TY - JOUR ED - Bobineau, Julien ED - Dembruk, Sofina ED - Eibensteiner, Lukas ED - Goldmann, Julius ED - Hesselbach, Robert ED - Koch, Christian ED - Ravasio, Paola T1 - promptus - Würzburger Beiträge zur Romanistik. Band 8 (2022) T2 - promptus - Würzburger Beiträge zur Romanistik N2 - Die Zeitschrift promptus – Würzburger Beiträge zur Romanistik erscheint einmal jährlich und wird durch den gemeinnützigen Verein promptus e.V. herausgegeben. Sie richtet sich an alle Nachwuchswissenschaftler im Bereich der romanistischen Sprach- und Literaturwissenschaft sowie der Fachdidaktik und bietet diesen die Möglichkeit, in einem frühen Stadium ihrer akademischen Laufbahn qualitativ hochwertige Arbeiten zu publizieren. Zudem versteht sich die Zeitschrift als Impulsgeber für junge romanistische Forschung, ohne sich dabei thematisch zu beschränken. KW - Literaturwissenschaft KW - Medien-/Kulturwissenschaft KW - Sprachwissenschaft KW - Fachdidaktik KW - Romanistik Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-329813 SN - 978-3-946101-08-6 SN - 2364-6705 SN - 2510-2613 VL - 8/2022 ER - TY - JOUR A1 - Schneider, Melanie T1 - « [C]’est absurde d’être bloqué sur une autoroute » – Das Motiv des Staus in der zeitgenössischen romanischen Literatur JF - promptus - Würzburger Beiträge zur Romanistik N2 - Due to an ever-increasing number of automobiles on the roads, automobility fails more and more to fulfil its promise of free individual mobility, leading to traffic density and congestions of unprecedented proportions. However, those conditions seem to possess an aesthetic potential which we seek to analyze in terms of literature. Therefore, we are going to look on three novels from Romance-language areas: Julio Cortázar’s short story La autopista del sur (1966), Carlo Lucarelli’s novel Autosole (1998) and Grégoire Gauchet’s novel Les robinsons de l’autoroute (2018). First, we will analyze the nature of deceleration/congestion by referring to human geographer Tim Cresswell’s concept of friction. Second, we will examine recurring motifs linked to the deceleration/congestion in all novels before taking a closer look at Gauchet’s novel where the friction not only applies to traffic but also to human relationships. The aim is to look at different literary representations of an everyday experience like traffic congestion and to see how literature deals with such an occurrence. KW - traffic congestion KW - friction KW - motorway KW - immobility KW - car culture Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-329807 SN - 2364-6705 VL - 8 ER - TY - JOUR A1 - Nabi, Haifaa T1 - La Nausée : Salut par l’art ou par les autres ? JF - promptus - Würzburger Beiträge zur Romanistik N2 - In this article dedicated to Jean-Paul Sartre’s first novel La Nausée, we analyze how the idea of conversion to art grows in the imagination of the hero, Antoine Roquentin. Furthermore we show that all the narrative actions in the novel are based on the hero’s communicational interaction with the other characters. This lonely person who complains in his diary about social exclusion, yet he converts to art not through his reflections, but through communica-ting with the other characters. Also, many critical studies on La Nausée have considered jazz music that the hero listens to in a café as the critical moment of his conversion. In our opinion this reflects juste one phase of a connected sequence of events through which the hero passes from a state of relational negativity and existential alienation to a state of openness, achieved again mainly by the virtue of other characters. KW - conversion to art KW - others KW - communication KW - writing KW - loneliness Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-329799 SN - 2364-6705 VL - 8 ER - TY - JOUR A1 - Kreiner, Lea T1 - Das Genus im Sprachvergleich: Genuszuweisung bei substantivischen Lehnwörtern im Deutschen und Spanischen JF - promptus - Würzburger Beiträge zur Romanistik N2 - This article examines principles of gender assignment in the German and Spanish language and in this way tries to answer the question of why loanwords are preferably assigned a particular gender and what criteria motivate this choice. After introducing some general aspects about gender as well as some important properties of the German and Spanish gender systems, this paper compares several formal (morphological and phonological) and semantic rules regarding gender assignment. Despite large structural differences between the languages, the comparison shows that the assignment rules prove to be in a sense cross-lingual, which do not only testify to the assumption but also the validity of an underlying system of rules. KW - gender assignment KW - loanwords KW - German KW - Spanish KW - contrastive linguistics Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-329784 SN - 2364-6705 VL - 8 ER - TY - JOUR A1 - Henk, Lars Thorben T1 - Édouard Louis’ «J’accuse». Ein spätmoderner Adept Zolas? JF - promptus - Würzburger Beiträge zur Romanistik N2 - French history of literature is undoubtedly characterized by a tradition of social criticism portraying the working class’ misery that can be traced back at least to the 19th century. Among these depictions, Zola’s novels have a prominent position. This is, among other aspects, due to their pretended scientific foundation and their pretentious claims to be scientific studies. The contemporary author Édouard Louis situates himself in this tradition of Zola’s naturalism. This invites us to examine the interrelation between Zola and Louis more closely. Based on the common ground of scientific foundation, scientific ambition and social commitment pursued in their novels, it will be demonstrated that Louis is a late-modern Zola whose milieu and character descriptions follow in detail Zola’s constructions. KW - Zola KW - misery KW - literature KW - scientific novel KW - Louis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-329777 SN - 2364-6705 VL - 8 ER - TY - JOUR A1 - Harjus, Jannis T1 - El aliento xeneize: Eine diskurslinguistische Analyse von Fangesängen der Anhänger des argentinischen Clubs Boca Juniors JF - promptus - Würzburger Beiträge zur Romanistik N2 - In this contribution, chants of the followers of the Argentine football team Boca Juniors are analyzed with regard to possible identity constructions and othering. The results of the corpus-driven discourse-linguistic analysis demonstrate in particular metaphors and topoi that can be highlighted as a constitutive part of the discursive construction of a Boca Juniors supporters’ identity and the otherings of River Plate hinchas. Through the use of certain metaphors and determined lexical fields that clearly call for acts of violence, a masculine ethos is discursively constructed among Bocas own followers, which goes far beyond comparable insulting and cheering chants of comparable European football teams. KW - superclásico KW - linguistic discourse analysis KW - football chants KW - Argentinian Spanish KW - topoi Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-329768 SN - 2364-6705 VL - 8 ER - TY - JOUR A1 - Haidacher, Bernhard T1 - The concept of confix in German, French, and Italian – a comparative study JF - promptus - Würzburger Beiträge zur Romanistik N2 - Despite some critical voices, in German linguistics the concept of confix can meanwhile be considered as an established morpheme category. Schmidt (1987) introduced the term into German to describe bound morphemes that are lexical, but not inflectable. Since the 2000s, an increasing number of publications deal with the phenomenon and the term has begun to enter linguistic reference works as well. In French, the situation is completely different due to the structure of the language (poor in compounds and mostly post-determinative). Although the term and the concept have originall y been coined by the French structuralist André Martinet ([1961] \(^3\)1980 ), the denomination itself is barely present in Romance linguistics. French researchers usually take different approaches to discuss the phenomenon (e.g., neoclassical compounds, constructed lexemes). In Italian, the denominations confisso/ confissazione are first used by De Mauro (1999), who adopts both the term and concept directly from Martinet; moreover, they can be found in some contributions on word formation and lexicology (e.g., Adamo/Della Valle 2008). Nevertheless, the Italian termino-logy remains heterogeneous, with some researchers still using the terms prefissoide/suffissoide coined by Migliorini (1963). As I will show by comparing the languages in question, the terminology and the concept of confixes vary greatly between Romance and Germanic languages. KW - morphology KW - confixes KW - word-formation KW - theoretical and contrastive linguistics KW - German/French/Italian Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-329756 SN - 2364-6705 VL - 8 ER - TY - JOUR A1 - Cristalli, Marco Antonio T1 - Ein Mann ohne Ehrgeiz, Konturen und Tatendrang – Parodierung von Männlichkeitsnormen in Jean-Philippe Toussaints Monsieur (1986) JF - promptus - Würzburger Beiträge zur Romanistik N2 - The nameless protagonist of the postmodern novel Monsieur, written by Belgian author Jean-Philippe Toussaint, can be described as a rather strange man. He lacks ambition, a drive for action and seems to be unfit for daily life. He constantly fails to accomplish his predestined role as a real man, as for instance to pay the bill for dinner when dating a woman. The scope of the present paper is to analyse, on the one hand, how this novel deconstructs hegemonial concepts of masculinity but, on the other hand, is in itself also a parody of the latter. KW - Cultural Anthropology KW - literary minimalism KW - Masculinity Studies KW - Postmodernism Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-329747 SN - 2364-6705 VL - 8 ER - TY - JOUR A1 - Brinkmann, Lisa Marie T1 - Zum Sprachkontakt Maya und Spanisch: Empirische Studien zur kontaktinduzierten Grammatikalisierung im Maya JF - promptus - Würzburger Beiträge zur Romanistik N2 - The aim of this article is to document the outcomes of language contact between Yucatecan Maya and Mexican Spanish. In order to do so, two theories are applied to newly assembled data, gathered during a field study in 2019 in YucaThe aim of this article is to document the outcomes of language contact between Yucatecan Maya and Mexican Spanish. In order to do so, two theories are applied to newly assembled data, gathered during a field study in 2019 in Yucatán: The Interface Hypothesis (Sorace 2011) and Heine/Kuteva’s contact-induced grammaticalization (2003). The village Xocén in which the field study was conducted is characterized by monolingualism in Maya as well as bilingualism in Spanish and Maya. Data was collected to investigate the influence of Spanish on Mayan morphology, especially on the use of the subjunctive. I propose that the data can best be explained by combining the Interface Hypothesis with Heine/Kutevas’s (2003) approach.tán: The Interface Hypothesis (Sorace 2011) and Heine/Kuteva’s cThe aim of this article is to document the outcomes of language contact between Yucatecan Maya and Mexican Spanish. In order to do so, two theories are applied to newly assembled data, gathered during a field study in 2019 in Yucatán: The Interface Hypothesis (Sorace 2011) and Heine/Kuteva’s contact-induced grammaticalization (2003). The village Xocén in which the field study was conducted is characterized by monolingualism in Maya as well as bilingualism in Spanish and Maya. Data was collected to investigate the influence of Spanish on Mayan morphology, especially on the use of the subjunctive. I propose that the data can best be explained by combining the Interface Hypothesis with Heine/Kutevas’s (2003) approach.ontact-induced grammaticalization (2003). The village Xocén in which the field study was conducted is characterized by monolingualism in Maya