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R Zimmer

Publications and source records attributed to R Zimmer.

At least 37 records · Page 2Linked to original sources
PubMed1999

Protein threading by recursive dynamic programming.

We present the recursive dynamic programming (RDP) method for the threading approach to three-dimensional protein structure prediction. RDP is based on the divide-and-conquer paradigm and maps the protein sequence whose backbone structure is to be found (the protein target) onto the known backbone structure of a model protein (the protein template) in a stepwise fashion, a technique that is similar to computing local alignments but utilising different cost functions. We begin by mapping parts of the target onto the template that show statistically significant similarity with the template sequence. After mapping, the template structure is modified in order to account for the mapped target residues. Then significant similarities between the yet unmapped parts of the target and the modified template are searched, and the resulting segments of the target are mapped onto the template. This recursive process of identifying segments in the target to be mapped onto the template and modifying the template is continued until no significant similarities between the remaining parts of target and template are found. Those parts which are left unmapped by the procedure are interpreted as gaps. The RDP method is robust in the sense that different local alignment methods can be used, several alternatives of mapping parts of the target onto the template can be handled and compared in the process, and the cost functions can be dynamically adapted to biological needs. Our computer experiments show that the RDP procedure is efficient and effective. We can thread a typical protein sequence against a database of 887 template domains in about 12 hours even on a low-cost workstation (SUN Ultra 5). In statistical evaluations on databases of known protein structures, RDP significantly outperforms competing methods. RDP has been especially valuable in providing accurate alignments for modeling active sites of proteins.RDP is part of the ToPLign system (GMD Toolbox for protein alignment) and can be accessed via the WWW independently or in concert with other ToPLign tools at http://cartan.gmd.de/ToPLign.html.

Amino Acid Sequence↗
PubMed1999

Application of parameter optimization to molecular comparison problems.

Various bioinformatics comparison problems require optimizing several different properties simultaneously. Often linear objective functions combine the values for different properties of solution candidates into a single score to allow for multivariate optimization. In this context, an essential question is how each property should be weighted. Frequently, no apparent measure is available to serve as a model for the score. However, if preferences of certain solution candidates over others in a training set are available, the implied partial ordering may be used to best possibly adjust the weights. We apply different strategies to optimize the parameterization of empirical scoring functions used for two molecular comparison problems, protein threading and small molecule superposition. Using well established evaluation methods, it can be shown that the results of both comparison methods are significantly improved by systematically choosing appropriate weights for the scoring function contributions.

Algorithms↗
PubMed1998

New scoring schemes for protein fold recognition based on Voronoi contacts.

MOTIVATION: The genome projects produce a wealth of protein sequences. Theoretical methods to predict possible structures and functions are needed for screening purposes, large-scale comparisons and in-depth analysis to identify worthwhile targets for further experimental research. Sequence-structure alignment is a basic tool for the identification of model folds for protein sequences and the construction of crude structural models. Empirical contact potentials (potentials of mean force) are used to optimize and evaluate such alignments. RESULTS: We propose new scoring schemes based on a contact definition derived from Voronoi decompositions of the three-dimensional coordinates of protein structures. We demonstrate that Voronoi potentials are superior to pure distance-based contact potentials with respect to recognition rate and significance for native folds. Moreover, the scoring scheme has the potential to provide a reasonable balance of detail and ion such that it is also useful for the recognition of distantly related (both homologous and non-homologous) proteins. This is demonstrated here on a set of structural alignments showing much better correspondence of native and model scores for the Voronoi potentials as compared to conventional distance-based potentials. AVAILABILITY: The potentials are made available via the program system ToPLign (URL: http://cartan.gmd.de/ToPLign.html). CONTACT: Ralf.Zimmer,Ralf.Thiele@gmd.de

Algorithms↗
PubMed1997

Construction and characterization of a large-fragment chicken bacterial artificial chromosome library.

