A test of a dual central pattern generator hypothesis for subcortical control of locomotion.

This study was designed to examine the nature of neural circuits involved in subcortical inter-limb coordination and reflex modulation mechanisms of locomotion. These circuits, called central pattern generators (CPGs), are believed to receive tonic input and generate rhythmically alternating sets of commands. Although CPGs have been theorized to exist in humans, their potential dual role in inter-limb coordination and reflex modulation is unclear. In the present study, nine participants walked on a treadmill, timing their heel-strikes to a metronome which varied the phase lag from 0.5 to 1.0 pi radians (0.1 pi intervals). A stimulus was delivered to the sural nerve and reflexes were measured in the ipsilateral and contralateral lower extremities through electromyography. The similarity between phase lag conditions for both temporal coordination (i.e., relative timing aspects between muscles and/or limbs) and reflex intensities suggested that they may be controlled by the same subcortical circuitry. Two plausible explanations exist: (1) a single CPG coordinates muscular contractions and phasically alters proprioceptive reflex modulation, as well as cutaneous input, using feed-forward control; (2) two separate circuits are strongly entrained, producing synchronous outputs for inter-limb coordination and reflex modulation. The out-of-phase task used in this study was limited in discerning such a difference, if it exists.     

Genetic control of H-Y synthesis. A hypothesis

Summary In view of the claimed serological H-Y positivity observed in patients with ovarian dysgenesis (for example, 45,X) and in XO mice (neither of whom have a Y chromosome), it is suggested that genetic control is exercised over the H-Y system by structural genes on the pairing segments of the X and Y chromosomes, acting on an autosomally coded H-Y precursor.     

Physiological parameters of gravitaxis in the flagellate Euglena gracilis obtained during a parabolic flight campaign

The unicellular freshwater flagellate Euglena gracilis and its close relative Astasia longa show a pronounced negative gravitaxis. Previous experiments revealed that gravitaxis is most likely mediated by an active physiological mechanism in which changes of the internal calcium concentration and the membrane potential play an important role. In a recent parabolic flight experiment on board an aircraft (ESA 29th parabolic flight campaign), changes of graviorientation, membrane potential and the cytosolic calcium concentration upon changes of the acceleration (between 1 x g(n), 1.8 x g(n), microgravity) were monitored by image analysis and photometric methods using Oxonol VI (membrane potential) and Calcium Crimson (cytosolic calcium concentration). The parabolic flight maneuvers performed by the aircraft resulted in transient phases of 1.8 x g(n) (about 20 s), microgravity (about 22 s) followed by 1.8 x g(n) (about 20 s). A transient increase in the intracellular calcium concentration was detected from lower to higher accelerations (1 x g(n) to 1.8 x g(n) or microgravity to 1.8 x g(n)). Oxonol VI-labeled cells showed a signal, which indicates a depolarization during the transition from 1 x g(n) to 1.8 x g(n), a weak repolarization in microgravity followed by a rapid repolarization in the subsequent 1 x g(n) phase. The results show good coincidence with observations of recent terrestrial and space experiments.     

A new hypothesis on mitotic control mechanism in eukaryotic cells: cell-specific mitosis-inhibiting protein excretion hypothesis.

Recent experimental studies on the regulatory mechanism of cell division in the regenerating rat liver have suggested that α₁acid glycoprotein is a primary mitotic inhibitor, whose intracellular concentration over a critical level inhibits cell division, while α₁-antitrypsin is one of secondary mitotic inhibitors, whose extracellular concentration below a critical level facilitates the excretion of the primary mitotic inhibitor from the hepatocyte, allowing cell division. Based on these findings, the essential part of the mitotic control mechanism in the regenerating rat liver is concretely discussed.To expand the basic concept to more general biological phenomena, the cell-specific mitosis-inhibiting protein excretion hypothesis is proposed. The hypothesis depends on two basic presuppositions: (1) Every cell has a cell-specific mitosis-inhibiting protein synthesized by the cell itself. (2) Every cell will be released from the suppression of cell division when the cell-specific mitosis-inhibiting protein has been excreted and the intracellular concentration of the protein has fallen below a critical level.On the basis of this hypothesis, the mitotic control mechanism in normal eukaryotic cells is briefly discussed on the level of the interrelation between cell division and cell differentiation, and the core of the puzzle of carcinogenesis, the problem of the so-called indefinite or autonomous proliferation of the cancer cell in the host, is also discussed.     

