@article{AlsheimerLinkJahnetal.2013,
  author    = {Alsheimer, Manfred and Link, Jana and Jahn, Daniel and Schmitt, Johannes and G{\"o}b, Eva and Baar, Johannes and Ortega, Sagrario and Benavente, Ricardo},
  title     = {The Meiotic Nuclear Lamina Regulates Chromosome Dynamics and Promotes Efficient Homologous Recombination in the Mouse},
  series = {PLoS Genetics},
  journal   = {PLoS Genetics},
  doi       = {10.1371/journal.pgen.1003261},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96285},
  year      = {2013},
  abstract  = {The nuclear lamina is the structural scaffold of the nuclear envelope and is well known for its central role in nuclear organization and maintaining nuclear stability and shape. In the past, a number of severe human disorders have been identified to be associated with mutations in lamins. Extensive research on this topic has provided novel important clues about nuclear lamina function. These studies have contributed to the knowledge that the lamina constitutes a complex multifunctional platform combining both structural and regulatory functions. Here, we report that, in addition to the previously demonstrated significance for somatic cell differentiation and maintenance, the nuclear lamina is also an essential determinant for germ cell development. Both male and female mice lacking the short meiosis-specific A-type lamin C2 have a severely defective meiosis, which at least in the male results in infertility. Detailed analysis revealed that lamin C2 is required for telomere-driven dynamic repositioning of meiotic chromosomes. Loss of lamin C2 affects precise synapsis of the homologs and interferes with meiotic double-strand break repair. Taken together, our data explain how the nuclear lamina contributes to meiotic chromosome behaviour and accurate genome haploidization on a mechanistic level.},
  language  = {en}
}
@article{BankogluTschoppSchmittetal.2016,
  author    = {Bankoglu, Ezgi Eyluel and Tschopp, Oliver and Schmitt, Johannes and Burkard, Philipp and Jahn, Daniel and Geier, Andreas and Stopper, Helga},
  title     = {Role of PTEN in Oxidative Stress and DNA Damage in the Liver of Whole-Body Pten Haplodeficient Mice},
  series = {PLoS One},
  volume    = {11},
  journal   = {PLoS One},
  number    = {11},
  doi       = {10.1371/journal.pone.0166956},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146970},
  pages     = {e0166956},
  year      = {2016},
  abstract  = {Type 2 diabetes (T2DM) and obesity are frequently associated with non-alcoholic fatty liver disease (NAFLD) and with an elevated cancer incidence. The molecular mechanisms of carcinogenesis in this context are only partially understood. High blood insulin levels are typical in early T2DM and excessive insulin can cause elevated reactive oxygen species (ROS) production and genomic instability. ROS are important for various cellular functions in signaling and host defense. However, elevated ROS formation is thought to be involved in cancer induction. In the molecular events from insulin receptor binding to genomic damage, some signaling steps have been identified, pointing at the PI3K/AKT pathway. For further elucidation Phosphatase and Tensin homolog (Pten), a tumour suppressor phosphatase that plays a role in insulin signaling by negative regulation of PI3K/AKT and its downstream targets, was investigated here. Dihydroethidium (DHE) staining was used to detect ROS formation in immortalized human hepatocytes. Comet assay and micronucleus test were performed to investigate genomic damage in vitro. In liver samples, DHE staining and western blot detection of HSP70 and HO-1 were performed to evaluate oxidative stress response. DNA double strand breaks (DSBs) were detected by immunohistostaining. Inhibition of PTEN with the pharmacologic inhibitor VO-OHpic resulted in increased ROS production and genomic damage in a liver cell line. Knockdown of Pten in a mouse model yielded increased oxidative stress levels, detected by ROS levels and expression of the two stress-proteins HSP70 and HO-1 and elevated genomic damage in the liver, which was significant in mice fed with a high fat diet. We conclude that PTEN is involved in oxidative stress and genomic damage induction in vitro and that this may also explain the in vivo observations. This further supports the hypothesis that the PI3K/AKT pathway is responsible for damaging effects of high levels of insulin.},
  language  = {en}
}
@article{BeckerRauSchmittetal.2015,
  author    = {Becker, Philip P. and Rau, Monika and Schmitt, Johannes and Malsch, Carolin and Hammer, Christian and Bantel, Heike and M{\"u}llhaupt, Beat and Geier, Andreas},
