Regulation of vesicular trafficking in presence of mutations in contractile proteins

The molecular and cellular mechanisms underlying disease phenotypes in dilated cardiomyopathy (DCM) are diverse and to date incompletely understood. Inherited mutations in genes encoding structural components of the sarcomere lead to DCM and have been studied previously. Moreover, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from patients carrying familial DCM mutations have been shown to recapitulate disease phenotypes such as sarcomere misalignment and reduced contractility. In addition, impaired β-adrenergic signaling was reported to represent an important diease phenotype in DCM. However, the consequences of inherited DCM mutations on molecular pathological signaling in cardiomyocytes are not yet completely clear. In presence of sarcomeric mutations, this study found disorganisation of sarcomeres to result in disturbed interactions between sarcomeric proteins, such as troponin T and tropomyosin. Moreover, interactions between sarcomeric proteins and proteins located at local microdomains, such as PKA (protein kinase A), were disturbed. Therefore, sarcomeric DCM mutations led to impaired local signaling and entailed reduced TnI phosphorylation upon β-adrenergic stimulation. Furthermore, interactions between sarcomeres and membrane-associated cytoskeleton-binding proteins, such as filament C and vinculin, were found to be disturbed. Together, these findings indicated that in presence of sarcomeric DCM mutations, defective interactions occur between sarcomeres and other cytoskeleton elements as well as the plasma membrane (PM). Defects in sarcomere-cytoskeleton-PM interactions were also discovered to lead to impaired actin polymerization at the PM and reduced plasma membrane PIP2 levels. This was discovered to further result in impaired cargo uptake and abnormal early endosome distribution. Disturbed uptake of cargo such as transferrin-bound iron caused decreased iron levels in the mitochondria and defective cardiomyocyte functions, such as reduced contractility. Moreover, Rho A activation was found to rescue these disease phenotypes, specifically the depletion of mitochondrial iron levels and the reduced contractility observed in presence of sarcomeric DCM mutations. This may represent a basis for potential future translational strategies. In addition, this study also showed that at cellular levels, replenishing intracellular iron could restore the depleted iron levels in mitochondria and rescue the impaired contractility in DCM iPSC-CMs. This provided further evidence for the benefits of iron supplementation, a treatment approach in patients with heart failure which is already in clinical use. Of note, left ventricular tissues from DCM patients with end-stage heart failure were found to display abnormal endosome distribution, compared to the left ventricular tissues from patients with preserved systolic left-ventricular function. This suggests that iron deficiency due to defective endocytosis may present a more general mechanism. Taken together, this study has discovered that disorganised sarcomere protein organization leads to impaired sarcomere- cytoskeleton-PM interactions, disturbed functions of cardiomyocyte signaling pathways, and defective uptake and distribution of cargo by clathrin-mediated endocytosis. This study provides potentially relevant directions for future translational therapeutic strategies.2023-03-2

How nonlinear processing shapes natural stimulus encoding in the retina

Understanding natural vision is one of the fundamental goals of sensory neuroscience. The only part of the visual system that may currently be amenable to such a complete understanding is the vertebrate retina, where there is increasing convergence of physiological and anatomical evidence that explain the transformation from visual stimulus to neural response. A first-order approximation of retinal processing assumes that the retina acts as a parallel stream of linear filters, interfacing between the photoreceptors and the axons of retinal ganglion cells, which form the optic nerve. Computational models based on linear filtering only partially capture the retinal output under naturalistic stimulation. The shortcomings of this linear picture of the retina come as no surprise in the light of the multiple examples of nonlinear processing within the retinal circuit. The prime example is associated with signal transduction between bipolar and ganglion cells, which can be highly nonlinear. However, these nonlinearities are mostly studied in isolation with targeted artificial visual stimuli, and their significance for natural stimuli is still unclear. Using multielectrode-array recordings from the isolated mouse retina, I investigated the necessity of nonlinear processing for natural image encoding and found differential sensitivity of ganglion cells to natural spatial structure. I then showed that this sensitivity is a property of nonlinearities acting over the receptive field center, and I established that different nonlinearity types can be found among different types of retinal ganglion cells. I developed models that can leverage nonlinear properties of the retinal circuit and tested their predictions with responses to natural scene stimuli. This modeling approach yielded complete nonlinear receptive field descriptions of major cell types in the mouse retina and could capture the retinal output under stimuli with naturalistic temporal dynamics. Together, I showed that nonlinear retinal processing is highly relevant for the encoding of natural scenes, extends functional descriptions of neuronal types beyond linear receptive fields, and can reduce the gap in predicting the retinal output to natural visual inputs.2023-02-2

