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Human nervous system function emulator.

This paper describes a modular, extensible, open-systems design for a multiprocessor network which emulates the major functions of the human nervous system. Interchangeable hardware/software components, a socketed software bus with plug-and-play capability and self diagnostics are included. The computer hardware is based on IEEE P996.1 bus cards. Its operating system utilizes IEEE 1275 standard software. Object oriented design techniques and programming are featured. A machine-independent high level script-based command language was created for this project. Neural anatomical structures which were emulated include the cortex, brainstem, cerebellum, spinal cord, autonomic and peripheral nervous systems. Motor, sensory, autoregulatory, and higher cognitive artificial intelligence, behavioral and emotional functions are provided. The author discusses how he has interfaced this emulator to machine vision, speech recognition/speech synthesis, an artificial neural network and a dexterous hand to form an android robotic platform.

Artificial Intelligence↗

Multichannel physiological monitor plus simultaneous full-duplex speech channel using a dial-up telephone line.

Because of bandwidth limitations, the Public Switched Telephone Network (PSTN) cannot normally accommodate simultaneous multichannel physiological signaling with speech. This communication describes work carried out to build a physiological monitoring system which can transmit up to six low-frequency data channels in the presence of a full-duplex speech channel using one telephone line.

Electrocardiography↗

Stimulation of monolayer networks in culture through thin-film indium-tin oxide recording electrodes.

Monolayer networks, obtained from murine spinal cord tissue and grown on a matrix of 64 photo-etched, indium-tin oxide (ITO) microelectrodes, can be electrically stimulated through such thin-film recording electrodes. Multichannel coordinated network activity can be evoked and spontaneous network activity can be modified by generation of additional, multichannel bursting. Although single pulses through 1 electrode may trigger network responses, networks generally react best to short trains of pulses. Response thresholds approximate standard physiological strength/duration relationships. Repetitive stimulation trains often generate network activity patterns akin to epileptiform activity. The ITO conductors remain stable for recording under warm saline for long periods of time (maximum test period: 8 months). However, most electrodes show a reduction in impedance after several thousand stimulus pulses. Electrode breakdown in the form of ITO oxidation and loss of light transmittance occurs before hydrolysis is observed but requires a combination of voltage levels and pulse lengths beyond that needed for effective network stimulation.

Animals↗

Inhibitory cotransmission or after-hyperpolarizing potentials can regulate firing in recurrent networks with excitatory metabotropic transmission.

Recurrent networks of neurons communicating via excitatory connections are common in the nervous system. In the absence of mechanisms to control firing (collectively termed negative feedback), these networks are likely to be bistable and unable to meaningfully encode input signals. In most recurrent circuits, negative feedback is provided by a specialized subpopulation of interneurons, but such neurons are absent from some systems, which therefore require other forms of negative feedback. One such circuit is found within the enteric nervous system of the intestine, where AH/Dogiel type II neurons are interconnected via excitatory synapses acting through metabotropic receptors to produce slow excitatory postsynaptic potentials (slow EPSPs). Negative feedback in this recurrent network may come from either inhibitory postsynaptic potentials arising from the terminals that produce slow EPSPs or from the after hyperpolarizing potentials (AHPs) characteristic of these neurons. We have examined these possibilities using mathematical analysis, based on the Wilson-Cowan model, and computer simulations. Analysis of steady states showed that, under appropriate conditions, both types of negative feedback can provide robust regulation of firing allowing the networks to encode input signals. Numerical simulations were performed using large, anatomically realistic networks with realistic models for metabotropic transmission and suppression of the AHP. In the presence of constant exogenous input, parameters controlling aspects of synaptic events were varied, confirming the analytical results for static stimuli. The simulated networks also responded to time varying inputs in a manner consistent with known physiology. In addition, simulation revealed that neurons in networks with inhibitory contransmission fired in erratic bursts, a phenomenon observed in neurons in unparalysed tissue. Thus, either inhibitory contransmission or AHPs, or both, can allow recurrent networks of AH/Dogiel type II neurons to encode ongoing inputs in a biologically useful way. These neurons appear to be intrinsic primary afferent neurons (IPANs), which implies that the IPANs in a region act in a coordinated fashion.

