Role of short-term cardiovascular regulation in heart period variability: a modeling study

A mathematical model of short-term cardiovascular regulation is used to investigate how heart period variability reflects the action of the autonomic regulatory mechanisms (vagal and sympathetic). The model includes the pulsating heart, the systemic (splanchnic and extrasplanchnic) and pulmonary circulation, the mechanical effect of respiration on venous return, two groups of receptors (arterial baroreceptors and lung stretch receptors), the sympathetic and vagal efferent branches, and a very low-frequency (LF) vasomotor noise. All model parameters were given on the basis of physiological data from the literature. We used data from humans whenever possible, whereas parameters for the regulation loops are derived from dog experiments. The model, with basal parameter values, produces a heart period power spectrum with two distinct peaks [a high frequency (HF) peak at the respiratory rate and a LF peak at approximately 0.1 Hz]. Sensitivity analysis on the mechanism gains suggests that the HF peak is mainly affected by the vagal mechanism, whereas the LF peak is increased by a high sympathetic gain and reduced by a high vagal gain. Moreover, the LF peak depends significantly on the reactivity of resistance vessels and is affected by noise, amplified by the sympathetic control loop at its resonance frequency. The model may represent a new tool to study alterations in the heart period spectrum on the basis of quantitative physiological hypotheses.     

The aluminium signal: New dimensions to mechanisms of aluminium tolerance

The physiological basis of plant reaction to and tolerance of aluminium (Al) is poorly understood. We review the results of investigations into Al toxicity and root physiology to develop a theoretical basis for explaining the reaction of the root to Al, including suggested roles for Ca²⁺, mucilaginous cap secretions and endogenous growth regulators in mediating a transmitted response between Al-damaged cap cells and the interacting cell populations of the cap and root. This information is used to identify possible mechanisms of Al tolerance, notably involving signal transduction, Al uptake pathways and root morphogenesis; and to briefly discuss how procedures selecting for Al tolerance may be improved by incorporating the concept of stimulus-response coupling. Similarities in the responses of roots to Al and other signals (e.g. gravity, light, mechanical impedance) are used to develop the hypothesis that roots respond to environmental signals by way of a common regulatory system. New research prospects for extending our perception of Al tolerance mechanisms are identified.     

Cardiac Rhythm Regulation in Children during the Initial Period of School Education under Conditions of the North

Cardiac rhythm parameters recorded in healthy children during the initial weeks of schoolwork immediately after the transition from kindergarten to the first grade of the elementary school or from the elementary school to the fifth grade of the middle school showed that their regulatory systems were stressed to different degrees, reflecting different costs of adaptation to environmental conditions. The most pronounced changes in these parameters were observed in the first graders: because of more significant stress (sometimes, overstress) of their regulatory mechanisms, in 70% of these children complete adaptation to new living conditions was associated with greater physiological costs. In the fifth graders, a similar situation was observed only in 25% of the children examined. The less pronounced physiological changes observed in 30% of the first graders and in 75% of the fifth graders can be related to the more mature state of their cardiac regulatory mechanisms, as well as to their greater adaptability to environmental conditions during the period examined.     

Aromaticl-amino acid decarboxylase: A neglected and misunderstood enzyme

Classically, aromaticl-amino acid decarboxylase (AADC) has been regarded as an unregulated, rather uninteresting enzyme. In this review, we describe advances made during the past 10 years, demonstrating that AADC is regulated both pre- and post-translation. The significance of such regulatory mechanisms is poorly understood at present, but the presence of tissue specific control of expression raises the real possibility of AADC being involved in processes other than neurotrasmitter synthesis. We further discuss clinical and physiological situations in which such regulatory mechanisms may be important, including the intriguing possibility of AADC gene regulation being linked to that of factors thought to have a role in apoptosis and its prevention. Special issue dedicated to Dr. Herman Bachelard.     

Evolution of regulated phenotypic expression during a transition to multicellularity

Multicellular organisms coordinate growth and differentiation from single cell starting points with developmental programs. While the evolutionary origins of these programs are unknown, it is likely that they are closely tied to the evolution of regulated—not stochastic—phenotypic expression. To determine how such regulation might arise, we consider experimental populations of Pseudomonas fluorescens which evolved stochastic switching in the lab. This switching is directly coupled with environmental oscillations generated by the bacteria themselves. This unique example of niche construction provides reliable information that organisms may incorporate into regulation of phenotypes. We use mathematical models to investigate the success of two forms of regulation that rely on sensing either external or internal information. We find that both strategies can outcompete stochastic strategies for certain combinations of parameters. In particular, external sensing mechanisms are very effective over a large range of parameter space—including parameters that correspond to poor sensing of the extracellular signal and gradual responses. We show with evolutionary simulations that this robustness makes them more likely to evolve from initially stochastically switching populations rather than internal sensing mechanisms which require more tuning of parameters. These results demonstrate that, within this oscillating system, if regulatory mechanisms can evolve to incorporate environmental information then their selective advantage is sufficient for them to fix in the population.     

