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PubMed1986

Development of cultured cardiac cells and difference of their structures in vivo.

Some interesting features in the morphological study of rat cardiac cells were obtained by use of the light and phase-contrast microscopy. The histological approach and comparison of the ultrastructures of the cultured cardiac cells with uncultured cells were included in the studies as a control. Four main points are discussed: the process of single beating cells that eventually constitutes the cell cluster and network, the function and histological content of the network, the mechanisms of synchronized beating cells, the substance of the cell surface coat and intercellular connection.

Animals↗

PubMed2004

Networks of local minima in optical system optimization.

We discuss a surprising new feature of the merit function landscape in optical system design. When certain conditions are satisfied, the local minima form a network in which all nodes are connected. Each link between two neighboring minima contains a saddle point with a Morse index of 1. For a simple global optimization search (the symmetric Cooke triplet), the network of the corresponding set of local minima is presented.

Journal Article↗

PubMed2000

PepTool and GeneTool: platform-independent tools for biological sequence analysis.

Although we are unable to discuss all of the functionality available in PepTool and GeneTool, it should be evident from this brief review that both packages offer a great deal in terms of functionality and ease-of-use. Furthermore, a number of useful innovations including platform-independent GUI design, networked parallelism, direct internet connectivity, database compression, and a variety of enhanced or improved algorithms should make these two programs particularly useful in the rapidly changing world of biological sequence analysis. More complete descriptions of the programs, algorithms and operation of PepTool and GeneTool are available on the BioTools web site (www.biotools.com), in the associated program user manuals and in the on-line Help pages.

Amino Acid Sequence↗

PubMed1993

[Biochemical profile of proteoglycans and glucosaminoglycans of the mammalian tectorial membrane].

The tectorial membrane is an acellular connective tissue which plays an essential role in cochlear function. While a comparatively large amount of information is available on the collagen network of the tectorial membrane, studies on the biochemical nature of this highly hydrated matrix, which is composed of proteoglycans (PGs) and glycosaminoglycans (GAGs), have been quite limited. Previous reports on the biochemical analysis of the tectorial membrane have failed to detect uronic acid, which is present in large amounts in all mammalian GAGs except keratan sulfate. Applying a colorimetric assay based on the binding of GAGs to cationic dye Safranin-0 in combination with enzymatic techniques, we were able to measure GAGs in the murine tectorial membrane. Approximately 0.3% uronic acid-containing GAGs (mainly in the form of chondroitin/dermatan sulfate) and 0.17% keratan sulfate were detected in the tectorial membrane (both on a wet weight basis). In addition, various types of electrophoresis revealed one large PG with a molecular mass similar to that of the large type cartilage PGs and three small PGs, containing chondroitin sulfate and keratan sulfate side chains, respectively. Judging by coelution of standards, one of the small PGs seemed to correspond to fibromodulin, which has at least one keratan sulfate side chain, and binds to type I and type II collagen to regulate collagen organization in tissues. Our results suggest: (1) Donnan equilibrium is established in the tectorial membrane because sulfated GAGs are highly negatively charged and consequently bring about an influx of large amounts of water and cations into the matrix.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2006

"Missing links" in borderline personality disorder: loss of neural synchrony relates to lack of emotion regulation and impulse control.

OBJECTIVE: Symptoms of borderline personality disorder (BPD) may reflect distinct breakdowns in the integration of posterior and frontal brain networks. We used a high temporal resolution measure (40-Hz gamma phase synchrony) of brain activity to examine the connectivity of brain function in BPD. METHODS: Unmedicated patients with BPD (n = 15) and age-and sex-matched healthy control subjects (n = 15) undertook a task requiring discrimination of salient from background tones. In response to salient stimuli, the magnitude and latency of peak gamma phase synchrony for early (0-150 ms post stimulus) and late (250-500 ms post stimulus) phases were calculated for frontal and posterior regions and for left and right hemispheres. We recorded skin conductance responses (SCRs) and reaction time (RT) simultaneously to examine the contribution of arousal and performance. RESULTS: Compared with controls, patients with BPD had a significant delay in early posterior gamma synchrony and a reduction in right hemisphere late gamma synchrony in response to salient stimuli. Both SCR onset and RT were also delayed in BPD, but independently from differences in synchrony. The delay in posterior synchrony was associated with cognitive symptoms, and reduced right hemisphere synchrony was associated with impulsivity. CONCLUSIONS: These findings suggest that distinct impairments in the functional connectivity of neural systems for orienting to salient input underlie core dimensions of cognitive disturbance and poor impulse control in BPD.

