Mevalonate pathway and male reproductive aging.

Male fertility declines with age. The mevalonate pathway, through which cholesterol and nonsteroidal isoprenoids are synthesized, plays key role in metabolic processes and is an essential pathway for cholesterol production and protein prenylation. Male reproductive aging is accompanied by dramatic changes in the metabolic microenvironment of the testis. Since the mevalonate pathway has an important role in spermatogenesis, we attempted to explore the association between male reproductive aging and the mevalonate pathway to explain the mechanism of male reproductive aging. Alterations in the mevalonate pathway may affect male reproductive aging by decreasing cholesterol synthesis and altering testis protein prenylation. Decreased cholesterol levels affect cholesterol modification, testosterone production, and remodeling of germ cell membranes. Aging-related metabolic disorders also affect the metabolic coupling between somatic cells and spermatogenic cells, leading to male fertility decline. Therefore, we hypothesized that alterations in the mevalonate pathway represent one of the metabolic causes of reproductive aging.

Oocytes orchestrate protein prenylation for mitochondrial function through selective inactivation of cholesterol biosynthesis in murine species.

Emerging research and clinical evidence suggest that the metabolic activity of oocytes may play a pivotal role in reproductive anomalies. However, the intrinsic mechanisms governing oocyte development regulated by metabolic enzymes remain largely unknown. Our investigation demonstrates that geranylgeranyl diphosphate synthase1 (Ggps1), the crucial enzyme in the mevalonate pathway responsible for synthesizing isoprenoid metabolite geranylgeranyl pyrophosphate from farnesyl pyrophosphate, is essential for oocyte maturation in mice. Our findings reveal that the deletion of Ggps1 that prevents protein prenylation in fully grown oocytes leads to subfertility and offspring metabolic defects without affecting follicle development. Oocytes that lack Ggps1 exhibit disrupted mitochondrial homeostasis and the mitochondrial defects arising from oocytes are inherited by the fetal offspring. Mechanistically, the excessive farnesylation of mitochondrial ribosome protein, Dap3, and decreased levels of small G proteins mediate the mitochondrial dysfunction induced by Ggps1 deficiency. Additionally, a significant reduction in Ggps1 levels in oocytes is accompanied by offspring defects when females are exposed to a high-cholesterol diet. Collectively, this study establishes that mevalonate pathway-protein prenylation is vital for mitochondrial function in oocyte maturation and provides evidence that the disrupted protein prenylation resulting from an imbalance between farnesyl pyrophosphate and geranylgeranyl pyrophosphate is the major mechanism underlying impairment of oocyte quality induced by high cholesterol.

Maternal and embryonic signals cause functional differentiation of luminal epithelial cells and receptivity establishment.

Embryo implantation requires temporospatial maternal-embryonic dialog. Using single-cell RNA sequencing for the uterus from 2.5 to 4.5 days post-coitum (DPC) and bulk sequencing for the corresponding embryos of 3.5 and 4.0 DPC pregnant mice, we found that estrogen-responsive luminal epithelial cells (EECs) functionally differentiated into adhesive epithelial cells (AECs) and supporting epithelial cells (SECs), promoted by progesterone. Along with maternal signals, embryonic Pdgfa and Efna3/4 signaling activated AECs and SECs, respectively, enhancing the attachment of embryos to the endometrium and furthering embryo development. This differentiation process was largely conserved between humans and mice. Notably, the developmental defects of SOX9-positive human endometrial epithelial cells (similar to mouse EEC) were related to thin endometrium, whereas functional defects of SEC-similar unciliated epithelial cells were related to recurrent implantation failure (RIF). Our findings provide insights into endometrial luminal epithelial cell development directed by maternal and embryonic signaling, which is crucial for endometrial receptivity.

Superlithiation Performance of Pyridinium Polymerized Ionic Liquids with Fast Li+ Diffusion Kinetics as Anode Materials for Lithium-Ion Battery.

