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New concepts in the study of tissue vascularization: a mathematical model of skin vascularization.

A preliminary study demonstrated the existence of a fractal structure for perforator arterial vessels of the skin and proved to be a useful tool to compare vascular trees on the basis of their complexity. Fractal analysis of axial-perforator arteriovenous vascular trees was performed on the skin of mice after injection of the arterial network by india ink. Fractal analysis was performed by box counting. Fractal dimension D was determined for 35 venous and 31 arterial perforator vessels (D = 1.302 and 1.264, respectively) and 5 venous and 3 arterial axial vessels (D = 1.374 and 1.328, respectively) (r2 > or = 0.985). All vascular networks show a fractal structure, characterized by a specific D. These values are relatively constant; D is a function of the anatomic and physiologic characteristics. There was no significant difference between venous and arterial networks, nor was there between axial and perforator networks (p < 0.05); this demonstrates a similar efficacy in terms of perfusion of the skin. A computer simulation based on fractal theory has been developed to reproduce the two kinds of vascular networks. Fractals are the result of a construction procedure that is repeated and repeated so that the iteration of a very simple rule can produce seemingly complex shapes, such as vascular networks. The basic module that is repeated in the whole structure is Y-shaped and is termed the generator; this generator is applied to a basic structure, called the initiator. After a few iterations, a vascular network is obtained. The difference between axial and perforator vascular networks is the choice of the initiator, whereas the generator is identical.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Variable kainate receptor distributions of oriens interneurons.

Interneuron kainate receptor (KAR) activation regulates normal network activity and modulates cell excitability. As a result, determining the subcellular distribution of KARs in a cell-specific manner is a necessary step toward understanding their role in network function. We have functionally mapped synaptic and extrasynaptic dendritic KARs on hippocampal oriens interneurons using local photolysis of caged glutamate. We find that the majority of trilaminar and oriens lacunosum-moleculare (O-LM) cells have uniform and continuous current densities along the lengths of their dendrites. However, there is a subpopulation of interneurons that have no KAR currents or currents exclusively at "hot spots" on the soma and dendrites. Finally, bistratified cells have KAR currents on all dendrites except those extending into the stratum radiatum. Thus KARs are functionally distributed in a cell-specific and cell-independent manner that may reflect the physiologically distinct roles they play in the hippocampal network.

Animals↗

Artificial neural network versus subjective scoring in predicting mortality in trauma patients.

OBJECTIVE: Current methods of trauma outcome prediction rely on clinical knowledge and experience. This makes the system a subjective score, because of intra-rater variability. This project aims to develop a neural network for predicting survival of trauma patients using standard, measured, physiological variables, and compare its predictive power with that obtained from current trauma scores. METHODS: The project uses 7688 patients admitted to the Swedish Medical Center, Colorado, U.S.A. between the years 2000-2003 inclusive. Neural Network software was used for data analysis to determine the best network design on which to base the model to be tested. The model is created using a minimum number of variables to produce an effective outcome predicting score. Initial variables were based on the current variables used in calculating the Revised Trauma Score, replacing the Glasgow Coma Scale (GCS) with a modified motor component of the GCS. Additional variables are added to the model until a suitable model is achieved. RESULTS: The best model used Multi-Layer Perceptrons, with 8 input variables, 5 hidden neurons and 1 output. It was trained on 5881 cases and tested independently on 1807 cases. The model was able to accurately predict 91% patient mortality. CONCLUSIONS: An ANN developed using pre-hospital physiological variables without using subjective scores resulted in good mortality prediction when applied to a test set. Its performance was too sensitive and requires refinement.

Adolescent↗

Current concepts in apoptosis: the physiological suicide program revisited.

