@article{JanzWalzCirnuetal.2024,
  author    = {Janz, Anna and Walz, Katharina and Cirnu, Alexandra and Surjanto, Jessica and Urlaub, Daniela and Leskien, Miriam and Kohlhaas, Michael and Nickel, Alexander and Brand, Theresa and Nose, Naoko and W{\"o}rsd{\"o}rfer, Philipp and Wagner, Nicole and Higuchi, Takahiro and Maack, Christoph and Dudek, Jan and Lorenz, Kristina and Klopocki, Eva and Erg{\"u}n, S{\"u}leyman and Duff, Henry J. and Gerull, Brenda},
  title     = {Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes},
  series = {Molecular Metabolism},
  volume    = {79},
  journal   = {Molecular Metabolism},
  issn      = {2212-8778},
  doi       = {10.1016/j.molmet.2023.101859},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350393},
  year      = {2024},
  abstract  = {Highlights • Loss of DNAJC19's DnaJ domain disrupts cardiac mitochondrial structure, leading to abnormal cristae formation in iPSC-CMs. • Impaired mitochondrial structures lead to an increased mitochondrial respiration, ROS and an elevated membrane potential. • Mutant iPSC-CMs show sarcomere dysfunction and a trend to more arrhythmias, resembling DCMA-associated cardiomyopathy. Background Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy. Methods We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19 which all lack the conserved DnaJ interaction domain. The mutant iPSC-CMs and their respective control cells were subjected to various analyses, including assessments of morphology, metabolic function, and physiological consequences such as Ca\(^{2+}\) kinetics, contractility, and arrhythmic potential. Validation of respiration analysis was done in a gene-edited HeLa cell line (DNAJC19tv\(_{HeLa}\)). Results Structural analyses revealed mitochondrial fragmentation and abnormal cristae formation associated with an overall reduced mitochondrial protein expression in mutant iPSC-CMs. Morphological alterations were associated with higher oxygen consumption rates (OCRs) in all three mutant iPSC-CMs, indicating higher electron transport chain activity to meet cellular ATP demands. Additionally, increased extracellular acidification rates suggested an increase in overall metabolic flux, while radioactive tracer uptake studies revealed decreased fatty acid uptake and utilization of glucose. Mutant iPSC-CMs also showed increased reactive oxygen species (ROS) and an elevated mitochondrial membrane potential. Increased mitochondrial respiration with pyruvate and malate as substrates was observed in mutant DNAJC19tv HeLa cells in addition to an upregulation of respiratory chain complexes, while cellular ATP-levels remain the same. Moreover, mitochondrial alterations were associated with increased beating frequencies, elevated diastolic Ca\(^{2+}\) concentrations, reduced sarcomere shortening and an increased beat-to-beat rate variability in mutant cell lines in response to β-adrenergic stimulation. Conclusions Loss of the DnaJ domain disturbs cardiac mitochondrial structure with abnormal cristae formation and leads to mitochondrial dysfunction, suggesting that DNAJC19 plays an essential role in mitochondrial morphogenesis and biogenesis. Moreover, increased mitochondrial respiration, altered substrate utilization, increased ROS production and abnormal Ca\(^{2+}\) kinetics provide insights into the pathogenesis of DCMA-related cardiomyopathy.},
  language  = {en}
}
@article{HalfmannCastioniWetzeletal.2024,
  author    = {Halfmann, Marie and Castioni, Noah and Wetzel, Lea and Koopmann, Anne and K{\"o}nig, Sarah and Schmieder, Astrid},
  title     = {Effects of the COVID-19 pandemic on the mental health of medical students and young physicians in Germany: Gender-specific results of an online survey},
  series = {Heliyon},
  volume    = {10},
  journal   = {Heliyon},
  number    = {1},
  issn      = {2405-8440},
  doi       = {10.1016/j.heliyon.2023.e23727},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350502},
  year      = {2024},