as well as bilingualism in Spanish and Maya. Data was collected to investigate the influence of Spanish on Mayan morphology, especially on the use of the subjunctive. I propose that the data can best be explained by combining the Interface Hypothesis with Heine/Kutevas’s (2003) approach. KW - Sprachkontakt KW - Yukatekisches Maya KW - mexikanisches Spanisch KW - Schnittstellenhypothese KW - kontaktinduzierte Grammatikalisierung Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-329734 SN - 2364-6705 VL - 8 ER - TY - JOUR A1 - Wobser, Marion A1 - Schummer, Patrick A1 - Appenzeller, Silke A1 - Kneitz, Hermann A1 - Roth, Sabine A1 - Goebeler, Matthias A1 - Geissinger, Eva A1 - Rosenwald, Andreas A1 - Maurus, Katja T1 - Panel sequencing of primary cutaneous B-cell lymphoma JF - Cancers N2 - Background: Primary cutaneous follicular B-cell lymphoma (PCFBCL) represents an indolent subtype of Non-Hodgkin’s lymphomas, being clinically characterized by slowly growing tumors of the skin and common cutaneous relapses, while only exhibiting a low propensity for systemic dissemination or fatal outcome. Up to now, only few studies have investigated underlying molecular alterations of PCFBCL with respect to somatic mutations. Objectives: Our aim was to gain deeper insight into the pathogenesis of PCFBCL and to delineate discriminatory molecular features of this lymphoma subtype. Methods: We performed hybridization-based panel sequencing of 40 lymphoma-associated genes of 10 cases of well-characterized PCFBCL. In addition, we included two further ambiguous cases of atypical B-cell-rich lymphoid infiltrate/B-cell lymphoma of the skin for which definite subtype attribution had not been possible by routine investigations. Results: In 10 out of 12 analyzed cases, we identified genetic alterations within 15 of the selected 40 target genes. The most frequently detected alterations in PCFBCL affected the TNFRSF14, CREBBP, STAT6 and TP53 genes. Our analysis unrevealed novel mutations of the BCL2 gene in PCFBCL. All patients exhibited an indolent clinical course. Both the included arbitrary cases of atypical B-cell-rich cutaneous infiltrates showed somatic mutations within the FAS gene. As these mutations have previously been designated as subtype-specific recurrent alterations in primary cutaneous marginal zone lymphoma (PCMZL), we finally favored the diagnosis of PCMZL in these two cases based on these molecular findings. Conclusions: To conclude, our molecular data support that PCFBCL shows distinct somatic mutations which may aid to differentiate PCFBCL from pseudo-lymphoma as well as from other indolent and aggressive cutaneous B-cell lymphomas. While the detected genetic alterations of PCFBCL did not turn out to harbor any prognostic value in our cohort, our molecular data may add adjunctive discriminatory features for diagnostic purposes on a molecular level. KW - B-cell lymphoma KW - primary cutaneous follicular B-cell lymphoma KW - targeted sequencing Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290330 SN - 2072-6694 VL - 14 IS - 21 ER - TY - JOUR A1 - Lüke, Florian A1 - Haller, Florian A1 - Utpatel, Kirsten A1 - Krebs, Markus A1 - Meidenbauer, Norbert A1 - Scheiter, Alexander A1 - Spoerl, Silvia A1 - Heudobler, Daniel A1 - Sparrer, Daniela A1 - Kaiser, Ulrich A1 - Keil, Felix A1 - Schubart, Christoph A1 - Tögel, Lars A1 - Einhell, Sabine A1 - Dietmaier, Wolfgang A1 - Huss, Ralf A1 - Dintner, Sebastian A1 - Sommer, Sebastian A1 - Jordan, Frank A1 - Goebeler, Maria-Elisabeth A1 - Metz, Michaela A1 - Haake, Diana A1 - Scheytt, Mithun A1 - Gerhard-Hartmann, Elena A1 - Maurus, Katja A1 - Brändlein, Stephanie A1 - Rosenwald, Andreas A1 - Hartmann, Arndt A1 - Märkl, Bruno A1 - Einsele, Hermann A1 - Mackensen, Andreas A1 - Herr, Wolfgang A1 - Kunzmann, Volker A1 - Bargou, Ralf A1 - Beckmann, Matthias W. A1 - Pukrop, Tobias A1 - Trepel, Martin A1 - Evert, Matthias A1 - Claus, Rainer A1 - Kerscher, Alexander T1 - Identification of disparities in personalized cancer care — a joint approach of the German WERA consortium JF - Cancers N2 - (1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy. KW - precision oncology KW - MTB KW - patient access KW - cancer care KW - outreach KW - real world data KW - outcomes research Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290311 SN - 2072-6694 VL - 14 IS - 20 ER - TY - JOUR A1 - Nees, Juliane A1 - Kiermeier, Senta A1 - Struewe, Farina A1 - Keymling, Myriam A1 - Maatouk, Imad A1 - Kratz, Christian P. A1 - Schott, Sarah T1 - Health behavior and cancer prevention among adults with Li-Fraumeni syndrome and relatives in Germany — a cohort description JF - Current Oncology N2 - Li-Fraumeni-syndrome (LFS) is a rare, highly penetrant cancer predisposition syndrome (CPS) caused by pathogenic variants (PVs) in TP53. Physical activity (PA) and a Mediterranean diet lead to cancer reduction or survival benefits and increased quality of life (QoL), but this is yet unstudied among LFS. TP53 PV carriers (PVC) and their relatives were questioned on dietary patterns (Mediterranean Diet Adherence Screener), PA (Freiburg Questionnaire), QoL (Short-form-Health-Survey-12), smoking, alcohol consumption and perception of cancer risk in a German bi-centric study from March 2020–June 2021. The study enrolled 70 PVC and 43 relatives. Women compared to men (6.49 vs. 5.38, p = 0.005) and PVC to relatives (6.59 vs. 5.51; p = 0.006) showed a healthier diet, associated with participation in surveillance (p = 0.04) and education (diet p = 0.02 smoking p = 0.0003). Women smoked less (2.91 vs. 5.91 packyears; p = 0.03), psychological well-being was higher among men (SF-12: males 48.06 vs. females 41.94; p = 0.004). PVC rated their own cancer risk statistically higher than relatives (72% vs. 38%, p < 0.001) however, cancer risk of the general population was rated lower (38% vs. 70%, p < 0.001). A relative’s cancer-related death increased the estimated personal cancer risk (p = 0.01). The possibilities of reducing cancer through self-determined health behavior among PVC and relatives has not yet been exhausted. Educating families with a CPS on cancer-preventive behavior requires further investigation with regard to acceptance and real-life implementation. KW - pathogenic TP53 germline variant KW - Li-Fraumeni syndrome KW - cancer prevention KW - physical activity KW - cancer predisposition KW - SF-12 KW - MEDAS Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290432 SN - 1718-7729 VL - 29 IS - 10 SP - 7768 EP - 7778 ER - TY - JOUR A1 - Förster, Carola Y. A1 - Shityakov, Sergey A1 - Scheper, Verena A1 - Lenarz, Thomas T1 - Linking cerebrovascular dysfunction to age-related hearing loss and Alzheimer’s disease — are systemic approaches for diagnosis and therapy required? JF - Biomolecules N2 - Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction, cognitive decline, and the accumulation of amyloid β peptide (Aβ) in the brain and tau-related lesions in neurons termed neurofibrillary tangles (NFTs). Aβ deposits and NFT formation are the central pathological hallmarks in AD brains, and the majority of AD cases have been shown to exhibit a complex combination of systemic comorbidities. While AD is the foremost common cause of dementia in the elderly, age-related hearing loss (ARHL) is the most predominant sensory deficit in the elderly. During aging, chronic inflammation and resulting endothelial dysfunction have been described and might be key contributors to AD; we discuss an intriguing possible link between inner ear strial microvascular pathology and blood–brain barrier pathology and present ARHL as a potentially modifiable and treatable risk factor for AD development. We present compelling evidence that ARHL might well be seen as an important risk factor in AD development: progressive hearing impairment, leading to social isolation, and its comorbidities, such as frailty, falls, and late-onset depression, link ARHL with cognitive decline and increased risk of dementia, rendering it tempting to speculate that ARHL might be a potential common molecular and pathological trigger for AD. Additionally, one could speculate that amyloid-beta might damage the blood–labyrinth barrier as it does to the blood–brain barrier, leading to ARHL pathology. Finally, there are options for the treatment of ARHL by targeted neurotrophic factor supplementation to the cochlea to improve cognitive outcomes; they can also prevent AD development and AD-related comorbidity in the future. KW - Alzheimer’s disease KW - age-related hearing loss KW - neurovasculature KW - blood–brain barrier KW - blood–labyrinth barrier KW - spiral ganglion neuron KW - pharmacotherapy KW - neurotrophic factor KW - inner ear Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297552 SN - 2218-273X VL - 12 IS - 11 ER - TY - JOUR A1 - Franco-Espin, Julio A1 - Gatius, Alaó A1 - Armengol, José Ángel A1 - Arumugam, Saravanan A1 - Moradi, Mehri A1 - Sendtner, Michael A1 - Calderó, Jordi A1 - Tabares, Lucia T1 - SMN is physiologically downregulated at wild-type motor nerve terminals but aggregates together with neurofilaments in SMA mouse models JF - Biomolecules N2 - Survival motor neuron (SMN) is an essential and ubiquitously expressed protein that participates in several aspects of RNA metabolism. SMN deficiency causes a devastating motor neuron disease called spinal muscular atrophy (SMA). SMN forms the core of a protein complex localized at the cytoplasm and nuclear gems and that catalyzes spliceosomal snRNP particle synthesis. In cultured motor neurons, SMN is also present in dendrites and axons, and forms part of the ribonucleoprotein transport granules implicated in mRNA trafficking and local translation. Nevertheless, the distribution, regulation, and role of SMN at the axons and presynaptic motor terminals in vivo are still unclear. By using conventional confocal microscopy and STED super-resolution nanoscopy, we found that SMN appears in the form of granules distributed along motor axons at nerve terminals. Our fluorescence in situ hybridization and electron microscopy studies also confirmed the presence of β-actin mRNA, ribosomes, and polysomes in the presynaptic motor terminal, key elements of the protein synthesis machinery involved in local translation in this compartment. SMN granules co-localize with the microtubule-associated protein 1B (MAP1B) and neurofilaments, suggesting that the cytoskeleton participates in transporting and positioning the granules. We also found that, while SMN granules are physiologically downregulated at the presynaptic element during the period of postnatal maturation in wild-type (non-transgenic) mice, they accumulate in areas of neurofilament aggregation in SMA mice, suggesting that the high expression of SMN at the NMJ, together with the cytoskeletal defects, contribute to impairing the bi-directional traffic of proteins and organelles between the axon and the presynaptic terminal. KW - spinal muscular atrophy KW - motor neuron degeneration KW - SMN granules KW - neuromuscular junction KW - β-actin mRNA KW - MAP1B KW - neurofilaments Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290263 SN - 2218-273X VL - 12 IS - 10 ER - TY - JOUR A1 - Fareed, Muhammad Mazhar A1 - Qasmi, Maryam A1 - Aziz, Shaan A1 - Völker, Elisabeth A1 - Förster, Carola Yvette A1 - Shityakov, Sergey T1 - The role of clusterin transporter in the pathogenesis of Alzheimer’s disease at the blood–brain barrier interface: a systematic review JF - Biomolecules N2 - Alzheimer’s disease (AD) is considered a chronic and debilitating neurological illness that is increasingly impacting older-age populations. Some proteins, including clusterin (CLU or apolipoprotein J) transporter, can be linked to AD, causing oxidative stress. Therefore, its activity can affect various functions involving complement system inactivation, lipid transport, chaperone activity, neuronal transmission, and cellular survival