Genetically inspired organoids prevent joint degeneration and alleviate chondrocyte senescence via Col11a1–HIF1α‐mediated glycolysis–OXPHOS metabolism shift

Abstract Introduction Developmental dysplasia of hip (DDH) is a hip joint disorder leading to subsequent osteoarthritis. Previous studies suggested collagen XI alpha 1 (COL11A1) as a potential gene in hip dysplasia and chondrocyte degeneration. However, no genetic association has reported COL11A1‐related cellular therapy as treatment of DDH and joint degeneration. Methods and Results We report identified genetic association between COL11A1 locus and DDH with genome‐wide association study (GWAS). Further exome sequencing for familial DDH patients was conducted in different populations to identify potential pathogenic Col11A1 variants for familiar DDH. Further studies demonstrated involvement of COL11A1 expression was down‐regulated in femoral head cartilage of DDH patients and Col11a1‐KO mice with induced DDH. Col11a1‐KO mice demonstrated aggravated joint degeneration and severe OA phenotype. To explore the underlying mechanism of Col11a1 in cartilage and DDH development, we generated scRNA‐seq profiles for DDH and Col11a1‐KO cartilage, demonstrating disrupted chondrocyte homeostasis and cellular senescence caused by Col11a1–HIF1α‐mediated glycolysis–OXPHOS shift in chondrocytes. Genetically and biologically inspired, we further fabricated an intra‐articular injection therapy to preventing cartilage degeneration by generating a Col11a1‐over‐expressed (OE) SMSC mini‐organoids. Col11a1‐OE organoids demonstrated superior chondrogenesis and ameliorated cartilage degeneration in DDH mice via regulating cellular senescence by up‐regulated Col11a1/HIF1α‐mediated glycolysis in chondrocytes. Conclusion We reported association between COL11A1 loci and DDH with GWAS and exome sequencing. Further studies demonstrated involvement of COL11A1 in DDH patients and Col11a1‐KO mice. ScRNA‐seq for DDH and Col11a1‐KO cartilage demonstrated disrupted chondrocyte homeostasis and cellular senescence caused by Col11a1–HIF1α‐mediated glycolysis–OXPHOS shift in chondrocytes. Genetically and biologically inspired, an intra‐articular injection therapy was fabricated to prevent cartilage degeneration with Col11a1‐OE SMSC organoids. Col11a1‐OE organoids ameliorated cartilage degeneration in DDH mice via regulating cellular senescence by up‐regulated Col11a1/HIF1α‐mediated glycolysis in chondrocytes

DNA methylation and transcriptome comparative analysis for Lvliang Black goats in distinct feeding pattern reveals epigenetic basis for environment adaptation

Different feeding patterns exhibit completely different and heritable growth properties in livestock, but the underlying epigenetic mechanisms remain unclear. Here, we investigated genome-wide DNA-methylation and gene expression under grazing and confinement regimen feeding strategies with Lvliang Black goat. We identified 102 differently expressed genes and 7,833 differentially methylated regions (DMRs) between the two groups. Integrating DNA-methylation and gene expression showed that genes in DMRs exhibit significantly different expression level (FDR < 0.05). KEGG pathway analysis indicated that most of the genes involved in environment adaptation pathways like lipid transpor and metabolism immunity. In sum, our data provided insight into the epigenetic mechanism underlying growth property difference resulting from distinct feeding patterns in goat, and also offered theoretical basis for the rational utilization of germplasm resources of local breeds. Supplemental data for this article is available online at https://doi.org/10.1080/13102818.2021.1914164

Construction of highly enantioenriched spirocyclopentaneoxindoles containing four consecutive stereocenters via thiourea-catalyzed asymmetric Michael–Henry cascade reactions

The thiourea-catalyzed asymmetric synthesis of highly enantioenriched spirocyclopentaneoxindoles containing chiral amide functional groups using simple 3-substituted oxindoles and nitrovinylacetamide as starting materials was achieved successfully. This protocol features operational simplicity, high atom economy, and high catalytic asymmetry, thus representing a versatile approach to the synthesis of highly enantioenriched spirocyclopentaneoxindoles

Paroxetine in the treatment of premature ejaculation: a systematic review and meta-analysis

