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Rhodopsins are the most universal biological light-energy transducers and abundant phototrophic mechanisms that evolved on Earth and have a remarkable diversity and potential for biotechnological applications. Recently, the first sodium-pumping rhodopsin KR2 from Krokinobacter eikastus was discovered and characterized. However, the existing structures of KR2 are contradictory, and the mechanism of Na+ pumping is not yet understood. Here, we present a structure of the cationic (non H+) light-driven pump at physiological pH in its pentameric form. We also present 13 atomic structures and functional data on the KR2 and its mutants, including potassium pumps, which show that oligomerization of the microbial rhodopsin is obligatory for its biological function. The studies reveal the structure of KR2 at nonphysiological low pH where it acts as a proton pump. The structure provides new insights into the mechanisms of microbial rhodopsins and opens the way to a rational design of novel cation pumps for optogenetics.
En 1943, Friedrich H. Tenbruck (1914-1994) obtient sa thèse de philosophe à l’Université de Marburg. Dans les années 1950, il se tourne vers la sociologie, devient entre autres pour quelques mois l’assistant de Max Horkheimer à l’Université de Francfort-sur-le-Main. Puis il occupe pendant cinq ans un poste de professeur assistant à Geneva/New York. Après son retour, en 1962, il est habilité à la direction de recherches avec un travail sur histoire et société en sociologie et sciences sociales à Fribourg, puis occupe à partir de 1963 la chaire de sociologie à l’Université de Francfort-sur-le-Main. En 1967, il devient professeur à l’Université de Tübingen. ...
Purpose: To investigate the efficacy and safety of Descemet membrane endothelial keratoplasty (DMEK) for corneal decompensation following primary Descemet stripping automated endothelial keratoplasty (DSAEK).
Methods: This was a retrospective case series of 15 patients that underwent DMEK surgery for corneal decompensation after failed DSAEK. Main outcome parameter was corrected distance visual acuity (CDVA) after DMEK and DSAEK. Secondary outcome measures included central corneal thickness (CCT), endothelial cell density (ECD), rebubbling rate, and primary graft failure after DMEK. Explanted DSAEK grafts were evaluated by light microscopy.
Results: The mean (±SD) time period between DSAEK and DMEK surgery was 15±8 months (range, 6–31 months). Preoperative CDVA was 1.72±0.62 (logMAR). After DMEK, CDVA improved significantly to 0.78±0.48 at 1 month and to 0.23±0.24 after 12 months (P=0.022). Visual acuity data after DMEK were significantly better compared to preoperative values. The average CCT after DMEK decreased significantly from 869±210 µm (preoperative) to 505±45 µm (1 month postoperative) (P<0.001) and remained stable over 12 months. The ECD decreased from 2,589±209/mm2 (preoperative) to 1,691±589/mm2 (12 months postoperative). Rebubbling DMEK was required in three patients (=20%).
Conclusion: DMEK represents a feasible and safe procedure in achieving better functional results compared to DSAEK. Visual acuity and optical quality can be effectively reestablished after unsuccessful primary DSAEK surgery even in patients with long-standing corneal decompensation. Further investigations are required to validate the preliminary clinical findings.
Le xviiie est le siècle de la révolution constitutionnelle moderne. Les droits de l’homme et du citoyen y furent proclamés, et le droit ancré dans la démocratie. Les choses ont commencé dans quelques États d’Amérique, leur unification a suivi, mais l’événement à proprement parler dramatique, qui allait faire de la révolution constitutionnelle un événement irréversible, fut la Révolution française de 1789. Revendiquer des constitutions fut l’élément dominant du xixe siècle, tenir la promesse de réaliser les droits de l’homme et la démocratie celui du xxe siècle. L’arc se tend sans peine de 1789 à 1989, et même après, il n’y a pas d’issue visible, pas d’alternative en vue. Même le vent froid de la globalisation n’a pas fait pâlir les espoirs utopiques orientés vers la démocratie et les droits de l’homme. ...
Mechanism of the electroneutral sodium/proton antiporter PaNhaP from transition-path shooting
(2019)
Na+/H+ antiporters exchange sodium ions and protons on opposite sides of lipid membranes. The electroneutral Na+/H+ antiporter NhaP from archaea Pyrococcus abyssi (PaNhaP) is a functional homolog of the human Na+/H+ exchanger NHE1, which is an important drug target. Here we resolve the Na+ and H+ transport cycle of PaNhaP by transition-path sampling. The resulting molecular dynamics trajectories of repeated ion transport events proceed without bias force, and overcome the enormous time-scale gap between seconds-scale ion exchange and microseconds simulations. The simulations reveal a hydrophobic gate to the extracellular side that opens and closes in response to the transporter domain motion. Weakening the gate by mutagenesis makes the transporter faster, suggesting that the gate balances competing demands of fidelity and efficiency. Transition-path sampling and a committor-based reaction coordinate optimization identify the essential motions and interactions that realize conformational alternation between the two access states in transporter function.
