TY - JOUR A1 - Luther, Christian H. A1 - Brandt, Philipp A1 - Vylkova, Slavena A1 - Dandekar, Thomas A1 - Müller, Tobias A1 - Dittrich, Marcus T1 - Integrated analysis of SR-like protein kinases Sky1 and Sky2 links signaling networks with transcriptional regulation in Candida albicans JF - Frontiers in Cellular and Infection Microbiology N2 - Fungal infections are a major global health burden where Candida albicans is among the most common fungal pathogen in humans and is a common cause of invasive candidiasis. Fungal phenotypes, such as those related to morphology, proliferation and virulence are mainly driven by gene expression, which is primarily regulated by kinase signaling cascades. Serine-arginine (SR) protein kinases are highly conserved among eukaryotes and are involved in major transcriptional processes in human and S. cerevisiae. Candida albicans harbors two SR protein kinases, while Sky2 is important for metabolic adaptation, Sky1 has similar functions as in S. cerevisiae. To investigate the role of these SR kinases for the regulation of transcriptional responses in C. albicans, we performed RNA sequencing of sky1Δ and sky2Δ and integrated a comprehensive phosphoproteome dataset of these mutants. Using a Systems Biology approach, we study transcriptional regulation in the context of kinase signaling networks. Transcriptomic enrichment analysis indicates that pathways involved in the regulation of gene expression are downregulated and mitochondrial processes are upregulated in sky1Δ. In sky2Δ, primarily metabolic processes are affected, especially for arginine, and we observed that arginine-induced hyphae formation is impaired in sky2Δ. In addition, our analysis identifies several transcription factors as potential drivers of the transcriptional response. Among these, a core set is shared between both kinase knockouts, but it appears to regulate different subsets of target genes. To elucidate these diverse regulatory patterns, we created network modules by integrating the data of site-specific protein phosphorylation and gene expression with kinase-substrate predictions and protein-protein interactions. These integrated signaling modules reveal shared parts but also highlight specific patterns characteristic for each kinase. Interestingly, the modules contain many proteins involved in fungal morphogenesis and stress response. Accordingly, experimental phenotyping shows a higher resistance to Hygromycin B for sky1Δ. Thus, our study demonstrates that a combination of computational approaches with integration of experimental data can offer a new systems biological perspective on the complex network of signaling and transcription. With that, the investigation of the interface between signaling and transcriptional regulation in C. albicans provides a deeper insight into how cellular mechanisms can shape the phenotype. KW - sky kinases KW - kinase signaling KW - network analysis KW - transcriptome KW - transcriptional regulation KW - phosphoproteome KW - Candida albicans Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311771 SN - 2235-2988 VL - 13 ER - TY - JOUR A1 - Massih, Bita A1 - Veh, Alexander A1 - Schenke, Maren A1 - Mungwa, Simon A1 - Seeger, Bettina A1 - Selvaraj, Bhuvaneish T. A1 - Chandran, Siddharthan A1 - Reinhardt, Peter A1 - Sterneckert, Jared A1 - Hermann, Andreas A1 - Sendtner, Michael A1 - Lüningschrör, Patrick T1 - A 3D cell culture system for bioengineering human neuromuscular junctions to model ALS JF - Frontiers in Cell and Developmental Biology N2 - The signals that coordinate and control movement in vertebrates are transmitted from motoneurons (MNs) to their target muscle cells at neuromuscular junctions (NMJs). Human NMJs display unique structural and physiological features, which make them vulnerable to pathological processes. NMJs are an early target in the pathology of motoneuron diseases (MND). Synaptic dysfunction and synapse elimination precede MN loss suggesting that the NMJ is the starting point of the pathophysiological cascade leading to MN death. Therefore, the study of human MNs in health and disease requires cell culture systems that enable the connection to their target muscle cells for NMJ formation. Here, we present a human neuromuscular co-culture system consisting of induced pluripotent stem cell (iPSC)-derived MNs and 3D skeletal muscle tissue derived from myoblasts. We used self-microfabricated silicone dishes combined with Velcro hooks to support the formation of 3D muscle tissue in a defined extracellular matrix, which enhances NMJ function and maturity. Using a combination of immunohistochemistry, calcium imaging, and pharmacological stimulations, we characterized and confirmed the function of the 3D muscle tissue and the 3D neuromuscular co-cultures. Finally, we applied this system as an in vitro model to study the pathophysiology of Amyotrophic Lateral Sclerosis (ALS) and found a decrease in neuromuscular coupling and muscle contraction in co-cultures with MNs harboring ALS-linked SOD1 mutation. In summary, the human 3D neuromuscular cell culture system presented here recapitulates aspects of human physiology in a controlled in vitro setting and is suitable for modeling of MND. KW - NMJ–neuromuscular junction KW - motoneuron (MN) KW - skeletal muscle KW - iPSC (induced pluripotent stem cells) KW - 3D cell culture Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304161 SN - 2296-634X VL - 11 ER - TY - JOUR A1 - Böck, Julia A1 - Maurus, Katja A1 - Gerhard-Hartmann, Elena A1 - Brändlein, Stephanie A1 - Kurz, Katrin S. A1 - Ott, German A1 - Anagnostopoulos, Ioannis A1 - Rosenwald, Andreas A1 - Zamò, Alberto T1 - Targeted panel sequencing in the routine diagnosis of mature T- and NK-cell lymphomas BT - report of 128 cases from two German reference centers JF - Frontiers in Oncology N2 - Diagnosing any of the more than 30 types of T-cell lymphomas is considered a challenging task for many