement (NREM) sleep in patients with major depressive disorder: a meta-analysis
No full textSlow-wave activity (SWA) during non-rapid eye movement (NREM) sleep is the primary marker of sleep homeostasis and proposed to reflect synaptic strength. SWA might be reduced in patients with major depressive disorder (MDD), potentially reflecting reduced synaptic strength (synaptic plasticity hypothesis of MDD). In view of inconsistent findings in the previous literature, the aim of this meta-analysis was to test the hypothesis of reduced SWA in patients with MDD compared to healthy controls. PubMed, CINAHL and PsychInfo were searched for original publications comparing SWA during NREM sleep in adult patients with MDD to healthy controls. A random-effects model for meta-analyses was calculated using Hedges' g. The study was pre-registered in the international prospective register of systematic reviews (PROSPERO CRD42024537138). Five studies comprising 229 participants were included. The meta-analysis demonstrated a significant reduction of SWA during NREM sleep in patients with MDD compared to healthy controls (p = 0.0003, g = −0.5, medium effect-size, confidence interval −0.8 to −0.2) with low heterogeneity (Q-test; p = 0.518, I2 = 0 %). This meta-analysis demonstrates a significant reduction of SWA during NREM sleep in patients with MDD compared to healthy controls, consistent with the concept of reduced synaptic strength in patients with MDD
Pulsed field ablation compared to thermal ablation techniques in atrial fibrillation: a German-wide in-hospital safety analysis
No full textQuality of diabetes mellitus healthcare and metabolic control during transition from paediatric to adult care: a systematic review and meta‐analysis
No full textAimsEmerging adults with chronic diseases like diabetes often experience a decline in health during the process of transition from paediatric to adult healthcare. This study assesses the impact of transition on healthcare quality of people with diabetes, focusing on glycated haemoglobin (HbA1c).MethodsWe conducted a systematic review and meta-analysis of the difference in HbA1c before and after transition following the PRISMA guidelines. A comprehensive search across four databases for studies of diabetes type 1 and 2 published between 2018 and 2024 was conducted. Risk of bias was assessed using the ROBINS-I tool for non-randomized studies.ResultsTwenty studies were included in the systematic review, fifteen to the meta-analysis. Eleven studies considered a structured or semi-structured transition programme: three reported a reduction in HbA1c (improved glycaemic control) and eight no significant difference. Nine studies considered no transition programme: four showed a worsening of glycaemic control and five no significant difference. Overall, the meta-analysis showed a worsening of glycaemic control post-transition with mean difference (MD) −1.75 mmol/mol (−0.16%) [95% confidence interval (CI) –5.24–1.75 mmol/mol (−0.48%–0.16%)], with considerable heterogeneity, where negative values indicate higher HbA1c post-transition. Subgroup analysis for transition programmes and usual care showed, respectively, significant improvement and worsening of glycaemic control with MD of 3.28 mmol/mol (0.30%) [95% CI 0.44–6.12 mmol/mol (0.04%–0.56%)] and −6.99 mmol/mol (−0.64%) [95% CI −11.79 to −2.19 mmol/mol (−1.08% to −0.20%)].ConclusionsFindings suggest that the transition to adult care may negatively affect glycaemic control in emerging adults with diabetes, whereas structured transition programmes can neutralize this effect and prevent consequences. Further investigations are needed to develop evidence-based guidelines for optimizing transition interventions
Enzymatic strategies for next-generation DNA synthesis: boosting efficiency and overcoming secondary structures
No full textChemical DNA synthesis is the gold standard for producing synthetic oligonucleotides. Despite four decades of success, fragment length and secondary DNA structure formation remain limitations, constraining access to long, complex sequences. Enzymatic de novo DNA synthesis has emerged as a promising next-generation alternative, offering a catalytic nature, higher coupling efficiencies, and uninterrupted strand growth. Recent advances, such as Codexis’ evolved terminal deoxynucleotidyl transferase (TdT) achieving near-chemical coupling efficiencies with 3′-phosphate-protected nucleotides, show that enzyme engineering is a viable path forward. The mitigation of secondary DNA structure formation is equally crucial to avoid synthesis stalls and complicated DNA assembly yet it remains surprisingly underexplored. This Perspective highlights current strategies to address both bottlenecks: improving TdT catalysis and controlling DNA folding. Together, these efforts could enable routine, cost-effective synthesis of kilobase-long, structure-rich sequences, transforming research and industrial applications alike
Energy underreporting in low calorie and carbohydrate-restrictive diets: epidemiological considerations
No full textBackgroundInaccurate energy intake assessments and dietary underreporting are important barriers to assess reliable health correlates of food consumption in nutritional epidemiology. Studies that do not account for this phenomenon may result in spurious diet–health associations. Whether underreporting occurs more frequently with special diets remains subject to investigation.ObjectivesThis study aimed to test the hypothesis whether low-calorie and carbohydrate-restrictive diets were associated with increased odds for energy intake underreporting and investigate whether a lower carbohydrate intake (in %/total energy intake) was associated with a higher discrepancy between self-reported energy intake and total energy expenditure.MethodsThis study used a predictive equation derived from 6497 doubly labeled water measurements to detect erroneous self-reported energy intake in the National Health and Nutrition Examination Surveys (NHANES, 2009–2018). Weighted underreporting prevalence was compared among 3 groups, namely, the United States general population without a special diet, individuals who reported low-calorie diets, and individuals who reported carbohydrate-restrictive diets. Crude and multivariate logistic binomial regression models were built to examine associations between diet and energy intake underreporter status.ResultsData from 18,150 adult NHANES participants ≥20 y were analyzed. Underreporting occurred almost twice as often in participants reporting low-calorie diets [38.84% (CI: 34.87, 42.95)] and carbohydrate-restrictive diets [43.83% (CI: 33.02, 55.26)] as compared with the general population [22.89% (CI: 21.88, 23.93)]. Both diets were associated with significantly higher odds for underreporting even after an adjustment for sociodemographic factors [odds ratio (OR): 2.32; CI: 1.93, 2.79 and OR: 2.86; CI: 1.85, 4.42, respectively]. Subanalyses in participants denying any weight loss intention/with stable weight revealed a comparable picture. The lowest level of agreement between total energy expenditure and self-reported energy intake was found in carbohydrate-restrictive diets.ConclusionsOur findings have far-reaching implications, especially with regard to studies that associated carbohydrate restriction or low-calorie diets with favorable health outcomes while not accounting for the herein-suggested phenomena