@article{EdgecockCarettaDavenneetal.2013, author = {Edgecock, T. R. and Caretta, O. and Davenne, T. and Densam, C. and Fitton, M. and Kelliher, D. and Loveridge, P. and Machida, S. and Prior, C. and Rogers, C. and Rooney, M. and Thomason, J. and Wilcox, D. and Wildner, E. and Efthymiopoulos, I. and Garoby, R. and Gilardoni, S. and Hansen, C. and Benedetto, E. and Jensen, E. and Kosmicki, A. and Martini, M. and Osborne, J. and Prior, G. and Stora, T. and Melo Mendonca, T. and Vlachoudis, V. and Waaijer, C. and Cupial, P. and Chanc{\´e}, A. and Longhin, A. and Payet, J. and Zito, M. and Baussan, E. and Bobeth, C. and Bouquerel, E. and Dracos, M. and Gaudiot, G. and Lepers, B. and Osswald, F. and Poussot, P. and Vassilopoulos, N. and Wurtz, J. and Zeter, V. and Bielski, J. and Kozien, M. and Lacny, L. and Skoczen, B. and Szybinski, B. and Ustrycka, A. and Wroblewski, A. and Marie-Jeanne, M. and Balint, P. and Fourel, C. and Giraud, J. and Jacob, J. and Lamy, T. and Latrasse, L. and Sortais, P. and Thuillier, T. and Mitrofanov, S. and Loiselet, M. and Keutgen, Th. and Delbar, Th. and Debray, F. and Trophine, C. and Veys, S. and Daversin, C. and Zorin, V. and Izotov, I. and Skalyga, V. and Burt, G. and Dexter, A. C. and Kravchuk, V. L. and Marchi, T. and Cinausero, M. and Gramegna, F. and De Angelis, G. and Prete, G. and Collazuol, G. and Laveder, M. and Mazzocco, M. and Mezzetto, M. and Signorini, C. and Vardaci, E. and Di Nitto, A. and Brondi, A. and La Rana, G. and Migliozzi, P. and Moro, R. and Palladino, V. and Gelli, N. and Berkovits, D. and Hass, M. and Hirsh, T. Y. and Schuhmann, M. and Stahl, A. and Wehner, J. and Bross, A. and Kopp, J. and Neuffer, D. and Wands, R. and Bayes, R. and Laing, A. and Soler, P. and Agarwalla, S. K. and Cervera Villanueva, A. and Donini, A. and Ghosh, T. and G{\´o}mez Cadenas, J. J. and Hern{\´a}ndez, P. and Mart{\´i}n-Albo, J. and Mena, O. and Burguet-Castell, J. and Agostino, L. and Buizza-Avanzini, M. and Marafini, M. and Patzak, T. and Tonazzo, A. and Duchesneau, D. and Mosca, L. and Bogomilov, M. and Karadzhov, Y. and Matev, R. and Tsenov, R. and Akhmedov, E. and Blennow, M. and Lindner, M. and Schwetz, T. and Fern{\´a}ndez Martinez, E. and Maltoni, M. and Men{\´e}ndez, J. and Giunti, C. and Gonz{\´a}lez Garc{\´i}a, M. C. and Salvado, J. and Coloma, P. and Huber, P. and Li, T. and L{\´o}pez Pav{\´o}n, J. and Orme, C. and Pascoli, S. and Meloni, D. and Tang, J. and Winter, W. and Ohlsson, T. and Zhang, H. and Scotto-Lavina, L. and Terranova, F. and Bonesini, M. and Tortora, L. and Alekou, A. and Aslaninejad, M. and Bontoiu, C. and Kurup, A. and Jenner, L. J. and Long, K. and Pasternak, J. and Pozimski, J. and Back, J. J. and Harrison, P. and Beard, K. and Bogacz, A. and Berg, J. S. and Stratakis, D. and Witte, H. and Snopok, P. and Bliss, N. and Cordwell, M. and Moss, A. and Pattalwar, S. and Apollonio, M.}, title = {High intensity neutrino oscillation facilities in Europe}, series = {Physical Review Special Topics-Accelerators and Beams}, volume = {16}, journal = {Physical Review Special Topics-Accelerators and Beams}, number = {2}, doi = {10.1103/PhysRevSTAB.16.021002}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126611}, pages = {21002}, year = {2013}, abstract = {The EUROnu project has studied three possible options for future, high intensity neutrino oscillation facilities in Europe. The first is a Super Beam, in which the neutrinos come from the decay of pions created by bombarding targets with a 4 MW proton beam from the CERN High Power Superconducting Proton Linac. The far detector for this facility is the 500 kt MEMPHYS water Cherenkov, located in the Frejus tunnel. The second facility is the Neutrino Factory, in which the neutrinos come from the decay of mu(+) and mu(-) beams in a storage ring. The far detector in this case is a 100 kt magnetized iron neutrino detector at a baseline of 2000 km. The third option is a Beta Beam, in which the neutrinos come from the decay of beta emitting isotopes, in particular He-6 and Ne-18, also stored in a ring. The far detector is also the MEMPHYS detector in the Frejus tunnel. EUROnu has undertaken conceptual designs of these facilities and studied the performance of the detectors. Based on this, it has determined the physics reach of each facility, in particular for the measurement of CP violation in the lepton sector, and estimated the cost of construction. These have demonstrated that the best facility to build is the Neutrino Factory. However, if a powerful proton driver is constructed for another purpose or if the MEMPHYS detector is built for astroparticle physics, the Super Beam also becomes very attractive.