Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects
. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a ...major role in its mechanism of action
; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation
. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase
, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase
, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aridity and heat are significant environmental stressors that affect sheep adaptation and adaptability, thus influencing immunity, growth, reproduction, production performance, and profitability. The ...aim of this study was to profile mRNA expression levels in the spleen of indigenous Kazakh sheep breed for comparative analysis with the exotic Suffolk breed. Spleen histomorphology was observed in indigenous Kazakh sheep and exotic Suffolk sheep raised in Xinjiang China. Transcriptome sequencing of spleen tissue from the two breeds were performed via Illumina high-throughput sequencing technology and validated by RT-qPCR. Blood cytokine and IgG levels differed between the two breeds and IgG and IL-1β were significantly higher in Kazakh sheep than in Suffolk sheep (p < 0.05), though spleen tissue morphology was the same. A total of 52.04 Gb clean reads were obtained and the clean reads were assembled into 67,271 unigenes using bioinformatics analysis. Profiling analysis of differential gene expression showed that 1158 differentially expressed genes were found when comparing Suffolk with Kazakh sheep, including 246 up-regulated genes and 912 down-regulated genes. Utilizing gene ontology annotation and pathway analysis, 21 immune- responsive genes were identified as spleen-specific genes associated with adaptive traits and were significantly enriched in hematopoietic cell lineage, natural killer cell-mediated cytotoxicity, complement and coagulation cascades, and in the intestinal immune network for IgA production. Four pathways and up-regulated genes associated with immune responses in indigenous sheep played indispensable and promoting roles in arid and hot environments. Overall, this study provides valuable transcriptome data on the immunological mechanisms related to adaptive traits in indigenous and exotic sheep and offers a foundation for research into adaptive evolution.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is ...unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.
Full text
Available for:
IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Increased lipogenesis has been linked to an increased cancer risk and poor prognosis; however, the underlying mechanisms remain obscure. Here we show that phosphatidic acid phosphatase (PAP) lipin-1, ...which generates diglyceride precursors necessary for the synthesis of glycerolipids, interacts with and is a direct substrate of the Src proto-oncogenic tyrosine kinase. Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. Alteration of the three tyrosine residues to phenylalanine (3YF-lipin-1) disables lipin-1 from mediating Src-enhanced glycerolipid synthesis, cell proliferation and xenograft growth. Re-expression of 3YF-lipin-1 in PyVT;Lpin1
mice fails to promote progression and metastasis of mammary tumours. Human breast tumours exhibit increased p-Tyr-lipin-1 levels compared to the adjacent tissues. Importantly, statistical analyses show that levels of p-Tyr-lipin-1 correlate with tumour sizes, lymph node metastasis, time to recurrence and survival of the patients. These results illustrate a direct lipogenesis-promoting role of the pro-oncogenic Src, providing a mechanistic link between obesity-associated mitogenic signaling and breast cancer malignancy.
AMPK and mTOR play principal roles in governing metabolic programs; however, mechanisms underlying the coordination of the two inversely regulated kinases remain unclear. In this study we found, most ...surprisingly, that the late endosomal/lysosomal protein complex v-ATPase-Ragulator, essential for activation of mTORC1, is also required for AMPK activation. We also uncovered that AMPK is a residential protein of late endosome/lysosome. Under glucose starvation, the v-ATPase-Ragulator complex is accessible to AXIN/LKB1 for AMPK activation. Concurrently, the guanine nucleotide exchange factor (GEF) activity of Ragulator toward RAG is inhibited by AXIN, causing dissociation from endosome and inactivation of mTORC1. We have thus revealed that the v-ATPase-Ragulator complex is also an initiating sensor for energy stress and meanwhile serves as an endosomal docking site for LKB1-mediated AMPK activation by forming the v-ATPase-Ragulator-AXIN/LKB1-AMPK complex, thereby providing a switch between catabolism and anabolism. Our current study also emphasizes a general role of late endosome/lysosome in controlling metabolic programs.
Display omitted
•Ragulator is essential for starvation-induced AMPK activation•LKB1-dependent activation of AMPK takes place on late endosome/lysosome•V-ATPase-Ragulator provides docking sites for AXIN/LKB1 endosomal translocation•V-ATPase-Ragulator is a switch between anabolism and catabolism
AMPK and mTOR regulate cellular balance between catabolism and anabolism. Zhang et al. show that the endosomal v-ATPase-Ragulator complex, required for mTORC1 activation when nutrients are abundant, is also essential in LKB1-mediated AMPK activation in response to energy stress, thus acting as a dual energy sensor.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In recent years, person re-identification (ReID) has received much attention since it is a fundamental task in intelligent surveillance systems and has widespread application prospects in numerous ...fields. Given an image of a pedestrian captured from one camera, the task is to identify this pedestrian from the gallery set captured by other multiple cameras. It is a challenging issue since the appearance of a pedestrian may suffer great changes across different cameras. The task has been greatly boosted by deep learning technology. There are mainly six types of deep learning-based methods designed for this issue, i.e. identification deep model, verification deep model, distance metric-based deep model, part-based deep model, video-based deep model and data augmentation-based deep model. In this paper, we first give a comprehensive review of current six types of deep learning methods. Second, we present the detailed descriptions of existing person ReID datasets. Then, some state-of-the-art performances of methods over recent years on several representative ReID datasets are summarized. Finally, we conclude this paper and discuss the future directions of the person ReID.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In the past, long-distance free-space quantum communication experiments could only be implemented at night. During the daytime, the bright background sunlight prohibits quantum communication in ...transmission under conditions of high channel loss over long distances. Here, by choosing a working wavelength of 1,550 nm and developing free-space single-mode fibre-coupling technology and ultralow-noise upconversion single-photon detectors, we have overcome the noise due to sunlight and demonstrate free-space quantum key distribution over 53 km during the day. The total channel loss is ∼48 dB, which is greater than the 40 dB channel loss between the satellite and ground and between low-Earth-orbit satellites. Our system thus demonstrates the feasibility of satellite-based quantum communication in daylight. Moreover, given that our working wavelength is located in the optical telecom band, our system is naturally compatible with ground fibre networks and thus represents an essential step towards a satellite-constellation-based global quantum network.