A large-insert bacterial artificial chromosome (BAC) library has been constructed from male chicken genomic DNA using the new pBeloBAC11 vector. The library was prepared in two parts, such that two-thirds of the BAC library (2976 clones) had an average insert size of 490 kb (80 clones analyzed), after optimization of transformation and HMW DNA size-selection conditions. Fragments of increased average size were cloned by coupling a second size strategy using pulsed-field gel electrophoresis with optimized electroporation that favored transformation of Escherichia coli DH10B cells with very large plasmids. The initial one-third of this library (1440 clones) was constructed using the standard protocols and had an average insert size of 180 kb (40 clones analyzed). The overall library consists, at present, of 4416 clones with a combined insert size average of 390 kb (ranging from 25 to 725 kb). At least 95% of the BAC clones contain inserts. This is partially due to a second color selection performed with respect to white colonies, as well as to the optimized ligation conditions used. Based on the percentage of clones with inserts and the analysis of insert sizes, we estimate this library to represent a 0.8-fold coverage of the chicken genome. Southern blot analysis and fluorescence in situ hybridization were performed to confirm the identity of the BAC inserts with chicken genomic DNA. Analysis of large chicken BAC inserts showed that they were stably propagated for at least 120 cell generations. The results indicate that the BAC system is able to carry stably very large genomic fragments of chicken DNA, this system translating into a powerful tool for physical mapping and positional cloning of the chicken genome.

Animals↗
PubMed1997

Variability of cerebral blood flow deficits in 99mTc-HMPAO SPECT in patients with Alzheimer's disease.

The purpose of this study was to analyse the frequency of the different pathological perfusion patterns in SPECT in a clinical, unselected population of patients with Alzheimer's disease. In 91 patients and 16 control subjects regional cerebral blood flow (rCBF) was measured with Single Photon Emission Computed Tomography (SPECT) using 99mTc-hexa-methyl-propyleneamine oxime (HMPAO). 95% confidence intervals obtained from the perfusion values of the control subjects were used to define normal perfusion ranges. The frequency of perfusion deficits in the left frontal, temporal, parietal and occipital lobes were 62.2%, 60.4%. 70.3% and 23.1%, respectively. In the right hemisphere the corresponding values were 60.4%, 58.2%, 63.7% and 9.9%. With the exception of the occipital lobes these frequencies were not significantly different. The analysis of the perfusion pattern of each patient revealed 35 different combinations of lobes with perfusion deficits. The temporo-parietal perfusion deficits were not more frequent than the temporofrontal perfusion deficits. These results suggest that in the clinical routine a high variety of heterogeneous rCBF patterns have to be expected.

Aged↗
PubMed1997

Generation of chicken Z-chromosome painting probes by microdissection for screening large-insert genomic libraries.

A strategy for rapid generation of chicken sex chromosome-Z painting probes has been developed using microdissection. Whole chromosome painting probes (WCPs) were prepared from 10-15 copies of mitotic metaphase chicken Z chromosomes. The microisolated chromosomes were subjected to PEG/proteinase K treatment in a collection drop to release DNA, which was then amplified using a degenerate oligonucleotide-primed shuttle PCR (DOP-Shuttle-PCR) strategy. Size distributions of the PCR products were analyzed by agarose gel electrophoresis and smears of DNA were revealed that ranged in size from 200-800 bp, without any evidence of preferential amplification. Both specificity and complexity of the probes have been analyzed by Southern blot and fluorescence in situ hybridization (FISH). Non-specific hybridization was efficiently blocked by using chicken competitor DNA. Analysis of the WCPs produced shows that collectively they provide uniform hybridization signals along the entire length of the chicken Z chromosome. To demonstrate one possible application of these complex probes, we screened a large-insert bacterial artificial chromosome (BAC) chicken genomic library to select Z chromosome-specific clones. To address specificity of the selected clones and to physically map them to the Z chromosome, FISH analysis was used. Of the 3 clones initially tested, one clone (C3) carrying a 250-kb insert mapped to the distal portion of the short arm of the chicken Z chromosome. Therefore, this technique has provided appropriate probes for screening large-insert genomic libraries. Further application of these probes includes the analysis of chromosome rearrangements, studies of cases of heteroploidy involving the Z chromosome, positional cloning of Z-linked genes and studies on mechanisms of sex-chromosome evolution in birds.

Animals↗
PubMed1996

Apolipoprotein E type 4 allele and Alzheimer's disease: effect on age at onset and relative risk in different age groups.