pathologists and currently requires morphological expertise as well as the integration of clinical data, immunophenotype, flow cytometry and clonality analyses. Even considering all available information, some margin of doubt might remain using the current diagnostic procedures. In recent times, the genetic landscape of most T-cell lymphomas has been elucidated, showing a number of diagnostically relevant mutations. In addition, recent data indicate that some of these genetic alterations might bear prognostic and predictive value. Extensive genetic analyses, such as whole exome or large panel sequencing are still expensive and time consuming, therefore limiting their application in routine diagnostic. We therefore devoted our effort to develop a lean approach for genetic analysis of T-cell lymphomas, focusing on maximum efficiency rather than exhaustively covering all possible targets. Here we report the results generated with our small amplicon-based panel that could be used routinely on paraffin-embedded and even decalcified samples, on a single sample basis in parallel with other NGS-panels used in our routine diagnostic lab, in a relatively short time and with limited costs. We tested 128 available samples from two German reference centers as part of our routine work up (among which 116 T-cell lymphomas), which is the largest routine diagnostic series reported to date. Our results showed that this assay had a very high rate of technical success (97%) and could detect mutations in the majority (79%) of tested T-cell lymphoma samples. KW - T-cell lymphoma KW - panel-sequencing KW - NGS KW - diagnostics KW - mutation KW - FFPE Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-326478 SN - 2234-943X VL - 13 ER - TY - JOUR A1 - Ding, Hao A1 - Seusing, Nelly A1 - Nasseroleslami, Bahman A1 - Anwar, Abdul Rauf A1 - Strauss, Sebastian A1 - Lotze, Martin A1 - Grothe, Matthias A1 - Groppa, Sergiu A1 - Muthuraman, Muthuraman T1 - The role of ipsilateral motor network in upper limb movement JF - Frontiers in Physiology N2 - The execution of voluntary movements is primarily governed by the cerebral hemisphere contralateral to the moving limb. Previous research indicates that the ipsilateral motor network, comprising the primary motor cortex (M1), supplementary motor area (SMA), and premotor cortex (PM), plays a crucial role in the planning and execution of limb movements. However, the precise functions of this network and its interplay in different task contexts have yet to be fully understood. Twenty healthy right-handed participants (10 females, mean age 26.1 ± 4.6 years) underwent functional MRI scans while performing biceps brachii representations such as bilateral, unilateral flexion, and bilateral flexion-extension. Ipsilateral motor evoked potentials (iMEPs) were obtained from the identical set of participants in a prior study using transcranial magnetic stimulation (TMS) targeting M1 while employing the same motor tasks. The voxel time series was extracted based on the region of interest (M1, SMA, ventral PM and dorsal PM). Directed functinal connectivity was derived from the extracted time series using time-resolved partial directed coherence. We found increased connectivity from left-PMv to both sides M1, as well as right-PMv to both sides SMA, in unilateral flexion compared to bilateral flexion. Connectivity from left M1 to left-PMv, and left-SMA to right-PMd, also increased in both unilateral flexion and bilateral flexion-extension compared to bilateral flexion. However, connectivity between PMv and right-M1 to left-PMd decreased during bilateral flexion-extension compared to unilateral flexion. Additionally, during bilateral flexion-extension, the connectivity from right-M1 to right-SMA had a negative relationship with the area ratio of iMEP in the dominant side. Our results provide corroborating evidence for prior research suggesting that the ipsilateral motor network is implicated in the voluntary movements and underscores its involvement in cognitive processes such as movement planning and coordination. Moreover, ipsilateral connectivity from M1 to SMA on the dominant side can modulate the degree of ipsilateral M1 activation during bilateral antagonistic contraction. KW - ipsilateral motor network KW - upper limb KW - ipsilateral motor evoked potential KW - voluntary movement KW - bilateral motor network Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321805 SN - 1664-042X VL - 14 ER - TY - JOUR A1 - Leonhardt, Jonas A1 - Winkler, Marcela A1 - Kollikowski, Anne A1 - Schiffmann, Lisa A1 - Quenzer, Anne A1 - Einsele, Hermann A1 - Löffler, Claudia T1 - Mind–body-medicine in oncology—from patient needs to tailored programs and interventions BT - a cross-sectional study JF - Frontiers in Psychology N2 - Introduction: National and international guidelines recommend early integration of evidence-based multimodal interventions and programs, especially with a focus on relaxation techniques and other Mind–Body-based methods to maintain the quality of life of oncology patients, improve treatment tolerability, and promote healthy lifestyle behaviors. Consequently, we aim to understand what drives patients and how they navigate integrative medicine to best advise them. This study aimed to detect possible topics of particular interest to patients and identify the patient groups that could benefit most from further programs. Furthermore, we aimed to investigate if patients are open-minded toward integrative oncology concepts and learn about their motivational level to maintain or change behavior. Methods: Between August 2019 and October 2020 we surveyed patients undergoing oncological therapy in a university oncological outpatient center using a custom-developed questionnaire based on established Mind–Body Medicine concepts. Results: We included 294 patients with various cancers. More than half reported problems sleeping through (61%) and 42% felt stressed