Action Potentials↗

Rana computatrix: progress report, 1984.

This paper describes an approach to analyzing mechanisms of visuomotor coordination that is twofold: top-down, to offer a coordinated control program of interacting schemata (functional units, underlying behavior, which can be activated in different combinations) to achieve behavior noted by neuroethologists; and bottom-up, to provide detailed models of neural networks that are consistent with known anatomy and physiology, but that involve additional assumptions, amenable to experimental testing, to yield a network capable of exhibiting appropriate behavior. Rana computatrix, an evolving series of models of frog and toad visuomotor coordination, is described.

Animals↗

ARACNE: an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context.

BACKGROUND: Elucidating gene regulatory networks is crucial for understanding normal cell physiology and complex pathologic phenotypes. Existing computational methods for the genome-wide "reverse engineering" of such networks have been successful only for lower eukaryotes with simple genomes. Here we present ARACNE, a novel algorithm, using microarray expression profiles, specifically designed to scale up to the complexity of regulatory networks in mammalian cells, yet general enough to address a wider range of network deconvolution problems. This method uses an information theoretic approach to eliminate the majority of indirect interactions inferred by co-expression methods. RESULTS: We prove that ARACNE reconstructs the network exactly (asymptotically) if the effect of loops in the network topology is negligible, and we show that the algorithm works well in practice, even in the presence of numerous loops and complex topologies. We assess ARACNE's ability to reconstruct transcriptional regulatory networks using both a realistic synthetic dataset and a microarray dataset from human B cells. On synthetic datasets ARACNE achieves very low error rates and outperforms established methods, such as Relevance Networks and Bayesian Networks. Application to the deconvolution of genetic networks in human B cells demonstrates ARACNE's ability to infer validated transcriptional targets of the cMYC proto-oncogene. We also study the effects of misestimation of mutual information on network reconstruction, and show that algorithms based on mutual information ranking are more resilient to estimation errors. CONCLUSION: ARACNE shows promise in identifying direct transcriptional interactions in mammalian cellular networks, a problem that has challenged existing reverse engineering algorithms. This approach should enhance our ability to use microarray data to elucidate functional mechanisms that underlie cellular processes and to identify molecular targets of pharmacological compounds in mammalian cellular networks.

Algorithms↗

A mathematical approach to the connectivity between the cortical visual areas of the macaque monkey.

The visual cortex of the macaque monkey is divided into many distinct visual information processing areas. In many cases, anatomical and physiological results allow one to determine the presence or the absence of neuronal connections from one area to another. We have approached the topology of this neuronal network within the mathematical framework of graph theory. At first, we studied the unknown part of the network, i.e. the part where anatomical and physiological results are lacking. Relying on a specific topological property of the network established on the known part, we developed an interpolation algorithm for reducing the level of uncertainty concerning the unknown part. From these results, we then constructed a connectional model of the neuronal network for the entire cortical visual system. Subsequently, a topological analysis of this model, with the help of factorial analysis and clustering technics, shows its structural properties and singular vertices. This analysis suggests the existence of two distinct classes of areas, one in the parietal part of the cortex and the other in the temporal part, which are connected to each other via relay areas, especially involving the frontal eye field. These results may help to understand the functional role of particular cortical areas in vision and, more generally, to explore how visual information flows within the visual cortex.

Algorithms↗

A novel theory: biological processes mostly involve two types of mediators, namely general and specific mediators Endogenous small radicals such as superoxide and nitric oxide may play a role of general mediator in biological processes.