Analysis of multiprotein-complex components pulled-down with STRIPAK in Sordaria macrospora

Der STRIPAK (striatin-interacting phosphatase and kinase)-Komplex ist in Pilzen und Tieren hoch konserviert. In dem filamentösen Ascomyceten Sordaria macrospora (Sm) kommt dem SmSTRIPAK eine wichtige Rolle bei der Hyphenfusion, sexuellen Entwicklung, Septierung und dem Wachstum zu. Durch Pulldown-Experimente mit SmSTRIPAK-Komponenten als Köder, konnten massenspektrometrisch eine Vielzahl möglicher Interaktionspartner identifiziert werden. Diese Arbeit gibt Einblicke in drei mögliche Interaktionspartner des SmSTRIPAK-Komplexes: ARP1 (actin-related protein 1), POM33 (pore-membrane protein of 33 kDa) und VAC14 (vacuolar-morphology protein 14). Sie alle sind selbst Komponenten großer und konservierter individueller Multiproteinkomplexe. ARP1 ist das am häufigsten vorkommende Protein in Dynactin und ist an dem retrograden Transport verschiedener Frachten auf Mikrotubuli durch den Dynein-Dynactin-Komplex beteiligt. In dieser Studie konnte gezeigt werden, dass SmARP1 für das Hyphenwachstum und die Pilzentwicklung wichtig ist. Mittels Fluoreszenzmikroskopie konnte gezeigt werden, dass die zelluläre Lokalisierung dieses Proteins dynamisch ist und es teilweise mit Zellkernen assoziiert ist, sowie subapikal in der Nähe des Spitzenkörpers (SPK) lokalisiert. Aufgrund dieser Charakteristika wurde SmARP1 als Markerprotein für aktiv wachsende Hyphen und Zellpolarität etabliert. Im zweiten Projekt wurde das Transmembranprotein POM33, welches in anderen Organismen mit dem Kernporenkomplex (NPC) assoziiert ist, analysiert. Dabei wurde gezeigt, dass die Eliminierung des Smpom33 Gens selbst unter Stressbedingungen keine Auswirkungen auf die sexuelle Entwicklung von S. macrospora hat. Darüber hinaus zeigten fluoreszenzmikroskopische Untersuchungen, dass SmPOM33 an der Kernhülle sowie am endoplasmatischen Retikulum (ER) lokalisiert. Nach einer massenspektrometrischen Analyse wurden Proteine des ERs als potenzielle Interaktions-partner identifiziert. Demnach ist SmPOM33 eher ein ER-Protein als ein Bestandteil des NPCs. Im dritten Projekt dieser Arbeit wurde das Protein VAC14 untersucht. Es ist die gerüstbildende Untereinheit des Fab1p/PIKfyve-Komplexes, der in Hefe an der Vakuolenmembran und in Säugetieren an den Membranen von Endolysosomen lokalisiert ist. Er regelt den Umsatz und die Synthese von PtdIns(3,5)P2, welches bei zahlreichen zellulären Prozessen wie Organellenmorphologie, Ansäuerung von Endolysosomen und Autophagie beteiligt ist. In dieser Studie wurde VAC14 zum ersten Mal in filamentösen Pilzen untersucht. Demnach kolokalisiert SmVAC14 mit dem ER, Golgi, vesikulären Membranen, frühen und späten Endosomen und der SmSTRIPAK-Komponente SCI1. Darüber hinaus zeigte die ∆vac14 Mutante deformierte Perithezien, eine Beeinträchtigung der Ascosporenbildung sowie eine veränderte Vakuolenmorphologie. Des Weiteren ist eine ∆vac14 Mutante sensitiver gegenüber verschiedenen Arten von Stress, ist jedoch nicht in dem Prozess der Autophagie beeinträchtigt. Diese Arbeit zeigt, dass die drei hier analysierten Proteine selbst Teil separater Multiproteinkomplexe sind und dass sowohl ARP1 als auch VAC14 für die korrekte sexuelle Entwicklung in S. macrospora erforderlich sind.The striatin-interacting phosphatase and kinase (STRIPAK)-complex is highly conserved and can be found in fungi and animals. In the filamentous ascomycete Sordaria macrospora (Sm), the SmSTRIPAK plays an important role in hyphal fusion, sexual development, septation and growth. In previous studies, pulldown experiments of SmSTRIPAK-components as baits coupled to liquid chromatography-mass spectrometry (LC-MS) provided a variety of possible interaction partners. This work gives insights into three of these pulled-down proteins, namely: the actin-related protein 1 (ARP1), the pore-membrane protein of 33 kDa (POM33) and the vacuolar-morphology protein 14 (VAC14), which are all part of large and conserved individual multiprotein complexes themselves. ARP1 is the most abundant protein in dynactin and is involved in mediating retrograde transport of various cargos on microtubules via the dynein-dynactin complex. In this study, SmARP1 was shown to be important for proper hyphal growth and fungal development. Fluorescence microscopy revealed that its localization is a dynamic process and that SmARP1 localizes subapical to the Spitzenkörper (SPK) as well as in close association with nuclei. Due to these characteristics, SmARP1 was established as a marker protein for actively growing hyphae and cell polarity. In the second project, the transmembrane protein POM33 as putative part of the nuclear-pore complex (NPC) was analyzed. Thereby it was shown that deletion of Smpom33 has no impact on sexual development even under stress conditions. Additionally, fluorescence microscopic investigations showed that SmPOM33 localizes at the nuclear envelope (NE) and the endoplasmic reticulum (ER). After LC-MS analysis, proteins of the ER were identified as potential interactors. This led to the conclusion that SmPOM33 is rather an ER protein than a component of the NPC. In the third project, VAC14 as scaffolding subunit of the Fab1p/PIKfyve-complex was investigated. Vac14p/ArPIKfyve localizes to the vacuolar membrane in yeast and to membranes of endolysosomes in mammals, respectively. There, it facilitates the turnover and synthesis of PtdIns(3,5)P2 that functions in multiple processes including organelle morphology, acidification of endolysosomes and autophagy. The data presented here investigated VAC14 for the first time in a filamentous fungus. In S. macrospora, SmVAC14 co-localizes with the ER, Golgi, vacuolar membranes, early and late endosomes and the SmSTRIPAK-component SCI1. Moreover, the ∆vac14 mutant showed deformed perithecia, impairment of ascospore formation, and altered vacuolar morphology. Furthermore, the ∆vac14 mutant displayed an increased sensitivity to diverse types of stresses; however, autophagy was not affected. This work revealed that the three proteins presumably interacting with components of the STRIPAK-complex analyzed here, likewise are part of separate multiprotein complexes, and ARP1 and VAC14 are also required for accurate sexual development in S. macrospora.2023-03-2