Adult↗

PubMed1987

[Regulation and dysregulations of immunoglobulin E synthesis].

Compared to other isotypes of immunoglobulins, IgE antibodies are present in exceedingly low concentrations in normal serum, because their synthesis is maintained under the strict control of several intricate regulatory mechanisms. These normally unapparent mechanisms become accessible to investigations in a number of pathological dysregulations. One may distinguish three orders of controls. An elementary isotypic circuit, constructed on the interactions between IgE Fc portions and IgE-binding molecules, directly regulates IgE synthesis by IgE-secreting B cells. IgE-binding molecules are themselves controlled by several lymphokine cascades, depending on external and genetic factors. The functioning of the IgE isotypic circuit is coordinated with other circuits, corresponding to other immunoglobulin isotypes, by means of an isotypic network, connected to other homeostatic systems of the organism. The dissection of these regulatory mechanisms and an understanding of their interactions are potentially useful for new therapeutic approaches.

Humans↗

PubMed2005

Inferring yeast cell cycle regulators and interactions using transcription factor activities.

BACKGROUND: Since transcription factors are often regulated at the post-transcriptional level, their activities, rather than expression levels may provide valuable information for investigating functions and their interactions. The recently developed Network Component Analysis (NCA) and its generalized form (gNCA) provide a robust framework for deducing the transcription factor activities (TFAs) from various types of DNA microarray data and transcription factor-gene connectivity. The goal of this work is to demonstrate the utility of TFAs in inferring transcription factor functions and interactions in Saccharomyces cerevisiae cell cycle regulation. RESULTS: Using gNCA, we determined 74 TFAs from both wild type and fkh1 fkh2 deletion mutant microarray data encompassing 1529 ORFs. We hypothesized that transcription factors participating in the cell cycle regulation exhibit cyclic activity profiles. This hypothesis was supported by the TFA profiles of known cell cycle factors and was used as a basis to uncover other potential cell cycle factors. By combining the results from both cluster analysis and periodicity analysis, we recovered nearly 90% of the known cell cycle regulators, and identified 5 putative cell cycle-related transcription factors (Dal81, Hap2, Hir2, Mss11, and Rlm1). In addition, by analyzing expression data from transcription factor knockout strains, we determined 3 verified (Ace2, Ndd1, and Swi5) and 4 putative interaction partners (Cha4, Hap2, Fhl1, and Rts2) of the forkhead transcription factors. Sensitivity of TFAs to connectivity errors was determined to provide confidence level of these predictions. CONCLUSION: By subjecting TFA profiles to analyses based upon physiological signatures we were able to identify cell cycle related transcription factors consistent with current literature, transcription factors with potential cell cycle dependent roles, and interactions between transcription factors.

Cell Cycle↗

PubMed2006

The development of cortical connections.

The cortex receives its major sensory input from the thalamus via thalamocortical axons, and cortical neurons are interconnected in complex networks by corticocortical and callosal axons. Our understanding of the mechanisms generating the circuitry that confers functional properties on cortical neurons and networks, although poor, has been advanced significantly by recent research on the molecular mechanisms of thalamocortical axonal guidance and ordering. Here we review recent advances in knowledge of how thalamocortical axons are guided and how they maintain order during that process. Several studies have shown the importance in this process of guidance molecules including Eph receptors and ephrins, members of the Wnt signalling pathway and members of a novel planar cell polarity pathway. Signalling molecules and transcription factors expressed with graded concentrations across the cortex are important in establishing cortical maps of the topography of sensory surfaces. Neural activity, both spontaneous and evoked, plays a role in refining thalamocortical connections but recent work has indicated that neural activity is less important than was previously thought for the development of some early maps. A strategy used widely in the development of corticocortical and callosal connections is the early overproduction of projections followed by selection after contact with the target structure. Here we discuss recent work in primates indicating that elimination of juvenile projections is not a major mechanism in the development of pathways feeding information forward to higher levels of cortical processing, although its use is common to developing feedback pathways.

Animals↗

PubMed2004

Gene co-regulation is highly conserved in the evolution of eukaryotes and prokaryotes.

