TY - JOUR A1 - Luu, Maik A1 - Schütz, Burkhard A1 - Lauth, Matthias A1 - Visekruna, Alexander T1 - The impact of gut microbiota-derived metabolites on the tumor immune microenvironment JF - Cancers N2 - Prevention of the effectiveness of anti-tumor immune responses is one of the canonical cancer hallmarks. The competition for crucial nutrients within the tumor microenvironment (TME) between cancer cells and immune cells creates a complex interplay characterized by metabolic deprivation. Extensive efforts have recently been made to understand better the dynamic interactions between cancer cells and surrounding immune cells. Paradoxically, both cancer cells and activated T cells are metabolically dependent on glycolysis, even in the presence of oxygen, a metabolic process known as the Warburg effect. The intestinal microbial community delivers various types of small molecules that can potentially augment the functional capabilities of the host immune system. Currently, several studies are trying to explore the complex functional relationship between the metabolites secreted by the human microbiome and anti-tumor immunity. Recently, it has been shown that a diverse array of commensal bacteria synthetizes bioactive molecules that enhance the efficacy of cancer immunotherapy, including immune checkpoint inhibitor (ICI) treatment and adoptive cell therapy with chimeric antigen receptor (CAR) T cells. In this review, we highlight the importance of commensal bacteria, particularly of the gut microbiota-derived metabolites that are capable of shaping metabolic, transcriptional and epigenetic processes within the TME in a therapeutically meaningful way. KW - tumor microenvironment (TME) KW - commensal bacteria KW - intratumoral microbiota KW - oncobiome KW - microbiota-derived metabolites KW - cancer immunotherapy Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311005 SN - 2072-6694 VL - 15 IS - 5 ER - TY - JOUR A1 - Wobser, Marion A1 - Goebeler, Matthias T1 - Special Issue “Cutaneous Lymphomas” JF - Cancers N2 - No abstract available KW - cutaneous lymphomas Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304180 SN - 2072-6694 VL - 15 IS - 5 ER - TY - JOUR A1 - Jede, Christian A1 - Henze, Laura J. A1 - Meiners, Kirstin A1 - Bogdahn, Malte A1 - Wedel, Marcel A1 - van Axel, Valeria T1 - Development and application of a dissolution-transfer-partitioning system (DTPS) for biopharmaceutical drug characterization JF - Pharmaceutics N2 - A variety of in vitro dissolution and gastrointestinal transfer models have been developed aiming to predict drug supersaturation and precipitation. Further, biphasic, one-vessel in vitro systems are increasingly applied to simulate drug absorption in vitro. However, to date, there is a lack of combining the two approaches. Therefore, the first aim of this study was to develop a dissolution-transfer-partitioning system (DTPS) and, secondly, to assess its biopredictive power. In the DTPS, simulated gastric and intestinal dissolution vessels are connected via a peristaltic pump. An organic layer is added on top of the intestinal phase, serving as an absorptive compartment. The predictive power of the novel DTPS was assessed to a classical USP II transfer model using a BCS class II weak base with poor aqueous solubility, MSC-A. The classical USP II transfer model overestimated simulated intestinal drug precipitation, especially at higher doses. By applying the DTPS, a clearly improved estimation of drug supersaturation and precipitation and an accurate prediction of the in vivo dose linearity of MSC-A were observed. The DTPS provides a useful tool taking both dissolution and absorption into account. This advanced in vitro tool offers the advantage of streamlining the development process of challenging compounds. KW - in vitro dissolution testing KW - in vitro dissolution methods KW - in vivo dissolution KW - oral drug absorption KW - oral bioavailability KW - gastrointestinal Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311149 SN - 1999-4923 VL - 15 IS - 4 ER - TY - JOUR A1 - Houben, Roland A1 - Celikdemir, Büke A1 - Kervarrec, Thibault A1 - Schrama, David T1 - Merkel cell polyomavirus: infection, genome, transcripts and its role in development of Merkel cell carcinoma JF - Cancers N2 - The best characterized polyomavirus family member, i.e., simian virus 40 (SV40), can cause different tumors in hamsters and can transform murine and human cells in vitro. Hence, the SV40 contamination of millions of polio vaccine doses administered from 1955–1963 raised fears that this may cause increased tumor incidence in the vaccinated population. This is, however, not the case. Indeed, up to now, the only polyomavirus family member known to be the most important cause of a specific human tumor entity is Merkel cell polyomavirus (MCPyV) in Merkel cell carcinoma (MCC). MCC is a highly deadly form of skin cancer for which the cellular origin is still uncertain, and which appears as two clinically very similar but molecularly highly different variants. While approximately 80% of cases are found to be associated with MCPyV the remaining MCCs carry a high mutational load. Here, we present an overview of the multitude of molecular functions described for the MCPyV encoded oncoproteins and non-coding RNAs, present the available MCC mouse models and discuss the increasing evidence that both, virus-negative and -positive MCC constitute epithelial tumors. KW - Merkel cell carcinoma KW - polyomavirus KW - T antigen Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305021 SN - 2072-6694 VL - 15 IS - 2 ER - TY - JOUR A1 - Kämmerer, Peer W. A1 - Tribius, Silke A1 - Cohrs, Lena A1 - Engler, Gabriel A1 - Ettl, Tobias A1 - Freier, Kolja A1 - Frerich, Bernhard A1 - Ghanaati, Shahram A1 - Gosau, Martin A1 - Haim, Dominik A1 - Hartmann, Stefan A1 - Heiland, Max A1 - Herbst, Manuel A1 - Hoefert, Sebastian A1 - Hoffmann, Jürgen A1 - Hölzle, Frank A1 - Howaldt, Hans-Peter A1 - Kreutzer, Kilian A1 - Leonhardt, Henry A1 - Lutz, Rainer A1 - Moergel, Maximilian A1 - Modabber, Ali A1 - Neff, Andreas A1 - Pietzka, Sebastian A1 - Rau, Andrea A1 - Reichert, Torsten E. A1 - Smeets, Ralf A1 - Sproll, Christoph A1 - Steller, Daniel A1 - Wiltfang, Jörg A1 - Wolff, Klaus-Dietrich A1 - Kronfeld, Kai A1 - Al-Nawas, Bilal T1 - Adjuvant radiotherapy in patients with squamous cell carcinoma of the oral cavity or oropharynx and solitary ipsilateral lymph node metastasis (pN1) — a prospective multicentric cohort study JF - Cancers N2 - (1) Background: Evaluation of impact of adjuvant radiation therapy (RT) in patients with oral squamous cell carcinoma of the oral cavity/oropharynx (OSCC) of up to 4 cm (pT1/pT2) and solitary ipsilateral lymph node metastasis (pN1). A non-irradiated group with clinical follow-up was chosen for control, and survival and quality of life (QL) were compared; (2) Methods: This prospective multicentric comprehensive cohort study included patients with resected OSCC (pT1/pT2, pN1, and cM0) who were allocated into adjuvant radiation therapy (RT) or observation. The primary endpoint was overall survival. Secondary endpoints were progression-free survival and QL after surgery; (3) Results: Out of 27 centers, 209 patients were enrolled with a median follow-up of 3.4 years. An amount of 137 patients were in the observation arm, and 72 received adjuvant irradiation. Overall survival did not differ between groups (hazard ratio (HR) 0.98 [0.55–1.73], p = 0.94). There were fewer neck metastases (HR 0.34 [0.15–0.77]; p = 0.01), as well as fewer local recurrences (HR 0.41 [0.19–0.89]; p = 0.02) under adjuvant RT. For QL, irradiated patients showed higher values for the symptom scale pain after 0.5, two, and three years (all p < 0.05). After six months and three years, irradiated patients reported higher symptom burdens (impaired swallowing, speech, as well as teeth-related problems (all p < 0.05)). Patients in the RT group had significantly more problems with mouth opening after six months, one, and two years (p < 0.05); (4) Conclusions: Adjuvant RT in patients with early SCC of the oral cavity and oropharynx does not seem to influence overall survival, but it positively affects progression-free survival. However, irradiated patients report a significantly decreased QL up to three years after therapy compared to the observation group. KW - oral squamous cell carcinoma KW - oropharyngeal carcinoma KW - surgery KW - resection KW - radiotherapy KW - survival KW - progression-free survival KW - quality of life KW - prospective KW - multicentric KW - lymph node KW - pN1 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311024 SN - 2072-6694 VL - 15 IS - 6 ER - TY - JOUR A1 - Kotlyar, Mischa J. A1 - Krebs, Markus A1 - Solimando, Antonio Giovanni A1 - Marquardt, André A1 - Burger, Maximilian A1 - Kübler, Hubert A1 - Bargou, Ralf A1 - Kneitz, Susanne A1 - Otto, Wolfgang A1 - Breyer, Johannes A1 - Vergho, Daniel C. A1 - Kneitz, Burkhard A1 - Kalogirou, Charis T1 - Critical evaluation of a microRNA-based risk classifier predicting cancer-specific survival in renal cell carcinoma with tumor thrombus of the inferior vena cava JF - Cancers N2 - (1) Background: Clear cell renal cell carcinoma extending into the inferior vena cava (ccRCC\(^{IVC}\)) represents a clinical high-risk setting. However, there is substantial heterogeneity within this patient subgroup regarding survival outcomes. Previously, members of our group developed a microRNA(miR)-based risk classifier — containing miR-21-5p, miR-126-3p and miR-221-3p expression — which significantly predicted the cancer-specific survival (CSS) of ccRCC\(^{IVC}\) patients. (2) Methods: Examining a single-center cohort of tumor tissue from n = 56 patients with ccRCC\(^{IVC}\), we measured the expression levels of miR-21, miR-126, and miR-221 