Biomedical subjects

Hanspeter Herzel

Publications and source records attributed to Hanspeter Herzel.

36 records · Page 2Linked to original sources

PubMed2005

Aggregation in Huntington's disease: insights through modelling.

Huntington's Disease (HD) is a late-onset, progressively degenerative brain disorder characterized by cell loss in the striatum and cortex. HD is caused by a polyglutamine (polyQ) expansion in the protein huntingtin (Htt). The mutant Htt is a substrate for caspases -2, -3 and -6. The cleavage of mutant Htt by caspase-2 has been suggested to underlie the selective neuronal death in HD. Once the mutant Htt is cleaved, a sticky and toxic fragment with the potential to form aggregates is released. The role of aggregation in the progression of HD has been extensively studied, yielding a plethora of ambivalent results. It has been shown that these are the diffuse, monomeric and oligomeric, forms of the mutant Htt fragment rather than the aggregates that are the major source of toxicity to the cells. We present here a mathematical model for aggregation in HD and discuss how it can relate to the selective neuronal death and the dependence of the disease onset on polyQ length. We describe the dynamical behavior of caspase-2, the release of monomeric forms of the mutant Htt fragment and the aggregation of these fragments through intermediate steps. Our model predicts that the concentration of toxic, intermediate oligomeric structures does not increase with increased caspase activity. We therefore suggest that the intermediate oligomeric forms of toxic Htt fragment do not account for selective and polyQ dependent neuronal death.

Age of Onset↗

PubMed2004

Sequence-related human proteins cluster by degree of evolutionary conservation.

Gene duplication followed by adaptive evolution is thought to be a central mechanism for the emergence of novel genes. To illuminate the contribution of duplicated protein-coding sequences to the complexity of the human genome, we study the connectivity of pairwise sequence-related human proteins and construct a network (N) of linked protein sequences with shared similarities. We find that (i) the connectivity distribution P (k) for k sequence-related proteins decays as a power law P (k) approximately k(-gamma) with gamma approximately 1.2 , (ii) the top rank of N consists of a single large cluster of proteins ( approximately 70%) , while bottom ranks consist of multiple isolated clusters, and (iii) structural characteristics of N show both a high degree of clustering and an intermediate connectivity ("small-world" features). We gain further insight into structural properties of N by studying the relationship between the connectivity distribution and the phylogenetic conservation of proteins in bacteria, plants, invertebrates, and vertebrates. We find that (iv) the proportion of sequence-related proteins increases with increasing extent of evolutionary conservation. Our results support that small-world network properties constitute a footprint of an evolutionary mechanism and extend the traditional interpretation of protein families.

Chromosome Mapping↗

PubMed2004

Periodicities of 10-11bp as indicators of the supercoiled state of genomic DNA.

DNA sequences contain information about the bendability and native conformation of DNA. For example, a repetition of certain dinucleotides at distances of 10-11bp supports wrapping around nucleosomes and supercoiled structures of bacterial DNA. We analyzed 86 eubacterial genomes, 16 archaea, and six genomes of higher eukaryotes. First, we discuss whether or not the observed periodicities represent indeed bendability signals. This claim is confirmed since: (1) dinucleotide signals are of comparable size to mononucleotide signals, (2) the signals are present in non-coding DNA as well, and (3) repeat masking has only a minor effect on 10-11bp periodicities. Moreover, the periodicities persist up to 150bp, comparable to the nucleosome size. We show that doublet peaks in Caenorhabditis elegans and some prokaryotes can be traced back to long-ranging modulations. In mammalian genomes, we find consistently spectral peaks as observed earlier in human chromosomes 20, 21 and 22. It has been shown in previous studies that archaea have periods of 10bp, whereas eubacteria exhibit 11bp periodicities. These differences reflect different supercoiled states of microbial DNA. Is the period of 10bp an archaeal or a thermophilic feature? This question is addressed by relating periodicities to optimal growth temperatures. It turns out that the archaea Methanopyrus kandleri (t(opt)=80 degrees C) and a Halobacterium strain (t(opt)=42 degrees C) both have longer periods of about 11bp. Eubacterial genomes have consistently periods around 11bp indicative of negative supercoiling.