Polymerized ionic liquids (PILs) with super ion diffusion kinetics have aroused considerable attention in rechargeable batteries, which are very promising to solve the problem of the slow ion diffusion kinetics in organic electrode materials. Theoretically, PILs incorporated redox groups are very suitable as anode materials to realize "superlithiation" performance, achieving high lithium storage capacity. In this study, redox pyridinium-based PILs (PILs-Py-400) have been synthesized through trimerization reactions by pyridinium ionic liquids with cyano groups under an appropriate temperature (400 °C). The positively charged skeleton, extended conjugated system, abundant micropores, and amorphous structure for PILs-Py-400 can boost the utilization efficiency of redox sites. A high capacity of 1643 mAh g-1 at 0.1 A g-1 (96.7% of the theoretical capacity) has been obtained, indicating intriguing 13 Li+ redox reactions in per repeating unit of one pyridinium ring, one triazine ring, and one methylene. Moreover, PILs-Py-400 exhibit excellent cycling stability with a capacity of around 1100 mAh g-1 at 1.0 A g-1 after 500 cycles, and the capacity retention is 92.2%.

Clinical implication and potential function of ARHGEF6 in acute myeloid leukemia: An in vitro study.

The roles of Rho GTPases in various types of cancer have been extensively studied, but the research of Rho guanine nucleotide exchange factors (GEFs) in cancer is not comprehensive. Rho guanine nucleotide exchange factor 6 (ARHGEF6) is an important member of the Rho GEFs family involved in cytoskeletal rearrangement, and it has not been investigated in acute myeloid leukemia (AML). Our research showed that the expression of ARHGEF6 was mainly higher in AML cell lines, meanwhile, was highest in the samples from patients with AML compared to other cancer types. High ARHGEF6 expression in AML was associated with a good prognosis. ARHGEF6low cases showed significantly higher overall survival (OS) after autologous or allogeneic HSCT (auto/allo-HSCT). High expression of ARHGEF6 downregulates the negative regulation of myeloid differentiation process and upregulates G protein-coupled receptor signaling pathway-related processes, among which HOXA9, HOXB6, and TRH have significant differential expression and prognostic impact in AML. Therefore, ARHGEF6 can become a prognostic marker in AML; ARHGEF6low patients can gain from auto/allo-HSCT.

The KLF7/PFKL/ACADL axis modulates cardiac metabolic remodelling during cardiac hypertrophy in male mice.

The main hallmark of myocardial substrate metabolism in cardiac hypertrophy or heart failure is a shift from fatty acid oxidation to greater reliance on glycolysis. However, the close correlation between glycolysis and fatty acid oxidation and underlying mechanism by which causes cardiac pathological remodelling remain unclear. We confirm that KLF7 simultaneously targets the rate-limiting enzyme of glycolysis, phosphofructokinase-1, liver, and long-chain acyl-CoA dehydrogenase, a key enzyme for fatty acid oxidation. Cardiac-specific knockout and overexpression KLF7 induce adult concentric hypertrophy and infant eccentric hypertrophy by regulating glycolysis and fatty acid oxidation fluxes in male mice, respectively. Furthermore, cardiac-specific knockdown phosphofructokinase-1, liver or overexpression long-chain acyl-CoA dehydrogenase partially rescues the cardiac hypertrophy in adult male KLF7 deficient mice. Here we show that the KLF7/PFKL/ACADL axis is a critical regulatory mechanism and may provide insight into viable therapeutic concepts aimed at the modulation of cardiac metabolic balance in hypertrophied and failing heart.

Mechanical characteristics and stability analysis of surrounding rock reinforcement in rectangular roadway.