Abstract Background Paroxetine is one of the selective serotonin reuptake inhibitors (SSRIs) used in the treatment of premature ejaculation (PE). However, this use is not approved in many countries. The purpose of this systematic review and meta-analysis is to review the efficacy and safety of paroxetine for PE patients. Methods We searched relevant randomized, controlled trials through May 2018, using PubMed, Embase and Cochrane Central Register. The main endpoint included intra-vaginal ejaculatory latency time (IELT) and side effects in the treatment of PE. Cochrane Collaboration’s Revman software, version 5.3, was used for statistical analysis. Results Out of 493 unique articles, a total of 19 randomized, controlled trials (RCTs) were reviewed. Quite a few RCTs were considered to have unclear risk of bias because of limited information. Pooled outcomes suggested that paroxetine was more effective than placebo, fluoxetine and escitalopram at increasing IELT (all p < 0.05). However, there existed a high level of heterogeneity in the paroxetine vs. fluoxetine groups and the paroxetine vs. placebo groups. Comparing paroxetine with tramadol, sertraline, phosphodiesterase 5 inhibitors (PDE5Is), local lidocaine gel, behaviour therapy or dapoxetine, we found that the increase in IELT was not statistically significant between groups. Paroxetine combined with tadalafil or behaviour therapy was more efficacious than paroxetine alone (all p < 0.05). Although the side effects in the combination group were more common than in the paroxetine alone group, the most common adverse events, such as nausea, muscle soreness, palpitation and flushing, were mild and tolerable. The main limitations of this systematic review and meta-analysis were the different definitions of PE and short follow-up times. Conclusions According to this systematic review and meta-analysis, paroxetine provided better efficacy than placebo, fluoxetine and escitalopram in the treatment of PE, with well-tolerated side effects. The combination group had better efficacy than the paroxetine alone group. Trial registration This review was reported in agreement with the PRISMA statement and was registered on PROSPERO 2018CRD42018097014

Biodegradable ZnLiCa ternary alloys for critical-sized bone defect regeneration at load-bearing sites: In vitro and in vivo studies

A novel biodegradable metal system, ZnLiCa ternary alloys, were systematically investigated both in vitro and in vivo. The ultimate tensile strength (UTS) of Zn0.8Li0.1Ca alloy reached 567.60 ± 9.56 MPa, which is comparable to pure Ti, one of the most common material used in orthopedics. The elongation of Zn0.8Li0.1Ca is 27.82 ± 18.35%, which is the highest among the ZnLiCa alloys. The in vitro degradation rate of Zn0.8Li0.1Ca alloy in simulated body fluid (SBF) showed significant acceleration than that of pure Zn. CCK-8 tests and hemocompatibility tests manifested that ZnLiCa alloys exhibit good biocompatibility. Real-time PCR showed that Zn0.8Li0.1Ca alloy successfully stimulated the expressions of osteogenesis-related genes (ALP, COL-1, OCN and Runx-2), especially the OCN. An in vivo implantation was conducted in the radius of New Zealand rabbits for 24 weeks, aiming to treat the bone defects. The Micro-CT and histological evaluations proved that the regeneration of bone defect was faster within the Zn0.8Li0.1Ca alloy scaffold than the pure Ti scaffold. Zn0.8Li0.1Ca alloy showed great potential to be applied in orthopedics, especially in the load-bearing sites

Multi-omics analyses reveal that the gut microbiome and its metabolites promote milk fat synthesis in Zhongdian yak cows

Background Yak cows produce higher quality milk with higher concentrations of milk fat than dairy cows. Recently, studies have found the yak milk yield and milk fat percentage have decreased significantly over the past decade, highlighting the urgency for yak milk improvement. Therefore, we aimed to analyze how the gut microbiome impacts milk fat synthesis in Zhongdian yak cows. Methods We collected milk samples from Zhongdian yak cows and analyzed the milk fat percentage, selecting five Zhongdian yak cows with a very high milk fat percentage (>7%, 8.70 ± 1.89%, H group) and five Zhongdian yak cows with a very low milk fat percentage (<5%, 4.12 ± 0.43%, L group), and then obtained gut samples of these ten Zhongdian yak cows through rectal palpation. Gut metagenomics, metabolomics, and conjoint metagenomics and metabolomics analyses were performed on these samples, identifying taxonomic changes, functional changes, and changes in gut microbes-metabolite interactions within the milk fat synthesis-associated Zhongdian yak cows gut microbiome, to identify potential regulatory mechanisms of milk fat at the gut microbiome level in Zhongdian yak cows. Results The metagenomics analysis revealed Firmicutes and Proteobacteria were significantly more abundant in the gut of the high-milk fat Zhongdian yak cows. These bacteria are involved in the biosynthesis of unsaturated fatty acids and amino acids, leading to greater efficiency in converting energy to milk fat. The metabolomics analysis showed that the elevated gut metabolites in high milk fat percentage Zhongdian yak cows were mainly enriched in lipid and amino acid metabolism. Using a combined metagenomic and metabolomics analysis, positive correlations between Firmicutes (Desulfocucumis, Anaerotignum, Dolosiccus) and myristic acid, and Proteobacteria (Catenovulum, Comamonas, Rubrivivax, Marivita, Succinimouas) and choline were found in the gut of Zhongdian yak cows. These interactions may be the main contributors to methanogen inhibition, producing less methane leading to higher-efficient milk fat production. Conclusions A study of the gut microbe, gut metabolites, and milk fat percentage of Zhongdian yak cows revealed that the variations in milk fat percentage between yak cows may be caused by the gut microbes and their metabolites, especially Firmicutes-myristic acid and Proteobacteria-choline interactions, which are important to milk fat synthesis. Our study provides new insights into the functional roles of the gut microbiome in producing small molecule metabolites and contributing to milk performance traits in yak cows