Apoptosis, or programmed cell death (PCD), involves a complex network of biochemical pathways that normally ensure a homeostatic balance between cellular proliferation and turnover in nearly all tissues. Apoptosis is essential for the body, as its deregulation can lead to several diseases. It plays a major role in a variety of physiological events, including embryonic development, tissue renewal, hormone-induced tissue atrophy, removal of inflammatory cells, and the evolution of granulation tissue into scar tissue. It also has an essential role in wound repair. The various cellular and biochemical mechanisms involved in apoptosis are not fully understood. However, there are two major pathways, the extrinsic pathway (receptor-mediated apoptotic pathway) and the intrinsic pathway (mitochondria-mediated apoptotic pathway), which are both well established. The key component in both is the activation of the caspase cascade. Caspases belong to the family of proteases that ultimately, by cleaving a set of proteins, cause disassembly of the cell. Although the caspase-mediated proteolytic cascade represents a central point in the apoptotic response, its initiation is tightly regulated by a variety of other factors. Among them, Bcl-2 family proteins, TNF and p53 play pivotal roles in the regulation of caspase activation and in the regulation of apoptosis. This review summarizes the established concepts in apoptosis as a physiological cell suicide program, highlighting the recent and significant advances in its study.

Animals↗

Integrating behavioral and neural data in a model of zebrafish network interaction.

The spinal neural networks of larval zebrafish (Danio rerio) generate a variety of movements such as escape, struggling, and swimming. Various mechanisms at the neural and network levels have been proposed to account for switches between these behaviors. However, there are currently no detailed demonstrations of such mechanisms. This makes determining which mechanisms are plausible extremely difficult. In this paper, we propose a detailed biologically plausible model of the interactions between the swimming and escape networks in the larval zebrafish, while taking into account anatomical and physiological evidence. We show that the results of our neural model generate the expected behavior when used to control a hydrodynamic model of carangiform locomotion. As a result, the model presented here is a clear demonstration of a plausible mechanism by which these distinct behaviors can be controlled. Interestingly, the networks are anatomically overlapping, despite clear differences in behavioral function and physiology.

Animals↗

[Plastic properties of the venous bed of the brain following disengagement of the external jugular veins at different stages of ontogenesis].

The capacity of the venous bed in the brain being great, even inconsiderable changes of the vein lumen can cause severe changes in the blood circulation without an enlargement of the cranial cavity volume. The progressing venous stagnation in the brain is a severe disease of not only the brain but also the whole organism. So, we attempted to study the character of compensatory redistribution of the pial venous system of the cerebrum in occlusion of both exterior jugular veins and to establish its developmental accomodative properties. The work has been performed on 45 dogs. The plasticity of the cerebral pial veins was found to drop with age, their reserving capacity-to grow and their carrying capacity-to decrease. Three successive phases are characteristic of the compensatory-adaptational changes: diffuse dilatation of the venous network, appearance of collaterals and their development against the background of reduction of the surrounding venous network.

Adaptation, Physiological↗

GABA(A) receptor diversity and pharmacology.

Because of its control of spike-timing and oscillatory network activity, gamma-aminobutyric acid (GABA)-ergic inhibition is a key element in the central regulation of somatic and mental functions. The recognition of GABA(A) receptor diversity has provided molecular tags for the analysis of distinct neuronal networks in the control of specific pharmacological and physiological brain functions. Neurons expressing alpha(1)GABA(A) receptors have been found to mediate sedation, whereas those expressing alpha(2)GABA(A) receptors mediate anxiolysis. Furthermore, associative temporal and spatial memory can be regulated by modulating the activity of hippocampal pyramidal cells via extrasynaptic alpha(5)GABA(A) receptors. In addition, neurons expressing alpha(3)GABA(A) receptors are instrumental in the processing of sensory motor information related to a schizophrenia endophenotype. Finally, during the postnatal development of the brain, the maturation of GABAergic interneurons seems to provide the trigger for the experience-dependent plasticity of neurons in the visual cortex, with alpha(1)GABA(A) receptors setting the time of onset of a critical period of plasticity. Thus, particular neuronal networks defined by respective GABA(A) receptor subtypes can now be linked to the regulation of various clearly defined behavioural patterns. These achievements are of obvious relevance for the pharmacotherapy of certain brain disorders, in particular sleep dysfunctions, anxiety disorders, schizophrenia and diseases associated with memory deficits.

Animals↗

Global strategies to integrate the proteome and metabolome.

A fundamental goal of proteomics is to assign physiological functions to all proteins encoded by eukaryotic and prokaryotic genomes. Of the many activities performed by proteins, the chemical transformations catalyzed by enzymes form the basis for most, if not all, metabolic and signaling pathways. Elucidation of these pathways and their integration into larger cellular networks require new strategies to rapidly and systematically identify physiological substrates of enzymes. Here, we review emerging technologies that aim to assign endogenous biochemical functions to enzymes by profiling the metabolome.