  title     = {Performance of serum microRNAs -122, -192 and -21 as biomarkers in patients with non-alcoholic steatohepatitis},
  series = {PLoS ONE},
  volume    = {10},
  journal   = {PLoS ONE},
  number    = {11},
  doi       = {10.1371/journal.pone.0142661},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145147},
  pages     = {e0142661},
  year      = {2015},
  abstract  = {Objectives Liver biopsies are the current gold standard in non-alcoholic steatohepatitis (NASH) diagnosis. Their invasive nature, however, still carries an increased risk for patients' health. The development of non-invasive diagnostic tools to differentiate between bland steatosis (NAFL) and NASH remains crucial. The aim of this study is the evaluation of investigated circulating microRNAs in combination with new targets in order to optimize the discrimination of NASH patients by non-invasive serum biomarkers. Methods Serum profiles of four microRNAs were evaluated in two cohorts consisting of 137 NAFLD patients and 61 healthy controls. In a binary logistic regression model microRNAs of relevance were detected. Correlation of microRNA appearance with known biomarkers like ALT and CK18-Asp396 was evaluated. A simplified scoring model was developed, combining the levels of microRNA in circulation and CK18-Asp396 fragments. Receiver operating characteristics were used to evaluate the potential of discriminating NASH. Results The new finding of our study is the different profile of circulating miR-21 in NASH patients (p<0.0001). Also, it validates recently published results of miR-122 and miR-192 to be differentially regulated in NAFL and NASH. Combined microRNA expression profiles with CK18-Asp396 fragment level scoring model had a higher potential of NASH prediction compared to other risk biomarkers (AUROC = 0.83, 95\% CI = 0.754-0.908; p<0.001). Evaluation of score model for NAFL (Score = 0) and NASH (Score = 4) had shown high rates of sensitivity (91\%) and specificity (83\%). Conclusions Our study defines candidates for a combined model of miRNAs and CK18-Asp396 levels relevant as a promising expansion for diagnosis and in turn treatment of NASH.},
  language  = {en}
}
@article{GoebSchmittBenaventeetal.2010,
  author    = {Goeb, Eva and Schmitt, Johannes and Benavente, Ricardo and Alsheimer, Manfred},
  title     = {Mammalian Sperm Head Formation Involves Different Polarization of Two Novel LINC Complexes},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68449},
  year      = {2010},
  abstract  = {Background: LINC complexes are nuclear envelope bridging protein structures formed by interaction of SUN and KASH proteins. They physically connect the nucleus with the peripheral cytoskeleton and are critically involved in a variety of dynamic processes, such as nuclear anchorage, movement and positioning and meiotic chromosome dynamics. Moreover, they are shown to be essential for maintaining nuclear shape. Findings: Based on detailed expression analysis and biochemical approaches, we show here that during mouse sperm development, a terminal cell differentiation process characterized by profound morphogenic restructuring, two novel distinctive LINC complexes are established. They consist either of spermiogenesis-specific Sun3 and Nesprin1 or Sun1g, a novel non-nuclear Sun1 isoform, and Nesprin3. We could find that these two LINC complexes specifically polarize to opposite spermatid poles likely linking to sperm-specific cytoskeletal structures. Although, as shown in co-transfection / immunoprecipitation experiments, SUN proteins appear to arbitrarily interact with various KASH partners, our study demonstrates that they actually are able to confine their binding to form distinct LINC complexes. Conclusions: Formation of the mammalian sperm head involves assembly and different polarization of two novel spermiogenesis-specific LINC complexes. Together, our findings suggest that theses LINC complexes connect the differentiating spermatid nucleus to surrounding cytoskeletal structures to enable its well-directed shaping and elongation, which in turn is a critical parameter for male fertility.},
  subject      = {Sperma},
  language  = {en}
}
@article{StrubeBlossBrownSpaetheetal.2015,
  author    = {Strube-Bloss, Martin F. and Brown, Austin and Spaethe, Johannes and Schmitt, Thomas and R{\"o}ssler, Wolfgang},
  title     = {Extracting the Behaviorally Relevant Stimulus: Unique Neural Representation of Farnesol, a Component of the Recruitment Pheromone of Bombus terrestris},