Animals↗

PubMed2004

Modeling feedback loops of the Mammalian circadian oscillator.

The suprachiasmatic nucleus governs daily variations of physiology and behavior in mammals. Within single neurons, interlocked transcriptional/translational feedback loops generate circadian rhythms on the molecular level. We present a mathematical model that reflects the essential features of the mammalian circadian oscillator to characterize the differential roles of negative and positive feedback loops. The oscillations that are obtained have a 24-h period and are robust toward parameter variations even when the positive feedback is replaced by a constantly expressed activator. This demonstrates the crucial role of the negative feedback for rhythm generation. Moreover, it explains the rhythmic phenotype of Rev-erbalpha-/- mutant mice, where a positive feedback is missing. The interplay of negative and positive feedback reveals a complex dynamics. In particular, the model explains the unexpected rescue of circadian oscillations in Per2Brdm1/Cry2-/- double-mutant mice (Per2Brdm1 single-mutant mice are arrhythmic). Here, a decrease of positive feedback strength associated with mutating the Per2 gene is compensated by the Cry2-/- mutation that simultaneously decreases the negative feedback strength. Finally, this model leads us to a testable prediction of a molecular and behavioral phenotype: circadian oscillations should be rescued when arrhythmic Per2Brdm1 mutant mice are crossed with Rev- erbalpha -/- mutant mice.

Adaptation, Physiological↗

PubMed2004

Bifurcation analysis of the regulatory modules of the mammalian G1/S transition.

MOTIVATION: Mathematical models of the cell cycle can contribute to an understanding of its basic mechanisms. Modern simulation tools make the analysis of key components and their interactions very effective. This paper focuses on the role of small modules and feedbacks in the gene-protein network governing the G1/S transition in mammalian cells. Mutations in this network may lead to uncontrolled cell proliferation. Bifurcation analysis helps to identify the key components of this extremely complex interaction network. RESULTS: We identify various positive and negative feedback loops in the network controlling the G1/S transition. It is shown that the positive feedback regulation of E2F1 and a double activator-inhibitor module can lead to bistability. Extensions of the core module preserve the essential features such as bistability. The complete model exhibits a transcritical bifurcation in addition to bistability. We relate these bifurcations to the cell cycle checkpoint and the G1/S phase transition point. Thus, core modules can explain major features of the complex G1/S network and have a robust decision taking function.

Animals↗

PubMed2004

HOMGL-comparing genelists across species and with different accession numbers.

UNLABELLED: Homology Gene List (HOMGL) is a web-based tool for comparing gene lists with different accession numbers and identifiers and between different organisms. UniGene, LocusLink, HomoloGene and Ensembl databases are utilized to map between these lists and to retrieve upstream or transcribed sequences for genes in these lists. We illustrate the use of HOMGL with respect to microarray studies and promoter analysis. AVAILABILITY: http://homgl.biologie.hu-berlin.de/

Algorithms↗

PubMed2004

High reproducibility of large-gel two-dimensional electrophoresis.

Two-dimensional gel electrophoresis (2-DE) facilitates the separation of thousands of proteins from highly complex protein mixtures and has become a central method in proteomics in recent years. In the present study, we examined the technical variability of large 2-DE gels with respect to sample preparation, electrophoresis procedure, data acquisition, and biological variation by analyzing a disease (Huntington's disease) and control state with a commercially available software package, PROTEOMWEAVER trade mark. Scatter plots and correlation coefficients were obtained to quantify both technical and biological variation. Even 2-DE gels run separately in both dimensions yielded correlation coefficients around 0.88 and deviations from the mean close to 20% for low-intensity spots. This indicates a high technical reproducibility of the 2-DE procedure developed in our laboratory. Variability within a biological condition was low and comparable to technical variation (at least 0.87). Two-dimensional (2-D) gels obtained from samples of different biological conditions (health vs. disease) achieved a variability similar to intracondition and technical variability. These findings highlight the importance of multiple gel and spot-by-spot comparisons to identify biological significant changes. Minor errors introduced by technical and biological variation allow a comparison of all gels within a study which facilitates the tackling of complex biological problems.

