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Thorsten Schmidt

Publications and source records attributed to Thorsten Schmidt.

18 recordsLinked to original sources
PubMed2026

Importin-8 silencing reduces Ataxin-3 aggregation and alleviates Machado-Joseph disease/spinocerebellar ataxia type 3.

Machado-Joseph disease (MJD) is a polyglutamine neurodegenerative disorder characterized by the formation of neuronal intranuclear Ataxin-3 inclusions. The nucleocytoplasmic transport is known to be profoundly dysregulated from early stages of neurodegeneration, further aggravating its progressive nature. To understand the contribution of these proteins in MJD, we screened the effect of 34 transport proteins on Ataxin-3 aggregation. Importin-8 (Ipo8 gene) was selected for further neuropathology and behavior analysis to evaluate its modulatory effect in vitro and in vivo. Our results showed that Ipo8 mRNA expression is increased in MJD and that, upon Ipo8 downregulation, Ataxin-3 aggregation and neuronal dysfunction are reduced in vitro and in vivo. Furthermore, Ipo8 silencing was demonstrated to alleviate ataxic traits in vivo. Collectively, our findings indicate that Importin-8 may exert its protective effect by modulating NF-kb/p65 and Argonaute-2 proteins, also previously linked to MJD, standing as a promising therapeutic target to delay disease progression.

Argonaute-2↗
PubMed2006

PEDANT genome database: 10 years online.

The PEDANT genome database provides exhaustive annotation of 468 genomes by a broad set of bioinformatics algorithms. We describe recent developments of the PEDANT Web server. The all-new Graphical User Interface (GUI) implemented in Javatrade mark allows for more efficient navigation of the genome data, extended search capabilities, user customization and export facilities. The DNA and Protein viewers have been made highly dynamic and customizable. We also provide Web Services to access the entire body of PEDANT data programmatically. Finally, we report on the application of association rule mining for automatic detection of potential annotation errors. PEDANT is freely accessible to academic users at http://pedant.gsf.de.

Computer Graphics↗
PubMed2006

Expression mapping of tetracycline-responsive prion protein promoter: digital atlasing for generating cell-specific disease models.

We present a digital atlas system that allows mapping of molecular expression patterns at cellular resolution through large series of histological sections. Using this system, we have mapped the distribution of a distinct marker, encoded by the LacZ reporter gene driven by the tetracycline-responsive prion protein promoter in double transgenic mice. The purpose is to evaluate the suitability of this promoter mouse line for targeting genes of interest to specific brain regions, essential for construction of inducible transgenic disease models. Following processing to visualize the promoter expression, sections were counterstained to simultaneously display cytoarchitectonics. High-resolution mosaic images covering entire coronal sections were collected through the mouse brain at intervals of 200 microm. A web-based application provides access to a customized virtual microscopy tool for viewing and navigation within and across the section images. For each section image, the nearest section in a standard atlas is defined, and annotations of key structures and regions inserted. Putative categorization of labeled cells was performed with use of distribution patterns, followed by cell size and shape, as parameters that were compared to legacy data. Among the ensuing results were expression of this promoter in putative glial cells in the cerebellum (and not in Purkinje cells), in putative glial cells in the substantia nigra, in pallidal glial cells or interneurons, and in distinct cell layers and regions of the hippocampus. The study serves as a precursor for a database resource allowing evaluation of the suitability of different promoter mouse lines for generating disease models.

Animals↗
PubMed2006

PROMPT: a protein mapping and comparison tool.

BACKGROUND: Comparison of large protein datasets has become a standard task in bioinformatics. Typically researchers wish to know whether one group of proteins is significantly enriched in certain annotation attributes or sequence properties compared to another group, and whether this enrichment is statistically significant. In order to conduct such comparisons it is often required to integrate molecular sequence data and experimental information from disparate incompatible sources. While many specialized programs exist for comparisons of this kind in individual problem domains, such as expression data analysis, no generic software solution capable of addressing a wide spectrum of routine tasks in comparative proteomics is currently available. RESULTS: PROMPT is a comprehensive bioinformatics software environment which enables the user to compare arbitrary protein sequence sets, revealing statistically significant differences in their annotation features. It allows automatic retrieval and integration of data from a multitude of molecular biological databases as well as from a custom XML format. Similarity-based mapping of sequence IDs makes it possible to link experimental information obtained from different sources despite discrepancies in gene identifiers and minor sequence variation. PROMPT provides a full set of statistical procedures to address the following four use cases: i) comparison of the frequencies of categorical annotations between two sets, ii) enrichment of nominal features in one set with respect to another one, iii) comparison of numeric distributions, and iv) correlation of numeric variables. Analysis results can be visualized in the form of plots and spreadsheets and exported in various formats, including Microsoft Excel. CONCLUSION: PROMPT is a versatile, platform-independent, easily expandable, stand-alone application designed to be a practical workhorse in analysing and mining protein sequences and associated annotation. The availability of the Java Application Programming Interface and scripting capabilities on one hand, and the intuitive Graphical User Interface with context-sensitive help system on the other, make it equally accessible to professional bioinformaticians and biologically-oriented users. PROMPT is freely available for academic users from http://webclu.bio.wzw.tum.de/prompt/.

