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At least 1,513 records · Page 84Linked to original sources
PubMed2005

Learning Petri net models of non-linear gene interactions.

Understanding how an individual's genetic make-up influences their risk of disease is a problem of paramount importance. Although machine-learning techniques are able to uncover the relationships between genotype and disease, the problem of automatically building the best biochemical model or "explanation" of the relationship has received less attention. In this paper, I describe a method based on random hill climbing that automatically builds Petri net models of non-linear (or multi-factorial) disease-causing gene-gene interactions. Petri nets are a suitable formalism for this problem, because they are used to model concurrent, dynamic processes analogous to biochemical reaction networks. I show that this method is routinely able to identify perfect Petri net models for three disease-causing gene-gene interactions recently reported in the literature.

Algorithms↗
PubMed2005

Hierarchical clustering of the correlation patterns: new method of domain identification in proteins.

New method of identification of dynamical domains in proteins - Hierarchical Clustering of the Correlation Patterns (HCCP) is proposed. HCCP allows to identify the domains using single three-dimensional structure of the studied proteins and does not require any adjustable parameters that can influence the results. The method is based on hierarchical clustering performed on the matrices of correlation patterns, which are obtained by the transformation of ordinary pairwise correlation matrices. This approach allows to extract additional information from the correlation matrices, which increases reliability of domain identification. It is shown that HCCP is insensitive to small variations of the pairwise correlation matrices. Particularly it produces identical results if the data obtained for the same protein crystallized with different spatial positions of domains are used for analysis. HCCP can utilize correlation matrices obtained by any method such as normal mode or essential dynamics analysis, Gaussian network or anisotropic network models, etc. These features make HCCP an attractive method for domain identification in proteins.

Algorithms↗
PubMed2006

Direct interaction between ER membrane-bound PTP1B and its plasma membrane-anchored targets.

The ubiquitously expressed protein tyrosine phosphatase PTP1B is involved in the regulation of numerous cellular signaling pathways. PTP1B is anchored to the ER membrane while many of its substrates are localized to the plasma membrane. This spatial separation raises the question how PTP1B can interact with its targets. In our study we demonstrate direct interaction of PTP1B with the Ser/Thr kinase PKCdelta, the non-receptor tyrosine kinase Src and the insulin receptor which all are key enzymes in cellular signaling cascades. Protein complex formation was visualized in vivo using Bimolecular Fluorescence Complementation (BiFC). We demonstrate that complex formation of PTP1B with plasma membrane-anchored proteins is possible without detachment of PTP1B from the ER. Our data indicate that the dynamic ER membrane network is in constant contact to the plasma membrane. Local attachments of the two membrane systems enable a direct communication of ER- and plasma membrane-anchored proteins. The reported formation of membrane junctions is an important step towards the understanding of signal transmissions between the ER and the plasma membrane.

Cell Line↗
PubMed2005

A dynamic fuzzy neural filter for separation of discontinuous adventitious sounds from vesicular sounds.

This paper presents a recurrent filter that performs real-time separation of discontinuous adventitious sounds from vesicular sounds. The filter uses two Dynamic Fuzzy Neural Networks, operating in parallel, to perform the task of separation of the lung sounds, obtained from patients with pulmonary pathology. Extensive experimental results, including fine/coarse crackles and squawks, are given, and a performance comparison with a series of other models is conducted, underlining the separation capabilities of the proposed filter and its improved performance with respect to its competing rivals.

Algorithms↗
PubMed2004

Separation of individual neurons using dielectrophoretic alternative current fields.

Experimental investigations into the dynamics of neuronal networks are a fundamental step towards understanding how the nervous system works. Memory formation and development are associated with changes in the electrical activity of the neurons. To understand the changes in the electrical activity, it is essential to conduct in vitro studies on individual neurons. Hence, there is an enormous need to develop novel ways for isolating and localizing individual neurons. To this end, we designed and fabricated a 4x4 multiple microelectrode array system to spatially arrange neurons by generating dielectrophoretic traps using gradient alternating current (AC) fields. We characterized the electric field distribution inside our test platform by using three-dimensional finite element modeling (FEM) and estimated the location of neurons over the electrode array. As the first stage in forming a neuronal network, dielectrophoretic AC fields were employed to separate the neurons from the glial cells and to position individual neurons over single electrodes. The extracellular electrical activity from a single neuron was recorded. The frequency spectrum of the electrical activity was generated using fast Fourier transformation analysis (FFT) to determine the characteristic burst rates of individual neurons.

