HOXA9 gene inhibits proliferation and differentiation and promotes apoptosis of bovine preadipocytes.

BACKGROUND: Hox gene family is an important transcription factor that regulates cell process, and plays a role in the process of adipocytes differentiation and fat deposition. Previous transcriptome sequencing studies have indicated that the Homeobox A9 gene (HOXA9) is a candidate gene for regulating the process of bovine lipid metabolism, but the function and specific mechanism of action remain unclear. Therefore, this study aims to explore the role of HOXA9 in the proliferation, differentiation and apoptosis of bovine preadipocytes through gain-of-function and lose-of-function. RESULT: It found HOXA9 highly expressed in bovine adipose tissue, and its expression level changed significantly during adipocytes differentiation process. It gave a hint that HOXA9 may be involved in the process of bovine lipid metabolism. The results of HOXA9 gain-of-function experiments indicated that HOXA9 appeared to act as a negative regulator not only in the differentiation but also in the proliferation of bovine preadipocytes, which is mainly reflected that overexpression of HOXA9 down-regulate the mRNA and protein expression level of PPARγ, CEBPα and FABP4 (P < 0.05). The mRNA expression level of CDK1, CDK2, PCNA, CCNA2, CCNB1, CCND1 and CCNE2, as well as the protein expression of CDK2 also significantly decreased. The decrease of lipid droplets content was the main characteristic of the phenotype (P < 0.01), which further supported the evidence that HOXA9 was a negative regulator of preadipocytes differentiation. The decrease of cell proliferation rate and EdU positive rate, as well as the limitation of transition of preadipocytes from G0/G1 phase to S phase also provided evidence for the inhibition of proliferation. Apart from this above, we noted an interesting phenomenon that overexpression of HOXA9 showed in a significant upregulation of both mRNA and protein level of apoptosis markers, accompanied by a significant increase in cell apoptosis rate. These data led us not to refute the fact that HOXA9 played an active regulatory role in apoptosis. HOXA9 loss-of-function experiments, however, yielded the opposite results. Considering that HOXA9 acts as a transcription factor, we predicted its target genes. Dual luciferase reporter assay system indicated that overexpression of HOXA9 inhibits activity of PCNA promoter. CONCLUSION: Taken together, we demonstrated for the first time that HOXA9 played a role as a negative regulatory factor in the differentiation and proliferation of preadipocytes, but played a positive regulatory role in apoptosis, and it may play a regulatory role by targeting PCNA. This study provides basic data for further exploring the regulatory network of intramuscular fat deposition in bovine.

Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB.

Nuclear factor κB (NF-κB) plays roles in various diseases. Many inflammatory signals, such as circulating lipopolysaccharides (LPSs), activate NF-κB via specific receptors. Using whole-genome CRISPR-Cas9 screens of LPS-treated cells that express an NF-κB-driven suicide gene, we discovered that the LPS receptor Toll-like receptor 4 (TLR4) is specifically dependent on the oligosaccharyltransferase complex OST-A for N-glycosylation and cell-surface localization. The tool compound NGI-1 inhibits OST complexes in vivo, but the underlying molecular mechanism remained unknown. We did a CRISPR base-editor screen for NGI-1-resistant variants of STT3A, the catalytic subunit of OST-A. These variants, in conjunction with cryoelectron microscopy studies, revealed that NGI-1 binds the catalytic site of STT3A, where it traps a molecule of the donor substrate dolichyl-PP-GlcNAc2-Man9-Glc3, suggesting an uncompetitive inhibition mechanism. Our results provide a rationale for and an initial step toward the development of STT3A-specific inhibitors and illustrate the power of contemporaneous base-editor and structural studies to define drug mechanism of action.

Sulforaphane-Enriched Extracts from Broccoli Exhibit Antimicrobial Activity against Plant Pathogens, Promising a Natural Antimicrobial Agent for Crop Protection.

