@article{FeldheimWendLaueretal.2022, author = {Feldheim, Jonas and Wend, David and Lauer, Mara J. and Monoranu, Camelia M. and Glas, Martin and Kleinschnitz, Christoph and Ernestus, Ralf-Ingo and Braunger, Barbara M. and Meybohm, Patrick and Hagemann, Carsten and Burek, Malgorzata}, title = {Protocadherin Gamma C3 (PCDHGC3) is strongly expressed in glioblastoma and its high expression is associated with longer progression-free survival of patients}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {15}, issn = {1422-0067}, doi = {10.3390/ijms23158101}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284433}, year = {2022}, abstract = {Protocadherins (PCDHs) belong to the cadherin superfamily and represent the largest subgroup of calcium-dependent adhesion molecules. In the genome, most PCDHs are arranged in three clusters, α, β, and γ on chromosome 5q31. PCDHs are highly expressed in the central nervous system (CNS). Several PCDHs have tumor suppressor functions, but their individual role in primary brain tumors has not yet been elucidated. Here, we examined the mRNA expression of PCDHGC3, a member of the PCDHγ cluster, in non-cancerous brain tissue and in gliomas of different World Health Organization (WHO) grades and correlated it with the clinical data of the patients. We generated a PCDHGC3 knockout U343 cell line and examined its growth rate and migration in a wound healing assay. We showed that PCDHGC3 mRNA and protein were significantly overexpressed in glioma tissue compared to a non-cancerous brain specimen. This could be confirmed in glioma cell lines. High PCDHGC3 mRNA expression correlated with longer progression-free survival (PFS) in glioma patients. PCDHGC3 knockout in U343 resulted in a slower growth rate but a significantly faster migration rate in the wound healing assay and decreased the expression of several genes involved in WNT signaling. PCDHGC3 expression should therefore be further investigated as a PFS-marker in gliomas. However, more studies are needed to elucidate the molecular mechanisms underlying the PCDHGC3 effects.}, language = {en} } @incollection{LutStarenkova2022, author = {Lut, Kateryna and Starenkova, Hanna}, title = {The Relationship between Language, Culture, and Development of Society}, series = {Studies in Modern English}, booktitle = {Studies in Modern English}, editor = {Lazebna, Nataliia and Kumar, Dinesh}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, doi = {10.25972/WUP-978-3-95826-199-0-63}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-296484}, publisher = {W{\"u}rzburg University Press}, pages = {63-72}, year = {2022}, abstract = {The paper analyses specific characteristics of language that influence the development of culture and societies. The problem of the connection between language and culture has occupied the minds of many famous scientists: some believe that language is a part of the culture as a whole; others think that language is only a form of cultural expression. Undoubtedly, language constitutes a vital component of the cultural background underlying social development. Language is an essential means of communication and interaction. However, language is at the same time sovereign about culture as a whole and can be separate from culture or compared to culture as an equal element (i.e., that language is neither a form nor a component of culture).}, language = {en} } @article{WenckerMarincolaSchoenfelderetal.2021, author = {Wencker, Freya D. R and Marincola, Gabriella and Schoenfelder, Sonja M. K. and Maaß, Sandra and Becher, D{\"o}rte and Ziebuhr, Wilma}, title = {Another layer of complexity in Staphylococcus aureus methionine biosynthesis control: unusual RNase III-driven T-box riboswitch cleavage determines met operon mRNA stability and decay}, series = {Nucleic Acids Research}, volume = {49}, journal = {Nucleic Acids Research}, number = {4}, doi = {10.1093/nar/gkaa1277}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259029}, pages = {2192-2212}, year = {2021}, abstract = {In Staphylococcus aureus, de novo methionine biosynthesis is regulated by a unique hierarchical pathway involving stringent-response controlled CodY repression in combination with a T-box riboswitch and RNA decay. The T-box riboswitch residing in the 5′ untranslated region (met leader RNA) of the S. aureus metICFE-mdh operon controls downstream gene transcription upon interaction with uncharged methionyl-tRNA. met leader and metICFE-mdh (m)RNAs undergo RNase-mediated degradation in a process whose molecular details are poorly understood. Here we determined the secondary structure of the met leader RNA and found the element to harbor, beyond other conserved T-box riboswitch structural features, a terminator helix which is target for RNase III endoribonucleolytic cleavage. As the terminator is a thermodynamically highly stable structure, it also forms posttranscriptionally in met leader/ metICFE-mdh read-through transcripts. Cleavage by RNase III releases the met leader from metICFE-mdh mRNA and initiates RNase J-mediated degradation of the mRNA from the 5′-end. Of note, metICFE-mdh mRNA stability varies over the length of the transcript with a longer lifespan towards the 3′-end. The obtained data suggest that coordinated RNA decay represents another checkpoint in a complex regulatory network that adjusts costly methionine biosynthesis to current metabolic requirements.