University of Tübingen

About: University of Tübingen is a education organization based out in Tübingen, Germany. It is known for research contribution in the topics: Population & Immune system. The organization has 40555 authors who have published 84108 publications receiving 3015320 citations. The organization is also known as: Eberhard Karls University & Eberhard-Karls-Universität Tübingen.

Specificity prediction of adenylation domains in nonribosomal peptide synthetases (NRPS) using transductive support vector machines (TSVMs)

Abstract: We present a new support vector machine (SVM)- based approach to predict the substrate specificity of subtypes of a given protein sequence family. We demonstrate the usefulness of this method on the example of aryl acid-activating and amino acid- activating adenylation domains (A domains) of nonri- bosomal peptide synthetases (NRPS). The residues of gramicidin synthetase A that are 8 Aaround the substrate amino acid and corresponding positions of other adenylation domain sequences with 397 known and unknown specificities were extracted and used to encode this physico-chemical fingerprint into normalized real-valued feature vectors based on the physico-chemical properties of the amino acids. The SVM software package SVM light was used for training and classification, with transductive SVMs to take advantage of the information inherent in unlabeled data. Specificities for very similar sub- strates that frequently show cross-specificities were pooled to the so-called composite specificities and predictive models were built for them. The reliab- ility of the models was confirmed in cross-validations and in comparison with a currently used sequence- comparison-based method. When comparing the predictions for 1230 NRPS A domains that are cur- rently detectable in UniProt, the new method was able to give a specificity prediction in an additional 18% of the cases compared with the old method. For 70% of the sequences both methods agreed, for ,6% they did not, mainly on low-confidence predic- tions by the existing method. None of the predictive methods could infer any specificity for 2.4% of the sequences, suggesting completely new types of specificity.

Genetic diagnosis of Mendelian disorders via RNA sequencing

Abstract: Across a variety of Mendelian disorders, ∼50-75% of patients do not receive a genetic diagnosis by exome sequencing indicating disease-causing variants in non-coding regions. Although genome sequencing in principle reveals all genetic variants, their sizeable number and poorer annotation make prioritization challenging. Here, we demonstrate the power of transcriptome sequencing to molecularly diagnose 10% (5 of 48) of mitochondriopathy patients and identify candidate genes for the remainder. We find a median of one aberrantly expressed gene, five aberrant splicing events and six mono-allelically expressed rare variants in patient-derived fibroblasts and establish disease-causing roles for each kind. Private exons often arise from cryptic splice sites providing an important clue for variant prioritization. One such event is found in the complex I assembly factor TIMMDC1 establishing a novel disease-associated gene. In conclusion, our study expands the diagnostic tools for detecting non-exonic variants and provides examples of intronic loss-of-function variants with pathological relevance.

Performance Test of an LSO-APD Detector in a 7-T MRI Scanner for Simultaneous PET/MRI

Abstract: PET combined with CT has proven to be a valuable multimodality imaging device revealing both functional and anatomic information. Although PET/CT has become completely integrated into routine clinical application and also has been used in small-animal imaging, CT provides only limited soft-tissue contrast and, in preclinical studies, exposes the animal to a relatively high radiation dose. Unlike CT, MRI provides good soft-tissue contrast even without application of contrast agents and, furthermore, does not require ionizing radiation. Methods: This project focused on combining a high-resolution PET scanner with a 7-T MRI system for animal research. Because classic PET detectors based on photomultiplier tubes cannot be used in high magnetic fields, we used a detector technology based on 10 × 10 lutetium oxyorthosilicate crystal arrays and 3 × 3 avalanche photodiode arrays. A ring of such PET detectors will ultimately be used as an insert for the 119-mm-diameter MRI bore. Results: Initial measurements with 1 PET detector module in the 7-T field during application of MRI sequences were encouraging. Position profiles from the PET detectors and a first MR image of a mouse could be acquired simultaneously. Conclusion: Further work will concentrate on the construction of a full PET detector ring with compact, integrated electronics.

Cutting Edge: Receptor-Mediated Endocytosis of Heat Shock Proteins by Professional Antigen-Presenting Cells

Abstract: Immunization with heat shock proteins (HSPs) induces Ag-specific CTL responses The specificity of the immune response is based on peptides associated with HSPs To investigate how exogenous HSP/peptide complexes gain access to the MHC class I-restricted Ag presentation pathway, we incubated the monocytic cell line P388D1 and the dendritic cell line D2SC/1 with gold-labeled HSPs gp96 and HSC70 We show that HSPs bind specifically to the surface of these APCs and are internalized spontaneously by receptor-mediated endocytosis, demonstrating the existence of specific receptors for HSPs on these cells In addition, we observe colocalization of internalized HSPs and surface MHC class I molecules in early and late endosomal structures These findings provide possible explanations for the immunogenicity of HSP/peptide complexes and for the transfer of HSP-associated peptides onto MHC class I molecules