using qRT-PCR. The prognostic impact of clinicopathological parameters and miR expression were investigated via single-variable and multivariable Cox regression. Referring to the previously established risk classifier, we performed Kaplan–Meier analyses for single miR expression levels and the combined risk classifier. Cut-off values and weights within the risk classifier were taken from the previous study. (3) Results: miR-21 and miR-126 expression were significantly associated with lymphonodal status at the time of surgery, the development of metastasis during follow-up, and cancer-related death. In Kaplan–Meier analyses, miR-21 and miR-126 significantly impacted CSS in our cohort. Moreover, applying the miR-based risk classifier significantly stratified ccRCC\(^{IVC}\) according to CSS. (4) Conclusions: In our retrospective analysis, we successfully validated the miR-based risk classifier within an independent ccRCC\(^{IVC}\) cohort. KW - kidney cancer KW - RCC KW - venous infiltration KW - biomarker KW - miR KW - risk stratification Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311040 SN - 2072-6694 VL - 15 IS - 7 ER - TY - JOUR A1 - Gorlova, Anna A1 - Svirin, Evgeniy A1 - Pavlov, Dmitrii A1 - Cespuglio, Raymond A1 - Proshin, Andrey A1 - Schroeter, Careen A. A1 - Lesch, Klaus-Peter A1 - Strekalova, Tatyana T1 - Understanding the role of oxidative stress, neuroinflammation and abnormal myelination in excessive aggression associated with depression: recent input from mechanistic studies JF - International Journal of Molecular Sciences N2 - Aggression and deficient cognitive control problems are widespread in psychiatric disorders, including major depressive disorder (MDD). These abnormalities are known to contribute significantly to the accompanying functional impairment and the global burden of disease. Progress in the development of targeted treatments of excessive aggression and accompanying symptoms has been limited, and there exists a major unmet need to develop more efficacious treatments for depressed patients. Due to the complex nature and the clinical heterogeneity of MDD and the lack of precise knowledge regarding its pathophysiology, effective management is challenging. Nonetheless, the aetiology and pathophysiology of MDD has been the subject of extensive research and there is a vast body of the latest literature that points to new mechanisms for this disorder. Here, we overview the key mechanisms, which include neuroinflammation, oxidative stress, insulin receptor signalling and abnormal myelination. We discuss the hypotheses that have been proposed to unify these processes, as many of these pathways are integrated for the neurobiology of MDD. We also describe the current translational approaches in modelling depression, including the recent advances in stress models of MDD, and emerging novel therapies, including novel approaches to management of excessive aggression, such as anti-diabetic drugs, antioxidant treatment and herbal compositions. KW - major depressive disorder (MDD) KW - aggression KW - neuroinflammation KW - oxidative stress KW - insulin receptor KW - myelination Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304917 SN - 1422-0067 VL - 24 IS - 2 ER - TY - JOUR A1 - Glaser, Kirsten A1 - Kern, David A1 - Speer, Christian P. A1 - Schlegel, Nicolas A1 - Schwab, Michael A1 - Thome, Ulrich H. A1 - Härtel, Christoph A1 - Wright, Clyde J. T1 - Imbalanced inflammatory responses in preterm and term cord blood monocytes and expansion of the CD14\(^+\)CD16\(^+\) subset upon toll-like receptor stimulation JF - International Journal of Molecular Sciences N2 - Developmentally regulated features of innate immunity are thought to place preterm and term infants at risk of infection and inflammation-related morbidity. Underlying mechanisms are incompletely understood. Differences in monocyte function including toll-like receptor (TLR) expression and signaling have been discussed. Some studies point to generally impaired TLR signaling, others to differences in individual pathways. In the present study, we assessed mRNA and protein expression of pro- and anti-inflammatory cytokines in preterm and term cord blood (CB) monocytes compared with adult controls stimulated ex vivo with Pam3CSK4, zymosan, polyinosinic:polycytidylic acid, lipopolysaccharide, flagellin, and CpG oligonucleotide, which activate the TLR1/2, TLR2/6, TLR3, TLR4, TLR5, and TLR9 pathways, respectively. In parallel, frequencies of monocyte subsets, stimulus-driven TLR expression, and phosphorylation of TLR-associated signaling molecules were analyzed. Independent of stimulus, pro-inflammatory responses of term CB monocytes equaled adult controls. The same held true for preterm CB monocytes—except for lower IL-1β levels. In contrast, CB monocytes released lower amounts of anti-inflammatory IL-10 and IL-1ra, resulting in higher ratios of pro-inflammatory to anti-inflammatory cytokines. Phosphorylation of p65, p38, and ERK1/2 correlated with adult controls. However, stimulated CB samples stood out with higher frequencies of intermediate monocytes (CD14\(^+\)CD16\(^+\)). Both pro-inflammatory net effect and expansion of the intermediate subset were most pronounced upon stimulation with Pam3CSK4 (TLR1/2), zymosan (TR2/6), and lipopolysaccharide (TLR4). Our data demonstrate robust pro-inflammatory and yet attenuated anti-inflammatory responses in preterm and term CB monocytes, along with imbalanced cytokine ratios. Intermediate monocytes, a subset ascribed pro-inflammatory features, might participate in this inflammatory state. KW - neonatal immunology KW - inflammation KW - preterm infants KW - monocytes KW - cord blood KW - monocyte subsets KW - cytokines KW - Toll-like receptor signaling Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311056 SN - 1422-0067 VL - 24 IS - 5 ER - TY - JOUR A1 - Watermann, Christoph A1 - Meyer, Malin Tordis A1 - Wagner, Steffen A1 - Wittekindt, Claus A1 - Klussmann, Jens Peter A1 - Erguen, Sueleyman A1 - Baumgart-Vogt, Eveline A1 - Karnati, Srikanth T1 - Peroxisomes are highly abundant and heterogeneous in human parotid glands JF - International Journal of Molecular Sciences N2 - The parotid gland is one of the major salivary glands producing a serous secretion, and it plays an essential role in the digestive and immune systems. Knowledge of peroxisomes in the human parotid gland is minimal; furthermore, the peroxisomal compartment and its enzyme composition in the different cell types of the human parotid gland have never been subjected to a detailed investigation. Therefore, we performed a comprehensive analysis of peroxisomes in the human parotid gland’s striated duct and acinar cells. We combined biochemical techniques with various light and electron microscopy techniques to determine the localization of parotid secretory proteins and different peroxisomal marker proteins in parotid gland tissue. Moreover, we analyzed the mRNA of numerous gene encoding proteins localized in peroxisomes using real-time quantitative PCR. The results confirm the presence of peroxisomes in all striated duct and acinar cells of the human parotid gland. Immunofluorescence analyses for various peroxisomal proteins showed a higher abundance and more intense staining in striated duct cells compared to acinar cells. Moreover, human parotid glands comprise high quantities of catalase and other antioxidative enzymes in discrete subcellular regions, suggesting their role in protection against oxidative stress. This study provides the first thorough description of parotid peroxisomes in different parotid cell types of healthy human tissue. KW - peroxisomes KW - parotid gland KW - human KW - catalase KW - differential expression KW - PSP KW - mRNA KW - immunofluorescence Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311079 SN - 1422-0067 VL - 24 IS - 5 ER - TY - JOUR A1 - Michalke, Bernhard A1 - Venkataramani, Vivek T1 - Editorial to the special issue “Homeostasis: metals and cellular redox and immunity status” JF - International Journal of Molecular Sciences N2 - No abstract available KW - homeostasis Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311061 SN - 1422-0067 VL - 24 IS - 5 ER - TY - JOUR A1 - Tejero, Rocio A1 - Alsakkal, Mohammad A1 - Hennlein, Luisa A1 - Lopez-Cabello, Ana M. A1 - Jablonka, Sibylle A1 - Tabares, Lucia T1 - Nifedipine ameliorates cellular differentiation defects of Smn-deficient motor neurons and enhances neuromuscular transmission in SMA mice JF - International Journal of Molecular Sciences N2 - In spinal muscular atrophy (SMA), mutations in or loss of the Survival Motor Neuron 1 (SMN1) gene reduce full-length SMN protein levels, which leads to the degeneration of a percentage of motor neurons. In mouse models of SMA, the development and maintenance of spinal motor neurons and the neuromuscular junction (NMJ) function are altered. Since nifedipine is known to be neuroprotective and increases neurotransmission in nerve terminals, we investigated its effects on cultured spinal cord motor neurons and motor nerve terminals of control and SMA mice. We found that application of nifedipine increased the frequency of spontaneous Ca\(^{2+}\) transients, growth cone size, cluster-like formations of Cav2.2 channels, and it normalized axon extension in SMA neurons in culture. At the NMJ, nifedipine significantly increased evoked and spontaneous release at low-frequency stimulation in both genotypes. High-strength stimulation revealed that nifedipine increased the size of the readily releasable pool (RRP) of vesicles in control but not SMA mice. These findings provide experimental evidence about the ability of nifedipine to prevent the appearance of developmental defects in SMA embryonic motor neurons in culture and reveal to which extent nifedipine