A great number of papers have shown that free radicals as well as bioactive molecules can play a role of mediator in a wide spectrum of biological processes, but the biological actions and chemical reactivity of the free radicals are quite different from that of the bioactive molecules, and that a wide variety of bioactive molecules can be easily modified by free radicals due to having functional groups sensitive to redox, and the significance of the interaction between the free radicals and the bioactive molecules in biological processes has been confirmed by the results of some in vitro and in vivo studies. Based on these evidence, this article presented a novel theory about the mediators of biological processes. The essentials of the theory are: (a) mediators of biological processes can be classified into general and specific mediators; the general mediators include two types of free radicals, namely superoxide and nitric oxide; the specific mediators include a wide variety of bioactive molecules, such as specific enzymes, transcription factors, cytokines and eicosanoids; (b) a general mediator can modify almost any class of the biomolecules, and thus play a role of mediator in nearly every biological process via diverse mechanisms; a specific mediator always acts selectively on certain classes of the biomolecules, and may play a role of mediator in different biological processes via a same mechanism; (c) biological processes are mostly controlled by networks of their mediators, so the free radicals can regulate the last consequence of a biological process by modifying some types of the bioactive molecules, or in cooperation with these bioactive molecules; the biological actions of superoxide and nitric oxide may be synergistic or antagonistic. According to this theory, keeping the integrity of these networks and the balance between the free radicals and the bioactive molecules as well as the balance between the free radicals and the free radical scavengers would be of vital importance for physiological processes, and disturbance of these networks and balances would be a critical factor of pathological processes. Therefore, the investigators who want to get a deep and full understanding of the mechanism of a biological process should pay attention to the roles of both free radical and bioactive molecule species, and the free radical scavengers, which are used for health protection, such a vitamin E and carotenoid, should be taken in a suitable dosage.

Models, Biological↗

Hair cycle-dependent plasticity of skin and hair follicle innervation in normal murine skin.

The innervation of normal, mature mammalian skin is widely thought to be constant. However, the extensive skin remodeling accompanying the transformation of hair follicles from resting stage through growth and regression back to resting (telogen-anagen-catagen-telogen) may also be associated with alteration of skin innervation. We, therefore, have investigated the innervation of the back skin of adolescent C57BL/6 mice at various stages of the depilation-induced hair cycle. By using antisera against neuronal (protein gene product 9.5 [PGP 9.5], neurofilament 150) and Schwann cell (S-100, myelin basic protein) markers, as well as against neural cell adhesion molecule (NCAM) and growth-associated protein-43 (GAP-43), we found a dramatic increase of single fibers within the dermis and subcutis during early anagen. This was paralleled by an increase in the number of anastomoses between the cutaneous nerve plexuses and by distinct changes in the nerve fiber supply of anagen vs. telogen hair follicles. The follicular isthmus, including the bulge, the seat of epithelial follicle stem cells, was found to be the most densely innervated skin area. Here, a defined subpopulation of nerve fibers increased in number during anagen and declined during catagen, accompanied by dynamic alterations in the expression of NCAM and GAP-43. Thus, our study provides evidence for a surprising degree of plasticity of murine skin innervation. Because hair cycle-associated tissue remodeling evidently is associated with tightly regulated sprouting and regression of nerve fibers, hair cycle-dependent alterations in murine skin and hair follicle innervation offer an intriguing model for studying the controlled rearrangement of neuronal networks in peripheral tissues under physiological conditions.

Animals↗

Altered gravitational forces affect the development of the static vestibuloocular reflex in fish (Oreochromis mossambicus).

