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OBJECTIVE-SIRT1, a class III histone/protein deacetylase, is known to interfere with the nuclear factor-B (NF-B) signaling pathway and thereby has an anti-inflammatory function. Because of the central role of NF-B in cytokine-mediated pancreatic ␤-cell damage, we postulated that SIRT1 might work in pancreatic ␤-cell damage models. RESEARCH DESIGN AND METHODS-RINm5F(RIN) cells or isolated rat islets were treated with interleukin-1␤ and interferon-␥. SIRT1 was activated by resveratrol, a pharmacological activator, or ectopic overexpression. The underlying mechanisms of SIRT1 against cytokine toxicity were further explored.RESULTS-Treatment of RIN cells with cytokines induced cell damage, and this damage was well correlated with the expression of the inducible form of nitric oxide (NO) synthase (iNOS) and NO production. However, SIRT1 overexpression completely prevented cytokine-mediated cytotoxicity, NO production, and iNOS expression. The molecular mechanism by which SIRT1 inhibits iNOS expression appeared to involve the inhibition of the NF-B signaling pathway through deacetylation of p65. In addition, SIRT1 activation by either resveratrol or adenoviraldirected overexpression of SIRT1 could prevent cytokine toxicity and maintain normal insulin-secreting responses to glucose in isolated rat islets.CONCLUSIONS-This study will provide valuable information not only into the mechanisms underlying ␤-cell destruction but also into the regulation of SIRT1 as a possible target to attenuate cytokine-induced ␤-cell damage. Diabetes 58:344-351, 2009

The role and contribution of the dense noradrenergic innervation in the ventral bed nucleus of the stria terminalis (vBNST) and anteroventral thalamic nucleus (AV) to biological function and animal behaviors is poorly understood due to the small size of these nuclei. The aim of this study was to compare norepinephrine release and uptake in the vBNST with that in the AV of anesthetized rats. Measurements were made in vivo with fast-scan cyclic voltammetry following electrical stimulation of noradrenergic projection pathways, either the dorsal noradrenergic bundle (DNB) or the ventral noradrenergic bundle (VNB). The substance detected was identified as norepinephrine based upon voltammetric, anatomical, neurochemical, and pharmacological evidence. Fast-scan cyclic voltammetry enables the selective monitoring of local norepinephrine overflow in the vBNST evoked by the stimulation of either the DNB or VNB while norepinephrine in the AV was only evoked by DNB stimulation. The α2-adrenoceptor antagonist, yohimbine, and the norepinephrine uptake inhibitor, desipramine, increased norepinephrine overflow and slowed its disappearance in both regions. However, control of extracellular norepinephrine by both autoreceptors and uptake was greater in the AV. The greater control exerted by autoreceptors and uptake in the AV resulted in reduced extracellular concentration compared to the vBNST when large numbers of stimulation pulses were employed. The differences in noradrenergic transmission observed in the terminal fields of the vBNST and the AV may differentially regulate activity in these two regions that both contain high densities of norepinephrine terminals.

Brain norepinephrine and dopamine regulate a variety of critical behaviors such as stress, learning, memory, and drug addiction. Here, we demonstrate differences in the regulation of in vivo neurotransmission for dopamine in the anterior nucleus accumbens (NAc) and norepinephrine in the ventral bed nucleus of the stria terminalis (vBNST) of the anesthetized rat. Release of the two catecholamines was measured simultaneously using fast-scan cyclic voltammetry (FSCV) at two different carbon-fiber microelectrodes, each implanted in the brain region of interest. Simultaneous dopamine and norepinephrine release was evoked by electrical stimulation of a region where the ventral noradrenergic bundle (VNB), the pathway of noradrenergic neurons, courses through the ventral tegmental area/substantia nigra (VTA/SN), the origin of dopaminergic cell bodies. The release and uptake of norepinephrine in the vBNST were both significantly slower than for dopamine in the NAc. Pharmacological manipulations in the same animal demonstrated that the two catecholamines are differently regulated. The combination of a dopamine autoreceptor antagonist and amphetamine significantly increased basal extracellular dopamine whereas a norepinephrine autoreceptor antagonist and amphetamine did not change basal norepinephrine concentration. α-Methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, decreased electrically evoked dopamine release faster than norepinephrine. The dual-microelectrode FSCV technique along with anatomical and pharmacological evidence confirms that dopamine in the NAc and norepinephrine in the vBNST can be monitored selectively and simultaneously in the same animal. The high temporal and spatial resolution of the technique enabled us to examine differences in the dynamics of extracellular norepinephrine and dopamine concurrently in two different limbic structures.

Metal halide perovskites are attracting great attention as next-generation light emitting materials due to their excellent emission properties with narrowband emission. [1][2][3][4] However, perovskite light-emitting didoes (PeLEDs) irrespective of their material types (polycrystals or nanocrystals) have not realized high luminance, high efficiency and long lifetime simultaneously, as they are influenced by the intrinsic limitations related to the trade-off properties between charge transport and confinement in each type of perovskite materials. [5][6][7][8] Here, we report an ultra-bright, efficient, and stable PeLEDs made of core/shell perovskite nanocrystals with a size of ~10 nm obtained using simple in-situ reaction of benzylphosphonic acid (BPA) additive with 3D polycrystalline perovskite films without separate synthesis process. During the reaction, large 3D crystals are split into nanocrystals and the BPA surrounds the nanocrystals, achieving strong carrier confinement. The BPA shell passivates the undercoordinated lead atoms by forming covalent bonds, and thereby greatly reduces trap density while maintaining good charge-transport properties of 3D perovskites. We demonstrate simultaneously efficient, bright, and stable PeLEDs that have maximum brightness of ~470,000 cd m -2 , maximum external quantum efficiency of 28.9 % (average = 25.2 ± 1.6 % over 40 devices), maximum current efficiency of 151 cd A -1 , and half-lifetime of 520 h at 1,000 cd m -2 (estimated half-lifetime >30,000 h at 100 cd m -2 ). Our work sheds great light on the possibility that PeLEDs can be commercialized in the future display industry.