frequently, invariably rating this as detrimental to their health. Moreover, a slight majority (52%) felt physically limited due to their disease and only 30% performed defined exercise programs. Women were significantly more likely to feel stressed and reported with alarming frequency that they often feel “everything was up to them.” The 40–65-year-olds reported significantly less restful sleep, more stress and were more dissatisfied with their situation. However, this group already used natural remedies most frequently and was most often motivated to use relaxation techniques in the next 6 months. The lower the perceived individual energy level (EL), the less frequently patients did sport, the more frequently they felt their disease impaired their activity, mostly feeling stressed and tense. We also found significant associations between negative emotions/thoughts and the variables “sleep,” “use of relaxation techniques,” “personal stress perception,” and “successful lifestyle modification.” Conclusion: Mind–Body programs that focus on patient’s individual resources, with tools to explore impairing patterns of self-perception and cognitive biases, can be a valuable resource for oncology patients and should therefore be part of an integrative medical treatment concept. KW - lifestyle habits KW - symptom burden KW - individual mind state KW - motivational level KW - stress Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321970 SN - 1664-1078 VL - 14 ER - TY - JOUR A1 - Hutmacher, Fabian T1 - Taking methodological pluralism seriously BT - considerations based on the work of Norbert Groeben JF - Frontiers in Psychology N2 - No abstract available. KW - methodological pluralism KW - quantitative methods KW - qualitative methods KW - replication crisis KW - Norbert Groeben Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-328221 SN - 1664-1078 VL - 14 ER - TY - JOUR A1 - Lenhard, Alexandra A1 - Minten, Marie-Pierre A1 - Lenhard, Wolfgang T1 - When biology takes over: TV formats like The Bachelor and The Bachelorette confirm evolutionary theories of partner selection JF - Frontiers in Psychology N2 - Introduction: In this study, we investigated the impact of age on mate selection preferences in males and females, and explored how the formation and duration of committed relationships depend on the sex of the person making the selection. Methods: To this end, we utilized data from the television dating shows The Bachelor and The Bachelorette. In these programs, either a single man (“bachelor”) or a woman (“bachelorette”) has the opportunity to select a potential long-term partner from a pool of candidates. Our analysis encompassed a total of n = 169 seasons from 23 different countries, beginning with the first airing in 2002. Results: We found that the likelihood of the final couple continuing their relationship beyond the broadcast was higher in The Bachelorette than in The Bachelor, although the duration of these relationships was not significantly influenced by the type of show. On average, women were younger, both when selecting their partner and when being chosen. However, men exhibited a greater preference for larger age differences than women. Furthermore, the age of the chosen male partners significantly increased with the age of the “bachelorettes,” whereas “bachelors” consistently favored women around 25.5 years old, regardless of their own age. Discussion: We discuss these findings within the context of parental investment theory and sexual strategies theory. KW - mating strategies KW - parental investment theory KW - sex differences KW - relationship duration KW - Cox proportional regression analysis Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325717 SN - 1664-1078 VL - 14 ER - TY - JOUR A1 - Simon, Johanna A1 - Parisi, Sandra A1 - Wabnitz, Katharina A1 - Simmenroth, Anne A1 - Schwienhorst-Stich, Eva-Maria T1 - Ten characteristics of high-quality planetary health education BT - results from a qualitative study with educators, students as educators and study deans at medical schools in Germany JF - Frontiers in Public Health N2 - Aim: The climate and ecological crises are considered fundamental threats to human health. Healthcare workers in general and doctors in particular can contribute as change agents in mitigation and adaptation. Planetary health education (PHE) aims to harness this potential. This study explores perspectives among stakeholders involved in PHE at German medical schools on the characteristics of high-quality PHE and compares them to existing PHE frameworks. Methods: In 2021, we conducted a qualitative interview study with stakeholders from German medical schools involved in PHE. Three different groups were eligible: faculty members, medical students actively involved in PHE, and study deans of medical schools. Recruitment was performed through national PHE networks and snowball sampling. Thematic qualitative text analysis according to Kuckartz was used for the analysis. Results were systematically compared to three existing PHE frameworks. Results: A total of 20 participants (13 female) from 15 different medical schools were interviewed. Participants covered a wide range of professional backgrounds and experience in PHE education. The analysis revealed ten key themes: (1) Complexity and systems thinking, (2) inter- and transdisciplinarity, (3) ethical dimension, (4) responsibility of health professionals, (5) transformative competencies including practical skills, (6) space for reflection and resilience building, (7) special role of students, (8) need for curricular integration, (9) innovative and proven didactic methods, and (10) education as a driver of innovation. Six of our themes showed substantial overlap with existing PHE frameworks. Two of our themes were only mentioned in one of the frameworks, and two others were not explicitly mentioned. Few important elements of the frameworks did not emerge from our