Antigenic competition and genetic control of the immune response. A hypothesis for intramolecular competition

A study has been made of antigenic competition between the (Phe,Glu) and Pro-Lys regions of three synthetic multichain polypeptides, (Phe,Glu)-Ala-Lys, (Tyr,Glu)-Pro-Lys and (Phe,Glu)-Pro-Lys. Two strains of mice have been compared, C3H/HeJ, potentially high responders to both (Phe,Glu) and Pro-Lys, and DBA/1, high responders to (Phe,Glu), but genetic low responders to Pro-Lys. In C3H/HeJ, both intramolecular competition, within the (Phe,Glu)-Pro-Lys molecule, and intermolecular competition, with mixtures of (Tyr,Glu)-Pro-Lys and (Phe,Glu)-Ala-Lys occur. In general, Pro-Lys is the dominant determinant and suppresses the response to (Phe, Glu). In DBA/1, on the other hand, intramolecular competition is absent, but intermolecular competition is still present. The injection of the polyribonucleotide poly (A)·poly (U) corrects the low response to Pro-Lys in DBA/1, and at the same time restores intramolecular competition. Intramolecular competition is, therefore, related to the level of the antibody response to the dominant antigenic region, Pro-Lys. In contrast, intermolecular competition is independent of the antibody response to Pro-Lys, but is related to the ratio of the antigens (Tyr,Glu)-Pro-Lys and (Phe,Glu)-Ala-Lys in the mixture injected.A model is suggested in which intramolecular competition is a result of competition between specific B cells for limiting antigen. The model relates competition to original antigenic sin and the enhancement and suppression mediated by antibody. Intermolecular competition seems to have a different mechanism and to be a T cell effect. The relevance of these findings to studies on the genetic control of the immune response is discussed.     

Epigenetic hypothesis tests for methylation and acetylation in a triple microarray system.

To fully elucidate the functional relationship between DNA methylation and histone hypoacetylation in gene silencing, we have developed an integrated "triple" microarray system that allows us to begin to decipher the influence of epigenetic hierarchies on the regulation of gene expression in cancer cells. Our hypothesis is that in the promoter region of a silenced gene, reversal of two epigenetic factors (i.e., DNA demethylation and/or histone hyperacetylation) is highly correlated with gene reexpression after treatment of the human epithelial ovarian cancer cell line CP70 with the drug combination 5-aza-2'-deoxycytidine (DAC), a demethylating agent, and trichostatin A (TSA), an inhibitor of histone deacetylases. To estimate the posterior probabilities for genes with altered expression, DNA methylation and histone acetylation status measured with a triple-microarray system, we have employed an established empirical Bayes model. Two methods have been proposed to test our hypothesis that DNA demethylation and histone hyperacetylation are highly correlated among those up-regulated genes. One method follows a weighted least squares regression, while the other is derived from a chi-square statistic. The data derived by these approaches, which have been further verified through bootstrap analyses, support the proposed epigenetic correlation (p-values are less than 0.001). Further simulations suggest that even if the constant variance and normality assumptions do not hold, the power of those two tests is robust.     

Ventilatory control in hypercapnia and exercise: optimization hypothesis

A model of the respiratory control system incorporating both chemical and respiratory neuromechanical feedbacks is proposed to describe the steady-state ventilatory responses to CO2 inhalation and exercise. It is postulated that ventilatory output (VE) is set by the respiratory center to minimize a net operating cost representing the conflicting challenges of arterial chemical imbalance and respiratory-mechanical discomfort (intolerance of effort), given, respectively, by a quadratic function of arterial PCO2 and a logarithmic function of VE. In addition, the system is assumed to be mechanically limited at maximum VE (Vmax). The predicted responses in VE during moderate hypercapnia, exercise, and ventilatory loading closely mimic those normally observed, even though no separate signal unique to exercise is assumed. As a quantitative validation, the model yielded good fits to ventilatory response data obtained in eight healthy subjects during eucapnic and hypercapnic exercise; the predicted Vmax averaged approximately 77% of the maximum voluntary ventilation in all subjects. The results demonstrate the plausibility of the proposed optimization mechanism and suggest an important role for respiratory-mechanical factors in the control of VE.     

The alphastat hypothesis in respiratory control and acid-base balance

This selective review 1) evaluates recent interpretations that broaden the definition of the alphastat hypothesis, 2) proposes that central chemoreception and acid-base regulation via ion transport involve proteins conforming to the alphastat hypothesis, and 3) describes, using recent evidence, possible candidates for these proteins. The alphastat hypothesis states that proteins that contain appropriate function-determining titratable groups maintain a constant charge state and unaltered function with temperature-dependent pH changes but can be very sensitive to isothermal pH changes. Appropriate groups, e.g., imidazole histidine, are determined by the pK and the effect of temperature on the pK. The hypothesis explains how protein structure and function can be conserved among a diversity of vertebrate and invertebrate pH values. It also suggests a mechanism for sensing or regulating temperature-independent pH changes, e.g., in central chemosensitivity and transmembrane ion exchange. Possible candidates for such alphastat-conforming proteins include two, the glutamate receptor and the Na(+)-H+ antiporter, for which recent evidence indicates the presence of numerous histidines at probable function-determining sites and demonstrates pH sensitivity inhibitable by the histidine blocker diethylpyrocarbonate (DEPC).     

Hydatidosis: changing concepts in epidemiology and speciation

Hydatidosis, caused by dog tapeworms of the genus Echinococcus, is one of the most important cestode infections of man. It is widely distributed and recent information points to a spread of the disease into areas previously free of it. This article reviews recent advances in understanding the biology of Echinococcus, relating these developments to the epidemiology of hydatid disease and its control.