  series = {PLoS One},
  volume    = {10},
  journal   = {PLoS One},
  number    = {9},
  doi       = {10.1371/journal.pone.0137413},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125875},
  pages     = {e0137413},
  year      = {2015},
  abstract  = {To trigger innate behavior, sensory neural networks are pre-tuned to extract biologically relevant stimuli. Many male-female or insect-plant interactions depend on this phenomenon. Especially communication among individuals within social groups depends on innate behaviors. One example is the efficient recruitment of nest mates by successful bumblebee foragers. Returning foragers release a recruitment pheromone in the nest while they perform a 'dance' behavior to activate unemployed nest mates. A major component of this pheromone is the sesquiterpenoid farnesol. How farnesol is processed and perceived by the olfactory system, has not yet been identified. It is much likely that processing farnesol involves an innate mechanism for the extraction of relevant information to trigger a fast and reliable behavioral response. To test this hypothesis, we used population response analyses of 100 antennal lobe (AL) neurons recorded in alive bumblebee workers under repeated stimulation with four behaviorally different, but chemically related odorants (geraniol, citronellol, citronellal and farnesol). The analysis identified a unique neural representation of the recruitment pheromone component compared to the other odorants that are predominantly emitted by flowers. The farnesol induced population activity in the AL allowed a reliable separation of farnesol from all other chemically related odor stimuli we tested. We conclude that the farnesol induced population activity may reflect a predetermined representation within the AL-neural network allowing efficient and fast extraction of a behaviorally relevant stimulus. Furthermore, the results show that population response analyses of multiple single AL-units may provide a powerful tool to identify distinct representations of behaviorally relevant odors.},
  language  = {en}
}
@phdthesis{Schmitt2008,
  author    = {Schmitt, Johannes},
  title     = {Proteine der Kernh{\"u}lle und deren Rolle bei der Umgestaltung des Zellkerns meiotischer und postmeiotischer Zellen von S{\"a}ugern},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-31203},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2008},
  abstract  = {W{\"a}hrend der Spermatogenese finden erstaunliche Differenzierungsprozessen statt. Reguliert wird die Spermatogenese sowohl hormonell als auch durch Wechselwirkungen zwischen verschiedenen Zelltypen und der extrazellul{\"a}rer Matrix. Unterteilt wird die Spermatogenese in drei funktionelle Einheiten. Die Proliferationsphase, die Meiose und die Spermiogenese. Im Laufe der Proliferationsphase gehen aus den Spermatogonien, Spermatocyten hervor, die die Meiose durchlaufen. W{\"a}hrend der Prophase I der Meiose kommt es zur Reduktion und Rekombination des genetischen Materials, was mit charakteristischen und h{\"o}chst dynamischen Bewegungsvorg{\"a}ngen der Telomere einhergeht. Auf die Meiose folgt die Spermiogenese, in der das genetische Material in seine „Transportform" {\"u}berf{\"u}hrt wird und aus einer station{\"a}ren, zellverbundenen Einheit ein mobiles autark funktionierendes Vehikel des genetischen Materials wird; das Spermium. Um das Verst{\"a}ndnis dieser Vorg{\"a}nge zu erweitern wurden in dieser Arbeit die Verteilungsmuster einiger Proteine in der Kernh{\"u}lle von Zellen der Spermatogenese, in Hinblick auf ihre dynamische Umverteilung untersucht. Bei diesen Proteinen handelte es sich um die SUN-Dom{\"a}nen Proteine und das meiosespezifische Lamin C2. Die SUN-Dom{\"a}nen Proteine sind Teil des membrandurchspannenden LINC-Komplexes, der Komponenten des Nukleoplasma mit denen des Cytoplasma verbindet. In dieser Arbeit konnte gezeigt werden, dass die SUN-Dom{\"a}nen Proteine, Sun1 und Sun2 w{\"a}hrend der Meiose exprimiert werden, und an den Anheftungsplatten meiotischer Chromosomen lokalisieren und deren dynamisches Verteilungsmuster dem Verteilungsmuster der Telomere w{\"a}hrend der Prophase I der Meiose entsprechen. Dies deutet darauf hin, dass Sun1 und Sun2 eine tragende Rolle, w{\"a}hrend der koordinierten Bewegungsprozessen der Prophase I der Meiose spielen. In der Spermiogenese sind die SUN-Dom{\"a}nen Proteine, Sun1 und Sun3 vertreten. Dabei weist deren unterschiedliche Lokalisation an entgegengesetzten Zellpolen darauf hin, dass Sun1 und Sun3 m{\"o}glicherweise unterschiedliche Funktionen bei der Umgestaltung des Spermienkopfes w{\"a}hrend der Spermiogenese erf{\"u}llen. Ein weiterer Schwerpunkt dieser Arbeit war die Etablierung einer Mauslinie um die Rolle von Lamin C2 in der Meiose untersuchen zu k{\"o}nnen. Hierzu wurde eine Lamin C2 Knock-out Studie begonnen. In ersten Untersuchungen der knock-out Tiere konnte eine Gr{\"o}ßenreduktion der Hoden beobachtet werden. Ebenso konnte ein Abbruch der Meiose vermerkt werden. Die Ergebnisse dieser Arbeit verdeutlichen, dass sowohl die SUN-Dom{\"a}nen Proteine, als auch Lamin C2, wichtige Rollen in dem komplexen Arrangement der Spermatogenese {\"u}bernehmen.},