Sulforaphane (SFN) is one of the hydrolysates of glucosinolates (GSLs), primarily derived from Brassica vegetables like broccoli. In clinical therapy, SFN has been proven to display antimicrobial, anticancer, antioxidant, and anti-inflammatory properties. However, the antimicrobial effects and mechanism of SFN against plant pathogens need to be further elucidated, which limits its application in agriculture. In this study, the genetic factors involved in SFN biosynthesis in 33 B. oleracea varieties were explored. The finding showed that besides the genetic background of different B. oleracea varieties, myrosinase and ESP genes play important roles in affecting SFN content. Subsequently, the molecular identification cards of these 33 B. oleracea varieties were constructed to rapidly assess their SFN biosynthetic ability. Furthermore, an optimized protocol for SFN extraction using low-cost broccoli curds was established, yielding SFN-enriched extracts (SFN-ee) containing up to 628.44 µg/g DW of SFN. The antimicrobial activity assay confirmed that SFN-ee obtained here remarkably inhibit the proliferation of nine tested microorganisms including four plant pathogens by destroying their membrane integrity. Additionally, the data demonstrated that exogenous application of SFN-ee could also induce ROS accumulation in broccoli leaves. These results indicated that SFN-ee should play a dual role in defense against plant pathogens by directly killing pathogenic cells and activating the ROS signaling pathway. These findings provide new evidence for the antimicrobial effect and mechanism of SFN against plant pathogens, and suggest that SFN-ee can be used as a natural plant antimicrobial agent for crop protection and food preservation.

Integrated transcriptome and DNA methylome analysis reveal the biological base of increased resistance to gray leaf spot and growth inhibition in interspecific grafted tomato scions.

BACKGROUND: Grafting is widely used as an important agronomic approach to deal with environmental stresses. However, the molecular mechanism of grafted tomato scions in response to biotic stress and growth regulation has yet to be fully understood. RESULTS: This study investigated the resistance and growth performance of tomato scions grafted onto various rootstocks. A scion from a gray leaf spot-susceptible tomato cultivar was grafted onto tomato, eggplant, and pepper rootstocks, creating three grafting combinations: one self-grafting of tomato/tomato (TT), and two interspecific graftings, namely tomato/eggplant (TE) and tomato/pepper (TP). The study utilized transcriptome and DNA methylome analyses to explore the regulatory mechanisms behind the resistance and growth traits in the interspecific graftings. Results indicated that interspecific grafting significantly enhanced resistance to gray leaf spot and improved fruit quality, though fruit yield was decreased compared to self-grafting. Transcriptome analysis demonstrated that, compared to self-grafting, interspecific graftings triggered stronger wounding response and endogenous immune pathways, while restricting genes related to cell cycle pathways, especially in the TP grafting. Methylome data revealed that the TP grafting had more hypermethylated regions at CHG (H = A, C, or T) and CHH sites than the TT grafting. Furthermore, the TP grafting exhibited increased methylation levels in cell cycle related genes, such as DNA primase and ligase, while several genes related to defense kinases showed decreased methylation levels. Notably, several kinase transcripts were also confirmed among the rootstock-specific mobile transcripts. CONCLUSIONS: The study concludes that interspecific grafting alters gene methylation patterns, thereby activating defense responses and inhibiting the cell cycle in tomato scions. This mechanism is crucial in enhancing resistance to gray leaf spot and reducing growth in grafted tomato scions. These findings offer new insights into the genetic and epigenetic contributions to agronomic trait improvements through interspecific grafting.

5'-Cytimidine Monophosphate Ameliorates H2O2-Induced Muscular Atrophy in C2C12 Myotubes by Activating IRS-1/Akt/S6K Pathway.