data. Conclusions: In the light of increased attention regarding the connections of the climate and ecological crises and health, our results can be useful for anyone working toward the integration of planetary health into medical schools' and any health professions' curricula and should be considered when designing and implementing new educational activities. KW - climate change KW - climate resilience KW - planetary health KW - planetary health education KW - medical education KW - transformative education KW - education for sustainable healthcare KW - eco health Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313856 SN - 2296-2565 VL - 11 ER - TY - JOUR A1 - Müller, Christina A1 - Domokos, Bruno A1 - Amersbach, Tanja A1 - Hausmayer, Eva-Maria A1 - Roßmann, Christin A1 - Wallmann-Sperlich, Birgit A1 - Bucksch, Jens T1 - Development and reliability testing of an audit toolbox for the assessment of the physical activity friendliness of urban and rural environments in Germany JF - Frontiers in Public Health N2 - Background: According to socio-ecological theories, physical activity behaviors are linked to the physical and social neighborhood environment. Reliable and contextually adapted instruments are needed to assess environmental characteristics related to physical activity. This work aims to develop an audit toolbox adapted to the German context, to urban and rural settings, for different population groups, and different types of physical activity; and to evaluate its inter-rater reliability. Methods: We conducted a systematic literature search to collect existing audit tools and to identify the latest evidence of environmental factors influencing physical activity in general, as well as in German populations. The results guided the construction of a category system for the toolbox. Items were assigned to the categories based on their relevance to physical activity and to the German context as well as their comprehensibility. We piloted the toolbox in different urban and rural areas (100 street segments, 15 parks, and 21 playgrounds) and calculated inter-rater reliability by Cohen's Kappa. Results: The audit toolbox comprises a basic streetscape audit with seven categories (land use and destinations, traffic safety, pedestrian infrastructure, cycling infrastructure, attractiveness, social environment, and subjective assessment), as well as supplementary tools for children and adolescents, seniors and people with impaired mobility, parks and public open spaces, playgrounds, and rural areas. 76 % of all included items had moderate, substantial, or almost perfect inter-rater reliability (κ > 0.4). Conclusions: The audit toolbox is an innovative and reliable instrument for the assessment of the physical activity friendliness of urban and rural environments in Germany. KW - built environment KW - physical activity KW - reliability KW - rural KW - urban KW - walkability Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-326116 SN - 2296-2565 VL - 11 ER - TY - JOUR A1 - Schrader, Hanna A1 - Ruck, Jessica A1 - Borgulya, Gábor A1 - Parisi, Sandra A1 - Ehlers-Mondorf, Jana A1 - Kaduszkiewicz, Hanna A1 - Joos, Stefanie A1 - Grau, Anna A1 - Linde, Klaus A1 - Gágyor, Ildikó T1 - Stress experiences of healthcare assistants in family practice at the onset of the COVID-19 pandemic BT - a mixed methods study JF - Frontiers in Public Health N2 - Background: At the beginning of the pandemic in 2020, healthcare assistants in general practices were confronted with numerous new challenges. The aim of the study was to investigate the stress factors of healthcare assistants in March/April 2020 as well as in the further course of the pandemic in 2020. Methods: From August to December 2020, 6,300 randomly selected healthcare assistants in four German states were invited to participate in the study. We performed a mixed methods design using semi-structured telephone interviews and a cross-sectional survey with quantitative and open questions. The feeling of psychological burden was assessed on a 6-point likert-scale. We defined stress factors and categorized them in patient, non-patient and organizational stress factors. The results of the three data sets were compared within a triangulation protocol. Results: One thousand two hundred seventy-four surveys were analyzed and 28 interviews with 34 healthcare assistants were conducted. Of the participants, 29.5% reported experiences of a very high or high feeling of psychological burden in March/April 2020. Worries about the patients’ health and an uncertainty around the new disease were among the patient-related stress factors. Non-patient-related stress factors were problems with the compatibility of work and family, and the fear of infecting relatives with COVID-19. Organizational efforts and dissatisfaction with governmental pandemic management were reported as organizational stress factors. Support from the employer and team cohesion were considered as important resources. Discussion: It is necessary to reduce stress among healthcare assistants by improving their working conditions and to strengthen their resilience to ensure primary healthcare delivery in future health crises. KW - healthcare assistants KW - COVID-19 pandemic KW - psychological burden KW - stress factors KW - primary care Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-327427 SN - 2296-2565 VL - 11 ER - TY - JOUR A1 - Rack, Christian A1 - Fernando, Tamara A1 - Yalcin, Murat A1 - Hotho, Andreas A1 - Latoschik, Marc Erich T1 - Who is Alyx? A new behavioral biometric dataset for user identification in XR JF - Frontiers in Virtual Reality N2 - Introduction: This paper addresses the need for reliable user identification in Extended Reality (XR), focusing on the scarcity of public datasets in this area. Methods: We present a new dataset collected from 71 users who played the game “Half-Life: Alyx” on an HTC Vive Pro for 45 min across two separate