  subject      = {Meiose},
  language  = {de}
}
@article{AlsheimerLinkLeubneretal.2014,
  author    = {Alsheimer, Manfred and Link, Jana and Leubner, Monika and Schmitt, Johannes and G{\"o}b, Eva and Benavente, Ricardo and Jeang, Kuan-Teh and Xu, Rener},
  title     = {Analysis of Meiosis in SUN1 Deficient Mice Reveals a Distinct Role of SUN2 in Mammalian Meiotic LINC Complex Formation and Function},
  doi       = {10.1371/journal.pgen.1004099},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111355},
  year      = {2014},
  abstract  = {LINC complexes are evolutionarily conserved nuclear envelope bridges, composed of SUN (Sad-1/UNC-84) and KASH (Klarsicht/ANC-1/Syne/homology) domain proteins. They are crucial for nuclear positioning and nuclear shape determination, and also mediate nuclear envelope (NE) attachment of meiotic telomeres, essential for driving homolog synapsis and recombination. In mice, SUN1 and SUN2 are the only SUN domain proteins expressed during meiosis, sharing their localization with meiosis-specific KASH5. Recent studies have shown that loss of SUN1 severely interferes with meiotic processes. Absence of SUN1 provokes defective telomere attachment and causes infertility. Here, we report that meiotic telomere attachment is not entirely lost in mice deficient for SUN1, but numerous telomeres are still attached to the NE through SUN2/KASH5-LINC complexes. In Sun12/2 meiocytes attached telomeres retained the capacity to form bouquetlike clusters. Furthermore, we could detect significant numbers of late meiotic recombination events in Sun12/2 mice. Together, this indicates that even in the absence of SUN1 telomere attachment and their movement within the nuclear envelope per se can be functional. Author summary: Correct genome haploidization during meiosis requires tightly regulated chromosome movements that follow a highly conserved choreography during prophase I. Errors in these movements cause subsequent meiotic defects, which typically lead to infertility. At the beginning of meiotic prophase, chromosome ends are tethered to the nuclear envelope (NE). This attachment of telomeres appears to be mediated by well-conserved membrane spanning protein complexes within the NE (LINC complexes). In mouse meiosis, the two main LINC components SUN1 and SUN2 were independently described to localize at the sites of telomere attachment. While SUN1 has been demonstrated to be critical for meiotic telomere attachment, the precise role of SUN2 in this context, however, has been discussed controversially in the field. Our current study was targeted to determine the factual capacity of SUN2 in telomere attachment and chromosome movements in SUN1 deficient mice. Remarkably, although telomere attachment is impaired in the absence of SUN1, we could find a yet undescribed SUN1-independent telomere attachment, which presumably is mediated by SUN2 and KASH5. This SUN2 mediated telomere attachment is stable throughout prophase I and functional in moving telomeres within the NE. Thus, our results clearly indicate that SUN1 and SUN2, at least partially, fulfill redundant meiotic functions.},
  language  = {en}
}
@article{EliasHeuschmannSchmittetal.2013,
  author    = {Elias, Johannes and Heuschmann, Peter U. and Schmitt, Corinna and Eckhardt, Frithjof and Boehm, Hartmut and Maier, Sebastian and Kolb-M{\"a}urer, Annette and Riedmiller, Hubertus and M{\"u}llges, Wolfgang and Weisser, Christoph and Wunder, Christian and Frosch, Matthias and Vogel, Ulrich},
  title     = {Prevalence dependent calibration of a predictive model for nasal carriage of methicillin-resistant Staphylococcus aureus},
  series = {BMC Infectious Diseases},
  journal   = {BMC Infectious Diseases},
  doi       = {10.1186/1471-2334-13-111},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96091},
  year      = {2013},