}, language = {en} } @article{JainVelezAcostaetal.2012, author = {Jain, M. and V{\´e}lez, J. I. and Acosta, M. T. and Palacio, L. G. and Balog, J. and Roessler, E. and Pineda, D. and Londo{\~n}o, A. C. and Palacio, J. D. and Arbelaez, A. and Lopera, F. and Elia, J. and Hakonarson, H. and Seitz, C. and Freitag, C. M. and Palmason, H. and Meyer, J. and Romanos, M. and Walitza, S. and Hemminger, U. and Warnke, A. and Romanos, J. and Renner, T. and Jacob, C. and Lesch, K.-P. and Swanson, J. and Castellanos, F. X. and Bailey-Wilson, J. E. and Arcos-Burgos, M. and Muenke, M.}, title = {A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD}, series = {Molecular Psychiatry}, volume = {17}, journal = {Molecular Psychiatry}, doi = {10.1038/mp.2011.59}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125128}, pages = {741-747}, year = {2012}, abstract = {In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10-8) and 11q and 17p (P<1 × 10-6). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.}, language = {en} } @article{BenoitAdelmanReinhardtetal.2016, author = {Benoit, Joshua B. and Adelman, Zach N. and Reinhardt, Klaus and Dolan, Amanda and Poelchau, Monica and Jennings, Emily C. and Szuter, Elise M. and Hagan, Richard W. and Gujar, Hemant and Shukla, Jayendra Nath and Zhu, Fang and Mohan, M. and Nelson, David R. and Rosendale, Andrew J. and Derst, Christian and Resnik, Valentina and Wernig, Sebastian and Menegazzi, Pamela and Wegener, Christian and Peschel, Nicolai and Hendershot, Jacob M. and Blenau, Wolfgang and Predel, Reinhard and Johnston, Paul R. and Ioannidis, Panagiotis and Waterhouse, Robert M. and Nauen, Ralf and Schorn, Corinna and Ott, Mark-Christoph and Maiwald, Frank and Johnston, J. Spencer and Gondhalekar, Ameya D. and Scharf, Michael E. and Raje, Kapil R. and Hottel, Benjamin A. and Armis{\´e}n, David and Crumi{\`e}re, Antonin Jean Johan and Refki, Peter Nagui and Santos, Maria Emilia and Sghaier, Essia and Viala, S{\`e}verine and Khila, Abderrahman and Ahn, Seung-Joon and Childers, Christopher and Lee, Chien-Yueh and Lin, Han and Hughes, Daniel S.T. and Duncan, Elizabeth J. and Murali, Shwetha C. and Qu, Jiaxin and Dugan, Shannon and Lee, Sandra L. and Chao, Hsu and Dinh, Huyen and Han, Yi and Doddapaneni, Harshavardhan and Worley, Kim C. and Muzny, Donna M. and Wheeler, David and Panfilio, Kristen A. and Jentzsch, Iris M. Vargas and Jentzsch, IMV and Vargo, Edward L. and Booth, Warren and Friedrich, Markus and Weirauch, Matthew T. and Anderson, Michelle A.E. and Jones, Jeffery W. and Mittapalli, Omprakash and Zhao, Chaoyang and Zhou, Jing-Jiang and Evans, Jay D. and Attardo, Geoffrey M. and Robertson, Hugh M. and Zdobnov, Evgeny M. and Ribeiro, Jose M.C. and Gibbs, Richard A. and Werren, John H. and Palli, Subba R. and Schal, Coby and Richards, Stephen}, title = {Unique features of a global human ectoparasite identified through sequencing of the bed bug genome}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, number = {10165}, doi = {10.1038/ncomms10165}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166221}, year = {2016}, abstract = {The bed bug, Cimex lectularius, has re-established itself as a ubiquitous human ectoparasite throughout much of the world during the past two decades. This global resurgence is likely linked to increased international travel and commerce in addition to widespread insecticide resistance. Analyses of the C. lectularius sequenced genome (650 Mb) and 14,220 predicted protein-coding genes provide a comprehensive representation of genes that are linked to traumatic insemination, a reduced chemosensory repertoire of genes related to obligate hematophagy, host-symbiont interactions, and several mechanisms of insecticide resistance. In addition, we document the presence of multiple putative lateral gene transfer events. Genome sequencing and annotation establish a solid foundation for future research on mechanisms of insecticide resistance, human-bed bug and symbiont-bed bug associations, and unique features of bed bug biology that contribute to the unprecedented success of C. lectularius as a human ectoparasite.