Transport of Na+ and K+ by an antiporter-related subunit from the Escherichia coli NADH dehydrogenase I produced in Saccharomyces cerevisiae

The NADH dehydrogenase I from Escherichia coli is a bacterial homolog of the mitochondrial complex I which translocates Na+ rather than H+. To elucidate the mechanism of Na+ transport, the C-terminally truncated NuoL subunit (NuoLN) which is related to Na+/H+ antiporters was expressed as a protein A fusion protein (ProtA-NuoLN) in the yeast Saccharomyces cerevisiae which lacks an endogenous complex I. The fusion protein inserted into membranes from the endoplasmatic reticulum (ER), as confirmed by differential centrifugation and Western analysis. Membrane vesicles containing ProtA-NuoLN catalyzed the uptake of Na+ and K+ at rates which were significantly higher than uptake by the control vesicles under identical conditions, demonstrating that ProtA-NuoLN translocated Na+ and K+ independently from other complex I subunits. Na+ transport by ProtA-NuoLN was inhibited by EIPA (5-(N-ethyl-N-isopropyl)-amiloride) which specifically reacts with Na+/H+ antiporters. The cation selectivity and function of the NuoL subunit as a transporter module of the NADH dehydrogenase complex is discusse

Vascular endothelial cells: heterogeneity and targeting approaches

Forming the inner layer of the vascular system, endothelial cells (ECs) facilitate a multitude of crucial physiological processes throughout the body. Vascular ECs enable the vessel wall passage of nutrients and diffusion of oxygen from the blood into adjacent cellular structures. ECs regulate vascular tone and blood coagulation as well as adhesion and transmigration of circulating cells. The multitude of EC functions is reflected by tremendous cellular diversity. Vascular ECs can form extremely tight barriers, thereby restricting the passage of xenobiotics or immune cell invasion, whereas, in other organ systems, the endothelial layer is fenestrated (e.g., glomeruli in the kidney), or discontinuous (e.g., liver sinusoids) and less dense to allow for rapid molecular exchange. ECs not only differ between organs or vascular systems, they also change along the vascular tree and specialized subpopulations of ECs can be found within the capillaries of a single organ. Molecular tools that enable selective vascular targeting are helpful to experimentally dissect the role of distinct EC populations, to improve molecular imaging and pave the way for novel treatment options for vascular diseases. This review provides an overview of endothelial diversity and highlights the most successful methods for selective targeting of distinct EC subpopulations

Traumatic Events, Social Adversity and Discrimination as Risk Factors for Psychosis - An Umbrella Review

Exposure to childhood trauma is a well-known risk factor for severe mental disorders including schizophrenia and other non-affective psychoses. Beyond childhood trauma, there is increasing evidence that bullying, social exclusion, and discrimination during adolescence and adulthood may increase the risk of developing a psychotic disorder, and that such forms of traumatization may also underlie the elevated psychosis risk among migrants or persons with a visible minority status. In this umbrella review, we systematically assess meta-analyses regarding trauma and social adversity. A systematic literature review yielded 11 meta-analyses that met inclusion criteria and could be summarized quantitatively with a random effect model. Furthermore, six meta-analyses were evaluated qualitatively. Heterogeneity and publication bias were apparent in several meta-analyses. We observed that most significant social risk factors for psychosis were vulnerability for racist discrimination [OR = 3.90 (3.25-4.70)], migration [OR = 2.22 (1.75-2.80)], and childhood adversities [OR = 2.81 (2.03-3.83)]. Furthermore, social factors increasing the risk for psychosis were variation/impairment of parental communication, aversive adult life events, bullying, and factors associated with social isolation and discrimination. In spite of these environmental risk factors, there is a lack of evidence regarding treatment of trauma and psychosis, although some psychotherapeutic and art therapy approaches appear to be promising. Beyond individual interventions, stigmatization, racism, and other forms of discrimination need to be targeted to increase solidarity and communal support

