Chronotyp und Depression bei Jugendlichen – ein Review

Depressive Erkrankungen gehen mit vielen Symptomen einher, die in Bezug zu einer tageszeitlichen Rhythmik und dem Schlafverhalten stehen. Die vielfältigen Zusammenhänge zwischen Schlaf, Depression und Tagesrhythmik sind nicht eindeutig geklärt. In den Forschungsarbeiten der letzten Jahre kommt dem Chronotyp eine besondere Bedeutung zu. Als biologisches Maß der inneren Uhr kann der Chronotyp – basierend auf Schlafzeiten – mit dem Munich ChronoType Questionnaire (MCTQ) bestimmt werden, als subjektive Präferenz für bestimmte Tageszeiten wird er mit dem Morningness-Eveningness-Questionnaire (MEQ) erfasst. Durch eine systematische Literaturrecherche konnten Studien identifiziert werden, die überwiegend einen Zusammenhang zwischen einem späten Chronotyp und depressiven Symptomen und depressiven Störungen zeigen. Dies ist besonders für Jugendliche relevant, da sich der Chronotyp zur Adoleszenz hin stark verändert. Bisher ist nicht geklärt, was am Zusammenhang zwischen Chronotyp und depressiver Störung Ursache und Wirkung ist und welche Faktoren als Moderator oder Mediator fungieren. Möglicherweise ist der Zusammenhang bidirektional: Einerseits ziehen sich Patienten mit depressiven Störungen häufig zurück und sind weniger Tageslicht ausgesetzt, was ihren Chronotyp später werden lässt. Andererseits führt eine Diskrepanz von Innenzeit (festgelegt durch die innere Uhr) und Außenzeit (z. B. durch Schul- und Arbeitszeiten) zu Problemen wie einer verringerten Schlafqualität und schlechteren Schulnoten, die wiederum im Zusammenhang mit Depressivität stehen können.Many patients with depressive disorders experience symptoms in relation to sleep behavior and daily rhythmicity. However, the multifaceted associations between sleep, depression and circadian rhythms are not fully understood. During the past years, the concept of chronotype has become increasingly popular in research. The Munich Chronotype Questionnaire (MCTQ) derives chronotype from sleep timing on work-free days and therefore represents a biological measure for the circadian clock, whereas the Morningness-Eveningness-Questionnaire (MEQ) assesses chronotype as a subjective preference for different activities at specific times of day. Chronotype changes with age, with adolescents and young adults being especially late types. We conducted a systematic literature research and identified studies that explore the association between chronotype (MEQ, MCTQ) and depressive symptoms or depressive disorders. Most of the studies showed an association between a late chronotype and depressive symptomatology. However, it is still unclear what is cause and effect. We propose a bidirectional relationship: On the one hand, due to reduced social and physical activity, depressed patients get less daylight which causes their chronotype to delay. On the other hand, a discrepancy between internal time (directed by the circadian clock) and external time (such as early school- or work starting times) can cause problems like reduced quality of sleep quality, daytime tiredness and worse grades in school, that are in turn associated with depressive symptoms

Variants in Miro1 cause alterations of ER-mitochondria contact sites in fibroblasts from Parkinson's disease patients

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many of the PD‐associated proteins are involved in mitochondrial quality control, e.g., PINK1, Parkin, and LRRK2, which were recently identified as regulators of mitochondrial‐endoplasmic reticulum (ER) contact sites (MERCs) linking mitochondrial homeostasis to intracellular calcium handling. In this context, Miro1 is increasingly recognized to play a role in PD pathology. Recently, we identified the first PD patients carrying mutations in RHOT1, the gene coding for Miro1. Here, we describe two novel RHOT1 mutations identified in two PD patients and the characterization of the cellular phenotypes. Methods: Using whole exome sequencing we identified two PD patients carrying heterozygous mutations leading to the amino acid exchanges T351A and T610A in Miro1. We analyzed calcium homeostasis and MERCs in detail by live cell imaging and immunocytochemistry in patient‐derived fibroblasts. Results: We show that fibroblasts expressing mutant T351A or T610A Miro1 display impaired calcium homeostasis and a reduced amount of MERCs. All fibroblast lines from patients with pathogenic variants in Miro1, revealed alterations of the structure of MERCs. Conclusion: Our data suggest that Miro1 is important for the regulation of the structure and function of MERCs. Moreover, our study supports the role of MERCs in the pathogenesis of PD and further establishes variants in RHOT1 as rare genetic risk factors for neurodegeneration

Structure guided fluorescence labeling reveals a two-step binding mechanism of neomycin to its RNA aptamer

