Biomedical subjects

Christian Hoppe

Publications and source records attributed to Christian Hoppe.

9 recordsLinked to original sources

PubMed2007

Structural analysis and prediction of protein mutant stability using distance and torsion potentials: role of secondary structure and solvent accessibility.

Analyzing the factors behind protein stability is a key research topic in molecular biology, and has direct implications on protein structure prediction and protein-protein interactions. We have analyzed protein stability upon point mutations using a distance-dependant pair potential representing mainly through-space interactions, and torsion angle potential representing mainly neighboring effects as a basic statistical mechanical setup for the analysis. The synergetic effect of accessible surface area and secondary structure preferences was used as a classifier for the potentials. In addition, short-, medium-, and long-range interactions of the protein environment were also analyzed. Two datasets of point mutations were taken for the comparison of theoretically predicted stabilizing energy values with experimental DeltaDeltaG and DeltaDeltaGH(2)O from thermal and chemical denaturation experiments. These include 1538 and 1603 mutations, respectively, and contain 101 proteins that share a wide range of sequence identity. The resulting force fields were carefully evaluated with different statistical tests. Results show a maximum correlation of 0.87 with a standard error of 0.71 kcal/mol between predicted and measured DeltaDeltaG values and a prediction accuracy of 85.3% (stabilizing or destabilizing) for all mutations together. A correlation of 0.77 (more than 80% prediction accuracy with a standard error of 0.95 kcal/mol) each for the test dataset of split-sample validation and fivefold crossvalidation was obtained and a correlation of 0.70 (77.4% prediction accuracy with a standard error of 1.17 kcal/mol) was shown by the jackknife test. The same model was implemented, and the results were analyzed for mutations with DeltaDeltaGH(2)O. A correlation of 0.78 (standard error 0.96 kcal/mol) was observed with a prediction efficiency of 84.65%. This model can be used for the future prediction of protein structural stability together with various experimental techniques.

Databases, Protein↗

PubMed2006

Elevated impulsivity and impaired decision-making cognition in heavy users of MDMA ("Ecstasy").

RATIONALE: In animal studies, the common club drug 3,4-methylendioxymethamphetamine (MDMA, "Ecstasy") consistently caused a prolonged loss of presynaptic serotonergic neurons, and evidence suggests that MDMA consumption may also affect the human serotonergic system. Serotonin (5-HT) has been implicated in the regulation of impulsivity and such executive functions as decision-making cognition. In fact, MDMA users have shown elevated impulsivity in two studies, but little is known about decision making in drug-free MDMA consumers. OBJECTIVE: The aim of this study was to examine the cognitive neurotoxicity of MDMA with regard to behavioral impulsivity and decision-making cognition. METHODS: Nineteen male, abstinent, heavy MDMA users; 19 male, abstinent cannabis users; and 19 male, drug-naïve controls were examined with the Matching Familiar Figures Test (MFFT) as well as with a Go/No-Go Task (GNG) for impulsivity and with a Gambling Task (GT) for executive functioning. RESULTS: MDMA users showed significantly elevated impulsivity in the MFFT Impulsivity score (I-score), but not in commission errors of the GNG, compared with controls. Cannabis users did not yield altered impulsivity compared with controls. In the GT, MDMA users performed significantly worse than cannabis consumers and controls, whereas cannabis users exhibited the same decision-making capacity as controls. In addition, the I-score as well as the decision-making performance was correlated with measures of MDMA intake. The I-score and the decision-making performance were also correlated. CONCLUSION: These results suggest that heavy use of MDMA may elevate behavioral impulsivity and impair decision-making cognition possibly mediated by a selective impairment of the 5-HT system.

Adult↗

PubMed2006

Discontinuation of anticonvulsant medication after epilepsy surgery in children.