Levels of Structural Integration Mediate the Impact of Metacognition on Functioning in Non-affective Psychosis: Adding a Psychodynamic Perspective to the Metacognitive Approach

Synthetic metacognition is defined by integrative and contextualizing processes of discrete reflexive moments. These processes are supposed to be needed to meet intrapsychic as well as interpersonal challenges and to meaningfully include psychotic experience in a personal life narrative. A substantial body of evidence has linked this phenomenon to psychosocial functioning and treatment options were developed. The concept of synthetic metacognition, measured with the Metacognition Assessment Scale-Abbreviated (MAS-A), rises hope to bridge gaps between therapeutic orientations and shares valuable parallels to modern psychodynamic constructs, especially the 'levels of structural integration' of the Operationalized Psychodynamic Diagnosis (OPD-2). As theoretical distinctions remain, aim of this study was to compare the predictive value of both constructs with regard to psychosocial functioning of patients with non-affective psychoses, measured with the International Classification of Functioning, Disability and Health (MINI-ICF-APP). It was further explored if levels of structural integration (OPD-LSIA) would mediate the impact of metacognition (MAS-A) on function (MINI-ICF-APP). Expert ratings of synthetic metacognition (MAS-A), the OPD-2 'levels of structural integration' axis (OPD-LSIA), psychosocial functioning (MINI-ICF-APP) and assessments of general cognition and symptoms were applied to 100 individuals with non-affective psychoses. Whereas both, MAS-A and OPD-LSIA, significantly predicted MINI-ICF-APP beyond cognition and symptoms, OPD-LSIA explained a higher share of variance and mediated the impact of MAS-A on MINI-ICF-APP. Levels of structural integration, including the quality of internalized object representations and unconscious interpersonal schemas, might therefore be considered as valuable predictors of social functioning and as one therapeutic focus in patients with non-affective psychoses. Structural integration might go beyond and form the base of a person's actual reflexive and metacognitive capabilities. Psychotherapeutic procedures specific for psychoses may promote and challenge a patient's metacognitive capacities, but should equally take the need for maturing structural skills into account. Modern psychodynamic approaches to psychosis are shortly presented, providing concepts and techniques for the implicit regulation of interpersonal experience and aiming at structural integration in this patient group

„Digitale Lerngemeinschaften“ im Praxissemester. Wahrnehmung eines Angebots zur Theorie-Praxis-Relationierung in der Lehrkräftebildung für das Fach Deutsch

Der Artikel stellt erste deutschdidaktische Befunde des Projekts DiLe („Digitale Lerngemeinschaften zur kohärenten Lernbegleitung im Jenaer Modell der Lehrerbildung“) vor. DiLe zielt darauf, die Kooperation zwischen Schule und Universität bei der Begleitung von Praxissemesterstudierenden zu verbessern. Schulische Mentor:innen im Praxissemester erhalten die Gelegenheit, mit Hilfe digitaler Fortbildungsbausteine ihr fachdidaktisches Wissen zu erweitern und im Dialog mit Praxissemesterstudieren-den auf Anforderungssituationen im Unterricht zu beziehen. Der Artikel untersucht, mit welchen Erwartungen die Teilnehmenden im Fach Deutsch in die Fortbildung starten, inwieweit sie diese erfüllt sehen und inwieweit sie deutschdidaktische Fortbildungsinhalte im digitalen Austausch aufgreifen. Als Daten dienen Kurzstatements der Teilnehmenden (prä/post), Mitschnitte von Videokonferenzen sowie nachträgliche Interviews, die allesamt inhaltsanalytisch ausgewertet wurden. Die Diskussion der Befunde geht darauf ein, inwieweit digital gesteuerte Vermittlungs- und Verständigungsprozesse zwischen den Beteiligten einen Beitrag zur Überwindung der doppelten Distanz zwischen Universität und Schule leisten können.   Abstract (english): Digital learning communities during the teaching practicum. Perception of an approach to the connection between theory and practice in the training of teachers of the subject German The article presents first results of the project DiLe („Digital Learning Communities for Coherent Learning Support in the Model of Teacher Education in Jena“). The project aims to improve the cooperation between school and university in the supervision of students in the 5-month teaching practicum. School mentors in the teaching practicum are given the opportunity to expand their academic knowledge of teaching German language and literature with the help of digital training modules. So, they can relate academic knowledge to the requirements of the classroom in a dialog with students in the teaching practicum. The article explores the expectations of the par-ticipants in the subject German. It also asks to what extent they see these expectations fulfilled and to what extent they take up the presented academic knowledge in the digital exchange. Our data consists of short statements of the participants (pre/post), recordings of video conferences as well as interviews. The discussion of the results addresses the extent to which digitally controlled teaching and communica-tion processes between the participants can help to overcome the double distance between university and school