pathways. This transporter is known to bind to the amyloid beta (Aβ) peptide, which is the major pathogenic factor of AD. On the other hand, this transporter is also active at the blood–brain barrier (BBB), a barrier that prevents harmful substances from entering and exiting the brain. Therefore, in this review, we discuss and emphasize the role of the CLU transporter and CLU-linked molecular mechanisms at the BBB interface in the pathogenesis of AD. KW - clusterin transporter KW - Wnt signaling KW - Alzheimer’s disease KW - AD pathogenesis KW - blood–brain barrier KW - apolipoprotein J Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290279 SN - 2218-273X VL - 12 IS - 10 ER - TY - JOUR A1 - Magni, Eva A1 - Leontiev, Wadim A1 - Soliman, Sebastian A1 - Dettwiler, Christian A1 - Klein, Christian A1 - Krastl, Gabriel A1 - Weiger, Roland A1 - Connert, Thomas T1 - Accuracy of the fluorescence-aided identification technique (FIT) for detecting residual composite remnants after trauma splint removal — a laboratory study JF - Applied Sciences N2 - Distinguishing composite remnants from tooth structure after trauma splint removal can be challenging. This study aimed to compare the Fluorescence-aided Identification Technique (FIT) with conventional light illumination (CONV) in terms of accuracy and time required for the detection of composite remnants after trauma splint removal. Ten bovine tooth models containing anterior teeth from 12 to 22 with composite remnants after trauma splint removal were used. These models were examined by 10 students and 10 general dentists. Each examiner assessed the 10 models using CONV or FIT three times with an interval of 2 weeks each using a prototype fluorescence-inducing headlamp with a spectral bandwidth of (405 ± 7) nm for FIT and a dental unit lamp for CONV. The examiners charted the location of identified composite remnants, and the procedure time needed for each method was recorded. Statistical analysis was performed with R 3.2.2 software with a significance level of α = 5%. FIT was more accurate and less time-consuming than CONV (p < 0.001). There were no significant differences between dentists and students concerning accuracy (CONV: p = 0.26; FIT: p = 0.73). Students performed FIT significantly faster than the dentists (p < 0.001). FIT is a quick and reliable method of identifying composite remnants after trauma splint removal. KW - composite detection KW - fluorescence-aided identification technique KW - titanium trauma splint (TTS) removal Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290252 SN - 2076-3417 VL - 12 IS - 19 ER - TY - JOUR A1 - Dong, Ruirui A1 - Wurm, Michael A1 - Taubenböck, Hannes T1 - Seasonal and diurnal variation of land surface temperature distribution and its relation to land use/land cover patterns JF - International Journal of Environmental Research and Public Health N2 - The surface urban heat island (SUHI) affects the quality of urban life. Because varying urban structures have varying impacts on SUHI, it is crucial to understand the impact of land use/land cover characteristics for improving the quality of life in cities and urban health. Satellite-based data on land surface temperatures (LST) and derived land use/cover pattern (LUCP) indicators provide an efficient opportunity to derive the required data at a large scale. This study explores the seasonal and diurnal variation of spatial associations from LUCP and LST employing Pearson correlation and ordinary least squares regression analysis. Specifically, Landsat-8 images were utilized to derive LSTs in four seasons, taking Berlin as a case study. The results indicate that: (1) in terms of land cover, hot spots are mainly distributed over transportation, commercial and industrial land in the daytime, while wetlands were identified as hot spots during nighttime; (2) from the land composition indicators, the normalized difference built-up index (NDBI) showed the strongest influence in summer, while the normalized difference vegetation index (NDVI) exhibited the biggest impact in winter; (3) from urban morphological parameters, the building density showed an especially significant positive association with LST and the strongest effect during daytime. KW - surface urban heat island (SUHI) KW - land use/cover pattern (LUCP) KW - land surface temperature (LST) KW - seasonal KW - diurnal Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290393 SN - 1660-4601 VL - 19 IS - 19 ER - TY - JOUR A1 - Bețiu, Alina M. A1 - Noveanu, Lavinia A1 - Hâncu, Iasmina M. A1 - Lascu, Ana A1 - Petrescu, Lucian A1 - Maack, Christoph A1 - Elmér, Eskil A1 - Muntean, Danina M. T1 - Mitochondrial effects of common cardiovascular medications: the good, the bad and the mixed JF - International Journal of Molecular Sciences N2 - Mitochondria are central organelles in the homeostasis of the cardiovascular system via the integration of several physiological processes, such as ATP generation via oxidative phosphorylation, synthesis/exchange of metabolites, calcium sequestration, reactive oxygen species (ROS) production/buffering and control of cellular survival/death. Mitochondrial impairment has been widely recognized as a central pathomechanism of almost all cardiovascular diseases, rendering these organelles important therapeutic targets. Mitochondrial dysfunction has been reported to occur in the setting of drug-induced toxicity in several tissues and organs, including the heart. Members of the drug classes currently used in the therapeutics of cardiovascular pathologies have been reported to both support and undermine mitochondrial function. For the latter case, mitochondrial toxicity is the consequence of drug interference (direct or off-target effects) with mitochondrial respiration/energy conversion, DNA replication, ROS production and detoxification, cell death signaling and mitochondrial dynamics. The present narrative review aims to summarize the beneficial and deleterious mitochondrial effects of common cardiovascular medications as described in various experimental models and identify those for which evidence for both types of effects is available in the literature. KW - cardiovascular drugs KW - drug toxicity KW - mitochondria function and morphology KW - adverse effects KW - lactic acidosis KW - drug intoxication KW - drug interaction Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297384 SN - 1422-0067 VL - 23 IS - 21 ER - TY - JOUR A1 - Esmaeilpour, Donya A1 - Broscheit, Jens Albert A1 - Shityakov, Sergey T1 - Cyclodextrin-based polymeric materials bound to corona protein for theranostic applications JF - International Journal of Molecular Sciences N2 - Cyclodextrins (CDs) are cyclic oligosaccharide structures that could be used for theranostic applications in personalized medicine. These compounds have been widely utilized not only for enhancing drug solubility, stability, and bioavailability but also for controlled and targeted delivery of small molecules. These compounds can be complexed with various biomolecules, such as peptides or proteins, via host-guest interactions. CDs are amphiphilic compounds with water-hating holes and water-absorbing surfaces. Architectures of CDs allow the drawing and preparation of CD-based polymers (CDbPs) with optimal pharmacokinetic and pharmacodynamic properties. These polymers can be cloaked with protein corona consisting of adsorbed plasma or extracellular proteins to improve nanoparticle biodistribution and half-life. Besides, CDs have become famous in applications ranging from biomedicine to environmental sciences. In this review, we emphasize ongoing research in biomedical fields using CD-based centered, pendant, and terminated polymers and their interactions with protein corona for theranostic applications. Overall, a perusal of information concerning this novel approach in biomedicine will help to implement this methodology based on host-guest interaction to improve therapeutic and diagnostic strategies. KW - cyclodextrin KW - theranostics KW - protein corona KW - nanomedicine KW - therapy KW - polymers Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297399 SN - 1422-0067 VL - 23 IS - 21 ER - TY - JOUR A1 - Nowacka-Chmielewska, Marta A1 - Grabowska, Konstancja A1 - Grabowski, Mateusz A1 - Meybohm, Patrick A1 - Burek, Malgorzata A1 - Małecki, Andrzej T1 - Running from stress: neurobiological mechanisms of exercise-induced stress resilience JF - International Journal of Molecular Sciences N2 - Chronic stress, even stress of a moderate intensity related to daily life, is widely acknowledged to be a predisposing or precipitating factor in neuropsychiatric diseases. There is a clear relationship between disturbances induced by stressful stimuli, especially long-lasting stimuli, and cognitive deficits in rodent models of affective disorders. Regular physical activity has a positive effect on the central nervous system (CNS) functions, contributes to an improvement in mood and of cognitive abilities (including memory and learning), and is correlated with an increase in the expression of the neurotrophic factors and markers of synaptic plasticity as well as a reduction in the inflammatory factors. Studies published so far show that the energy challenge caused by physical exercise can affect the CNS by improving cellular bioenergetics, stimulating the processes responsible for the removal of damaged organelles and molecules, and attenuating inflammation processes. Regular physical activity brings another important benefit: increased stress robustness. The evidence from animal studies is that a sedentary lifestyle is associated with stress vulnerability, whereas a physically active lifestyle is associated with stress resilience. Here, we have performed a comprehensive PubMed Search Strategy for accomplishing an exhaustive literature review. In this review, we discuss the findings from experimental studies on the molecular and neurobiological mechanisms underlying the impact of exercise on brain resilience. A thorough understanding of the mechanisms underlying the neuroprotective potential of preconditioning exercise and of the role of exercise in stress resilience, among other things, may open further options for prevention and therapy in the treatment of CNS diseases. KW - stress KW - stress resilience KW - anxiety KW - depression KW - neuropsychiatric disorders KW - physical activity KW - exercise Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297407 SN - 1422-0067 VL - 23 IS - 21 ER - TY - JOUR A1 - Sedaghat-Hamedani, Farbod A1 - Rebs, Sabine A1 - Kayvanpour, Elham A1 - Zhu, Chenchen A1 - Amr, Ali A1 - Müller, Marion A1 - Haas, Jan A1 - Wu, Jingyan A1 - Steinmetz, Lars M. A1 - Ehlermann, Philipp A1 - Streckfuss-Bömeke, Katrin A1 - Frey, Norbert A1 - Meder, Benjamin T1 - Genotype complements the phenotype: identification of the pathogenicity of an LMNA splice variant by nanopore long-read sequencing in a large DCM family JF - International Journal of Molecular Sciences N2 - Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and is of familial origin in 20–40% of cases. Genetic testing by next-generation sequencing (NGS) has yielded a definite diagnosis in many cases; however, some remain elusive. In this study, we used a combination of NGS, human-induced pluripotent-stem-cell-derived cardiomyocytes (iPSC-CMs) and nanopore long-read sequencing to identify the causal variant in a multi-generational pedigree of DCM. A four-generation family with familial DCM was investigated. Next-generation sequencing (NGS) was performed on 22 family members. Skin biopsies from two affected family members were used to generate iPSCs, which were then differentiated into iPSC-CMs. Short-read RNA sequencing was used for the evaluation of the target gene expression, and long-read RNA nanopore sequencing was used to evaluate the relevance of the splice variants. The pedigree suggested a highly penetrant, autosomal dominant mode of