Effect of regulatory mechanism on hyperbolic reaction network properties

The notion that the regulated and flux-controlling enzyme in a metabolic network need not correspond suggests that the purpose of regulation may not be flux homeostasis under all physiological circumstances. Additionally, the fact that diversity in the function of intact metabolic networks exists suggests that in addition to time constant separation, other kinetic structure/regulatory mechanism patterns exist. In order to compliment and expand prior work on identifying kinetic structure-property relationships in networks, the present work explores in a general way how the control, dynamic, and energetic properties of metabolic networks depend on operating point, kinetic structure, and regulatory mechanism. The basic feature of trade-offs between properties is illustrated and used as a basis for indicating how particular subsets of structure, regulatory mechanism, and operating point emphasize certain properties that can be associated with a physiological function. Examples of scavenging trace metabolites and amphibolite coordination are proposed. Microstructure logic in terms of turnover number distributions as well as a potential mixed polynomial network analysis approach are also discussed.     

Reversible,functional amyloids: towards an understanding of their regulation in yeast and humans

Protein aggregates, and in particular amyloids, are generally considered to be inherently irreversible aberrant clumps, and are often associated with pathologies, such as Alzheimer’s disease, Parkinson’s disease, or systemic amyloidosis. However, recent evidence demonstrates that some aggregates are not only fully reversible, but also perform essential physiological functions. Despite these new findings, very little is known about how these functional protein aggregates are regulated in a physiological context. Here, we take the yeast pyruvate kinase Cdc19 as an example of a protein forming functional, reversible, solid, amyloid-like aggregates in response to stress conditions. Cdc19 aggregation is regulated via an aggregation-prone low complexity region (LCR). In favorable growth conditions, this LCR is prevented from aggregating by phosphorylation or oligomerization, while upon glucose starvation it becomes exposed and allows aggregation. We suggest that LCR phosphorylation, oligomerization or partner-binding may be general and widespread mechanisms regulating LCR-mediated reversible protein aggregation. Moreover, we show that, as predicted by computational tools, Cdc19 forms amyloid-like aggregates in vitro. Interestingly, we also observe striking similarities between Cdc19 and its mammalian counterpart, PKM2. Indeed, also PKM2 harbors a LCR and contains several peptides with high amyloidogenic propensity, which coincide with known phosphorylation sites. Thus, we speculate that the formation of reversible, amyloid-like aggregates may be a general physiological mechanism for cells to adapt to stress conditions, and that the underlying regulatory mechanisms may be conserved from yeast to humans.     

Volume regulation in cortical collecting duct cells: role of AQP2

BACKGROUND INFORMATION: The renal CCD (cortical collecting duct) plays a role in final volume and concentration of urine by a process that is regulated by the antidiuretic hormone, [arginine]vasopressin. This hormone induces an increase in water permeability due to the translocation of AQP2 (aquaporin 2) from the intracellular vesicles to the apical membrane of principal cells. During the transition from antidiuresis to diuresis, CCD cells are exposed to changes in environmental osmolality, and cell-volume regulation may be especially important for the maintenance of intracellular homoeostasis. Despite its importance, cell-volume regulation in CCD cells has not been widely investigated. Moreover, no studies have been carried out till date to evaluate the putative role of AQPs during this process in renal cells. RESULTS: In the present study, we have studied the regulatory cell-volume responses to hypo-osmotic or hyperosmotic challenges in two CCD cell lines: one not expressing AQPs and the other stably transfected with AQP2. We have used a fluorescent probe technique in which the acquisition of single-cell kinetic data can be simultaneously recorded with the intracellular pH. Experiments with hyperosmotic mannitol media demonstrated that, independent of AQP2 expression, CCD cells shrink but fail to show regulatory volume increase, at least under the studied conditions. In contrast, under hypo-osmotic shocks, regulatory volume decrease occurs and the activation of these mechanisms is more rapid in AQP2 transfected cells. This regulatory response takes place in parallel with intracellular acidification, which is faster in cells expressing AQP2. The acidification and the initial regulatory volume decrease response were inhibited by glibenclamide and BaCl2 only in AQP2 cells. CONCLUSIONS: These results suggest that increases in the osmotic water permeability due to the expression of AQP2 are critical for a rapid activation of regulatory volume decrease mechanisms, which would be linked to cystic fibrosis transmembrane conductance regulator and to barium-sensitive potassium channels.     