The effect of the apolipoprotein E (apoE) genotype on the age at onset of Alzheimer's disease (AD) and the relative risk conferred by the apoE epsilon 4 allele were studied in 91 patients and 69 healthy age-matched controls. According to the age of presentation, which varied from 44 to 95 years, subjects were divided into four groups. The inheritance of at least one epsilon 4 allele was associated with a significant reduction of the age at onset by 7.7 years among patients who were 83 years or older when examined. A weaker inverse relationship between the epsilon 4 allele and the age at onset was also observed among patients who were aged 44-63 years at presentation. The effect of the epsilon 4 allele was minimal or absent in the two intermediate age categories. The relative risk of AD conferred by the inheritance of at least one epsilon 4 allele showed no consistent age-related pattern. The overall risk expressed as an odds ratio was 5.0 (95% CI 2.4-10.5). With respect to the limitations of the study, we tentatively conclude (1) that the effect of the apoE epsilon 4 allele on the age at onset is not restricted to AD patients of a particular age, in accordance with current hypotheses on the role of apoE gene products in the biology of AD; (2) that the relative risk of AD associated with the epsilon 4 allele is not significantly modulated by age. Although the apoE epsilon 4 allele is an important susceptibility factor for AD occurring in middle age as well as in later life, it is of limited value in routine clinical diagnosis and should not be used for predictive testing in asymptomatic individuals.

Age Factors↗
PubMed1995

Apolipoprotein E genotype in patients with Alzheimer's disease: implications for the risk of dementia among relatives.

Numerous studies have shown that the risk of Alzheimer's disease (AD) is associated with the dose of the epsilon 4 allele of apolipoprotein E (ApoE). However, more than one third of AD patients lack epsilon 4 and many persons having epsilon 4 survive cognitively intact to old age. We evaluated the lifetime risk of disease in 3,999 first-degree relatives of 549 probands who met the criteria for probable or definite AD and whose ApoE genotypes were known. ApoE genotypes for relatives were not determined. After age 65 the risk among relatives was proportional, as much as 7 to 10% at age 85, to the number of epsilon 4 alleles present in the proband. Risks to relatives of ApoE 2/2 and 2/3 probands were nearly identical at all ages to risks for relatives of ApoE 3/3 probands. The expected proportion of relatives having at least one epsilon 4 allele was calculated for each genotype group based on the distribution of parents, sibs, and offspring in the sample. Among relatives in the ApoE 3/3 group, the lifetime risk for AD by age 90 was three times greater than the expected proportion of epsilon 4 carriers, suggesting that factors other than ApoE contribute to AD susceptibility. Furthermore, the 44% risk of AD by age 93 among relatives of ApoE 4/4 probands indicates that as many as 50% of people having at least one epsilon 4 allele do not develop AD. We also found that among male relatives, risk of AD in the ApoE 3/4 group was similar to that for the ApoE 3/3 group but significantly less than the risk for the ApoE 4/4 group. In contrast, among female relatives the risk for the ApoE 3/4 group was nearly twice that for the ApoE 3/3 group and identical to the risk for the ApoE 4/4 group. These findings are consistent with a sex-modification effect of the E4 isoform on disease susceptibility.

Age of Onset↗
PubMed1995

Recursive dynamic programming for adaptive sequence and structure alignment.

We propose a new alignment procedure that is capable of aligning protein sequences and structures in a unified manner. Recursive dynamic programming (RDP) is a hierarchical method which, on each level of the hierarchy, identifies locally optimal solutions and assembles them into partial alignments of sequences and/or structures. In contrast to classical dynamic programming, RDP can also handle alignment problems that use objective functions not obeying the principle of prefix optimality, e.g. scoring schemes derived from energy potentials of mean force. For such alignment problems, RDP aims at computing solutions that are near-optimal with respect to the involved cost function and biologically meaningful at the same time. Towards this goal, RDP maintains a dynamic balance between different factors governing alignment fitness such as evolutionary relationships and structural preferences. As in the RDP method gaps are not scored explicitly, the problematic assignment of gap cost parameters is circumvented. In order to evaluate the RDP approach we analyse whether known and accepted multiple alignments based on structural information can be reproduced with the RDP method. For this purpose, we consider the family of ferredoxins as our prime example. Our experiments show that, if properly tuned, the RDP method can outperform methods based on classical sequence alignment algorithms as well as methods that take purely structural information into account.