inheritance. The phenotype of the family was suggestive of laminopathy, but previous genetic testing using both Sanger and panel sequencing only yielded conflicting evidence for LMNA p.R644C (rs142000963), which was not fully segregated. By re-sequencing four additional affected family members, further non-coding LMNA variants could be detected: rs149339264, rs199686967, rs201379016, and rs794728589. To explore the roles of these variants, iPSC-CMs were generated. RNA sequencing showed the LMNA expression levels to be significantly lower in the iPSC-CMs of the LMNA variant carriers. We demonstrated a dysregulated sarcomeric structure and altered calcium homeostasis in the iPSC-CMs of the LMNA variant carriers. Using targeted nanopore long-read sequencing, we revealed the biological significance of the variant c.356+1G>A, which generates a novel 5′ splice site in exon 1 of the cardiac isomer of LMNA, causing a nonsense mRNA product with almost complete RNA decay and haploinsufficiency. Using novel molecular analysis and nanopore technology, we demonstrated the pathogenesis of the rs794728589 (c.356+1G>A) splice variant in LMNA. This study highlights the importance of precise diagnostics in the clinical management and workup of cardiomyopathies. KW - familial DCM KW - laminopathy KW - long-read sequencing KW - nanopore KW - induced pluripotent stem cell cardiomyocytes Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290415 SN - 1422-0067 VL - 23 IS - 20 ER - TY - JOUR A1 - Rajendran, Ranjithkumar A1 - Rajendran, Vinothkumar A1 - Gupta, Liza A1 - Shirvanchi, Kian A1 - Schunin, Darja A1 - Karnati, Srikanth A1 - Giraldo-Velásquez, Mario A1 - Berghoff, Martin T1 - Interferon beta-1a versus combined interferon beta-1a and oligodendrocyte-specific FGFR1 deletion in experimental autoimmune encephalomyelitis JF - International Journal of Molecular Sciences N2 - Recombinant beta interferons-1 (IFNβ-1) are used as first line therapies in patients with relapsing multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the CNS. IFNβ-1a/b has moderate effects on the prevention of relapses and slowing of disease progression. Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) are known to play a key role in the pathology of MS and its model EAE. To investigate the effects of short-term treatment with s.c. IFNβ-1a versus the combined application of s.c. IFNβ-1a and oligodendrocyte-specific deletion of FGFR1 (Fgfr1\(^{ind−/−}\) mice) in MOG\(_{35-55}\)-induced EAE. IFNβ-1a (30 mg/kg) was applied s.c. from days 0–7 p.i. of EAE in controls and Fgfr1\(^{ind−/−}\) mice. FGFR signaling proteins associated with inflammation/degeneration in MS/EAE were analyzed by western blot in the spinal cord. Further, FGFR1 in Oli-neu oligodendrocytes were inhibited by PD166866 and treated with IFNβ-1a (400 ng/mL). Application of IFNβ-1a over 8 days resulted in less symptoms only at the peak of disease (days 9–11) compared to controls. Application of IFNβ-1a in Fgfr1\(^{ind−/−}\) mice resulted in less symptoms primarily in the chronic phase of EAE. Fgfr1\(^{ind−/−}\) mice treated with IFNβ-1a showed increased expression of pERK and BDNF. In Oli-neu oligodendrocytes, treatment with PD166866 and IFNβ-1a also showed an increased expression of pERK and BDNF/TrkB. These data suggest that the beneficial effects in the chronic phase of EAE and on signaling molecules associated with ERK and BDNF expression are caused by the modulation of FGFR1 and not by interferon beta-1a. FGFR may be a potential target for therapy in MS. KW - FGFR1 KW - interferon beta-1a KW - oligodendrocytes KW - EAE KW - multiple sclerosis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290401 SN - 1422-0067 VL - 23 IS - 20 ER - TY - JOUR A1 - Solimando, Antonio G. A1 - Palumbo, Carmen A1 - Pragnell, Mary Victoria A1 - Bittrich, Max A1 - Argentiero, Antonella A1 - Krebs, Markus T1 - Aplastic anemia as a roadmap for bone marrow failure: an overview and a clinical workflow JF - International Journal of Molecular Sciences N2 - In recent years, it has become increasingly apparent that bone marrow (BM) failures and myeloid malignancy predisposition syndromes are characterized by a wide phenotypic spectrum and that these diseases must be considered in the differential diagnosis of children and adults with unexplained hematopoiesis defects. Clinically, hypocellular BM failure still represents a challenge in pathobiology-guided treatment. There are three fundamental topics that emerged from our review of the existing data. An exogenous stressor, an immune defect, and a constitutional genetic defect fuel a vicious cycle of hematopoietic stem cells, immune niches, and stroma compartments. A wide phenotypic spectrum exists for inherited and acquired BM failures and predispositions to myeloid malignancies. In order to effectively manage patients, it is crucial to establish the right diagnosis. New theragnostic windows can be revealed by exploring BM failure pathomechanisms. KW - hematopoietic stem cells KW - bone marrow immune-microenvironment KW - bone marrow failure KW - cytopenia KW - aplastic anemia Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290440 SN - 1422-0067 VL - 23 IS - 19 ER - TY - JOUR A1 - Banicka, Veronika A1 - Martens, Marie Christine A1 - Panzer, Rüdiger A1 - Schrama, David A1 - Emmert, Steffen A1 - Boeckmann, Lars A1 - Thiem, Alexander T1 - Homozygous CRISPR/Cas9 knockout generated a novel functionally active exon 1 skipping XPA variant in melanoma cells JF - International Journal of Molecular Sciences N2 - Defects in DNA repair pathways have been associated with an improved response to immune checkpoint inhibition (ICI). In particular, patients with the nucleotide excision repair (NER) defect disease Xeroderma pigmentosum (XP) responded impressively well to ICI treatment. Recently, in melanoma patients, pretherapeutic XP gene expression was predictive for anti-programmed cell death-1 (PD-1) ICI response. The underlying mechanisms of this finding are still to be revealed. Therefore, we used CRISPR/Cas9 to disrupt XPA in A375 melanoma cells. The resulting subclonal cell lines were investigated by Sanger sequencing. Based on their genetic sequence, candidates from XPA exon 1 and 2 were selected and further analyzed by immunoblotting, immunofluorescence, HCR and MTT assays. In XPA exon 1, we established a homozygous (c.19delG; p.A7Lfs*8) and a compound heterozygous (c.19delG/c.19_20insG; p.A7Lfs*8/p.A7Gfs*55) cell line. In XPA exon 2, we generated a compound heterozygous mutated cell line (c.206_208delTTG/c.208_209delGA; p.I69_D70delinsN/p.D70Hfs*31). The better performance of the homozygous than the heterozygous mutated exon 1 cells in DNA damage repair (HCR) and post-UV-C cell survival (MTT), was associated with the expression of a novel XPA protein variant. The results of our study serve as the fundamental basis for the investigation of the immunological consequences of XPA disruption in melanoma. KW - DNA repair KW - nucleotide excision repair KW - XPA KW - CRISPR KW - knockout KW - protein variant KW - melanoma KW - A375 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290427 SN - 1422-0067 VL - 23 IS - 19 ER - TY - JOUR A1 - Butt, Elke A1 - Howard, Cory M. A1 - Raman, Dayanidhi T1 - LASP1 in cellular signaling and gene expression: more than just a cytoskeletal regulator JF - Cells N2 - LIM and SH3 protein 1 was originally identified as a structural cytoskeletal protein with scaffolding function. However, recent data suggest additional roles in cell signaling and gene expression, especially in tumor cells. These novel functions are primarily regulated by the site-specific phosphorylation of LASP1. This review will focus on specific phosphorylation-dependent interaction between LASP1 and cellular proteins that orchestrate primary tumor progression and metastasis. More specifically, we will describe the role of LASP1 in chemokine receptor, and PI3K/AKT signaling. We outline the nuclear role for LASP1 in terms of epigenetics and transcriptional regulation and modulation of oncogenic mRNA translation. Finally, newly identified roles for the cytoskeletal function of LASP1 next to its known canonical F-actin binding properties are included. KW - LASP1 KW - AKT KW - CXCR4 KW - structure KW - cytoskeleton KW - phosphorylation KW - transcriptional regulation KW - epigenetics KW - nucleus Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297447 SN - 2073-4409 VL - 11 IS - 23 ER - TY - JOUR A1 - Schwan, Carsten A1 - Lang, Alexander E. A1 - Schlosser, Andreas A1 - Fujita-Becker, Setsuko A1 - AlHaj, Abdulatif A1 - Schröder, Rasmus R. A1 - Faix, Jan A1 - Aktories, Klaus A1 - Mannherz, Hans Georg T1 - Inhibition of Arp2/3 complex after ADP-ribosylation of Arp2 by binary Clostridioides toxins JF - Cells N2 - Clostridioides bacteria are responsible for life threatening infections. Here, we show that in addition to actin, the binary toxins CDT, C2I, and Iota from Clostridioides difficile, botulinum, and perfrigens, respectively, ADP-ribosylate the actin-related protein Arp2 of Arp2/3 complex and its additional components ArpC1, ArpC2, and ArpC4/5. The Arp2/3 complex is composed of seven subunits and stimulates the formation of branched actin filament networks. This activity is inhibited after ADP-ribosylation of Arp2. Translocation of the ADP-ribosyltransferase component of CDT toxin into human colon carcinoma Caco2 cells led to ADP-ribosylation of cellular Arp2 and actin followed by a collapse of the lamellipodial extensions and F-actin network. Exposure of isolated mouse colon pieces to CDT toxin induced the dissolution of the enterocytes leading to luminal aggregation of cellular debris and the collapse of the mucosal organization. Thus, we identify the Arp2/3 complex as hitherto unknown target of clostridial ADP-ribosyltransferases. KW - actin KW - ADP-ribosyltransferases KW - Arp2/3 complex KW - Clostridioides binary toxins Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297454 SN - 2073-4409 VL - 11 IS - 22 ER - TY - JOUR A1 - Wulf, Maximilian A1 - Barkovits, Katalin A1 - Schork, Karin A1 - Eisenacher, Martin A1 - Riederer, Peter A1 - Gerlach, Manfred A1 - Eggers, Britta A1 - Marcus, Katrin T1 - The proteome of neuromelanin granules in dementia with Lewy bodies JF - Cells N2 - Neuromelanin granules (NMGs) are organelle-like structures present in the human substantia nigra pars compacta. In addition to neuromelanin, NMGs contain proteins, lipids and metals. As NMG-containing dopaminergic neurons are preferentially lost in Parkinson’s disease and dementia with Lewy bodies (DLB), it is assumed that NMGs may play a role in neurodegenerative processes. Until now, this role is not completely understood and needs further investigation. We therefore set up an exploratory proteomic study to identify differences in the proteomic profile of NMGs from DLB patients (n = 5) compared to healthy controls (CTRL, n = 5). We applied a laser microdissection and mass-spectrometry-based approach, in which we used targeted mass spectrometric experiments for validation. In NMG-surrounding (SN\(_{Surr.