Age-related muscle atrophy (sarcopenia), characterized by reduced skeletal muscle mass and muscle strength, is becoming increasingly prevalent worldwide, which is especially true for older people, and can seriously damage health and quality of life in older adults. This study aims to investigate the beneficial effects of 5'-cytimidine monophosphate (CMP) on H2O2-induced muscular atrophy in C2C12 myotubes. C2C12 myotubes were treated with H2O2 in the presence and absence of CMP and the changes in the anti-oxidation, mitochondrial functions, and expression of sarcopenia-related proteins were observed. Immunofluorescence analysis showed that CMP significantly increased the diameter of myotubes. We found that CMP could increase the activity of antioxidant enzymes and improve mitochondrial dysfunction, as well as reduce inflammatory cytokine levels associated with sarcopenia. RNA-seq analysis showed that CMP could relieve insulin resistance and promote protein digestion and absorption. Western blot analysis further confirmed that CMP could promote the activation of the IRS-1/Akt/S6K signaling pathway and decrease the expression of MuRF1 and Atrogin-1, which are important markers of muscle atrophy. The above results suggest that CMP protects myotubes from H2O2-induced atrophy and that its potential mechanism is associated with activating the IRS-1/Akt/S6K pathway to promote protein synthesis by improving mitochondrial dysfunction and insulin resistance. These results indicate that CMP can improve aging-related sarcopenia.

The impact of transferred air bubble position on clinical pregnancy rate in FET cycles.

We aim to investigate the correlation of the position of the transferred air bubble with the clinical pregnancy rate (PR) in frozen-thawed embryo transfer(FET) cycles. A prospective clinical study was carried out at Reproductive medicine center of West China Second University Hospital between June 2020 and May 2021. 1159 women underwent FET were included in this study. Transabdominal ultrasonographic guidance was used during the transfer procedure. The distance from the air bubble to endometrial cavity fundus（DAF）was measured in the freeze-frame ultrasound immediately after ET. In group DAF ≤3mm, 3-15mm and ≥15mm, the clinical PR in women transferred with cleavage embryos were 33.3% (7/21), 55.0% (153/280), and 31.3% (5/16), respectively, the difference was statistically significant (P＜0.05). Among women transferred with blastocysts, the clinical PR was 63.0% (34/54), 68.5% (485/708) and 55.0% (44/80), respectively, the difference was statistically significant (P＜0.05). In multivariate logistic regression model for clinical PR, the clinical PR was associated with age, embryo quality, number of embryo transferred, and endometrial thickness. DAF was an independent risk factor influencing clinical PR in blastocysts FET cycles rather than in cleavage embryos FET cycles.In conclusion, our results suggested that DAF was associated with the clinical PR and DAF between 3mm and 15mm is the optimal position in blastocysts FET cycles.

Efficacy and safety profiles of dolutegravir plus lamivudine vs . bictegravir/emtricitabine/tenofovir alafenamide in therapy-naïve adults with HIV-1.