could still increase neurotransmission at the NMJ in SMA mice under different functional demands. KW - spinal muscular atrophy KW - motor neurons KW - synaptic transmission KW - neuromuscular junction KW - calcium channels KW - nifedipine KW - growth cone KW - axons KW - synaptic vesicles KW - postsynaptic potentials Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313636 SN - 1422-0067 VL - 24 IS - 8 ER - TY - JOUR A1 - Jost, Priska A1 - Klein, Franziska A1 - Brand, Benjamin A1 - Wahl, Vanessa A1 - Wyatt, Amanda A1 - Yildiz, Daniela A1 - Boehm, Ulrich A1 - Niemeyer, Barbara A. A1 - Vaeth, Martin A1 - Alansary, Dalia T1 - Acute downregulation but not genetic ablation of murine MCU impairs suppressive capacity of regulatory CD4 T cells JF - International Journal of Molecular Sciences N2 - By virtue of mitochondrial control of energy production, reactive oxygen species (ROS) generation, and maintenance of Ca\(^{2+}\) homeostasis, mitochondria play an essential role in modulating T cell function. The mitochondrial Ca\(^{2+}\) uniporter (MCU) is the pore-forming unit in the main protein complex mediating mitochondrial Ca\(^{2+}\) uptake. Recently, MCU has been shown to modulate Ca\(^{2+}\) signals at subcellular organellar interfaces, thus fine-tuning NFAT translocation and T cell activation. The mechanisms underlying this modulation and whether MCU has additional T cell subpopulation-specific effects remain elusive. However, mice with germline or tissue-specific ablation of Mcu did not show impaired T cell responses in vitro or in vivo, indicating that ‘chronic’ loss of MCU can be functionally compensated in lymphocytes. The current work aimed to specifically investigate whether and how MCU influences the suppressive potential of regulatory CD4 T cells (Treg). We show that, in contrast to genetic ablation, acute siRNA-mediated downregulation of Mcu in murine Tregs results in a significant reduction both in mitochondrial Ca\(^{2+}\) uptake and in the suppressive capacity of Tregs, while the ratios of Treg subpopulations and the expression of hallmark transcription factors were not affected. These findings suggest that permanent genetic inactivation of MCU may result in compensatory adaptive mechanisms, masking the effects on the suppressive capacity of Tregs. KW - mitochondrial calcium uniporter KW - regulatory T cells KW - suppressive capacity Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313621 SN - 1422-0067 VL - 24 IS - 9 ER - TY - JOUR A1 - Boeckel, Hannah A1 - Karsten, Christian M. A1 - Göpel, Wolfgang A1 - Herting, Egbert A1 - Rupp, Jan A1 - Härtel, Christoph A1 - Hartz, Annika T1 - Increased expression of anaphylatoxin C5a-receptor-1 in neutrophils and natural killer cells of preterm infants JF - International Journal of Molecular Sciences N2 - Preterm infants are susceptible to infection and their defense against pathogens relies largely on innate immunity. The role of the complement system for the immunological vulnerability of preterm infants is less understood. Anaphylatoxin C5a and its receptors C5aR1 and -2 are known to be involved in sepsis pathogenesis, with C5aR1 mainly exerting pro-inflammatory effects. Our explorative study aimed to determine age-dependent changes in the expression of C5aR1 and C5aR2 in neonatal immune cell subsets. Via flow cytometry, we analyzed the expression pattern of C5a receptors on immune cells isolated from peripheral blood of preterm infants (n = 32) compared to those of their mothers (n = 25). Term infants and healthy adults served as controls. Preterm infants had a higher intracellular expression of C5aR1 on neutrophils than control individuals. We also found a higher expression of C5aR1 on NK cells, particularly on the cytotoxic CD56\(^{dim}\) subset and the CD56\(^-\) subset. Immune phenotyping of other leukocyte subpopulations revealed no gestational-age-related differences for the expression of and C5aR2. Elevated expression of C5aR1 on neutrophils and NK cells in preterm infants may contribute to the phenomenon of “immunoparalysis” caused by complement activation or to sustained hyper-inflammatory states. Further functional analyses are needed to elucidate the underlying mechanisms. KW - preterm infants KW - C5a KW - C5aR1 KW - neutrophils KW - NK cells KW - innate immunity KW - sepsis Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321196 SN - 1422-0067 VL - 24 IS - 12 ER - TY - JOUR A1 - Salvador, Ellaine A1 - Köppl, Theresa A1 - Hörmann, Julia A1 - Schönhärl, Sebastian A1 - Bugaeva, Polina A1 - Kessler, Almuth F. A1 - Burek, Malgorzata A1 - Ernestus, Ralf-Ingo A1 - Löhr, Mario A1 - Hagemann, Carsten T1 - Tumor Treating Fields (TTFields) induce cell junction alterations in a human 3D in vitro model of the blood-brain barrier JF - Pharmaceutics N2 - In a recent study, we showed in an in vitro murine cerebellar microvascular endothelial cell (cerebEND) model as well as in vivo in rats that Tumor-Treating Fields (TTFields) reversibly open the blood–brain barrier (BBB). This process is facilitated by delocalizing tight junction proteins such as claudin-5 from the membrane to the cytoplasm. In investigating the possibility that the same effects could be observed in human-derived cells, a 3D co-culture model of the BBB was established consisting of primary microvascular brain endothelial cells (HBMVEC) and immortalized pericytes, both of human origin. The TTFields at a frequency of 100 kHz administered for 72 h increased the permeability of our human-derived BBB model. The integrity of the BBB had already recovered 48 h post-TTFields, which is earlier than that observed in cerebEND. The data presented herein validate the previously observed effects of TTFields in murine models. Moreover, due to the fact that human cell-based in vitro models more closely resemble patient-derived entities, our findings are highly relevant for pre-clinical studies. KW - blood-brain barrier KW - Tumor-Treating Fields (TTFields) KW - CNS disorders KW - human brain microvascular endothelial cells (HBMVEC) KW - human cells KW - 3D in vitro model Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304830 SN - 1999-4923 VL - 15 IS - 1 ER - TY - JOUR A1 - Sitter, Magdalena A1 - Fröhlich, Corinna A1 - Kranke, Peter A1 - Markus, Christian A1 - Wöckel, Achim A1 - Rehn, Monika A1 - Bartmann, Catharina A1 - Frieauff, Eric A1 - Meybohm, Patrick A1 - Pecks, Ulrich A1 - Röder, Daniel T1 - ECMO-Therapie bei COVID-19-ARDS in der Schwangerschaft ermöglicht den Erhalt einer Schwangerschaft mit termingerechter Entbindung T1 - ECMO therapy for COVID-19 ARDS (Acute Respiratory Distress Syndrome) during pregnancy enables preservation of pregnancy and full-term delivery JF - Die Anaesthesiologie N2 - No abstract available. KW - ECMO-Therapie KW - COVID-19-ARDS KW - Schwangerschaft KW - ECMO therapy KW - COVID-19-ARDS KW - pregnancy Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-346762 VL - 72 IS - 3 ER - TY - JOUR A1 - Cucher, Marcela A. A1 - Mariconti, Mara A1 - Manciulli, Tommaso A1 - Vola, Ambra A1 - Rosenzvit, Mara C. A1 - Brehm, Klaus A1 - Kamenetzky, Laura A1 - Brunetti, Enrico T1 - Circulating small RNA profiling of patients with alveolar and cystic echinococcosis JF - Biology N2 - Alveolar (AE) and cystic (CE) echinococcosis are two parasitic diseases caused by the tapeworms Echinococcus multilocularis and E. granulosus sensu lato (s. l.), respectively. Currently, AE and CE are mainly diagnosed by means of imaging techniques, serology, and clinical and epidemiological data. However, no viability markers that indicate parasite state during infection are available. Extracellular small RNAs (sRNAs) are short non-coding RNAs that can be secreted by cells through association with extracellular vesicles, proteins, or lipoproteins. Circulating sRNAs can show altered expression in pathological states; hence, they are intensively studied as biomarkers for several diseases. Here, we profiled the sRNA transcriptomes of AE and CE patients to identify novel biomarkers to aid in medical decisions when current diagnostic procedures are inconclusive. For this, endogenous and parasitic sRNAs were analyzed by sRNA sequencing in serum from disease negative, positive, and treated patients and patients harboring a non-parasitic lesion. Consequently, 20 differentially expressed sRNAs associated with AE, CE, and/or non-parasitic lesion were identified. Our results represent an in-depth characterization of the effect E. multilocularis and E. granulosus s. l. exert on the extracellular sRNA landscape in human infections and provide a set of novel candidate biomarkers for both AE and CE detection. KW - echinococcosis KW - small RNA KW - extracellular KW - circulating KW - microRNA KW - serum KW - tapeworm KW - diagnosis KW - marker KW - Echinococcus Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319270 SN - 2079-7737 VL - 12 IS - 5 ER - TY - JOUR A1 - Conrad, David A1 - Kehl, Alexandra A1 - Müller, Tobias A1 - Klopfleisch, Robert A1 - Aupperle-Lellbach, Heike T1 - Immunohistochemical and molecular genetic analysis of canine digital mast cell tumours JF - Animals N2 - Grading, immunohistochemistry and c-kit mutation status are criteria for assessing the prognosis and therapeutic options of canine cutaneous mast cell tumours (MCTs). As a subset, canine digital MCTs have rarely been explored in this context. Therefore, in this retrospective study, 68 paraffin-embedded canine digital MCTs were analysed, and histological grading was assessed according to Patnaik and Kiupel. The immunohistochemical markers KIT and Ki67 were used, as well as polymerase chain reaction (PCR) for mutational screening in c-kit exons 8, 9, 11 and 14. Patnaik grading resulted in 22.1% grade I, 67.6% grade II and 10.3% grade III tumours. Some 86.8% of the digital MCTs were Kiupel