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Parey, Kristian Kurt ; Lasham, Jonathan ; Mills, Deryck J. ; Djurabekova, Amina ; Haapanen, Outi ; Galemou Yoga, Etienne ; Xie, Hao ; Kühlbrandt, Werner ; Sharma, Vivek ; Vonck, Janet ; Zickermann, Volker
Mitochondrial NADH:ubiquinone oxidoreductase (complex I) is a 1-MDa membrane protein complex with a central role in energy metabolism. Redox-driven proton translocation by complex I contributes substantially to the proton motive force that drives ATP synthase. Several structures of complex I from bacteria and mitochondria have been determined, but its catalytic mechanism has remained controversial. We here present the cryo-EM structure of complex I from Yarrowia lipolytica at 2.1-Å resolution, which reveals the positions of more than 1600 protein-bound water molecules, of which ~100 are located in putative proton translocation pathways. Another structure of the same complex under steady-state activity conditions at 3.4-Å resolution indicates conformational transitions that we associate with proton injection into the central hydrophilic axis. By combining high-resolution structural data with site-directed mutagenesis and large-scale molecular dynamic simulations, we define details of the proton translocation pathways and offer insights into the redox-coupled proton pumping mechanism of complex I.
Dietrich, Anya ; Pinzuti, Edoardo ; Cabral-Calderı́n, Yuranny ; Müller-Dahlhaus, Florian ; Wibral, Michael ; Tüscher, Oliver
Human behaviour is inextricably linked to the interaction of emotion and cognition. For decades, emotion and cognition were perceived as separable processes, yet with mutual interactions. Recently, this differen-tiation has been challenged by more integrative approaches, but without addressing the exact neurophysiological basis of their interaction. Here, we aimed to uncover neurophysiological mechanisms of emotion-cognition interaction. We used an emotional Flanker task paired with EEG/FEM beamforming in a large cohort (N=121) of healthy human participants, obtaining high temporal and fMRI-equivalent spatial resolution. Spatially, emotion and cognition processing overlapped in the right inferior frontal gyrus (rIFG), specifically in pars triangularis. Temporally, emotion and cognition processing overlapped during the transition from emotional to cognitive processing, with a stronger interaction in β-band power leading to worse behavioral performance. Despite functionally segregated subdivisions in rIFG, frequency-specific information flowed extensively within IFG and top-down to visual areas (V2, Precuneus) – explaining the behavioral interference effect. Thus, for the first time we here show the neural mechanisms of emotion-cognition interaction in space, time, frequency and information transfer with high temporal and spatial resolution, revealing a central role for β-band activity in rIFG. Our results support the idea that rIFG plays a broad role in both inhibitory control and emotional interference inhibition as it is a site of convergence in both processes. Furthermore, our results have potential clinical implications for understanding dysfunctional emotion-cognition interaction and emotional interference inhibition in psychiatric disor-ders, e.g. major depression and substance use disorder, in which patients have difficulties in regulating emotions and executing inhibitory control.
Diabetes mellitus Typ 2 (T2D) ist eine der häufigsten Stoffwechselerkrankungen mit weltweit steigender Inzidenz. Zur Vermeidung von Folgeerkrankungen und Senkung des enormen ökonomischen Drucks steht die Suche nach wirksamen Therapiekonzepten im Fokus aktueller Forschung.
Die Vitamin D (VD) Konzentration (25(OH)D3 und 1,25(OH)2D3) hat Einfluss auf Bodymaßindex (BMI), Glukosestoffwechsel, Insulinsekretion und -resistenz sowie die β-Zellfunktion. Niedrige VD Konzentrationen wirken sich ungünstig auf den Blutzucker oder den BMI aus und ein VD Mangel (25(OH)D3 < 20 ng/ml) ist mit einem erhöhten Risiko für Diabetes mellitus Typ 2 assoziiert. Während eine VD Einnahme das Risiko für einen VD Mangel reduziert, zeigen sich kaum Einflüsse auf die Glucosehomöostase. Die berichteten Effekte einer VD Einnahme in der Prävention oder Behandlung eines T2D rangieren von einer verbesserten Stoffwechseleinstellung bis zur Verschlechterung der Erkrankung.