}\)) tissue of DLB patients, we found evidence for ongoing oxidative damage and an impairment of protein degradation. As a potentially disease-related mechanism, we found α-synuclein and protein S100A9 to be enriched in NMGs of DLB cases, while the abundance of several ribosomal proteins was significantly decreased. As S100A9 is known to be able to enhance the formation of toxic α-synuclein fibrils, this finding points towards an involvement of NMGs in pathogenesis, however the exact role of NMGs as either neuroprotective or neurotoxic needs to be further investigated. Nevertheless, our study provides evidence for an impairment of protein degradation, ongoing oxidative damage and accumulation of potentially neurotoxic protein aggregates to be central mechanisms of neurodegeneration in DLB. KW - neuromelanin granules KW - neurodegeneration KW - dementia with Lewy bodies KW - proteomics KW - stress granules KW - substantia nigra pars compacta Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297465 SN - 2073-4409 VL - 11 IS - 22 ER - TY - JOUR A1 - Koenig, Leopold A1 - Ramme, Anja Patricia A1 - Faust, Daniel A1 - Mayer, Manuela A1 - Flötke, Tobias A1 - Gerhartl, Anna A1 - Brachner, Andreas A1 - Neuhaus, Winfried A1 - Appelt-Menzel, Antje A1 - Metzger, Marco A1 - Marx, Uwe A1 - Dehne, Eva-Maria T1 - A human stem cell-derived brain-liver chip for assessing blood-brain-barrier permeation of pharmaceutical drugs JF - Cells N2 - Significant advancements in the field of preclinical in vitro blood-brain barrier (BBB) models have been achieved in recent years, by developing monolayer-based culture systems towards complex multi-cellular assays. The coupling of those models with other relevant organoid systems to integrate the investigation of blood-brain barrier permeation in the larger picture of drug distribution and metabolization is still missing. Here, we report for the first time the combination of a human induced pluripotent stem cell (hiPSC)-derived blood-brain barrier model with a cortical brain and a liver spheroid model from the same donor in a closed microfluidic system (MPS). The two model compounds atenolol and propranolol were used to measure permeation at the blood–brain barrier and to assess metabolization. Both substances showed an in vivo-like permeation behavior and were metabolized in vitro. Therefore, the novel multi-organ system enabled not only the measurement of parent compound concentrations but also of metabolite distribution at the blood-brain barrier. KW - blood-brain barrier (BBB) model KW - human induced pluripotent stem cells (hiPSCs) KW - microphysiological systems (MPS) KW - multi-organ chip KW - brain–liver chip Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290375 SN - 2073-4409 VL - 11 IS - 20 ER - TY - JOUR A1 - Schmitt, Andrea A1 - Tatsch, Laura A1 - Vollhardt, Alisa A1 - Schneider-Axmann, Thomas A1 - Raabe, Florian J. A1 - Roell, Lukas A1 - Heinsen, Helmut A1 - Hof, Patrick R. A1 - Falkai, Peter A1 - Schmitz, Christoph T1 - Decreased oligodendrocyte number in hippocampal subfield CA4 in schizophrenia: a replication study JF - Cells N2 - Hippocampus-related cognitive deficits in working and verbal memory are frequent in schizophrenia, and hippocampal volume loss, particularly in the cornu ammonis (CA) subregions, was shown by magnetic resonance imaging studies. However, the underlying cellular alterations remain elusive. By using unbiased design-based stereology, we reported a reduction in oligodendrocyte number in CA4 in schizophrenia and of granular neurons in the dentate gyrus (DG). Here, we aimed to replicate these findings in an independent sample. We used a stereological approach to investigate the numbers and densities of neurons, oligodendrocytes, and astrocytes in CA4 and of granular neurons in the DG of left and right hemispheres in 11 brains from men with schizophrenia and 11 brains from age- and sex-matched healthy controls. In schizophrenia, a decreased number and density of oligodendrocytes was detected in the left and right CA4, whereas mean volumes of CA4 and the DG and the numbers and density of neurons, astrocytes, and granular neurons were not different in patients and controls, even after adjustment of variables because of positive correlations with postmortem interval and age. Our results replicate the previously described decrease in oligodendrocytes bilaterally in CA4 in schizophrenia and point to a deficit in oligodendrocyte maturation or a loss of mature oligodendrocytes. These changes result in impaired myelination and neuronal decoupling, both of which are linked to altered functional connectivity and subsequent cognitive dysfunction in schizophrenia. KW - schizophrenia KW - hippocampus KW - CA4 KW - dentate gyrus KW - postmortem KW - stereology KW - oligodendrocyte KW - neuron Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290360 SN - 2073-4409 VL - 11 IS - 20 ER - TY - JOUR A1 - Jarausch, Johannes A1 - Neuenroth, Lisa A1 - Andag, Reiner A1 - Leha, Andreas A1 - Fischer, Andreas A1 - Asif, Abdul R. A1 - Lenz, Christof A1 - Eidizadeh, Abass T1 - Influence of shear stress, inflammation and BRD4 inhibition on human endothelial cells: a holistic proteomic approach JF - Cells N2 - Atherosclerosis is an important risk factor in the development of cardiovascular diseases. In addition to increased plasma lipid concentrations, irregular/oscillatory shear stress and inflammatory processes trigger atherosclerosis. Inhibitors of the transcription modulatory bromo- and extra-terminal domain (BET) protein family (BETi) could offer a possible therapeutic approach due to their epigenetic mechanism and anti-inflammatory properties. In this study, the influence of laminar shear stress, inflammation and BETi treatment on human endothelial cells was investigated using global protein expression profiling by ion mobility separation-enhanced data independent acquisition mass spectrometry (IMS-DIA-MS). For this purpose, primary human umbilical cord derived vascular endothelial cells were treated with TNFα to mimic inflammation and exposed to laminar shear stress in the presence or absence of the BRD4 inhibitor JQ1. IMS-DIA-MS detected over 4037 proteins expressed in endothelial cells. Inflammation, shear stress and BETi led to pronounced changes in protein expression patterns with JQ1 having the greatest effect. To our knowledge, this is the first proteomics study on primary endothelial cells, which provides an extensive database for the effects of shear stress, inflammation and BETi on the endothelial proteome. KW - HUVEC KW - shear stress KW - endothelial KW - proteomic KW - BRD4 KW - JQ1 KW - DIA-MS KW - BET Inhibitor KW - atherosclerosis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-289872 SN - 2073-4409 VL - 11 IS - 19 ER - TY - JOUR A1 - Wußmann, Maximiliane A1 - Groeber-Becker, Florian Kai A1 - Riedl, Sabrina A1 - Alihodzic, Dina A1 - Padaric, Daniel A1 - Gerlitz, Lisa A1 - Stallinger, Alexander A1 - Liegl-Atzwanger, Bernadette A1 - Zweytick, Dagmar A1 - Rinner, Beate T1 - In model, in vitro and in vivo killing efficacy of antitumor peptide RDP22 on MUG-Mel2, a patient derived cell line of an aggressive melanoma metastasis JF - Biomedicines N2 - The host defense derived peptide was assessed in different model systems with increasing complexity employing the highly aggressive NRAS mutated melanoma metastases cell line MUG-Mel2. Amongst others, fluorescence microscopy and spectroscopy, as well as cell death studies were applied for liposomal, 2D and 3D in vitro models including tumor spheroids without or within skin models and in vivo mouse xenografts. Summarized, MUG-Mel2 cells were shown to significantly expose the negatively charged lipid phosphatidylserine on their plasma membranes, showing they are successfully targeted by RDP22. The peptide was able to induce cell death in MUG-Mel2 2D and 3D cultures, where it was able to kill tumor cells even inside the core of tumor spheroids or inside a melanoma organotypic model. In vitro studies indicated cell death by apoptosis upon peptide treatment with an LC\(_{50}\) of 8.5 µM and seven-fold specificity for the melanoma cell line MUG-Mel2 over normal dermal fibroblasts. In vivo studies in mice xenografts revealed effective tumor regression upon intratumoral peptide injection, indicated by the strong clearance of pigmented tumor cells and tremendous reduction in tumor size and proliferation, which was determined histologically. The peptide RDP22 has clearly shown high potential against the melanoma cell line MUG-Mel2 in vitro and in vivo. KW - melanoma metastases KW - NRAS mutation KW - antitumor peptide KW - tumor model systems KW - phosphatidylserine Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297525 SN - 2227-9059 VL - 10 IS - 11 ER - TY - JOUR A1 - Oliveira-Ferrer, Leticia A1 - Schmalfeldt, Barbara A1 - Dietl, Johannes A1 - Bartmann, Catharina A1 - Schumacher, Udo A1 - Stürken, Christine T1 - Ovarian cancer-cell pericellular hyaluronan deposition negatively impacts prognosis of ovarian cancer patients JF - Biomedicines N2 - Background: Hyaluronan (HA), a component of the extracellular matrix, is frequently increased under pathological conditions including cancer. Not only stroma cells but also cancer cells themselves synthesize HA, and the interaction of HA with its cognate receptors promotes malignant progression and metastasis. Methods: In the present study, HA deposition in tissue sections was analyzed by hyaluronan-binding protein (HABP) ligand histochemistry in 17 borderline tumors and 102 primary and 20 recurrent ovarian cancer samples. The intensity and, particularly, localization of the HA deposition were recorded: for the localization, the pericellular deposition around the ovarian cancer cells was distinguished from the deposition within the stromal compartment. These histochemical data were correlated with clinical and pathological parameters. Additionally, within a reduced subgroup of ovarian cancer samples (n = 70), the RNA levels of several HA-associated genes were correlated with the HA localization and intensity. Results: Both stroma-localized and pericellular tumor-cell-associated HA deposition were observed. Cancer-cell pericellular HA deposition, irrespective of its staining intensity, was significantly associated with malignancy, and in the primary ovarian cancer cohort, it represents an independent unfavorable prognostic marker for overall survival. Furthermore, a significant association between high CD44, HAS2 and HAS3 mRNA levels and a cancer-cell pericellular HA-deposition pattern was noted. In contrast, stromal hyaluronan deposition had no impact on ovarian cancer prognosis. Conclusions: In conclusion, the site of HA deposition is of prognostic value, but the amount deposited is not. The significant association of only peritumoral cancer-cell HA deposition with high CD44 mRNA expression levels suggests a pivotal role of the CD44–HA signaling axis for malignant progression in ovarian cancer. KW - ovarian cancer KW - stromal hyaluronan KW - tumor-associated hyaluronan staining pattern KW - hyaluronan-related enzymes Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297539 SN - 2227-9059 VL - 10 IS - 11 ER - TY - JOUR A1 - Hartrampf, Philipp E. A1 - Weinzierl, Franz-Xaver A1 - Serfling, Sebastian E. A1 - Pomper, Martin G. A1 - Rowe, Steven P. A1 - Higuchi, Takahiro A1 - Seitz, Anna Katharina A1 - Kübler, Hubert A1 - Buck, Andreas K. A1 - Werner, Rudolf A. T1 - Hematotoxicity and nephrotoxicity in prostate cancer patients undergoing radioligand therapy with [\(^{177}\)Lu]Lu-PSMA I&T JF - Cancers N2 - (1) Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) has shown remarkable results in patients with advanced prostate cancer. We aimed to evaluate the toxicity profile of the PSMA ligand [\(^{177}\)Lu]Lu-PSMA I&T. (2) Methods: 49 patients with metastatic, castration-resistant prostate cancer treated with at least three cycles of [\(^{177}\)Lu]Lu-PSMA I&T were evaluated. Prior to and after RLT, we compared leukocytes, hemoglobin, platelet counts, and renal functional parameters (creatinine, eGFR, n = 49; [\(^{99m}\)Tc]-MAG3-derived tubular extraction rate (TER), n = 42). Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and KDIGO Society. To identify predictive factors, we used Spearman's rank correlation coefficient. (3) Results: A substantial fraction of the patients already showed impaired renal function and reduced leukocyte counts at baseline. Under RLT, 11/49 (22%) patients presented with nephrotoxicity CTCAE I or II according to creatinine, but 33/49 (67%) according to eGFR. Only 5/42 (13%) showed reduced TER, defined as <70% of the age-adjusted mean normal values. Of all renal functional parameters, absolute changes of only 2% were recorded. CTCAE-based re-categorization was infrequent, with creatinine worsening from I to II in 2/49 (4.1%; GFR, 1/49 (2%)). Similar results were recorded for KDIGO (G2 to G3a, 1/49 (2%); G3a to G3b, 2/49 (4.1%)). After three cycles, follow-up eGFR correlated negatively with age (r = −0.40, p = 0.005) and the eGFR change with Gleason score (r = −0.35, p < 0.05) at baseline. Leukocytopenia CTCAE II occurred only in 1/49 (2%) (CTCAE I, 20/49 (41%)) and CTCAE I thrombocytopenia in 7/49 (14%), with an absolute decrease of 15.2% and 16.6% for leukocyte and platelet counts. Anemia CTCAE II occurred in 10/49 (20%) (CTCAE I, 36/49 (73%)) with a decrease in hemoglobin of 4.7%. (4) Conclusions: After PSMA-targeted therapy using [\(^{177}\)Lu]Lu-PSMA I&T, no severe (CTCAE III/IV) toxicities occurred, thereby demonstrating that serious adverse renal or hematological events are unlikely to be a frequent phenomenon with this agent. KW - PSMA KW - radioligand therapy KW - RLT KW - \(^{177}\)Lu KW - nephrotoxicity KW - hematotoxicity KW - CTCAE Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254825 SN - 2072-6694 VL - 14 IS - 3 ER - TY - JOUR A1 - Kelm, Matthias A1 - Kusan, Simon A1 - Surat, Güzin A1 - Anger, Friedrich A1 - Reibetanz, Joachim A1 - Germer, Christoph-Thomas A1 - Schlegel, Nicolas A1 - Flemming, Sven T1 - Disease- and medication-specific differences of the microbial spectrum in perianal fistulizing Crohn’s Disease — relevant aspects for antibiotic therapy JF - Biomedicines N2 - Perianal fistulizing Crohn’s Disease (CD) with abscess formation represents an aggressive phenotype in Inflammatory Bowel Disease (IBD) with increased morbidity. Treatment is multidisciplinary and includes antibiotics, but knowledge about the microbial spectrum is rare often resulting in inadequate antimicrobial therapy. In this single center retrospective study, all patients who were operated due to perianal abscess formation were retrospectively analyzed and the microbial spectrum evaluated. Patients were divided into a CD and non-CD group with further subgroup analysis. 138 patients were finally included in the analysis with 62 patients suffering from CD. Relevant differences were detected for the microbial spectrum with anaerobic bacteria being significantly more often isolated from non-CD patients. In a subgroup-analysis of CD patients only, medical therapy had a relevant effect on the microbial spectrum since Streptococcus groups and Enterobacterales were significantly more often isolated in patients treated with steroids compared to those being treated by antibodies. In conclusion, the microbial spectrum of patients suffering from CD varies significantly from non-CD patients and immunosuppressive medication has a relevant effect on isolated pathogens. Based on that, adaption of antibiotic treatment might be discussed in the future. KW - fistulizing Crohn’s Disease KW - microbial spectrum KW - anorectal abscess KW - perianal fistulas Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290281 SN - 2227-9059 VL - 10 IS - 11 ER - TY - JOUR A1 - Kempf, Florian A1 - Scharnagl, Julian A1 - Heil, Stefan A1 - Schilling, Klaus T1 - Self-organizing control-loop recovery for predictive networked formation control of fractionated spacecraft JF - Aerospace N2 - Going beyond the current trend of cooperating multiple small satellites we arrive at fractionated satellite architectures. Here the subsystems of all satellites directly self-organize and cooperate among themselves to achieve a common mission goal. Although this leads to a further increase of the advantages of the initial trend it also introduces new challenges, one of which is how to perform closed-loop control of a satellite over a network of subsystems. We present a two-fold approach to deal with the two main disturbances, data losses in the network and failure of the controller, in a networked predictive formation control scenario. To deal with data loss an event based networked model predictive control approach is extended to enable it to adapt to changing network conditions. The controller failure detection and compensation approach is tailored for a possibly large network of heterogeneous cooperating actuator- and controller nodes. The self-organized control task redistribution uses an auction-based methodology. It scales well with the number of nodes and allows to optimize for continuing good control performance despite the controller switch. The stability and smooth control behavior of our approach during a self-organized controller failure compensation while also being subject to data losses was demonstrated on a hardware testbed using as mission a formation control scenario. KW - networked predictive control KW - fractionated spacecraft KW - controller failure recovery KW - self-organization KW - formation control KW - auction based task assignment Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288041 SN - 2226-4310 VL - 9 IS - 10 ER - TY - JOUR A1 - Kustiati, Ulayatul A1 - Ergün, Suleyman A1 - Karnati, Srikanth A1 - Nugrahaningsih, Dwi Aris Agung A1 - Kusindarta, Dwi Liliek A1 - Wihadmadyatami, Hevi T1 - Ethanolic extract of Ocimum sanctum Linn. Inhibits cell migration of human lung adenocarcinoma cells (A549) by downregulation of integrin αvβ3, α5β1, and VEGF JF - Scientia Pharmaceutica N2 - Adenocarcinoma lung cancer is a type of non-small cell lung carcinoma (NSCLC), which accounts for 85% of lung cancer incidence globally. The therapies that are being applied, both conventional therapies and antibody-based treatments, are still found to have side effects. Several previous studies have demonstrated the ability of the ethanolic extract of Ocimum sanctum Linn. (EEOS) as an ethnomedicine with anti-tumor properties. The aim of this study was to determine the effect of Ocimum sanctum Linn. ethanolic extract in inhibiting the proliferation, angiogenesis, and migration of A549 cells (NSCLC). The adhesion as well as the migration assay was performed. Furthermore, enzyme-linked immunosorbent assay (ELISA) was used to measure the expression of αvβ3 integrins, α5β1 integrins, and VEGF. The cells were divided into the following treatment groups: control (non-treated/NT), positive control (AP3/inhibitor β3 80 µg/mL), cisplatin (9 µg/mL), and EEOS at concentrations of 50, 70, 100, and 200 µg/mL. The results showed that EEOS inhibits the adhesion ability and migration of A549 cells, with an optimal concentration of 200 µg/mL. ELISA testing showed that the group of A549 cells given EEOS 200 µg/mL presented a decrease in the optimal expression of integrin α5β1, integrin αvβ3, and VEGF. KW - EEOS KW - A549 cell line KW - integrin α5β1 KW - integrin αvβ3 KW - VEGF Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290540 SN - 2218-0532 VL - 90 IS - 4 ER - TY - JOUR A1 - Garg, Tushar A1 - Werner, Rudolf A. A1 - Chung, Hyun Woo A1 - Khatri, Wajahat A1 - Pienta, Kenneth J. A1 - Pomper, Martin G. A1 - Gorin, Michael A. A1 - Saad, Elie A1 - Rowe, Steven P. T1 - Association of true positivity with serum prostate-specific antigen levels and other clinical factors in indeterminate PSMA-RADS-3A lesions identified on \(^{18}\)F-DCFPyL PET/CT scans JF - Tomography N2 - The use of prostate-specific membrane antigen targeted PET imaging for the evaluation of prostate cancer has increased significantly in the last couple of decades. When evaluating these imaging findings based on the PSMA reporting and data system version 1.0, which categorize lesions based on their likelihood of prostate cancer involvement, PSMA-RADS-3A lesions are commonly seen, which are indeterminate for the presence of disease. A total of 28 patients with 171 PSMA-RADS-3A lesions on \(^{18}\)F-DCFPyL PET/CT scans from June 2016 to May 2017 who had follow-up cross-sectional imaging over time were included in this study. The PSA levels of patients with PSMA-RADS-3A lesions were categorized into four groups, 0–0.2, 0.2–1, 1–2, and >2 ng/mL. The pre-operative Gleason score of these patients was categorized into two groups, Gleason score < 7 or ≥7. The median age for these patients was 72.5 years (range 59–81). The median PSA value for patients with positive lesions was significantly higher than those with negative lesions (5.8 ng/mL vs. 0.2 ng/mL, p < 0.0001). The lesion positivity rate was significantly higher in patients with PSA > 1 ng/mL (18.2% vs. 81.9%, p < 0.001). On ROC analysis, the highest classification accuracy was seen at PSA ≥ 0.6 ng/mL of 80.12% (95% CI = 73.69–86.16%), and the area under the curve was 71.32% (95% CI = 61.9–80.7%, p < 0.0001). A total of 96.4% (108/112) of patients with positive lesions and 86.4% (51/59) of patients with negative lesions had a PSMA-RADS-4/5 lymph node on the initial \(^{18}\)F-DCFPyL PET/CT scan (p = 0.02). In patients with a Gleason score ≥ 7, the presence of positive PSMA-RADS-3A lesions was higher, compared to negative PSMA-RADS-3A lesions (p = 0.049). Higher PSA levels in patients with PSMA-RADS-3A lesions can point towards the presence of true positivity. PSA levels may be considered in deciding whether to call an indeterminate lesion on PSMA PET. KW - prostate cancer KW - prostate-specific antigen KW - PSMA-RADS KW - \(^{18}\)F-DCFPyL PET/CT KW - Gleason score Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290510 SN - 2379-139X VL - 8 IS - 6 SP - 2639 EP - 2647 ER - TY - JOUR A1 - Hutin, Stephanie A1 - Ling, Wai Li A1 - Tarbouriech, Nicolas A1 - Schoehn, Guy A1 - Grimm, Clemens A1 - Fischer, Utz A1 - Burmeister, Wim P. T1 - The vaccinia virus DNA helicase structure from combined single-particle cryo-electron microscopy and AlphaFold2 prediction JF - Viruses N2 - Poxviruses are large DNA viruses with a linear double-stranded DNA genome circularized at the extremities. The helicase-primase D5, composed of six identical 90 kDa subunits, is required for DNA replication. D5 consists of a primase fragment flexibly attached to the hexameric C-terminal polypeptide (res. 323–785) with confirmed nucleotide hydrolase and DNA-binding activity but an elusive helicase activity. We determined its structure by single-particle cryo-electron microscopy. It displays an AAA+ helicase core flanked by N- and C-terminal domains. Model building was greatly helped by the predicted structure of D5 using AlphaFold2. The 3.9 Å structure of the N-terminal domain forms a well-defined tight ring while the resolution decreases towards the C-terminus, still allowing the fit of the predicted structure. The N-terminal domain is partially present in papillomavirus E1 and polyomavirus LTA helicases, as well as in a bacteriophage NrS-1 helicase domain, which is also closely related to the AAA+ helicase domain of D5. Using the Pfam domain database, a D5_N domain followed by DUF5906 and Pox_D5 domains could be assigned to the cryo-EM structure, providing the first 3D structures for D5_N and Pox_D5 domains. The same domain organization has been identified in a family of putative helicases from large DNA viruses, bacteriophages, and selfish DNA elements. KW - DNA replication KW - helicase KW - Pfam domain KW - poxvirus KW - cryo-electron microscopy KW - structure prediction KW - SF3 helicase KW - orthopoxvirus KW - DNA helicase Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290523 SN - 1999-4915 VL - 14 IS - 10 ER - TY - JOUR A1 - Hill, Aileen A1 - Dossow, Vera von A1 - Heyland, Daren K. A1 - Rossaint, Rolf A1 - Meybohm, Patrick A1 - Fox, Henrik A1 - Morshuis, Michiel A1 - Elke, Gunnar A1 - Panholzer, Bernd A1 - Haneya, Assad A1 - Böning, Andreas A1 - Niemann, Bernd A1 - Zayat, Rashad A1 - Moza, Ajay A1 - Stoppe, Christian T1 - Preoperative nutritional optimization and physical exercise for patients scheduled for elective implantation for a left-ventricular assist device — The PROPER-LVAD study JF - Surgeries N2 - Background: Prehabilitation is gaining increasing interest and shows promising effects on short- and long-term outcomes among patients undergoing major