Kratz C.P.,Hannover Medical School |
Franke L.,University Hospital Magdeburg |
Peters H.,Institute of Medical and Human Genetics |
Kohlschmidt N.,Institute For Klinische Genetik |
And 28 more authors.
British Journal of Cancer | Year: 2015
Background:Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These 'RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown.Methods:We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry.Results:We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4.Conclusions:These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours. © 2015 Cancer Research UK. All rights reserved.
Huffmeier U.,Friedrich - Alexander - University, Erlangen - Nuremberg |
Bergboer J.G.M.,Radboud University Nijmegen |
Becker T.,University of Bonn |
Armour J.A.,University of Nottingham |
And 11 more authors.
Journal of Investigative Dermatology | Year: 2010
Recently, a deletion of two late cornified envelope (LCE) genes within the epidermal differentiation complex on chromosome 1 was shown to be overrepresented in 1,426 psoriasis vulgaris (PsV) patients of European ancestry. In this study, we report a confirmation of this finding in 1,354 PsV patients and 937 control individuals of German origin. We found an allele frequency of the deletion of 70.9% in PsV patients and of 64.9% in control individuals (X2= 17.44, P2.97 × 10-5, odds ratio (95% confidence interval)1.31 (1.15-1.48)). The overall copy number of the two LCE genes had no influence on the age of onset, but we observed a dosage effect at the genotype level. There was no evidence of statistically significant interaction with copy number of the Β-defensin cluster on 8p23.1 or with an IL-23R pathway variant in a combined data set of German and Dutch individuals, whereas evidence for interaction with the PSORS1 risk allele in German individuals was marginal and did not remain significant after correction for multiple testing. Our study confirms the recently published finding that the deletion of the two LCE genes is a susceptibility factor for PsV with dosage effect, while, because of power limitation, no final conclusion regarding interaction with other PsV risk factors can be made at this stage. © 2010 The Society for Investigative Dermatology.
Cordiglieri C.,Max Planck Institute of Neurobiology |
Cordiglieri C.,Instituto Neurologico Carlo Besta |
Odoardi F.,Max Planck Institute of Neurobiology |
Odoardi F.,Foundation University |
And 18 more authors.
Brain | Year: 2010
Nicotinic acid adenine dinucleotide phosphate represents a newly identified second messenger in T cells involved in antigen receptor-mediated calcium signalling. Its function in vivo is, however, unknown due to the lack of biocompatible inhibitors. Using a recently developed inhibitor, we explored the role of nicotinic acid adenine dinucleotide phosphate in autoreactive effector T cells during experimental autoimmune encephalomyelitis, the animal model for multiple sclerosis. We provide in vitro and in vivo evidence that calcium signalling controlled by nicotinic acid adenine dinucleotide phosphate is relevant for the pathogenic potential of autoimmune effector T cells. Live two photon imaging and molecular analyses revealed that nicotinic acid adenine dinucleotide phosphate signalling regulates T cell motility and re-activation upon arrival in the nervous tissues. Treatment with the nicotinic acid adenine dinucleotide phosphate inhibitor significantly reduced both the number of stable arrests of effector T cells and their invasive capacity. The levels of pro-inflammatory cytokines interferon-gamma and interleukin-17 were strongly diminished. Consecutively, the clinical symptoms of experimental autoimmune encephalomyelitis were ameliorated. In vitro, antigen-triggered T cell proliferation and cytokine production were evenly suppressed. These inhibitory effects were reversible: after wash-out of the nicotinic acid adenine dinucleotide phosphate antagonist, the effector T cells fully regained their functions. The nicotinic acid derivative BZ194 induced this transient state of non-responsiveness specifically in post-activated effector T cells. Naïve and long-lived memory T cells, which express lower levels of the putative nicotinic acid adenine dinucleotide phosphate receptor, type 1 ryanodine receptor, were not targeted. T cell priming and recall responses in vivo were not reduced. These data indicate that the nicotinic acid adenine dinucleotide phosphate/calcium signalling pathway is essential for the recruitment and the activation of autoaggressive effector T cells within their target organ. Interference with this signalling pathway suppresses the formation of autoimmune inflammatory lesions and thus might qualify as a novel strategy for the treatment of T cell mediated autoimmune diseases. © 2010 The Author(s).
Vendl C.,University of Zürich |
Vendl C.,University of Wollongong |
Clauss M.,University of Zürich |
Stewart M.,University of Wollongong |
And 6 more authors.