Differences between species have been suggested to largely reside in the network of connections among the genes. Nevertheless, the rate at which these connections evolve has not been properly quantified. Here, we measure the extent to which co-regulation between pairs of genes is conserved over large phylogenetic distances; between two eukaryotes Caenorhabditis elegans and Saccharomyces cerevisiae, and between two prokaryotes Escherichia coli and Bacillus subtilis. We first construct a reliable set of co-regulated genes by combining various functional genomics data from yeast, and subsequently determine conservation of co-regulation in worm from the distribution of co-expression values. For B.subtilis and E.coli, we use known operons and regulons. We find that between 76 and 80% of the co-regulatory connections are conserved between orthologous pairs of genes, which is very high compared with previous estimates and expectations regarding network evolution. We show that in the case of gene duplication after speciation, one of the two inparalogous genes tends to retain its original co-regulatory relationship, while the other loses this link and is presumably free for differentiation or sub-functionalization. The high level of co-regulation conservation implies that reliably predicted functional relationships from functional genomics data in one species can be transferred with high accuracy to another species when that species also harbours the associated genes.

Animals↗

PubMed2005

Biomechanics of the lung parenchyma: critical roles of collagen and mechanical forces.

The biomechanical properties of connective tissues play fundamental roles in how mechanical interactions of the body with its environment produce physical forces at the cellular level. It is now recognized that mechanical interactions between cells and the extracellular matrix (ECM) have major regulatory effects on cellular physiology and cell-cycle kinetics that can lead to the reorganization and remodeling of the ECM. The connective tissues are composed of cells and the ECM, which includes water and a variety of biological macromolecules. The macromolecules that are most important in determining the mechanical properties of these tissues are collagen, elastin, and proteoglycans. Among these macromolecules, the most abundant and perhaps most critical for structural integrity is collagen. In this review, we examine how mechanical forces affect the physiological functioning of the lung parenchyma, with special emphasis on the role of collagen. First, we overview the composition of the connective tissue of the lung and their complex structural organization. We then describe how mechanical properties of the parenchyma arise from its composition as well as from the architectural organization of the connective tissue. We argue that, because collagen is the most important load-bearing component of the parenchymal connective tissue, it is also critical in determining the homeostasis and cellular responses to injury. Finally, we overview the interactions between the parenchymal collagen network and cellular remodeling and speculate how mechanotransduction might contribute to disease propagation and the development of small- and large-scale heterogeneities with implications to impaired lung function in emphysema.

Animals↗

PubMed2006

Embryonic stem cell-derived neurons form functional networks in vitro.

Embryonic stem (ES) cells provide a flexible and unlimited source for a variety of neuronal types. Because mature neurons establish neuronal networks very easily, we tested whether ES-derived neurons are capable of generating functional networks and whether these networks, generated in vitro, are capable of processing information. Single-cell electrophysiology with pharmacological antagonists demonstrated the presence of both excitatory and inhibitory synaptic connections. Extracellular recording with planar multielectrode arrays showed that spontaneous bursts of electrical activity are present in ES-derived networks with properties remarkably similar to those of hippocampal neurons. When stimulated with extracellular electrodes, ES-derived neurons fired action potentials, and the evoked electrical activity spread throughout the culture. A statistical analysis indicated that ES-derived networks discriminated between stimuli of different intensity at a single trial level, a key feature for an efficient information processing. Thus, ES-derived neurons provide a novel in vitro strategy to create functional networks with defined computational properties.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1997

Behavioral function of glutamatergic interneurons in the feeding system of Lymnaea: plateauing properties and synaptic connections with motor neurons.

Intracellular recording techniques were used to examine the electrical properties and behavioral function of a novel type of retraction phase interneuron, the N2 ventral (N2v) cells in the feeding network of the snail Lymnaea. The N2vs were compared with the previously identified N2 cells that now are renamed the N2 dorsal (N2d) cells. The N2vs are a bilaterally symmetrical pair of electrotonically coupled plateauing interneurons that are located on the ventral surfaces of the buccal ganglia. Their main axons project to the opposite buccal ganglion, but they have an additional fine process in the postbuccal nerve. N2v plateaus that outlast the duration of the stimulus can be triggered by depolarizing current pulses and prematurely terminated by applied hyperpolarizing pulses. Gradually increasing the amplitude of depolarizing pulses reveals a clear threshold for plateau initiation. N2v plateauing persists in a high Mg2+/nominally zero Ca2+ saline that blocks chemical synaptic connections, suggesting an endogenous mechanism for plateau generation. The N2vs fire sustained bursts of action potentials throughout the N2/rasp phase of the fictive feeding cycle and control the retraction phase feeding motor neurons. The N2vs excite the B3 and B9 feeding motor neurons to fire during the rasp phase of the feeding cycle. They also inhibit the B7 and B8 feeding motor neurons. The B8 cells recover from inhibition and fire during the following swallowing phase. These synaptic connections appear to be monosynaptic as they persist in high Mg2+/high Ca2+ (HiDi) saline that blocks polysynaptic pathways. Strong current-induced plateaus in the N2vs generate brief inhibitory postsynaptic responses in the B4CL rasp phase motor neurons, but this was due to the indirect N2v --> N2d --> B4CL pathway. The N2vs are coupled electrotonically to the N2d cells, and triggering plateau in a N2v usually induced one or two spikes in a N2d. Previous experiments showed that the N2ds generate plateau potentials during a fictive feeding cycle. Here we show that the main component of the "plateauing" waveform is due to the electrotonic coupling with the N2v cells. The differential synaptic connections of the N2v and N2d cells with retraction phase motor neurons results in a sequence of motor neuron burst activity B9 --> B4CL --> B8 that produces the full retraction (rasp --> swallow) movements of the feeding apparatus (buccal mass). We conclude that the N2v cells are an essential component of the interneuronal network required to produce feeding motor neuron activity.

