Dehydration and ionic conductance quantization in nanopores

There has been tremendous experimental progress in the last decade in identifying the structure and function of biological pores (ion channels) and fabricating synthetic pores. Despite this progress, many questions still remain about the mechanisms and universal features of ionic transport in these systems. In this paper, we examine the use of nanopores to probe ion transport and to construct functional nanoscale devices. Specifically, we focus on the newly predicted phenomenon of quantized ionic conductance in nanopores as a function of the effective pore radius - a prediction that yields a particularly transparent way to probe the contribution of dehydration to ionic transport. We study the role of ionic species in the formation of hydration layers inside and outside of pores. We find that the ion type plays only a minor role in the radial positions of the predicted steps in the ion conductance. However, ions with higher valency form stronger hydration shells, and thus, provide even more pronounced, and therefore, more easily detected, drops in the ionic current. Measuring this phenomenon directly, or from the resulting noise, with synthetic nanopores would provide evidence of the deviation from macroscopic (continuum) dielectric behavior due to microscopic features at the nanoscale and may shed light on the behavior of ions in more complex biological channels.Comment: 13 pages, 10 figure

Design of Microwave Vitrification Systems for Radioactive Waste

Oak Ridge National Laboratory (ORNL) is involved in the research and development of high-power microwave heating systems for the vitrification of DOE radioactive sludges. Design criteria for a continuous microwave vitrification system capable of processing a surrogate filtercake sludge representative of a typical waste-water treatment operation are discussed. A prototype 915 MHz, 75 kW microwave vitrification system or `microwave melter` is described along with some early experimental results that demonstrate a 4 to 1 volume reduction of a surrogate ORNL filtercake sludge

Distinct degassing pulses during magma invasion in the stratified Karoo Basin – New insights from hydrothermal fluid flow modelling

Magma emplacement in organic‐rich sedimentary basins is a main driver of past environmental crises. Using a 2D numerical model, we investigate the process of thermal cracking in contact aureoles of cooling sills and subsequent transport and emission of thermogenic methane by hydrothermal fluids. Our model includes a Mohr‐Coulomb failure criterion to initiate hydrofracturing and a dynamic porosity/permeability. We investigate the Karoo Basin, taking into account host‐rock material properties from borehole data, realistic total organic carbon content, and different sill geometries. Consistent with geological observations, we find that thermal plumes quickly rise at the edges of saucer‐shaped sills, guided along vertically fractured high permeability pathways. Contrastingly, less focused and slower plumes rise from the edges and the central part of flat‐lying sills. Using a novel upscaling method based on sill‐to‐sediment ratio we find that degassing of the Karoo Basin occurred in two distinct phases during magma invasion. Rapid degassing triggered by sills emplaced within the top 1.5 km emitted ~1.6·103 Gt of thermogenic methane, while thermal plumes originating from deeper sills, carrying a 12‐times greater mass of methane, may not reach the surface. We suggest that these large quantities of methane could be re‐mobilized by the heat provided by neighboring sills. We conclude that the Karoo LIP may have emitted as much as ~22.3·103 Gt of thermogenic methane in the half million years of magmatic activity, with emissions up to 3 Gt/year. This quantity of methane and the emission rates can explain the negative δ13C excursion of the Toarcian environmental crisis. Key Points Sill geometry and emplacement depth as well as intruded host rock type are the main factors controlling methane mobilization and degassing Dehydration‐related porosity increase and pore‐pressure‐induced hydrofracturing are important mechanisms for a quick transport of methane from sill to the surface The Karoo Basin may have degassed ~22.3·103 Gt of thermogenic methane in the half million years of magmatic activit

Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy.

Gain-of-function (GOF) variants in K+ channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased K+ currents lead to network hyperexcitability. Here, we introduce a human Na+-activated K+ (KNa) channel variant (KCNT1-Y796H) into mice and, using a multiplatform approach, find motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar to those of human patients. Although the variant increases KNa currents in cortical excitatory and inhibitory neurons, there is an increase in the KNa current across subthreshold voltages only in inhibitory neurons, particularly in those with non-fast-spiking properties, resulting in inhibitory-neuron-specific impairments in excitability and action potential (AP) generation. We further observe evidence of synaptic rewiring, including increases in homotypic synaptic connectivity, accompanied by network hyperexcitability and hypersynchronicity. These findings support inhibitory-neuron-specific mechanisms in mediating the epileptogenic effects of KCNT1 channel GOF, offering cell-type-specific currents and effects as promising targets for therapeutic intervention

The development of a stakeholder-endorsed national strategic plan for advancing pain education across Canadian physiotherapy programs

