Programmed cell death in Caenorhabditis elegans requires activation of the caspase CED-3, which strictly depends on CED-4. CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. Despite recent advances, major questions remain unanswered. Importantly, how CED-4 recognizes CED-3 and how such binding facilitates CED-3 activation remain completely unknown. Here we demonstrate that the L2' loop of CED-3 directly binds CED-4 and plays a major role in the formation of an active CED-4-CED-3 holoenzyme. The crystal structure of the CED-4 apoptosome bound to the L2' loop fragment of CED-3, determined at 3.2 Å resolution, reveals specific interactions between a stretch of five hydrophobic amino acids from CED-3 and a shallow surface pocket within the hutch of the funnel-shaped CED-4 apoptosome. Structure-guided biochemical analysis confirms the functional importance of the observed CED-4-CED-3 interface. Structural analysis together with published evidence strongly suggest a working model in which two molecules of CED-3 zymogen, through specific recognition, are forced into the hutch of the CED-4 apoptosome, consequently undergoing dimerization and autocatalytic maturation. The mechanism of CED-3 activation represents a major revision of the prevailing model for initiator caspase activation.

To detect γ-Glutamyl Transpeptidase (GGT) activity in vitro and in vivo, a bioluminescence probe with high sensitivity and specificity was well designed and synthesized. This probe can be recognized by GGT and release strong bioluminescence with its further reaction with luciferase. The performance of this probe was demonstrated in vitro and in cells. Finally, we applied the probe for detection of GGT activity in xenograft model.

Post-operative acute kidney injury (AKI) is one of the most common and serious complications after major surgery and is significantly associated with increased risks of morbidity and mortality. This meta-analysis was conducted to evaluate the effects of perioperative dexmedetomidine (Dex) administration on the occurrence of AKI and the outcomes of recovery after non-cardiac surgery.

Human intake of selenium (Se) mainly occurs through the food chain, and is largely dependent on the bioavailability of soil Se. Sulfur (S) and phosphorus (P) also as essential nutrients for plants, their antagonistic with Se effects on Se bioavailability should be considered. We conducted pot experiments to investigate the interaction effect on the bioavailability of Se in the soil using a sequential extraction method and diffusive gradients in thin films (DGT). The results showed that the root and shoot Se of pak choi increased at most 340%-360% with S and P application, while the Se uptake by pak choi was slightly inhibited when S and P application was 100 mg kg-1. With high S and P application, pak choi Se had a high bioaccumulation factor (BAF) and low translocation factor (TF), and soil Soluble-Se (SOL-Se) increased 178%-299%, which due to the competitive adsorption of S, P with Se and changes in soil pH that lead to the transformation of soil Se fractions. In addition, the available Se concentration in soil measured by the DGT (CDGT-Se) increased by 866% with exogenous S and P application, and its source was HA-Se. However, CDGT-Se failed to show a good linear relationship with the Se content of pak choi. The application of DGT to assess the bioavailability of Se in soils where Se is present in the steady state needs to be further explored. We discuss the effect of S and P application on the bioavailability of soil Se and provide evidence for agricultural production and rational fertilizer use on Se-rich land.

Non-alcoholic fatty liver disease (NAFLD) is a potentially serious disease that affects 30 % of the global population and poses a significant risk to human health. However, to date, no safe, effective and appropriate treatment modalities are available. In recent years, ferroptosis has emerged as a significant mode of cell death and has been found to play a key regulatory role in the development of NAFLD. In this study, we found that arbutin (ARB), a natural antioxidant derived from Arctostaphylos uva-ursi (L.), inhibits the onset of ferroptosis and ameliorates high-fat diet-induced NAFLD in vivo and in vitro. Using reverse docking, we identified the demethylase fat mass and obesity-related protein (FTO) as a potential target of ARB. Subsequent mechanistic studies revealed that ARB plays a role in controlling methylation of the SLC7A11 gene through inhibition of FTO. In addition, we demonstrated that SLC7A11 could alleviate the development of NAFLD in vivo and in vitro. Our findings identify the FTO/SLC7A11 axis as a potential therapeutic target for the treatment of NAFLD. Specifically, we show that ARB alleviates NAFLD by acting on the FTO/SLC7A11 pathway to inhibit ferroptosis.

Studies have shown a correlation between obesity and mitochondrial calcium homeostasis, yet it is unclear whether and how Mcu regulates adipocyte lipid deposition. This study aims to provide new potential target for the treatment of obesity and related metabolic diseases, and to explore the function of Mcu in adipose tissue.

A super-enhancer (SE) is a huge cluster of multiple enhancers that control the key genes for cell identity and function. The rise of advanced chromatin immunoprecipitation sequencing (ChIP-seq) technology such as Cleavage Under Targets and Tagmentation (CUT&Tag) allows more SEs to be discovered. However, SE studies in Luchuan and Duroc pigs are very rare in animal husbandry.

Changes in activated areas of the brain during ankle active dorsiflexion and ankle active plantar flexion were observed in six healthy subjects using functional magnetic resonance imaging. Excited areas of ankle active dorsiflexion involved the bilateral primary motor area and the primary somatosensory area, as well as the bilateral supplementary sensory area, the primary visual area, the right second visual area, and the vermis of cerebellum. Excited areas of ankle active plantar flexion included the ipsilateral supplementary motor area, the limbic system, and the contralateral corpus striatum. Fine movements of the cerebral cortex control the function of the ankle dorsiflexion to a larger extent than ankle plate flexion, and the function of ankle plate flexion is more controlled by the subcortical area.