Animals↗

PubMed1990

The adaptive base of the neural hierarchy: elementary motivational controls on network function.

This chapter has explored a hierarchical approach to motivation, based on the idea of a vertical integration among brainstem, limbic, paralimbic, and neocortical systems. When viewed in the traditional manner, this hierarchy has been seen in terms of top-down control, with the neocortical regions exerting higher-level, converging influences over the lower regions. When viewed from an evolutionary perspective, the hierarchy proves to be balanced by a complementary pattern of divergent projections ascending from the lower to the higher levels. These ascending systems respond first to the adaptively significant properties of a stimulus, including its novelty, conspicuousness, and need relatedness. By means of their increasingly specific projection patterns, the elementary motivational mechanisms support a progressive narrowing of activity within the cortex. Selection begins with activity in ascending brainstem systems, organizing the primordial states of tonic activation and phasic arousal. Although these states are relatively general, they bias information processing in specific ways by modulating both the spatial and temporal span of attention. As limbic circuits are recruited, certain classes of adaptive response and perceptual processes are potentiated, bringing into play postural orientations and global perceptions of the environment. This response and perceptual processing promotes activity within the interoceptive fields of the paralimbic cortices, leading to primitive hedonic and energetic representations. Back-projections from paralimbic to successive neocortical fields allow these affective representations to aid further in narrowing sensory and response options. Multiple levels of representation thus work together in gradually focusing and articulating the representations forming within the hierarchical networks of the neocortex. The recent evidence on neocortical architecture shows that cortical areas tend to be most closely connected with other regions of the same level of architectonic differentiation. Thus the functional units of the cortex may be not lobes or even hemispheres but the growth rings sharing a specific laminar architecture and dense horizontal interconnections. Functional binding--the integration of the distributed representations of the cortex--may take place across these horizontal lines. Furthermore, the density of horizontal interconnections decreases for the more recently evolved neocortical growth rings, such that the primary and sensory and motor cortices are relatively isolated from all but the adjacent architectonic ring. This suggests that the most important functional binding in the cortex occurs at the more primitive, paralimbic network levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Brain↗

PubMed1994

Deviation in cerebral excitability: possible clinical implications.

Schizophrenia, a chemical signaling disorder in the brain, is also a deteriorating neurological disorder. The deficit in cerebral excitability, and associated reduced synaptic density, imply a risk of cortical breakdown of circuitry accompanied by an insufficient fill-in mechanism, and persistent silent spots, but no total loss of function, only dysfunction. This is subjectively experienced as deficiencies of cognition, perception and sensorimotor phenomena depending upon localization and connections of the disconnected circuitry. Considering the adversity inherent in this neural network, both the fast Hebbian pre-post form of learning and the slow pre-modulatory coincidence form of learning are probably impaired. The use of Feed Back Loops which usually govern our behaviour might also be impaired. In addition, we have to consider the daily problem of insufficient drive and motivation. Manic depressive psychosis, a chemical signaling disorder in the brain, is a true functional psychosis. The raised excitatory drive and raised synaptic density imply raised risk of uncoupling of circadian rhythms via the direct glutamatergic input to the suprachiasmatic nucleus of hypothalamus (SCN). This episodic brain stem dysfunction illustrates how a deficit in inhibition renders the brain unstable. The requirements of the fast Hebbian form of learning should easily be met, and neither should the slow forms of learning present a problem in networks characterized by excessive density.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral Cortex↗

PubMed2003

Human dental pulp vasculogenesis evaluated by CD34 antigen expression and morphological arrangement.