BACKGROUND: Dual regimen dolutegravir (DTG) plus lamivudine (3TC) has demonstrated non-inferior efficacy compared to DTG-based three-drug regimens (3DRs), yet directly comparative data regarding the efficacy and safety of DTG + 3TC and bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) for therapy-naïve people with human immunodeficiency virus (HIV)-1 (PWH) are still limited. We aimed to assess the antiviral potency and safety profiles of DTG + 3TC vs. B/F/TAF based on antiretroviral therapy (ART)-naïve PWH in China. METHODS: This retrospective multicenter study enrolled PWH initiating ART with DTG + 3TC or B/F/TAF from 2020 to 2022 in Guangdong and Guangxi. We analyzed response rates based on target not detected (TND) status using intention-to-treat (ITT) analysis. Subgroups were formed based on baseline viral load (VL) (<100,000 vs . ≥100,000 copies/mL) and CD4 + cell count (<200 vs . ≥200 cell/µL). Median time to TND VL was assessed by Kaplan-Meier method. We also measured changes from baseline in CD4 + cell counts, CD4/CD8 ratio, lipid parameters, weight, creatinine (Cr), estimated glomerular filtration rate (eGFR), and drug-related adverse effects (DRAEs). RESULTS: We enrolled 280 participants, including 137 (48.9%) on DTG + 3TC and 143 (51.1%) on B/F/TAF. At week 48, 96.4% (132/137) on DTG+3TC and 100% (143/143) on B/F/TAF achieved TND ( P = 0.064). At week 12, TND responses were higher with B/F/TAF (78.3% [112/143]) than DTG+3TC (30.7% [42/137]) ( P <0.001). This trend held across subgroups. B/F/TAF achieved TND faster (12 weeks) than DTG+3TC (24 weeks) ( P <0.001). No differences were seen in CD4 + cell count and CD4/CD8 ratio, except in the high-VL subgroup, where B/F/TAF showed better recovery. DRAEs were significantly lower with B/F/TAF (4.9% [7/143]) than with DTG + 3TC (13.1% [18/137]) ( P = 0.016). Lipid parameters, body weight, and Cr increased in both groups over 48 weeks, with DTG+3TC showing a more favorable effect on triglycerides, high-density lipoprotein (HDL) cholesterol, and weight gain. CONCLUSIONS: In this real-life study, B/F/TAF led to a faster viral decline and fewer DRAEs compared to DTG+3TC. No significant difference was observed in the TND rate at week 48, regardless of baseline VL and CD4 + cell count. CD4 + recovery was superior for B/F/TAF in participants with high VL. The DTG + 3TC regimen had less impact on metabolic changes than B/F/TAF.

Phenylalanine-Arginine-ß-Naphthylamide Enhances the Photobactericidal Effect of Methylene Blue on Pseudomonas aeruginosa.

Objective: To investigate the effectiveness, dosing sequence, concentration, and mechanism of antimicrobial photodynamic inactivation (aPDI) using methylene blue (MB) plus phenylalanine-arginine-ß-naphthylamide (PAßN) against Pseudomonas aeruginosa. Methods: P. aeruginosa bacterial suspension was incubated with MB for different times (5-240 min), and then, 10 J/cm2 red light was irradiated. The efflux pump inhibitor (EPI) PAßN (10-100 µg/mL) was combined with MB (1-20 µM) in different sequences (PAßN-first, PAßN+MB, PAßN-after). Colony-forming units were then determined by serial dilution. Results: Using MB 10 µM plus 10 J/cm2, the killing effect of MB-aPDI on P. aeruginosa increased first and then decreased with longer incubation time. The killing effect of MB+PAßN-aPDI on P. aeruginosa was better than that of MB-aPDI (p < 0.05) by up to 2 logs. PAßN-first had the best killing effect, whereas PAßN-after had the worst killing effect. The killing effect increased with PAßN concentration and at 100 µg/mL reached 5.1 logs. Conclusions: The EPI PAßN enhanced the bactericidal effect of MB-aPDI on P. aeruginosa, especially when added before MB. It is proposed that MB is a substrate of the resistance-nodulation-division family efflux pump.

A Rotating Triboelectric Nanogenerator Driven by Bidirectional Swing for Water Wave Energy Harvesting.

Due to the simple installation and convenient maintenance, the floating water wave energy harvesting devices have significant economic advantages. Mass power density is the most important index to evaluate the advancement of floating wave energy harvesting devices. Herein, a self-adaptive rotating triboelectric nanogenerator (SR-TENG) with a compound pendulum and a functional gear-set is provided for wave energy harvesting. First, a compound pendulum structure with a low center of gravity and high moment of inertia is obtained by the geometric design and mechanical study. Besides, compared with the previous triboelectric nanogenerator with one-way clutch, SR-TENG can harvest twice the kinetic energy utilization through the functional gear-set. Importantly, depending on the structure design, the SR-TENG obtains the average mass power density of 45.18 mW kg-1 under low frequency driving conditions, which is about 10 times the reference electromagnetic generator with a similar structure and size. This result shows that the SR-TENG has a significant advantage in small water wave energy harvesting. These findings provide an important example of the floating water wave energy harvesting devices.