Empowering Clinicians and Democratizing Data Science: Large Language Models Automate Machine Learning for Clinical Studies

A knowledge gap persists between Machine Learning (ML) developers (e.g., data scientists) and practitioners (e.g., clinicians), hampering the full utilization of ML for clinical data analysis. We investigated the potential of the chatGPT Advanced Data Analysis (ADA), an extension of GPT-4, to bridge this gap and perform ML analyses efficiently. Real-world clinical datasets and study details from large trials across various medical specialties were presented to chatGPT ADA without specific guidance. ChatGPT ADA autonomously developed state-of-the-art ML models based on the original study's training data to predict clinical outcomes such as cancer development, cancer progression, disease complications, or biomarkers such as pathogenic gene sequences. Strikingly, these ML models matched or outperformed their published counterparts. We conclude that chatGPT ADA offers a promising avenue to democratize ML in medicine, making advanced analytics accessible to non-ML experts and promoting broader applications in medical research and practice

Collaborative Training of Medical Artificial Intelligence Models with non-uniform Labels

Artificial intelligence (AI) methods are revolutionizing medical image analysis. However, robust AI models require large multi-site datasets for training. While multiple stakeholders have provided publicly available datasets, the ways in which these data are labeled differ widely. For example, one dataset of chest radiographs might contain labels denoting the presence of metastases in the lung, while another dataset of chest radiograph might focus on the presence of pneumonia. With conventional approaches, these data cannot be used together to train a single AI model. We propose a new framework that we call flexible federated learning (FFL) for collaborative training on such data. Using publicly available data of 695,000 chest radiographs from five institutions - each with differing labels - we demonstrate that large and heterogeneously labeled datasets can be used to train one big AI model with this framework. We find that models trained with FFL are superior to models that are trained on matching annotations only. This may pave the way for training of truly large-scale AI models that make efficient use of all existing data.Comment: 2 figures, 3 tables, 5 supplementary table

Modeling Incoherent Discourse in Non-Affective Psychosis

Background: Computational linguistic methodology allows quantification of speech abnormalities in non-affective psychosis. For this patient group, incoherent speech has long been described as a symptom of formal thought disorder. Our study is an interdisciplinary attempt at developing a model of incoherence in non-affective psychosis, informed by computational linguistic methodology as well as psychiatric research, which both conceptualize incoherence as associative loosening. The primary aim of this pilot study was methodological: to validate the model against clinical data and reduce bias in automated coherence analysis. Methods: Speech samples were obtained from patients with a diagnosis of schizophrenia or schizoaffective disorder, who were divided into two groups of n = 20 subjects each, based on different clinical ratings of positive formal thought disorder, and n = 20 healthy control subjects. Results: Coherence metrics that were automatically derived from interview transcripts significantly predicted clinical ratings of thought disorder. Significant results from multinomial regression analysis revealed that group membership (controls vs. patients with vs. without formal thought disorder) could be predicted based on automated coherence analysis when bias was considered. Further improvement of the regression model was reached by including variables that psychiatric research has shown to inform clinical diagnostics of positive formal thought disorder. Conclusions: Automated coherence analysis may capture different features of incoherent speech than clinical ratings of formal thought disorder. Models of incoherence in non-affective psychosis should include automatically derived coherence metrics as well as lexical and syntactic features that influence the comprehensibility of speech