  abstract  = {Background Published models predicting nasal colonization with Methicillin-resistant Staphylococcus aureus among hospital admissions predominantly focus on separation of carriers from non-carriers and are frequently evaluated using measures of discrimination. In contrast, accurate estimation of carriage probability, which may inform decisions regarding treatment and infection control, is rarely assessed. Furthermore, no published models adjust for MRSA prevalence. Methods Using logistic regression, a scoring system (values from 0 to 200) predicting nasal carriage of MRSA was created using a derivation cohort of 3091 individuals admitted to a European tertiary referral center between July 2007 and March 2008. The expected positive predictive value of a rapid diagnostic test (GeneOhm, Becton \& Dickinson Co.) was modeled using non-linear regression according to score. Models were validated on a second cohort from the same hospital consisting of 2043 patients admitted between August 2008 and January 2012. Our suggested correction score for prevalence was proportional to the log-transformed odds ratio between cohorts. Calibration before and after correction, i.e. accurate classification into arbitrary strata, was assessed with the Hosmer-Lemeshow-Test. Results Treating culture as reference, the rapid diagnostic test had positive predictive values of 64.8\% and 54.0\% in derivation and internal validation corhorts with prevalences of 2.3\% and 1.7\%, respectively. In addition to low prevalence, low positive predictive values were due to high proportion (> 66\%) of mecA-negative Staphylococcus aureus among false positive results. Age, nursing home residence, admission through the medical emergency department, and ICD-10-GM admission diagnoses starting with "A" or "J" were associated with MRSA carriage and were thus included in the scoring system, which showed good calibration in predicting probability of carriage and the rapid diagnostic test's expected positive predictive value. Calibration for both probability of carriage and expected positive predictive value in the internal validation cohort was improved by applying the correction score. Conclusions Given a set of patient parameters, the presented models accurately predict a) probability of nasal carriage of MRSA and b) a rapid diagnostic test's expected positive predictive value. While the former can inform decisions regarding empiric antibiotic treatment and infection control, the latter can influence choice of screening method.},
  language  = {en}
}
@article{DiaoMoussetHorsburghetal.2016,
  author    = {Diao, Wenwen and Mousset, Mathilde and Horsburgh, Gavin J. and Vermeulen, Cornelis J. and Johannes, Frank and van de Zande, Louis and Ritchie, Michael G. and Schmitt, Thomas and Beukeboom, Leo W.},
  title     = {Quantitative Trait Locus Analysis of Mating Behavior and Male Sex Pheromones in Nasonia Wasps},
  series = {G3: Genes Genomes Genetics},
  volume    = {6},
  journal   = {G3: Genes Genomes Genetics},
  number    = {6},
  doi       = {10.1534/g3.116.029074},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165412},
  pages     = {1549-1562},
  year      = {2016},
  abstract  = {A major focus in speciation genetics is to identify the chromosomal regions and genes that reduce hybridization and gene flow. We investigated the genetic architecture of mating behavior in the parasitoid wasp species pair Nasonia giraulti and Nasonia oneida that exhibit strong prezygotic isolation. Behavioral analysis showed that N. oneida females had consistently higher latency times, and broke off the mating sequence more often in the mounting stage when confronted with N. giraulti males compared with males of their own species. N. oneida males produce a lower quantity of the long-range male sex pheromone (4R,5S)-5-hydroxy-4-decanolide (RS-HDL). Crosses between the two species yielded hybrid males with various pheromone quantities, and these males were used in mating trials with females of either species to measure female mate discrimination rates. A quantitative trait locus (QTL) analysis involving 475 recombinant hybrid males (F2), 2148 reciprocally backcrossed females (F3), and a linkage map of 52 equally spaced neutral single nucleotide polymorphism (SNP) markers plus SNPs in 40 candidate mating behavior genes revealed four QTL for male pheromone amount, depending on partner species. Our results demonstrate that the RS-HDL pheromone plays a role in the mating system of N. giraulti and N. oneida, but also that additional communication cues are involved in mate choice. No QTL were found for female mate discrimination, which points at a polygenic architecture of female choice with strong environmental influences.},