  abstract  = {Background Healthcare workers and medical students faced new challenges during the COVID-19 pandemic. Processes within many hospitals were completely disrupted. In addition, the face to face teaching of medical students was drastically reduced. Those at risk of developing mental health problems appear to be younger health care workers and women. Objective To investigate potential COVID-19 pandemic-related gender differences in psychological distress among medical students and physicians in their first years of practice. Design and setting An anonymous survey was carried out online between December 1, 2021, and March 31, 2022, at the Mannheim Medical Faculty and the W{\"u}rzburg Medical Faculty, Germany, after obtaining informed consent. Primary outcome measures were changes in anxiety and depression symptoms using the Hospital Anxiety and Depression Scale (HADS), and changes in participants' current quality of life using the WHO Quality of Life BREF. Results The results show wave-like courses for perceived anxiety and burden overlapping with the course of the COVID-19 incidence. In comparison to men, women showed a significant higher increase in HADS (p = 0.005) and a reduced life quality (p = 0.007) after COVID-19. Both sexes showed different frequencies of the factors influencing quality of life, with the presence of a previous mental illness and mean anxiety having a significant higher negative impact in women. Conclusion Future and young female physicians reported a disproportionate higher burden during COVID-19 compared to their male colleges. These observations suggest an increased need for support and prevention efforts especially in this vulnerable population.},
  language  = {en}
}
@article{DuskeClausKroneetal.2024,
  author    = {Duske, Helene and Claus, Heike and Krone, Manuel and L{\^a}m, Thi{\^e}n-Tr{\´i}},
  title     = {Prevalence of piperacillin/tazobactam resistance in invasive \(Haemophilus\) \(influenzae\) in Germany},
  series = {JAC-Antimicrobial Resistance},
  volume    = {6},
  journal   = {JAC-Antimicrobial Resistance},
  number    = {1},
  issn      = {2632-1823},
  doi       = {10.1093/jacamr/dlad148},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350424},
  year      = {2024},
  abstract  = {Background Haemophilus influenzae (Hi) is a Gram-negative bacterium that may cause sepsis or meningitis, treatment of which mainly includes β-lactam antibiotics. Since 2019 EUCAST breakpoints for piperacillin/tazobactam have been available. Little is known about the prevalence and mechanisms of piperacillin/tazobactam resistance in Hi. Objectives To provide reliable prevalence data for piperacillin/tazobactam resistance in Hi in Germany, to evaluate different antibiotic susceptibility testing methods and to examine possible resistance mechanisms. Methods According to EUCAST breakpoints, the MIC for piperacillin/tazobactam resistance is >0.25 mg/L. All invasive Hi in Germany from 2019 were examined by gradient agar diffusion (GAD) for piperacillin/tazobactam susceptibility. Piperacillin/tazobactam broth microdilution (BMD), piperacillin GAD on tazobactam-containing agar [piperacillin GAD on Mueller-Hinton agar with horse blood (MH-F)/tazobactam) and piperacillin/tazobactam agar dilution (AD) were used for confirmation. Phenotypic testing was complemented by ftsI sequencing. Results Piperacillin/tazobactam GAD resulted in 2.9\% (21/726) resistant Hi. BMD did not confirm piperacillin/tazobactam resistance. Two strains were found resistant by AD, of which one was also resistant using piperacillin GAD on MH-F/tazobactam. Overall, we found two strains with a piperacillin/tazobactam MIC >0.25 mg/L in at least two different tests (0.3\%). Both were β-lactamase-producing amoxicillin/clavulanate-resistant with PBP3 mutations characterized as group III-like+. Relevant PBP3 mutations occurred in six strains without phenotypic piperacillin/tazobactam resistance. These mutations suggest a reduced efficacy of β-lactam antibiotics in these isolates. Conclusions Piperacillin/tazobactam resistance prevalence in invasive Hi is low in Germany. Reduced susceptibility was correlated with PBP3 mutations, in particular with group III mutations.},
  language  = {en}
}
@article{WiesslerTalucciPiroetal.2024,
  author    = {Wiessler, Anna-Lena and Talucci, Ivan and Piro, Inken and Seefried, Sabine and H{\"o}rlin, Verena and Baykan, Bet{\"u}l B. and T{\"u}z{\"u}n, Erdem and Schaefer, Natascha and Maric, Hans M. and Sommer, Claudia and Villmann, Carmen},
  title     = {Glycine receptor β-targeting autoantibodies contribute to the pathology of autoimmune diseases},
  series = {Neurology: Neuroimmunology \& Neuroinflammation},
  volume    = {11},
  journal   = {Neurology: Neuroimmunology \& Neuroinflammation},
  number    = {2},
  doi       = {10.1212/NXI.0000000000200187},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349958},
  year      = {2024},