Two yeast PUF proteins negatively regulate a single mRNA

mRNA stability and translation are regulated by protein repressors that bind 3'-untranslated regions. PUF proteins provide a paradigm for these regulatory molecules: like other repressors, they inhibit translation, enhance mRNA decay, and promote poly(A) removal. Here we show that a single mRNA in Saccharomyces cerevisiae, encoding the HO endonuclease, is regulated by two distinct PUF proteins, Puf4p and Mpt5p. These proteins bind to adjacent sites and can co-occupy the mRNA. Both proteins are required for full repression and deadenylation in vivo; their removal dramatically stabilizes the mRNA. The two proteins act through overlapping but non-identical mechanisms: repression by Puf4p is dependent on deadenylation, whereas repression by Mpt5p can occur through additional mechanisms. Combinatorial action of the two regulatory proteins may allow responses to specific environmental cues and be common in 3'-untranslated region-mediated control.     

Human Systemic Reactions to a Dosed Exposure to Hypoxia: A Multiparameter Study

Human physiological reactions to acute hypoxic hypoxia were studied. Analysis of simultaneously recorded parameters of various physiological systems showed the following: activation of the general antihypoxic defense system is based on the formation of an intricate structure of intra- and intersystemic relations of specific and nonspecific elements of adaptation that support vital body functions during environmental oxygen deficit. These specific elements become more important in more severe hypoxia, which suppresses metabolism in some organs and tissues because of redistribution of blood flow. These factors allow the body to function at a lower oxygen tension in its tissues owing to an increased efficiency of mitochondria as a result of changes in the kinetics of enzymes of the mitochondrial respiratory chain. In acute hypoxia, the structure of intra- and intersystemic relations is rather intricate; its functional hierarchy is maintained by stronger individual amplitude-related controlling factors and by modulation of their phase- and time-related links. Advanced stages of hypoxia are associated with disintegration of central regulatory mechanisms, which is manifested by disturbances in amplitude-frequency and spatiotemporal parameters of the brain bioelectrical activity, changes in phasic interactions between elements of regulatory mechanisms, and signs of deregulation and decompensation of vital functions. The interpretation of the results is based on the general theory of adaptation, Medvedev's idea of adaptation as a successive involvement of genetically predetermined and newly-formed regulatory programs of the brain, Anokhin's theory of functional systems, and modern concepts of molecular and biochemical mechanisms of hypoxia. It was concluded that artificial normobaric hypoxia is a unique, biologically adequate model that makes it possible to study the rearrangements in systemic and autonomic regulatory mechanisms in response to strictly determined changes in the environmental concentration of oxygen as a principal factor supporting life.     

Quantitative aspects of the regulation of ovarian development in selected anautogenous Diptera: integration of endocrinology and nutrition

Aspects of the influence of nutrition on the degree of ovarian development in selected anautogenous Diptera are reviewed. The Diptera considered are several mosquito species, with emphasis on Aedes aegypti, the house fly, Musca domestica, the Australian bush fly, M. vetustissima and the blowflies, Lucilia cuprina and Phormia regina. All the selected species display discrete ovarian cycles in which all oocytes destined to reach maturity in a particular ovarian cycle develop synchronously. In these species, the proportion of females maturing oocytes and, where such data exist, the number of oocytes they mature are positively correlated with the amount of any particular nitrogen-containing material ingested or given by enema or by infusion. In addition, the degree of ovarian development may be affected by the chemical composition of nitrogen-containing food. Possible physiological bases for the observed relationships are discussed. Available evidence suggests that whether or not a female matures any oocytes is hormonally regulated and that the number of oocytes matured is probably regulated by the availability of nutrients. Some approaches that might further elucidate the physiological regulatory mechanisms involved in ovarian development are outlined.     