Animals↗

PubMed2004

Nonlinear phenomena in contemporary vocal music.

Complex and multiphonic voice signals of vocal improvisors are analyzed within the framework of nonlinear dynamics. Evidence is given that nonlinear phenomena are extensively used by performers associated with contemporary music. Narrow-band spectrograms of complex vocalizations are used to visualize the appearance of nonlinear phenomena (spectral bifurcation diagrams). Possible production mechanisms are discussed in connection with previous research, personal performance and pedagogical experience. Examples for period doubling, biphonation and irregular aperiodic phonation in vocal sonorities of contemporary vocal improvisors are given, and glottal whistle production encompassed with biphonation and triphonation is shown. Furthermore, coincidences of harmonics-formant matching associated with abrupt transitions to subharmonics and biphonation in the vocal output are provided. This also shows the recurrent use of nonlinear phenomena by performers. It is argued that mechanisms such as source-tract coupling or vocal fold desynchronization due to asymmetry are used in a reproducible way for musical tasks.

Acoustics↗

PubMed2004

A model of the mammalian circadian oscillator including the REV-ERBalpha module.

Many cellular and physiological processes have been shown to display a rhythm of about 24 hours. This so-called circadian rhythm is based on a system of interlocked negative and positive molecular feedback loops. Here we extend a previous model of the circadian oscillator by including REV-ERBalpha as an additional component. This new model will allow us to investigate the function of an additional negative feedback loop via REV-ERBalpha. We obtain circadian oscillations with the correct period and phase relations between clock components. Parameter variations that correspond to clock-gene mutations reproduce experimental results: With parameter variations mimicking the Bmal1(-/-) and the Per2(Brdm1) mutation the oscillations cease to exist. In contrast, the system shows sustained oscillations if we use a parameter set that reflects the Rev-erbalpha mutation. The model also accounts for the differential effect of the Cry1(-/-) and Cry2(-/-) mutations on the circadian period. The simulations of the extended model indicate that the original model is robust with respect to the incorporation of the additional component. Depending on the kinetics of the Per2/Cry transcriptional activation by BMAL1, an increasing BMAL1 expression leads to either an increase or decrease of the clock period. This indicates that overexpression experiments could help to characterize the impact of BMAL1 on Per2/Cry transcription.

Animals↗

PubMed2004

Prediction of cis-regulatory elements of coregulated genes.

We present a computational pipeline to predict cis-regulatory elements composing results based on different algorithms: Clover, Cluster-Buster, an own implementation of human/rat/mouse sequence identity and our ITB algorithm. The procedure uses information from the human genome sequence, NCBI gene annotations, verified eukaryotic promoters (EPD), experimentally proven binding sites (Transfac) and homologies to mouse and rat (HomGL/HomoloGene). We test the approach on 18 upstream regions of experimentally verified AP-1 target genes. About a half of the known sites belong to high-scoring candidates. Three top-scoring elements are confirmed by Cluster-Buster and high homologies. The same analysis we applied to genes found to be up- or downregulated due to mutated RAS. We performed a detailed literature and computational search for promoter regions. Indications of overrepresented Elk-1 and AP-1 motifs are found via a comparison with shuffled sequences. In some promoters consistent predictions of clustered binding sites were obtained.

Animals↗

PubMed2003

How robust are switches in intracellular signaling cascades?