Predictor of cognitive impairment: metabolic syndrome or circadian syndrome.

BACKGROUND: It was reported that metabolic syndrome increases the risk for cognitive impairment and circadian rhythm may influence cognition behavior. Identifying the potential risk factors is essential to screen individuals with neuronal dysfunction, neuronal loss, and cognitive decline and prevent cognitive impairment and dementia development. METHODS: We clarified participants by the presence of metabolic syndrome (MetS) and circadian syndrome (CircS) and employed three multivariable Generalized Estimating Equation (GEE) models to control the potential confounding factors and estimate the ß values for cognitive function using as referents those had neither MetS nor CircS at baseline. The cognitive function consists of episodic memory and executive function was estimated via the modified Telephone Interview for Cognitive Status (TICS) every two years until 2015. RESULTS: The mean age of the participants was 58.80 (8.93) years and 49.92% (male). The prevalence of MetS and CircS was 42.98% and 36.43%, respectively. 1,075 (11.00%) and 435 (4.45%) participants had either MetS or CircS alone and 3,124 (31.98%) had both CircS and MetS. Participants with both MetS and CircS compared with normal had a significantly decreased cognitive function score during the 4-years cohort (ß = -0.32, 95% CI: -0.63, -0.01) with the complete model, as well as among participants who suffered from CircS alone (ß = -0.82, 95% CI: -1.47, -0.16), while not among participants with MetS alone (ß = 0.13, 95% CI: -0.27, 0.53). Specifically, compared with the normal population a significantly lower score was discovered in the episodic memory (ß = -0.51, 95% CI: -0.95, -0.07), while slightly lower in executive function (ß = -0.33, 95% CI: -0.68, -0.01) among individuals with CircS alone. CONCLUSIONS: Individuals with CircS alone or both MetS and CircS have a high risk of cognitive impairment. The association was even stronger in participants with CircS alone than those with both MetS and CircS, suggesting CircS probably have a stronger association with cognitive functioning than MetS and could be a better predictor for cognitive impairment.

Construction of rigid amine-linked three-dimensional covalent organic frameworks for selectively capturing carbon dioxide.

A highly rigid amine-linked 3D COF was constructed from two orthogonal building blocks (spirobifluorene and bicarbazole) through a post-synthetic chemical reduction. The rigid 3D framework decreased the conformational flexibility of the amine linkages, and thus showed a fully preserved crystallinity and porosity. The amine moieties in the 3D COF afforded abundant chemisorptive sites for selectively capturing CO2.

Safe Rice Production in Cd-Contaminated Paddy Soil: Strategy and Environmental Implications.

This field study explored safe rice production in Cd-contaminated red paddy soil by application of the combined Si-/Se- containing foliar inhibitors (Si or Se) and the mixture amendments of quicklime (Q), polyacrylamide (A), or/and sepiolite (S) at low (1) and high (2) application rates. The results showed that all treatments increased soil pH and decreased total P and soil organic matter (excluding QSe2). With the increasing application rates, QAS significantly decreased the available Cd because of the enhanced stabilization, while QSi and QSe significantly increased the available Cd because of the inhibited plant uptake. After remediation, QA1, QSi2, and QSe2 most effectively decreased the uptake Cd by rice to meet the threshold of National Food Safety Standard of China. The treatments excluding Q1, QA1, QSi1, and QSi2 did not dramatically change the bacterial community structure in soil. Collectively, QSe2 was recommended for remediating Cd-contaminated red paddy soil.

Anti-Hyperuricemic Effect of Anserine Based on the Gut-Kidney Axis: Integrated Analysis of Metagenomics and Metabolomics.

