Biomedical subjects

R Heinrich

Publications and source records attributed to R Heinrich.

At least 19 recordsLinked to original sources

PubMed2006

[Geriatrics in Bavaria-Database (GiB-DAT): Conception, structure and results of implementation (part I)].

In the year 2000, a database was implemented in Bavaria, covering the majority of geriatric clinics. Benchmarking statistics are generated in quarterly periods and scientifically analyzed. Actually, 41 of the 57 geriatric clinics in Bavaria participate in the project 'Geriatrics in Bavaria-Database' (GiB-DAT). For geriatric rehabilitation, the coverage is 82.4%. In addition, all 7 geriatric day clinics participate; thus, a total of 24,000 cases are documented each year. Therefore, GiB-DAT is the largest database for geriatric rehabilitation in Germany and Europe. To make documentation more effective and easy, new software (GERIDOCTM) has been generated which is integrated in the process of daily treatment. GiB-DAT offers good data quality, especially concerning completeness of items. This manuscript describes conception and construction of GiB-DAT and identifies differences compared to the Geriatric Minimum-Dataset (GEMIDAS), a nationwide geriatric database in Germany.

Aged↗

PubMed2006

[Geriatrics in Bavaria-Database (GiB-DAT): Basic data analysis of geriatric rehabilitation in Bavaria and analysis of inter-clinic variability (part II)].

OBJECTIVE: Presentation and comparison of basic data from geriatric rehabilitation in Bavaria with analysis of statistical influences on characteristic values like length of stay and Barthel Index. Are differences between participating clinics due to patient characteristics? SETTING: There were a total of 21 656 data records of the Geriatrics in Bavaria- Database (GiB-DAT) collected by 35 clinics within 1 year. RESULTS (PERCENTAGE OR MEAN): 70.6% female patients, age 80.0 years, 95.9% enrollment from acute care hospitals, length of stay in previous hospitals 24.3 days, length of stay in geriatric rehabilitation 24.6 days. DIAGNOSIS: 41.7% orthopedics, 24.9% neurological, 33.4% others. Barthel Index on admission 44.1 points, on discharge 65.8 points (difference 21.8 points). We found a large variance of all items between participating clinics. Variance for Barthel Index and length of stay is partly cleared up by regression analysis (multinomial logistic) and is mostly due to patient characteristics. CONCLUSIONS: Basic data of Bavarian geriatric rehabilitation clinics is matching with nationwide reference statistics. Differences exist for the lower rate of stroke and direct enrollment of outpatients. A simple ranking of outcome parameters (e. g. Barthel Index) does not make sense due to multiple influencing factors.

Aged↗

PubMed2006

Primary mouse hepatocytes for systems biology approaches: a standardized in vitro system for modelling of signal transduction pathways.

Complex cellular networks regulate regeneration, detoxification and differentiation of hepatocytes. By combining experimental data with mathematical modelling, systems biology holds great promises to elucidate the key regulatory mechanisms involved and predict targets for efficient intervention. For the generation of high-quality quantitative data suitable for mathematical modelling a standardised in vitro system is essential. Therefore the authors developed standard operating procedures for the preparation and cultivation of primary mouse hepatocytes. To reliably monitor the dynamic induction of signalling pathways, the authors established starvation conditions and evaluated the extent of starvation-associated stress by quantifying several metabolic functions of cultured primary hepatocytes, namely activities of glutathione-S-transferase, glutamine synthetase, CYP3A as well as secretion of lactate and urea into the culture medium. Establishment of constant metabolic activities after an initial decrease compared with freshly isolated hepatocytes showed that the cultured hepatocytes achieve a new equilibrium state that was not affected by our starving conditions. To verify the highly reproducible dynamic activation of signalling pathways in the in vitro system, the authors examined the JAK-STAT, SMAD, PI3 kinase, MAP kinase, NF-kappaB and Wnt/beta-catenin signalling pathways. For the induction of gp130, JAK1 and STAT3 phosphorylation IL6 was used, whereas TGFbeta was applied to activate the phosphorylation of SMAD1, SMAD2 and SMAD3. Both Akt/PKB and ERK1/2 phosphorylation were stimulated by the addition of hepatocyte growth factor. The time-dependent induction of a pool of signalling competent beta-catenin was monitored in response to the inhibition of GSK3beta. To analyse whether phosphorylation is actually leading to transcriptional responses, luciferase reporter gene constructs driven by multiple copies of TGFbeta-responsive motives were applied, demonstrating a dose-dependent increase in luciferase activity. Moreover, the induction of apoptosis by the TNF-like cytokine Fas ligand was studied in the in vitro system. Thus, the mouse hepatocyte in vitro system provides an important basis for the generation of high-quality quantitative data under standardised cell culture conditions that is essential to elucidate critical hepatocellular functions by the systems biology approach.