Characterization of Synaptic Transmission Abnormalities in Neurological Disorders of the Presynaptic Terminal

Seminal methodological advancements in the field of human genetics now allow for low-cost sequencing of complete coding genomes, and rich sources of corresponding data now exist for healthy and patient cohorts, allowing for the identification of possibly pathogenic variations. However, lagging behind is the identification of mechanisms by which such variations lead to disease, both at the molecular and cellular levels. Multiple genetic studies of neurodevelopmental and neuropsychiatric disorders now point to a central role of synaptic transmission in the etiology of such disorders. This project aims to shed light on molecular mechanisms and synaptic transmission abnormalities underlying a novel disorder of the presynaptic terminal – associated with variations in the UNC13A gene that translates into the Munc13-1 protein. Munc13-1 is a large, multi-domain protein absolutely essential for priming synaptic vesicles (SV) to the active zone plasma membrane. The absence of Munc13-1 in mice leads to severely compromised synaptic transmission that is lethal. Evidence also exists pointing to the fact that Munc13-1 is pivotal for nervous system function in humans. Recently, the first patient with a de novo variant in the Munc13-1 protein, was described. The patient phenotype was characterized by a dyskinetic movement disorder, developmental delay and autism. The patient variant, P814L, leads to a gain of function of both excitatory and inhibitory synaptic transmission – neurons expressing this variant exhibited an increase in the basal SV release probability and aberrant patterns of short-term synaptic plasticity during trains of action potentials. Following this publication, a collaboration with the group of Prof. Dr. med. Anita Rauch from the Institute of Medical Genetics at the University of Zurich was initiated. This research group excels in the collection of patient data and in in-depth genetic analysis of human material. By now, around 40 patients were identified, who carry de novo or biallelic variants in the UNC13A gene, presenting with variable neurological and neuropsychiatric conditions. The patient variants are distributed over the entire Munc13-1 protein sequence and in every functional domain. In this thesis, I am presenting electrophysiological and immunocytochemistry data analysing the functional consequences of five patient variants, characterized using the mouse hippocampal autaptic neuron culture system. One variant mirroring the phenotype of the previously reported P814L mutation confirms the reproducibility of our experimental system and its ability to accurately capture a phenotypic-functional relationship. Beyond that, I distinguish two distinct mechanisms in disease. One group of patients accumulating in the highly conserved C2B-MUN-Linker domain elicits a gain of function in synaptic transmission properties. In contrast, a second group of patients accumulates on the less conserved N-terminus and displays a loss of function phenotype in our electrophysiological measurements. My findings uncover two distinct mechanisms governing disease manifestation in UNC13A patients, and emphasize the significance of genetic variants in synaptic proteins as causal for brain disorders.2023-01-1