Young fish (Oreochromis mossambicus) were exposed to microgravity (micro g) for 9 to 10 days during space missions STS-55 and STS-84, or to hypergravity (hg) for 9 days. Young animals (stages 11-12), which had not yet developed the roll-induced static vestibuloocular reflex (rVOR) at micro g- and hg-onset, and older ones (stages 14-16), which had already developed the rVOR, were used. For several weeks afterwards, the rVOR was recorded after termination of mug and hg. Here are the main results: (1) In the stage 11-12 fish, the rVOR gain (response angle/roll angle) measured for roll angles 15 degrees, 30 degrees, and 45 degrees was not affected by microgravity if animals were rolled from the horizontal to the inclined posture, but was increased significantly if animals were rolled in the opposite manner. The rVOR amplitude (maximal eye movement during a complete 360 degrees roll) of micro g animals increased significantly by 25% compared to 1g controls during the first postflight week, but decreased to the control level during the second postflight week. Microgravity had no effect in stage 14-16 fish on either rVOR gain or amplitude. (2) After 3g exposure, both rVOR gain and amplitude were significantly reduced for both stage 11-12 and stage 15 fish. One g readaptation was completed during the second post-3g week. Hypergravity at 2 or 2.5 g had no effect. (3) Hypergravity at all three levels tested (2g, 2.5g, and 3g) accelerated the morphological development as assessed by external morphological markers. Exposure to micro g- or 3g-periods during an early developmental period modifies the physiological properties of the neuronal network underlying the static rVOR; in susceptible developmental stages, these modifications include sensitization by microgravity and desensitization by hypergravity.

Animals↗

Proteome profiling and its use in metabolic and cellular engineering.

Proteome profiling of microorganisms makes it possible to generate valuable knowledge that can be used for the development of metabolic and cellular engineering strategies, which consequently are used to enhance the yield and productivity of native or foreign bioproducts and to modify cellular properties to improve mid-stream and down-stream processes. Advances in two-dimensional gel electrophoresis technology combined with mass spectrometry allow the creation of global scale proteome contents which can be used to elucidate valuable information on the dynamics of the metabolic, signaling and regulatory networks apart from understanding the physiological changes. In this paper, we review the approaches of exploiting the proteome profiling results to the development of the strategies for the metabolic and cellular engineering of microorganisms.

Electrophoresis, Gel, Two-Dimensional↗

Differential stimulation of prostaglandin G/H synthase-2 in osteocytes and other osteogenic cells by pulsating fluid flow.

Mechanical stress produces flow of fluid in the osteocytic lacunar-canalicular network, which is likely the physiological signal for the adaptive response of bone. We compared the induction of prostaglandin G/H synthase-2 (PGHS-2) by pulsating fluid flow (PFF) and serum in osteocytes, osteoblasts, and periosteal fibroblasts, isolated from 18-day-old fetal chicken calvariae. A serum-deprived mixed population of primarily osteocytes and osteoblasts responded to serum with a two- to threefold induction of PGHS-2 mRNA. Serum stimulated PGHS-2-derived PGE(2) release from osteoblasts and osteocytes but not from periosteal fibroblasts as NS-398, a PGHS-2 blocker, inhibited PGE(2) release from osteocytes and osteoblasts with 65%, but not that from periosteal fibroblasts. On the other hand PFF (0.7 Pa, 5 Hz) stimulated (3 fold) PGHS-2 mRNA only in OCY. The related PGE(2) response could be completely inhibited by NS-398. We conclude that osteocytes have a higher intrinsic sensitivity for loading-derived fluid flow than osteoblasts or periosteal fibroblasts.

Animals↗

Developmental aspects of pediatric fMRI: considerations for image acquisition, analysis, and interpretation.

Functional MRI provides a powerful means to identify and trace the evolution, development, and consolidation of cognitive neural networks through normal childhood. Neural network perturbations due to disease and other adverse factors during development can also be explored. Studies performed to date suggest that normal children older than 5 years show activation maps comparable to adults for similar cognitive paradigms. Minor differences in adult and pediatric activation maps may reflect age dependent strategies or maturation of cognitive networks. However, there are important physiologic and anatomic differences in children, varying with age, that may affect the acquisition, analysis, and interpretation of pediatric fMRI data. Differences between children and adult fMRI comparison studies may reflect technical aspects of data acquisition as much as developmental and brain maturation factors.