Abstract Background The Canadian Pain Task Force recently advanced an action plan calling for improved entry-level health professional pain education. However, there is little research to inform the collaboration and coordination across stakeholders that is needed for its implementation. Aims This manuscript reports on the development of a stakeholder-generated strategic plan to improve pain education across all Canadian physiotherapy (PT) programs. Methods Participants included representatives from the following stakeholder groups: people living with pain (n = 1); PT students and recent graduates (n = 2); educators and directors from every Canadian PT program (n = 24); and leaders of Canada?s national PT professional association (n = 2). Strategic priorities were developed through three steps (1) stakeholder-generated data was collected and analyzed; (2) a draft strategic plan was developed and refined; and (2) stakeholder endorsement of the final plan was assessed. The project was primarily implemented online, between 2016 and 2018. Results The plan was developed through five iterative versions. Stakeholders unanimously endorsed a plan that included five priorities focusing on uptake of best evidence across (1) national PT governance groups and (2) within individual PT programs; (3) partnering with people living with pain in pain education; (4) advocacy for the PT role in pain management; and (5) advancing pain education research. Conclusion This plan is expected to help Canadian stakeholders work toward national improvements in PT pain education and to serve as a useful template for informing collaboration on entry-level pain education within other professions and across different geographic regions

Modern Electronic Techniques Applied to Physics and Engineering

Contains reports on seven research projects.Office of Scientific Research and Development (OSRD) OEMsr-26

Voltage-Gated Ion Channel Dysfunction Precedes Cardiomyopathy Development in the Dystrophic Heart

Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is associated with severe cardiac complications including cardiomyopathy and cardiac arrhythmias. Recent research suggests that impaired voltage-gated ion channels in dystrophic cardiomyocytes accompany cardiac pathology. It is, however, unknown if the ion channel defects are primary effects of dystrophic gene mutations, or secondary effects of the developing cardiac pathology.To address this question, we first investigated sodium channel impairments in cardiomyocytes derived from dystrophic neonatal mice prior to cardiomyopahty development, by using the whole cell patch clamp technique. Besides the most common model for DMD, the dystrophin-deficient mdx mouse, we also used mice additionally carrying an utrophin mutation. In neonatal cardiomyocytes, dystrophin-deficiency generated a 25% reduction in sodium current density. In addition, extra utrophin-deficiency significantly altered sodium channel gating parameters. Moreover, also calcium channel inactivation was considerably reduced in dystrophic neonatal cardiomyocytes, suggesting that ion channel abnormalities are universal primary effects of dystrophic gene mutations. To assess developmental changes, we also studied sodium channel impairments in cardiomyocytes derived from dystrophic adult mice, and compared them with the respective abnormalities in dystrophic neonatal cells. Here, we found a much stronger sodium current reduction in adult cardiomyocytes. The described sodium channel impairments slowed the upstroke of the action potential in adult cardiomyocytes, and only in dystrophic adult mice, the QRS interval of the electrocardiogram was prolonged.Ion channel impairments precede pathology development in the dystrophic heart, and may thus be considered potential cardiomyopathy triggers

Advances in gene therapy for muscular dystrophies

Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments

iNOS Ablation Does Not Improve Specific Force of the Extensor Digitorum Longus Muscle in Dystrophin-Deficient mdx4cv Mice

Nitrosative stress compromises force generation in Duchenne muscular dystrophy (DMD). Both inducible nitric oxide synthase (iNOS) and delocalized neuronal NOS (nNOS) have been implicated. We recently demonstrated that genetic elimination of nNOS significantly enhanced specific muscle forces of the extensor digitorum longus (EDL) muscle of dystrophin-null mdx4cv mice (Li D et al J. Path. 223:88–98, 2011). To determine the contribution of iNOS, we generated iNOS deficient mdx4cv mice. Genetic elimination of iNOS did not alter muscle histopathology. Further, the EDL muscle of iNOS/dystrophin DKO mice yielded specific twitch and tetanic forces similar to those of mdx4cv mice. Additional studies suggest iNOS ablation did not augment nNOS expression neither did it result in appreciable change of nitrosative stress markers in muscle. Our results suggest that iNOS may play a minor role in mediating nitrosative stress-associated force reduction in DMD

Marginal Level Dystrophin Expression Improves Clinical Outcome in a Strain of Dystrophin/Utrophin Double Knockout Mice

Inactivation of all utrophin isoforms in dystrophin-deficient mdx mice results in a strain of utrophin knockout mdx (uko/mdx) mice. Uko/mdx mice display severe clinical symptoms and die prematurely as in Duchenne muscular dystrophy (DMD) patients. Here we tested the hypothesis that marginal level dystrophin expression may improve the clinical outcome of uko/mdx mice. It is well established that mdx3cv (3cv) mice express a near-full length dystrophin protein at ∼5% of the normal level. We crossed utrophin-null mutation to the 3cv background. The resulting uko/3cv mice expressed the same level of dystrophin as 3cv mice but utrophin expression was completely eliminated. Surprisingly, uko/3cv mice showed a much milder phenotype. Compared to uko/mdx mice, uko/3cv mice had significantly higher body weight and stronger specific muscle force. Most importantly, uko/3cv outlived uko/mdx mice by several folds. Our results suggest that a threshold level dystrophin expression may provide vital clinical support in a severely affected DMD mouse model. This finding may hold clinical implications in developing novel DMD therapies