Action Potentials↗
PubMed2006

Neural recording and stimulation of dissociated hippocampal cultures using microfabricated three-dimensional tip electrode array.

There is increasing interest in interfacing dissociated neuronal cultures with planar multielectrode arrays (MEAs) for the study of the dynamics of neuronal networks. Here we report on the successful use of three-dimensional tip electrode arrays (3D MEAs), originally developed for use with brain slices, for recording and stimulation of cultured neurons. We observed that many neurons grew directly on protruding electrode surface, appearing to make excellent contact. A larger than usual portion of extracellular spikes had large positive peaks, while most of the spikes from conventional two-dimensional electrode arrays had large negative spikes. This may be due to the direct capacitive coupling situation provided by relatively large electrode surface area.

Action Potentials↗
PubMed2006

Two different reorganization patterns after rehabilitative therapy: an exploratory study with fMRI and TMS.

We used two complementary methods to investigate cortical reorganization in chronic stroke patients during treatment with a defined motor rehabilitation program. BOLD ("blood oxygenation level dependent") sensitive functional magnetic resonance imaging (fMRI) and intracortical inhibition (ICI) and facilitation (ICF) measured with transcranial magnetic stimulation (TMS) via paired pulse stimulation were used to investigate cortical reorganization before and after "constraint-induced movement therapy" (CI). The motor hand function improved in all subjects after CI. BOLD signal intensity changes within affected primary sensorimotor cortex (SMC) before and after CI showed a close correlation with ICI (r = 0.93) and ICF (r = 0.76) difference before and after therapy. Difference in number of voxels and ICI difference before and after CI also showed a close correlation (r = 0.92) in the affected SMC over the time period of training. A single subject analysis revealed that patients with intact hand area of M1 ("the hand knob") and its descending motor fibers (these patients revealed normal motor evoked potentials [MEP] from the affected hand) showed decreasing ipsilesional SMC activation which was paralleled by an increase in intracortical excitability. This pattern putatively reflects increasing synaptic efficiency. When M1 or its descending pyramidal tract was lesioned (MEP from the affected hand was pathologic) ipsilesional SMC activation increased, accompanied by decreased intracortical excitability. We suggest that an increase in synaptic efficiency is not possible here, which leads to reorganization with extension, shift and recruitment of additional cortical areas of the sensorimotor network. The inverse dynamic process between both complementary methods (activation in fMRI and intracortical excitability determined by TMS) over the time period of CI illustrates the value of combining methods for understanding brain reorganization.

Aged↗
PubMed2005

Searching for "the top" in top-down control.

Although numerous theoretical models implicate the prefrontal cortex (PFC) as a source of top-down control signals, empirical support is limited. In this review, we highlight direct evidence for this view of PFC function and discuss several lines of other supportive findings. Most evidence to-date is only suggestive due to methodological challenges in tracking the spatiotemporal dynamics of cortical networks. However, we discuss several promising approaches that could further our understanding of the role of the PFC in goal-directed behavior.

Animals↗
PubMed2004

Capping protein: new insights into mechanism and regulation.

Temporal and spatial control of the actin cytoskeleton are crucial for a range of eukaryotic cellular processes. Capping protein (CP), a ubiquitous highly conserved heterodimer, tightly caps the barbed (fast-growing) end of the actin filament and is an important component in the assembly of various actin structures, including the dynamic branched filament network at the leading edge of motile cells. New research into the molecular mechanism of how CP interacts with the actin filament in vitro and the function of CP in vivo, including discoveries of novel interactions of CP with other proteins, has greatly enhanced our understanding of the role of CP in regulating the actin cytoskeleton.

Actin Cytoskeleton↗
PubMed2006

Precision mapping of the metabolome.

The global study of the structure and dynamics of metabolic networks has been hindered by a lack of techniques that identify metabolites and their biochemical relationship in complex mixtures. The recent application of Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) to metabolomic analysis suggests a way to tackle the problem. A lower-cost alternative to high-field FTICR-MS, the Orbitrap mass analyzer, promises accelerated activity in this area. Here, we show how the ultra-high mass accuracy and resolution provided by this new generation of mass spectrometers can help to identify metabolites and connect them into metabolic networks. Data from perturbation studies and isotope-tracking experiments can complement this information to create metabolic maps de novo and chart unexplored areas of metabolism.

Algorithms↗
PubMed2006

Slow-waves in the olfactory system: an olfactory perspective on cortical rhythms.