Since all-or-none decisions of the cell are controlled by extracellular signals, cells have biochemical switches within their intracellular signaling networks. Central elements of these switches are multisite phosphorylation, enzymic saturation, and amplification by cascades. Moreover, positive feedback can contribute to switch-like behavior termed also ultrasensitivity. Here we analyse the robustness of these mechanisms exemplified by models of the three-molecule MAPK-cascade and the single-molecule Goldbeter-Koshland switch. We show that the ultrasensitivity in the MAPK-cascades is more robust against changes of the kinetic parameters than the Goldbeter-Koshland switch. If multiple parameters are changed randomly, the effects of parameter changes can compensate each other in the cascade leading to a remarkable robustness of the switch-like behavior. The different degrees of robustness can be traced back to the different mechanisms of generating ultrasensitivity. While in the Goldbeter-Koshland switch the saturation of the enzymes are crucial, in the MAPK-cascade the adjustment of working ranges determines the ultrasensitivity. Our results indicate that amplification of ultrasensitivity in cascades and multisite phosphorylation might be a design principle to achieve robust switches.

Animals↗

PubMed2003

Repeats and correlations in human DNA sequences.

We study the nucleotide-nucleotide mutual information function I(k) of the DNA sequences of the three completely sequenced human chromosomes 20, 21, and 22. We find in each human chromosome (i) the absence of the k=3 base pair (bp) sequence periodicity characteristic for protein coding regions, (ii) the absence of the k=10-11 bp sequence periodicity characteristic for both protein secondary structure and DNA bendability, and (iii) the presence of significant statistical dependencies at about k=135 bp and at about k=165 bp. We investigate to which degree the density and composition of interspersed repeats might explain these observed statistical patterns in all three human chromosomes. We use simple stochastic models to substitute known interspersed repeats and find by numerical studies that (iv) the presence of interspersed repeats dominates short-range correlations as measured by I(k) on the scale of several hundred base pairs in human chromosomes 20, 21, and 22. On the other hand, we find that (v) interspersed repeats contribute only weakly to long-range correlations due to the clustering of highly abundant Alu repeats.

Alu Elements↗

PubMed2003

Experimental and computational analysis of transcriptional start sites in the cyanobacterium Prochlorococcus MED4.

In contrast to certain model eubacteria, little is known as to where transcription is initiated in the genomes of cyanobacteria, which are largely distinct from other prokaryotes. In this work, 25 transcription start sites (TSS) of 21 different genes of Prochlorococcus sp. MED4 were determined experimentally. The data suggest more than one TSS for the genes ftsZ, petH, psbD and ntcA. In contrast, the rbcL-rbcS operon encoding ribulose 1,5-bisphosphate carboxylase/oxygenase lacks a detectable promoter and is co-transcribed with the upstream located gene ccmK. The entire set of experimental data was used in a genome-wide scan for putative TSS in Prochlorococcus. A -10 element could be defined, whereas at the -35 position there was no element common to all investigated sequences. However, splitting the data set into sub-classes revealed different types of putative -35 boxes. Only one of them resembled the consensus sequence TTGACA recognized by the vegetative sigma factor (sigma70) of enterobacteria. Using a scoring matrix of the -10 element, more than 3000 TSS were predicted, about 40% of which were estimated to be functional. This is the first systematic study of transcription initiation sites in a cyanobacterium.

Base Sequence↗

PubMed2002

Identification of distinct antibody epitopes and mimotopes from a peptide array of 5520 randomly generated sequences.

We used a relatively small library of 5520 randomly generated single 15-mer peptides prepared by SPOT synthesis as an array of 28.5x19.0 cm to identify epitopes for three distinct monoclonal antibodies, namely anti-p24 (human immunodeficiency virus (HIV)-1) monoclonal anibody (mab) CB4-1, anti-interleukin-10 (IL-10) mab CB/RS/13, and anti-transforming growth factor alpha (TGFalpha) mab Tab2. Initially identified peptide ligands mostly had very low affinities for the antibodies with dissociation constants around 10(-4) M. Subsequent identification of residues critical for the antibody interactions involved complete L-amino acid substitutional analyses. Several substitutions resulted in analogs with dissociation constants in the low micromolar and high nanomolar range. Specifically binding peptides with key residue patterns matching the wild-type epitopes were identified for all three antibodies. In addition, for antibody CB4-1 mimotopes that showed no homology to the known epitope were selected. Our results suggest that a very limited library diversity, although far from covering the entire sequence repertoire, can suffice to rapidly and economically select peptidic antibody epitopes and mimotopes.