Animals↗

Prestressed F-actin networks cross-linked by hinged filamins replicate mechanical properties of cells.

We show that actin filaments, shortened to physiological lengths by gelsolin and cross-linked with recombinant human filamins (FLNs), exhibit dynamic elastic properties similar to those reported for live cells. To achieve elasticity values of comparable magnitude to those of cells, the in vitro network must be subjected to external prestress, which directly controls network elasticity. A molecular requirement for the strain-related behavior at physiological conditions is a flexible hinge found in FLNa and some FLNb molecules. Basic physical properties of the in vitro filamin-F-actin network replicate the essential mechanical properties of living cells. This physical behavior could accommodate passive deformation and internal organelle trafficking at low strains yet resist externally or internally generated high shear forces.

Actins↗

Resonant spatiotemporal learning in large random recurrent networks.

Taking a global analogy with the structure of perceptual biological systems, we present a system composed of two layers of real-valued sigmoidal neurons. The primary layer receives stimulating spatiotemporal signals, and the secondary layer is a fully connected random recurrent network. This secondary layer spontaneously displays complex chaotic dynamics. All connections have a constant time delay. We use for our experiments a Hebbian (covariance) learning rule. This rule slowly modifies the weights under the influence of a periodic stimulus. The effect of learning is twofold: (i) it simplifies the secondary-layer dynamics, which eventually stabilizes to a periodic orbit; and (ii) it connects the secondary layer to the primary layer, and realizes a feedback from the secondary to the primary layer. This feedback signal is added to the incoming signal, and matches it (i.e., the secondary layer performs a one-step prediction of the forthcoming stimulus). After learning, a resonant behavior can be observed: the system resonates with familiar stimuli, which activates a feedback signal. In particular, this resonance allows the recognition and retrieval of partial signals, and dynamic maintenance of the memory of past stimuli. This resonance is highly sensitive to the temporal relationships and to the periodicity of the presented stimuli. When we present stimuli which do not match in time or space, the feedback remains silent. The number of different stimuli for which resonant behavior can be learned is analyzed. As with Hopfield networks, the capacity is proportional to the size of the second, recurrent layer. Moreover, the high capacity displayed allows the implementation of our model on real-time systems interacting with their environment. Such an implementation is reported in the case of a simple behavior-based recognition task on a mobile robot. Finally, we present some functional analogies with biological systems in terms of autonomy and dynamic binding, and present some hypotheses on the computational role of feedback connections.

Brain↗

Use of World Wide Web server and browser software to support a first-year medical physiology course.

We describe the use of a World Wide Web (Web) server to support a team-taught physiology course for first-year medical students. Our objectives were to reduce the number of formal lecture hours and enhance student enthusiasm by using more multimedia materials and creating opportunities for interactive learning. On-line course materials, consisting of administrative documents, lecture notes, animations, digital movies, practice tests, and grade reports, were placed on a departmental computer with an Internet connection. Students used Web browsers to access on-line materials from a variety of computing platforms on campus, at home, and at remote sites. To assess use of the materials and their effectiveness, we analyzed 1) log files from the server, and 2) the results of a written course evaluation completed by all students. Lecture notes and practice tests were the most-used documents. The students' evaluations indicated that computer use in class made the lecture material more interesting, while the on-line documents helped reinforce lecture materials and the textbook. We conclude that the effectiveness of on-line materials depends on several different factors, including 1) the number of instructors that provide materials; 2) the quantity of other materials handed out; 3) the degree to which computer use is demonstrated in class and integrated into lectures; and 4) the ease with which students can access the materials. Finally, we propose that additional implementation of Internet-based resources beyond what we have described would further enhance a physiology course for first-year medical students.

Computer Communication Networks↗

Neural network simulations of the nervous system.

Present knowledge of brain mechanisms is mainly based on anatomical and physiological studies. Such studies are however insufficient to understand the information processing of the brain. The present new focus on neural network studies is the most likely candidate to fill this gap. The present paper reviews some of the history and current status of neural network studies. It signals some of the essential problems for which answers have to be found before substantial progress in the field can be made.

Animals↗

The Ets family contains transcriptional activators and repressors involved in angiogenesis.