sessions. The dataset includes motion and eye-tracking data, along with physiological data from a subset of 31 users. Benchmark performance is established using two state-of-the-art deep learning architectures, Convolutional Neural Networks (CNN) and Gated Recurrent Units (GRU). Results: The best model achieved a mean accuracy of 95% for user identification within 2 min when trained on the first session and tested on the second. Discussion: The dataset is freely available and serves as a resource for future research in XR user identification, thereby addressing a significant gap in the field. Its release aims to facilitate advancements in user identification methods and promote reproducibility in XR research. KW - dataset KW - behaviometric KW - deep learning KW - physiological dataset KW - user identification Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-353979 SN - 2673-4192 VL - 4 ER - TY - JOUR A1 - Winkler, Markus H. A1 - Li, Yonghui A1 - Pauli, Paul A1 - Mühlberger, Andreas T1 - Modulation of smoking cue reactivity by social context—Implications for exposure therapy in virtual reality JF - Frontiers in Virtual Reality N2 - Rationale: Social factors are considered important for the initiation and maintenance of drug abuse. Virtual reality (VR) research on cue reactivity and exposure frequently incorporates social stimuli as part of complex drug-intake scenarios. Attempts are rarely made to dissect the impact of the different components and their interactive effects. The present study critically extends this line of research by investigating the modulatory effects of social context on the reactivity evoked by proximal smoking cues. Methods: Thirty-two smokers and 33 never-smokers were presented in VR with proximal cues and neutral stimuli, embedded in a social context or a neutral context. A virtual hand model was used to translate real hand movements into VR. Each trial started with the presentation of the different stimulus–context combinations. Discrete stimuli were presented on the table in front of the participants, and contextual stimuli were presented at the end of the table. Afterward, participants were instructed to grasp the target stimulus (a cigarette vs. a pencil) in front of them. After successful contact, the stimulus appeared in the virtual hand. Modulation of cue reactivity by social context was assessed by self-report, physiological measures, and overt approach behavior. Results: The results revealed modulatory effects of social context on the responses to proximal smoking cues in smokers. In contrast to never-smokers, smoking cues evoked craving in smokers, which was attenuated in a social context. Furthermore, social context increased the latency to approach and contact the cigarette in the group of smokers but did not affect behavioral approach responses in never-smokers. Other data provided indications for interactive, but also main effects of cues and contexts. Interestingly, cue-evoked craving was increased after contact with the virtual cigarette. Conclusion: The present study critically extends previous research by providing evidence for the modulation of cue reactivity by social context. The results are particularly important given the well-established role of drug-associated environmental contexts in the stimulus control of addictive behaviors. Our results emphasize the need to address social context effects on cue reactivity in basic research and treatment and further suggest that changes in the perceived availability of smoking might enhance or inhibit cue-evoked reactivity. KW - cue reactivity KW - social context KW - cue exposure therapy KW - cue availability KW - smoking KW - substance use disorders KW - addiction KW - virtual reality Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-306199 VL - 4 ER - TY - JOUR A1 - Vollmer, Andreas A1 - Saravi, Babak A1 - Breitenbuecher, Niko A1 - Mueller-Richter, Urs A1 - Straub, Anton A1 - Šimić, Luka A1 - Kübler, Alexander A1 - Vollmer, Michael A1 - Gubik, Sebastian A1 - Volland, Julian A1 - Hartmann, Stefan A1 - Brands, Roman C. T1 - Realizing in-house algorithm-driven free fibula flap set up within 24 hours BT - a pilot study evaluating accuracy with open-source tools JF - Frontiers in Surgery N2 - Objective: This study aims to critically evaluate the effectiveness and accuracy of a time safing and cost-efficient open-source algorithm for in-house planning of mandibular reconstructions using the free osteocutaneous fibula graft. The evaluation focuses on quantifying anatomical accuracy and assessing the impact on ischemia time. Methods: A pilot study was conducted, including patients who underwent in-house planned computer-aided design and manufacturing (CAD/CAM) of free fibula flaps between 2021 and 2023. Out of all patient cases, we included all with postoperative 3D imaging in the study. The study utilized open-source software tools for the planning step, and three-dimensional (3D) printing techniques. The Hausdorff distance and Dice coefficient metrics were used to evaluate the accuracy of the planning procedure. Results: The study assessed eight patients (five males and three females, mean age 61.75 ± 3.69 years) with different diagnoses such as osteoradionecrosis and oral squamous cell carcinoma. The average ischemia time was 68.38 ± 27.95 min. For the evaluation of preoperative planning vs. the postoperative outcome, the mean Hausdorff Distance was 1.22 ± 0.40. The Dice Coefficients yielded a mean of 0.77 ± 0.07, suggesting a satisfactory concordance between the planned and postoperative states. Dice Coefficient and Hausdorff Distance revealed significant correlations with ischemia time (Spearman's rho = −0.810, p = 0.015 and Spearman's rho = 0.762, p = 0.028, respectively). Linear regression models adjusting for disease type further substantiated these findings. Conclusions: The in-house planning algorithm not only achieved high anatomical accuracy, as reflected