A physiological analogy of the niche for projecting the potential distribution of plants

Aim  To develop a physiologically based model of the plant niche for use in species distribution modelling. Location  Europe. Methods  We link the Thornley transport resistance (TTR) model with functions which describe how the TTR’s model parameters are influenced by abiotic environmental factors. The TTR model considers how carbon and nutrient uptake, and the allocation of these assimilates, influence growth. We use indirect statistical methods to estimate the model parameters from a high resolution data set on tree distribution for 22 European tree species. Results  We infer, from distribution data and abiotic forcing data, the physiological niche dimensions of 22 European tree species. We found that the model fits were reasonable (AUC: 0.79–0.964). The projected distributions were characterized by a false positive rate of 0.19 and a false negative rate 0.12. The fitted models are used to generate projections of the environmental factors that limit the range boundaries of the study species. Main conclusions  We show that physiological models can be used to derive physiological niche dimensions from species distribution data. Future work should focus on including prior information on physiological rates into the parameter estimation process. Application of the TTR model to species distribution modelling suggests new avenues for establishing explicit links between distribution and physiology, and for generating hypotheses about how ecophysiological processes influence the distribution of plants.     

Reverse engineering of regulatory networks: simulation studies on a genetic algorithm approach for ranking hypotheses

Reverse engineering algorithms (REAs) aim at using gene expression data to reconstruct interactions in regulatory genetic networks. This may help to understand the basis of gene regulation, the core task of functional genomics. Collecting data for a number of environmental conditions is necessary to reengineer even the smallest regulatory networks with reasonable confidence. We systematically tested the requirements for the experimental design necessary for ranking alternative hypotheses about the structure of a given regulatory network. A genetic algorithm (GA) was used to explore the parameter space of a multistage discrete genetic network model with fixed connectivity and number of states per node. Our results show that it is not necessary to determine all parameters of the genetic network in order to rank hypotheses. The ranking process is easier the more experimental environmental conditions are used for the data set. During the ranking, the number of fixed parameters increases with the number of environmental conditions, while some errors in the hypothetical network structure may pass undetected, due to a maintained dynamical behaviour.     

Fat to the fire: the regulation of lipid oxidation with exercise and environmental stress

Lipids are an important fuel for submaximal aerobic exercise. The ways in which lipid oxidation is regulated during locomotion is an area of active investigation. Indeed, the integration between cellular regulation of lipid metabolism and whole-body exercise performance is a fascinating but often overlooked research area. Additionally, the interaction between environmental stress, exercise, and lipid oxidation has not been sufficiently examined. There are many functional and structural steps as fatty acids are mobilized, transported, and oxidized in working muscle, which may serve either as regulatory points for responding to acute or chronic stimuli or as raw material for natural selection. At the whole-animal level, the partitioning of lipids and carbohydrates across exercise intensities is remarkably similar among mammals, which suggests that there is conservation in regulatory mechanisms. Conversely, the proportions of circulatory and intramuscular fuels differ between species and across exercise intensities. Responses to acute and chronic environmental stress likely involve the interaction of genetic and nongenetic changes in the fatty acid pathway. Determining which of these factors help regulate the fatty acid pathway and what impact they have on whole-animal lipid oxidation and performance is an important area of future research. Using an integrative approach to complete the information loop from gene to physiological function provides the most powerful mode of analysis.     

Coordination of gene expression with growth rate: A feedback or a feed-forward strategy?

In the budding yeast, a large fraction of genes is coordinately regulated with growth rate. We argue that this correlation does not reflect a direct feedback from growth rate to gene expression. Rather, what appears to be a response to growth rate is dominated by environmental sensing. External parameters, such as nutrition or temperature, feed-forward to define gene expression pattern that is tuned to the evolutionary-predicted growth rate. While such a feed-forward strategy requires fine-tuning of signaling mechanisms, and is limited in the range of environments that can be monitored, it enables advanced preparation to physiological changes that predictably occur following environmental switching. The capacity to anticipate and prepare for changing conditions was probably a major selection force during yeast evolution.     

Dynamic Stabilization in the PU1-GATA1 Circuit Using a Model with Time-Dependent Kinetic Change

The PU.1 and GATA1 genes play an important role in the differentiation of blood stem cells. The protein levels expressed by these genes are thought to be regulated by a self-excitatory feedback loop for each gene and a cross-inhibitory feedback loop between the two genes. A mathematical model that captures the dynamical interaction between these two genes reveals that constant levels of self-excitation and cross-inhibition allow the most self-exciting or cross-inhibiting gene to dominate the system. However, since biological systems rarely exist in an unchanging equilibrium, we modeled this gene circuit using discrete time-dependent changes in the parameters in lieu of steady state parameters. These time-dependent parameters lead to new phenomena, including the development of new limit cycles and basins of attraction. These phenomena are not present in models using constant parameter values. Our findings suggest that even small perturbations in the PU.1 and GATA1 feedback loops may substantially alter the gene expression and therefore the cell phenotype. These time-dependent parameter models may also have implications for other gene systems and provide new ways to understand the mechanisms of cellular differentiation.