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Network dynamics and cell physiology.

Complex assemblies of interacting proteins carry out most of the interesting jobs in a cell, such as metabolism, DNA synthesis, movement and information processing. These physiological properties play out as a subtle molecular dance, choreographed by underlying regulatory networks. To understand this dance, a new breed of theoretical molecular biologists reproduces these networks in computers and in the mathematical language of dynamical systems.

CDC2 Protein Kinase↗

Sleep networks and the anatomic and physiologic connections with respiratory control.

A central neuronal network regulates airway functions from the nares to the bronchioles and is an integral component of a regulatory system for brain control of breathing and airway patency during wakefulness and sleep. This network, components of which include sleep generating sites and monoaminergic neurons in particular, is characterized by reciprocal interconnections, parallel organization, and state-dependent activity patterns, which can be influenced by both genes and environment. Sleep generating neurons are interconnected with the monoaminergic containing cells to the extent that sleep-related changes in upper and lower airway patency could be due to inhibitory influences of sleep-activated neurons on serotonergic and noradrenergic producing cells. Neurochemical studies and physiologic experiments show that serotonergic and noradrenergic producing cells can make parallel pathways, directly innervating the hypoglossal motor cells regulating upper airway dilating muscles, and vagal preganglionic neurons providing cholinergic outflow to the airways. Activation of serotonergic and noradrenergic cell groups preferentially increases activity of the genioglossus muscle, but diminishes cholinergic outflow to the airways. Hence, inhibition of monoaminergic neurons during sleep may lead to a decrease in upper airway dilating forces and an elevation of cholinergic outflow to the airways. Qualitatively different responses of hypoglossal and airway-related vagal preganglionic neurons (AVPNs) occur in response to endogenously released serotonin or norepinephrine and could be related to its simultaneous action on different serotonin or norepinephrine receptor subtypes. Dysfunction of monaminergic cell groups during sleep may predispose to upper airway occlusion as well as bronchoconstriction. Pharmacological corrections of alterations of these transmitter specific converging systems might be an avenue for treatment of sleep related airway disorders such as sleep apnea and worsening of asthma.

Animals↗

Revalidation of the Score for Neonatal Acute Physiology in the Vermont Oxford Network.

OBJECTIVES: Our specific objectives were (1) to document the performance of the revised Score for Neonatal Acute Physiology and the revised Score for Neonatal Acute Physiology Perinatal Extension in predicting death in the Vermont Oxford Network, compared with published normative values; (2) to determine whether this performance could be improved through recalibration of the weights for individual score items; (3) to determine the impact of including congenital anomalies in the predictive model; and (4) to compare performance against that of the Vermont Oxford Network risk adjustment, separately and in combination. METHODS: Fifty-eight Vermont Oxford Network centers collected data prospectively for the revised Score for Neonatal Acute Physiology in the first 12 hours after admission of infants in 2002. RESULTS: Data were collected for 10,469 infants, and analyses were undertaken for 9897 who met inclusion criteria. The median revised Score for Neonatal Acute Physiology was 5, and the mean birth weight was 1951 g. Recalibration of the revised Score for Neonatal Acute Physiology and revised Score for Neonatal Acute Physiology Perinatal Extension resulted in minimal changes in their discriminatory abilities. The Vermont Oxford Network risk adjustment performed similarly, compared with the revised Score for Neonatal Acute Physiology Perinatal Extension. CONCLUSIONS: Current score performance was similar to that observed previously, which suggests that the revised Score for Neonatal Acute Physiology and revised Score for Neonatal Acute Physiology Perinatal Extension have not decalibrated over the 7 years since the first cohort was assembled, despite advances in neonatal care during that period. Addition of congenital anomalies to the revised Score for Neonatal Acute Physiology Perinatal Extension improved discrimination significantly, particularly for infants with birth weights of >1500 g. The Vermont Oxford Network risk adjustment performed similarly, compared with the revised Score for Neonatal Acute Physiology Perinatal Extension.

Apgar Score↗

The amyloid precursor protein and its network of interacting proteins: physiological and pathological implications.

The amyloid precursor protein (APP) is an ubiquitous receptor-like molecule involved in the pathogenesis of Alzheimer's disease that generates beta-amyloid peptides and causes plaque formation. APP and some of its C-terminal proteolytic fragments (CTFs) have also been shown to be in the center of a complex protein-protein network, where selective phosphorylation of APP C-terminus may regulate the interaction with cytosolic phosphotyrosine binding (PTB) domain or Src homology 2 (SH2) domain containing proteins involved in cell signaling. We have recently described an interaction between tyrosine-phosphorylated CTFs and ShcA adaptor protein which is highly enhanced in AD brain, and a new interaction between APP and the adaptor protein Grb2 both in human brain and in neuroblastoma cultured cells. These data suggest a possible role in cell signaling for APP and its CTFs, in a manner similar to that previously reported for other receptors, through a tightly regulated coupling with intracellular adaptors to control the signaling of the cell. In this review, we discuss the significance of these novel findings for AD development.