Over the past few years, it has become clear that oscillatory dynamics of cortical networks are closely involved in sensory coding, attention, memory and sleep. Although most experimental and theoretical studies have focused on the neocortex, we believe that progress in understanding cortical oscillations can be advanced by also considering the olfactory system--which shares many basic properties with the neocortex and shows similar oscillatory patterns. Besides offering the advantage of a greater experimental tractability, the olfactory cortex might prove to be instrumental in uncovering general functional principles of neocortical oscillations, by virtue of the potentially important role of olfaction during neocortical evolution. In this article, we illustrate how such an evolution-based comparative approach can provide novel insights into neocortical slow-wave sleep oscillations and their relationship to respiration.

Animals↗
PubMed2006

Targeting information-processing deficit in schizophrenia: a novel approach to psychotherapeutic drug discovery.

Current observations indicate that dysfunction of neuronal circuitry dynamics contributes to the abnormal information processing in the brain in schizophrenia. It is presumed that disrupted auditory gating, abnormal P300-evoked potentials and deficits in mismatch negativity in schizophrenic patients indicate impaired processing of information. Recently, abnormalities in neuronal synchrony and oscillatory activity have been postulated as the mechanisms that underlie the distorted perception and cognitive dysfunction associated with schizophrenia. These novel observations might reveal the pathophysiology of the disorder, and indicate potential targets for antipsychotic drug therapy. Neuronal circuitry dynamics, such as network oscillations and sensory-gating processes, are conserved phylogenetically, which provides excellent opportunities for designing translational biomarkers. Whether preclinical, experimental compounds that impact on network oscillations and sensory processing (such as agonists and modulators of alpha7 nicotinic acetylcholine receptors) elicit the same neurophysiological events in schizophrenic patients and, subsequently, improve perception and cognitive functions will be determined when these drug candidates are available clinically.

Animals↗
PubMed2006

Activity of omnipause neurons during "staircase saccades" elicited by persistent microstimulation of the superior colliculus.

We have recorded the activity of omnipause neurons (OPNs) in the raphe interpositus during so-called staircase saccades produced by prolonged activation of the superior colliculus (SC) by microstimulation. By showing that OPNs cyclically pause during the periodic movements produced by the steady activation function, we reveal the functional relationship of the OPNs within the recurrent brainstem network that produces dynamic, closed-loop, and feedback control of saccades. Despite persistent, steady activation of the SC, the OPNs followed the periodic activity of the brainstem burst generator. This reveals a dominant influence of the oscillating brainstem circuit over descending control from the SC.

Animals↗
PubMed2006

What it means to measure a single molecule in a solution by fluorescence fluctuation spectroscopy.

Traditional methodologies in micro- and nanofluidics measure biological mechanisms as an average of a population of molecules as only their combined effect can be detected. Fluorescence fluctuation spectroscopy methods such as fluorescence correlation spectroscopy (FCS) and two-color fluorescence cross-correlation spectroscopy (FCCS) are used as alternative experimental approaches in ultrasensitive analytics at the single-molecule level. However, what is the measurement time in which one is able to study just one single molecule in solution without immobilizing it? Existing theories are inadequate since they do not predict the meaningful time as a function of the concentration of other molecules of the same kind in bulk solution. This situation produces considerable concern, and experimental hypotheses differ according to which single-molecule detection methods are thought to have greater validity. This subject is clearly at the forefront of research and should be of great interest to experimental medical scientists. As will be seen in this article, it is worthwhile to obtain a correct form of the meaningful-time relationship through theoretical means. The new ideas are comprehensively presented, and this relationship is a new concept at this time. The meaningful time for studying just one molecule without immobilization specifies the time parameter in the selfsame molecule likelihood estimator. Possible users for this concept are those working in biotechnological applications dealing with gene technology. Furthermore, the concept is of interest for a great number of medical, pharmaceutical and chemical laboratories. It may serve as a foundation for further work in single-cell biology. It is suspected that heterogeneities play a much larger role inside the cell than in free solution--a perfect opportunity for single-molecule studies and, thus, a novel hypothesis regarding structure and dynamics of cellular networks is first presented for the minimal neurotrophin network model.

Fluorescent Dyes↗
PubMed2003

Slowly getting a clue on CD95 ligand biology.

