RepoMed (Medizinische Hochschule Hannover)
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Hereditäre Netzhautdystrophien: eine quantitative Analyse mittels Spectral Domain Optischer Kohärenztomographie segmentierter Netzhautschichten
Full text linkStructure of the human nonmuscle myosin 2A motor domain: insights into isoform-specific mechanochemistry
Full text linkNonmuscle myosin 2A (NM2A) is the predominant myosin isoform in nonmuscle cells. Together with its paralogues NM2B and NM2C, NM2A enables tension and force generation, driving essential cellular processes such as membrane protrusion and retraction, directed migration, adhesion, and cytokinesis. The NM2 isoforms display paralogue-specific mechanochemical characteristics that support their specific cellular functions. Here, we determined the structure of the human NM2A motor domain, addressing a critical gap in understanding myosin family diversification. Based on our experimentally resolved 2.1 Å structure of the NM2A motor domain in its nucleotide-free state, we demonstrate, through integrative modeling of NM2-actin complexes and molecular dynamics simulations, how sequence differences between NM2A and NM2B underpin their functional specialization. Loop2 emerges as a critical determinant of isoform-specific behavior. Comparative analysis of ATP interaction fingerprints across NM2 isoforms reveals a conserved ATP binding mechanism. These findings illuminate an allosteric energy transduction pathway that connects sequence variation to actin-binding dynamics, providing mechanistic insight into isoform-specific cytoskeletal functions
The post-reactive structures of Leishmania major UDP-sugar pyrophosphorylase provide insights into the product release mechanism
Full text linkBiosynthesis of the nucleotide sugars UDP-glucose (UDP-Glc) and UDP-galactose (UDP-Gal) is intimately connected and essential for the viability of trypanosomatid parasites. In the genus Leishmania, it is controlled by the UDP-glucose pyrophosphorylase (UGP) and UDP-sugar pyrophosphorylase (USP). In contrast to UGP, USP has a broad substrate specificity and may generate several UDP-sugars in vitro, including UDP-Glc and UDP-Gal. This enzyme, present in protozoan parasites (including Leishmania species and Trypanosoma cruzi) and in plants, most likely plays a role in salvaging monosaccharides. In order to gain a detailed mechanistic understanding of USPs, we determined high-resolution X-ray structures of Leishmania major USP (LmUSP) in post-reactive states. Several positions of the byproduct pyrophosphate (PPi) were identified and revealed a product release channel in the forward reaction, as well as the geometries of post-reactive Michaelis product complexes. The conformational changes of functional loops (hinge loop-1, hinge loop-2, and the nucleotide-binding loop) showed dynamic effects accompanying the product release process. Structural information about the post-reactive states of LmUSP also includes the metastable binding position of a magnesium (Mg2+) ion in the active site. The proposed product release mechanism was substantiated by molecular dynamics simulations and can serve as a model for other UDP-sugar pyrophosphorylases.IMPORTANCETo survive in the hostile environment of the sandfly gut, the parasite Leishmania relies on a range of phosphoglycans made of mannose-phosphate and galactose. In these glucose-limiting conditions, mannogen potentially serves as a reservoir for the synthesis of these crucial glycoconjugates, whereas galactose likely arises from recycling. The enzyme UDP-sugar pyrophosphorylase (USP) is responsible for the activation of this monosaccharide. This enzyme has a relaxed specificity and converts UTP and a range of sugar-1-phosphate to the corresponding UDP-sugar and pyrophosphate (PPi). Here, we determined high-resolution X-ray structures of Leishmania major USP (LmUSP) in post-reactive states. The data provide insight into the product release mechanism for UDP-sugar pyrophosphorylases. Considering the conservation of the residues involved in the coordination of PPi amongst USP enzymes, this mechanism is relevant for all USPs. This work completes our knowledge of the catalytic mechanism of trypanosomatid uridylyltransferases, which are genetically validated drug targets
Auditory rehabilitation after temporal bone fracture with cochlear implants: a case control study
Full text linkCore signature of rejection-associated cytokines and chemokines in endomyocardial biopsies after heart transplantation
Full text linkBackground: Rejection remains a limiting factor for survival after heart transplantation (HTx), and predictive biomarkers are still missing. Therefore, we aimed to define the cytokine/chemokine microenvironment in endomyocardial biopsies (EMB) and plasma after HTx and to identify patterns that reflect ischemia/ reperfusion injury as well as allograft rejection. Therefore, we hypothesize distinct cytokine/chemokine patterns in heart biopsies with histopathologically proven rejection compared with the microenvironment in unsuspicious biopsies. Methods: EMB (n = 181; n = 52 patients) and peripheral blood samples (n = 147; n = 52 patients) were obtained between 6 days and 5 years after HTx. 50 immune proteins in EMB tissue lysates and plasma were quantified, and concentrations were compared between EMB with and without histopathologically defined acute rejection (AR), and correlation analyses between tissue and plasma were performed. Results: Regarding rejection status, distinct cytokine/chemokine patterns were identified with significantly higher concentrations of CCL4, CXCL9, and CXCL10 in EMB with acute rejection (p < 0.001). In addition, we identified individual long-term dynamics of patients after HTx associated with rejection. Elevated chemokine concentrations were also detected in EMB of patients with donor-specific antibodies (DSAs). Moreover, significantly different patterns were observed between heart tissue and plasma without direct correlations. Conclusion: A core signature was defined for EMB with histopathologically proven AR, consisting of high concentrations of CXCL9, CXCL10, CCL3, and CCL4. This EMB chemokine signature was clearly distinct from plasma samples, arguing for a local protein microenvironment associated with AR. Further research is also needed with the help of AI to translate the different approaches for the detection and prediction of AR into clinical practice
A possible role of tetrodotoxin-sensitive Na+ channels for oxidation-induced late Na+ currents in cardiomyocytes
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