Adaptor Proteins, Signal Transducing↗

[Functional anatomy of the pelvic veins in women].

Pelvic veins and lower extremities veins form a functional unit resulting in the interaction of their pathology. The intrapelvic venous system consists of two independent networks, under physiological conditions: the parietal and the visceral networks. The main collectors are the internal iliac veins, the ovarian superior rectal veins. The original venous plexi, located in the sub-peritoneal pelvic connective tissue, remain open because of the adhesion of their wall to the parietal pelvic fascia. The parietal venous network, abundant and supplied with valves, includes the retro-public and sacral plexi. The usual venous drainage is encouraged by abundant anastomoses, the decrease or even the absence of valves and the abdominal pressure. When this pressure increases, especially during walking, this encourages pelvic drainage. Occasional venous drainage is observed in case of obstruction of the usual collectors. Anatomical obstacles to the drainage, besides thrombosis and tumors, are essentially: compression of the left common iliac vein by the right common iliac artery, and direct compression of the inferior vena cava by the uterus during pregnancy which compresses it against the spine. It is responsible for gravidic postural shock, and an increased abdominal pressure, exceeding 20 mmHg. The main supply pathways are the ovarian veins and the vertebral plexi. This large, low-pressure avalvular plexus may function easily in both directions caudo-cranial and cranio-caudal. The relationship of this plexus with the roots of the sciatic nerve explain certain sciaticas during pregnancy. Dilatation of the ovarian veins during pregnancy cause a so called syndrome of the ovarian vein. Various venous compressions during pregnancy are responsible for some hematurias, increased collateral abdominal circulation, and turgescent haemorrhoids and vulvar varicose veins.

Abdomen↗

[A method for transfering physiological data through GSM wireless communication network].

This article describes a method for transfering physiological data through GSM wireless communication network. The data of heart rate and body temperature are collected by a microcontroller and transmitted through serial ports to the GSM data module, which then transmits the data to a remote terminal through GSM network. This method ensures cheap and stable long-distance data transfer within the coverage of the GSM network.

Body Temperature↗

Cortical networks for visual reaching: physiological and anatomical organization of frontal and parietal lobe arm regions.

The functional and structural properties of the dorsolateral frontal lobe and posterior parietal proximal arm representations were studied in macaque monkeys. Physiological mapping of primary motor (MI), dorsal premotor (PMd), and posterior parietal (area 5) cortices was performed in behaving monkeys trained in an instructed-delay reaching task. The parietofrontal corticocortical connectivities of these same areas were subsequently examined anatomically by means of retrograde tracing techniques. Signal-, set-, movement-, and position-related directional neuronal activities were distributed nonuniformly within the task-related areas in both frontal and parietal cortices. Within the frontal lobe, moving caudally from PMd to the MI, the activity that signals for the visuo-spatial events leading to target localization decreased, while the activity more directly linked to movement generation increased. Physiological recordings in the superior parietal lobule revealed a gradient-like distribution of functional properties similar to that observed in the frontal lobe. Signal- and set-related activities were encountered more frequently in the intermediate and ventral part of the medial bank of the intraparietal sulcus (IPS), in area MIP. Movement-and position-related activities were distributed more uniformly within the superior parietal lobule (SPL), in both dorsal area 5 and in MIP. Frontal and parietal regions sharing similar functional properties were preferentially connected through their association pathways. As a result of this study, area MIP, and possibly areas MDP and 7m as well, emerge as the parietal nodes by which visual information may be relayed to the frontal lobe arm region. These parietal and frontal areas, along with their association connections, represent a potential cortical network for visual reaching. The architecture of this network is ideal for coding reaching as the result of a combination between visual and somatic information.

Animals↗

Physiological studies on fibrin network structure.