}, language = {en} } @article{BrevikvanDonkelaarWeberetal.2016, author = {Brevik, Erlend J and van Donkelaar, Marjolein M. J. and Weber, Heike and S{\´a}nchez-Mora, Cristina and Jacob, Christian and Rivero, Olga and Kittel-Schneider, Sarah and Garcia-martinez, Iris and Aebi, Marcel and van Hulzen, Kimm and Cormand, Bru and Ramos-Quiroga, Josep A and Lesch, Klaus-Peter and Reif, Andreas and Ribases, Marta and Franke, Barbara and Posserud, Maj-Britt and Johansson, Stefan and Lundervold, Astri J. and Haavik, Jan and Zayats, Tetyana}, title = {Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder}, series = {American Journal of Medical Genetics Part B-Neuropsychiatric Genetics}, volume = {171B}, journal = {American Journal of Medical Genetics Part B-Neuropsychiatric Genetics}, number = {5}, organization = {IMAGE Consortium}, doi = {10.1002/ajmg.b.32434}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-188116}, pages = {733-747}, year = {2016}, abstract = {Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40\%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P<5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders.}, language = {en} } @article{BiehlMerzDresleretal.2016, author = {Biehl, Stefanie C. and Merz, Christian J. and Dresler, Thomas and Heupel, Julia and Reichert, Susanne and Jacob, Christian P. and Deckert, J{\"u}rgen and Herrmann, Martin J.}, title = {Increase or Decrease of fMRI Activity in Adult Attention Deficit/ Hyperactivity Disorder: Does It Depend on Task Difficulty?}, series = {International Journal of Neuropsychopharmacology}, volume = {19}, journal = {International Journal of Neuropsychopharmacology}, number = {10}, doi = {10.1093/ijnp/pyw049}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147551}, pages = {pyw049}, year = {2016}, abstract = {Background: Attention deficit/hyperactivity disorder has been shown to affect working memory, and fMRI studies in children and adolescents with attention deficit/hyperactivity disorder report hypoactivation in task-related attentional networks. However, studies with adult attention deficit/hyperactivity disorder patients addressing this issue as well as the effects of clinically valid methylphenidate treatment are scarce. This study contributes to closing this gap. Methods: Thirty-five adult patients were randomized to 6 weeks of double-blind placebo or methylphenidate treatment. Patients completed an fMRI n-back working memory task both before and after the assigned treatment, and matched healthy controls were tested and compared to the untreated patients. Results: There were no whole-brain differences between any of the groups. However, when specified regions of interest were investigated, the patient group showed enhanced BOLD responses in dorsal and ventral areas before treatment. This increase was correlated with performance across all participants and with attention deficit/hyperactivity disorder symptoms in the patient group. Furthermore, we found an effect of treatment in the right superior frontal gyrus, with methylphenidate-treated patients exhibiting increased activation, which was absent in the placebo-treated patients. Conclusions: Our results indicate distinct activation differences between untreated adult attention deficit/hyperactivity disorder patients and matched healthy controls during a working memory task. These differences might reflect compensatory efforts by the patients, who are performing at the same level as the healthy controls. We furthermore found a positive effect of methylphenidate on the activation of a frontal region of interest. These observations contribute to a more thorough understanding of adult attention deficit/hyperactivity disorder and provide impulses for the evaluation of therapy-related changes.}, language = {en} } @article{SemmlerSacconiBachetal.2014, author = {Semmler, Anna-Lena and Sacconi, Sabrina and Bach, J. Elisa and Liebe, Claus and B{\"u}rmann, Jan and Kley, Rudolf A. and Ferbert, Andreas and Anderheiden, Roland and Van den Bergh, Peter and Martin, Jean-Jacques and De Jonghe, Peter and Neuen-Jacob, Eva and M{\"u}ller, Oliver and Deschauer, Marcus and Bergmann, Markus and Schr{\"o}der, J. Michael and Vorgerd, Matthias and Schulz, J{\"o}rg B. and Weis, Joachim and Kress, Wolfram and Claeys, Kristl G.