The Ets family contains a growing number of transcriptional activators and inhibitors, which activity is regulated by phosphorylation and protein-protein interactions. Among these factors, Ets1, Erg1 and Fli1 are expressed in endothelial cells during angiogenesis in normal and pathological development. The expression of these transcription factors is regulated by angiogenic factors in cultured endothelial cells, as well as by various stresses occurring during angiogenesis. Transfection experiments and transgenic mice analysis revealed that Ets family members are involved in the transcriptional regulation of endothelial specific genes such as those encoding Tie1 and -2, VEGFR1 and -2 and VE-Cadherin. In vitro studies plead for a role of Ets family members in endothelial cell adhesion, spreading and motility. Gene inactivation experiments show that Ets1 is dispensable for embryonic development. The phenotype of knocked-out embryos indicates that Tel is required for maintenance of the developing vascular network in the yolk sac. Altogether, we suggest that Ets family members act both positively and negatively during the different steps of the angiogenic process. The regulation of the initiation of gene transcription arises from the combined activity of different transcriptional regulators. Therefore very few transcription factors are specific for a physiological process, or a given cell type. The transcriptional network that regulates blood vessel formation involves transcription factors which are expressed in a variety of situations. The Lung Kruppel Like Factor (LKLF) which is required for blood vessel stabilisation during murine development is also expressed in the primitive vertebrae and in the lung of the adult (C.T. Kuo, M.L. Veselits, K.P. Barton, M.M. Lu, C. Clendenin, J.M. Leiden, The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilisation during murine embryogenesis, Genes Dev. 11 (22) (1997) 2996-3006). Scl/Tal1 which is essential for angiogenic remodelling of the yolk sac capillary network (J.E. Visvader, Y. Fujiwara, S.H. Orkin, Unsuspected role for the T-cell leukemia protein SCL/tal-1 in vascular development, Genes Dev. 12 (4) (1998) 473-479), is involved in blood cell development and is also expressed in the developing brain. The EPAS transcription factor which was thought to be endothelial cell specific in the mouse embryo (H. Tian, S.L. McKnight, D.W. Russell, Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells, Genes Dev. 11 (1) (1997) 72-82) is also expressed in the liver, kidney and cells of the sympathetic nervous system of the chick embryo (J. Favier, H. Kempf, P. Corvol, J.M. Gasc, Cloning and expression pattern of EPAS1 in the chicken embryo. Colocalization with tyrosine hydroxylase, FEBS Lett. 462 (1-2) (1999) 19-24). Ets1, which expression was originally detected in lymphoid cells of adult tissues, has been the first transcription factor to be identified in endothelial cells during angiogenesis in the embryo (B. Vandenbunder, L. Pardanaud, T. Jaffredo, M.A. Mirabel, D. Stehelin, Complementary patterns of expression of c-etsl, c-myb and c-myc in the blood-forming system of the chick embryo, Development 107 (1989) 265-274 [5]) and in tumours (N. Wernert, M.B. Raes, P. Lassalle, M.P. Dehouck, B. Gosselin, B. Vandenbunder, D. Stehelin, The c-ets 1 proto-oncogene is a transcription factor expressed in endothelial cells during tumor vascularisation and other forms of angiogenesis in man, Am. J. Path. 140 (1992) 119-127 [6]). Since then, the Ets family has extended and this review will emphasise the relationships between these factors and angiogenesis.

Animals↗

The hydraulic system of trees: theoretical framework and numerical simulation

Empirical studies pose the problem of the physiological integration of the tree organism, which is also important on the scale of ecosystems. Recently, spatially distributed models emerged, which approach this problem by reflecting the close linkage between physiological processes and the structures of trees and tree stands. In the case of water flow, the tree organism can be regarded as hydraulic system and the branched tree architecture as hydraulic network. Previous models of the hydraulic system either did not take into account the network structure, or they had shortcomings regarding the translation of the underlying physiological assumptions by the discrete computation method. We have developed a theoretical framework which takes the form of a numerical simulation model of tree water flow. A discrete initial boundary value problem (IBVP) combines the phenomena of Darcy flow, water storage and conductivity losses in the hydraulic network. The software HYDRA computes the solution of the IBVP. The theoretical derivation and model tests corroborate the consistent translation of the physiological assumptions by the computational method. Simulation studies enabled us to formulate hypotheses on the following points: (1) differences in the hydraulic segmentation between Picea abies and Thuja occidentalis, (2) responses of the hydraulic system to rapid transpiration changes and to a scenario of drought stress, and (3) how these responses depend on architectural quantities of the trees. The simulation studies demonstrated our possibilities of deriving theoretically well-founded hypotheses about the functioning of the hydraulic system and its relation to system structure. The numerical simulation model is designed as a tool for structure-function studies, which is able to treat tree architecture as independent variable. The model supports the integration of data on tree level, and it can be used for computer experiments which quantify the dynamics of the hydraulic system according to the concepts of system theory. Copyright 1999 Academic Press.

