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Insulin sensitizers, while effective in glucose-lowering for diabetes control, are linked to an increased risk of heart disease through mechanisms that are not well understood. In this study, we investigated the molecular mechanisms underlying the effects of insulin sensitization on cardiac sinus node dysfunction. We used pharmacologic or genetic approaches to enhance insulin sensitivity, by treating with pioglitazone or rosiglitazone, or through phosphatase and tensin homolog (PTEN) deletion in cardiomyocytes respectively. We employed an angiotensin II (Ang II)-induced hypertensive animal model which causes sinus node dysfunction and accumulation of oxidized calcium/calmodulin-dependent protein kinase II (CaMKII), which also serves as a biomarker for this defect. While neither PTEN deficiency nor insulin sensitizers caused sinus node dysfunction in normotensive mice, both accelerated the onset of sinus node dysfunction and CaMKII oxidation in hypertensive mice. These abnormalities were accompanied by a significant defect in autophagy as revealed by unc-51 like autophagy activating kinase 1 (ULK1) signaling. Indeed, mice deficient in ulk1 in cardiomyocytes and the sinus node also showed early onset of slow atrial impulse conduction with frequent sinus pauses and upregulated CaMKII oxidation following Ang II infusion similar to that seen with PTEN deficiency, or treatment with insulin sensitizers. To further elucidate the role of autophagy in sinus node dysfunction, we treated mice with a peptide D-Tat-beclin1 that enhanced autophagy, which significantly abrogated the frequent sinus pauses and accumulation of oxidized CaMKII induced by insulin sensitizers treatment, or PTEN deficiency in hypertensive animals. Together, these findings provide clear evidence of the detrimental cardiac effects of insulin sensitization that occurs through failure of autophagy-mediated proteolytic clearance. [ABSTRACT FROM AUTHOR]

In this paper, we demonstrate nondestructive readout memory characteristics of a bistable resistor (biristor) with an n+-p-n+ Si nanowire (SiNW) channel on a bendable substrate. The SiNW channel is fabricated using a top--down route, which is compatible with the current complementary metal-oxide-semiconductor technology. The SiNW biristor shows the outstanding memory characteristics such as a retention time of 10 s and a current sensing margin of ~23-μA at room temperature. These memory characteristics originate from a positive feedback process resulting from impact ionization near the p-n junction. Moreover, the positive feedback mechanism is comprehensively investigated using device simulation. [ABSTRACT FROM AUTHOR]

Motivation: Modulation of regulatory circuits governing the metabolic processes is a crucial step for developing microbial cell factories. Despite the prevalence of in silico strain design algorithms, most of them are not capable of predicting required modifications in regulatory networks. Although a few algorithms may predict relevant targets for transcriptional regulator (TR) manipulations, they have limited reliability and applicability due to their high dependency on the availability of integrated metabolic/regulatory models. Results: We present BeReTa (Beneficial Regulator Targeting), a new algorithm for prioritization of TR manipulation targets, which makes use of unintegrated network models. BeReTa identifies TR manipulation targets by evaluating regulatory strengths of interactions and beneficial effects of reactions, and subsequently assigning beneficial scores for the TRs. We demonstrate that BeReTa can predict both known and novel TR manipulation targets for enhanced production of various chemicals in Escherichia coli. Furthermore, through a case study of antibiotics production in Streptomyces coelicolor, we successfully demonstrate its wide applicability to even less-studied organisms. To the best of our knowledge, BeReTa is the first strain design algorithm exclusively designed for predicting TR manipulation targets. [ABSTRACT FROM AUTHOR]

Kaempferol exerts cardioprotective actions through incompletely understood mechanisms. This study investigated the molecular mechanisms underlying the cardioprotective effects of kaempferol in sinus node dysfunction (SND) heart. Here, we demonstrate that angiotensin II (Ang II) infusion causes SND through oxidized calmodulin kinase II (CaMKII). In contrast to this, kaempferol protects sinus node against Ang II-induced SND. Ang II evoked apoptosis with caspase-3 activation in sinus nodal cells. However, kaempferol lowered the CaMKII oxidization and the sinus nodal cell death. To block the CaMKII oxidization, gene of p47phox, a cytosolic subunit of NADPH oxidase, was deleted using Cas9 KO plasmid. In the absence of p47phox, sinus nodal cells were highly resistance to Ang II-induced apoptosis, suggesting that oxidized-CaMKII contributed to sinus nodal cell death. In Langendorff heart from Ang II infused mice, kaempferol preserved normal impulse formation at right atrium. These data suggested that kaempferol protects sinus node via inhibition of CaMKII oxidization and may be useful for preventing SND in high risk patients. [ABSTRACT FROM AUTHOR]