}, language = {en} } @phdthesis{Adenugba2021, author = {Adenugba, Akinbami Raphael}, title = {Functional analysis of the gene organization of the pneumoviral attachment protein G}, doi = {10.25972/OPUS-12814}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128146}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {The putative attachment protein G of pneumonia virus of mice (PVM), a member of the Pneumoviruses, is an important virulence factor with so far ambiguous function in a virus-cell as well as in virus-host context. The sequence of the corresponding G gene is characterized by significant heterogeneity between and even within strains, affecting the gene and possibly the protein structure. This accounts in particular for the PVM strain J3666 for which two differing G gene organizations have been described: a polymorphism in nucleotide 65 of the G gene results in the presence of an upstream open reading frame (uORF) that precedes the main ORF in frame (GJ366665A) or extension of the major G ORF for 18 codons (GJ366665U). Therefore, this study was designed to analyse the impact of the sequence variations in the respective G genes of PVM strains J3666 and the reference strain 15 on protein expression, replication and virulence. First, the controversy regarding the consensus sequence of PVM J3666 was resolved. The analysis of 45 distinct cloned fragments showed that the strain separated into two distinct virus populations defined by the sequence and structure of the G gene. This division was further supported by nucleotide polymorphisms in the neighbouring M and SH genes. Sequential passage of this mixed strain in the cell line standardly used for propagation of virus stocks resulted in selection for the GJ366665A-containing population in one of two experiments pointing towards a moderate replicative advantage. The replacement of the G gene of the recombinant PVM 15 with GJ366665A or GJ366665U, respectively, using a reverse genetic approach indicated that the presence of uORF within the GJ366665A significantly reduced the expression of the main G ORF on translational level while the potential extension of the ORF in GJ366665U increased G protein expression. In comparison, the effect of the G gene-structure on virus replication was inconsistent and dependent on cell line and type. While the presence of uORF correlated with a replication advantage in the standardly used BHK-21 cells and primary murine embryonic fibroblasts, replication in the murine macrophage cell line RAW 264.7 did not. In comparison, the GJ366665U variant was not associated with any effect on replication in cultured cells at all. Nonetheless, in-vivo analysis of the recombinant viruses associated the GJ366665U gene variant, and hence an increased G expression, with higher virulence whereas the GJ366665A gene, and therefore an impaired G expression, conferred an attenuated phenotype to the virus. To extend the study to other G gene organizations, a recombinant PVM expressing a G protein without the cytoplasmic domain and for comparison a G-deletion mutant, both known to be attenuated in vivo, were studied. Not noticed before, this structure of the G gene was associated with a 75\% reduction in G protein expression and a significant attenuation of replication in macrophage-like cells. This attenuation was even more prominent for the virus lacking G. Taking into consideration the higher reduction in G protein levels compared to the GJ366665A variant indicates that a threshold amount of G is required for efficient replication in these cells. In conclusion, the results gathered indicated that the expression levels of the G protein were modulated by the sequence of the 5' untranslated region of the gene. At the same time the G protein levels modulated the virulence of PVM.}, subject = {G glycoprotein}, language = {en} } @article{WhisnantJuergesHennigetal.2020, author = {Whisnant, Adam W. and J{\"u}rges, Christopher S. and Hennig, Thomas and Wyler, Emanuel and Prusty, Bhupesh and Rutkowski, Andrzej J. and L'hernault, Anne and Djakovic, Lara and G{\"o}bel, Margarete and D{\"o}ring, Kristina and Menegatti, Jennifer and Antrobus, Robin and Matheson, Nicholas J. and K{\"u}nzig, Florian W. H. and Mastrobuoni, Guido and Bielow, Chris and Kempa, Stefan and Liang, Chunguang and Dandekar, Thomas and Zimmer, Ralf and Landthaler, Markus and Gr{\"a}sser, Friedrich and Lehner, Paul J. and Friedel, Caroline C. and Erhard, Florian and D{\"o}lken, Lars}, title = {Integrative functional genomics decodes herpes simplex virus 1}, series = {Nature Communications}, volume = {11}, journal = {Nature Communications}, doi = {10.1038/s41467-020-15992-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229884}, year = {2020}, abstract = {The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDA-approved oncolytic virus Imlygic. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of ORFs as well as N-terminal extensions (NTEs) and truncations. We show that NTEs with non-canonical start codons govern the subcellular protein localization and packaging of key viral regulators and structural proteins. We extend the current nomenclature to include all viral gene products and provide a genome browser that visualizes all the obtained data from whole genome to single-nucleotide resolution. Here, using computational integration of multi-omics data, the authors provide a detailed transcriptome and translatome of herpes simplex virus 1 (HSV-1), including previously unidentified ORFs and N-terminal extensions. The study also provides a HSV-1 genome browser and should be a valuable resource for further research.