Nowadays, developing effective intervention substances for hyperuricemia has become a public health issue. Herein, the therapeutic ability of anserine, a bioactive peptide, was validated through a comprehensive multiomics analysis of a rat model of hyperuricemia. Anserine was observed to improve liver and kidney function and modulate urate-related transporter expressions in the kidneys. Urine metabolomics showed that 15 and 9 metabolites were significantly increased and decreased, respectively, in hyperuricemic rats after the anserine intervention. Key metabolites such as fructose, xylose, methionine, erythronic acid, glucaric acid, pipecolic acid and trans-ferulic acid were associated with ameliorating kidney injury. Additionally, anserine regularly changed the gut microbiota, thereby ameliorating purine metabolism abnormalities and alleviating inflammatory responses. The integrated multiomics analysis indicated that Saccharomyces, Parasutterella excrementihominis and Emergencia timonensis were strongly associated with key differential metabolites. Therefore, we propose that anserine improved hyperuricemia via the gut-kidney axis, highlighting its potential in preventing and treating hyperuricemia.

Daphnetin contributes to allergen-induced Th2 cytokine expression and type 2-immune responses in atopic dermatitis and asthma.

Daphne koreana Nakai is a cherished medicinal plant in the Changbai Mountain region of China. It can be incorporated into medicinal meals and used for various skin diseases by infiltrating liquor. Daphnetin (7,8-dihydroxycoumarin, Dap.) is a main constituent of D. koreana Nakai, which has been used to treat inflammatory conditions and immune disorders due to its numerous pharmacological activities, including anti-oxidant, anti-inflammatory, analgesic, etc. Atopic dermatitis (AD) and allergic asthma are typical diseases of type 2-immune responses. In the present study, the therapeutic potential of Dap. against AD and allergic asthma was investigated using animal and cell experiments. AD-like lesions were induced by repeated application of 1-chloro-2,4-dinitrobenzene (DNCB) to the shaved dorsal skin of BALB/c mice. Ovalbumin (OVA) induction was utilized to establish a mouse asthma model. A passive cutaneous anaphylaxis (PCA) mouse ear model and immunoglobulin E (IgE)/bovine serum albumin (BSA)-stimulated RBL-2H3 cells were used for in vitro assays. The skin lesions and serum and tissue homogenates of the mice were analyzed using histological analysis, immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA), respectively, in order to investigate the anti-AD effects of Dap. Histological analysis was performed on the allergic asthma model to observe inflammatory cell infiltration in the lung tissues. Total IgE and OVA-specific IgE in the serum were measured by ELISA. The levels of inflammatory cytokines in BALF were detected by ELISA. In addition, ELISA and western blotting were performed for the in vitro analysis of RBL-2H3 cells. The results showed that Dap. inhibited the development of DNCB-induced AD-like lesions in the BALB/c mice by reducing the severity of the lesions, epidermal thickness and mast cell infiltration; this was accompanied by reduced levels of IgE and inflammatory cytokines [interleukin (IL)-4, IL-5, IL-9, IL-13, IL-33 and thymic stromal lymphopoietin (TSLP)]. In the allergic asthma model, Dap. reduced the number of infiltrated inflammatory cells in the lung tissues. Moreover, the levels of total serum IgE and OVA-specific IgE were reduced in the high daphnetin dose groups (Dap., -100 mg kg-1). Dap. administered at a dose of -100 mg kg-1 decreased the levels of inflammatory cytokines (IL-4, IL-5, IL-9, IL-13, IL-33 and TSLP in BALF). Furthermore, Dap. administered to IgE-sensitized mice effectively attenuated the IgE-triggered PCA reaction. In vitro, Dap. decreased the expression levels of histamine, IL-4, IL-6, IL-13, MIP-1α and INF-α, and reduced the protein expression levels of phosphorylated MAPKs, P-Lyn and P-syk in the RBL-2H3 cells. Therefore, Dap. can be represented as a potential therapeutic strategy for the treatment of allergic inflammatory conditions via immunoregulation.

Application of Physiologically Based Pharmacokinetic Modeling to Predict Maternal Pharmacokinetics and Fetal Exposure to Oxcarbazepine.

