Cx43-hemichannel function and regulation in physiology and pathophysiology: insights from the bovine corneal endothelial cell system and beyond

Intercellular communication in primary bovine corneal endothelial cells (BCECs) is mainly driven by the release of extracellular ATP through Cx43 hemichannels. Studying the characteristics of Ca2+-wave propagation in BCECs, an important form of intercellular communication, in response to physiological signaling events has led to the discovery of important insights in the functional properties and regulation of native Cx43 hemichannels. Together with ectopic expression models for Cx43 hemichannels and truncated/mutated Cx43 versions, it became very clear that loop/tail interactions play a key role in controlling the activity of Cx43 hemichannels. Interestingly, the negative regulation of Cx43 hemichannels by enhanced actin/myosin contractility seems to impinge upon loss of these loop/tail interactions essential for opening Cx43 hemichannels. Finally, these molecular insights have spurred the development of novel peptide tools that can selectively inhibit Cx43 hemichannels, but neither Cx43 gap junctions nor hemichannels formed by other Cx isoforms. These tools now set the stage to hunt for novel physiological functions for Cx43 hemichannels in primary cells and tissues and to tackle disease conditions associated with excessive, pathological Cx43-hemichannel openings

Controlling cell-matrix traction forces by extracellular geometry

We present a minimal continuum model of strongly adhering cells as active contractile isotropic media and use the model to study the effect of the geometry of the adhesion patch in controlling the spatial distribution of traction and cellular stresses. Activity is introduced as a contractile, hence negative, spatially homogeneous contribution to the pressure. The model shows that patterning of adhesion regions can be used to control traction stress distribution and yields several results consistent with experimental observations. Specifically, the cell spread area is found to increase with substrate stiffness and an analytic expression for the dependence is obtained for circular cells. The correlation between the magnitude of traction stresses and cell boundary curvature is also demonstrated and analyzed.Comment: 12 pages, 4 figure

A delay recruitment model of the cardiovascular control system.

Copyright will be owned by Springer. We develop a nonlinear delay-differential equation for the human cardiovascular control system, and use it to explore blood pressure and heart rate variability under short-term baroreflex control. The model incorporates an intrinsically stable heart rate in the absence of nervous control, and features baroreflex influence on both heart rate and peripheral resistance. Analytical simplifications of the model allow a general investigation of the rôles played by gain and delay, and the effects of ageing.

Nitrate pollution from horticultural production systems : tools for policy and advice from field to catchment scales

The implementation of the Nitrates Directive has imposed a requirement to restrict N fertiliser and manuring practices on farms across the EU in order to reduce nitrate losses to water. These requirements have since been extended by the more demanding Water Framework Directive, which broadens the focus from the control of farm practices to a consideration of the impacts of pollutants from all sources on water quality at a catchment or larger scale. Together, these Directives set limits for water quality, and identify general strategies for how these might be achieved. However, it is the responsibility of policy makers in each Nation State to design the details of the management practices and environmental protection measures required to meet the objectives of the legislation, to ensure they are appropriate for their specific types of land use and climate. This paper describes various modelling tools for comparing different cropping and land use strategies, and illustrates with examples how they can inform policy makers about the environmental benefits of changing management practices and how to prioritise them. The results can help to provide the specific advice on N fertiliser and land use management required by farmers and growers at a field scale, and by environmental managers at a catchment or larger scale. A further example of how results from multiple catchments can be up-scaled and compared using Geographic Information Systems is also outlined

Iso-osmotic regulation of nitrate accumulation in lettuce (Lactuca sativa L.)