Inthis study, we present the steep switching characteristics of bendablefeedback field-effect transistors (FBFETs) consisting of p–i–n nanowires (NWs) and dual-top-gatestructures. As a result of a positive feedback loop in the intrinsicchannel region, our FBFET features the outstanding switching characteristicsof an on/off current ratio of approximately 106, and pointsubthreshold swings (SSs) of 18–19 mV/dec in the n-channeloperation mode and of 10–23 mV/dec in the p-channel operationmode. Not only can these devices operate in n- or p-channel modes,their switching characteristics can also be modulated by adjustingthe gate biases. Moreover, the device maintains its steep SS characteristics,even when the substrate is bent. This study demonstrates the promisingpotential of bendable NW FBFETs for use as low-power components inintegrated circuits or memory devices. [ABSTRACT FROM AUTHOR]

Tunnel field-effect transistors (TFETs) with a subthreshold swing (SS)<60 mV/dec are expected to be active devices in low-power flexible systems, potentially lowering operational voltage by virtue of steep switching behavior via band-to-band tunneling. In silicon (Si) channel materials, however, it still remains a challenge to obtain SS smaller than 60 mV/dec. In this study, we experimentally demonstrate the sub-60 mV/dec operation of a flexible semi-around gate TFET on a plastic substrate using Si nanowires (SiNWs) as the channel material. With the combined advantages of selectively thinned SiNW channels (width ~15 nm and height ~40 nm) and high-κ (Al2O3 ~7 nm) gate dielectric, in conjunction with an abrupt degenerate source junction, the device with a channel length of ~500 nm exhibits a minimal SS of ~42 mV/dec at room temperature. Moreover, mechanical bendability of the device indicates that it has stable and good fatigue properties, providing an important step towards the realization of steep-slope switches for low-power and energy-efficient flexible electronics. [ABSTRACT FROM AUTHOR]

In this study, we propose newly designed feedback field-effect transistors that utilize the positive feedback of charge carriers in single-gated silicon channels to achieve steep switching behaviors. The band diagram, I–V characteristics, subthreshold swing, and on/off current ratio are analyzed using a commercial device simulator. Our proposed feedback field-effect transistors exhibit subthreshold swings of less than 0.1 mV dec−1, an on/off current ratio of approximately 1011, and an on-current of approximately 10−4 A at room temperature, demonstrating that the switching characteristics are superior to those of other silicon-based devices. In addition, the device parameters that affect the device performance, hysteresis characteristics, and temperature-dependent device characteristics are discussed in detail. [ABSTRACT FROM AUTHOR]

Examines the application of palladium (Pd) spheres to the heterogeneous catalysts for Suzuki coupling reactions of aryl halides with arylboronic acids. Use of scanning electron microscope in determining the Pd spheres; Effects of mercaptopropylsilyl on the silica sphere surfaces; Catalytic activities of Pd spheres.

Aims Autophagy is essential to maintain tissue homeostasis, particularly in long-lived cells such as cardiomyocytes. Whereas many studies support the importance of autophagy in the mechanisms underlying obesity-related cardiac dysfunction, the role of autophagy in cardiac lipid metabolism remains unclear. In the heart, lipotoxicity is exacerbated by cardiac lipoprotein lipase (LPL), which mediates accumulation of fatty acids to the heart through intravascular triglyceride (TG) hydrolysis. Methods and results In both genetic and dietary models of obesity, we observed a substantial increase in cardiac LPL protein levels without any change in messenger ribonucleic acid (mRNA). This was accompanied by a dramatic down-regulation of autophagy in the heart, as revealed by reduced levels of unc-51 like kinase-1 (ULK1) protein. To further explore the relationship between cardiac LPL and autophagy, we generated cardiomyocyte-specific knockout mice for ulk1 (Myh6-cre/ulk1fl/fl), Lpl (Myh6-cre/Lplfl/fl), and mice with a combined deficiency (Myh6-cre/ulk1fl/fl Lplfl/fl). Similar to genetic and dietary models of obesity, Myh6-cre/ulk1fl/fl mice had a substantial increase in cardiac LPL levels. When these mice were fed a high-fat diet (HFD), they showed elevated cardiac TG levels and deterioration in heart function. However, with combined deletion of LPL and ULK1 in Myh6-cre/ulk1fl/fl Lplfl/fl mice, HFD feeding did not lead to alterations in levels of TG or diacylglycerol, or in cardiac function. To further elucidate the role of autophagy in cardiac lipid metabolism, we infused a peptide that enhanced autophagy (D-Tat-beclin1). This effectively lowered LPL levels at the coronary lumen by restoring autophagy in the genetic model of obesity. This decrease in cardiac luminal LPL was associated with a reduction in TG levels and recovery of cardiac function. Conclusion These results provide clear evidence of the critical role of modulating cardiac LPL activity through autophagy-mediated proteolytic clearance as a potential novel strategy to overcome obesity-related cardiomyopathy. [ABSTRACT FROM AUTHOR]