Since the ligand for the death factor CD95 (CD95L) was identified almost a decade ago, it has been established that this molecule (CD95L, FasL, Apo-1L, CD178, TNFSF6, APT1LG1) has multiple immunoregulatory and pathophysiologically relevant functions. CD95L does not only act as a death factor when externalized with secretory lysosomes on cytotoxic T and NK cells or when expressed on CD4(+) T cells in the course of activation-induced cell death, it is also a key molecule for the establishment of immune privilege or tumor cell survival and may serve as a costimulatory molecule during T cell activation. Moreover, alterations of expression or shedding of different forms of CD95L are associated with many diseases including various malignancies, HIV infection, autoimmune disorders (systemic lupus erythematodes, rheumatoid arthritis), acute myocardial infarction, traumatic injury and many others. In most cases, however, the physiological link between altered CD95L expression and pathophysiology is unknown. Given the potency of the molecule to regulate death and survival of many different cell types, the control of CD95L production, transport, storage, shedding and release is of tremendous biological and clinical interest. This commentary aims at briefly summarizing the current knowledge, hypotheses and controversies about CD95L as a multifunctional ligand and receptor. It touches upon the complex networks of intracellular dynamics of protein transport and trafficking and the potential bidirectional signal transduction capacity of CD95L with a focus on molecular interactions that have been worked out over the past years.

Alleles↗
PubMed1988

Associative neural network model for the generation of temporal patterns. Theory and application to central pattern generators.

Cyclic patterns of motor neuron activity are involved in the production of many rhythmic movements, such as walking, swimming, and scratching. These movements are controlled by neural circuits referred to as central pattern generators (CPGs). Some of these circuits function in the absence of both internal pacemakers and external feedback. We describe an associative neural network model whose dynamic behavior is similar to that of CPGs. The theory predicts the strength of all possible connections between pairs of neurons on the basis of the outputs of the CPG. It also allows the mean operating levels of the neurons to be deduced from the measured synaptic strengths between the pairs of neurons. We apply our theory to the CPG controlling escape swimming in the mollusk Tritonia diomedea. The basic rhythmic behavior is shown to be consistent with a simplified model that approximates neurons as threshold units and slow synaptic responses as elementary time delays. The model we describe may have relevance to other fixed action behaviors, as well as to the learning, recall, and recognition of temporally ordered information.

Animals↗
PubMed1994

Molecular biology of aging.

Aging is an extremely complex biologic phenomenon of immense importance. Currently we have only a poor and incomplete understanding of the fundamental molecular mechanisms involved. Despite numerous observations and diverse theories, no unifying or proven hypotheses have emerged. It is reasonable to conclude, however, that aging is a multifactorial process composed of both genetic and environmental components. Each physiologic system within an organism, each tissue within a system, and each cell type with a tissue appears to have its own trajectory of aging. Thus, aging must be studied as parts of a whole and understood as the sum of its parts. Cellular "clocks" exist and operate in the absence of higher-order "clocks". However, higher-order clocks are certainly in place in vivo, but their relationship to cellular clocks is not well understood. All aging changes have a cellular basis, and aging is perhaps best studied, fundamentally, at the cellular level under defined and controlled environmental conditions. Aging changes at the cellular level must be viewed, however, as components of a hierarchical, dynamic, and interacting network whose functional integrity progressively deteriorates with time. The powerful tools of molecular biology are now being applied by scientists to evaluate the leading hypotheses. The results of these studies should serve to advance our understanding of aging and to focus future research efforts. This work should provide the scientific foundation to enhance the quality of life for people suffering the failings of age.

Aging↗
PubMed2002

Spinal plasticity mediated by postsynaptic L-type Ca2+ channels.

In the spinal cord, motoneurons and specific subgroups of interneurons express L-type Ca(2+) channels. As elsewhere, these dihydropyridine-sensitive channels mediate a slowly activating inward current in response to depolarisation and show little or no inactivation. The slow kinetics for activation and deactivation provide voltage-sensitive properties in a time range from hundreds of milliseconds to tens of seconds and lead to plateau potentials, bistability and wind-up in neurons in both sensory and motor networks. This slow dynamics is in part due to facilitation of L-type Ca(2+) channels by depolarisation. The voltage sensitivity of L-type Ca(2+) channels is also regulated by a range of metabotropic transmitter receptors. Up-regulation is mediated by receptors for glutamate, acetylcholine, noradrenaline and serotonin in motoneurons and by receptors for glutamate and substance P in plateau-generating dorsal horn interneurons. In both cell types, L-type Ca(2+) channels are down-regulated by activation of GABA(B) receptors. In this way, metabotropic regulation in cells expressing L-type Ca(2+) channels provides mechanisms for flexible adjustment of excitability and of the contribution of plateau currents to the intrinsic properties. This type of regulation also steers the magnitude and compartmental distribution of Ca(2+) influx during depolarisation, thus providing a signal for local synaptic plasticity.

Animals↗