}, language = {en} } @article{EvdokimovDinkelFranketal.2020, author = {Evdokimov, Dimitar and Dinkel, Philine and Frank, Johanna and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Characterization of dermal skin innervation in fibromyalgia syndrome}, series = {PLoS One}, volume = {15}, journal = {PLoS One}, number = {1}, doi = {10.1371/journal.pone.0227674}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229299}, year = {2020}, abstract = {Introduction We characterized dermal innervation in patients with fibromyalgia syndrome (FMS) as potential contribution to small fiber pathology. Methods Skin biopsies of the calf were collected (86 FMS patients, 35 healthy controls). Skin was immunoreacted with antibodies against protein gene product 9.5, calcitonine gene-related peptide, substance P, CD31, and neurofilament 200 for small fiber subtypes. We assessed two skin sections per patient; on each skin section, two dermal areas (150 x 700 mu m each) were investigated for dermal nerve fiber length (DNFL). Results In FMS patients we found reduced DNFL of fibers with vessel contact compared to healthy controls (p<0.05). There were no differences for the other nerve fiber subtypes. Discussion We found less dermal nerve fibers in contact with blood vessels in FMS patients than in controls. The pathophysiological relevance of this finding is unclear, but we suggest the possibility of a relationship with impaired thermal tolerance commonly reported by FMS patients.}, language = {en} } @article{FeldheimKesslerSchmittetal.2020, author = {Feldheim, Jonas and Kessler, Almuth F. and Schmitt, Dominik and Salvador, Ellaine and Monoranu, Camelia M. and Feldheim, Julia J. and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Hagemann, Carsten}, title = {Ribosomal Protein S27/Metallopanstimulin-1 (RPS27) in Glioma — A New Disease Biomarker?}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {5}, issn = {2072-6694}, doi = {10.3390/cancers12051085}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203648}, year = {2020}, abstract = {Despite its significant overexpression in several malignant neoplasms, the expression of RPS27 in the central nervous system (CNS) is widely unknown. We identified the cell types expressing RPS27 in the CNS under normal and disease conditions. We acquired specimens of healthy brain (NB), adult pilocytic astrocytoma (PA) World Health Organization (WHO) grade I, anaplastic PA WHO grade III, gliomas WHO grade II/III with or without isocitrate dehydrogenase (IDH) mutation, and glioblastoma multiforme (GBM). RPS27 protein expression was examined by immunohistochemistry and double-fluorescence staining and its mRNA expression quantified by RT-PCR. Patients' clinical and tumor characteristics were collected retrospectively. RPS27 protein was specifically expressed in tumor cells and neurons, but not in healthy astrocytes. In tumor tissue, most macrophages were positive, while this was rarely the case in inflamed tissue. Compared to NB, RPS27 mRNA was in mean 6.2- and 8.8-fold enhanced in gliomas WHO grade II/III with (p < 0.01) and without IDH mutation (p = 0.01), respectively. GBM displayed a 4.6-fold increased mean expression (p = 0.02). Although RPS27 expression levels did not affect the patients' survival, their association with tumor cells and tumor-associated macrophages provides a rationale for a future investigation of a potential function during gliomagenesis and tumor immune response.}, language = {en} } @article{BakhtiarizadehHosseinpourShahhoseinietal.2018, author = {Bakhtiarizadeh, Mohammad Reza and Hosseinpour, Batool and Shahhoseini, Maryam and Korte, Arthur and Gifani, Peyman}, title = {Weighted gene co-expression network analysis of endometriosis and identification of functional modules associated with its main hallmarks}, series = {Frontiers in Genetics}, volume = {9}, journal = {Frontiers in Genetics}, number = {453}, doi = {10.3389/fgene.2018.00453}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177376}, year = {2018}, abstract = {Although many genes have been identified using high throughput technologies in endometriosis (ES), only a small number of individual genes have been analyzed functionally. This is due to the complexity of the disease that has different stages and is affected by various genetic and environmental factors. Many genes are upregulated or downregulated at each stage of the disease, thus making it difficult to identify key genes. In addition, little is known about the differences between the different stages of the disease. We assumed that the study of the identified genes in ES at a system-level can help to better understand the molecular mechanism of the disease at different stages of the development. We used publicly available microarray data containing archived endometrial samples from women with minimal/mild endometriosis (MMES), mild/severe endometriosis (MSES) and without endometriosis. Using weighted gene co-expression analysis (WGCNA), functional modules were derived from normal endometrium (NEM) as the reference sample. Subsequently, we tested whether the topology or connectivity pattern of the modules was preserved in MMES and/or MSES. Common and specific hub genes were identified in non-preserved