low-grade. Aberrant KIT staining patterns II and III were found in 58.8%, and a count of more than 23 Ki67-positive cells in 52.3% of the cases. Both parameters were significantly associated with an internal tandem duplication (ITD) in c-kit exon 11 (12.7%). French Bulldogs, which tend to form well-differentiated cutaneous MCTs, had a higher proportion of digital high-grade MCTs and ITD in c-kit exon 11 compared with mongrels. Due to its retrospective nature, this study did not allow for an analysis of survival data. Nevertheless, it may contribute to the targeted characterisation of digital MCTs. KW - dog KW - digit KW - toe KW - CD117 KW - Ki67 KW - KIT KW - grading KW - PCR KW - sequencing KW - c-kit Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319199 SN - 2076-2615 VL - 13 IS - 10 ER - TY - JOUR A1 - Dresia, Kai A1 - Kurudzija, Eldin A1 - Deeken, Jan A1 - Waxenegger-Wilfing, Günther T1 - Improved wall temperature prediction for the LUMEN rocket combustion chamber with neural networks JF - Aerospace N2 - Accurate calculations of the heat transfer and the resulting maximum wall temperature are essential for the optimal design of reliable and efficient regenerative cooling systems. However, predicting the heat transfer of supercritical methane flowing in cooling channels of a regeneratively cooled rocket combustor presents a significant challenge. High-fidelity CFD calculations provide sufficient accuracy but are computationally too expensive to be used within elaborate design optimization routines. In a previous work it has been shown that a surrogate model based on neural networks is able to predict the maximum wall temperature along straight cooling channels with convincing precision when trained with data from CFD simulations for simple cooling channel segments. In this paper, the methodology is extended to cooling channels with curvature. The predictions of the extended model are tested against CFD simulations with different boundary conditions for the representative LUMEN combustor contour with varying geometries and heat flux densities. The high accuracy of the extended model’s predictions, suggests that it will be a valuable tool for designing and analyzing regenerative cooling systems with greater efficiency and effectiveness. KW - neural network KW - surrogate model KW - heat transfer KW - machine learning KW - LUMEN KW - rocket engine KW - regenerative cooling Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319169 SN - 2226-4310 VL - 10 IS - 5 ER - TY - JOUR A1 - Heidt, Christina A1 - Kämmerer, Ulrike A1 - Fobker, Manfred A1 - Rüffer, Andreas A1 - Marquardt, Thorsten A1 - Reuss-Borst, Monika T1 - Assessment of intestinal permeability and inflammation bio-markers in patients with rheumatoid arthritis JF - Nutrients N2 - Increased intestinal permeability and inflammation, both fueled by dysbiosis, appear to contribute to rheumatoid arthritis (RA) pathogenesis. This single-center pilot study aimed to investigate zonulin, a marker of intestinal permeability, and calprotectin, a marker of intestinal inflammation, measured in serum and fecal samples of RA patients using commercially available kits. We also analyzed plasma lipopolysaccharide (LPS) levels, a marker of intestinal permeability and inflammation. Furthermore, univariate, and multivariate regression analyses were carried out to determine whether or not there were associations of zonulin and calprotectin with LPS, BMI, gender, age, RA-specific parameters, fiber intake, and short-chain fatty acids in the gut. Serum zonulin levels were more likely to be abnormal with a longer disease duration and fecal zonulin levels were inversely associated with age. A strong association between fecal and serum calprotectin and between fecal calprotectin and LPS were found in males, but not in females, independent of other biomarkers, suggesting that fecal calprotectin may be a more specific biomarker than serum calprotectin is of intestinal inflammation in RA. Since this was a proof-of-principle study without a healthy control group, further research is needed to validate fecal and serum zonulin as valid biomarkers of RA in comparison with other promising biomarkers. KW - rheumatoid arthritis KW - zonulin KW - calprotectin KW - LPS KW - fecal short-chain fatty acids KW - fiber intake KW - intestinal permeability KW - intestinal inflammation Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319377 SN - 2072-6643 VL - 15 IS - 10 ER - TY - JOUR A1 - Holzmann-Littig, Christopher A1 - Stadler, David A1 - Popp, Maria A1 - Kranke, Peter A1 - Fichtner, Falk A1 - Schmaderer, Christoph A1 - Renders, Lutz A1 - Braunisch, Matthias Christoph A1 - Assali, Tarek A1 - Platen, Louise A1 - Wijnen-Meijer, Marjo A1 - Lühnen, Julia A1 - Steckelberg, Anke A1 - Pfadenhauer, Lisa A1 - Haller, Bernhard A1 - Fuetterer, Cornelia A1 - Seeber, Christian A1 - Schaaf, Christian T1 - Locating medical information during an infodemic: information seeking behavior and strategies of health-care workers in Germany JF - Healthcare N2 - Background: The COVID-19 pandemic has led to a flood of — often contradictory — evidence. HCWs had to develop strategies to locate information that supported their work. We investigated the information-seeking of different HCW groups in Germany. Methods: In December 2020, we conducted online surveys on COVID-19 information sources, strategies, assigned trustworthiness, and barriers — and in February 2021, on COVID-19 vaccination information sources. Results were analyzed descriptively; group comparisons were performed using χ\(^2\)-tests. Results: For general COVID-19-related medical information (413 participants), non-physicians most often selected official websites (57%), TV (57%), and e-mail/newsletters (46%) as preferred information sources — physicians chose official websites (63%), e-mail/newsletters (56%), and professional journals (55%). Non-physician HCWs used Facebook/YouTube more frequently. The main barriers were insufficient time and access issues. Non-physicians chose abstracts (66%), videos (45%), and webinars (40%) as preferred information strategy; physicians: overviews with algorithms (66%), abstracts (62%), webinars (48%). Information seeking on COVID-19 vaccination (2700 participants) was quite similar, however, with newspapers being more often used by non-physicians (63%) vs. physician HCWs (70%). Conclusion: Non-physician HCWs more often consulted public information sources. Employers/institutions should ensure the supply of professional, targeted COVID-19 information for different HCW groups. KW - COVID-19 KW - infodemic KW - health-care workers KW - HCW KW - information strategies KW - emergency information Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319306 SN - 2227-9032 VL - 11 IS - 11 ER - TY - JOUR A1 - Salihoglu, Rana A1 - Srivastava, Mugdha A1 - Liang, Chunguang A1 - Schilling, Klaus A1 - Szalay, Aladar A1 - Bencurova, Elena A1 - Dandekar, Thomas T1 - PRO-Simat: Protein network simulation and design tool JF - Computational and Structural Biotechnology Journal N2 - PRO-Simat is a simulation tool for analysing protein interaction networks, their dynamic change and pathway engineering. It provides GO enrichment, KEGG pathway analyses, and network visualisation from an integrated database of more than 8 million protein-protein interactions across 32 model organisms and the human proteome. We integrated dynamical network simulation using the Jimena framework, which quickly and efficiently simulates Boolean genetic regulatory networks. It enables simulation outputs with in-depth analysis of the type, strength, duration and pathway of the protein interactions on the website. Furthermore, the user can efficiently edit and analyse the effect of network modifications and engineering experiments. In case studies, applications of PRO-Simat are demonstrated: (i) understanding mutually exclusive differentiation pathways in Bacillus subtilis, (ii) making Vaccinia virus oncolytic by switching on its viral replication mainly in cancer cells and triggering cancer cell apoptosis and (iii) optogenetic control of nucleotide processing protein networks to operate DNA storage. Multilevel communication between components is critical for efficient network switching, as demonstrated by a general census on prokaryotic and eukaryotic networks and comparing design with synthetic networks using PRO-Simat. The tool is available at https://prosimat.heinzelab.de/ as a web-based query server. KW - network simulation KW - protein analysis KW - signalling pathways KW - dynamic protein-protein interactions KW - optogenetics KW - oncolytic virus KW - DNA storage Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350034 SN - 2001-0370 VL - 21 ER - TY - JOUR A1 - Hausman, Hannah A1 - Kubik, Veit T1 - Delayed metacomprehension judgments do not directly improve learning from texts JF - Journal of Intelligence N2 - Making judgments of learning (JOLs) after studying can directly improve learning. This JOL reactivity has been shown for simple materials but has scarcely been investigated with educationally relevant materials such as expository texts. The few existing studies have not yet reported any consistent gains in text comprehension due to providing JOLs. In the present study, we hypothesized that increasing the chances of covert retrieval attempts when making JOLs after each of five to-be-studied text passages would produce comprehension benefits at 1 week compared to restudy. In a between-subjects design, we manipulated both whether participants (N = 210) were instructed to covertly retrieve the texts, and whether they made delayed target-absent JOLs. The results indicated that delayed, target-absent JOLs did not improve text comprehension after 1 week, regardless of whether prior instructions to engage in covert