Networks were developed in fibrinogen solution under pathophysiological conditions of clotting and their permeability and turbidity were measured. Mass-Length ratio of fibrin fibres (a measure of fibre thickness) was derived from two independent methods based on turbidity (mu T) and permeability (mu P). Both mu T and mu P increased as thrombin concentration was decreased. Data are in agreement with the concept that the fibrin network develops initially as a mesh of protofibrils. Fibrin monomer generated subsequently is incorporated into the existing network making individual fibres thicker. Consequently, slow fibrin monomer generation promotes thicker fibres. When the concentration of thrombin or fibrinogen was altered systematically, mu T and mup were found to mirror each other except when the fibrinogen concentration was increased at low thrombin concentrations. This breakdown between the two derivations of mass-length ratio is discussed in terms of the two network model.

Blood Coagulation↗

The rapid onset of elasticity during the assembly of the bacterial cell-division protein FtsZ.

FtsZ, a prokaryotic homolog of eukaryotic tubulin, is a major constituent of the bacterial Z-ring, which contracts the cell wall during cell division. Because the mechanical properties of FtsZ are unknown, its function in the maintenance and constriction of the Z-ring is not well understood. Here, quantitative rheometry shows that, at physiological concentrations, FtsZ filaments form, extremely rapidly, highly elastic networks within physiological time scales ( approximately minutes), much faster than other major dynamic cytoskeletal filaments, including microtubule, actin, and vimentin in eukaryotes. FtsZ networks display a relatively low viscosity and a high resilience against shear stresses, as well as an elasticity that depends weakly on concentration, G approximately C(0.57), a power-law dependence consistent with crosslinked flexible filaments. Calcium, whose intracellular concentration increases during bacterial division, further enhances the elasticity of FtsZ networks through filament bundling, an effect that occurs in the presence of GTP, not GDP. These studies suggest that FtsZ filaments have the toughness to provide strong mechanical support for the maintenance and circumferential constriction of the bacterial Z-ring.

Actins↗

A model for neural representation of binocular disparity in striate cortex: distributed representation and veto mechanism.

A model in striate cortex is proposed for a distributed neural representation of binocular disparity with a simple cell. In the model, disparity is represented by "far", "near" and "tuned inhibitory" simple cells. However, the representation will be vetoed by model cells where disparity is excessively large. The veto mechanism consists of a neural network of the model cell which received output from simple cells and which interacts with neighbors. The mechanism is necessary, the model cell responds like a simple cell, and the network is physiologically plausible in the brain. Computer simulation on the neural network model with random dot stereography indicates reasonable performance.

Computer Simulation↗

Reversible stress softening of actin networks.

The mechanical properties of cells play an essential role in numerous physiological processes. Organized networks of semiflexible actin filaments determine cell stiffness and transmit force during mechanotransduction, cytokinesis, cell motility and other cellular shape changes. Although numerous actin-binding proteins have been identified that organize networks, the mechanical properties of actin networks with physiological architectures and concentrations have been difficult to measure quantitatively. Studies of mechanical properties in vitro have found that crosslinked networks of actin filaments formed in solution exhibit stress stiffening arising from the entropic elasticity of individual filaments or crosslinkers resisting extension. Here we report reversible stress-softening behaviour in actin networks reconstituted in vitro that suggests a critical role for filaments resisting compression. Using a modified atomic force microscope to probe dendritic actin networks (like those formed in the lamellipodia of motile cells), we observe stress stiffening followed by a regime of reversible stress softening at higher loads. This softening behaviour can be explained by elastic buckling of individual filaments under compression that avoids catastrophic fracture of the network. The observation of both stress stiffening and softening suggests a complex interplay between entropic and enthalpic elasticity in determining the mechanical properties of actin networks.

Actins↗

Probabilistic neural network prediction of ascites in broilers based on minimally invasive physiological factors.

A Probabilistic Neural Network (PNN) was trained to predict ascites in broilers based on minimally invasive inputs (i.e., physiological factors that do not require the death of the bird). A PNN is a supervised, three-layer, artificial neural network that classifies input patterns (e.g., physiological data) into specific output categories (e.g., ascites or no ascites). The PNN inputs were O2 level in the blood, body weight, electrocardiogram (ECG), hematocrit, S wave, and heart rate of individual birds. These data were from three experiments that have been described previously (Roush et al., 1996a,b). The three data sets were pooled into a combined data set for a total of 170 observations. From the pooled data, a training set (117 birds), a calibration set (17 birds), and a verification set (36 birds) were extracted. The PNN was trained on the training data set. To prevent the PNN from overfitting the training data, the neural network was evaluated on its ability to make correct predictions of the calibration data set. At the point at which the neural network made the highest number of correct classifications for the calibration data set, the trained neural network was saved on the computer. When the PNN was applied to the complete data set, the sensitivity or proportion of the birds with ascites that the PNN correctly diagnosed was 0.97 (75/77 birds). The specificity or proportion of birds that the PNN made a correct diagnosis of not having ascites was 0.98 (91/93 birds). When the PNN was applied to the verification data set, which was not subjected to neural network training, the sensitivity was 0.95 (19/20) and the specificity was 0.88 (14/16 birds). Use of models developed with artificial neural networks may enhance the diagnosis of ascites in broilers. The results may be useful in choosing and developing broiler strains that do not have a propensity for ascites.