Journal Article↗

The psychoneuroimmunological system: a recently evolved networking organ system.

The phenomenon of psychological influences on immune activity and general physiology has generated a great deal of interest in the last decade. Several theories have been proposed to understand the evolution and the nature of this bi-directional communication and/or influence. It is shown that the existing theories do not fully explain most phenomena associated with this communication. A theory--the networking organ theory--is also suggested that could resolve the issue. The information obtained from recent studies on evolutionary history and the fossil record have been used as the basis for understanding the phenomenon of psychoneuroimmunology. In essence, we are not looking at the unification of the mind and the body, but at a recently evolved system that lends sophistication to the existing connection between the mind and the body.

Animals↗

Anti-apoptotic activity of p53 maps to the COOH-terminal domain and is retained in a highly oncogenic natural mutant.

The tumour suppressor p53 plays a complex role in the regulation of apoptosis. High levels of wild type p53 potentiate the apoptotic response, while physiological range, low levels of the protein have an anti-apoptotic activity in serum starved immortalized fibroblasts. Here we report that primary fibroblast-like cells that show normal growth control are also efficiently protected from apoptosis by the endogenous p53 activity. The capacity to inhibit apoptosis is not restricted to the wild type protein: the R-->H175 p53 mutant fully retains the anti-apoptotic activity of the wild type p53, providing a possible explanation for its high oncogenicity. Using a series of point and deletion mutants of p53 under the control of tetracycline-regulated promoter we show that certain mutants, like the wild type, protect cells at low levels but lead to apoptosis when overexpressed. This latter effect is lost upon deletion of a proline-rich domain in the NH2 part of the protein. The anti-apoptotic activity can be mapped to the extreme carboxy-terminal part of the protein and is therefore independent of other well characterized p53 activities. Our results add a new level of complexity to the network of interactions mediated by p53 in normal physiology and pathology.

Animals↗

Plastic and nonplastic pyramidal cells perform unique roles in a network capable of adaptive redundancy reduction.

Pyramidal cells show marked variation in their morphology, including dendritic structure, which is correlated with physiological diversity; however, it is not known how this variation is related to a cell's role within neural networks. In this report, we describe correlations among electrosensory lateral line lobe (ELL) pyramidal cells' highly variable dendritic morphology and their ability to adaptively cancel redundant inputs via an anti-Hebbian form of synaptic plasticity. A subset of cells, those with the largest apical dendrites, are plastic, but those with the smallest dendrites are not. A model of the network's connectivity predicts that efficient redundancy reduction requires that nonplastic cells provide feedback input to those that are plastic. Anatomical results confirm the model's prediction of optimal network architecture. These results provide a demonstration of different roles for morphological/physiological variants of a single cell type within a neural network performing a well-defined function.

Action Potentials↗

Modeling of pain using artificial neural networks.

In dealing with human nervous system, the sensation of pain is as sophisticated as other physiological phenomena. To obtain an acceptable model of the pain, physiology of the pain has been analysed in the present paper. Pain mechanisms are explained in block diagram representation form. Because of the nonlinear interactions existing among different sections in the diagram, artificial neural networks (ANNs) have been exploited. The basic patterns associated with chronic and acute pain have been collected and then used to obtain proper features for training the neural networks. Both static and dynamic representations of the ANNs were used in this regard. The trained networks then were employed to predict response of the body when it is exposed to special excitations. These excitations have not been used in the training phase and their behavior is interesting from the physiological view. Some of these predictions can be inferred from clinical experimentations. However, more clinical tests have to be accomplished for some of the predictions.

Acute Disease↗