retrieval were provided. Based on the two-stage model of JOLs, we reasoned that participants’ retrieval attempts during metacomprehension judgments were either insufficient (i.e., due to a quick familiarity assessment) or were ineffective (e.g., due to low retrieval success). KW - JOL reactivity KW - judgments of learning KW - metacomprehension KW - covert retrieval Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323361 SN - 2079-3200 VL - 11 IS - 7 ER - TY - JOUR A1 - Reppenhagen, Stephan A1 - Becker, Roland A1 - Kugler, Andreas A1 - John, Dominik A1 - Kopf, Sebastian A1 - Anetzberger, Hermann T1 - Hand dominance is not of significance in performing fundamental arthroscopic skills simulation training tasks JF - Arthroscopy, Sports Medicine, and Rehabilitation N2 - Purpose To compare the performance of the dominant and nondominant hand during fundamental arthroscopic simulator training. Methods Surgical trainees who participated in a 2-day simulator training course between 2021 and 2023 were classified, according to their arthroscopic experience in beginners and competents. Only right-handed individuals with complete data sets were included in the study. Ambidexterity was trained using a box trainer (Fundamentals of Arthroscopic Surgery Training, Virtamed AG, Schlieren, Switzerland).Two tasks, periscoping for learning camera guidance and triangulation for additional instrument handling, were performed 4 times with the camera in the dominant hand and then in the nondominant hand. For each task, exercise time, camera path length, and instrument path length were recorded and analyzed. Results Out of 94 participants 74 right-handed individuals (22 females, 52 males) were classified to novices (n = 43, less than 10 independently performed arthroscopies) and competents (n = 31, more than 10 independently performed arthroscopies). Competents performed significantly better than novices. No significant difference was found after changing the guiding hand for the camera from the dominant to the nondominant hand regarding the camera path length and the instrument path length. Notably, tasks were performed even faster when using the camera in the nondominant hand. Conclusions Our data demonstrate that the learned manual skills during basic arthroscopic training are quickly transferred to the contralateral side. In consequence, additional fundamental skills training for camera guidance and instrument handling of the nondominant hand are not necessary. Clinical Relevance For skillful arthroscopy, camera guidance and instrument handing must be equally mastered with both hands. It is important to understand how hand dominance may affect learning during arthroscopic simulator training. KW - hand dominance KW - physical therapy KW - arthroscopic simulator training KW - rehabilitation KW - sports therapy KW - sports medicine KW - orthopedics Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350432 SN - 2666-061X VL - 5 IS - 5 ER - TY - JOUR A1 - Renner, Tobias A1 - Otto, Paul A1 - Kübler, Alexander C. A1 - Hölscher-Doht, Stefanie A1 - Gbureck, Uwe T1 - Novel adhesive mineral-organic bone cements based on phosphoserine and magnesium phosphates or oxides JF - Journal of Materials Science: Materials in Medicine N2 - Present surgical situations require a bone adhesive which has not yet been developed for use in clinical applications. Recently, phosphoserine modified cements (PMC) based on mixtures of o-phosphoserine (OPLS) and calcium phosphates, such as tetracalcium phosphate (TTCP) or α-tricalcium phosphate (α-TCP) as well as chelate setting magnesium phosphate cements have gained increasing popularity for their use as mineral bone adhesives. Here, we investigated new mineral-organic bone cements based on phosphoserine and magnesium phosphates or oxides, which possess excellent adhesive properties. These were analyzed by X-ray diffraction, Fourier infrared spectroscopy and electron microscopy and subjected to mechanical tests to determine the bond strength to bone after ageing at physiological conditions. The novel biomineral adhesives demonstrate excellent bond strength to bone with approximately 6.6–7.3 MPa under shear load. The adhesives are also promising due to their cohesive failure pattern and ductile character. In this context, the new adhesive cements are superior to currently prevailing bone adhesives. Future efforts on bone adhesives made from phosphoserine and Mg2+ appear to be very worthwhile. Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357342 VL - 34 ER - TY - JOUR A1 - Marquardt, André A1 - Hartrampf, Philipp A1 - Kollmannsberger, Philip A1 - Solimando, Antonio G. A1 - Meierjohann, Svenja A1 - Kübler, Hubert A1 - Bargou, Ralf A1 - Schilling, Bastian A1 - Serfling, Sebastian E. A1 - Buck, Andreas A1 - Werner, Rudolf A. A1 - Lapa, Constantin A1 - Krebs, Markus T1 - Predicting microenvironment in CXCR4- and FAP-positive solid tumors — a pan-cancer machine learning workflow for theranostic target structures JF - Cancers N2 - (1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database — representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets. KW - machine learning KW - tumor microenvironment KW - immune infiltration KW - angiogenesis KW - mRNA KW - miRNA KW - transcriptome Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305036 SN - 2072-6694 VL - 15 IS - 2 ER - TY - JOUR A1 - Feldheim, Jonas A1 - Kessler, Almuth F. A1 - Feldheim, Julia J. A1 - Schmitt, Dominik A1 - Oster, Christoph A1 - Lazaridis, Lazaros A1 - Glas, Martin A1 - Ernestus, Ralf-Ingo A1 - Monoranu, Camelia M. A1 - Löhr, Mario A1 - Hagemann, Carsten T1 - BRMS1 in gliomas — an expression analysis JF - Cancers N2 - The metastatic suppressor BRMS1 interacts with critical steps of the metastatic cascade in many cancer entities. As gliomas rarely metastasize, BRMS1 has mainly been neglected in glioma research. However, its interaction partners, such as NFκB, VEGF, or MMPs, are old acquaintances in neurooncology. The steps regulated by BRMS1, such as invasion, migration, and apoptosis, are commonly dysregulated in gliomas. Therefore, BRMS1 shows potential as a regulator of glioma behavior. By bioinformatic analysis, in addition to our cohort of 118 specimens, we determined BRMS1 mRNA and protein expression as well as its correlation with the clinical course in astrocytomas IDH mutant, CNS WHO grade 2/3, and glioblastoma IDH wild-type, CNS WHO grade 4. Interestingly, we found BRMS1 protein expression to be significantly decreased in the aforementioned gliomas, while BRMS1 mRNA appeared to be overexpressed throughout. This dysregulation was independent of patients’ characteristics or survival. The protein and mRNA expression differences cannot be finally explained at this stage. However, they suggest a post-transcriptional dysregulation that has been previously described in other cancer entities. Our analyses present the first data on BRMS1 expression in gliomas that can provide a starting point for further investigations. KW - glioblastoma KW - metastasis KW - suppressor KW - behavior KW - mRNA KW - protein Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319225 SN - 2072-6694 VL - 15 IS - 11 ER - TY - JOUR A1 - Wünsch, Anna Chiara A1 - Ries, Elena A1 - Heinzelmann, Sina A1 - Frabschka, Andrea A1 - Wagner, Peter Christoph A1 - Rauch, Theresa A1 - Koderer, Corinna A1 - El-Mesery, Mohamed A1 - Volland, Julian Manuel A1 - Kübler, Alexander Christian A1 - Hartmann, Stefan A1 - Seher, Axel T1 - Metabolic silencing via methionine-based amino acid restriction in head and neck cancer JF - Current Issues in Molecular Biology N2 - In recent years, various forms of caloric restriction (CR) and amino acid or protein restriction (AAR or PR) have shown not only success in preventing age-associated diseases, such as type II diabetes and cardiovascular diseases, but also potential for cancer therapy. These strategies not only reprogram metabolism to low-energy metabolism (LEM), which is disadvantageous for neoplastic cells, but also significantly inhibit proliferation. Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumour types, with over 600,000 new cases diagnosed annually worldwide. With a 5-year survival rate of approximately 55%, the poor prognosis has not improved despite extensive research and new adjuvant therapies. Therefore, for the first time, we analysed the potential of methionine restriction (MetR) in selected HNSCC cell lines. We investigated the influence of MetR on cell proliferation and vitality, the compensation for MetR by homocysteine, the gene regulation of different amino acid transporters, and the influence of cisplatin on cell proliferation in different HNSCC cell lines. KW - amino acid restriction KW - caloric restriction KW - methionine KW - HNSCC KW - SCCHN KW - cisplatin KW - amino acid transporter KW - SLC-family KW - cell vitality KW - low energy metabolism Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319257 SN - 1467-3045 VL - 45 IS - 6 SP - 4557 EP - 4573 ER - TY - JOUR A1 - Nickl, Vera A1 - Eck, Juliana A1 - Goedert, Nicolas A1 - Hübner, Julian A1 - Nerreter, Thomas A1 - Hagemann, Carsten A1 - Ernestus, Ralf-Ingo A1 - Schulz, Tim A1 - Nickl, Robert Carl A1 - Keßler, Almuth Friederike A1 - Löhr, Mario A1 - Rosenwald, Andreas A1 - Breun, Maria A1 - Monoranu, Camelia Maria T1 - Characterization and optimization of the tumor microenvironment in patient-derived organotypic slices and organoid models of glioblastoma JF - Cancers N2 - While glioblastoma (GBM) is still challenging to treat, novel immunotherapeutic approaches have shown promising effects in preclinical settings. However, their clinical breakthrough is hampered by complex interactions of GBM with the tumor microenvironment (TME). Here, we present an analysis of TME composition in a patient-derived