Hauke Brunkhorst
(2009)
Hauke Brunkhorst ist ein deutscher Soziologe, geboren 1945 in Marne (Holstein). Er studierte Deutsche Literaturwissenschaft, Philosophie, Erziehungswissenschaft und Soziologie in Kiel, Freiburg und Frankfurt. 1978 wurde er promoviert (Praxisbezug und Theoriebildung). 1982 folgte seine Habilitation im Fach Erziehungswissenschaft an der Universität Frankfurt, 1985 die Habilitation im Fach Soziologie ebendort. Von 1985 bis 1997 hatte er Professuren und Gastprofessuren am IAS in Wien und an den Universitäten Frankfurt, Duisburg und der FU Berlin inne. 1995 bis 1997 war Brunkhorst Research Fellow des Kulturwissenschaftlichen Instituts des Wissenschaftszentrums Nordrhein-Westfalen. Seit 1997 ist er Professor für Soziologie an der Universität in Flensburg.
With an increased understanding of the tumor biology of squamous cell carcinoma of the head and neck (SCCHN), targeted therapies have found their way into the clinical treatment routines against this entity. Nevertheless, to date platinum-based cytostatic agents remain the first line choice and targeting the epidermal growth factor-receptor (EGFR) with combined cetuximab and radiation therapy remains the only targeted therapy approved in the curative setting. Investigation of immune checkpoint inhibitors (ICI), such as antibodies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1, resulted in a change of paradigms in oncology and in the first approval of new drugs for treating SCCHN. Nivolumab and pembrolizumab, two anti-PD-1 antibodies, were the first agents shown to improve overall survival for patients with metastatic/recurrent tumors in recent years. Currently, several clinical trials investigate the role of ICI in different therapeutic settings. A robust set of biomarkers will be an inevitable tool for future individualized treatment approaches including radiation dose de-escalation and escalation strategies. This review aims to summarize achieved goals, the current status and future perspectives regarding targeted therapies and ICI in the management of SCCHN.
Pierre Monnet - notice
(2013)
Pierre Monnet (geb. 1963), seit 2011 Direktor des Institut Français d’Histoire en Allemagne in Frankfurt am Main, ist "directeur d’études" an der Ecole des hautes études en sciences sociales (EHESS). Er studierte Geschichte an der Sorbonne, der Ecole normale supérieure sowie der EHESS. Nach seiner Promotion an der EHESS 1994 lehrte er mittelalterliche Geschichte an der Universität Dijon-Bourgogne. Von 1996 bis 2003 war er stellvertretender Direktor, anschließend Direktor der Mission historique française en Allemagne. Nachdem seiner Habilitation im Jahr 2002, war er bis 2005 Professor für mittelalterliche Geschichte an der Universität Versailles Saint-Quentin-en-Yvelines. Von 2007 bis 2011 war er stellvertretender Direktor, anschließend Direktor der Deutsch-Französischen Universität. Seine persönlichen Arbeitsschwerpunkte sind: Mehrsprachigkeit in der mittelalterlichen Stadt, politische Kultur des spätmittelalterlichen Reiches unter den Luxemburgern, Geschichte der Stadt Frankfurt im Spätmittelalter.
Cyanobacteria are photoautotrophic microorganisms present in almost all ecologically niches on Earth. They exist as single-cell or filamentous forms and the latter often contain specialized cells for N2 fixation known as heterocysts. Heterocysts arise from photosynthetic active vegetative cells by multiple morphological and physiological rearrangements including the absence of O2 evolution and CO2 fixation. The key function of this cell type is carried out by the metalloprotein complex known as nitrogenase. Additionally, many other important processes in heterocysts also depend on metalloproteins. This leads to a high metal demand exceeding the one of other bacteria in content and concentration during heterocyst development and in mature heterocysts. This review provides an overview on the current knowledge of the transition metals and metalloproteins required by heterocysts in heterocyst-forming cyanobacteria. It discusses the molecular, physiological, and physicochemical properties of metalloproteins involved in N2 fixation, H2 metabolism, electron transport chains, oxidative stress management, storage, energy metabolism, and metabolic networks in the diazotrophic filament. This provides a detailed and comprehensive picture on the heterocyst demands for Fe, Cu, Mo, Ni, Mn, V, and Zn as cofactors for metalloproteins and highlights the importance of such metalloproteins for the biology of cyanobacterial heterocysts.