Development of a Generally Applicable Machine Learning Potential with Accurate Long-Range Electrostatic Interactions

Machine learning potentials (MLPs) have become an indispensable tool for large-scale atomistic simulations, due to their accuracy comparable with ab-initio methods at considerably reduced computational cost. The development of MLPs has attracted increasing attention and numerous relevant applications in materials science, physics and chemistry have been reported. Most MLPs up to date are based on the approximation of locality, meaning that only short-range atomic interactions are considered. The total energy of the system can be decomposed into a sum of environment-dependent atomic energies. This approximation works well for the majority of systems and allows the MLPs to describe systems containing thousands of atoms with very high accuracy by just training on configurations of small systems. Moreover, they can incorporate long-range electrostatic interactions by employing fixed charges or more flexible environment-dependent charges. Despite countless encouraging developments of MLPs, they are unable to describe non-local effects arising from long-range charge transfer and multiple charge states. This shortcoming prevents the study of many interesting phenomena such as chemical interactions involving protonation/deprotonation and biological processes. A new generation of MLPs such as charge equilibration via neural network technique (CENT) and Becke population neural network (BpopNN) is now beginning to emerge in an effort to address these long standing challenges. In this thesis, the limitations of conventional MLPs are overcome by introducing a fourth-generation high-dimensional neural network potential (4G-HDNNP), which combines accurate atomic energies with a charge equilibration scheme relying on environment dependent atomic electronegativities. 4G-HDNNP describes the correct global charge distribution of the system, resulting in a markedly improved potential energy surface. The capabilities of the method have been demonstrated for a set of benchmark systems that involves non-local charge transfer, where existing methods fail even at the qualitative level. Finally, an extension of the 4G-HDNNP, namely the electrostatically embedded 4G-HDNNP (ee4G-HDNNP), is proposed to further enhance the description of non-local effects, and the general transferability to different configurations that are not covered in the reference data set. The promising improvements of ee4G-HDNNP compared to the 4G-HDNNP have been shown on a large data set of both neutral and charged sodium chloride clusters with large structural diversity. This novel method is anticipated to become a reliable tool for the study of many complex biological and electrochemical problems, while existing ab-initio methods combined with modern computer technology are still computationally demanding for large-scale atomistic simulations.2023-06-2

Engineering of a bacteriophytochrome-derived reversibly switchable fluorescent protein for the application in super-resolution microscopy in the near-infrared window

The developments of fluorescence microscopy techniques has advanced our understanding of biological systems on a cellular level. In recent years, several super-resolution microscopy techniques overcame the diffraction barrier thereby allowing unprecedented insights in the subcellular structures down to the molecular level. Reversible saturable optical linear fluorescence transition (RESOLFT) microscopy, as one of these techniques, allows for the formation of super-resolved images by utilizing low light intensities in the kW/cm2 range, which makes it a suitable tool for live cell super-resolution imaging. The RESOLFT concept relies on-switching fluorophores between a fluorescent on- and non-fluorescent off-state. To date, most RESOLFT applications depend on reversibly switchable fluorescent proteins (RSFP), which are excited and switched by light in the visible region of the electromagnetic spectrum. In order to transfer RESOLFT to the near-infrared (NIR) region of the electromagnetic spectrum, which exhibits reduced scattering and phototoxicity, a new class of RSFPs is required. Bacteriophytochromes as NIR-photoreceptors in bacteria act as suitable templates for engineering a NIR-RSFP. In this work, the monomeric bacteriophytochrome-derived PhotostablE Nir rEversibly switchable fLuOrescent ProteEin (PENELOPE) was engineered using site-directed and random mutagenesis. PENELOPE exhibits a strong photostability, fast off-switching and allows RESOLFT imaging in the NIR window for the first time. NIR-RESOLFT microscopy was performed by using a single wavelength. This was enabled by harnessing the remarkable ability of PENELOPE to thermally relax to the on-state within milliseconds after off-switching. This allowed the substitution of the conventional on-switching step with a thermal relaxation step, which additionally reduced the applied light doses during imaging. Furthermore, RESOLFT microscopy was successfully performed in fixed mammalian cells using a genetically encoded RSFP for the first time. The implementation of a time-saving pixel hop scan approach in conjunction with a novel proposed switching state model for PENELOPE, ushers PENELOPE into low light dose NIR super-resolution microscopy.2023-06-0