Bezüglich des Ansprechens auf eine VD Einnahme zeigt sich eine große individuelle Varianz. In welchem Ausmaß der genetische Hintergrund das individuelle Ansprechen auf eine VD Einnahme bei Patienten mit T2D beeinflusst wurde bislang jedoch kaum erforscht.
In dieser Arbeit wurde der Einfluss genetischer Varianten (SNPs - Single nucleotide polymorphisms) des VD Stoffwechsels auf (1) Anfälligkeit für T2D, (2) 25(OH)D3 und 1,25(OH)2D3 Plasma Konzentrationen sowie (3) Änderungen in der Stoffwechseleinstellung nicht insulinabhängiger Typ 2 Diabetiker unter VD3 Substitution untersucht. Dafür wurden zwölf SNPs in fünf Genen des VD Stoffwechsels (CYP2R1 (Cytochrom P450 2R1), CYP27B1, DBP (VD Bindeprotein), VDR (VD Rezeptor), CYP24A1 analysiert. 553 Patienten mit T2D und 916 gesunde Kontrollen aus Frankfurt am Main und Umgebung wurden mittels restriction fragment length polymorphism (RFLP) und realtime polymerase chain reaction (rtPCR) genotypisiert. Die VD Plasma-Konzentrationen (25(OH)D3 und 1,25(OH)2D3) wurden per 125Iod-Radioimmunoassay gemessen.
Ein erhöhtes Risiko an Diabetes mellitus Typ 2 zu erkranken ergab sich für die Allele VDR rs7975232 „G“, rs1544410 „G“ und CYP2R1 rs10741657 „A“.
Diabetiker wiesen im Vergleich zu gesunden Kontrollen erniedrigte 25(OH)D3 und 1,25(OH)2D3 auf. Das Risiko eines T2D bei Vorliegen eines VD Mangels war in unserer Kohorte um das 13,9 fache erhöht.
Eine genotypenabhängige Reduktion der 25(OH)D3 Plasma-Konzentrationen bei Patienten ergab sich für die Genotypen CYP27B1 rs10877012 „CC“, DBP rs4588 „CC“, rs7041 „GG“, CYP24A1 rs2585426 „CG“ und rs2248137 „CG“. Eine verringerte 1,25(OH)2D3 Plasma-Konzentration ergab sich für den Genotyp DBP rs4588 „CC“.
Der genetisch Einfluss auf Änderungen in der Stoffwechseleinstellung nicht insulinabhängiger Typ 2 Diabetiker unter VD3 Substitution wurde im Rahmen einer doppelt-verblindeten randomisierten Studie untersucht. 65 Patienten erhielten über 6 Monate entweder 1904 IU Vitamin D Öl (25(OH)D3) oder ein Placebo-Öl. Alle drei Monate wurden die Vitamin D Konzentrationen, der HbA1c, die Parathormonkonzentration (PTH) und das C-Peptid bis zu einem 6 monatigen Follow-up bestimmt.
Während bei Trägern des Genotyps CPY24A1 rs2296241 „GG“ trotz VD Einnahme keine Änderung der Plasma 25(OH)D3 Werte zu verzeichnen waren, ergaben sich für die Genotypen DBP 4588 „CC“ and VDR rs1544410 „GG“ höhere 25(OH)D3 Konzentrationen bis zum Ende des Nachbeobachtungszeitraums. Eine signifikante Suppression des PTH konnte bei den Genotypen CYP2R1 rs10741657 „AG“, DBP rs4588 „CC“, VDR rs2228570 „TC“ und CYP24A1 ra2248137 „GG“ beobachtet werden.
Diese Studie bestätigt VD Mangel als Risikofaktor für T2D. Sie zeigt deutlich, dass genetische Varianten des VD Systems für T2D prädisponieren und anteilig den VD Stoffwechsel regulieren. Auch die Auswirkungen einer VD3 Einnahme, messbar im Anstieg der 25(OH)D3 Konzentration und der Suppression des PTH, sind durch die Gene des VD Systems beeinflusst.
Cardiovascular disease (CVD) is the leading cause of death in the western world. Aging as the major risk factor for the development of CVD leads to structural changes in the heart and the vasculature. In addition to endothelial cells, mural cells, including smooth muscle cells and pericytes, form the vascular wall. Pericytes are defined as the perivascular cells located in the basement membrane of the capillaries, which are the smallest components of the vascular system and ensure the gas exchange in the tissue. In the different parts of the terminal vascular bed, pericytes receive different phenotypes and organ-specific functions. In addition to the stabilization of the vascular wall, pericytes are relevant for the formation of new vessels. Due to their potential of multipotent stem cells, pericytes can differentiate into different cell types and thus take a position in developmental processes. Pericytes play a crucial role in the development and diseases of the vascular system. Moreover, pericyte coverage is reduced in the aged heart. Nonetheless, the function of pericytes in the heart and their importance during cardiac aging is not completely understood.