Computational Biology↗
PubMed2006

Will my protein crystallize? A sequence-based predictor.

We propose a machine-learning approach to sequence-based prediction of protein crystallizability in which we exploit subtle differences between proteins whose structures were solved by X-ray analysis [or by both X-ray and nuclear magnetic resonance (NMR) spectroscopy] and those proteins whose structures were solved by NMR spectroscopy alone. Because the NMR technique is usually applied on relatively small proteins, sequence length distributions of the X-ray and NMR datasets were adjusted to avoid predictions biased by protein size. As feature space for classification, we used frequencies of mono-, di-, and tripeptides represented by the original 20-letter amino acid alphabet as well as by several reduced alphabets in which amino acids were grouped by their physicochemical and structural properties. The classification algorithm was constructed as a two-layered structure in which the output of primary support vector machine classifiers operating on peptide frequencies was combined by a second-level Naive Bayes classifier. Due to the application of metamethods for cost sensitivity, our method is able to handle real datasets with unbalanced class representation. An overall prediction accuracy of 67% [65% on the positive (crystallizable) and 69% on the negative (noncrystallizable) class] was achieved in a 10-fold cross-validation experiment, indicating that the proposed algorithm may be a valuable tool for more efficient target selection in structural genomics. A Web server for protein crystallizability prediction called SECRET is available at http://webclu.bio.wzw.tum.de:8080/secret.

Amino Acid Sequence↗
PubMed2005

The PEDANT genome database in 2005.

The PEDANT genome database (http://pedant.gsf.de) contains pre-computed bioinformatics analyses of publicly available genomes. Its main mission is to provide robust automatic annotation of the vast majority of amino acid sequences, which have not been subjected to in-depth manual curation by human experts in high-quality protein sequence databases. By design PEDANT annotation is genome-oriented, making it possible to explore genomic context of gene products, and evaluate functional and structural content of genomes using a category-based query mechanism. At present, the PEDANT database contains exhaustive annotation of over 1,240,000 proteins from 270 eubacterial, 23 archeal and 41 eukaryotic genomes.

Computational Biology↗
PubMed2005

Feasibility of pulmonary ventilation visualization with aerosolized magnetic resonance contrast media.

OBJECTIVE: The objective of this study was to evaluate a new approach to noninvasive magnetic resonance assessment of human pulmonary ventilation with aerosolized Gd-DTPA. MATERIALS AND METHODS: Fifteen experimental procedures were carried out in 15 healthy volunteers on a 1.5-T imager. For a timespan of 10 minutes, the subjects spontaneously inhaled a commercially available Gd-DTPA magnetic resonance contrast agent in aerosolized form through an inflatable facemask. Gd-DTPA was aerosolized by means of a small-particle generator with integrated heater to increase aerosol production. Respiratory gated dynamic T1-weighted turbo spin echo images were obtained before and after contrast agent aerosol administration. After nebulization, homogeneity of aerosol distribution was graded by 2 experienced readers and pulmonary signal intensity (SI) changes were measured in corresponding regions of both lungs. RESULTS: Pulmonary ventilation visualization, and hence contrast agent delivery, was rated homogeneously distributed by both readers in 14 of 15 cases (93.3%) and slightly inhomogeneous in 1 case (6.7%). Pulmonary SI increased by an average of +37% +/- 8.5 (range, 10-48%). Allergic responses were not noted. CONCLUSIONS: Human ventilation imaging with aerosolized gadolinium-chelates is viable. The presented modality might evolve as an alternative to current nuclear medicine and magnetic resonance image ventilation imaging procedures, avoiding radiation exposure while offering functional ventilation assessment with an acceptable temporal and spatial resolution. Nevertheless, further evaluation is required to define the potential of gadolinium-based ventilation magnetic resonance imaging in illustrating lung disease.