Anti-apoptotic and neuroprotective erythropoietin/CRLF3-signalling in insects and humans

The cytokine receptor like factor 3 (CRLF3) evolved together with the eumetazoan nervous system and is present in all major groups of Animalia. Based on sequence similarities, CRLF3 was assigned to the family of class 1 cytokine receptors which also includes the classical erythropoietin receptor (EpoR). CRLF3 misregulation has been associated with several human diseases, but neither its ligand nor a particular function have been reported. Erythropoietin (Epo) is a vertebrate-specific helical cytokine that regulates erythropoiesis and activates cytoprotective pathways in various tissues including the nervous system. Neuroprotective functions of Epo are partially mediated by EpoR but also by additional, partly unidentified receptors. In insects, CRLF3 was identified to respond to human recombinant Epo and the naturally occurring Epo splice variant EV-3. Activation of CRLF3 in insects stimulates anti-apoptotic processes via JAK/STAT intracellular signalling. Even though many efforts were made in order to characterize CRLF3-mediated responses, downstream effectors beyond JAK/STAT remained elusive. My thesis combines studies on CRLF3-mediated anti-apoptotic mechanisms in insects and the functional characterisation of human CRLF3 in iPSC (induced pluripotent stem cell) -derived neurons. Studies on Locusta migratoria and Tribolium castaneum revealed a pro-apoptotic role of acetylcholinesterase (AChE coded by ace) that was previously reported for vertebrates. Similar to those studies, reduction of AChE levels and inhibition of AChE activity prevented apoptotic death in hypoxiaexposed primary neuron cultures. Moreover, apoptogenic stimuli increased ace expression supporting the association of AChE with increased apoptosis under challenging conditions. Experiments in T. castaneum indicated that both types of AChE (AChE-1 transcribed from ace-1 and AChE-2 transcribed from ace-2) promote apoptosis and are upregulated by apoptogenic stimuli. However, stressinduced upregulation of AChE-1 was prevented by neuroprotective concentrations of Epo. This indicated that Epo/CRLF3-stimulated neuroprotection is mediated through suppression of pro-apoptotic ace-1 expression. Whether this Epo-stimulated protective mechanism is specific to insects or also present in other species remains to be studied. In order to determine the endogenous ligand of insect CRLF3 (insects do not possess Epo) I used locust hemolymph as potential source for its identification. I first demonstrated that locust hemolymph protects both L. migratoria and T. castaneum primary neurons from hypoxia-induced apoptosis. The protective effect was absent after RNAi-mediated knockdown of CRLF3 expression. Thus, locust hemolymph contains a ligand that is sufficiently conserved to activate CRLF3 in different insect species. Fractionation of locust hemolymph by size exclusion chromatography generated two (out of >11) fractions with particular neuroprotective potency. These hemolymph fractions will be used to separate and identify the CRLF3 ligand. In order to determine the function of human CRLF3, I generated CRLF3-knockout lines from two fibroblast-derived human iPSC lines by CRISPR/Cas9 gene editing. CRLF3 KO lines, along with wild type and isogenic controls, were differentiated into neuronal-like cells expressing cell type-specific markes and presenting characteristic morphology. After differentiation, neuronal-like cells were exposed to rotenone, an inhibitor of respiratory chain complex I, which induced apoptosis in all cell lines. The addition of the Epo splice variant EV-3 prevented rotenone-induced cell death in wild type and isogenic controls but not in CRLF3 KO neurons. This demonstrates that human CRLF3 is a neuroprotective receptor similar to its previously determined function in insects. Moreover, CRLF3 is identified as the first known receptor for EV-3 and vice versa, human CRLF3 is deorphanized by identifying EV-3 as one of its endogenous ligands. Taken together, my work has identifyed CRLF3 as a new player in neuroprotection that may account for various previously described Epo-mediated cytoprotective functions in the nervous system and other tissues. Specific activation of CRLF3-mediated beneficial pathways may interfere with degenerative processes without coactivation of EpoR and its associated adverse side effects.2023-05-2