To study the pericyte population in the aging heart, we have performed single-nucleus RNA-sequencing analysis comparing hearts from 12-weeks-old (young) and 18-month-old (old) mice. The detailed analysis of 336 differentially expressed genes (DEG) revealed that Rgs5 is downregulated in aged pericytes. Regulator of G-protein signaling 5 (RGS5), an established marker for pericytes, is involved the regulation of the blood pressure and in the formation of various cardiovascular diesases, including cardiac hypertrophy, myocardial infarction and atherosclerosis. We have furthermore confirmed this observation in vivo. Gene ontology (GO) analysis of DEG revealed that aged pericytes are characterized by the downregulation of genes involved in cell adhesion. Further, we have performed cell biology approaches using human brain vascular pericytes (hBVP) to investigate the role of Rgs5 in pericytes in vitro. Efficient knockdown of RGS5, although has no effect on cellular metabolism, viability and endothelial permeability, induces a reduction of pericyte adhesion to both a gelatine matrix and endothelial cells in a 3D matrigel culture. This was associated with the formation of filopodia. The altered phenotype suggested a changing identity of the pericytes. We could confirm that a loss of RGS5 causes a decreased expression of the pericyte markers PDGFRb and NOTCH3 and also leads to an overexpression of COL1A1, a fibroblast marker.
Together, our findings suggest that RGS5 is required for pericyte adhesion to endothelial cells and its downregulation in the aged mural cells could explain the reduction of pericyte coverage in the aged hearts. Further, RGS5 may be the key regulator for pericyte identity, as pericytes show an altered expression profile of cellular markers. The dedifferentiation of pericytes to a more fibroblast-like cell type could explain the increased fibrosis during age-related cardiac remodeling. We believe that RGS5 is a great candidate to explore and study the molecular mechanisms that regulate pericyte function in the heart, both in homeostasis and during aging.
Providing an interactive undergraduate elective on safety culture online – concept and evaluation
(2022)
Müller, Angelina ; Sawicki, Olga Anastasia ; Pommee, Marina ; Blazejewski, Tatjana ; Schneider, Kyra ; Moskovits, Judith ; Petersen, Juliana ; Müller, Beate
Background: The COVID-19 pandemic has made it more difficult to maintain high quality in medical education. As online formats are often considered unsuitable, interactive workshops and seminars have particularly often been postponed or cancelled. To meet the challenge, we converted an existing interactive undergraduate elective on safety culture into an online event. In this article, we describe the conceptualization and evaluation of the elective.
Methods: The learning objectives of the safety culture elective remained unchanged, but the teaching methods were thoroughly revised and adapted to suit an online setting. The online elective was offered as a synchronous two-day course in winter semester 2020/21 during the “second wave” of the COVID-19 pandemic in Germany. At the end of each day, participating students evaluated the elective by completing an online survey. Items were rated on a six-point Likert scale. We used SPSS for data analysis.
Results: Twenty medical undergraduates completed the elective and rated it extremely positively (1.1 ± 0.2). Students regard safety culture as very important and felt the learning objectives had been achieved. Moreover, they were very satisfied with the design and content of the elective, and especially with interactive elements like role-play. Around 55% of participants would recommend continuing to offer the online elective after the pandemic.
Conclusions: It makes sense to offer undergraduate medical students online elective courses on safety culture, especially during a pandemic. The elective described here can serve as a best practice example of how to teach safety culture to undergraduates, especially when physical presence is unfeasible. Electives requiring a high degree of interaction can also function well online.
Rosbach, Nicolas ; Wenger-Alakmeh, Katharina Johanna ; Lahrsow, Maximilian ; Mahmoudi, Scherwin ; Bernatz, Simon ; Vogl, Thomas J. ; Schreckenbach, Tobias ; Pession, Ursula ; Gruber-Rouh, Tatjana
Rationale and objectives: The objective of this study was to analyze the role of dynamic magnetic resonance imaging (MRI) in patients who suffered from groin pain and whose physical examination and ultrasound returned inconclusive/indefinite results, as well as in patients receiving an ongoing assessment for a previous herniotomy.