by the Dice Coefficients and Hausdorff Distance metrics, but this accuracy also exhibited a significant correlation with reduced ischemia time. This underlines the critical role of meticulous planning in surgical outcomes. Additionally, the algorithm's open-source nature renders it cost-efficient, easy to learn, and broadly applicable, offering promising avenues for enhancing both healthcare affordability and accessibility. KW - mandibular KW - reconstruction KW - preoperative KW - planning KW - ischemia KW - osteocutaneous KW - fibula KW - graft KW - computer-aided KW - design KW - manufacturing (CAD/CAM) Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-353945 N1 - Funding The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article. VL - 10 ER - TY - JOUR A1 - Diesendorf, Viktoria A1 - Roll, Valeria A1 - Geiger, Nina A1 - Fähr, Sofie A1 - Obernolte, Helena A1 - Sewald, Katherina A1 - Bodem, Jochen T1 - Drug-induced phospholipidosis is not correlated with the inhibition of SARS-CoV-2 - inhibition of SARS-CoV-2 is cell line-specific JF - Frontiers in Cellular and Infection Microbiology N2 - Recently, Tummino et al. reported that 34 compounds, including Chloroquine and Fluoxetine, inhibit SARS-CoV-2 replication by inducing phospholipidosis, although Chloroquine failed to suppress viral replication in Calu-3 cells and patients. In contrast, Fluoxetine represses viral replication in human precision-cut lung slices (PCLS) and Calu-3 cells. Thus, it is unlikely that these compounds have similar mechanisms of action. Here, we analysed a subset of these compounds in the viral replication and phospholipidosis assays using the Calu-3 cells and PCLS as the patient-near system. Trimipramine and Chloroquine induced phospholipidosis but failed to inhibit SARS-CoV-2 replication in Calu-3 cells, which contradicts the reported findings and the proposed mechanism. Fluoxetine, only slightly induced phospholipidosis in Calu-3 cells but reduced viral replication by 2.7 orders of magnitude. Tilorone suppressed viral replication by 1.9 orders of magnitude in Calu-3 cells without causing phospholipidosis. Thus, induction of phospholipidosis is not correlated with the inhibition of SARS-CoV-2, and the compounds act via other mechanisms. However, we show that compounds, such as Amiodarone, Tamoxifen and Tilorone, with antiviral activity on Calu-3 cells, also inhibited viral replication in human PCLS. Our results indicate that antiviral assays against SARS-CoV-2 are cell-line specific. Data from Vero E6 can lead to non-transferable results, underlining the importance of an appropriate cell system for analysing antiviral compounds against SARS-CoV-2. We observed a correlation between the active compounds in Calu-3 cells and PCLS. KW - SARS-CoV-2 KW - phospholipidosis KW - Vero E6 KW - PCLS KW - Calu-3 KW - antivirals KW - Tamoxifen KW - cell line-specificity Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-326202 SN - 2235-2988 VL - 13 ER - TY - JOUR A1 - Siegmund, Daniela A1 - Zaitseva, Olena A1 - Wajant, Harald T1 - Fn14 and TNFR2 as regulators of cytotoxic TNFR1 signaling JF - Frontiers in Cell and Developmental Biology N2 - Tumor necrosis factor (TNF) receptor 1 (TNFR1), TNFR2 and fibroblast growth factor-inducible 14 (Fn14) belong to the TNF receptor superfamily (TNFRSF). From a structural point of view, TNFR1 is a prototypic death domain (DD)-containing receptor. In contrast to other prominent death receptors, such as CD95/Fas and the two TRAIL death receptors DR4 and DR5, however, liganded TNFR1 does not instruct the formation of a plasma membrane-associated death inducing signaling complex converting procaspase-8 into highly active mature heterotetrameric caspase-8 molecules. Instead, liganded TNFR1 recruits the DD-containing cytoplasmic signaling proteins TRADD and RIPK1 and empowers these proteins to trigger cell death signaling by cytosolic complexes after their release from the TNFR1 signaling complex. The activity and quality (apoptosis versus necroptosis) of TNF-induced cell death signaling is controlled by caspase-8, the caspase-8 regulatory FLIP proteins, TRAF2, RIPK1 and the RIPK1-ubiquitinating E3 ligases cIAP1 and cIAP2. TNFR2 and Fn14 efficiently recruit TRAF2 along with the TRAF2 binding partners cIAP1 and cIAP2 and can thereby limit the availability of these molecules for other TRAF2/cIAP1/2-utilizing proteins including TNFR1. Accordingly, at the cellular level engagement of TNFR2 or Fn14 inhibits TNFR1-induced RIPK1-mediated effects reaching from activation of the classical NFκB pathway to induction of apoptosis and necroptosis. In this review, we summarize the effects of TNFR2- and Fn14-mediated depletion of TRAF2 and the cIAP1/2 on TNFR1 signaling at the molecular level and discuss the consequences this has in vivo. KW - apoptosis KW - Fn14 KW - necroptosis KW - TNF KW - TNFR1 KW - TNFR2 KW - TRAF2 KW - TWEAK Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-354304 SN - 2296-634X VL - 11 ER - TY - JOUR A1 - Sammeth, Michael A1 - Ursache, Nicu-Cosmin A1 - Alboaie, Sînică T1 - OpenDSU: digital sovereignty in PharmaLedger JF - Frontiers in Blockchain N2 - Introduction: Distributed ledger networks, chiefly those based on blockchain technologies, currently are heralding a next-generation of computer systems that aims to suit modern users’ demands. Over the recent years, several technologies for blockchains, off-chaining strategies, as well as decentralised and respectively self-sovereign identity systems have shot up so fast that standardisation of the protocols is lagging behind, severely hampering the interoperability of different approaches. Moreover, most of the currently available solutions for distributed ledgers focus on either home users or enterprise use case scenarios, failing to provide integrative solutions addressing the needs of both. Methods: Herein, we introduce the OpenDSU platform that allows to interoperate generic