  language  = {en}
}
@techreport{GrigorjewMetzgerHossfeldetal.2020,
  author    = {Grigorjew, Alexej and Metzger, Florian and Hoßfeld, Tobias and Specht, Johannes and G{\"o}tz, Franz-Josef and Schmitt, J{\"u}rgen and Chen, Feng},
  title     = {Technical Report on Bridge-Local Guaranteed Latency with Strict Priority Scheduling},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-198310},
  year      = {2020},
  abstract  = {Bridge-local latency computation is often regarded with caution, as historic efforts with the Credit-Based Shaper (CBS) showed that CBS requires network wide information for tight bounds. Recently, new shaping mechanisms and timed gates were applied to achieve such guarantees nonetheless, but they require support for these new mechanisms in the forwarding devices. This document presents a per-hop latency bound for individual streams in a class-based network that applies the IEEE 802.1Q strict priority transmission selection algorithm. It is based on self-pacing talkers and uses the accumulated latency fields during the reservation process to provide upper bounds with bridge-local information. The presented delay bound is proven mathematically and then evaluated with respect to its accuracy. It indicates the required information that must be provided for admission control, e.g., implemented by a resource reservation protocol such as IEEE 802.1Qdd. Further, it hints at potential improvements regarding new mechanisms and higher accuracy given more information.},
  subject      = {Echtzeit},
  language  = {en}
}
@techreport{GrigorjewMetzgerHossfeldetal.2020,
  author    = {Grigorjew, Alexej and Metzger, Florian and Hoßfeld, Tobias and Specht, Johannes and G{\"o}tz, Franz-Josef and Chen, Feng and Schmitt, J{\"u}rgen},
  title     = {Asynchronous Traffic Shaping with Jitter Control},
  doi       = {10.25972/OPUS-20582},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-205824},
  pages     = {8},
  year      = {2020},
  abstract  = {Asynchronous Traffic Shaping enabled bounded latency with low complexity for time sensitive networking without the need for time synchronization. However, its main focus is the guaranteed maximum delay. Jitter-sensitive applications may still be forced towards synchronization. This work proposes traffic damping to reduce end-to-end delay jitter. It discusses its application and shows that both the prerequisites and the guaranteed delay of traffic damping and ATS are very similar. Finally, it presents a brief evaluation of delay jitter in an example topology by means of a simulation and worst case estimation.},
  subject      = {Echtzeit},
  language  = {en}
}
@phdthesis{Schmitt2021,
  author    = {Schmitt, Johannes Christian},
  title     = {{\"U}ber das Expressionsverhalten von Reparatur- und ABC- Transporter-Genen sowie inflammatorischen Signalwegen im Kolon- und Pankreaskarzinom},
  doi       = {10.25972/OPUS-24988},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-249884},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {Das Mikromilieu solider Tumor (tumor mircoenvironment, TME) weist verschiedene Besonderheiten auf, von denen bekannt ist, dass sie zu Chemotherapieresistenz und Tumorprogression beitragen k{\"o}nnen. Neben der Extrazellul{\"a}ren Matrix (ECM), den cancer associated cells (CAC) und diversen Entz{\"u}ndungszellen tragen auch chemische und physikalische Besonderheiten (Hypoxie, Azidose, erh{\"o}hter Gewebedruck, oxidativer Stress und N{\"a}hrstoffmangel) zu Tumorprogression und Chemotherapieresistenz bei. Zudem wissen wir, dass Hitzeschock-Proteine (HSPs), Toll-like Rezeptoren (TLRs) und ABC-Transporter mit erh{\"o}hter Chemotherapieresistenz und Tumorprogression im Pankreas- und Kolonkarzinom einhergehen. Hier wurde untersucht, ob ein in vitro induzierter N{\"a}hrstoffmangel im HT29 Kolonkarzinom, im Panc-1 Pankreaskarzinom und im MIA PaCa-2 Pankreaskarzinom zu einer gesteigerten Expression von HSP70, HSP90, MDR1, ABCB5 und TLR1 bis TLR10 auf mRNA und Proteinebene f{\"u}hrt. Zudem wurde unter allen Versuchsbedingungen die Stoffwechselaktivit{\"a}t {\"u}ber einen MTS-Test gemessen. Der N{\"a}hrstoffmangel wurde {\"u}ber die Kultivierung in einem Hybridomamedium, welches als proteinfreies Medium gilt und {\"u}ber die Kultivierung in einem serumfreien Medium induziert. Es zeigte sich, dass insbesondere die entdifferenzierte Panc-1 Pankreaskarzinomzelllinie eine erh{\"o}hte Resistenz gegen{\"u}ber dem induzierten N{\"a}hrstoffmangel aufwies. Auf mRNA-Ebene zeigten sich bei allen drei Tumorzelllinien