Publisher's version (útgefin grein)The ability of the cytidine analog Ç m f to act as a position specific reporter of RNA-dynamics was spectroscopically evaluated. Ç m f-labeled single-and double-stranded RNAs differ in their fluorescence lifetimes, quantum yields and anisotropies. These observables were also influenced by the nucleobases flanking Ç m f. This conformation and position specificity allowed to investigate the binding dynamics and mechanism of neomycin to its aptamer N1 by independently incorporating Ç m f at four different positions within the aptamer. Remarkably fast binding kinetics of neomycin binding was observed with stopped-flow measurements, which could be satisfactorily explained with a two-step binding. Conformational selection was identified as the dominant mechanism.Deutsche Forschungsgemeinschaft (DFG) through the Collaborative Research Center (CRC) 902; ‘Molecular Principles of RNA-based Regulation’ sub-projects A7, B14 and Mercator Fellowship. Funding for open access charge: DFG (CRC902); sub-projects A7, B14 and Mercator Fellowship.Peer Reviewe

Hippocampal overexpression of NOS1AP promotes endophenotypes related to mental disorders.

BACKGROUND Nitric oxide synthase 1 adaptor protein (NOS1AP; previously named CAPON) is linked to the glutamatergic postsynaptic density through interaction with neuronal nitric oxide synthase (nNOS). NOS1AP and its interaction with nNOS have been associated with several mental disorders. Despite the high levels of NOS1AP expression in the hippocampus and the relevance of this brain region in glutamatergic signalling as well as mental disorders, a potential role of hippocampal NOS1AP in the pathophysiology of these disorders has not been investigated yet. METHODS To uncover the function of NOS1AP in hippocampus, we made use of recombinant adeno-associated viruses to overexpress murine full-length NOS1AP or the NOS1AP carboxyterminus in the hippocampus of mice. We investigated these mice for changes in gene expression, neuronal morphology, and relevant behavioural phenotypes. FINDINGS We found that hippocampal overexpression of NOS1AP markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density, and changed dendritic spine morphology at CA1 synapses. At the behavioural level, we observed an impairment in social memory and decreased spatial working memory capacity. INTERPRETATION Our data provide a mechanistic explanation for a highly selective and specific contribution of hippocampal NOS1AP and its interaction with the glutamatergic postsynaptic density to cross-disorder pathophysiology. Our findings allude to therapeutic relevance due to the druggability of this molecule. FUNDING This study was funded in part by the DFG, the BMBF, the Academy of Finland, the NIH, the Japanese Society of Clinical Neuropsychopharmacology, the Ministry of Education of the Russian Federation, and the European Community

Eisosome proteins assemble into a membrane scaffold

Membrane organization by eisosomes is mediated by self-assembly of its main components into a membrane-bound protein scaffold with lipid-binding specificity

Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability

Interprofessional nutrition management – implementation and evaluation of a course for medical and nursing students using research-based learning method

Objective: The aim of the teaching project "Interprofessional Nutrition Management in Inpatient and Home Care" of the Medical Faculty of the Heinrich Heine University (HHU) and the Fliedner University of Applied Sciences Düsseldorf (FFH) was to test an interprofessional training session on the topic of malnutrition using the method of research-based learning to evaluate feasibility.Method: In the teaching project for medical and nursing students, research-based learning was applied in a case-based cross-sector setting. The teaching project was assessed quantitatively by the participating students through questionnaires and four newly-developed scales. The modeling and reliability of the scales (from 1 to 5) was confirmed by an exploratory factor analysis and Cronbach's alpha. The scales were evaluated descriptively and through inferential statistics.Results: The medical (n=21) and nursing students (n=25) rated the teaching project positively. Across all professional groups, the social context between the students (M=4.6) and the relevance of the topic (M=4.47) were rated very highly. The use of research-based learning (M=3.9) and the final assessment of the training session (M=3.9) were rated as satisfactory.Conclusions: The method of research-based learning proved to be very suitable for interprofessional education, as it enabled situations which encouraged the health professionals to learn from one another, about one another and with one another. Through the interdisciplinary discussion of malnutrition, cooperation skills and initial competences in nutritional management can be cultivated in future doctors and nursing staff even during training.Zielsetzung: Ziel des Lehrprojektes "Interprofessionelles Ernährungsmanagement in der stationären und häuslichen Versorgung" der Medizinischen Fakultät der Heinrich-Heine-Universität (HHU) und der Fliedner Fachhochschule Düsseldorf (FFH) war es eine interprofessionelle Lehrveranstaltung zum Schnittstellenthema Mangelernährung mit der Methode des Forschenden Lernens zu erproben und deren Machbarkeit zu evaluieren.Methodik: In dem Lehrprojekt für Medizin- und Pflegestudierende wurde Forschendes Lernen in einem fallbasierten sektorenübergreifenden Setting angewendet. Das Lehrprojekt wurde quantitativ mittels Fragebogen und vier neuentwickelten Skalen von den teilnehmenden Studierenden bewertet. Die Modellbildung und die Reliabilität der Skalen (Breite 1-5) wurde durch eine explorative Faktorenanalyse und Cronbachs Alpha abgesichert. Die Skalen wurden deskriptiv sowie inferenzstatistisch ausgewertet.Ergebnisse: Die Medizin- (n=21) und Pflegestudierenden (n=25) evaluierten das Lehrprojekt positiv. Berufsgruppenübergreifend wurde das Sozialklima zwischen den Studierenden (M=4,6) und die Relevanz des Themas (M=4,47) sehr hoch eingeschätzt. Die Anwendung des Forschenden Lernens (M=3,9) und die abschließende Einschätzung der Lehrveranstaltung (M=3,9) wurden als zufriedenstellend bewertet.Schlussfolgerungen: Die Methode des Forschenden Lernens erwies sich für interprofessionelle Ausbildung als sehr geeignet, da sie Lernsituationen ermöglichte, in welchen das von-, über- und miteinander Lernen der Gesundheitsberufe gefördert wurde. Durch die professionsübergreifende Auseinandersetzung mit Mangelernährung können bereits in der Ausbildung Kooperationskompetenzen und erste Handlungskompetenzen für Ernährungsmanagement bei den zukünftigen Ärztinnen und Ärzten und Pflegenden angebahnt werden