Amino Acid Sequence↗
PubMed1995

The dynamics of pulsatile flow in distensible model arteries.

Deposits and blockages are often found in the carotid, coronary, renal and femoral arteries. This paper deals with laser-Doppler velocity measurements in models of bifurcations of the human femoral arteries. Several models were prepared for the studies: a simplified 35 degrees glass model, two elastic-silicone-rubber models with a wall thickness of 1 mm and 2 mm, and true-to-scale rigid and elastic models. These measurements give a clearer picture of how hemodynamics influences the formation of atherosclerotic plaques where there is a hardening of the arterial walls and a loss of elasticity. In addition to the effects of elasticity, the influence of the flow's pulsatility were studied. The measurements were done in steady and pulsatile flow. From the velocity measurements the shear stresses were calculated.

Arteries↗
PubMed1994

Phylogenetic analysis of the Coscoroba coscoroba using mitochondrial srRNA gene sequences.

In order to study the phylogenetic relationships among Coscoroba, goose, and swan lineages, sequences for the complete mitochondrial small ribosomal RNA (srRNA) gene were determined from five waterfowl species. Parsimony and distance analyses support the branching of Coscoroba prior to the divergence of geese and swans, and maximum likelihood analyses give almost equal support to that pattern and to the sister group relationship between Coscoroba and swans. The monophyly of the geese was confirmed at a statistically significant level. In sequence comparisons among waterfowl, transitions increase linearly with transversions, and so we conclude that the lack of complete resolution of Coscoroba's position is not due to sequence saturation alone, but also reflects relatively close branching times.

Animals↗
PubMed1994

[The apolipoprotein E-epsilon 4 allele is a risk factor for Alzheimer disease with early and late onset].

The apolipoprotein E genotype was determined in 50 patients with clinically diagnosed and prospectively confirmed Alzheimer's disease of mild to moderate severity and in 50 healthy age- and sex-matched controls. The frequency of the epsilon 4 allele was increased in the patients irrespective of the age at onset and of a possible familial transmission of the disease. It was associated with a relative risk of 2.97. In patients who experienced first symptoms after the age of 65 years there was an inverse correlation between the number of epsilon 4 alleles and age at onset. The results suggest that in the absence of amyloid precursor protein mutations and of a gene which has not yet been precisely localized on chromosome 14, apolipoprotein E is involved in the pathogenesis of Alzheimer's disease. It probably exerts its influence by an acceleration or retardation of amyloid formation and/or tau hyperphosphorylation.

Aged↗
PubMed1991

[Visual evoked potentials in Alzheimer's and Parkinson disease].

Harding et al. suggested at first that an increase of P2 latency in flash VEP without an increase of P2 latency in pattern reversal VEP may be a diagnostic marker of Alzheimer's disease. Up to now there is no convincing evidence for this hypothesis. The purpose of the present study was to examine this hypotheses in an extended group of patients with Alzheimer's disease (n = 36). In addition, a group of patients with Parkinson's disease (n = 8) without dementia syndrome and a group of healthy elderly controls (n = 46) was investigated in order to determine the sensitivity and specificity of these VEP parameters. The results confirmed significant group differences between patients with Alzheimer's disease and healthy controls concerning the increase of Flash P2 latency and unchanged latency of P2 in the pattern reversal VEP. No significant correlations were found between duration of illness and mental test scores. The group differences of P2 latency in the flash VEP for patients with Parkinson's disease and healthy controls were also significant. Therefore, the increase of flash P2 latency in VEP does not seem to be specific for Alzheimer's disease nor for dementia syndrome. The pathological mechanism causing the flash P2 latency increase in a remarkable number of neuropsychiatric patients should be elucidated in further experimental investigations.

Aged↗
PubMed1991

[Manifestations of Alzheimer's disease in daily living].