Animals↗

PubMed2006

Can biochemical properties serve as selective pressure for gene selection during inter-species and endosymbiotic lateral gene transfer?

During the evolution of endosymbiosis, only one orthologous gene, either from the invader or the invaded genome, is preserved. Genetic and environmental factors are usually invoked to explain this gene preference. How biochemical parameters can play a role in the selection of genes that code for enzymes that constitute a metabolic pathway is explored. Simple Michaelis-Menten-like enzymes are considered whose kinetic parameters are randomly generated to construct two parallel homologous pathways to account for the contributions of the invaded and the invader. Steady-state fluxes as targets of natural selection are focused. Enzymes are eliminated one by one so that the total flux through the pathway is least disturbed. Analysis of the results, done by different criteria, indicate that the maximal velocities, both forward and backward, are more influential in selection than the respective Michaelis constants. This inclination disappears as metabolite concentrations are increased. It is shown that kinetic selection criteria can result in a mosaicism of enzymes in the same pathway in terms of their genetic origin. Analysis of the results using the control coefficient paradigm disclosed an expected robust correlation between flux control coefficients of enzymes and their selective elimination. Similar analyses, performed for the case of single gene transfer or for gene replication with subsequent mutation, yielded essentially similar results. The results conform with the phenomenon of genetic mosaicism found in phylogenetic analyses of single or double endosymbioses and lateral gene transfer.

Animals↗

PubMed2006

Hierarchy of metabolic compounds based on their synthesising capacity.

The concept of scopes is applied to analyse large metabolic networks. Scopes are defined as sets of metabolites that can be synthesised by a metabolic network when it is provided with given seeds (Sets of initial metabolic compounds). Thus, scopes represent synthesising capacities of the seeds in the network. A hierarchy is discussed in the sense that compounds, which are part of the scope of another compound, possess scopes themselves that are subsets of the former scope. This hierarchy is analysed by means of a directed acyclic graph. Using a simple chemical model, it is found that this hierarchy contains specific structures that can, to a large extent, be explained by the chemical composition of the participating compounds. In this way, it represents a new kind of map of metabolic networks, arranging the metabolic compounds according to their chemical capacity.

Algorithms↗

PubMed2006

Expansion of signal transduction networks.

Signal transduction networks of different cell types show a large variety in their structural design. In this paper, basic structural properties of signal transduction networks are investigated. For this, such networks with the recently developed method of network expansion are analysed. This method allows for a structural analysis of networks by calculating signal expansion profiles when provided with certain compounds, for example growth factors, inactive kinases and so on (seed compounds), to initiate such an expansion. The presented results may put forth valuable hints on the evolution of signalling networks.

Algorithms↗

PubMed2005

Analysing the robustness of cellular rhythms.

