Background: TRPM2 channels play an essential role in cell death following oxidative stress. Results: Dominant negative TRPM2-S decreases growth of neuroblastoma xenografts and increases doxorubicin sensitivity through modulation of HIF-1/2␣ expression, mitophagy, and mitochondrial function. Conclusion: TRPM2 is important for neuroblastoma growth and viability through modulation of HIF-1/2␣. Significance: Modulation of TRPM2 may be a novel approach in cancer therapeutics.

Phospholemman (PLM) regulates cardiac Na+/Ca2+ exchanger (NCX1) and Na+-K+-ATPase in cardiac myocytes. PLM, when phosphorylated at Ser68, disinhibits Na+-K+-ATPase but inhibits NCX1. PLM regulates cardiac contractility by modulating Na+-K+-ATPase and/or NCX1. In this study, we first demonstrated that adult mouse cardiac myocytes cultured for 48 h had normal surface membrane areas, t-tubules, and NCX1 and sarco(endo)plasmic reticulum Ca2+-ATPase levels, and retained near normal contractility, but α1-subunit of Na+-K+-ATPase was slightly decreased. Differences in contractility between myocytes isolated from wild-type (WT) and PLM knockout (KO) hearts were preserved after 48 h of culture. Infection with adenovirus expressing green fluorescent protein (GFP) did not affect contractility at 48 h. When WT PLM was overexpressed in PLM KO myocytes, contractility and cytosolic Ca2+ concentration ([Ca2+]i) transients reverted back to those observed in cultured WT myocytes. Both Na+-K+-ATPase current ( Ipump) and Na+/Ca2+ exchange current ( INaCa) in PLM KO myocytes rescued with WT PLM were depressed compared with PLM KO myocytes. Overexpressing the PLMS68E mutant (phosphomimetic) in PLM KO myocytes resulted in the suppression of INaCa but had no effect on Ipump. Contractility, [Ca2+]i transient amplitudes, and sarcoplasmic reticulum Ca2+ contents in PLM KO myocytes overexpressing the PLMS68E mutant were depressed compared with PLM KO myocytes overexpressing GFP. Overexpressing the PLMS68A mutant (mimicking unphosphorylated PLM) in PLM KO myocytes had no effect on INaCa but decreased Ipump. Contractility, [Ca2+]i transient amplitudes, and sarcoplasmic reticulum Ca2+ contents in PLM KO myocytes overexpressing the S68A mutant were similar to PLM KO myocytes overexpressing GFP. We conclude that at the single-myocyte level, PLM affects cardiac contractility and [Ca2+]i homeostasis primarily by its direct inhibitory effects on Na+/Ca2+ exchange.

Phosphorylation at serine 68 of phospholemman (PLM) in response to beta-adrenergic stimulation results in simultaneous inhibition of cardiac Na(+)/Ca(2+) exchanger NCX1 and relief of inhibition of Na(+)-K(+)-ATPase. The role of PLM in mediating beta-adrenergic effects on in vivo cardiac function was investigated with congenic PLM-knockout (KO) mice. Echocardiography showed similar ejection fraction between wild-type (WT) and PLM-KO hearts. Cardiac catheterization demonstrated higher baseline contractility (+dP/dt) but similar relaxation (-dP/dt) in PLM-KO mice. In response to isoproterenol (Iso), maximal +dP/dt was similar but maximal -dP/dt was reduced in PLM-KO mice. Dose-response curves to Iso (0.5-25 ng) for WT and PLM-KO hearts were superimposable. Maximal +dP/dt was reached 1-2 min after Iso addition and declined with time in WT but not PLM-KO hearts. In isolated myocytes paced at 2 Hz. contraction and intracellular Ca(2+) concentration ([Ca(2+)](i)) transient amplitudes and [Na(+)](i) reached maximum 2-4 min after Iso addition, followed by decline in WT but not PLM-KO myocytes. Reducing pacing frequency to 0.5 Hz resulted in much smaller increases in [Na(+)](i) and no decline in contraction and [Ca(2+)](i) transient amplitudes with time in Iso-stimulated WT and PLM-KO myocytes. Although baseline Na(+)-K(+)-ATPase current was 41% higher in PLM-KO myocytes because of increased alpha(1)- but not alpha(2)-subunit activity, resting [Na(+)](i) was similar between quiescent WT and PLM-KO myocytes. Iso increased alpha(1)-subunit current (I(alpha1)) by 73% in WT but had no effect in PLM-KO myocytes. Iso did not affect alpha(2)-subunit current (I(alpha2)) in WT and PLM-KO myocytes. In both WT and NCX1-KO hearts, PLM coimmunoprecipitated with Na(+)-K(+)-ATPase alpha(1)- and alpha(2)-subunits, indicating that association of PLM with Na(+)-K(+)-ATPase did not require NCX1. We conclude that under stressful conditions in which [Na(+)](i) was high, beta-adrenergic agonist-mediated phosphorylation of PLM resulted in time-dependent reduction in inotropy due to relief of inhibition of Na(+)-K(+)-ATPase.

the electromagnetic waves and thus enables versatile functionalities in a planar structure. [15,16] To date, a majority of the studies have been focused on plasmonic metasurfaces involving metallic elements. A prime example is the metasurface composed of spatially varying metallic scatters distributed in one direction. However, plasmonic metasurfaces are difficult to move beyond the limitations of the inherent Ohmic losses and the orthogonal polarization conversion efficiency. [17,18] Efforts have been made to increase the polarization conversion efficiency [10,[19][20][21][22] or to avoid polarization conversion (Huygens surface) by employing multilayer plasmonic metasurfaces, [17,[23][24][25][26][27][28] but these designs introduce other problems. For example, extra loss from dielectric spacers is brought in. Meanwhile, the multilayer design becomes complex and also increases the fabrication challenges.Recently, all-dielectric metasurfaces have drawn enormous attentions. Free from the material loss, all-dielectric metasurfaces have been demonstrated to be able to manipulate lightmatter interactions and manifest exotic photonic behavior with a very high efficiency, far beyond their metallic counterparts. [29] For efficient wavefront engineering, dielectric metasurfaces also play an essential role by utilizing simultaneous excitation of Mie-type electric and magnetic resonances, [30,31] or effective waveguiding effect, [32,33] or the geometric phase concept. [34][35][36] Furthermore, to maximize the usability, controlling the polarization dependence is usually considered in the design. [35][36][37][38][39] However, such studies on dielectric metasurfaces for efficient wavefront engineering thus far, are mainly performed at optical and infrared frequencies. [40] With the rapid development of terahertz technology, the terahertz regime is also in great demand for various highly efficient, flexible, and low-cost functional devices, where the use of the all-dielectric metasurface is a promising solution.In this article, we numerically and experimentally demonstrate polarization-dependent, transmission-type all-silicon dielectric metasurfaces for manipulation of terahertz wavefront. The proposed polarization-dependent metasurface functions as two different devices with respect to the x-and y-polarizations. An efficiency around 60% could be achieved for both the Recently, metasurfaces made up of dielectric structures have drawn enormous attentions in the optical and infrared regimes due to their high efficiency and designing freedom in manipulating light propagation. Such advantages can also be introduced to terahertz frequencies where efficient functional devices are still lacking. Here, polarization-dependent all-silicon terahertz dielectric metasurfaces are proposed and experimentally demonstrated. The metasurfaces are composed of anisotropic rectangular-shaped silicon pillars on silicon substrate. Each metasurface holds dual different functions depending on the incident polarizations. Furthermore, to suppress the r...