Discussion: The ergogenic effects of hyperventilation, notable especially in later sprint sets, may be explained by prolonged anaerobic energy supply processes via phosphocreatine, glycolysis or ...glycogenolysis, and delayed excitation/contraction failure, enabling powerful force generations to be maintained for the sprinting duration. Furthermore, improved performance would be expected to lead to...
A single somatic mutation, V617F, in Janus kinase 2 (JAK2) is one of the causes of myeloproliferative neoplasms (MPNs), including primary myelofibrosis, and the JAK2V617F mutant kinase is a ...therapeutic target in MPN. However, inhibition of wild-type (WT) JAK2 can decrease the erythrocyte or platelet (PLT) count. Our selective JAK2 inhibitor, NS-018, suppressed the growth of Ba/F3 cells harboring JAK2V617F more strongly than that of cells harboring WT JAK2. The 4.3-fold JAK2V617F selectivity of NS-018 is higher than the 1.0- to 2.9-fold selectivity of seven existing JAK2 inhibitors. NS-018 also inhibited erythroid colony formation in JAK2V617F transgenic mice at significantly lower concentrations than in WT mice. In keeping with the above results, in a JAK2V617F bone marrow transplantation mouse model with a myelofibrosis-like disease, NS-018 reduced leukocytosis and splenomegaly, improved bone marrow fibrosis and prolonged survival without decreasing the erythrocyte or PLT count in the peripheral blood. By exploring the X-ray co-crystal structure of NS-018 bound to JAK2, we identified unique hydrogen-bonding interactions between NS-018 and Gly993 as a plausible explanation for its JAK2V617F selectivity. These results suggest that NS-018 will have therapeutic benefit for MPN patients through both its efficacy and its reduced hematologic adverse effects.
The real and imaginary optical conductivities in disordered semiconductors (and metals) do not follow classical Drude's law in the near infrared region. We discuss an origin of the anomalous free ...carrier absorption in metallic (and near metallic) states of chalcogenide materials (phase-change GST), dye-sensitized nanocrystalline TiO2 and nanocrystalline silicon films. A series sequence of “localized” and “extended” state type behavior of carriers produces a Lorentz-type resonance which is caused by “bound” (localized) electrons. The analytical expressions were fit to the experimental data and produced various important physical parameters such as the numbers of free and localized carriers, the scattering time of free carriers, tunneling time of localized carriers, and the Drude dc conductivity in the system. We also discuss whether the present model has generated reasonable physical parameters.
► A new model for interpreting the anomalous free carrier absorption in nanomaterials. ► Optical conductivity in THz-frequencies for metallic GST, nanocrystalline TiO2 and silicon films. ► A Lorentz-type resonance originated from a series sequence of free and tunneling carriers. ► Common features of THz-conductivities in nanomaterials.
Hereditary dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurologic disorder characterized by variable combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis ...and dementia. By specifically searching published brain cDNA sequences for the presence of CAG repeats we identified unstable expansion of a CAG in a gene on chromosome 12 in all the 22 DRPLA patients examined. A good correlation between the size of the CAG repeat expansion and the ages of disease onset is found in this group. Patients with earlier onset tended to have a phenotype of progressive myoclonus epilepsy and larger expansions. We propose that the wide variety of clinical manifestations of DRPLA can now be explained by the variable unstable expansion of the CAG repeat.
Aberrant activation of Janus kinase 2 (JAK2) caused by somatic mutation of JAK2 (JAK2V617F) or the thrombopoietin receptor (MPLW515L) plays an essential role in the pathogenesis of myeloproliferative ...neoplasms (MPNs), suggesting that inhibition of aberrant JAK2 activation would have a therapeutic benefit. Our novel JAK2 inhibitor, NS-018, was highly active against JAK2 with a 50% inhibition (IC(50)) of <1 n, and had 30-50-fold greater selectivity for JAK2 over other JAK-family kinases, such as JAK1, JAK3 and tyrosine kinase 2. In addition to JAK2, NS-018 inhibited Src-family kinases. NS-018 showed potent antiproliferative activity against cell lines expressing a constitutively activated JAK2 (the JAK2V617F or MPLW515L mutations or the TEL-JAK2 fusion gene; IC(50)=11-120 n), but showed only minimal cytotoxicity against most other hematopoietic cell lines without a constitutively activated JAK2. Furthermore, NS-018 preferentially suppressed in vitro erythropoietin-independent endogenous colony formation from polycythemia vera patients. NS-018 also markedly reduced splenomegaly and prolonged the survival of mice inoculated with Ba/F3 cells harboring JAK2V617F. In addition, NS-018 significantly reduced leukocytosis, hepatosplenomegaly and extramedullary hematopoiesis, improved nutritional status, and prolonged survival in JAK2V617F transgenic mice. These results suggest that NS-018 will be a promising candidate for the treatment of MPNs.
Highlights ► Growth of the ischemic depolarization area can be visualized with NADH fluorescence. ► Lidocaine infusion, started before ischemia, reduced the infarct volume. ► Lidocaine reduced the ...area in which the intensity of NADH fluorescence is increased. ► Lidocaine did not decrease the number of peri-infarct depolarizations. ► Lidocaine did not change the duration of depolarization causing neuronal damage.
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