Autonomous oscillations at the cellular level are important for various timing and signalling functions. The rhythms depend on environmental influences in a specific manner. In particular, the period of some rhythms has been shown to be very robust to certain environmental factors whereas other rhythms show a high sensitivity towards these factors. It is discussed that the robustness of the systems towards environmental changes results from underlying design principles. However, a comparison of robustness properties of different rhythms is lacking. Here we analyse the sensitivity of the oscillatory period with respect to parameter variations in models describing oscillations in calcium signalling, glycolysis and the circadian system. By comparing models for the same and different rhythms it is shown that the sensitivity depends on the oscillatory mechanism rather than the details of the model description. In particular, we find models of calcium oscillations to be very sensitive, those for glycolytic oscillations intermediately sensitive and models for circadian rhythms very robust. The results are discussed with respect to the temperature dependency of the rhythms. The question of what impact design principles have on the robustness of an oscillator, is addressed more explicitly by a direct comparison of systems with positive and negative feedback regulation for various reaction chain lengths. We find that the systems with negative feedback are more robust than corresponding systems with positive feedback. An increase in the length of the reaction chain under regulation leads to a decrease in sensitivity.

Algorithms↗

PubMed2002

Intracellular signal propagation in a two-dimensional autocatalytic reaction model.

We study a simple reaction scheme in a two-dimensional lattice of particles or molecules with a refractory state. We analyze the dynamics of the propagating front as a function of physical-chemical properties of the host medium. The anisotropy of the medium significantly affects the smoothness of the wave front. Similarly, if particles or molecules may diffuse slowly to neighboring sites, then the front wave is more likely to be irregular. Both situations affect the ability of the whole system to relax to the original state, which is a required feature in the biological cells. Attempts to map this simple reaction scheme to reactions involved in the intracellular pathways suggest that, in some cases, signal transduction might take both connotation of a random walk and a propagating wave, depending on the local density of the medium. In particular, a sufficient condition for the appearance of waves in high-density regions of the media, is the existence of at least one autocatalytic reaction in the chain of reactions characterizing the pathway.

Biophysical Phenomena↗

PubMed2002

mAChRs in the grasshopper brain mediate excitation by activation of the AC/PKA and the PLC second-messenger pathways.

The species-specific sound production of acoustically communicating grasshoppers can be stimulated by pressure injection of both nicotinic and muscarinic agonists into the central body complex and a small neuropil situated posterior and dorsal to it. To determine the role of muscarinic acetylcholine receptors (mAChRs) in the control of acoustic communication behavior and to identify the second-messenger pathways affected by mAChR-activation, muscarinic agonists and membrane-permeable drugs known to interfere with specific mechanisms of intracellular signaling pathways were pressure injected to identical sites in male grasshopper brains. Repeated injections of small volumes of muscarine elicited stridulation of increasing duration associated with decreased latencies. This suggested an accumulation of excitation over time that is consistent with the suggested role of mAChRs in controlling courtship behavior: to provide increasing arousal leading to higher intensity of stridulation and finally initiating a mating attempt. At sites in the brain where muscarine stimulation was effective, stridulation could be evoked by forskolin, an activator of adenylate cyclase (AC); 8-Br-cAMP-activating protein kinase A (PKA); and 3-isobuty-1-methylxanthine, leading to the accumulation of endogenously generated cAMP through inhibition of phosphodiesterases. This suggested that mAChRs mediate excitation by stimulating the AC/cAMP/PKA pathway. In addition, muscarine-stimulated stridulation was inhibited by 2'-5'-dideoxyadenonsine and SQ 22536, two inhibitors of AC; H-89 and Rp-cAMPS, two inhibitors of PKA; and by U-73122 and neomycin, two agents that inhibit phospholipase C (PLC) by independent mechanisms. Because the inhibition of AC, PKA, or PLC by various individually applied substances entirely suppressed muscarine-evoked stridulation in a number of experiments, activation of both pathways, AC/cAMP/PKA and PLC/IP(3)/diacylglycerine, appeared to be necessary to mediate the excitatory effects of mAChRs. With these studies on an intact "behaving" grasshopper preparation, we present physiological relevance for mAChR-evoked excitation mediated by sequential activation of the AC- and PLC-initiated signaling pathways that has been reported in earlier in vitro studies.