Aging↗

Vascular patterning by Eph receptor tyrosine kinases and ephrins.

During vertebrate development, morphologically and functionally very different tissue types and organ systems need to be generated and organised in close coordination with each other. Blood vessels, which become critically required during early embryogenesis and remain indispensable throughout life, need to integrate into a great diversity of tissue types and adapt to both local and systemic requirements of the organism. Far from being randomly placed and uniformly shaped tubes, blood vessels form, with some degree of flexibility, a highly organised and precisely arranged network. Their differentiation, ultrastructure and physiology are well adapted to the requirements and functions of the surrounding tissues. How coordinated development and differentiation are achieved at a molecular level remains to be characterised. This review highlights the large family of Eph receptor tyrosine kinases and their ligands, called ephrins, which, because of their versatile functions in many cell and tissue types and their molecular complexity, might well provide one example of a control system integrating blood vessel and tissue morphogenesis.

Animals↗

Origins and evolutionary diversification of the nuclear receptor superfamily.

Nuclear receptors (NRs), which include those for steroid and thyroid hormones as well as retinoids, are encoded by a large gene superfamily that has evolved to regulate nearly every facet of metazoan life, from development to basic metabolism. This article reviews the conservation in structure and function of distinct receptors across different species and attempts to draw conclusions as to the evolution of this gene superfamily. Although sequences related to NRs can be found in plants and yeast, gene sequence analyses suggest that the NR ancestor(s) first appeared in the early metazoans and subsequently diversified into the six receptor sub-families, which were already recognisable at the time of the Arthropoda-Chordata split over 700 million years ago. At the time when a primitive NR emerged, the basic components of the transcription regulatory machinery, which are conserved from yeast to vertebrates, were already in place and the ancestral NR must have evolved with the ability to communicate with them. The first such NRs likely acted as monomers and in a ligand-independent fashion. As members of the NR superfamily acquired the ability to hetero- and homodimerise, and to bind and be regulated by ligands, the functional complexity of the NR superfamily increased. This exponentially increasing complexity subsequently provided a potential driving force for evolution of higher organisms by supplying a sophisticated regulatory gene network that could control complex physiological processes during development and in adult organisms.

Amino Acid Sequence↗

Histidine biosynthesis in plants.

The study of histidine metabolism has never been at the forefront of interest in plant systems despite the significant role that the analysis of this pathway has played in development of the field of molecular genetics in microbes. With the advent of methods to analyze plant gene function by complementation of microbial auxotrophic mutants and the complete analysis of plant genome sequences, strides have been made in deciphering the histidine pathway in plants. The studies point to a complex evolutionary origin of genes for histidine biosynthesis. Gene regulation studies have indicated novel regulatory networks involving histidine. In addition, physiological studies have indicated novel functions for histidine in plants as chelators and transporters of metal ions. Recent investigations have revealed intriguing connections of histidine in plant reproduction. The exciting new information suggests that the study of plant histidine biosynthesis has finally begun to flower.

Arabidopsis↗

The ON and OFF channels of the visual system.

In the vertebrate retina, all photoreceptors hyperpolarize in response to light. In the outer retina, at the bipolar cell level, a dual system is created from the cones forming the ON and OFF channels. In the rod system a similar arrangement is found, but the ON and OFF channels in many species are formed using an amacrine cell network in the inner retina. Physiological experiments in which the ON bipolar cells are pharmacologically blocked reveal that in the primate the two channels remain largely segregated in the geniculostriate system until they reach the cortex, where they converge upon single cells. Behavioral studies show that following ON channel block, notable deficits arise in the detection of light increments but not light decrements. These and related studies suggest that the ON and OFF channels optimize information transfer to the CNS by providing excitatory signals for both increases and decreases in light energy.

Animals↗