From the perspective offered by diagnostic criteria, cognitive rating scales and psychometric tests, Alzheimer's disease appears to be primarily a continuous decline of memory and intelligence. Changes in other areas of behaviour often go unrecognized at examination or are considered insignificant. A completely different view is offered by the reports of care-givers. Here, impairment of everyday activities, abnormal emotional and social behaviours are the most important features. To examine the everyday manifestation of Alzheimer's disease at greater detail, a questionnaire for care-givers was developed. Observations of patients' behaviours as recorded on this instrument demonstrate the presence of significant changes of affect and drive even in mild stages of the disorder. They show only weak associations with cognitive symptoms and cannot be explained as psychological reactions. The non-cognitive aspects of Alzheimer's disease deserve particular diagnostic and therapeutic interest.

Activities of Daily Living↗
PubMed1990

Evaluation and comparison of the interaction between alcohol and moclobemide or clomipramine in healthy subjects.

The interaction of clomipramine and moclobemide with alcohol was compared in a double blind parallel groups study in 24 healthy volunteers. Moclobemide was given at the highest recommended therapeutic dose (200 mg t.i.d.) and clomipramine in a subtherapeutic dose (25 mg b.i.d.) because of its poor tolerance in healthy subjects. Psychometric evaluations were performed during a placebo run-in phase; after a 5-day treatment period; assessments were made before, and again 1 h and 4 h after alcohol ingestion. Alcohol doses were pre-determined for each subject in order to produce a blood alcohol concentration of 0.6 g/l 1 h after alcohol intake and this individual alcohol dose was given on test days. The day before alcohol intake tests for autonomic functions were made to assess the anticholinergic effects of the drugs. Alcohol significantly increased body sway, decreased critical flicker fusion frequency, prolonged choice reaction time, impaired copying skills, impaired memory and increased the subjective feelings of satisfaction and tension. Drugs increased the effect of alcohol on body sway and this was essentially due to clomipramine. Clomipramine both without and with alcohol increased body sway, prolonged choice reaction time more than did moclobemide. Clomipramine seemed to diminish alcohol-induced memory impairment in one of the memory tests used. Subjects taking clomipramine had significantly more adverse effects after alcohol ingestion than did subjects of the moclobemide group. In contrast to moclobemide, clomipramine produced a moderate but significant drop in standing systolic blood pressure and a clear inhibition of salivary excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Comparison of the monoamine oxidase inhibiting properties of two reversible and selective monoamine oxidase-A inhibitors moclobemide and toloxatone, and assessment of their effect on psychometric performance in healthy subjects.

1. The effects of two reversible, predominantly monoamine oxidase-A (MAO-A) inhibitors, moclobemide (150 mg three times daily) and toloxatone (400-200-400 mg day-1) on monoamine metabolites and psychometric performance were compared in a double-blind placebo controlled crossover study in 12 healthy subjects. 2. After 7 days of moclobemide/toloxatone/placebo administration subjects were hospitalized for 24 h on day 8. Blood samples were drawn every 2 h for determination of plasma noradrenaline (NA), 3,4-dihydroxyphenylglycol (DHPG), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA). Urine was collected for measurements of normetanephrine and 3-methoxytyramine excretion. Psychometric performance (short- and long-term memory, critical flicker fusion frequency, choice reaction time) and subjective feelings were assessed before each drug intake (in the morning, at noon, in the evening). 3. Compared with placebo, both reversible monoamine oxidase inhibitors decreased the plasma concentration of DHPG and HVA. The overall fall in DHPG (AUC from 0 to 24 h) was 44% during moclobemide and 12% during toloxatone (P less than 0.001) and the overall decrease in HVA was 38% and 20% (P less than 0.005) on moclobemide and toloxatone, respectively. 4. Before the next drug intake, MAO-A inhibition, as judged by the decrease of plasma DHPG concentration, was significantly different from placebo with moclobemide but not with toloxatone. 5. Moclobemide, but not toloxatone, exerted a moderate, but significant inhibition of the deamination of 5-hydroxytryptamine (5-HT) as judged by the fall in plasma 5-HIAA concentration. Neither drug influenced plasma NA concentration. 6. A significant rise in urinary excretion of normetanephrine was observed on moclobemide and to a lesser extent on toloxatone. The urinary excretion of 3-methoxytyramine was significantly raised by moclobemide but not by toloxatone. 7. Neither moclobemide nor toloxatone altered memory function, vigilance, subjective feelings or sleep characteristics of the subjects.

Adult↗