Acetylcholine↗

PubMed2001

The AP-1 repressor, JDP2, is a bona fide substrate for the c-Jun N-terminal kinase.

The Jun dimerization protein 2 (JDP2) is a novel member of the basic leucine zipper family of transcription factors. JDP2 binds DNA as a homodimer and heterodimer with ATF2 and Jun proteins but not with c-Fos proteins. JDP2 overexpression represses activating protein 1 transcription activity. Whereas JDP2 mRNA and protein levels are stable following different cell stimuli, JDP2 is rapidly phosphorylated upon UV irradiation, oxidative stress and low levels of translation inhibitor. The c-Jun N-terminal kinase phosphorylates JDP2 both in vitro and in vivo. JDP2 contains a putative consensus JNK docking-site and a corresponding phosphoacceptor site. Substitution of threonine 148 to an alanine residue blocks JNK-dependent JDP2 phosphorylation. Our data indicate that JDP2 is a bona fide substrate for the c-Jun N-terminal kinase. The precise role of JDP2 phosphorylation on its function is not yet known.

Animals↗

PubMed2001

A role for muscarinic excitation: control of specific singing behavior by activation of the adenylate cyclase pathway in the brain of grasshoppers.

Muscarinic acetylcholine receptors exert slow and prolonged synaptic effects in both vertebrate and invertebrate nervous systems. Through activation of G proteins, they typically decrease intracellular cAMP levels by inhibition of adenylate cyclase or stimulate phospholipase C and the turnover of inositol phosphates. In insects, muscarinic receptors have been credited with two main functions: inhibition of transmitter release from sensory neuron terminals and regulation of the excitability of motoneurons and interneurons. Our pharmacological studies with intact and behaving grasshoppers revealed a functional role for muscarinic acetylcholine receptors as being the basis for specific arousal in defined areas of the brain, underlying the selection and control of acoustic communication behavior. Periodic injections of acetylcholine into distinct areas of the brain elicited songs of progressively increasing duration. Coinjections of the muscarinic receptor antagonist scopolamine and periodic stimulations with muscarine identified muscarinic receptor activation as being the basis for the underlying accumulation of excitation. In contrast to reports from other studies on functional circuits, muscarinic excitation was apparently mediated by activation of the adenylate cyclase pathway. Stimulation of adenylate cyclase with forskolin and of protein kinase A with 8-Br-cAMP mimicked the stimulatory effects of muscarine whereas inhibition of adenylate cyclase with SQ22536 and of protein kinase A with H-89 and Rp-cAMPs suppressed muscarine-stimulated singing behavior. Activation of adenylate cyclase by muscarinic receptors has previously been reported from studies on membrane preparations and heterologous expression systems, but a physiological significance of this pathway remained to be demonstrated in an in vivo preparation.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2001

Mathematical analysis of a mechanism for autonomous metabolic oscillations in continuous culture of Saccharomyces cerevisiae.

Autonomous metabolic oscillations were observed in aerobic continuous culture of Saccharomyces cerevisiae. Experimental investigation of the underlying mechanism revealed that several pathways and regulatory couplings are involved. Here a hypothetical mechanism including the sulfate assimilation pathway, ethanol degradation and respiration is transformed into a mathematical model. Simulations confirm the ability of the model to produce limit cycle oscillations which reproduce most of the characteristic features of the system.

Cell Respiration↗

PubMed2001

Birhythmicity, trirhythmicity and chaos in bursting calcium oscillations.