The adrenal glands consist of an outer cortex and an inner medulla, and their primary purposes include hormone synthesis and secretion. The adrenal cortex produces a complex array of steroid hormones, whereas the medulla is part of the sympathetic nervous system and produces the catecholamines epinephrine and norepinephrine. In the mouse, GATA binding protein (GATA) 4 and GATA6 transcription factors are coexpressed in several embryonic tissues, including the adrenal cortex. To explore the roles of GATA4 and GATA6 in mouse adrenal development, we conditionally deleted these genes in adrenocortical cells using the Sf1Cre strain of animals. We report here that mice with Sf1Cre-mediated double deletion of Gata4 and Gata6 genes lack identifiable adrenal glands, steroidogenic factor 1-positive cortical cells and steroidogenic gene expression in the adrenal location. The inactivation of the Gata6 gene alone (Sf1Cre;Gata6(flox/flox)) drastically reduced the adrenal size and corticosterone production in the adult animals. Adrenocortical aplasia is expected to result in the demise of the animal within 2 weeks after birth unless glucocorticoids are provided. In accordance, Sf1Cre;Gata4(flox/flox)Gata6(flox/flox) females depend on steroid supplementation to survive after weaning. Surprisingly, Sf1Cre;Gata4(flox/flox)Gata6(flox/flox) males appear to live normal lifespans as vital steroidogenic synthesis shifts to their testes. Our results reveal a requirement for GATA factors in adrenal development and provide a novel tool to characterize the transcriptional network controlling adrenocortical cell fates.

As a promising group of natural bioactive lipids, ether-phospholipids (ether-PLs), exhibit the ability to attenuate high-fat diet (HFD)-induced lipid accumulation and atherosclerosis. However, the underlying mechanism is unclear. Autophagy has been implicated in the regulation of obesity. Therefore, we investigated the effects of dietary ether-PLs on hepatic steatosis and the activation of hypothalamic autophagy. HFD-fed C57BL/6J mice were orally administered with ether-PLs (150 mg/kg body weight) including plasmenyl phosphatidylethanolamine (PE-P) and plasmanyl phosphatidylcholine (PC-O) for three days or eight weeks. Ether-PLs supplementation relieved diet-induced hepatic lipid accumulation and regulated the hypothalamic peroxisome proliferator-activated receptor gamma (PPARγ) and CD36. Notably, PE-P activated hypothalamic autophagy more strongly than PC-O, with an increased ratio of microtubule-associated protein light chain 3 II/I (LC3II/I) and reduced p62/sequestosome-1 (p62) accumulation by rescuing the HFD-impaired autophagy-lysosome fusion. The phosphorylation of ULK1 mediated by Akt-mTOR and AMPK, was involved in ether-PLs activated autophagy. Furthermore, the enhanced hypothalamic autophagy promoted the production of α-melanocyte-stimulating hormone (α-MSH), which has been reported to maintain energy balance. It is concluded that ether-PLs ameliorated HFD-induced hypothalamic autophagy and ameliorated hepatic steatosis. Ether-PLs could thus be an attractive autophagy-enhancers against chronic HFD-induced obesity.

As an autoimmune central nervous system disease characterized by inflammation and demyelination, neuromyelitis optica (NMO) has been extensively investigated. A specific antigenic target, astrocytic water channel aquaporin-4 (AQP4) has already been identified, and it can be recognized explicitly by the autoantibody marker NMO-IgG. Along with the immune attacks, clinical disabilities would gradually accumulate. As there has been no validated and well-recognized therapy for NMO till now, preventing and postponing attack using immunosuppressive therapies is the primary treatment option.

Ca2+-regulated photoproteins responsible for bioluminescence of a variety of marine organisms are single-chain globular proteins within the inner cavity of which the oxygenated coelenterazine, 2-hydroperoxycoelenterazine, is tightly bound. Alongside with native coelenterazine, photoproteins can also use its synthetic analogues as substrates to produce flash-type bioluminescence. However, information on the effect of modifications of various groups of coelenterazine and amino acid environment of the protein active site on the bioluminescent properties of the corresponding semi-synthetic photoproteins is fragmentary and often controversial. In this paper, we investigated the specific bioluminescence activity, light emission spectra, stopped-flow kinetics and sensitivity to calcium of the semi-synthetic aequorins and obelins activated by novel coelenterazine analogues and the recently reported coelenterazine derivatives. Several semi-synthetic photoproteins activated by the studied coelenterazine analogues displayed sufficient bioluminescence activities accompanied by various changes in the spectral and kinetic properties as well as in calcium sensitivity. The poor activity of certain semi-synthetic photoproteins might be attributed to instability of some coelenterazine analogues in solution and low efficiency of 2-hydroperoxy adduct formation. In most cases, semi-synthetic obelins and aequorins displayed different properties upon being activated by the same coelenterazine analogue. The results indicated that the OH-group at the C-6 phenyl ring of coelenterazine is important for the photoprotein bioluminescence and that the hydrogen-bond network around the substituent in position 6 of the imidazopyrazinone core could be the reason of different bioluminescence activities of aequorin and obelin with certain coelenterazine analogues.