deutliche Expressionssteigerungen. Diese waren insbesondere im Hybridomamedium nachweisbar und traten beim HT29-Kolonkarzinom nach 48h und im Panc-1 Pankreaskarzinom bereits nach 24h auf. Besonders intensive Expressionssteigerungen konnten im HT29 Kolonkarzinom bei ABCB5, TLR7 und TLR9 nachgewiesen werden. Die Expression von MDR1 war insbesondere im MIA PaCa-2 Pankreaskarzinom gesteigert. Auf Proteinebene konnte im HT29 Kolonkarzinom eine Expressionssteigerung bei HSP90 und TLR6 nachgewiesen werden. Die Ergebnisse lassen zwei Interpretationen zu. Zum einen k{\"o}nnte {\"u}ber den N{\"a}hrstoffmangel eine aggressivere Subpopulation selektioniert worden sein. In diesem Zusammenhang konnten die Expressionsdaten des Tumorstammzellmarkers CD133 leider nicht ausgewertet werden. Alternativ kann angenommen werden, dass die untersuchten Tumorzelllinien ihren aggressiven Ph{\"a}notyp erst unter N{\"a}hrstoffmangelbedingungen, wie wir sie regelm{\"a}ßig in soliden Tumoren finden, zur Expression bringen.},
  subject      = {International Conference on Tumor Microenvironment (4 : 2007 : Florenz)},
  language  = {de}
}
@article{RaselliHearnWyssetal.2019,
  author    = {Raselli, Tina and Hearn, Tom and Wyss, Annika and Atrott, Kirstin and Peter, Alain and Frey-Wagner, Isabelle and Spalinger, Marianne R. and Maggio, Ewerton M. and Sailer, Andreas W. and Schmitt, Johannes and Schreiner, Philipp and Moncsek, Anja and Mertens, Joachim and Scharl, Michael and Griffiths, William J. and Bueter, Marco and Geier, Andreas and Rogler, Gerhard and Wang, Yuqin and Misselwitz, Benjamin},
  title     = {Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis},
  series = {Journal of Lipid Research},
  volume    = {60},
  journal   = {Journal of Lipid Research},
  number    = {7},
  doi       = {10.1194/jlr.M093229},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225004},
  pages     = {1270-1283},
  year      = {2019},
  abstract  = {Nonalcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2) and its oxysterol ligand 7 alpha,25-dihydroxycholesterol (7 alpha,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in the livers of NASH patients by LC-MS and tested the role of the EBI2-7 alpha,25-diHC system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared with controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype-related differences were observed in Ebi2(-/-) mice and mice with defects in the 7 alpha,25-diHC synthesizing enzymes CH25H and CYP7B1 compared with wild-type littermate controls, arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by the enhanced level of 7 alpha-hydroxycholest-4-en-3-one and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.},
  language  = {en}
}
@article{StreinzerChakravortyNeumayeretal.2019,
  author    = {Streinzer, Martin and Chakravorty, Jharna and Neumayer, Johann and Megu, Karsing and Narah, Jaya and Schmitt, Thomas and Bharti, Himender and Spaethe, Johannes and Brockmann, Axel},
  title     = {Species composition and elevational distribution of bumble bees (Hymenoptera, Apidae, Bombus Latreille) in the East Himalaya, Arunachal Pradesh, India},
  series = {ZooKeys},
  volume    = {851},
  journal   = {ZooKeys},
  doi       = {10.3897/zookeys.851.32956},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201937},
  pages     = {71-89},
  year      = {2019},
  abstract  = {The East Himalaya is one of the world's most biodiverse ecosystems. However, very little is known about the abundance and distribution of many plant and animal taxa in this region. Bumble bees are a group of cold-adapted and high elevation insects that fulfil an important ecological and economical function as pollinators of wild and agricultural flowering plants and crops. The Himalayan mountain range provides ample suitable habitats for bumble bees. Systematic study of Himalayan bumble bees began a few decades ago and the main focus has centred on the western region, while the eastern part of the mountain range has received little attention and only a few species have been verified. During a three-year survey, more than 700 bumble bee specimens of 21 species were collected in Arunachal Pradesh, the largest of the north-eastern states of India. The material included a range of species that were previously known from a limited number of collected specimens, which highlights the unique character of the East Himalayan ecosystem. Our results are an important first step towards a future assessment of species distribution, threat, and conservation. Clear elevation patterns of species diversity were observed, which raise important questions about the functional adaptations that allow bumble bees to thrive in this particularly moist region in the East Himalaya.},