modules. Accordingly, hub genes were detected in the non-preserved modules at each stage. We identified sixteen co-expression modules. Of the 16 modules, nine were non-preserved in both MMES and MSES whereas five were preserved in NEM, MMES, and MSES. Importantly, two non-preserved modules were found in either MMES or MSES, highlighting differences between the two stages of the disease. Analyzing the hub genes in the non-preserved modules showed that they mostly lost or gained their centrality in NEM after developing the disease into MMES and MSES. The same scenario was observed, when the severeness of the disease switched from MMES to MSES. Interestingly, the expression analysis of the new selected gene candidates including CC2D2A, AEBP1, HOXB6, IER3, and STX18 as well as IGF-1, CYP11A1 and MMP-2 could validate such shifts between different stages. The overrepresented gene ontology (GO) terms were enriched in specific modules, such as genetic disposition, estrogen dependence, progesterone resistance and inflammation, which are known as endometriosis hallmarks. Some modules uncovered novel co-expressed gene clusters that were not previously discovered.}, language = {en} } @article{KumarNaumannAigneretal.2015, author = {Kumar, Praveen and Naumann, Ulrike and Aigner, Ludwig and Wischhusen, Joerg and Beier, Christoph P and Beier, Dagmar}, title = {Impaired TGF-β induced growth inhibition contributes to the increased proliferation rate of neural stem cells harboring mutant p53}, series = {American Journal of Cancer Research}, volume = {5}, journal = {American Journal of Cancer Research}, number = {11}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144262}, pages = {3436-3445}, year = {2015}, abstract = {Gliomas have been classified according to their histological properties. However, their respective cells of origin are still unknown. Neural progenitor cells (NPC) from the subventricular zone (SVZ) can initiate tumors in murine models of glioma and are likely cells of origin in the human disease. In both, p53 signaling is often functionally impaired which may contribute to tumor formation. Also, TGF-beta, which under physiological conditions exerts a strong control on the proliferation of NPCs in the SVZ, is a potent mitogen on glioma cells. Here, we approach on the crosstalk between p53 and TGF-beta by loss of function experiments using NPCs derived from p53 mutant mice, as well as pharmacological inhibition of TGF-beta signaling using TGF-beta receptor inhibitors. NPC derived from p53 mutant mice showed increased clonogenicity and more rapid proliferation than their wildtype counterparts. Further, NPC derived from p53\(^{mut/mut}\) mice were insensitive to TGF-beta induced growth arrest. Still, the canonical TGF-beta signaling pathway remained functional in the absence of p53 signaling and expression of key proteins as well as phosphorylation and nuclear translocation of SMAD2 were unaltered. TGF-beta-induced p21 expression could, in contrast, only be detected in p53\(^{wt/wt}\) but not in p53\(^{mut/mut}\) NPC. Conversely, inhibition of TGF-beta signaling using SB431542 increased proliferation of p53\(^{wt/wt}\) but not of p53\(^{mut/mut}\) NPC. In conclusion, our data suggest that the TGF-beta induced growth arrest in NPC depends on functional p53. Mutational inactivation of p53 hence contributes to increased proliferation of NPC and likely to the formation of hyperplasia of the SVZ observed in p53 deficient mice in vivo.}, language = {en} } @article{GarciaMartinezBrunkAvalosetal.2015, author = {Garc{\´i}a-Mart{\´i}nez, Jorge and Brunk, Michael and Avalos, Javier and Terpitz, Ulrich}, title = {The CarO rhodopsin of the fungus Fusarium fujikuroi is a light-driven proton pump that retards spore germination}, series = {Scientific Reports}, volume = {5}, journal = {Scientific Reports}, number = {7798}, doi = {10.1038/srep07798}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149049}, year = {2015}, abstract = {Rhodopsins are membrane-embedded photoreceptors found in all major taxonomic kingdoms using retinal as their chromophore. They play well-known functions in different biological systems, but their roles in fungi remain unknown. The filamentous fungus Fusarium fujikuroi contains two putative rhodopsins, CarO and OpsA. The gene carO is light-regulated, and the predicted polypeptide contains all conserved residues required for proton pumping. We aimed to elucidate the expression and cellular location of the fungal rhodopsin CarO, its presumed proton-pumping activity and the possible effect of such function on F. fujikuroi growth. In electrophysiology experiments we confirmed that CarO is a green-light driven proton pump. Visualization of fluorescent CarO-YFP expressed in F. fujikuroi under control of its native promoter revealed higher accumulation in spores (conidia) produced by light-exposed mycelia. Germination analyses of conidia from carO\(^{-}\) mutant and carO\(^{+}\) control strains showed a faster development of light-exposed carO-germlings. In conclusion, CarO is an active proton pump, abundant in light-formed conidia, whose activity slows down early hyphal development under light. Interestingly, CarO-related rhodopsins are typically found in plant-associated fungi, where green light dominates the phyllosphere. Our data provide the first reliable clue on a possible biological role of a fungal rhodopsin.}, language = {en} }