Agricultural land use change impacts soil CO2 emission and its C-13-isotopic signature in central China

Land use change has been widely considered as a key driver of global carbon (C) dynamics. However, the impact of agricultural land use change on soil respiration and its C-13-isotopic signature of CO2 are not fully understood. Therefore, we conducted a field experiment to investigate the seasonal variation of soil CO2 flux and its C-13-isotopic signature and their relationships with biotic factors and abiotic factors under land use conversion from croplands to afforested land (woodland and shrubland) after 30 years. Measurement of CO2 flux was conducted once a month for a whole year. The results showed that the conversion cropland to afforested land significantly increased soil CO2 flux and lowered the delta C-13 of soil CO2. The soil CO2 flux showed similar seasonal patterns among land use types with the highest (994.87 mg m(-2) h(-1)) in summer and the lowest (25.53 mg m(-2) h(-1)) in winter. The soil CO2 flux was positively related to soil organic C and labile C of topsoil (0-10 cm), as well as soil temperature, whereas the delta C-13 of soil CO2 emission was positively correlated with the delta C-13 of microbial biomass and negatively correlated with soil temperature. Overall, our results reveal that subject to long-term land use change, soil CO2 fluxes significantly increase in afforested land due to improved availability of soil C, and its C-13-isotopic signature are strongly related to isotope signature of plant litter inputs

Menin orchestrates hepatic glucose and fatty acid uptake via deploying the cellular translocation of SIRT1 and PPARγ

Abstract Background Menin is a scaffold protein encoded by the Men1 gene, which interacts with various transcriptional proteins to activate or repress cellular processes and is a key mediator in multiple organs. Both liver-specific and hepatocyte-specific Menin deficiency promotes high-fat diet-induced liver steatosis in mice, as well as insulin resistance and type 2 diabetic phenotype. The potential link between Menin and hepatic metabolism homeostasis may provide new insights into the mechanism of fatty liver disease. Results Disturbance of hepatic Menin expression impacts metabolic pathways associated with non-alcoholic fatty liver disease (NAFLD), including the FoxO signaling pathway, which is similar to that observed in both oleic acid-induced fatty hepatocytes model and biopsied fatty liver tissues, but with elevated hepatic Menin expression and inhibited FABP1. Higher levels of Menin facilitate glucose uptake while restraining fatty acid uptake. Menin targets the expression of FABP3/4/5 and also CD36 or GK, PCK by binding to their promoter regions, while recruiting and deploying the cellular localization of PPARγ and SIRT1 in the nucleus and cytoplasm. Accordingly, Menin binds to PPARγ and/or FoxO1 in hepatocytes, and orchestrates hepatic glucose and fatty acid uptake by recruiting SIRT1. Conclusion Menin plays an orchestration role as a transcriptional activator and/or repressor to target downstream gene expression levels involved in hepatic energy uptake by interacting with the cellular energy sensor SIRT1, PPARγ, and/or FoxO1 and deploying their translocations between the cytoplasm and nucleus, thereby maintaining metabolic homeostasis. These findings provide more evidence suggesting Menin could be targeted for the treatment of hepatic steatosis, NAFLD or metabolic dysfunction-associated fatty liver disease (MAFLD), and even other hepatic diseases. Graphical Abstrac