  language  = {en}
}
@article{HamannBankmannMoraMazaetal.2022,
  author    = {Hamann, Catharina S. and Bankmann, Julian and Mora Maza, Hanna and Kornhuber, Johannes and Zoicas, Iulia and Schmitt-B{\"o}hrer, Angelika},
  title     = {Social fear affects limbic system neuronal activity and gene expression},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {15},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23158228},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284274},
  year      = {2022},
  abstract  = {Social anxiety disorder (SAD) is a highly prevalent and comorbid anxiety disorder with rather unclear underlying mechanisms. Here, we aimed to characterize neurobiological changes occurring in mice expressing symptoms of social fear and to identify possible therapeutic targets for SAD. Social fear was induced via social fear conditioning (SFC), a validated animal model of SAD. We assessed the expression levels of the immediate early genes (IEGs) cFos, Fosl2 and Arc as markers of neuronal activity and the expression levels of several genes of the GABAergic, serotoninergic, oxytocinergic, vasopressinergic and neuropeptide Y (NPY)-ergic systems in brain regions involved in social behavior or fear-related behavior in SFC+ and SFC- mice 2 h after exposure to a conspecific. SFC+ mice showed a decreased number and density of cFos-positive cells and decreased expression levels of IEGs in the dorsal hippocampus. SFC+ mice also showed alterations in the expression of NPY and serotonin system-related genes in the paraventricular nucleus of the hypothalamus, basolateral amygdala, septum and dorsal raphe nucleus, but not in the dorsal hippocampus. Our results describe neuronal alterations occurring during the expression of social fear and identify the NPY and serotonergic systems as possible targets in the treatment of SAD.},
  language  = {en}
}
@article{RauSchmittBergetal.2018,
  author    = {Rau, Monika and Schmitt, Johannes and Berg, Thomas and Kremer, Andreas E. and Stieger, Bruno and Spanaus, Katharina and Bengsch, Bertram and Romero, Marta R. and Marin, Jose J. and Keitel, Verena and Klinker, Hartwig and Tony, Hans-Peter and M{\"u}llhaupt, Beat and Geier, Andreas},
  title     = {Serum IP-10 levels and increased DPPIV activity are linked to circulating CXCR3+ T cells in cholestatic HCV patients},
  series = {PLoS ONE},
  volume    = {13},
  journal   = {PLoS ONE},
  number    = {12},
  doi       = {10.1371/journal.pone.0208225},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177674},
  pages     = {e0208225},
  year      = {2018},
  abstract  = {Background \& aims Serum interferon-gamma-inducible protein-10 (IP-10) is elevated in cholestatic liver diseases and predicts response to antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. Dipeptidylpeptidase 4 (DPPIV) cleaves active IP-10 into an inactive form, which inhibits recruitment of CXCR3+ T cells to the liver. In this study the link between IP-10 levels, DPPIV activity in serum and CXCR3+ T cells is analysed in cholestatic and non-cholestatic liver patients. Methods In serum DPPIV activity (by enzymatic assay), IP-10 (by ELISA) and bile acids (BA) (by enzymatic assay) were analysed in 229 naive HCV genotype (GT) 1 patients and in 16 patients with cholestatic liver disease. In a prospective follow-up (FU) cohort of 27 HCV GT 1 patients peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ cells were measured by FACS. Results In 229 HCV patients serum IP-10 levels correlated positively to DPPIV serum activity. Higher IP-10 levels and DPPIV activity were detected in cholestatic and in cirrhotic HCV patients. Increased IP-10 serum levels were associated with therapeutic non-response to antiviral treatment with pegylated-interferon and ribavirin. In the HCV FU cohort elevated IP-10 serum levels and increased BA were associated with higher frequencies of peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ T cells. Positive correlation between serum IP-10 levels and DPPIV activity was likewise validated in patients with cholestatic liver diseases. Conclusions A strong correlation between elevated serum levels of IP-10 and DPPIV activity was seen in different cholestatic patient groups. Furthermore, in cholestatic HCV patients a functional link to increased numbers of peripheral CXCR3+ immune cells could be observed. The source of DPPIV release in cholestatic patients remains open.},
  language  = {en}
}