organoid model (PDO) as well as in organotypic slice cultures (OSC). To obtain a more realistic model for immunotherapeutic testing, we introduce an enhanced PDO model. We manufactured PDOs and OSCs from fresh tissue of GBM patients and analyzed the TME. Enhanced PDOs (ePDOs) were obtained via co-culture with PBMCs (peripheral blood mononuclear cells) and compared to normal PDOs (nPDOs) and PT (primary tissue). At first, we showed that TME was not sustained in PDOs after a short time of culture. In contrast, TME was largely maintained in OSCs. Unfortunately, OSCs can only be cultured for up to 9 days. Thus, we enhanced the TME in PDOs by co-culturing PDOs and PBMCs from healthy donors. These cellular TME patterns could be preserved until day 21. The ePDO approach could mirror the interaction of GBM, TME and immunotherapeutic agents and may consequently represent a realistic model for individual immunotherapeutic drug testing in the future. KW - glioblastoma KW - organoids KW - slice culture KW - tumormicroenvironment Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319249 SN - 2072-6694 VL - 15 IS - 10 ER - TY - JOUR A1 - Laqua, Fabian Christopher A1 - Woznicki, Piotr A1 - Bley, Thorsten A. A1 - Schöneck, Mirjam A1 - Rinneburger, Miriam A1 - Weisthoff, Mathilda A1 - Schmidt, Matthias A1 - Persigehl, Thorsten A1 - Iuga, Andra-Iza A1 - Baeßler, Bettina T1 - Transfer-learning deep radiomics and hand-crafted radiomics for classifying lymph nodes from contrast-enhanced computed tomography in lung cancer JF - Cancers N2 - Objectives: Positron emission tomography (PET) is currently considered the non-invasive reference standard for lymph node (N-)staging in lung cancer. However, not all patients can undergo this diagnostic procedure due to high costs, limited availability, and additional radiation exposure. The purpose of this study was to predict the PET result from traditional contrast-enhanced computed tomography (CT) and to test different feature extraction strategies. Methods: In this study, 100 lung cancer patients underwent a contrast-enhanced \(^{18}\)F-fluorodeoxyglucose (FDG) PET/CT scan between August 2012 and December 2019. We trained machine learning models to predict FDG uptake in the subsequent PET scan. Model inputs were composed of (i) traditional “hand-crafted” radiomics features from the segmented lymph nodes, (ii) deep features derived from a pretrained EfficientNet-CNN, and (iii) a hybrid approach combining (i) and (ii). Results: In total, 2734 lymph nodes [555 (20.3%) PET-positive] from 100 patients [49% female; mean age 65, SD: 14] with lung cancer (60% adenocarcinoma, 21% plate epithelial carcinoma, 8% small-cell lung cancer) were included in this study. The area under the receiver operating characteristic curve (AUC) ranged from 0.79 to 0.87, and the scaled Brier score (SBS) ranged from 16 to 36%. The random forest model (iii) yielded the best results [AUC 0.871 (0.865–0.878), SBS 35.8 (34.2–37.2)] and had significantly higher model performance than both approaches alone (AUC: p < 0.001, z = 8.8 and z = 22.4; SBS: p < 0.001, z = 11.4 and z = 26.6, against (i) and (ii), respectively). Conclusion: Both traditional radiomics features and transfer-learning deep radiomics features provide relevant and complementary information for non-invasive N-staging in lung cancer. KW - computed tomography KW - computational neural networks KW - lymphatic metastasis KW - carcinoma KW - non-small-cell lung KW - small-cell lung Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319231 SN - 2072-6694 VL - 15 IS - 10 ER - TY - JOUR A1 - Barthold, Martina A1 - Jurkutat, Anne A1 - Goetz, Regina A1 - Schubring, Lucia A1 - Spiegler, Juliane A1 - Fries, Ann-Sophie A1 - Kiesel, Lucia A1 - Klepper, Joerg T1 - Timing of ketogenic dietary therapy (KDT) introduction and its impact on cognitive profiles in children with Glut1-DS — a preliminary study JF - Children N2 - The aim of this research was to characterize cognitive abilities in patients with Glut1-Deficiency syndrome (Glut1DS) following ketogenic diet therapy (KDT). Methods: The cognitive profiles of eight children were assessed using the Wechsler Intelligence Scale (WISC-IV). The effect of ketogenic diet therapy (KDT) on individual subareas of intelligence was analyzed considering the potential influence of speech motor impairments. Results: Patients with Glut1DS showed a wide range of cognitive performance levels. Some participants showed statistically and clinically significant discrepancies between individual subdomains of intelligence. Both variables, KDT initiation as well as duration, had a positive effect on the overall IQ score. Significant correlations were partially found between the time of KDT initiation and the level of IQ scores, depending on the presence of expressive language test demands of the respective subtests of the WISC-IV. Accordingly, the participants benefited les in the linguistic cognitive domain. The discrepancies in cognitive performance profiles of patients with Glut1DS can be attributed to the possibility of a negative distortion of the results due to the influence of speech motor impairments. Conclusions: The individual access skills of test persons should be more strongly considered in test procedures for the assessment of intelligence to reduce the negative influence of motor deficits on test performance. Specific characterization and systematization of the speech disorder are indispensable for determining the severity of speech motor impairment in Glut1DS. Therefore, a stronger focus on dysarthria during diagnosis and therapy is necessary. KW - Glut1DS KW - ketogenic dietary therapy (KDT) KW - cognitive profile KW - Wechsler intelligence scale (WISC-IV) KW - speech motor impairment KW - movement disorder Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313569 SN - 2227-9067 VL - 10 IS - 4 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 - 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 - 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 - 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 - 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 - 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 - McFleder, Rhonda L. A1 - Makhotkina, Anastasiia A1 - Groh, Janos A1 - Keber, Ursula A1 - Imdahl, Fabian A1 - Peña Mosca, Josefina A1 - Peteranderl, Alina A1 - Wu, Jingjing A1 - Tabuchi, Sawako A1 - Hoffmann, Jan A1 - Karl, Ann-Kathrin A1 - Pagenstecher, Axel A1 - Vogel, Jörg A1 - Beilhack, Andreas A1 - Koprich, James B. A1 - Brotchie, Jonathan M. A1 - Saliba, Antoine-Emmanuel A1 - Volkmann, Jens A1 - Ip, Chi Wang T1 - Brain-to-gut trafficking of alpha-synuclein by CD11c\(^+\) cells in a mouse model of Parkinson’s disease JF - Nature Communications N2 - Inflammation in the brain and gut is a critical component of several neurological diseases, such as Parkinson’s disease (PD). One trigger of the immune system in PD is aggregation of the pre-synaptic protein, α-synuclein (αSyn). Understanding the mechanism of propagation of αSyn aggregates is essential to developing disease-modifying therapeutics. Using a brain-first mouse model of PD, we demonstrate αSyn trafficking from the brain to the ileum of male mice. Immunohistochemistry revealed that the ileal αSyn aggregations are contained within CD11c+ cells. Using single-cell RNA sequencing, we demonstrate that ileal CD11c\(^+\) cells are microglia-like and the same subtype of cells is activated in the brain and ileum of PD mice. Moreover, by utilizing mice expressing the photo-convertible protein, Dendra2, we show that CD11c\(^+\) cells traffic from the brain to the ileum. Together these data provide a mechanism of αSyn trafficking between the brain and gut. KW - antigen-presenting cells KW - neuroimmunology KW - Parkinson's disease Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357696 VL - 14 ER - TY - JOUR A1 - Hilger, Kirsten A1 - Häge, Anne-Sophie A1 - Zedler, Christina A1 - Jost, Michael A1 - Pauli, Paul T1 - Virtual reality to understand pain-associated approach behaviour: a proof-of-concept study JF - Scientific Reports N2 - Pain-associated approach and avoidance behaviours are critically involved in the development and maintenance of chronic pain. Empirical research suggests a key role of operant learning mechanisms, and first experimental paradigms were developed for their investigation within a controlled laboratory setting. We introduce a new Virtual Reality paradigm to the study of pain-related behaviour and investigate pain experiences on multiple dimensions. The paradigm evaluates the effects of three-tiered heat-pain stimuli applied contingent versus non-contingent with three types of arm movements in naturalistic virtual sceneries. Behaviour, self-reported pain-related fear, pain expectancy and electrodermal activity were assessed in 42 healthy participants during an acquisition phase (contingent movement-pain association) and a modification phase (no contingent movement-pain association). Pain-associated approach behaviour, as measured by arm movements followed by a severe heat stimulus, quickly decreased in-line with the arm movement-pain contingency. Slower effects were observed in fear of movement-related pain and pain expectancy ratings. During the subsequent modification phase, the removal of the pain contingencies modified all three indices. In both phases, skin conductance responses resemble the pattern observed for approach behaviour, while skin conductance levels equal the pattern observed for the self-ratings. Our findings highlight a fast reduction in approach behaviour in the face of acute pain and inform about accompanying psychological and physiological processes. We discuss strength and limitations of our paradigm for future investigations with the ultimate goal of gaining a comprehensive