Characterizing the SUMOylation of APC4 and the Function of APC4 Within Neurons

The Anaphase Promoting Complex (APC/C) is an E3 ubiquitin ligase that is involved in multiple molecular processes in eukaryotic cells. It is regulated by an intricate system of post-translational modifications that enables the complex to quickly target different sets of proteins for degradation by the proteasome. The APC/C is best known for its function in regulating the cell cycle, but it is also expressed in non- dividing cells like neurons, where its function is less clear. In the present study, I first sought to elucidate the function of the SUMOylation of APC4, a component of the APC/C, in HEK293 cells and in neurons. In the second part of my study, I tried to determine the function of APC4 in neurons. In regards to the first research focus, I show that APC4 is SUMOylated, and I found that this SUMOylation does not influence the subcellular localization of APC4 or the assembly of the APC/C. I show further that endogenous APC4 is localized to the nucleus and to the cytoplasm of HEK293 cells and neurons, and I found that APC4 is more heavily SUMOylated in the nucleus of HEK293 cells and in the cytoplasm of cortical neurons obtained from a mouse brain. My attempts to determine the role of APC4 SUMOylation in the regulation of the neuronal APC/C were confounded by the fact that my experimental results challenged the earlier notions of the current list of candidate neuronal substrates of the APC/C. In regards to my second research direction, I knocked out the gene encoding APC4, ANAPC4, in cultured neurons and conducted biochemical and morphological analyses of the mutant neurons. In contrast to prior publications, I found that FEZ1, ID1, and NEUROD2 are not substrates of the cortical APC/C. ID1 levels were instead depleted in ANAPC4 knockout cultures, indicating that ID1 is downstream of a substrate of the APC/C. I further show that ANAPC4 knockout neurons have an increase in the number of primary neurites, but they had no changes in the length of their neurites or in their number of branches. Altogether, these ANAPC4 knockout data indicate that many of the previously proposed neuronal substrates of the APC/C are in fact not targeted by the APC/C. Future studies must focus on elucidating the function of the APC/C in neurons and in determining how the SUMOylation of APC4 influences the ubiquitylation of these substrates. In general, the information contained in the present thesis may be important for the development of novel drug targets to treat cancer and possibly diseases of the nervous system.2023-05-3

The Ties that Bind: Party Social Identity and the Relevance of Ideology for the Chinese Communist Party

This thesis seeks to answer the question why ideology still matters for the Chinese Communist Party in its relations with its own members and, importantly, what its purpose is. In other words, it wants to understand how ideology is supposed to shape the relations between the Party and its own members and cadres. Building on mostly qualitative textual research of both Party-internal documents as well as publicly available Party publications, the thesis relies on an innovative theoretical framework to answer its research questions. It builds on a political science approach to ideology and combines it with a theoretical approach to social identity and self-categorisation from social psychology. Based on these, the thesis argues that ideology still matters for the Party in relation with its members and cadres because the Party believes that there is a close link between good behaviour, organisational loyalty and ideology. Building on this, the main argument of the thesis is that, through ideological narratives, the Party seeks to create a social identity for its own members and cadres, the core of which is the Party itself. Equally through ideological narratives, it manipulates this social identity in order to make it meaningful for Party members. Importantly, the thesis argues that at the core of this social identity is the Party itself, rather than a particular political belief system.2023-06-2

Subtalar Arthroereisis with the Vario Subtalar System® for treatment of the symptomatic, juvenile flatfoot - a radiological and clinical retrospective evaluation

Der retrospektive Vergleich von präoperativen und postoperativen Röntgenbildern des Fußes und Befragungen mit der AOFAS-Scale ergab eine signifikante Stellungsveränderung des Fußes und eine Beschwerdereduktion nach subtalarer Arthrorise mit dem Vario Subtalar System® bei 27 Patienten mit juvenilem Pes planovalgus.The retrospectice comparison of preoperative und postoperative x-ray pictures of the foot and the evaluation of a survey with the AOFAS-questonaire following the arthroereisis with the Vario Subtalar System® in 27 children with juvenile flatfeet showed a significant change of the foot from flatfoot deformity to plantigrade footposition and significantly reduced symptoms.2023-01-1