PURPOSE: To evaluate the long-term outcome of medication-reduction/discontinuation trials after epilepsy surgery in pediatric patients. METHODS: Of the total Bonn pediatric surgical sample (1988-2001; n=251), we were able to obtain postsurgical follow-up data for 232 patients. We surveyed 140 of these patients by using a standardized telephone interview that addressed medication-reduction/discontinuation trials. RESULTS: Of the 140 surveyed patients, 102 completely discontinued medication. Seven of these patients had recurring seizures that were controlled again after restarting the medication. Of 102 patients, 101 were completely seizure free during the 3 months before the survey. Postsurgical epileptic events before the trial significantly increased the risk for recurring epileptic events after the trial. Two surveyed patients lost postsurgical seizure freedom after medication reduction. We were also able to identify from the records another nine patients with complete medication discontinuation and seven patients with medication reduction. Two of these latter patients lost postsurgical seizure freedom despite restarting their medication. The total rate of patients with medication-reduction/discontinuation trials was 55%. The seizure recurrence rate in these patients was 10%. Recurring seizures could not be controlled by restarted medication in 3% of the trials. Currently, 90% of patients with discontinuation trials were seizure free without medication. CONCLUSIONS: The reduction/withdrawal of anticonvulsant medication after successful epilepsy surgery has a low risk of seizure recurrence for pediatric patients in long-term follow-up, particularly in cases of complete postsurgical seizure freedom before the trial.

Adult↗

PubMed2006

Recent developments of the chemistry development kit (CDK) - an open-source java library for chemo- and bioinformatics.

The Chemistry Development Kit (CDK) provides methods for common tasks in molecular informatics, including 2D and 3D rendering of chemical structures, I/O routines, SMILES parsing and generation, ring searches, isomorphism checking, structure diagram generation, etc. Implemented in Java, it is used both for server-side computational services, possibly equipped with a web interface, as well as for applications and client-side applets. This article introduces the CDK's new QSAR capabilities and the recently introduced interface to statistical software.

Computational Biology↗

PubMed2005

Association between scalp hair-whorl direction and hemispheric language dominance.

Asymmetry is a common phenomenon in higher organisms. In humans, the cortical representation of language exhibits a high degree of asymmetry with a prevalence of about 90% of left hemispheric dominance, the underlying mechanisms of which are largely unknown. Another sign that exhibits a form of lateralization is the scalp hair-whorl direction, which is either clockwise or anti-clockwise. The scalp hair-whorl develops from the same germ layer as the nervous system, the ectoderm, between the 10th and 16th week in utero and has been shown to be associated with various neurodevelopmental disorders. Here, we use an established fMRI paradigm to examine the association of a solely biological marker of asymmetry, hair-whorl direction and language lateralization. We show that the mechanism that influences hair-whorl direction and handedness [Klar, A.J.S., 2003. Human handedness and scalp hair-whorl direction develop from a common genetic mechanism. Genetics 1651, 269-276.] also affects cerebral language dominance.

Adult↗

PubMed2005

Classification and comparison of ligand-binding sites derived from grid-mapped knowledge-based potentials.

We describe the application of knowledge-based potentials implemented in the MOE program to compare the ligand-binding sites of several proteins. The binding probabilities for a polar and a hydrophobic probe are calculated on a grid to allow easy comparison of binding sites of superimposed related proteins. The method is fast and simple enough to simultaneously use structural information of multiple proteins of a target family. The method can be used to rapidly cluster proteins into subfamilies according to the similarity of hydrophobic and polar fields of their ligand-binding sites. Regions of the binding site which are common within a protein family can be identified and analysed for the design of family-targeted libraries or those which differ for improvement of ligand selectivity. The field-based hierarchical clustering is demonstrated for three protein families: the ligand-binding domains of nuclear receptors, the ATP-binding sites of protein kinases and the substrate binding sites of proteases. More detailed comparisons are presented for serine proteases of the chymotrypsin family, for the peroxisome proliferator-activated receptor subfamily of nuclear receptors and for progesterone and androgen receptor. The results are in good accordance with structure-based analysis and highlight important differences of the binding sites, which have been also described in the literature.

Binding Sites↗

PubMed2005

Prediction of protein thermostability with a direction- and distance-dependent knowledge-based potential.