  abstract  = {Background and Objectives Stiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are rare neurologic disorders of the CNS. Until now, exclusive GlyRα subunit-binding autoantibodies with subsequent changes in function and surface numbers were reported. GlyR autoantibodies have also been described in patients with focal epilepsy. Autoimmune reactivity against the GlyRβ subunits has not yet been shown. Autoantibodies against GlyRα1 target the large extracellular N-terminal domain. This domain shares a high degree of sequence homology with GlyRβ making it not unlikely that GlyRβ-specific autoantibody (aAb) exist and contribute to the disease pathology. Methods In this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyRβ. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyRβ binding and define aAb binding to distinct protein regions. Preadsorption approaches of aAbs using living cells and the purified extracellular receptor domain were further used. Finally, functional consequences for inhibitory neurotransmission upon GlyRβ aAb binding were resolved by whole-cell patch-clamp recordings. Results Among 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyRβ aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyRβ colocalized with the scaffold protein gephyrin independent of the presence of GlyRα1. At the functional level, binding of GlyRβ aAb from both patients to its target impair glycine efficacy. Discussion Our study establishes GlyRβ as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyRα1-positive sera, which alter glycine potency, aAbs against GlyRβ impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyRβ aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.},
  language  = {en}
}
@article{BreyerGruenerKleinetal.2024,
  author    = {Breyer, Maximilian and Gr{\"u}ner, Julia and Klein, Alexandra and Finke, Laura and Klug, Katharina and Sauer, Markus and {\"U}{\c{c}}eyler, Nurcan},
  title     = {\(In\) \(vitro\) characterization of cells derived from a patient with the GLA variant c.376A>G (p.S126G) highlights a non-pathogenic role in Fabry disease},
  series = {Molecular Genetics and Metabolism Reports},
  volume    = {38},
  journal   = {Molecular Genetics and Metabolism Reports},
  issn      = {22144269},
  doi       = {10.1016/j.ymgmr.2023.101029},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350295},
  year      = {2024},
  abstract  = {Highlights • The GLA variant S126G is not associated with Fabry symptoms in the presented case • S126G has no effect on α-GAL A activity or Gb3 levels in this patient • S126G sensory neurons show no electrophysiological abnormalities Abstract Fabry disease (FD) is a life-limiting disorder characterized by intracellular globotriaosylceramide (Gb3) accumulations. The underlying α-galactosidase A (α-GAL A) deficiency is caused by variants in the gene GLA. Variants of unknown significance (VUS) are frequently found in GLA and challenge clinical management. Here, we investigated a 49-year old man with cryptogenic lacunar cerebral stroke and the chance finding of the VUS S126G, who was sent to our center for diagnosis and initiation of a costly and life-long FD-specific treatment. We combined clinical examination with in vitro investigations of dermal fibroblasts (HDF), induced pluripotent stem cells (iPSC), and iPSC-derived sensory neurons. We analyzed α-GAL A activity in iPSC, Gb3 accumulation in all three cell types, and action potential firing in sensory neurons. Neurological examination and small nerve fiber assessment was normal except for reduced distal skin innervation. S126G iPSC showed normal α-GAL A activity compared to controls and no Gb3 deposits were found in all three cell types. Baseline electrophysiological characteristics of S126G neurons showed no difference compared to healthy controls as investigated by patch-clamp recordings. We pioneer multi-level cellular characterization of the VUS S126G using three cell types derived from a patient and provide further evidence for the benign nature of S126G in GLA, which is of great importance in the management of such cases in clinical practice.},
  language  = {en}
}
@article{JaenschEvdokimovEgenolfetal.2024,
  author    = {J{\"a}nsch, Sarah and Evdokimov, Dimitar and Egenolf, Nadine and Meyer zu Altenschildesche, Caren and Kreß, Luisa and {\"U}{\c{c}}eyler, Nurcan},
  title     = {Distinguishing fibromyalgia syndrome from small fiber neuropathy: a clinical guide},
  series = {Pain Reports},
  volume    = {9},
  journal   = {Pain Reports},
  number    = {1},
  doi       = {10.1097/PR9.0000000000001136},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350306},
  year      = {2024},