understanding of the mechanisms involved in chronic pain development, maintenance, and its therapy. KW - anxiety KW - human behaviour Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357817 VL - 13 ER - TY - JOUR A1 - Sexauer, Moritz A1 - Bhasin, Hemal A1 - Schön, Maria A1 - Roitsch, Elena A1 - Wall, Caroline A1 - Herzog, Ulrike A1 - Markmann, Katharina T1 - A micro RNA mediates shoot control of root branching JF - Nature Communications N2 - Plants extract mineral nutrients from the soil, or from interactions with mutualistic soil microbes via their root systems. Adapting root architecture to nutrient availability enables efficient resource utilization, particularly in patchy and dynamic environments. Root growth responses to soil nitrogen levels are shoot-mediated, but the identity of shoot-derived mobile signals regulating root growth responses has remained enigmatic. Here we show that a shoot-derived micro RNA, miR2111, systemically steers lateral root initiation and nitrogen responsiveness through its root target TML (TOO MUCH LOVE) in the legume Lotus japonicus, where miR2111 and TML were previously shown to regulate symbiotic infections with nitrogen fixing bacteria. Intriguingly, systemic control of lateral root initiation by miR2111 and TML/HOLT (HOMOLOGUE OF LEGUME TML) was conserved in the nonsymbiotic ruderal Arabidopsis thaliana, which follows a distinct ecological strategy. Thus, the miR2111-TML/HOLT regulon emerges as an essential, conserved factor in adaptive shoot control of root architecture in dicots. KW - evolutionary developmental biology KW - plant development KW - plant molecular biology KW - plant signalling Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357472 VL - 14 ER - TY - JOUR A1 - Stebani, Jannik A1 - Blaimer, Martin A1 - Zabler, Simon A1 - Neun, Tilmann A1 - Pelt, Daniël M. A1 - Rak, Kristen T1 - Towards fully automated inner ear analysis with deep-learning-based joint segmentation and landmark detection framework JF - Scientific Reports N2 - Automated analysis of the inner ear anatomy in radiological data instead of time-consuming manual assessment is a worthwhile goal that could facilitate preoperative planning and clinical research. We propose a framework encompassing joint semantic segmentation of the inner ear and anatomical landmark detection of helicotrema, oval and round window. A fully automated pipeline with a single, dual-headed volumetric 3D U-Net was implemented, trained and evaluated using manually labeled in-house datasets from cadaveric specimen (N = 43) and clinical practice (N = 9). The model robustness was further evaluated on three independent open-source datasets (N = 23 + 7 + 17 scans) consisting of cadaveric specimen scans. For the in-house datasets, Dice scores of 0.97 and 0.94, intersection-over-union scores of 0.94 and 0.89 and average Hausdorf distances of 0.065 and 0.14 voxel units were achieved. The landmark localization task was performed automatically with an average localization error of 3.3 and 5.2 voxel units. A robust, albeit reduced performance could be attained for the catalogue of three open-source datasets. Results of the ablation studies with 43 mono-parametric variations of the basal architecture and training protocol provided task-optimal parameters for both categories. Ablation studies against single-task variants of the basal architecture showed a clear performance beneft of coupling landmark localization with segmentation and a dataset-dependent performance impact on segmentation ability. KW - anatomy KW - bone imaging KW - diagnosis KW - medical imaging KW - software KW - three-dimensional imaging KW - tomography Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357411 VL - 13 ER - TY - JOUR A1 - Gründahl, Marthe A1 - Weiß, Martin A1 - Stenzel, Kilian A1 - Deckert, Jürgen A1 - Hein, Grit T1 - The effects of everyday-life social interactions on anxiety-related autonomic responses differ between men and women JF - Scientific Reports N2 - Social buffering, a phenomenon where social presence can reduce anxiety and fear-related autonomic responses, has been studied in numerous laboratory settings. The results suggest that the familiarity of the interaction partner influences social buffering while also providing some evidence for gender effects. In the laboratory, however, it is difficult to mimic the complexity of real-life social interactions. Consequently, the social modulation of anxiety and related autonomic responses in everyday life remains poorly understood. We used smartphone-based Ecological Momentary Assessment (EMA) combined with wearable electrocardiogram sensors to investigate how everyday-life social interactions affect state anxiety and related cardiac changes in women and men. On five consecutive days, 96 healthy young participants (53% women) answered up to six EMA surveys per day, indicating characteristics of their most recent social interaction and the respective interaction partner(s). In women, our results showed lower heart rate in the presence of a male interaction partner. Men showed the same effect with female interaction partners. Moreover, only women showed decreased heart rate and increased heart rate variability with increasing interaction partner familiarity. These findings specify the conditions under which social interactions reduce anxiety-related responses in women and men. KW - physiology KW - psychology Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357840 VL - 13 ER - TY - JOUR A1 - Weiß, Martin A1 - Gründahl, Marthe A1 - Deckert, Jürgen A1 - Eichner, Felizitas A. A1 - Kohls, Mirjam A1 - Störk, Stefan A1 - Heuschmann, Peter U. A1 - Hein, Grit T1 - Differential network interactions between psychosocial factors, mental health, and health-related quality of life in women and men JF - Scientific Reports N2 - Psychosocial factors affect mental health and health-related quality of life (HRQL) in a complex manner, yet gender differences in these interactions remain poorly understood. We investigated whether psychosocial factors such as social support and personal and work-related concerns impact mental health and HRQL differentially in women and men during the first year of the COVID-19 pandemic. Between June and October 2020, the first part of a COVID-19-specific program was conducted within the “Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB)” cohort study, a representative age- and gender-stratified sample of the general population of Würzburg, Germany. Using psychometric networks, we first established the complex relations between personal social support, personal and work-related concerns, and their interactions with anxiety, depression, and HRQL. Second, we tested for gender differences by comparing expected influence, edge weight differences, and stability of the networks. The network comparison revealed a significant difference in the overall network structure. The male (N = 1370) but not the female network (N = 1520) showed a positive link between work-related concern and anxiety. In both networks, anxiety was the most central variable. These findings provide further evidence that the complex interplay of psychosocial factors with mental health and HRQL decisively depends on gender. Our results are relevant for the development of gender-specific interventions to increase resilience in times of pandemic crisis. KW - anxiety KW - depression KW - human behaviour KW - quality of life Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357858 VL - 13 ER - TY - JOUR A1 - Huestegge, Lynn A1 - Pieczykolan, Aleks A1 - Koch, Iring T1 - A Gestalt account of human behavior is supported by evidence from switching between single and dual actions JF - Scientific Reports N2 - The question of how behavior is represented in the mind lies at the core of psychology as the science of mind and behavior. While a long-standing research tradition has established two opposing fundamental views of perceptual representation, Structuralism and Gestalt psychology, we test both accounts with respect to action representation: Are multiple actions (characterizing human behavior in general) represented as the sum of their component actions (Structuralist view) or holistically (Gestalt view)? Using a single-/dual-response switch paradigm, we analyzed switches between dual ([A + B]) and single ([A], [B]) responses across different effector systems and revealed comparable performance in partial repetitions and full switches of behavioral requirements (e.g., in [A + B] → [A] vs. [B] → [A], or [A] → [A + B] vs. [B] → [A + B]), but only when the presence of dimensional overlap between responses allows for Gestalt formation. This evidence for a Gestalt view of behavior in our paradigm challenges some fundamental assumptions in current (tacitly Structuralist) action control theories (in particular the idea that all actions are represented compositionally with reference to their components), provides a novel explanatory angle for understanding complex, highly synchronized human behavior (e.g., dance), and delimitates the degree to which complex behavior can be analyzed in terms of its basic components. KW - cognitive neuroscience KW - human behaviour KW - learning and memory Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357862 VL - 13 ER - TY - JOUR A1 - Vogel, P. A1 - Rückert, M. A. A1 - Greiner, C. A1 - Günther, J. A1 - Reichl, T. A1 - Kampf, T. A1 - Bley, T. A. A1 - Behr, V. C. A1 - Herz, S. T1 - iMPI: portable human-sized magnetic particle imaging scanner for real-time endovascular interventions JF - Scientific Reports N2 - Minimally invasive endovascular interventions have become an important tool for the treatment of cardiovascular diseases such as ischemic heart disease, peripheral artery disease, and stroke. X-ray fluoroscopy and digital subtraction angiography