Cancer Council of Western Australia and the Sir Charles Gairdner Research Advisory Group.
Cardiac cells express more than one isoform of the Na, K-ATPase (NKA), the heteromeric enzyme that creates the Na(+) and K(+) gradients across the plasmalemma. Cardiac isozymes contain one catalytic α-subunit isoform (α1, α2, or α3) associated with an auxiliary β-subunit isoform (β1 or β2). Past studies using biochemical approaches have revealed minor kinetic differences between isozymes formed by different α-β isoform combinations; these results make it difficult to understand the physiological requirement for multiple isoforms. In intact cells, however, NKA enzymes operate in a more complex environment, which includes a substantial transmembrane potential. We evaluated the voltage dependence of human cardiac NKA isozymes expressed in Xenopus oocytes, and of native NKA isozymes in rat ventricular myocytes, using normal mammalian physiological concentrations of Na(+)o and K(+)o. We demonstrate that although α1 and α3 pumps are functional at all physiologically relevant voltages, α2β1 pumps and α2β2 pumps are inhibited by ∼75% and ∼95%, respectively, at resting membrane potentials, and only activate appreciably upon depolarization. Furthermore, phospholemman (FXYD1) inhibits pump function without significantly altering the pump's voltage dependence. Our observations provide a simple explanation for the physiological relevance of the α2 subunit (∼20% of total α subunits in rat ventricle): they act as a reserve and are recruited into action for extra pumping during the long-lasting cardiac action potential, where most of the Na(+) entry occurs. This strong voltage dependence of α2 pumps also helps explain how cardiotonic steroids, which block NKA pumps, can be a beneficial treatment for heart failure: by only inhibiting the α2 pumps, they selectively reduce NKA activity during the cardiac action potential, leading to an increase in systolic Ca(2+), due to reduced extrusion through the Na/Ca exchanger, without affecting resting Na(+) and Ca(2+) concentrations.
We present the details of a method to perform molecular-dynamics (MD) simulations without thermostat and with very small temperature fluctuations ±ΔT starting with MD step 1. It involves preparing the supercell at the time t = 0 in physically correct microstates using the eigenvectors of the dynamical matrix. Each initial microstate corresponds to a different distribution of kinetic and potential energies for each vibrational mode (the total energy of each microstate is the same). Averaging the MD runs over many initial microstates further reduces ΔT. The electronic states are obtained using first-principles theory (density-functional theory in periodic supercells). Three applications are discussed: the lifetime and decay of vibrational excitations, the isotope dependence of thermal conductivities, and the flow of heat at an interface.
The interactions between thermal phonons and defects are conventionally described as scattering processes, an idea proposed almost a century ago. In this contribution, ab-initio molecular-dynamics simulations provide atomic-level insight into the nature of these interactions. The defect is the Si|X interface in a nanowire containing a δ-layer (X is C or Ge). The phonon-defect interactions are temperature dependent and involve the trapping of phonons for meaningful lengths of time in defect-related, localized, vibrational modes. No phonon scattering occurs and the momentum of the phonons released by the defect is unrelated to the momentum of the phonons that generated the excitation. The results are extended to the interactions involving only bulk phonons and to phonon-defect interactions at high temperatures. These do resemble scattering since phonon trapping occurs for a length of time short enough for the momentum of the incoming phonon to be conserved.
Understanding how heat flows across interfaces is vital to energy efficiency and thermal stability of many electrical devices. However, the thermal resistance caused by the interface between two materials, termed Kapitza resistance, remains poorly understood. To that end, several first‐principles molecular dynamic simulations and a detailed analysis of the phonon processes and associated transfer of heat at the interfaces of both c‐Si|a‐SiO2 and c‐Si|c‐Ge are presented. It is found that in both cases the interface properties are very important. In the case of c‐Si|a‐SiO2, it is found that interface modes cause inelastic phonon interactions and play a significant role in the total energy transferred. In the case of c‐Si|a‐SiO2, one is able to quantify this effect and find that there is a small set of interface modes which carry >10% of the heat, and decrease the ultimate thermal boundary resistance by 26.5%.
The interactions between heat flow and an oxide layer in Si are studied within two temperature windows using non‐equilibrium ab initio molecular‐dynamics (MD). The model system is a H‐saturated Si nanowire containing an amorphous SiOx layer. The nanowire is in a large 1‐D periodic box which prevents thermal contamination between image nanowires. The results show that the oxide acts as barrier to heat flow and substantially increases the time required for the system to reach thermal equilibrium. This effect is caused by the higher‐frequency vibrational modes in the oxide relative to Si, and is unrelated to the low thermal conductivity of SiOx. A new first‐principles method to calculate the Kapitza resistance of the interface directly from the MD data is proposed.
BackgroundAvailability and access to the detection of resistance to anti-tuberculosis drugs remains a significant challenge in Malawi due to limited diagnostic services. The Xpert® MTB/RIF can detect Mycobacterium tuberculosis and resistance to rifampicin in a single, rapid assay. Rifampicin-resistant M. tuberculosis has not been well studied in Malawi.ObjectivesWe aimed to determine mutations in the rifampicin resistance determining region (RRDR) of the rpoB gene of M. tuberculosis strains which were defined as resistant to rifampicin by the Xpert MTB/RIF assay.MethodsRifampicin-resistant isolates from 43 adult patients (≥ 18 years) from various districts of Malawi were characterised for mutations in the RRDR (codons 507–533) of the rpoB gene by DNA sequencing.ResultsMutations were found in 37/43 (86%) of the resistant isolates in codons 511, 512, 513, 516, 522, 526 and 531. The most common mutations were in codons 526 (38%), 531 (29.7%) and 516 (16.2%). Mutations were not found in 6/43 (14%) of the resistant isolates. No novel rpoB mutations other than those previously described were found among the rifampicin-resistant M. tuberculosis complex strains.ConclusionThis study is the first to characterise rifampicin resistance in Malawi. The chain-termination DNA sequencing employed in this study is a standard method for the determination of nucleotide sequences and can be used to confirm rifampicin resistance obtained using other assays, including the Xpert MTB/RIF. Further molecular cluster analysis, such as spoligotyping and DNA finger printing, is still required to determine transmission dynamics and the epidemiological link of the mutated strains.
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