Animals↗

The use of Apple Macintosh computers and Hypercard in teaching physiology laboratories.

A network of Apple Macintosh computers has been integrated into existing undergraduate physiology laboratories. Hypercard software programs replace the traditional laboratory handout; the text contains a number of buttons linked to cards that provide additional information on a particular subject. This additional information includes theory, the use of various instruments, expected results, and details on how to perform data analysis. This system of information layering allows students to work independently, at their own pace, and allows them to learn as much or as little as they consider necessary. Each computer is interfaced with a MacLab/4 data-acquisition unit, which permits the computer screen to display a four-channel chart recorder or a two-channel oscilloscope.

Computer Communication Networks↗

Concentrated solutions of salivary MUC5B mucin do not replicate the gel-forming properties of saliva.

We have developed a new approach to study the molecular organization of salivary mucus and salivary mucins using confocal fluorescence recovery after photobleaching (confocal-FRAP). MUC5B mucin, its reduced subunit and T-domains were prepared from saliva and fluorescently labelled. The translational self-diffusion coefficients were determined up to 3.6 mg/ml by confocal-FRAP. The results suggest that, in solutions of purified MUC5B mucin, at concentrations at which the hydrodynamic domains overlap, the intermolecular interactions are predominantly due to dynamic entanglements, and there was no evidence of specific self-association of MUC5B mucin, or of its subunits, or T-domains. The analysis of the salivary mucus gel also showed no specific interactions with the purified MUC5B components, but it was much less permeable than expected from its MUC5B content. The saliva was completely permeable to microspheres of 207 nm diameter, but showed size-dependent effects on the diffusion of larger microspheres (499 nm and 711 nm diameter). From these analyses the salivary mucus was shown to be both permeable and dynamic, and with the characteristics of a semi-dilute transient network at physiological concentration. Comparison of the results from saliva and purified MUC5B mucin solutions showed that the network properties of saliva were equivalent to a solution of purified MUC5B mucin of 10-20 times higher concentration. This showed that saliva has additional structure and organization not present in the purified MUC5B mucin and suggests there are other interactions and/or components within saliva that combine with MUC5B to produce its complete properties.

Chromatography, Gel↗

Remote continuous physiological monitoring in the home.

As part of a larger study we established a remote physiological monitoring network to investigate cardiorespiratory function during sleep in 400 infants in their homes. The objective of the study was to link measurements made at three weeks and three months of age with detailed measurements of maternal and fetal nutrition during pregnancy and subsequent outcome (growth, development and cardiorespiratory diseases). Five infants per night were monitored anywhere within a radius of 10 miles (16 km) of the remote hub. Of 800 overnight studies on 64 (of 400) infants, 99 were completed. Options allowed downloading data from monitor memory as well as review (on- and off-line) from the infants' or nurses' homes, the hub and the Oxford telemonitoring centre. The reasons for these measurements being made at home were to ensure physiological accuracy and to reduce cost. The network was effectively run by local community nurses; with the exception of the size and cost of the monitors, it had all the elements of a remote primary-care clinical service.

Community Health Services↗

Vitamin A and carotenoids as antioxidants in a physiological context.

Under selected conditions, vitamin A and carotenoids can both accept and donate electrons, and carotenoids can also quench singlet oxygen. Thus both sets of compounds can theoretically participate in a biological antioxidant network. Under physiological conditions, vitamin A esters are transported and stored in a lipid matrix that contains other antioxidants, and retinol and its active metabolites are largely bound in clefts of specific retinoid-binding proteins. Thus, vitamin A seems to be protected in vivo by other antioxidants and proteins rather than protecting other molecules. Carotenoids are largely distributed in lipoproteins, membranes, and the lipid phases of intracellular structures, usually together with vitamin E. Carotenoids can interact with other antioxidants in vitro, but whether they play similar significant roles in vivo is not clear. Nonetheless, some genetic conditions and precancerous lesions respond to carotenoids, and the dietary intake of carotenoids has been associated with a reduced risk of several chronic diseases. Carotenoids seem to act per se in such systems rather than by their conversion into vitamin A.

Animals↗