surgery. The effect of multimodal, interdisciplinary prehabilitation has not yet been studied in patients with severe heart failure scheduled for the implantation of a left-ventricular assist device (LVAD). Methods: This randomized controlled multi-center study evaluates the effect of preoperative combined optimization of nutritional and functional status. Patients in the intervention group are prescribed daily in-bed cycling and oral nutrition supplements (ONS) from study inclusion until the day before LVAD-implantation. Patients in the control group receive standard of care treatment. The primary outcomes for the pilot study that involves 48 patients are safety (occurrence of adverse events), efficacy (group separation regarding the intake of macronutrients), feasibility of the trial protocol (compliance (percentage of received interventions) and confirmation of recruitment rates. Secondary outcomes include longitudinal measurements of muscle mass, muscle strength, physical function and quality of life, next to traditional clinical outcomes (30-day mortality, hospital and ICU length of stay, duration of mechanical ventilation and number of complications and infections). If the pilot study is successful, a larger confirmatory, international multicenter study is warranted. KW - prehabilitation KW - medical nutrition therapy KW - in-bed cycling KW - left-ventricular assist device KW - trial protocol KW - clinical trial KW - oral nutrition supplements Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288317 SN - 2673-4095 N1 - Funding: This investigator-initiated trial is supported by a grant from Fresenius Kabi Deutschland (Fresenius Kabi Deutschland GmbH, Else-Kröner-Straße 1, 61352 Bad Homburg). The oral nutrition supplements (Fresubin PRO®) are provided by Fresenius Kabi Germany. VL - 3 IS - 4 SP - 284 EP - 296 ER - TY - JOUR A1 - Pluta, Natalie A1 - Hoffjan, Sabine A1 - Zimmer, Frederic A1 - Köhler, Cornelia A1 - Lücke, Thomas A1 - Mohr, Jennifer A1 - Vorgerd, Matthias A1 - Nguyen, Hoa Huu Phuc A1 - Atlan, David A1 - Wolf, Beat A1 - Zaum, Ann-Kathrin A1 - Rost, Simone T1 - Homozygous inversion on chromosome 13 involving SGCG detected by short read whole genome sequencing in a patient suffering from limb-girdle muscular dystrophy JF - Genes N2 - New techniques in molecular genetic diagnostics now allow for accurate diagnosis in a large proportion of patients with muscular diseases. Nevertheless, many patients remain unsolved, although the clinical history and/or the muscle biopsy give a clear indication of the involved genes. In many cases, there is a strong suspicion that the cause must lie in unexplored gene areas, such as deep-intronic or other non-coding regions. In order to find these changes, next-generation sequencing (NGS) methods are constantly evolving, making it possible to sequence entire genomes to reveal these previously uninvestigated regions. Here, we present a young woman who was strongly suspected of having a so far genetically unsolved sarcoglycanopathy based on her clinical history and muscle biopsy. Using short read whole genome sequencing (WGS), a homozygous inversion on chromosome 13 involving SGCG and LINC00621 was detected. The breakpoint in intron 2 of SGCG led to the absence of γ-sarcoglycan, resulting in the manifestation of autosomal recessive limb-girdle muscular dystrophy 5 (LGMDR5) in the young woman. KW - inversion KW - sarcoglycanopathy KW - whole genome sequencing (WGS) KW - next generation sequencing (NGS) KW - LGMDR5 KW - muscle disease KW - genetic diagnostics Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288122 SN - 2073-4425 VL - 13 IS - 10 ER - TY - JOUR A1 - vom Dahl, Christian A1 - Müller, Christoph Emanuel A1 - Berisha, Xhevat A1 - Nagel, Georg A1 - Zimmer, Thomas T1 - Coupling the cardiac voltage-gated sodium channel to channelrhodopsin-2 generates novel optical switches for action potential studies JF - Membranes N2 - Voltage-gated sodium (Na\(^+\)) channels respond to short membrane depolarization with conformational changes leading to pore opening, Na\(^+\) influx, and action potential (AP) upstroke. In the present study, we coupled channelrhodopsin-2 (ChR2), the key ion channel in optogenetics, directly to the cardiac voltage-gated Na\(^+\) channel (Na\(_v\)1.5). Fusion constructs were expressed in Xenopus laevis oocytes, and electrophysiological recordings were performed by the two-microelectrode technique. Heteromeric channels retained both typical Na\(_v\)1.5 kinetics and light-sensitive ChR2 properties. Switching to the current-clamp mode and applying short blue-light pulses resulted either in subthreshold depolarization or in a rapid change of membrane polarity typically seen in APs of excitable cells. To study the effect of individual K\(^+\) channels on the AP shape, we co-expressed either K\(_v\)1.2 or hERG with one of the Na\(_v\)1.5-ChR2 fusions. As expected, both delayed rectifier K\(^+\) channels shortened AP duration significantly. K\(_v\)1.2 currents remarkably accelerated initial repolarization, whereas hERG channel activity efficiently restored the resting membrane potential. Finally, we investigated the effect of the LQT3 deletion mutant ΔKPQ on the AP shape and noticed an extremely prolonged AP duration that was directly correlated to the size of the non-inactivating Na\(^+\) current fraction. In conclusion, coupling of ChR2 to a voltage-gated Na\(^+\) channel generates optical switches that are useful for studying the effect of individual ion channels on the AP shape. Moreover, our novel optogenetic approach provides the potential for an application in pharmacology and optogenetic tissue-engineering. KW - optogenetics KW - channelrhodopsin KW - voltage-gated Na\(^+\) channel KW - action potential KW - delayed rectifier potassium channel KW - hERG KW - long QT syndrome Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288228 SN - 2077-0375 VL - 12 IS - 10 ER - TY - JOUR A1 - Just, Janina A1 - Siller, Hans-Stefan T1 - The role of mathematics in STEM secondary classrooms: a systematic literature review JF - Education Sciences N2 - Nowadays, science, technology, engineering, and mathematics (STEM) play a critical role in a nation’s global competitiveness and prosperity. Thus, there is a need to educate students in these subjects to meet the current and future demands of personal life and society. While applications, especially in science, engineering, and technology, are directly obvious, mathematics underpins the other STEM disciplines. It is recognized that mathematics is the foundation for all other STEM disciplines; the role of mathematics in classrooms is not clear yet. Therefore, the question arises: What is the current role of mathematics in secondary STEM classrooms? To answer this question, we conducted a systematic literature review based on three publication databases (Web of Science, ERIC, and EBSCO Teacher Referral Center). This literature review paper is intended to contribute to the current state of the role of mathematics in STEM education in secondary classrooms. Through the search, starting with 1910 documents, only 14 eligible documents were found. In these, mathematics is often seen as a minor matter and a means to an end in the eyes of science educators. From this, we conclude that the role of mathematics in the STEM classroom should be further strengthened. Overall, the paper highlights a major research gap, and proposes possible initial solutions to close it. KW - STEM education KW - role of mathematics in STEM KW - literature review KW - STEM integration KW - STEM classroom KW - secondary education Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288075 SN - 2227-7102 VL - 12 IS - 9 ER - TY - JOUR A1 - Steinmann, Rebekka A1 - Cortegoso Valdivia, Pablo A1 - Nowak, Tanja A1 - Koulaouzidis, Anastasios T1 - An overview of the evolution of capsule endoscopy research — text-mining analysis and publication trends JF - Diagnostics N2 - There has been a steady increase (annual percentage growth rate of 19.2%, average of 18.3 citations per document) in capsule endoscopy (CE) publications from a global, interdisciplinary research community on a growing range of CE applications over the last 20+ years. We here present the status of CE as a field of research, tracing its evolution over time and providing insight into its potential for diagnostics, prevention and treatment of gastrointestinal (GI) tract diseases. To portray the development of the CE research landscape in the 2000–2021 time span, we analyzed 5764 scientific publications. Analyses were performed using the R language and environment for statistical computing and graphics and VOSviewer, a software developed for scientific literature analysis by scientometricians. The aim of this paper is to provide a wide comprehensive analysis of the trends in CE publications. We thus performed subgroup analysis on the selected papers, including indications, annual percentage growth rate, average citations per document, most publications from research areas/interdisciplinary field of the articles, geography, collaboration networks through institutions, specific clinical keywords and device type. The firm increase in CE publications over the last two decades highlights the overall strength of the technology in GI applications. Furthermore, the introduction to the field of artificial intelligence (AI) tools has been promoting a range of technological advances that keep on affecting the diagnostic potential of CE. KW - capsule endoscopy KW - research KW - meta-view Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288515 SN - 2075-4418 VL - 12 IS - 9 ER - TY - JOUR A1 - Seethaler, Marius A1 - Hertlein, Tobias A1 - Hopke, Elisa A1 - Köhling, Paul A1 - Ohlsen, Knut A1 - Lalk, Michael A1 - Hilgeroth, Andreas T1 - Novel effective fluorinated benzothiophene-indole hybrid antibacterials against S. aureus and MRSA strains JF - Pharmaceuticals N2 - Increasing antibacterial drug resistance threatens global health, unfortunately, however, efforts to find novel antibacterial agents have been scaled back by the pharmaceutical industry due to concerns about a poor return on investment. Nevertheless, there is an urgent need to find novel antibacterial compounds to combat antibacterial drug resistance. The synthesis of novel drugs from natural sources is mostly cost-intensive due to those drugs’ complicated structures. Therefore, it is necessary to find novel antibacterials by simple synthesis to become more attractive for industrial production. We succeeded in the discovery of four antibacterial compound (sub)classes accessible in a simple one-pot reaction based on fluorinated benzothiophene-indole hybrids. They have been evaluated against various S. aureus and MRSA strains. Structure- and substituent-dependent activities have been found within the (sub)classes and promising lead compounds have been identified. In addition, bacterial pyruvate kinase was found to be the molecular target of the active compounds. In conclusion, simple one-pot synthesis of benzothiophene-indoles represents a promising strategy for the search of novel antimicrobial compounds. KW - antibacterial drug resistance KW - structure activity KW - synthesis KW - inhibition KW - substituent Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288253 SN - 1424-8247 VL - 15 IS - 9 ER - TY - JOUR A1 - Schlund, Jonas A1 - German, Reinhard A1 - Pruckner, Marco T1 - Synergy of unidirectional and bidirectional smart charging of electric vehicles for frequency containment reserve power provision JF - World Electric Vehicle Journal N2 - Besides the integration of renewable energies, electric vehicles pose an additional challenge to modern power grids. However, electric vehicles can also be a flexibility source and contribute to the power system stability. Today, the power system still heavily relies on conventional technologies to stay stable. In order to operate a future power