Pregnancy is associated with physiological changes that may affect drug pharmacokinetics (PKs). The aim of this study was to establish a maternal-fetal physiologically based pharmacokinetic (PBPK) model of oxcarbazepine (OXC) and its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (MHD), to (1) assess differences in pregnancy, (2) predict changes in PK target parameters of these molecules following the current dosing regimen, (3) assess predicted concentrations of these molecules in the umbilical vein at delivery, and (4) compare different methods for estimating drug placental penetration. Predictions using the pregnancy PBPK model of OXC resulted in maternal concentrations within a 2-fold error, and extrapolation of the model to early-stage pregnancies indicated that changes in median PK parameters remained above target thresholds, requiring increased frequency of monitoring. The dosing simulation results suggested dose adjustment in the last two trimesters. We generally recommend that women administer ≥ 1.5× their baseline dose of OXC during their second and third trimesters. Test methods for predicting placental transfer showed varying performance, with the in vitro method showing the highest predictive accuracy. Exposure to MHD in maternal and fetal venous blood was similar. Overall, the above-mentioned models can enhance understanding of the maternal-fetal PK behavior of drugs, ultimately informing drug-treatment decisions for pregnant women and their fetuses.

LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progression.

Lysyl-oxidase like-2 (LOXL2) regulates extracellular matrix remodeling and promotes tumor invasion and metastasis. Altered metabolism is a core hallmark of cancer, however, it remains unclear whether and how LOXL2 contributes to tumor metabolism. Here, we found that LOXL2 and its catalytically inactive L2Δ13 splice variant boost glucose metabolism of esophageal tumor cells, facilitate tumor cell proliferation and promote tumor development in vivo. Consistently, integrated transcriptomic and metabolomic analysis of a knock-in mouse model expressing L2Δ13 gene revealed that LOXL2/L2Δ13 overexpression perturbs glucose and lipid metabolism. Mechanistically, we identified aldolase A, glyceraldehyde-3-phosphate dehydrogenase and enolase as glycolytic proteins that interact physically with LOXL2 and L2Δ13. In the case of aldolase A, LOXL2/L2Δ13 stimulated its mobilization from the actin cytoskeleton to enhance aldolase activity during malignant transformation. Using stable isotope labeling of amino acids in cell culture (SILAC) followed by proteomic analysis, we identified LOXL2 and L2Δ13 as novel deacetylases that trigger metabolic reprogramming. Both LOXL2 and L2Δ13 directly catalyzed the deacetylation of aldolase A at K13, resulting in enhanced glycolysis which subsequently reprogramed tumor metabolism and promoted tumor progression. High level expression of LOXL2/L2Δ13 combined with decreased acetylation of aldolase-K13 predicted poor clinical outcome in patients with esophageal cancer. In summary, we have characterized a novel molecular mechanism that mediates the pro-tumorigenic activity of LOXL2 independently of its classical amine oxidase activity. These findings may enable the future development of therapeutic agents targeting the metabolic machinery via LOXL2 or L2Δ13. HIGHLIGHT OF THE STUDY: LOXL2 and its catalytically inactive isoform L2Δ13 function as new deacetylases to promote metabolic reprogramming and tumor progression in esophageal cancer by directly activating glycolytic enzymes such as aldolase A.

Association of handgrip strength with all-cause mortality: a nationally longitudinal cohort study in China.