The increasing use of enzymes in industrial processes and the importance of understanding protein folding and stability have led to several attempts to predict and quantify the effect of every possible amino acid exchange (mutation) on the thermostability of proteins. In this article we describe a knowledge-based discrimination function that acts as a fast and reliable guide in protein engineering and optimization. The function used consists of two parts, a pairwise energy function based on a distance- and direction-dependent atomic description of the amino acid environment, and a torsion angle energy function. In a first step a training set of 11 proteins including 646 mutant proteins with experimentally determined thermostability was used to optimize the knowledge-based energy functions. The resulting potential function was then tested using a test mutant database consisting of 918 various point mutations introduced in 27 proteins. The best correlation coefficient obtained for the experimental data and the predicted thermostability for the training set is r = 0.81 (561 data points). A total of 76% of the mutations could be predicted correctly as being either stabilizing or destabilizing. The results for the test set are r = 0.74 (747 data points) and 72%, respectively. The global correlation over the combined data (1308 mutants) obtained is 0.78.

Databases, Protein↗

PubMed2004

Depressed mood and memory impairment in temporal lobe epilepsy as a function of focus lateralization and localization.

OBJECTIVE: Memory disorders and depressed mood are prominent psychological symptoms of temporal lobe epilepsies (TLEs). We examined the interaction of depressive mood and memory as a function of focus localization. METHODS: One hundred fifty-two TLE patients with right mesial (n=37, RTLE-AHS), right lateral (n=31, RTLE-LAT), left mesial (n=42, LTLE-AHS), and left lateral (n=42, LTLE-LAT) lesions and epilepsies underwent comprehensive presurgical evaluation and neuropsychological assessment of mood and memory. Univariate and multivariate analyses of covariance (ANCOVAs) and partial correlation analyses were performed to reveal interactions of depression and memory as a function of focus localization. RESULTS: No differences between the study groups were revealed for depression, indicating a general risk of 30% for depressed mood (BDI>12) in patients with TLE. ANCOVAs revealed significant main effects of focus side (left: verbal learning deficits; right: figural learning deficits) and site (mesial at disadvantage) on learning and memory scores. Correlation analyses revealed interactions between memory and mood only in LTLE-LAT patients. CONCLUSIONS: Although the data provide evidence that side and site of the epileptogenic region differentially affect material specific memory performance, there was no evidence of a specific temporal target region for depressive mood. In the majority of the patients, depressed mood and memory impairment appeared as independent rather than as related symptoms of TLE. In LTLE-LAT, however, mood was significantly related to verbal and figural memory performance. Epilepsy-driven pathological left temporofrontal circuits are discussed as a prerequisite for the coupling of mood disorders and memory impairment in this specific patient subgroup which is also known from the psychiatric major depression syndrome.

Adult↗

PubMed2002

The Adaptive Digit Ordering Test: clinical application, reliability, and validity of a verbal working memory test.

In the face of ample experimental evidence on the importance of working memory capacity for everyday life, there is a growing need for measures suited for clinical assessment of working memory. For this purpose, the Adaptive Digit Ordering Test (DOT-A), a new version of a digit ordering test introduced by Cooper et al. [Brain 114 (1991) 2095], was developed in analogy to the Digit spans. In Study 1, we investigated DOT-A performance in patients with Parkinson's disease (PD) and patients with frontal lobe damage, as these groups often exhibit working memory impairments within the framework of executive dysfunctions. In comparison with matched controls, both patient groups showed reduced performance in DOT-A but not in Digit span performance. This pattern was found to be particularly sensitive for patients with PD. In Study 2, DOT-A performance was assessed in 50 healthy subjects carefully selected according to demographic criteria in order to ensure representativity. Parallel test and split-half correlations indicated sufficient reliability of the DOT-A. Concurrent validity was confirmed by significant correlation with a well-established working memory test (two-back task). We conclude that DOT-A is a promising diagnostic instrument, and its economy and direct comparability to the Wechsler Digit spans and high sensitivity for patient populations make it especially well-suited for assessment in clinical practice.

Journal Article↗