system based on renewable energies only, we need to understand the flexibility potential of assets such as electric vehicles and become able to use their flexibility. In this paper, we analyzed how vast amounts of coordinated charging processes can be used to provide frequency containment reserve power, one of the most important ancillary services for system stability. Therefore, we used an extensive simulation model of a virtual power plant of millions of electric vehicles. The model considers not only technical components but also the stochastic behavior of electric vehicle drivers based on real data. Our results show that, in 2030, electric vehicles have the potential to serve the whole frequency containment reserve power market in Germany. We differentiate between using unidirectional and bidirectional chargers. Bidirectional chargers have a larger potential but also result in unwanted battery degradation. Unidirectional chargers are more constrained in terms of flexibility, but do not lead to additional battery degradation. We conclude that using a mix of both can combine the advantages of both worlds. Thereby, average private cars can provide the service without any notable additional battery degradation and achieve yearly earnings between EUR 200 and EUR 500, depending on the volatile market prices. Commercial vehicles have an even higher potential, as the results increase with vehicle utilization and consumption. KW - smart charging KW - electric vehicles KW - simulation KW - ancillary services KW - smart grid Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288324 SN - 2032-6653 VL - 13 IS - 9 ER - TY - JOUR A1 - Nyawale, Helmut A. A1 - Moremi, Nyambura A1 - Mohamed, Mohamed A1 - Njwalila, Johnson A1 - Silago, Vitus A1 - Krone, Manuel A1 - Konje, Eveline T. A1 - Mirambo, Mariam M. A1 - Mshana, Stephen E. T1 - High seroprevalence of SARS-CoV-2 in Mwanza, northwestern Tanzania: a population-based survey JF - International Journal of Environmental Research and Public Health N2 - The transmission of the SARS-CoV-2 virus, which causes COVID-19, has been documented worldwide. However, the evidence of the extent to which transmission has occurred in different countries is still to be established. Understanding the magnitude and distribution of SARS-CoV-2 through seroprevalence studies is important in designing control and preventive strategies in communities. This study investigated the seropositivity of the SARS-CoV-2 virus antibodies in the communities of three different districts in the Mwanza region, Tanzania. A household cross-sectional survey was conducted in September 2021 using the modified African Centre for Disease and Prevention (ACDC) survey protocol. A blood sample was obtained from one member of each of the selected households who consented to take part in the survey. Immunochromatographic rapid test kits were used to detect IgM and IgG SARS-CoV-2 antibodies, followed by descriptive data analysis. Overall, 805 participants were enrolled in the study with a median age of 35 (interquartile range (IQR):27–47) years. The overall SARS-CoV-2 seropositivity was 50.4% (95%CI: 46.9–53.8%). The IgG and IgM seropositivity of the SARS-CoV-2 antibodies was 49.3% and 7.2%, respectively, with 6.1% being both IgG and IgM seropositive. A history of runny nose (aOR: 1.84, 95%CI: 1.03–3.5, p = 0.036), loss of taste (aOR: 1.84, 95%CI: 1.12–4.48, p = 0.023), and living in Ukerewe (aOR: 3.55, 95%CI: 1.68–7.47, p = 0.001) and Magu (aOR: 2.89, 95%CI: 1.34–6.25, p= 0.007) were all independently associated with SARS-CoV-2 IgM seropositivity. Out of the studied factors, living in the Ukerewe district was independently associated with IgG seropositivity (aOR 1.29, CI 1.08–1.54, p = 0.004). Twenty months after the first case of COVID-19 in Tanzania, about half of the studied population in Mwanza was seropositive for SARS-CoV-2. KW - SARS-CoV-2 KW - COVID-19 KW - seroprevalence KW - antibodies KW - Mwanza KW - Tanzania Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288134 SN - 1660-4601 VL - 19 IS - 18 ER - TY - JOUR A1 - Tanoey, Justine A1 - Baechle, Christina A1 - Brenner, Hermann A1 - Deckert, Andreas A1 - Fricke, Julia A1 - Günther, Kathrin A1 - Karch, André A1 - Keil, Thomas A1 - Kluttig, Alexander A1 - Leitzmann, Michael A1 - Mikolajczyk, Rafael A1 - Obi, Nadia A1 - Pischon, Tobias A1 - Schikowski, Tamara A1 - Schipf, Sabine M. A1 - Schulze, Matthias B. A1 - Sedlmeier, Anja A1 - Moreno Velásquez, Ilais A1 - Weber, Katharina S. A1 - Völzke, Henry A1 - Ahrens, Wolfgang A1 - Gastell, Sylvia A1 - Holleczek, Bernd A1 - Jöckel, Karl-Heinz A1 - Katzke, Verena A1 - Lieb, Wolfgang A1 - Michels, Karin B. A1 - Schmidt, Börge A1 - Teismann, Henning A1 - Becher, Heiko T1 - Birth order, Caesarean section, or daycare attendance in relation to child- and adult-onset type 1 diabetes: results from the German National Cohort JF - International Journal of Environmental Research and Public Health N2 - (1) Background: Global incidence of type 1 diabetes (T1D) is rising and nearly half occurred in adults. However, it is unclear if certain early-life childhood T1D risk factors were also associated with adult-onset T1D. This study aimed to assess associations between birth order, delivery mode or daycare attendance and type 1 diabetes (T1D) risk in a population-based cohort and whether these were similar for childhood- and adult-onset T1D (cut-off age 15); (2) Methods: Data were obtained from the German National Cohort (NAKO Gesundheitsstudie) baseline assessment. Self-reported diabetes was classified as T1D if: diagnosis age ≤ 40 years and has been receiving insulin treatment since less than one year after diagnosis. Cox regression was applied for T1D risk analysis; (3) Results: Analyses included 101,411 participants (100 childhood- and 271 adult-onset T1D cases). Compared to “only-children”, HRs for second- or later-born individuals were 0.70 (95% CI = 0.50–0.96) and 0.65 (95% CI = 0.45–0.94), respectively, regardless of parental diabetes, migration background, birth year and perinatal factors. In further analyses, higher birth order reduced T1D risk in children and adults born in recent decades. Caesarean section and daycare attendance showed no clear associations with T1D risk; (4) Conclusions: Birth order should be considered in both children and adults’ T1D risk assessment for early detection. KW - perinatal KW - adult-onset KW - late-onset KW - autoimmune KW - delivery mode KW - sex KW - offspring KW - NAKO Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286216 SN - 1660-4601 VL - 19 IS - 17 ER - TY - JOUR A1 - Schaffarczyk, Alois A1 - Koehn, Silas A1 - Oggiano, Luca A1 - Schaffarczyk, Kai T1 - Aerodynamic benefits by optimizing cycling posture JF - Applied Sciences N2 - An approach to aerodynamically optimizing cycling posture and reducing drag in an Ironman (IM) event was elaborated. Therefore, four commonly used positions in cycling were investigated and simulated for a flow velocity of 10 m/s and yaw angles of 0–20° using OpenFoam-based Nabla Flow CFD simulation software software. A cyclist was scanned using an IPhone 12, and a special-purpose meshing software BLENDER was used. Significant differences were observed by changing and optimizing the cyclist’s posture. Aerodynamic drag coefficient (CdA) varies by more than a factor of 2, ranging from 0.214 to 0.450. Within a position, the CdA tends to increase slightly at yaw angles of 5–10° and decrease at higher yaw angles compared to a straight head wind, except for the time trial (TT) position. The results were applied to the IM Hawaii bike course (180 km), estimating a constant power output of 300 W. Including the wind distributions, two different bike split models for performance prediction were applied. Significant time saving of roughly 1 h was found. Finally, a machine learning approach to deduce 3D triangulation for specific body shapes from 2D pictures was tested. KW - aerodynamic drag reduction KW - cycling KW - machine learning KW - drag area Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285942 SN - 2076-3417 VL - 12 IS - 17 ER - TY - JOUR A1 - Reschke, Moritz A1 - Salvador, Ellaine A1 - Schlegel, Nicolas A1 - Burek, Malgorzata A1 - Karnati, Srikanth A1 - Wunder, Christian A1 - Förster, Carola Y. T1 - Isosteviol sodium (STVNA) reduces pro-inflammatory cytokine IL-6 and GM-CSF in an in vitro murine stroke model of the blood–brain barrier (BBB) JF - Pharmaceutics N2 - Early treatment with glucocorticoids could help reduce both cytotoxic and vasogenic edema, leading to improved clinical outcome after stroke. In our previous study, isosteviol sodium (STVNA) demonstrated neuroprotective effects in an in vitro stroke model, which utilizes oxygen-glucose deprivation (OGD). Herein, we tested the hypothesis that STVNA can activate glucocorticoid receptor (GR) transcriptional activity in brain microvascular endothelial cells (BMECs) as previously published for T cells. STVNA exhibited no effects on transcriptional activation of the glucocorticoid receptor, contrary to previous reports in Jurkat cells. However, similar to dexamethasone, STVNA inhibited inflammatory marker IL-6 as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. Based on these results, STVNA proves to be beneficial as a possible prevention and treatment modality for brain ischemia-reperfusion injury-induced blood–brain barrier (BBB) dysfunction. KW - IL-6 KW - ischemia KW - isosteviol sodium (STVNA) KW - dexamethasone KW - glucocorticoid receptor KW - cerebEND Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286275 SN - 1999-4923 VL - 14 IS - 9 ER - TY - JOUR A1 - Floren, Andreas A1 - Linsenmair, Karl Eduard A1 - Müller, Tobias T1 - Diversity and functional relevance of canopy arthropods in Central Europe JF - Diversity N2 - Although much is known about the ecology and functional importance of canopy arthropods in temperate forests, few studies have tried to assess the overall diversity and investigate the composition and dynamics of tree-specific communities. This has impeded a deeper understanding of the functioning of forests, and of how to maintain system services. Here, we present the first comprehensive data of whole arthropod communities, collected by insecticidal knockdown (fogging) from 1159 trees in 18 study areas in Central Europe during the last 25 years. The data includes 3,253,591 arthropods from 32 taxa (order, suborder, family) collected on 24 tree species from 18 genera. Fogging collects free-living, ectophytic arthropods in approximately the same number as they occur in the trees. To our knowledge, these are the most comprehensive data available today on the taxonomic composition of arboreal fauna. Assigning all arthropods to their feeding guild provided a proxy of their functional importance. The data showed that the canopy communities were regularly structured, with a clear dominance hierarchy comprised of eight ‘major taxa’ that represented 87% of all arthropods. Despite significant differences in the proportions of taxa on deciduous and coniferous trees, the composition of the guilds was very similar. The individual tree genera, on the other hand, showed significant differences in guild composition, especially when different study areas and years were compared, whereas tree-specific traits, such as tree height, girth in breast height or leaf cover, explained little of the overall variance. On the ordinal level, guild composition also differed significantly between managed and primary forests, with a simultaneous low within-group variability, indicating that management is a key factor determining the distribution of biodiversity and guild composition. KW - temperate forests KW - insecticidal knockdown KW - community structure KW - functional diversity KW - guild constancy KW - forest management KW - pristine forests KW - Bialowieza Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285924 SN - 1424-2818 VL - 14 IS - 8 ER -