are used to precisely guide these procedures, but they are associated with radiation exposure for patients and clinical staff. Magnetic Particle Imaging (MPI) is an emerging imaging technology using time-varying magnetic fields combined with magnetic nanoparticle tracers for fast and highly sensitive imaging. In recent years, basic experiments have shown that MPI has great potential for cardiovascular applications. However, commercially available MPI scanners were too large and expensive and had a small field of view (FOV) designed for rodents, which limited further translational research. The first human-sized MPI scanner designed specifically for brain imaging showed promising results but had limitations in gradient strength, acquisition time and portability. Here, we present a portable interventional MPI (iMPI) system dedicated for real-time endovascular interventions free of ionizing radiation. It uses a novel field generator approach with a very large FOV and an application-oriented open design enabling hybrid approaches with conventional X-ray-based angiography. The feasibility of a real-time iMPI-guided percutaneous transluminal angioplasty (PTA) is shown in a realistic dynamic human-sized leg model. KW - biomedical engineering KW - electrical and electronic engineering KW - imaging KW - three-dimensional imaging Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357794 VL - 13 ER - TY - JOUR A1 - Bachert, Antonia A1 - Scheiner, Ricarda T1 - The ant’s weapon improves honey bee learning performance JF - Scientific Reports N2 - Formic acid is the main component of the ant’s major weapon against enemies. Being mainly used as a chemical defense, the acid is also exploited for recruitment and trail marking. The repelling effect of the organic acid is used by some mammals and birds which rub themselves in the acid to eliminate ectoparasites. Beekeepers across the world rely on this effect to control the parasitic mite Varroa destructor. Varroa mites are considered the most destructive pest of honey bees worldwide and can lead to the loss of entire colonies. Formic acid is highly effective against Varroa mites but can also kill the honeybee queen and worker brood. Whether formic acid can also affect the behavior of honey bees is unknown. We here study the effect of formic acid on sucrose responsiveness and cognition of honey bees treated at different live stages in field-relevant doses. Both behaviors are essential for survival of the honey bee colony. Rather unexpectedly, formic acid clearly improved the learning performance of the bees in appetitive olfactory conditioning, while not affecting sucrose responsiveness. This exciting side effect of formic acid certainly deserves further detailed investigations. KW - animal behaviour KW - animal physiology Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358064 VL - 13 ER - TY - JOUR A1 - Gruschwitz, Philipp A1 - Hartung, Viktor A1 - Kleefeldt, Florian A1 - Ergün, Süleyman A1 - Lichthardt, Sven A1 - Huflage, Henner A1 - Hendel, Robin A1 - Kunz, Andreas Steven A1 - Pannenbecker, Pauline A1 - Kuhl, Philipp Josef A1 - Augustin, Anne Marie A1 - Bley, Thorsten Alexander A1 - Petritsch, Bernhard A1 - Grunz, Jan-Peter T1 - Standardized assessment of vascular reconstruction kernels in photon-counting CT angiographies of the leg using a continuous extracorporeal perfusion model JF - Scientific Reports N2 - This study evaluated the influence of different vascular reconstruction kernels on the image quality of CT angiographies of the lower extremity runoff using a 1st-generation photon-counting-detector CT (PCD-CT) compared with dose-matched examinations on a 3rd-generation energy-integrating-detector CT (EID-CT). Inducing continuous extracorporeal perfusion in a human cadaveric model, we performed CT angiographies of eight upper leg arterial runoffs with radiation dose-equivalent 120 kVp acquisition protocols (CTDIvol 5 mGy). Reconstructions were executed with different vascular kernels, matching the individual modulation transfer functions between scanners. Signal-to-noise-ratios (SNR) and contrast-to-noise-ratios (CNR) were computed to assess objective image quality. Six radiologists evaluated image quality subjectively using a forced-choice pairwise comparison tool. Interrater agreement was determined by calculating Kendall’s concordance coefficient (W). The intraluminal attenuation of PCD-CT images was significantly higher than of EID-CT (414.7 ± 27.3 HU vs. 329.3 ± 24.5 HU; p < 0.001). Using comparable kernels, image noise with PCD-CT was significantly lower than with EID-CT (p ≤ 0.044). Correspondingly, SNR and CNR were approximately twofold higher for PCD-CT (p < 0.001). Increasing the spatial frequency for PCD-CT reconstructions by one level resulted in similar metrics compared to EID-CT (CNRfat; EID-CT Bv49: 21.7 ± 3.7 versus PCD-CT Bv60: 21.4 ± 3.5). Overall image quality of PCD-CTA achieved ratings superior to EID-CTA irrespective of the used reconstruction kernels (best: PCD-CT Bv60; worst: EID-CT Bv40; p < 0.001). Interrater agreement was good (W = 0.78). Concluding, PCD-CT offers superior intraluminal attenuation, SNR, and CNR compared to EID-CT in angiographies of the upper leg arterial runoff. Combined with improved subjective image quality, PCD-CT facilitates the use of sharper convolution kernels and ultimately bears the potential of improved vascular structure assessability. KW - experimental models of disease KW - preclinical research KW - translational research Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357912 VL - 13 ER - TY - JOUR A1 - Kirsch, Wladimir A1 - Kunde, Wilfried T1 - Human perception of spatial frequency varies with stimulus orientation and location in the visual field JF - Scientific Reports N2 - Neuroanatomical variations across the visual field of human observers go along with corresponding variations of the perceived coarseness of visual stimuli. Here we show that horizontal gratings are perceived as having lower spatial frequency than vertical gratings when occurring along the horizontal meridian of the visual field, whereas gratings occurring along the vertical meridian show the exact opposite effect. This finding indicates a new peculiarity of processes operating along the cardinal axes of the visual field. KW - neuroscience KW - psychology Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357888 VL - 13 ER - TY - JOUR A1 - Kroner-Weigl, Niklas A1 - Chu, Jin A1 - Rudert, Maximilian A1 - Alt, Volker A1 - Shukunami, Chisa A1 - Docheva, Denitsa T1 - Dexamethasone is not sufficient to facilitate tenogenic differentiation of dermal fibroblasts in a 3D organoid model JF - Biomedicines N2 - Self-assembling three-dimensional organoids that do not rely on an exogenous scaffold but maintain their native cell-to-cell and cell-to-matrix interactions represent a promising model in the field of tendon tissue engineering. We have identified dermal fibroblasts (DFs) as a potential cell type for generating functional tendon-like tissue. The glucocorticoid dexamethasone (DEX) has been shown to regulate cell proliferation and facilitate differentiation towards other mesenchymal lineages. Therefore, we hypothesized that the administration of DEX could reduce excessive DF proliferation and thus, facilitate the tenogenic differentiation of DFs using a previously established 3D organoid model combined with dose-dependent application of DEX. Interestingly, the results demonstrated that DEX, in all tested concentrations, was not sufficient to notably induce the tenogenic differentiation of human DFs and DEX-treated organoids did not have clear advantages over untreated control organoids. Moreover, high concentrations of DEX exerted a negative impact on the organoid phenotype. Nevertheless, the expression profile of tendon-related genes of untreated and 10 nM DEX-treated DF organoids was largely comparable to organoids formed by tendon-derived cells, which is encouraging for further investigations on utilizing DFs for tendon tissue engineering. KW - 3D organoids KW - dermal fibroblasts KW - dexamethasone KW - scaffold-free KW - tenogenic differentiation KW - tendon tissue engineering Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311234 SN - 2227-9059 VL - 11 IS - 3 ER - TY - JOUR A1 - Griebel, Matthias A1 - Segebarth, Dennis A1 - Stein, Nikolai A1 - Schukraft, Nina A1 - Tovote, Philip A1 - Blum, Robert A1 - Flath, Christoph M. T1 - Deep learning-enabled segmentation of ambiguous bioimages with deepflash2 JF - Nature Communications N2 - Bioimages frequently exhibit low signal-to-noise ratios due to experimental conditions, specimen characteristics, and imaging trade-offs. Reliable segmentation of such ambiguous images is difficult and laborious. Here we introduce deepflash2, a deep learning-enabled segmentation tool for bioimage analysis. The tool addresses typical challenges that may arise during the training, evaluation, and application of deep learning models on ambiguous data. The tool’s training and evaluation pipeline uses multiple expert annotations and deep model ensembles to achieve accurate results. The application pipeline supports various use-cases for expert annotations and includes a quality assurance mechanism in the form of uncertainty measures. Benchmarked against other tools, deepflash2 offers both high predictive accuracy and efficient computational resource usage. The tool is built upon established deep learning libraries and enables sharing of trained model ensembles with the research community. deepflash2 aims to simplify the integration of deep learning into bioimage analysis projects while improving accuracy and reliability. KW - machine learning KW - microscopy KW - quality control KW - software Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357286 VL - 14 ER -