We have analyzed various types of complex calcium oscillations. The oscillations are explained with a model based on calcium-induced calcium release (CICR). In addition to the endoplasmic reticulum as the main intracellular Ca2+ store, mitochondrial and cytosolic Ca2+ binding proteins are also taken into account. This model was previously proposed for the study of the physiological role of mitochondria and the cytosolic proteins in gene rating complex Ca2+ oscillations [1]. Here, we investigated the occurrence of different types of Ca2+ oscillations obtained by the model, i.e. simple oscillations, bursting, and chaos. In a bifurcation diagram, we have shown that all these various modes of oscillatory behavior are obtained by a change of only one model parameter, which corresponds to the physiological variability of an agonist. Bursting oscillations were studied in more detail because they express birhythmicity, trirhythmicity and chaotic behavior. Two different routes to chaos are observed in the model: in addition to the usual period doubling cascade, we also show intermittency. For the characterization of the chaotic behavior, we made use of return maps and Lyapunov exponents. The potential biological role of chaos in intracellular signaling is discussed.

Algorithms↗

PubMed2001

Ratcheting in post-translational protein translocation: a mathematical model.

We have developed a non-steady-state mathematical model describing post-translational protein translocation across the endoplasmic reticulum membrane. Movement of the polypeptide chain through the channel in the endoplasmic reticulum membrane is considered to be a stochastic process which is biased at the lumenal side of the channel by the binding of BiP (Kar2p), a member of the Hsp70 family of ATPases (ratcheting model). Assuming that movement of the chain through the channel is caused by passive diffusion (Brownian ratchet), the model describes all available experimental data. The optimum set of model parameters indicates that the ratcheting mechanism functions at near-maximum rate, being relatively insensitive to variations of the association or dissociation rate constants of BiP or its concentration. The estimated rate constant for diffusion of a polypeptide inside the channel indicates that the chain makes contact with the walls of the channel. Since fitting of the model to the data required that the backward rate constant be larger than the forward constant during early diffusion steps, translocation must occur against a force. The latter may arise, for example, from the unfolding of the polypeptide chain in the cytosol. Our results indicate that the ratchet can transport polypeptides against a free energy of about 25 kJ/mol without significant retardation of translocation. The modeling also suggests that the BiP ratchet is optimized, allowing fast translocation to be coupled with minimum consumption of ATP and rapid dissociation of BiP in the lumen of the ER. Finally, we have estimated the maximum hydrophobicity of a polypeptide segment up to which lateral partitioning from the channel into the lipid phase does not result in significant retardation of translocation.

Adenosine Triphosphate↗

PubMed2001

Evolutionary optimization of metabolic pathways. Theoretical reconstruction of the stoichiometry of ATP and NADH producing systems.

The structural design of ATP and NADH producing systems, such as glycolysis and the citric acid cycle (TCA), is analysed using optimization principles. It is assumed that these pathways combined with oxidative phosphorylation have reached, during their evolution, a high efficiency with respect to ATP production rates. On the basis of kinetic and thermodynamic principles, conclusions are derived concerning the optimal stoichiometry of such pathways. Extending previous investigations, both the concentrations of adenine nucleotides as well as nicotinamide adenine dinucleotides are considered variable quantities. This implies the consideration of the interaction of an ATP and NADH producing system, an ATP consuming system, a system coupling NADH consumption with ATP production and a system consuming NADH decoupled from ATP production. It is examined in what respect real metabolic pathways can be considered optimal by studying a large number of alternative pathways. The kinetics of the individual reactions are described by linear or bilinear functions of reactant concentrations. In this manner, the steady-state ATP production rate can be calculated for any possible ATP and NADH producing pathway. It is shown that most of the possible pathways result in a very low ATP production rate and that the very efficient pathways share common structural properties. Optimization with respect to the ATP production rate is performed by an evolutionary algorithm. The following results of our analysis are in close correspondence to the real design of glycolysis and the TCA cycle. (1) In all efficient pathways the ATP consuming reactions are located near the beginning. (2) In all efficient pathways NADH producing reactions as well as ATP producing reactions are located near the end. (3) The number of NADH molecules produced by the consumption of one energy-rich molecule (glucose) amounts to four in all efficient pathways. A distance measure and a measure for the internal ordering of reactions are introduced to study differences and similarities in the stoichiometries of metabolic pathways.