Combinatorial Chemistry Techniques↗

PubMed2002

Nonlinear analysis of irregular animal vocalizations.

Animal vocalizations range from almost periodic vocal-fold vibration to completely atonal turbulent noise. Between these two extremes, a variety of nonlinear dynamics such as limit cycles, subharmonics, biphonation, and chaotic episodes have been recently observed. These observations imply possible functional roles of nonlinear dynamics in animal acoustic communication. Nonlinear dynamics may also provide insight into the degree to which detailed features of vocalizations are under close neural control, as opposed to more directly reflecting biomechanical properties of the vibrating vocal folds themselves. So far, nonlinear dynamical structures of animal voices have been mainly studied with spectrograms. In this study, the deterministic versus stochastic (DVS) prediction technique was used to quantify the amount of nonlinearity in three animal vocalizations: macaque screams, piglet screams, and dog barks. Results showed that in vocalizations with pronounced harmonic components (adult macaque screams, certain piglet screams, and dog barks), deterministic nonlinear prediction was clearly more powerful than stochastic linear prediction. The difference, termed low-dimensional nonlinearity measure (LNM), indicates the presence of a low-dimensional attractor. In highly irregular signals such as juvenile macaque screams, piglet screams, and some dog barks, the detectable amount of nonlinearity was comparatively small. Analyzing 120 samples of dog barks, it was further shown that the harmonic-to-noise ratio (HNR) was positively correlated with LNM. It is concluded that nonlinear analysis is primarily useful in animal vocalizations with strong harmonic components (including subharmonics and biphonation) or low-dimensional chaos.

Animals↗

PubMed2001

Extracting information from cDNA arrays.

High-density DNA arrays allow measurements of gene expression levels (messenger RNA abundance) for thousands of genes simultaneously. We analyze arrays with spotted cDNA used in monitoring of expression profiles. A dilution series of a mouse liver probe is deployed to quantify the reproducibility of expression measurements. Saturation effects limit the accessible signal range at high intensities. Additive noise and outshining from neighboring spots dominate at low intensities. For repeated measurements on the same filter and filter-to-filter comparisons correlation coefficients of 0.98 are found. Next we consider the clustering of gene expression time series from stimulated human fibroblasts which aims at finding co-regulated genes. We analyze how preprocessing, the distance measure, and the clustering algorithm affect the resulting clusters. Finally we discuss algorithms for the identification of transcription factor binding sites from clusters of co-regulated genes. (c) 2001 American Institute of Physics.

Journal Article↗

PubMed1995

Nonlinear dynamics of the voice: Signal analysis and biomechanical modeling.

Irregularities in voiced speech are often observed as a consequence of vocal fold lesions, paralyses, and other pathological conditions. Many of these instabilities are related to the intrinsic nonlinearities in the vibrations of the vocal folds. In this paper, bifurcations in voice signals are analyzed using narrow-band spectrograms. We study sustained phonation of patients with laryngeal paralysis and data from an excised larynx experiment. These spectrograms are compared with computer simulations of an asymmetric 2-mass model of the vocal folds. (c) 1995 American Institute of Physics.

Journal Article↗

PubMedDate not supplied

Alternans and 2:1 rhythms in an ionic model of heart cells.

ECG alternans is commonly held to be an indicator of electrical instability of the heart, but the development of alternans has not yet been fully understood theoretically. We investigate the onset of alternans and 2:1 rhythms for stimulation at increasing frequencies in the Beeler-Reuter model, a simple ionic model of cardiac tissue. We find hysteresis and bistability at the onset of alternans; well-timed stimuli can switch between the two limit cycles. We determine quantitatively the effect of blocking specific ionic currents. Moreover, we find that calcium buffers generally promote alternans.

Action Potentials↗