MiR-200c-3p modulates cisplatin resistance in biliary tract cancer by ZEB1-independent mechanisms

Biliary tract cancer is a major global health issue in cancer-related mortality. Therapeutic options are limited, and cisplatin-based treatment schedules represent the mainstay of first-line therapeutic strategies. Although the gain of survival by the addition of cisplatin to gemcitabine is moderate, acquired cisplatin resistance frequently leads to treatment failures with mechanisms that are still poorly understood. Epithelial–mesenchymal transition (EMT) is a dynamic process that changes the shape, function, and gene expression pattern of biliary tract cancer cells. In this study, we explored the influence of the EMT-regulating miR-200c-3p on cisplatin sensitivity in biliary tract cancer cells. Using gain of function experiments, we demonstrated that miR-200c-3p regulates epithelial cell markers through the downregulation of the transcription factor ZEB1. MiR-200c-3p upregulation led to a decreased sensitivity against cisplatin, as observed in transient overexpression models as well as in cell lines stably overexpressing miR-200c-3p. The underlying mechanism seems to be independent of miR-200c-3p’s influence on ZEB1 expression, as ZEB1 knockdown resulted in the opposite effect on cisplatin resistance, which was abolished when ZEB1 knockdown and miR-200c-3p overexpression occurred in parallel. Using a gene panel of 40 genes that were previously associated with cisplatin resistance, two (Dual Specificity Phosphatase 16 (DUSP16) and Stratifin (SFN)) were identified as significantly (>2 fold, p-value < 0.05) up-regulated in miR-200c-3p overexpressing cells. In conclusion, miR-200c-3p might be an important contributor to cisplatin resistance in biliary tract cancer, independently of its interaction with ZEB1

Assessment of treatment response in cardiac sarcoidosis based on myocardial 18^{18}F-FDG uptake

OBJECTIVE Immunosuppressive therapy for cardiac sarcoidosis (CS) still largely consists of corticosteroid monotherapy. However, high relapse rates after tapering and insufficient efficacy are significant problems. The objective of this study was to investigate the efficacy and safety of non-biological and biological disease-modifying anti-rheumatic drugs (nb/bDMARDs) considering control of myocardial inflammation assessed by $^{18}$F-fluorodeoxyglucose positron emission tomography/computed tomography ($^{18}$F-FDG PET/CT) of the heart. METHODS We conducted a retrospective analysis of treatment response to nb/bDMARDs of all CS patients seen in the sarcoidosis center of the University Hospital Zurich between January 2016 and December 2020. RESULTS We identified 50 patients with CS. Forty-five patients with at least one follow-up PET/CT scan were followed up for a mean of 20.5 ± 12.8 months. Most of the patients were treated with prednisone and concomitant nb/bDMARDs. At the first follow-up PET/CT scan after approximately 6.7 ± 3 months, only adalimumab showed a significant reduction in cardiac metabolic activity. Furthermore, comparing all serial follow-up PET/CT scans (143), tumor necrosis factor inhibitor (TNFi)-based therapies showed statistically significant better suppression of myocardial $^{18}$F-FDG uptake compared to other treatment regimens. On the last follow-up, most adalimumab-treated patients were inactive (n = 15, 48%) or remitting (n = 11, 35%), and only five patients (16%) were progressive. TNFi was safe even in patients with severely reduced left ventricular ejection fraction (LVEF), and a significant improvement in LVEF under TNFi treatment was observed. CONCLUSION TNFi shows better control of myocardial inflammation compared to nbDMARDs and corticosteroid monotherapies in patients with CS. TNFi was efficient and safe even in patients with severely reduced LVEF