Adult↗
PubMed2005

Radiation dose reduction to the male gonads during MDCT: the effectiveness of a lead shield.

OBJECTIVE: Our study was designed to quantify the effect of a standard gonad shield on the testicular radiation exposure due to scatter during routine abdominopelvic MDCT. SUBJECTS AND METHODS: Routine abdominopelvic MDCT was performed in 34 patients with gonadal lead shielding and 32 patients without this shielding; the testes were not exposed to the direct beam during the examination. We estimated the testicular dose administered with thermoluminescent dosimetry, taking into account each patient's body weight and body mass index (BMI). RESULTS: With a 1-mm lead shield, the mean testicular dose was reduced from 2.40 to 0.32 mSv, a reduction of 87%. The difference was found to be statistically significant (p < 0.0001). No correlation between testicular dose and body weight or BMI was found. CONCLUSION: Shielding the male gonads reduces the testicular radiation dose during abdominopelvic MDCT significantly and can be recommended for routine use.

Adult↗
PubMed2004

Phase-inversion tissue harmonic imaging compared with conventional B-mode ultrasound in the evaluation of pancreatic lesions.

The aim of this study was to compare the diagnostic sensitivity, specificity, and image quality of conventional B-mode US (BM) and phase-inversion tissue harmonic imaging (PTHI) regarding pancreatic pathology. In a prospective study, 107 patients, aged between 28 and 85 years, underwent US examinations of the pancreas with both BM and PTHI in a randomly chosen order. As diagnostic reference, either contrast-enhanced CT or MRI examinations of the upper abdomen were obtained in all patients. Sensitivity and specificity were evaluated using the Student's t test. Differences in overall image quality, lesion conspicuity, fluid-solid differentiation, and delineation of the pancreatic tail were analyzed using Wilcoxon's signed ranks test and Bowker's symmetry test. Sixteen of 107 examined patients (15%) were non-diagnostic and excluded due to technical limitations such as abdominal gas. A total of 60 pancreatic lesions (cysts, acute pancreatitis, dilatation of the pancreatic duct, calcifications, and solid tumors) were diagnosed by CT or MRI. Phase-inversion tissue harmonic imaging had a higher sensitivity of 70% (14 of 20) than BM (60%; 24 of 40) for the detection of pancreatic lesions; however, the difference was not statistically significant ( p=0.46). In the assessment of lesions <1 cm of size, PTHI had a sensitivity of 70% and BM 46.7%, whereby the difference again was not statistically significant. Phase-inversion tissue harmonic imaging proved to be superior to BM regarding overall image quality ( p<0.0001), lesion conspicuity ( p=0.0045), and fluid-solid differentiation ( p=0.0002), as well as the delineation of the pancreatic tail ( p<0.0001). These differences were statistically significant. The statistically significant improvement of image quality with regards to lesion conspicuity, fluid-solid differentiation, and delineation of the pancreatic tail favors the use of PTHI when evaluating the pancreas with US. Sensitivity for pancreatic lesions is increased with PTHI in comparison with conventional sonography (BM), especially in lesions <1 cm in diameter, although the difference was not statistically significant.

Adult↗
PubMed2004

Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis.

Autosomal dominant cerebellar ataxias are hereditary neurodegenerative disorders that are known as spinocerebellar ataxias (SCA) in genetic nomenclature. In the pregenomic era, ataxias were some of the most poorly understood neurological disorders; the unravelling of their molecular basis enabled precise diagnosis in vivo and explained many clinical phenomena such as anticipation and variable phenotypes even within one family. However, the discovery of many ataxia genes and loci in the past decade threatens to cause more confusion than optimism among clinicians. Therefore, the provision of guidance for genetic testing according to clinical findings and frequencies of SCA subtypes in different ethnic groups is a major challenge. The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent. Elucidation of the pathogenesis of SCA hopefully will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically.

Cell Death↗
PubMed2003

Transgenic rat model of Huntington's disease.

