Voltage- and cold-dependent gating of single TRPM8 ion channels

Transient receptor potential (TRP) channels play critical roles in cell signaling by coupling various environmental factors to changes in membrane potential that modulate calcium influx. TRP channels are typically activated in a polymodal manner, thus integrating multiple stimuli. Although much progress has been made, the underlying mechanisms of TRP channel activation are largely unknown. The TRPM8 cation channel has been extensively investigated as a major neuronal cold sensor but is also activated by voltage, calcium store depletion, and some lipids as well as by compounds that produce cooling sensations, such as menthol or icilin. Several models of TRPM8 activation have been proposed to explain the interaction between these diverse stimuli. However, a kinetic scheme is not yet available that can describe the detailed single-channel kinetics to gain further insight into the underlying gating mechanism. To work toward this goal, we investigated voltage-dependent single-channel gating in cell-attached patches at two different temperatures (20 and 30°C) using HEK293 cells stably expressing TRPM8. Both membrane depolarization and cooling increased channel open probability (Po) mainly by decreasing the duration of closed intervals, with a smaller increase in the duration of open intervals. Maximum likelihood analysis of dwell times at both temperatures indicated gating in a minimum of five closed and two open states, and global fitting over a wide range of voltages identified a seven-state model that described the voltage dependence of Po, the single-channel kinetics, and the response of whole-cell currents to voltage ramps and steps. The major action of depolarization and cooling was to accelerate forward transitions between the same two sets of adjacent closed states. The seven-state model provides a general mechanism to account for TRPM8 activation by membrane depolarization at two temperatures and can serve as a starting point for further investigations of multimodal TRP activation

Elastic-plastic modelling of unsaturated soil using results from a new triaxial test with controlled suction

This paper examines the constitutive behaviour of a compacted highly plastic sand–clay mixture. Three series of tests evaluated components of a possible elastic-plastic constitutive model for unsaturated stress–strain behaviour. The tests examined the influence of suction on yield stress under external isotropic loading and the influence of suction on shear strength. The results examine the behaviour of highly plastic clay subjected to generalised (triaxial) stresses that include shear, isotropic and suction loading. The data represent an important new resource of information on a densely compacted, strongly expansive, sand–bentonite mixture that was loaded independently by external stresses and internal suctions. The suctions were also measured by sensors buried in the specimens. They have been interpreted in an elastic-plastic framework to produce values for some of the material properties needed for the model. The results and associated discussion provide new insights into the behaviour of unsaturated highly plastic clay materials. </jats:p

GEOSTYNTHETIC REINFORCE MENT FOR EMBANKMENTS OVER DEGRADING DISCONTINUOUS PERMAFROST SUBJECTED TO PRESSTRESSING

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Seepage, leaching, and embankment instability

Water-retention dykes at a hydroelectric generating station in southeastern Manitoba experienced irregular instabilities over many years after they were heightened in the late 1940s. Samples from an unstable section of dyke showed considerable reductions in gypsum content and increased brittleness compared with those of neighbouring unloaded clay. The samples also showed that lowering the content of gypsum reduced the sizes of yield loci and the strains required for strain softening to occur. These observations and the time-dependent nature of the problem suggested that seepage from the forebay had leached naturally occurring cementation from the foundation clay and subsequently changed its behaviour. Stress–deformation modeling indicated the foundation clay had yielded during initial construction and again when the dykes were heightened. Seepage from the forebay occurred at different rates in different locations through the irregular sand–silt partings that are generally present in proglacial clays. Leaching and strain softening were therefore also irregular. Leaching led to reduction in the size of the yield loci and therefore increased the volume of soil that yielded under loading from the dyke. In slope-stability modeling, excess pore-water pressures arising from time-dependent brittleness were sufficient to cause instability of the dykes. </jats:p

Influence of suction on the strength and stiffness of compacted sand-bentonite

The paper proposes a new elastic-plastic framework for unsaturated, high-plasticity, clayey soils and sand-clay mixtures. The framework considers possible coupling of stress- and suction-induced hardening, leading to a yield surface that is closed or "capped" as suctions increase. This produces a stress state boundary surface in three-dimensional p-q-s stress space (where p is the net mean stress, q is the deviator stress, and s is the matric suction) which differs from that of other conceptual models of its kind. Yielding, a hardening law, and failure criteria for saturated soils are incorporated into the stress state boundary surface. Two parameters, equivalent pressure p(e) and stress ratio eta(s), are introduced to form the basis of the proposed elastic-plastic framework for highly plastic soils with high suctions. This provides an alternative for the stress variables net mean stress and matric suction that are commonly used in modeling unsaturated soils with lower plasticity and lower suctions. This framework has allowed results of experiments on an unsaturated sand-bentonite mixture to be successfully described using elastoplasticity. Yield and failure envelopes associated with the proposed state boundary surface in p-q-s space can be normalized using p(e) and eta(s) in such a way that they agree with a comparable envelope for saturated specimens

Effects of near-surface environmental conditions on instability of an unsaturated soil slope

In 1999, after a period of extensive rainfall, two shallow slope failures developed in the right-of-way of Provincial Road 259 near Virden, Manitoba. The rainfall caused dissipation of soil suction in the near-surface soil, thereby reducing shear resistance and triggering failure. A research project was initiated between the Geotechnical Group at the University of Manitoba and the Manitoba Department of Highways and Transportation to assess the mechanism of failure. The project included a field investigation program, laboratory testing program, and advanced numerical modeling to identify the cause of failure. The results demonstrate that the rainfall resulted in dissipation of the suction in the soil slope, resulting in a reduction in the soil shear strength that triggered shallow failures. The dissipation of the soil suction has been modeled using a time-dependent seepage model that accounts for the flux boundary condition that existed at the ground surface