  abstract  = {Introduction: Fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) are distinct pain conditions that share commonalities and may be challenging as for differential diagnosis. Objective: To comprehensively investigate clinical characteristics of women with FMS and SFN to determine clinically applicable parameters for differentiation. Methods: We retrospectively analyzed medical records of 158 women with FMS and 53 with SFN focusing on pain-specific medical and family history, accompanying symptoms, additional diseases, and treatment. We investigated data obtained using standardized pain, depression, and anxiety questionnaires. We further analyzed test results and findings obtained in standardized small fiber tests. Results: FMS patients were on average ten years younger at symptom onset, described higher pain intensities requiring frequent change of pharmaceutics, and reported generalized pain compared to SFN. Pain in FMS was accompanied by irritable bowel or sleep disturbances, and in SFN by paresthesias, numbness, and impaired glucose metabolism (P < 0.01 each). Family history was informative for chronic pain and affective disorders in FMS (P < 0.001) and for neurological disorders in SFN patients (P < 0.001). Small fiber pathology in terms of skin denervation and/or thermal sensory threshold elevation was present in 110/158 (69.7 \%) FMS patients and 39/53 (73.6 \%) SFN patients. FMS patients mainly showed proximally reduced skin innervation and higher corneal nerve branch densities (p<0.001) whereas SFN patients were characterized by reduced cold detection and prolonged electrical A-delta conduction latencies (P < 0.05). Conclusions: Our data show that FMS and SFN differ substantially. Detailed pain, drug and family history, investigating blood glucose metabolism, and applying differential small fiber tests may help to improve diagnostic differentiation and targeted therapy.},
  language  = {en}
}
@article{TrifaultMamontovaCossaetal.2024,
  author    = {Trifault, Barbara and Mamontova, Victoria and Cossa, Giacomo and Ganskih, Sabina and Wei, Yuanjie and Hofstetter, Julia and Bhandare, Pranjali and Baluapuri, Apoorva and Nieto, Blanca and Solvie, Daniel and Ade, Carsten P. and Gallant, Peter and Wolf, Elmar and Larsen, Dorthe H. and Munschauer, Mathias and Burger, Kaspar},
  title     = {Nucleolar detention of NONO shields DNA double-strand breaks from aberrant transcripts},
  series = {Nucleic Acids Research},
  volume    = {52},
  journal   = {Nucleic Acids Research},
  number    = {6},
  doi       = {10.1093/nar/gkae022},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350208},
  pages     = {3050-3068},
  year      = {2024},
  abstract  = {RNA-binding proteins emerge as effectors of the DNA damage response (DDR). The multifunctional non-POU domain-containing octamer-binding protein NONO/p54\(^{nrb}\) marks nuclear paraspeckles in unperturbed cells, but also undergoes re-localization to the nucleolus upon induction of DNA double-strand breaks (DSBs). However, NONO nucleolar re-localization is poorly understood. Here we show that the topoisomerase II inhibitor etoposide stimulates the production of RNA polymerase II-dependent, DNA damage-inducible antisense intergenic non-coding RNA (asincRNA) in human cancer cells. Such transcripts originate from distinct nucleolar intergenic spacer regions and form DNA-RNA hybrids to tether NONO to the nucleolus in an RNA recognition motif 1 domain-dependent manner. NONO occupancy at protein-coding gene promoters is reduced by etoposide, which attenuates pre-mRNA synthesis, enhances NONO binding to pre-mRNA transcripts and is accompanied by nucleolar detention of a subset of such transcripts. The depletion or mutation of NONO interferes with detention and prolongs DSB signalling. Together, we describe a nucleolar DDR pathway that shields NONO and aberrant transcripts from DSBs to promote DNA repair.},
  language  = {en}
}
@article{HofstetterOgunleyeKutschkeetal.2024,
  author    = {Hofstetter, Julia and Ogunleye, Ayoola and Kutschke, Andr{\´e} and Buchholz, Lisa Marie and Wolf, Elmar and Raabe, Thomas and Gallant, Peter},
  title     = {Spt5 interacts genetically with Myc and is limiting for brain tumor growth in Drosophila},
  series = {Life Science Alliance},
  volume    = {7},
  journal   = {Life Science Alliance},
  number    = {1},
  issn      = {2575-1077},
  doi       = {10.26508/lsa.202302130},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350197},
  year      = {2024},