Adenosine Triphosphate↗

PubMed2001

Agonistic behavior in naïve juvenile lobsters depleted of serotonin 5,7-dihydroxytryptamine.

We have been exploring the role of serotonin in fighting behavior in lobsters using a specific model of agonistic behavior, the establishment of hierarchical relationships between pairs of socially naive juvenile lobsters. We selected this model because the behavior is easily evoked, readily quantifiable, and the effects of experience are eleminated by using socially naive animals. In these studies we injected a specific neurotoxin, 5,7-dihydroxytryptamine, into juvenile lobsters over a 4-week period and then measured the effects on fighting behavior. This treatment reduces the levels of serotonin in the nervous system and immunocytochemical studies show a dramatic reduction in neuropil staining for the amine. Control animals received vehicle injection alone. All injected animals were paired against larger or smaller non-injected opponents, and three successive 30-min fights were carried out and statistically analyzed. The results were surprising: As with elevations of serotonin, reduced levels of serotonin increased the amount of time animals engaged in fighting behavior. No significant effects were seen on who initiated encounters, who retreated first, or who the eventual winner would be. Thus, in this model, elevation or reduction of serotonergic function increases the tendency of animals to engage in agonistic encounters.

5,7-Dihydroxytryptamine↗

PubMed2001

Pharmacological brain stimulation releases elaborate stridulatory behaviour in gomphocerine grasshoppers--conclusions for the organization of the central nervous control.

Grasshoppers produce a variety of sounds generated by complex movements of the hindlegs. Stridulation, performed in the context of partner finding, mating and rivalry, can be released by pressure injection of cholinergic agonists into the protocerebrum. Particularly stimulation with muscarinic agonists induced long-lasting stridulation that resembled the natural behaviour to an astonishing degree, not only with respect to their temporal structure and right/left coordination, but also to changes in the song sequences according to the progress of courtship stridulation, even including accessory movements of other parts of the body. According to the complexity of their stridulatory behaviour ten gomphocerine species were chosen for this comparative study. The results indicate that the protocerebrum fulfils two important tasks in the control of stridulation: (1) it integrates sensory input relevant to stridulation that represents a certain behavioural situation and internal state of arousal, and (2) it selectively activates and deactivates the thoracic networks that generate the appropriate movement and sound patterns. With the knowledge of the natural behaviour and the accessibility to pharmacological and electrophysiological studies, the cephalic control system for stridulation in grasshoppers appears to be a suitable model for how the brain selects and controls appropriate behaviours for a given situation.

Animal Communication↗

PubMed2001

Intercellular Ca2+ wave propagation through gap-junctional Ca2+ diffusion: a theoretical study.

Intercellular regenerative calcium waves in systems such as the liver and the blowfly salivary gland have been hypothesized to spread through calcium-induced calcium release (CICR) and gap-junctional calcium diffusion. A simple mathematical model of this mechanism is developed. It includes CICR and calcium removal from the cytoplasm, cytoplasmic and gap-junctional calcium diffusion, and calcium buffering. For a piecewise linear approximation of the calcium kinetics, expressions in terms of the cellular parameters are derived for 1) the condition for the propagation of intercellular waves, and 2) the characteristic time of the delay of a wave encountered at the gap junctions. Intercellular propagation relies on the local excitation of CICR in the perijunctional space by gap-junctional calcium influx. This mechanism is compatible with low effective calcium diffusivity, and necessitates that CICR can be excited in every cell along the path of a wave. The gap-junctional calcium permeability required for intercellular waves in the model falls in the range of reported gap-junctional permeability values. The concentration of diffusive cytoplasmic calcium buffers and the maximal rate of CICR, in the case of inositol 1,4,5-trisphosphate (IP3) receptor calcium release channels set by the IP(3) concentration, are shown to be further determinants of wave behavior.

Animals↗