Full text
Available for:
IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UL, UM, UPUK
Background
Obesity may impact surgical outcomes of gastrectomy. Whether visceral fat area (VFA) is a better obesity parameter than body mass index (BMI) is still controversial. The aim of this study ...is to compare the accuracy and effectiveness of VFA and BMI in predicting the short-term surgical outcomes of gastrectomy.
Methods
Patients who were diagnosed with gastric cancer were measured for BMI and VFA preoperatively and then divided into a VFA-H (VFA-high) group and VFA-L (VFA-low) group, at the cutoff point of 100 cm
2
, and a BMI-H (BMI-high) group and BMI-L (BMI-low) group, at the cutoff point of 25 kg/m
2
. The short-term surgical outcomes were compared between the different groups.
Results
In total, 276 patients were enrolled in this study; 55 (19.9%) patients were classified into the BMI-H group, and 122 (44.2%) patients were classified into the VFA-H group. There was a significant correlation between BMI and VFA (
r
= 0.652,
p
< 0.001). Compared with the VFA-L group, the VFA-H group had a higher incidence of postoperative complications (31.1% vs. 13.0%;
p
< 0.001), longer operation duration (270.0 (235.0–305.0) vs. 255.0 (223.8–295.0),
p
= 0.046), and more blood loss (100.0 (100.0–150.0) vs. 80.0 (80.0–100.0),
p
< 0.001), while the BMI-H group had more blood loss than the BMI-L group (100.0 (100.0–120.0) vs. 100.0(80.0–100.0),
p
= 0.006). Logistic regression showed that VFA was an independent risk factor for postoperative complications (odds ratio 2.813, 95% CI 1.523–5.194;
p
= 0.001).
Conclusion
For gastric cancer patients, VFA is superior to BMI in accurately and effectively illuminating the impact of obesity on short-term surgical outcomes.
Trial Registration
Clinicaltrials.gov
: NCT02800005.
Full text
Available for:
EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aim
To objectively assess the safety, feasibility, advantages and disadvantages and health economics benefits of vaginal natural orifice transluminal endoscopic surgery (vNOTES) versus transumbilical ...laparoendoscopic single‐site surgery (TU‐LESS) in ovarian cystectomy.
Methods
We retrospectively analyzed the data of all patients in our hospital who had undergone vNOTES and TU‐LESS ovarian cystectomy due to ‘unilateral ovarian cyst’ from March 2019 to May 2020. Patients were classified into vNOTES group (86) and TU‐LESS group (210) based on surgical paths. The patients' general characteristics and perioperative outcomes were compared.
Results
All 296 patients completed surgery with no need to switch to conventional laparoscopy or laparotomy procedures. There were no complications of Grade III, IV, V in Clavien‐Dindo classification. There were two patients in the vNOTES group and four patients in the TU‐LESS group with complications of Grade I, all of whom were treated with antipyretic drugs for postoperative fever. One patient in the TU‐LESS group presented the complication of Grade II and was treated with blood transfusion due to postoperative anemia. The two groups had similar general characteristics. Perioperative outcomes: The visual analogue scale (VAS) scores 24 h postoperation were significantly lower in the vNOTES group than in the TU‐LESS group. The cosmetic scores were significantly higher in the vNOTES group than in the TU‐LESS group. Postoperative stay and time of flatus after surgery were significantly shorter in the vNOTES group than in the TU‐LESS group. There was not significant statistical differences between the two groups in operation time, estimated blood loss, Hb decrease at 48 h postoperation, maximum body temperature in 48 h after surgery and hospital costs.
Conclusion
It was proved to be safe and feasible in ovarian cystectomy by vNOTES. It worked better than TU‐LESS in relieving postoperative pain, shortening postoperative stay and improving cosmetic effects and so on. As an emerging surgical path, large sample multicenter randomized controlled trials are required to further verify its safety and advantages.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Plasmon-mediated photocatalytic water splitting has attracted extensive attention due to its bright future in using visible light, but the enhancement mechanism is still unclear, and the efficiency ...remains low. Herein, a dual-plasmonic-antenna strategy that allows efficient generation of energetic hot electrons and strong electromagnetic fields simultaneously has been developed to boost the photocatalytic hydrogen evolution reaction (HER). Au@CdS core–shell nanoparticles are assembled on Ag@SiO2 shell-isolated nanoparticles, forming dual-plasmonic-antenna nanocomposites. Transient absorption spectroscopic experiments and electromagnetic field simulations demonstrate that both hot-electron transfer and plasmon-induced resonance energy transfer exist in this system. The Au@CdS antenna can generate energetic hot electrons to trigger the HER, while the Ag@SiO2 antenna produces strong electromagnetic fields to promote the generation and separation of hot carriers, thus significantly improving the HER performance under visible light irradiation. Such a dual-plasmonic-antenna concept overcomes the intrinsic limitation of traditional plasmonic photocatalytic materials and offers unique opportunities to develop efficient photocatalysts.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
PDF