Huntington's disease (HD) is a late manifesting neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat of more than 39 units in a gene of unknown function. Several mouse models have been reported which show rapid progression of a phenotype leading to death within 3-5 months (transgenic models) resembling the rare juvenile course of HD (Westphal variant) or which do not present with any symptoms (knock-in mice). Owing to the small size of the brain, mice are not suitable for repetitive in vivo imaging studies. Also, rapid progression of the disease in the transgenic models limits their usefulness for neurotransplantation. We therefore generated a rat model transgenic of HD, which carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter. This is the first transgenic rat model of a neurodegenerative disorder of the brain. These rats exhibit adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and slowly progressive motor dysfunction as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. As in HD patients, in vivo imaging demonstrates striatal shrinkage in magnetic resonance images and a reduced brain glucose metabolism in high-resolution fluor-deoxy-glucose positron emission tomography studies. This model allows longitudinal in vivo imaging studies and is therefore ideally suited for the evaluation of novel therapeutic approaches such as neurotransplantation.

Animals↗
PubMed2003

New experience with the paracardial right ventricular axial flow micropump impella elect 600.

Beating heart surgery is still challenging and could be made safer using assisted circulation. We evaluated clinical outcome following beating heart myocardial revascularisation using the impella elect system with intracardial left ventricular (LV) and paracardial right ventricular (RV) microaxial pumps in eight patients. Clinical course was uneventful. There were no device-related complications. The paracardial design of the RV-pump is a great advantage compared to the former intracardial design because it eliminates arrhythmia and LV hypovolemia. Support by microaxial pumps can make beating heart surgery safer and applicable for more complex cases.

Aged↗
PubMed2003

Diagnostic accuracy of phase-inversion tissue harmonic imaging versus fundamental B-mode sonography in the evaluation of focal lesions of the kidney.

OBJECTIVE: We compared phase-inversion tissue harmonic imaging with fundamental B-mode sonography in the evaluation of focal lesions of the kidney. SUBJECTS AND METHODS: For our prospective study, 114 patients underwent sonography of the kidneys in both modes, fundamental B-mode sonography and phase-inversion tissue harmonic imaging, in a randomly chosen scanning order. Imaging parameters were standardized. Sonographic diagnoses were made under real-time conditions by the examining radiologist. All sonographic diagnoses were compared with a diagnostic reference modality: contrast-enhanced CT, contrast-enhanced MR imaging, or histopathology. Three radiologists different from the examiners evaluated overall image quality, lesion conspicuity, and fluid-solid differentiation for both modalities using hard-copy images. RESULTS: In 70 patients, fundamental B-mode sonography as the first technique depicted 73 of 111 lesions 10 mm or larger and enabled 71 lesions to be correctly characterized (sensitivity, 65.8%; accuracy, 64.0%). As the first mode, phase-inversion tissue harmonic imaging depicted 57 of 65 focal lesions and enabled 54 lesions to be accurately classified in 44 patients (sensitivity, 87.7%; accuracy, 83.1%). The differences in sensitivity and accuracy were statistically significant (95% confidence interval). For overall image quality, lesion conspicuity, and fluid-solid differentiation phase-inversion harmonic imaging was superior to fundamental B-mode sonography (p < 0.0001). CONCLUSION: Phase-inversion tissue harmonic imaging is superior to fundamental B-mode sonography in the sonography of focal kidney lesions because phase-inversion tissue harmonic imaging has better overall image quality, lesion conspicuity, and fluid-solid differentiation. In six cases, phase-inversion tissue harmonic imaging added crucial diagnostic information that changed patient management.

Adult↗
PubMed2002

Location of the H atoms in ammonium persulphate by deuteron NMR. Verification by X-ray diffraction.

It is demonstrated that H atoms can be located by the spectroscopic method of deuteron NMR. The requirement is that the 'heavy-atom' positions are known from diffraction studies. The technique allows an accuracy of the order of 0.01 A. The compound studied is ammonium persulphate (APS), (NH(4))(2)S(2)O(8). APS crystallizes in space group P2(1)/n with lattice parameters a = 6.1340 (2), b = 7.9324 (3), c = 7.7541 (3) A and beta = 94.966 (1) degrees at T = 118 K. In perdeuterated crystals of APS, only one of the deuterons of every ND(4)(+) ion becomes localized at low temperatures. Therefore, most of this work uses samples with 9% deuteration. In such crystals, most of the ammonium ions containing deuterons come in the form of NDH(3)(+) ions. At T < 25 K, the single deuteron of these ions becomes localized in one of four equilibrium sites. The deuteron site occupancies differ from each other and are measured at 17 K. The deuterons are located in three steps. (i) The deuteron quadrupole-coupling (QC) tensors are measured at 17 K. Their unique principal directions are identified, as is well justified, with the N-D bond directions. (ii) The fine structure of a deuteron NMR line is analyzed in terms of the magnetic dipole-dipole interactions between all nuclei in an NDH(3)(+) ion to obtain the N-D and D-H internuclear distances. (iii) An empirical relation between deuteron QC constants and D.O distances in N-D.O hydrogen bonds is exploited to assign the N-D bond vectors to the appropriate N atom of which there are four in the unit cell. The results are highly relevant for an understanding of the complex tunnelling and stochastic reorientation dynamics of the ammonium ions in APS. They are verified by a complementary X-ray diffraction study.