blockchain technologies, organised–and possibly cascaded in a hierarchical fashion–in domains. To achieve this flexibility, we seamlessly integrated a set of well conceived components that orchestrate off-chain data and provide granularly resolved and cryptographically secure access levels, intrinsically nested with sovereign identities across the different domains. The source code and extensive documentation of all OpenDSU components described herein are publicly available under the MIT open-source licence at https://opendsu.com. Results: Employing our platform to PharmaLedger, an inter-European network for the standardisation of data handling in the pharmaceutical industry and in healthcare, we demonstrate that OpenDSU can cope with generic demands of heterogeneous use cases in both, performance and handling substantially different business policies. Discussion: Importantly, whereas available solutions commonly require a predefined and fixed set of components, no such vendor lock-in restrictions on the blockchain technology or identity system exist in OpenDSU, making systems built on it flexibly adaptable to new standards evolving in the future. KW - opendsu KW - blockchain interoperability KW - off-chain data KW - blockchain anchoring KW - self-sovereign identities KW - pharmaledger KW - blockchain in healthcare KW - blockchain in the pharmaceutical industry Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320458 SN - 2624-7852 VL - 6 ER - TY - JOUR A1 - Lisowski, Dominik A1 - Lutyj, Paul A1 - Abazari, Arya A1 - Weick, Stefan A1 - Traub, Jan A1 - Polat, Bülent A1 - Flentje, Michael A1 - Kraft, Johannes T1 - Impact of Radiotherapy on Malfunctions and Battery Life of Cardiac Implantable Electronic Devices in Cancer Patients JF - Cancers N2 - Purpose: This study analyses a large number of cancer patients with CIEDs for device malfunction and premature battery depletion by device interrogation after each radiotherapy fraction and compares different guidelines in regard to patient safety. Methods: From 2007 to 2022, a cohort of 255 patients was analyzed for CIED malfunctions via immediate device interrogation after every RT fraction. Results: Out of 324 series of radiotherapy treatments, with a total number of 5742 CIED interrogations, nine device malfunctions (2.8%) occurred. Switching into back-up/safety mode and software errors occurred four times each. Once, automatic read-out could not be performed. The median prescribed cumulative dose at planning target volume (PTV) associated with CIED malfunction was 45.0 Gy (IQR 36.0–64.0 Gy), with a median dose per fraction of 2.31 Gy (IQR 2.0–3.0 Gy). The median maximum dose at the CIED at time of malfunction was 0.3 Gy (IQR 0.0–1.3 Gy). No correlation between CIED malfunction and maximum photon energy (p = 0.07), maximum dose at the CIED (p = 0.59) nor treatment localization (p = 0.41) could be detected. After excluding the nine malfunctions, premature battery depletion was only observed three times (1.2%). Depending on the national guidelines, 1–9 CIED malfunctions in this study would have been detected on the day of occurrence and in none of the cases would patient safety have been compromised. Conclusion: Radiation-induced malfunctions of CIEDs and premature battery depletion are rare. If recommendations of national safety guidelines are followed, only a portion of the malfunctions would be detected directly after occurrence. Nevertheless, patient safety would not be compromised. KW - battery depletion KW - cardiac implantable electronic devices (CIED) KW - cardiac resynchronization therapy (CRT) KW - implantable cardioverter defibrillator (ICD) KW - CIED malfunction; pacemaker (PM) KW - radiotherapy (RT) Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358008 SN - 2072-6694 VL - 15 IS - 19 ER - TY - JOUR A1 - Kraemer, Markus A1 - Becker, Jana A1 - Bley, Thorsten Alexander A1 - Steinbrecher, Andreas A1 - Minnerup, Jens A1 - Hellmich, Bernhard T1 - Diagnostik und Therapie der Riesenzellarteriitis T1 - Diagnostics and treatment of giant cell arteritis JF - Der Nervenarzt N2 - Die Riesenzellarteriitis (RZA) ist in der Altersgruppe der über 50-Jährigen die häufigste idiopathische systemische Vaskulitis. Die Erkrankung bedarf einer zeitnahen Diagnostik und Therapie, um schwere Komplikationen wie eine Erblindung oder einen Schlaganfall zu vermeiden. Die Rezidivneigung erfordert eine mehrjährige, zum Teil lebenslange Glukokortikoid(GC)-Therapie, was das Risiko GC-induzierter Langzeitnebenwirkungen erhöht. Daher wird bei der Mehrzahl der Patienten eine additive GC-einsparende Therapie empfohlen. Hierzu steht der Anti-IL-6-Rezeptor-Antikörper Tocilizumab in subkutaner Applikation als zugelassene Substanz zur Verfügung, alternativ kann Methotrexat (MTX) eingesetzt werden (off-label). N2 - Giant cell arteritis (GCA) is the most common idiopathic systemic vasculitis in the age group over 50 years. It requires prompt diagnostics and treatment to avoid severe complications, such as visual loss or stroke. The tendency to relapse makes a glucocorticoid (GC) treatment necessary for several years and sometimes lifelong, which increases the risk of GC-induced long-term side effects. Therefore, additive GC-sparing treatment is recommended in the majority of patients. For this purpose, the anti-IL‑6 receptor antibody tocilizumab is available as an approved substance for subcutaneous application; alternatively, methotrexate (MTX) can be used (off-label). KW - Riesenzellarteriitis KW - Diagnose KW - Therapie KW - Glukokortikoide KW - Glukokortikoideinsparende Therapie KW - Tocilizumab KW - Methotrexat KW - giant cell arteritis KW - diagnosis KW - therapy KW - glucocorticoids KW - glucocorticoid-sparing agents KW - Tocilizumab KW - Methotrexate Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307771 SN - 0028-2804 SN - 1433-0407 VL - 93 IS - 8 ER - TY - JOUR A1 - Barlinn, J. A1 - Winzer, S. A1 - Worthmann, H. A1 - Urbanek, C. A1 - Häusler, K. G. A1 - Günther, A. A1 - Erdur, H. A1 - Görtler, M. A1 - Busetto, L. A1 - Wojciechowski, C. A1 - Schmitt, J. A1 - Shah, Y. A1 - Büchele, B. A1 - Sokolowski, P. A1 - Kraya, T. A1 - Merkelbach, S. A1 - Rosengarten, B. A1 - Stangenberg-Gliss, K. A1 - Weber, J. A1 - Schlachetzki, F. A1 - Abu-Mugheisib, M. A1 - Petersen, M. A1 - Schwartz, A. A1 - Palm, F. A1 - Jowaed, A. A1 - Volbers, B. A1 - Zickler, P. A1 - Remi, J. A1 - Bardutzky, J. A1 - Bösel, J. A1 - Audebert, H. J. A1 - Hubert, G. J. A1 - Gumbinger, C. T1 - Telemedizin in der Schlaganfallversorgung – versorgungsrelevant für Deutschland T1 - Telemedicine in stroke—pertinent to stroke care in Germany JF - Der Nervenarzt N2 - Hintergrund und Ziel Telemedizinische Schlaganfall-Netzwerke tragen dazu bei, die Schlaganfallversorgung und insbesondere den Zugang zu zeitkritischen Schlaganfalltherapien in vorrangig strukturschwachen, ländlichen Regionen zu gewährleisten. Ziel ist eine Darstellung der Nutzungsfrequenz und regionalen Verteilung dieser Versorgungsstruktur. Methoden Die Kommission „Telemedizinische Schlaganfallversorgung“ der Deutschen Schlaganfall-Gesellschaft führte eine Umfragestudie in allen Schlaganfall-Netzwerken durch. Ergebnisse In Deutschland sind 22 telemedizinische Schlaganfall-Netzwerke aktiv, welche insgesamt 43 Zentren (pro Netzwerk: Median 1,5, Interquartilsabstand [IQA] 1–3) sowie 225 Kooperationskliniken (pro Netzwerk: Median 9, IQA 4–17) umfassen und an einem unmittelbaren Zugang zur Schlaganfallversorgung für 48 Mio. Menschen teilhaben. Im Jahr 2018 wurden 38.211 Telekonsile (pro Netzwerk: Median 1340, IQA 319–2758) durchgeführt. Die Thrombolyserate betrug 14,1 % (95 %-Konfidenzintervall 13,6–14,7 %), eine Verlegung zur Thrombektomie wurde bei 7,9 % (95 %-Konfidenzintervall 7,5–8,4 %) der ischämischen Schlaganfallpatienten initiiert. Das Finanzierungssystem ist uneinheitlich mit einem Vergütungssystem für die Zentrumsleistungen in nur drei Bundesländern. Diskussion Etwa jeder 10. Schlaganfallpatient wird telemedizinisch behandelt. Die telemedizinischen Schlaganfall-Netzwerke erreichen vergleichbar hohe Lyseraten und Verlegungen zur Thrombektomie wie neurologische Stroke-Units und tragen zur Sicherstellung einer flächendeckenden Schlaganfallversorgung bei. Eine netzwerkübergreifende Sicherstellung der Finanzierung und einheitliche Erhebung von Qualitätssicherungsdaten haben das Potenzial diese Versorgungsstruktur zukünftig weiter zu stärken. N2 - Background and objective Telemedical stroke networks improve stroke care and provide access to time-dependent acute stroke treatment in predominantly rural regions. The aim is a presentation of data on its utility and regional distribution. Methods The working group on telemedical stroke care of the German Stroke Society performed a survey study among all telestroke networks. Results Currently, 22 telemedical stroke networks including 43 centers (per network: median 1.5, interquartile range, IQR, 1–3) as well as 225 cooperating hospitals (per network: median 9, IQR 4–17) operate in Germany and contribute to acute stroke care delivery to 48 million people. In 2018, 38,211 teleconsultations (per network: median 1340, IQR 319–2758) were performed. The thrombolysis rate was 14.1% (95% confidence interval 13.6–14.7%) and transfer for thrombectomy was initiated in 7.9% (95% confidence interval 7.5–8.4%) of ischemic stroke patients. Financial reimbursement differs regionally with compensation for telemedical stroke care in only three federal states. Conclusion Telemedical stroke care is utilized in about 1 out of 10 stroke patients in Germany. Telemedical stroke networks achieve similar rates of thrombolysis and transfer for thrombectomy compared with neurological stroke units and contribute to stroke care in rural regions. Standardization of network structures, financial assurance and uniform quality measurements may further strengthen the importance of telestroke networks in the future. KW - Schlaganfall KW - Stroke-Unit KW - Telemedizin KW - Schlaganfall-Netzwerk KW - Umfragestudie KW - stroke KW - stroke unit KW - telemedicine KW - stroke networks KW - survey Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307752 SN - 0028-2804 SN - 1433-0407 VL - 92 IS - 6 ER - TY - JOUR A1 - Wagner, N. A1 - Crippa, L. A1 - Amaricci, A. A1 - Hansmann, P. A1 - Klett, M. A1 - König, E. J. A1 - Schäfer, T. A1 - Di Sante, D. A1 - Cano, J. A1 - Millis, A. J. A1 - Georges, A. A1 - Sangiovanni, G. T1 - Mott insulators with boundary zeros JF - Nature Communications N2 - The topological classification of electronic band structures is based on symmetry properties of Bloch eigenstates of single-particle Hamiltonians. In parallel, topological field theory has opened the doors to the formulation and characterization of non-trivial phases of matter driven by strong electron-electron interaction. Even though important examples of topological Mott insulators have been constructed, the relevance of the underlying non-interacting band topology to the physics of the Mott phase has remained unexplored. Here, we show that the momentum structure of the Green’s function zeros defining the “Luttinger surface" provides a topological characterization of the Mott phase related, in the simplest description, to the one of the single-particle electronic dispersion. Considerations on the zeros lead to the prediction of new phenomena: a topological Mott insulator with an inverted gap for the bulk zeros must possess gapless zeros at the boundary, which behave as a form of “topological antimatter” annihilating conventional edge states. Placing band and Mott topological insulators in contact produces distinctive observable signatures at the interface, revealing the otherwise spectroscopically elusive Green’s function zeros. KW - electronic properties and materials KW - topological insulators Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358150 VL - 14 ER -