OBJECTIVES: Handgrip strength is considered a vital and reliable measure of comprehensive physical assessments, whereas the association of handgrip strength with overall mortality risk among Chinese adults was less studied. We prospectively investigated the association between handgrip strength and all-cause mortality among Chinese middle-aged and older people based on data from the China Health and Retirement Longitudinal Study (CHARLS).3 DESIGN: Longitudinal cohort study. METHODS: Grip strength was assessed for both hands by a dynamometer. Odds ratios (ORs)4 and 95 % confidence intervals (CIs)5 were estimated applying logistic regression models with adjustments for age, body mass index, ethnicity, education level, annual household income, marital status, drinking, smoking, physical activity, and medical insurance among men and women. Deaths were ascertained by each follow-up survey in which the household member who lived with the participants were inquired. RESULTS: Over an average follow-up period of approximately 8 years among the screened 11,618 participants ≥45 years old, 1290 deaths were documented. The age range was 45-93 for men and 45-96 for women. Greater handgrip strength was associated with a lower overall mortality risk, with adjusted ORs (comparing with extreme tertiles) of 0.47 (95 % CI: 0.35-0.64; P-trend<0.001) in men and 0.51 (95 % CI: 0.24-1.08; P-trend = 0.059) in women. Such inverse association seemed stronger among younger men (OR = 0.29, 95 % CI: 0.18-0.45), compared with the older men (OR = 0.49, 95 % CI: 0.33-0.73; P-interaction = 0.023). CONCLUSIONS: Handgrip strength was inversely associated with all-cause mortality risk, especially among the younger men. Further investigations are warranted to elucidate the underlying mechanism.

Self-Powered Seawater Electrolysis Based on a Triboelectric Nanogenerator for Hydrogen Production.

Water splitting for yielding high-purity hydrogen represents the ultimate choice to reduce carbon dioxide emission owing to the superior energy density and zero-pollution emission after combustion. However, the high electricity consumption and requirement of large quantities of pure water impede its large-scale application. Here, a triboelectric nanogenerator (W-TENG) converting offshore wind energy into electricity is proposed for commercial electric energy saving and cost reduction. By introducing PTFE/POM dielectric pairs with matched HOMO/LUMO band gap energy, a high charge density is achieved to promote the output of W-TENG. With the impedance matching design of transformers with the internal resistance of W-TENG, the output current is further enhanced from 1.42 mA to 54.5 mA with a conversion efficiency of more than 92.0%. Furthermore, benefiting from the high electrocatalytic activity (overpotential = 166 mV and Tafel slope = 181.2 mV dec-1) of a carbon paper supported NiCoP-MOF catalyst, natural seawater can be adopted as a resource for in situ hydrogen production without acid or alkaline additives. Therefore, the self-powered seawater electrolysis system achieves a H2 production rate as high as 1273.9 µL min-1 m-2 with a conversion efficiency of 78.9%, demonstrating a more practical strategy for conversion of wind energy into renewable hydrogen energy.

L2Δ13, a splicing isoform of lysyl oxidase-like 2, causes adipose tissue loss via the gut microbiota and lipid metabolism.

Obesity is primarily characterized by the dysregulation of lipid metabolism and gut microbiota. Here, we found that the body weight of transgenic mice overexpressing L2Δ13, a selectively spliced isoform of lysyl oxidase-like 2 (LOXL2), was lower than that of wild-type (WT) mice. Numerous microbiotas were significantly changed and most microbial metabolites were abnormal in L2Δ13 mice. Lipid metabolites in feces were negatively correlated with those in plasma, suggesting that L2Δ13 may affect lipid uptake, and potentially, adipose tissue homeostasis. This was supported by the weight loss and decreased area of adipose tissue in L2Δ13 mice. Adipogenic differentiation of primary stromal vascular fraction cells showed that the lipid droplets of L2Δ13 cells were significantly smaller than those of WT cells. Adipocyte differentiation-associated genes were also downregulated in adipose tissue from L2Δ13 mice. Thus, L2Δ13 can induce adipose tissue loss in mice by affecting gut microbiota homeostasis and multi-tissue lipid metabolism.

Preparation of a Large Amount of Ultrathin Graphdiyne.

We report a facile strategy to prepare a large amount of ultrathin graphdiyne (GDY) with good crystallinity in the mixture of oil-water systems. By simply mixing the solution of GDY monomer in CHCl3 and the copper acetate solution as a catalyst in water and stirring at room temperature, ultrathin GDY films with a thickness of ∼4 nm were obtained in a yield of 95 %. This work provides a feasible path for the substantial preparation of GDY films and may pave the way to the development of substantial preparation of the GDY materials.