Material and methods: For this study, 25 patients 14 women and 11 men were selected with a mean age of 41.6 years, including clinical complaints, such as groin pain and or a previous herniotomies. These patients underwent dynamic MRI. Reports were created by a radiology resident and a radiology consultant. Clinical and ultrasound documentation were compared to with imaging results from the MRI.
Results: The results of the dynamic MRI were negative for 23 patients (92%) and positive for two patients (8%). One patient suffered from an indirect hernia and one from a femoral hernia. A repeated hernia was an excluding for the preoperated patients with pain and ongoing assessment.
Conclusions: Dynamic MRI shows substantially higher diagnostic performance in exclusion of inguinal hernia, when compared to a physical examination and ultrasound. The examination can also be used in assessments to analyze the operation’s results.
Reif-Leonhard, Christine ; Lemke, Dorothea ; Holz, Franziska ; Ahrens, Kira F. ; Fehr, Christoph ; Steffens, Markus ; Grube, Michael ; Freitag, Christine M. ; Kölzer, Sarah C. ; Schlitt, Sabine ; Gebhardt, Rebekka ; Gädeke, Theresa Rita ; Schmidt, Helga ; Gerlach, Ferdinand M. ; Wolff, Kira ; Stäblein, Michael ; Hauschild, Nora ; Beig, Inga ; Wagner, Louisa ; Müller, Juliane ; Verhoff, Marcel A. ; Schlang, Christiane ; Reif, Andreas
The consequences of the current COVID-19 pandemic for mental health remain unclear, especially regarding the effects on suicidal behaviors. To assess changes in the pattern of suicide attempt (SA) admissions and completed suicides (CS) in association with the COVID-19 pandemic. As part of a longitudinal study, SA admissions and CS are systematically documented and analyzed in all psychiatric hospitals in Frankfurt/Main (765.000 inhabitants). Number, sociodemographic factors, diagnoses and methods of SA and CS were compared between the periods of March–December 2019 and March–December 2020. The number of CS did not change, while the number of SA significantly decreased. Age, sex, occupational status, and psychiatric diagnoses did not change in SA, whereas the percentage of patients living alone while attempting suicide increased. The rate and number of intoxications as a SA method increased and more people attempted suicide in their own home, which was not observed in CS. Such a shift from public places to home is supported by the weekday of SA, as the rate of SA on weekends was significantly lower during the pandemic, likely because of lockdown measures. Only admissions to psychiatric hospitals were recorded, but not to other institutions. As it seems unlikely that the number of SA decreased while the number of CS remained unchanged, it is conceivable that the number of unreported SA cases increased during the pandemic. Our data suggest that a higher number of SA remained unnoticed during the pandemic because of their location and the use of methods associated with lower lethality.
The ongoing SARS-CoV-2 pandemic is characterized by poor outcome and a high mortality especially in the older patient cohort. Up to this point there is a lack of data characterising COVID-19 patients in Germany admitted to intensive care (ICU) vs. non-ICU patients. German Reimbursement inpatient data covering the period in Germany from January 1st, 2020 to December 31th, 2021 were analyzed. 561,379 patients were hospitalized with COVID-19. 24.54% (n = 137,750) were admitted to ICU. Overall hospital mortality was 16.69% (n = 93,668) and 33.36% (n = 45,947) in the ICU group. 28.66% (n = 160,881) of all patients suffer from Cardiac arrhythmia and 17.98% (n = 100,926) developed renal failure. Obesity showed an odds-ratio ranging from 0.83 (0.79–0.87) for WHO grade I to 1.13 (1.08–1.19) for grade III. Mortality-rates peaked in April 2020 and January 2021 being 21.23% (n = 4539) and 22.99% (n = 15,724). A third peak was observed November and December 2021 (16.82%, n = 7173 and 16.54%, n = 9416). Hospitalized COVID-19 patient mortality in Germany is lower than previously shown in other studies. 24.54% of all patients had to be treated in the ICU with a mortality rate of 33.36%. Congestive heart failure was associated with a higher risk of death whereas low grade obesity might have a protective effect on patient survival. High admission numbers are accompanied by a higher mortality rate.