Journal of Experimental Biology | Year: 2015
Fundamental differences in methane (CH4) production between macropods (kangaroos) and ruminants have been suggested and linked to differences in the composition of the forestomach microbiome. Using six western grey kangaroos (Macropus fuliginosus) and four red kangaroos (Macropus rufus), we measured daily absoluteCH4 production in vivo aswell asCH4 yield (CH4 per unit of intake of dry matter, gross energy or digestible fibre) by open-circuit respirometry. Two food intake levels were tested using a chopped lucerne hay (alfalfa) diet. Bodymass-specific absoluteCH4 production resembled values previously reported in wallabies and non-ruminant herbivores such as horses, and did not differ with food intake level, although there was no concomitant proportionate decrease in fibre digestibility with higher food intake. In contrast, CH4 yield decreased with increasing intake, and was intermediate between values reported for ruminants and non-ruminant herbivores. These results correspond to those in ruminants and other non-ruminant specieswhere increased intake (and hence a shorter digesta retention in the gut) leads to a lower CH4 yield.We hypothesize that rather than harbouring a fundamentally different microbiomein their foregut, the microbiome ofmacropods is in a particular metabolic state more tuned towards growth (i.e. biomass production) rather thanCH4 production. This is due to the short digesta retention time inmacropods and the known distinct 'digestawashing' in the gut of macropods, where fluids move faster than particles and hence most likely wash out microbes from the forestomach. Although our data suggest that kangaroos only produce about 27% of the body mass-specific volume of CH4 of ruminants, it remains to be modelled with species-specific growth rates and production conditions whether or not significantly lower CH4 amounts are emitted per kg of meat in kangaroo than in beef or mutton production. © 2015. Published by The Company of Biologists Ltd.
Dong Z.,University of Go ttingen |
Wang K.,University of Go ttingen |
Linh Dang T.K.,University of Go ttingen |
Welter M.,University of Go ttingen |
And 3 more authors.
BMC Bioinformatics | Year: 2014
Background: The identification of protein-protein interaction sites is a computationally challenging task and important for understanding the biology of protein complexes. There is a rich literature in this field. A broad class of approaches assign to each candidate residue a real-valued score that measures how likely it is that the residue belongs to the interface. The prediction is obtained by thresholding this score.Some probabilistic models classify the residues on the basis of the posterior probabilities. In this paper, we introduce pairwise conditional random fields (pCRFs) in which edges are not restricted to the backbone as in the case of linear-chain CRFs utilized by Li et al. (2007). In fact, any 3D-neighborhood relation can be modeled. On grounds of a generalized Viterbi inference algorithm and a piecewise training process for pCRFs, we demonstrate how to utilize pCRFs to enhance a given residue-wise score-based protein-protein interface predictor on the surface of the protein under study. The features of the pCRF are solely based on the interface predictions scores of the predictor the performance of which shall be improved.Results: We performed three sets of experiments with synthetic scores assigned to the surface residues of proteins taken from the data set PlaneDimers compiled by Zellner et al. (2011), from the list published by Keskin et al. (2004) and from the very recent data set due to Cukuroglu et al. (2014). That way we demonstrated that our pCRF-based enhancer is effective given the interface residue score distribution and the non-interface residue score are unimodal.Moreover, the pCRF-based enhancer is also successfully applicable, if the distributions are only unimodal over a certain sub-domain. The improvement is then restricted to that domain. Thus we were able to improve the prediction of the PresCont server devised by Zellner et al. (2011) on PlaneDimers.Conclusions: Our results strongly suggest that pCRFs form a methodological framework to improve residue-wise score-based protein-protein interface predictors given the scores are appropriately distributed. A prototypical implementation of our method is accessible at http://ppicrf.informatik.uni-goettingen.de/index.html. © 2014 Dong et al.; licensee BioMed Central Ltd.
Marchenko N.D.,State University of New York at Stony Brook |
Hanel W.,State University of New York at Stony Brook |
Li D.,State University of New York at Stony Brook |
Becker K.,State University of New York at Stony Brook |
And 3 more authors.
Cell Death and Differentiation | Year: 2010
The activity of p53 as an inducible transcription factor depends on its rapid nuclear stabilization after stress. However, surprisingly, mechanism(s) that regulate nuclear p53 accumulation are not well understood. The current model of stress-induced nuclear accumulation holds that a decrease in p53 nuclear export leads to its nuclear stabilization. We show here that regulated nuclear import of p53 also has a critical function. p53 import is mediated by binding to the importin-α3 adapter and is negatively regulated by ubiquitination. p53 harbors several nuclear localization signals (NLS), with the major NLS I located at amino-acids 305-322. We find that direct binding of p53 to importin-α3 depends on the positive charge contributed by lysine residues 319-321 within NLS I. The same lysines are also targets of MDM2-mediated ubiquitination. p53 ubiquitination occurs primarily in unstressed cells, but decreases dramatically after stress. Importin-α3 preferentially interacts with non-ubiquitinated p53. Thus, under normal growth conditions, ubiquitination of Lys 319-321 negatively regulates p53-importin-α3 binding, thereby restraining p53 import. Conversely, stress-induced accumulation of non-ubiquitinated p53 in the cytoplasm promotes interaction with importin-α3 and rapid import. In later phases of the stress response, blocked nuclear export also takes effect. We propose that p53 nuclear import defines an important novel level of regulation in the p53-mediated stress response. © 2010 Macmillan Publishers Limited All rights reserved.
Banaschewski T.,Central Institute of Mental Health |
Blomeyer D.,Central Institute of Mental Health |
Buchmann A.F.,Central Institute of Mental Health |
Poustka L.,Central Institute of Mental Health |
And 2 more authors.
Behavioral and Brain Sciences | Year: 2011
Developmental, epidemiological, and neurobiological studies indicate that the adaptive and maladaptive functions, as well as immediate and long-term consequences of drug use, may vary by age. Early initiation seems to be associated with a reduced ability to use drugs purposely in a temporally stable, non-addictive manner. Prevention strategies should consider social environmental factors and aim to delay age at initiation. © 2011 Cambridge University Press.