Vasculogenesis describes the process by which endothelial precursor cells form new blood vessels. To characterize the topography and the cellular processes underlying vascularization of human dental pulp, we examiend the expression of the human hematopoietic progenitor cell antigen CD34. Dental pulps, obtained from deciduous and permanent teeth, were morphologically examined at light- and electron-microscope levels and by expression of CD34. The findings indicate that vasculogenesis of dental pulp is a complicated process starting from single CD34(+) cells. These subsequently coalesce to form solid vascular cords inside the developing connective tissue, which later hollows. Pericytes were embedded within the fully formed microvessels' basement membrane. The presence of CD34(+) endothelial cells in permanent teeth reveals that the process of vasculogenesis persists into adult life, where it contributes to continuous adjustment of vessel and network structures in response to functional needs and dental tissue homeostasis.

Adolescent↗

PubMed2005

Reorganization of language-related neuronal networks in patients with left temporal lobe epilepsy - an fMRI study.

To investigate the inter- and intrahemispheric reorganization of the language cortex in left temporal lobe epilepsy (TLE) with left-sided hippocampal sclerosis. A functional magnetic resonance imaging was performed on 13 right-handed patients suffering from medically intractable left TLE, and in 13 sex- and age-matched healthy controls. The activation paradigm used was a silent word generation task. A language laterality index (LI) was calculated from the number of activated voxels in the right and left anterior two-thirds of the hemispheres. Significant differences between the patients and the controls were observed in the activation of the left-sided inferior frontal gyrus. Less consistent findings in this region, as well as the relative protection of Broca's area from the activation, were revealed in the patients. In addition, different patterns of activation were proven in the cerebellum and other cortical as well as subcortical brain structures within both hemispheres. Significant differences were also found in the values of the language LIs between the investigated groups: these values suggested a more bihemispheric language representation in the patients. As anticipated, lateralization of the language functions in the epileptics significantly decreased in connection with an earlier age of initial insult. Our results support the hypothesis of a significant intra- and interhemispheric functional reorganization of language-related neuronal networks in left TLE.

Adult↗

PubMed2005

A network representation of protein structures: implications for protein stability.

This study views each protein structure as a network of noncovalent connections between amino acid side chains. Each amino acid in a protein structure is a node, and the strength of the noncovalent interactions between two amino acids is evaluated for edge determination. The protein structure graphs (PSGs) for 232 proteins have been constructed as a function of the cutoff of the amino acid interaction strength at a few carefully chosen values. Analysis of such PSGs constructed on the basis of edge weights has shown the following: 1), The PSGs exhibit a complex topological network behavior, which is dependent on the interaction cutoff chosen for PSG construction. 2), A transition is observed at a critical interaction cutoff, in all the proteins, as monitored by the size of the largest cluster (giant component) in the graph. Amazingly, this transition occurs within a narrow range of interaction cutoff for all the proteins, irrespective of the size or the fold topology. And 3), the amino acid preferences to be highly connected (hub frequency) have been evaluated as a function of the interaction cutoff. We observe that the aromatic residues along with arginine, histidine, and methionine act as strong hubs at high interaction cutoffs, whereas the hydrophobic leucine and isoleucine residues get added to these hubs at low interaction cutoffs, forming weak hubs. The hubs identified are found to play a role in bringing together different secondary structural elements in the tertiary structure of the proteins. They are also found to contribute to the additional stability of the thermophilic proteins when compared to their mesophilic counterparts and hence could be crucial for the folding and stability of the unique three-dimensional structure of proteins. Based on these results, we also predict a few residues in the thermophilic and mesophilic proteins that can be mutated to alter their thermal stability.

Computer Simulation↗

PubMed1996

Reversible deactivation of cerebral network components.

Reversible deactivation techniques have shown that the cerebral network: (1) is dynamic, its functions depending on contemporaneous processing elsewhere in the network; (2) is composed of single nodes that contribute to several behaviors; (3) possesses an inherent plasticity that tends to minimize lesion-induced deficits; and (4) comprises feedforward and lateral connections that contribute in different ways to network operations. The next major advances in understanding network operations will probably be made by applying a combination of behavioral, neuron-recording and deactivation techniques. The greatest near-term gains are likely to be made in understanding the contributions that feedback projections make to cerebral network function.

Animals↗