}, title = {Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies}, series = {Orphanet Journal of Rare Diseases}, volume = {9}, journal = {Orphanet Journal of Rare Diseases}, number = {121}, issn = {1750-1172}, doi = {10.1186/s13023-014-0121-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115623}, year = {2014}, abstract = {Background: Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogeneous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with multisystemic involvement. Methods: We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n = 43) and particularly focused on the associated multisystemic symptoms. Results: We identified 14 heterozygous mutations (diagnostic yield of 37\%), among them the novel p. Pro209Gln mutation in the BAG3 gene, which was associated with onset in adulthood, a mild phenotype and an axonal sensorimotor polyneuropathy, in the absence of giant axons at the nerve biopsy. We revealed several novel clinical phenotypes and unusual multisystemic presentations with previously described mutations: hearing impairment with a FLNC mutation, dysphonia with a mutation in DES and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p. Gly154Ser mutation in CRYAB. Interestingly, we detected a polyneuropathy in 28\% of the MFM patients, including a BAG3 and a MYOT case, and hearing impairment in 13\%, including one patient with a FLNC mutation and two with mutations in the DES gene. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29\%). Conclusions: We conclude that extraskeletal symptoms frequently occur in MFM, particularly cardiac and respiratory involvement, polyneuropathy and/or deafness. BAG3 mutations should be considered even in cases with a mild phenotype or an adult onset. We identified a genetic defect in one of the known genes in less than half of the MFM patients, indicating that more causative genes are still to be found. Next generation sequencing techniques should be helpful in achieving this aim.}, language = {en} } @article{ZayatsJacobsenKleppeetal.2016, author = {Zayats, T and Jacobsen, KK and Kleppe, R and Jacob, CP and Kittel-Schneider, S and Ribas{\´e}s, M and Ramos-Quiroga, JA and Richarte, V and Casas, M and Mota, NR and Grevet, EH and Klein, M and Corominas, J and Bralten, J and Galesloot, T and Vasquez, AA and Herms, S and Forstner, AJ and Larsson, H and Breen, G and Asherson, P and Gross-Lesch, S and Lesch, KP and Cichon, S and Gabrielsen, MB and Holmen, OL and Bau, CHD and Buitelaar, J and Kiemeney, L and Faraone, SV and Cormand, B and Franke, B and Reif, A and Haavik, J and Johansson, S}, title = {Exome chip analyses in adult attention deficit hyperactivity disorder}, series = {Translational Psychiatry}, volume = {6}, journal = {Translational Psychiatry}, number = {e923}, doi = {10.1038/tp.2016.196}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-168297}, year = {2016}, abstract = {Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1\%); (2) single marker association tests of common variants (MAF⩾1\%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E-06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E-08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E-07); the PSD locus (P=7.58E-08) and ZCCHC4 locus (P=1.79E-06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E-05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD.}, language = {en} } @article{KlaukeWinterGajewskaetal.2012, author = {Klauke, Benedikt and Winter, Bernward and Gajewska, Agnes and Zwanzger, Peter and Reif, Andreas and Herrmann, Martin J. and Dlugos, Andrea and Warrings, Bodo and Jacob, Christian and M{\"u}hlberger, Andreas and Arolt, Volker and Pauli, Paul and Deckert, J{\"u}rgen and Domschke, Katharina}, title = {Affect-Modulated Startle: Interactive Influence of Catechol-O-Methyltransferase Val158Met Genotype and Childhood Trauma}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {6}, doi = {10.1371/journal.pone.0039709}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132184}, pages = {e39709}, year = {2012}, abstract = {The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system - partly conferred by catechol-O-methyltransferase (COMT) gene variation - for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders.}, language = {en} } @article{RamachandranShearerJacobetal.2012, author = {Ramachandran, Vinoy K. and Shearer, Neil and Jacob, Jobin J. and Sharma, Cynthia M. and Thompson, Arthur}, title = {The architecture and ppGpp-dependent expression of the primary transcriptome of Salmonella Typhimurium during invasion gene expression}, series = {BMC Genomics}, volume = {13}, journal = {BMC Genomics}, number = {25}, doi = {10.1186/1471-2164-13-25}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130625}, year = {2012}, abstract = {Background: Invasion of intestinal epithelial cells by Salmonella enterica serovar Typhimurium (S. Typhimurium) requires expression of the extracellular virulence gene expression programme (STEX), activation of which is dependent on the signalling molecule guanosine tetraphosphate (ppGpp). Recently, next-generation transcriptomics (RNA-seq) has revealed the unexpected complexity of bacterial transcriptomes and in this report we use differential RNA sequencing (dRNA-seq) to define the high-resolution transcriptomic architecture of wildtype S. Typhimurium and a ppGpp null strain under growth conditions which model STEX. In doing so we show that ppGpp plays a much wider role in regulating the S. Typhimurium STEX primary transcriptome than previously recognised. Results: Here we report the precise mapping of transcriptional start sites (TSSs) for 78\% of the S. Typhimurium open reading frames (ORFs). The TSS mapping enabled a genome-wide promoter analysis resulting in the prediction of 169 alternative sigma factor binding sites, and the prediction of the structure of 625 operons. We also report the discovery of 55 new candidate small RNAs (sRNAs) and 302 candidate antisense RNAs (asRNAs). We discovered 32 ppGpp-dependent alternative TSSs and determined the extent and level of ppGpp-dependent coding and non-coding transcription. We found that 34\% and 20\% of coding and non-coding RNA transcription respectively was ppGpp-dependent under these growth conditions, adding a further dimension to the role of this remarkable small regulatory molecule in enabling rapid adaptation to the infective environment. Conclusions: The transcriptional architecture of S. Typhimurium and finer definition of the key role ppGpp plays in regulating Salmonella coding and non-coding transcription should promote the understanding of gene regulation in this important food borne pathogen and act as a resource for future research.}, language = {en} } @article{HaakeHaackSchaeferetal.2023, author = {Haake, Markus and Haack, Beatrice and Sch{\"a}fer, Tina and Harter, Patrick N. and Mattavelli, Greta and Eiring, Patrick and Vashist, Neha and Wedekink, Florian and Genssler, Sabrina and Fischer, Birgitt and Dahlhoff, Julia and Mokhtari, Fatemeh and Kuzkina, Anastasia and Welters, Marij J. P. and Benz, Tamara M. and Sorger, Lena and Thiemann, Vincent and Almanzar, Giovanni and Selle, Martina and Thein, Klara and Sp{\"a}th, Jacob and Gonzalez, Maria Cecilia and Reitinger, Carmen and Ipsen-Escobedo, Andrea and Wistuba-Hamprecht, Kilian and Eichler, Kristin and Filipski, Katharina and Zeiner, Pia S. and Beschorner, Rudi and Goedemans, Renske and Gogolla, Falk Hagen and Hackl, Hubert and Rooswinkel, Rogier W. and Thiem, Alexander and Romer Roche, Paula and Joshi, Hemant and P{\"u}hringer, Dirk and W{\"o}ckel, Achim and Diessner, Joachim E. and R{\"u}diger, Manfred and Leo, Eugen and Cheng, Phil F. and Levesque, Mitchell P. and Goebeler, Matthias and Sauer, Markus and Nimmerjahn, Falk and Schuberth-Wagner, Christine and Felten, Stefanie von and Mittelbronn, Michel and Mehling, Matthias and Beilhack, Andreas and van der Burg, Sjoerd H. and Riedel, Angela and Weide, Benjamin and Dummer, Reinhard and Wischhusen, J{\"o}rg}, title = {Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment}, series = {Nature Communications}, volume = {14}, journal = {Nature Communications}, doi = {10.1038/s41467-023-39817-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357333}, year = {2023}, abstract = {Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don't respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.}, language = {en} }