Journal Article↗
PubMed2002

High levels of the onco-protein Gfi-1 accelerate T-cell proliferation and inhibit activation induced T-cell death in Jurkat T-cells.

Gfi-1 is a nuclear zinc finger protein with the activity of a transcriptional repressor and the ability to predispose for the development of T-cell lymphoma when expressed constitutively at high levels. Whereas thymic T-cell precursors express endogenous Gfi-1, mature peripheral T-cells lack Gfi-1 but upregulate its expression transiently after antigenic stimulation and activation of Erk1/2 demonstrating a role of Gfi-1 in T-cell activation. Here we show that constitutive expression of Gfi-1 accelerates S phase entry of primary, resting T-cells upon antigenic stimulation. In addition, high level Gfi-1 expression inhibits phorbol ester induced G1 arrest and activation induced cell death in Jurkat T-cells. We demonstrate that these effects of Gfi-1 concur with lower absolute levels and hyperphosphorylation of the pocket protein pRb. Moreover, phorbol ester induced expression of the negative cell cycle regulator p21(WAF1) is blocked in the presence of Gfi-1. These findings suggest that Gfi-1 contributes to T-cell lymphomagenesis by overriding a late G1 cell cycle checkpoint which controls activation induced death and S phase entry of T-cells.

Animals↗
PubMed2002

Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1.

The transcriptional repressor Gfi1 is a nuclear zinc-finger protein expressed in T-cell precursors in the thymus and in activated mature T lymphocytes. Previous experiments have shown that Gfi1 is involved in T-cell lymphomagenesis and in the development of T-cell progenitors. Here we show that Gfi1 is also expressed outside the lymphoid system in granulocytes and activated macrophages, cells that mediate innate immunity (that is, non-specific immunity). We have generated Gfi1-deficient mice (Gfi1-/-) and show that these animals are severely neutropenic and accumulate immature monocytic cells in blood and bone marrow. Their myeloid precursor cells are unable to differentiate into granulocytes upon stimulation with granulocyte colony-stimulating factor (G-CSF) but can develop into mature macrophages. We found that Gfi1-/- macrophages produce enhanced levels of inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-10 (IL-10) and IL-1beta, when stimulated with bacterial lipopolysaccharide (LPS) and that Gfi1-/- mice succumb to low doses of this endotoxin that are tolerated by wildtype mice. We conclude that Gfi1 influences the differentiation of myeloid precursors into granulocytes or monocytes and acts in limiting the inflammatory immune response.

Animals↗
PubMed2002

Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions.

Intracellular aggregates commonly forming neuronal intranuclear inclusions are neuropathological hallmarks of spinocerebellar ataxia type 3 and of other disorders characterized by expanded polyglutamine-(poly-Q) tracts. To characterize cellular responses to these aggregates, we performed an immunohistochemical analysis of neuronal intranuclear inclusions in pontine neurons of patients affected by spinocerebellar ataxia type 3, using a panel of antibodies directed against chaperones and proteasome subunits. A subset of the neuronal intranuclear inclusions stained positively for the chaperones Hsp90alpha and HDJ-2, a member of the Hsp40 family. Most neuronal intranuclear inclusions were ubiquitin positive, suggesting degradation by ubiquitin-dependent proteasome pathways. Surprisingly, only a fraction of neuronal intranuclear inclusions were immunopositive for antibodies directed against subunits of the 20S proteolytic core, whereas most inclusions were stained by antibodies directed against subunits of the 11S and 19S regulatory particles. These results suggest that the proteosomal proteolytic machinery that actively degrades neuronal intranuclear inclusions is assembled in only a fraction of pontine neurons in end stage spinocerebellar ataxia type 3. The dissociation between regulatory subunits and the proteolytic core and the changes in subcellular subunit distribution suggest perturbations of the proteosomal machinery in spinocerebellar ataxia type 3 brains.

Adenosine Triphosphatases↗