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OBJECTIVE--We have previously shown that serum insulin levels decrease threefold and blood glucose levels remain normal in mice fed a leucine-deficient diet, suggesting increased insulin sensitivity. The goal of the current study is to investigate this possibility and elucidate the underlying cellular mechanisms. RESEARCH DESIGN AND METHODS--Changes in metabolic parameters and expression of genes and proteins involved in regulation of insulin sensitivity were analyzed in mice, human HepG2 cells, and mouse primary hepatocytes under leucine deprivation. RESULTS--We show that leucine deprivation improves hepatic insulin sensitivity by sequentially activating general control non-derepressible (GCN)2 and decreasing mammalian target of rapamycin/S6K1 signaling. In addition, we show that activation of AMP-activated protein kinase also contributes to leucine deprivation-increased hepatic insulin sensitivity. Finally, we show that leucine deprivation improves insulin sensitivity under insulin-resistant conditions. CONCLUSIONS--This study describes mechanisms underlying increased hepatic insulin sensitivity under leucine deprivation. Furthermore, we demonstrate a novel function for GCN2 in the regulation of insulin sensitivity. These observations provide a rationale for short-term dietary restriction of leucine for the treatment of insulin resistance and associated metabolic diseases. Diabetes 60:746-756, 2011, Insulin resistance is a common feature of many metabolic diseases, including type 2 diabetes and nonalcoholic fatty liver diseases. The hallmark of insulin resistance is reduced glucose uptake in muscle [...]

Dermal hyperpigmentation stands out among the various skin pigmentation phenotypes in chickens, where most other pigmentation variants affect feather color and patterning predominantly. Despite numerous black chicken breeds worldwide, only a select few exhibit comprehensive black pigmentation, which encompasses the skin, meat, flesh, and bones. The process of skin melanin pigmentation is intricate and develops successively. Historically, research has concentrated primarily on specific developmental points or stages, but fewer studies have examined the entire transcriptome across the timeline of the development of the embryo integument. In our investigation, we undertook the sequencing of chicken embryo skin samples from day 4 to day 13 of incubation. Our results showed that melanoblasts continued to migrate from E4 to the epidermis until E12. Beginning with E6, melanin was synthesized and transferred to epidermal cells and feather follicles in large quantities, and genes such as DCT, TYR, TYRP1,and MITFplayed a key role in this process, which is significantly different from that of white-skinned chickens. There were 854 differentially expressed genes between E7 and E8. At this stage, melanocytes formed dendritic forms and transferred melanin to keratinocytes, while the dorsal skin became visibly dark. In addition, CDH3, which is a core factor involved in a variety of biological processes, may have an important impact on skin melanin pigmentation. Collectively, our findings unveiled a phased relationship between the canonical pathway and the non-canonical pathway from E4 to E13. These analyses illuminated the gene regulatory mechanism and provided foundational data that pertained to pigmentation in chickens.

ABSTRACTHuman Atg4 homologs are cysteine proteases, which play key roles in the macroautophagy/autophagy process by cleaving Atg8 homologs for conjugation to lipid membranes and for deconjugation of Atg8 homologs from membranes. Expression of ATG4B is significantly increased in colorectal cancer cells compared to normal cells, suggesting that ATG4B may be important for cancer biology. Inhibition of ATG4B may reduce the autophagy activity, thereby sensitizing cancer cells to therapeutic agents. Thus, developing specific and potent ATG4B inhibitors for research as well as for potential therapeutic uses is highly needed. In this study, we integrated in silicoscreening and in vitroassays to discover a potent ATG4B inhibitor, named S130, from a noncommercial library. This chemical binds to ATG4B with strong affinity and specifically suppresses the activity of ATG4B but not other proteases. S130 did not cause the impairment of autophagosome fusion, nor did it result in the dysfunction of lysosomes. Instead, S130 might attenuate the delipidation of LC3-II on the autolysosomes to suppress the recycling of LC3-I, which normally occurs after LC3-II cleavage by ATG4B. Intriguingly, S130 induced cell death, which was accompanied with autophagy stress and could be further exacerbated by nutrient deprivation. Such cytotoxicity could be partially reversed by enhancing ATG4B activity. Finally, we found that S130 was distributed in tumor tissues in vivo and was also effective in arresting the growth of colorectal cancer cells. Thus, this study indicates that ATG4B is a potential anticancer target and S130 might be a novel small-molecule candidate for future cancer therapy.

With the rapid development of aerospace technology, super-large-scale space structures have become the preferred solution for major aerospace countries to carry out in-orbit missions. Therefore, a scalable self-attaching/assembling robotic cluster (S2A2RC) system which can realize the component-level in-orbit assembly task requirements of ultra-large-scale space truss structures is proposed in this paper. On this basis, a monitoring system with self-powered sensor based on the triboelectric nanogenerator (TENG) technology is proposed. The sensory system is used to monitor the crawling state of the robot, the grasping state of the manipulator, and the assembly state of the truss components during the in-orbit assembly process in real time. In conclusion, the S2A2RC system is proposed in this paper, with the noticeable advantages in terms of the multi-functionalities, the cost, the power consumption, the signal reliability, and the minimized data size. Meanwhile, the S2A2RC system shows great potential for many other large-scale spacecrafts.

Cyclosporin A (CsA) induces renal tubular epithelial cells apoptosis and necrosis following in vitroexposure. The mechanisms of CsA-induced apoptosis have been studied intensively, whereas the mechanisms of necrosis remain to be elucidated. Necroptosis has been described as programmed necrosis. This study investigated the ability of CsA to induce necroptosis in the rat tubular cell line NRK-52E. The NRK-52E cells were incubated with CsA for 24 hours with or without necrostatin-1 (Nec-1). The majority of the NRK-52E cells died of necrosis as indicated by LDH leakage, Hoechst 33342/PI staining, and flow cytometry analysis. Cell death was significantly reduced by Nec-1 pretreated before CsA exposure. CsA-induced apoptosis and necrosis were also compared in NRK-52E cells with or without knockdown of receptor interaction protein 3 (RIP3) expression using small interfering RNA. Moreover, the role of reactive oxygen species (ROS) in CsA-induced cell death was also attempted. The result suggests that necroptosis contributes to the CsA-induced cytotoxicity in NRK-52E cells. Meanwhile, RIP3 and ROS are involved in CsA-induced necroptosis. To our knowledge, this is the first report on necroptosis in CsA-induced renal tubular cell death pathways, which might offer a novel protective target for CsA nephrotoxicity.

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