Concerns about possible health hazards arising from human consumption of lettuce and other edible vegetable crops with high concentrations of nitrate have generated demands for a greater understanding of processes involved in its uptake and accumulation in order to devise more sustainable strategies for its control. This paper evaluates a proposed iso-osmotic mechanism for the regulation of nitrate accumulation in lettuce (Lactuca sativa L.) heads. This mechanism assumes that changes in the concentrations of nitrate and all other endogenous osmotica (including anions, cations and neutral solutes) are continually adjusted in tandem to minimise differences in osmotic potential of the shoot sap during growth, with these changes occurring independently of any variations in external water potential. The hypothesis was tested using data from six new experiments, each with a single unique treatment comprising a separate combination of light intensity, N source (nitrate with or without ammonium) and nitrate concentration carried out hydroponically in a glasshouse using a butterhead lettuce variety. Repeat measurements of plant weights and estimates of all of the main soluble constituents (nitrate, potassium, calcium, magnesium, organic anions, chloride, phosphate, sulphate and soluble carbohydrates) in the shoot sap were made at intervals from about 2 weeks after transplanting until commercial maturity, and the data used to calculate changes in average osmotic potential in the shoot. Results showed that nitrate concentrations in the sap increased when average light levels were reduced by between 30 and 49 % and (to a lesser extent) when nitrate was supplied at a supra-optimal concentration, and declined with partial replacement of nitrate by ammonium in the external nutrient supply. The associated changes in the proportions of other endogenous osmotica, in combination with the adjustment of shoot water content, maintained the total solute concentrations in shoot sap approximately constant and minimised differences in osmotic potential between treatments at each sampling date. There was, however, a gradual increase in osmotic potential (ie a decline in total solute concentration) over time largely caused by increases in shoot water content associated with the physiological and morphological development of the plants. Regression analysis using normalised data (to correct for these time trends) showed that the results were consistent with a 1:1 exchange between the concentrations of nitrate and the sum of all other endogenous osmotica throughout growth, providing evidence that an iso-osmotic mechanism (incorporating both concentration and volume regulation) was involved in controlling nitrate concentrations in the shoot

The Ca2+ transient as a feedback sensor controlling cardiomyocyte ionic conductances in mouse populations.

Conductances of ion channels and transporters controlling cardiac excitation may vary in a population of subjects with different cardiac gene expression patterns. However, the amount of variability and its origin are not quantitatively known. We propose a new conceptual approach to predict this variability that consists of finding combinations of conductances generating a normal intracellular Ca2+ transient without any constraint on the action potential. Furthermore, we validate experimentally its predictions using the Hybrid Mouse Diversity Panel, a model system of genetically diverse mouse strains that allows us to quantify inter-subject versus intra-subject variability. The method predicts that conductances of inward Ca2+ and outward K+ currents compensate each other to generate a normal Ca2+ transient in good quantitative agreement with current measurements in ventricular myocytes from hearts of different isogenic strains. Our results suggest that a feedback mechanism sensing the aggregate Ca2+ transient of the heart suffices to regulate ionic conductances

On Neuromechanical Approaches for the Study of Biological Grasp and Manipulation

Biological and robotic grasp and manipulation are undeniably similar at the level of mechanical task performance. However, their underlying fundamental biological vs. engineering mechanisms are, by definition, dramatically different and can even be antithetical. Even our approach to each is diametrically opposite: inductive science for the study of biological systems vs. engineering synthesis for the design and construction of robotic systems. The past 20 years have seen several conceptual advances in both fields and the quest to unify them. Chief among them is the reluctant recognition that their underlying fundamental mechanisms may actually share limited common ground, while exhibiting many fundamental differences. This recognition is particularly liberating because it allows us to resolve and move beyond multiple paradoxes and contradictions that arose from the initial reasonable assumption of a large common ground. Here, we begin by introducing the perspective of neuromechanics, which emphasizes that real-world behavior emerges from the intimate interactions among the physical structure of the system, the mechanical requirements of a task, the feasible neural control actions to produce it, and the ability of the neuromuscular system to adapt through interactions with the environment. This allows us to articulate a succinct overview of a few salient conceptual paradoxes and contradictions regarding under-determined vs. over-determined mechanics, under- vs. over-actuated control, prescribed vs. emergent function, learning vs. implementation vs. adaptation, prescriptive vs. descriptive synergies, and optimal vs. habitual performance. We conclude by presenting open questions and suggesting directions for future research. We hope this frank assessment of the state-of-the-art will encourage and guide these communities to continue to interact and make progress in these important areas