Comparison of years of life lost to 1,565 suicides versus 10,650 COVID-19 deaths in 2020 in Sweden : four times more years of life lost per suicide than per COVID-19 death

Background: The burden of disease from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is large; however, suicide affects the population year after year. From a public health perspective, it is important to not neglect contributors to the total burden of disease. The aim of this paper is to compare years of life lost (YLL) to suicide with those lost to coronavirus disease 2019 (COVID-19). Methods: A nationwide cohort study in 2020, in Sweden. YLL was measured as the sex- and age-specific remaining life expectancy at the time of the person’s death based on the death risks that pertained to the Swedish population in 2019. YLL to suicide was compared to YLL to COVID-19 and presented by sex and age groups. Suicide deaths in 2020 were estimated as the annual average of suicides in 2015–2019. Results: Annual average of suicide was 1,565, whereof 1,076 (68.8%) men and 489 (31.2%) women. In 2020, 10,650 persons died of COVID-19, whereof 5,681 (53.3%) men and 4,969 (46.7%) women. Estimated total YLL to suicide and COVID-19 in 2020 was 53,237 and 90,116, respectively. The COVID-19 YLL to suicide YLL ratio in 2020 was 1.69 (90,116/53,237). Men accounted for 67.1% of suicide YLL and of 56.4% of COVID-19 YLL. Those 44 years or younger accounted for 60.3% of suicide YLL and 3.9% of COVID-19 YLL. Those 75 years and older accounted for 2.9% of suicide YLL and 60.9% of COVID-19 YLL. On average, each suicide generates 34 YLL (53,237/1,565), and each COVID-19 death generates 8.5 YLL (90,116/10,650). Conclusions: YLL to suicide affects Sweden year after year, foremost attributable to the younger age groups, whereas YLL to COVID-19 is foremost attributable to the elderly. On average, each suicide generates four times more YLL than a COVID-19 death. Enormous efforts and resources have been put on tackling the pandemic, and without these, the burden would probably have been much larger. However, from a public health perspective, it is important to not neglect other contributors to the total burden of disease where national efforts also may have an impact

Overview of innovative technologies in liquid-liquid extraction regarding flexibility

As a result of increasing market volatility and product diversification the technology requirements will change in the future. Flexibility needs to be increased, enabling a large operating window while maintaining intensive mass and energy transfer and resource-efficiency. A promising approach is using innovative small-scale technologies. To assess flexibility, the technologies must be characterized in a wide range of operating parameters and physical properties. Therefore, research work on innovative technologies for liquid-liquid extraction is presented

Knockdown of the ADHD candidate gene Diras2 in murine hippocampal primary cells

Objective: The DIRAS2 gene is associated with ADHD, but its function is largely unknown. Thus, we aimed to explore the genes and molecular pathways affected by DIRAS2. Method: Using short hairpin RNAs, we downregulated Diras2 in murine hippocampal primary cells. Gene expression was analyzed by microarray and affected pathways were identified. We used quantitative real-time polymerase chain reaction (qPCR) to confirm expression changes and analyzed enrichment of differentially expressed genes in an ADHD GWAS (genome-wide association studies) sample. Results: Diras2 knockdown altered expression of 1,612 genes, which were enriched for biological processes involved in neurodevelopment. Expression changes were confirmed for 33 out of 88 selected genes. These 33 genes showed significant enrichment in ADHD patients in a gene-set-based analysis. Conclusion: Our findings show that Diras2 affects numerous genes and thus molecular pathways that are relevant for neurodevelopmental processes. These findings may further support the hypothesis that DIRAS2 is linked to etiological processes underlying ADHD. (J. of Att. Dis. 2021; 25(4) 572-583)