  abstract  = {The transcription factor SPT5 physically interacts with MYC oncoproteins and is essential for efficient transcriptional activation of MYC targets in cultured cells. Here, we use Drosophila to address the relevance of this interaction in a living organism. Spt5 displays moderate synergy with Myc in fast proliferating young imaginal disc cells. During later development, Spt5-knockdown has no detectable consequences on its own, but strongly enhances eye defects caused by Myc overexpression. Similarly, Spt5-knockdown in larval type 2 neuroblasts has only mild effects on brain development and survival of control flies, but dramatically shrinks the volumes of experimentally induced neuroblast tumors and significantly extends the lifespan of tumor-bearing animals. This beneficial effect is still observed when Spt5 is knocked down systemically and after tumor initiation, highlighting SPT5 as a potential drug target in human oncology.},
  language  = {en}
}
@article{ScheinerDaunkeSeideletal.2023,
  author    = {Scheiner, Christin and Daunke, Andrea and Seidel, Alexandra and Mittermeier, Sabrina and Romanos, Marcel and K{\"o}lch, Michael and Buerger, Arne},
  title     = {LessStress - how to reduce stress in school: evaluation of a universal stress prevention in schools: study protocol of a cluster-randomised controlled trial},
  series = {Trials},
  volume    = {24},
  journal   = {Trials},
  number    = {1},
  doi       = {10.1186/s13063-022-06970-x},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300393},
  year      = {2023},
  abstract  = {Background Chronic stress is detrimental to health, and children and young people have had to cope with significantly more stress since the start of the COVID-19 pandemic. In particular, stress at school and in relation to learning is a major problem in this age group. Studies in Germany have indicated that the pandemic has led to a reduced quality of life (QoL) and an increased risk for psychiatric disorders in children and adolescents. Schools are an ideal setting for interventions against stress, which is one of the strongest predictors for the development of psychosocial problems. The present study seeks to address stress by means of a short prevention training programme in schools, including emotion regulation, mindfulness, and self-compassion. In addition to information material for self-study, students should have the opportunity to actively deal with the topic of stress and develop coping strategies within a short space of time. In contrast to very long stress reduction programmes that often last several weeks, the programme is delivered in just 90 min. Methods The effectiveness of the short and economical prevention programme LessStress will be examined in a cluster-randomised controlled trial (RCT) encompassing 1894 students. At several measurement time points, students from two groups (intervention and control) will be asked about their subjectively perceived stress levels, among other aspects. Due to the clustered nature of the data, mainly multilevel analyses will be performed. Discussion In Germany, there are no nationwide universal prevention programmes for students against stress in schools, and this gap has become more evident since the outbreak of the pandemic. Universal stress prevention in schools may be a starting point to promote resilience. By dealing with stress in a healthy way, mental health can be strengthened and maintained. Moreover, to reach at-risk students at an early stage, we advocate for a stronger networking between child psychiatry and schools.},
  language  = {en}
}
@article{Klug2023,
  author    = {Klug, Florian},
  title     = {The Theologian's Socratic Role in today's Scientific World},
  series = {Doctrine \& Life},
  volume    = {73},
  journal   = {Doctrine \& Life},
  number    = {2},
  issn      = {0012-4664},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303554},
  pages     = {35-45},
  year      = {2023},
  abstract  = {In the scientific search for truth, the correspondence theory is predominant to decipher what counts as true. In this approach, scientific knowledge becomes empirically demonstrable and thus enclosed to the sphere of immanence. However, in theology's approach to question the given status of being human and the world's development as creation, theology does not adhere to answers that are contained within the sphere of demonstrable knowledge or mundanity, and thereby theology presents a fundamentally different conception of truth, Jesus Christ the living truth. In opposition to drawing on empirical proof, I want to reread Christian theology in a Socratic manner that employs irony to question overly simple methodologies and seek further insights what it means to be human and be engaged in the scientific search for truth if the authority of knowledge does not lie within humanity's grasp. In doing so, theology's role is an annoying, yet necessary irritation within the field of today's academia.},
  language  = {en}
}