The stability of surrounding rock with bolt support depends on the stability within the reinforcement range. To understand the reinforcing mechanism of a rectangular roadway bolt fully and accurately, a quantitative method for evaluating the stability of the surrounding rock of a rectangular roadway must be developed. First, a roof beam model of a rectangular tunnel is established according to the deformation law of surrounding rock. Based on the elastic-plastic theory, the deflection calculation formula can be derived, and the ultimate load of the roof beam can be obtained under the plastic state without support. Second, based on the reinforcement effect of bolts, a model of a surrounding rock reinforcement body is established, the physical and mechanical properties of this body are deduced, and a method for evaluating the stability of surrounding rock is derived. Finally, by considering actual engineering cases, the theoretical calculation results of surrounding rock deformation are compared with the numerical simulation and field monitoring results. Moreover, the influence of different parameters of the bolt support on the mechanical characteristics and stability of reinforcement is investigated. The results show that the theoretical calculations approximate the numerical simulation and field monitoring values, thus verifying the rationality of the theory. The physical and mechanical properties and stability of the surrounding rock reinforcement body are considerably affected by changes in bolt length and spacing. The anchor design must apply the following principle: the bolt must either be long and sparsely spaced or short and densely spaced. The theory presented in this paper provides a relatively simple and fast quantitative calculation method for the study of the surrounding rock stability of bolt-supported rectangular roadways.

Gonadal white adipose tissue is important for gametogenesis in mice through maintenance of local metabolic and immune niches.

Gonadal white adipose tissue (gWAT) can regulate gametogenesis via modulation of neuroendocrine signaling. However, the effect of gWAT on the local microenvironment of the gonad was largely unknown. Herein, we ruled out that gWAT had a neuroendocrine effect on gonad function through a unilateral lipectomy strategy, in which cutting off epididymal white adipose tissue could reduce seminiferous tubule thickness and decrease sperm counts only in the adjacent testis and epididymis of the affected gonad. Consistent with the results in males, in females, ovary mass was similarly decreased by lipectomy. We determined that the defects in spermatogenesis were mainly caused by augmented apoptosis and decreased proliferation of germ cells. Transcriptome analysis suggested that lipectomy could disrupt immune privilege and activate immune responses in both the testis and ovary on the side of the lipectomy. In addition, lipidomics analysis in the testis showed that the levels of lipid metabolites such as free carnitine were elevated, whereas the levels of glycerophospholipids such as phosphatidylcholines and phosphatidylethanolamines were decreased, which indicated that the metabolic niche was also altered. Finally, we show that supplementation of phosphatidylcholine and phosphatidylethanolamine could partially rescue the observed phenotype. Collectively, our findings suggest that gWAT is important for gonad function by not only affecting whole-body homeostasis but also via maintaining local metabolic and immune niches.

A novel nano delivery system targeting different stages of osteoclasts.

Osteoclast (OC) abnormalities represent osteoporosis's critical mechanism (OP). OCs undergo multiple processes that range from monocytic to functional. Different drugs target OCs at different developmental stages; however, almost no Suitable drug-targeted delivery systems exist. Therefore, we designed two dual-targeting nanoparticles to target OCs at different functional stages. Using the calcitonin gene-related peptide receptor (CGRPR), which OC precursors highly express, and specific TRAPpeptides screened in the bone resorption lacuna, where mature OCs function, respectively, two types of dual-targeted nanoparticles were constructed. Afterwards, nanoparticles were grafted with hyaluronic acid (HA), which specifically binds to CD44 on the surface of the OCs. In vivo and in vitro experiments show that both nanoparticles have noticeable targeting effects on OCs. This suggests that dual-targeting nanoparticles designed for different functional periods of OC can be well targeted to the corresponding OC, and further promote the more precise delivery of drugs used to treat OP.

ceRNA Network and Functional Enrichment Analysis of Preeclampsia by Weighted Gene Coexpression Network Analysis.

BACKGROUND: Preeclampsia (PE) is a multisystemic syndrome which has short- and long-term risk to mothers and children and has pluralistic etiology. OBJECTIVE: This study is aimed at constructing a competitive endogenous RNA (ceRNA) network for pathways most related to PE using a data mining strategy based on weighted gene coexpression network analysis (WGCNA). METHODS: We focused on pathways involving hypoxia, angiogenesis, and epithelial mesenchymal transition according to the gene set variation analysis (GSVA) scores. The gene sets of these three pathways were enriched by gene set enrichment analysis (GSEA). WGCNA was used to study the underlying molecular mechanisms of the three pathways in the pathogenesis of PE by analyzing the relationship among pathways and genes. The soft threshold power (ß) and topological overlap matrix allowed us to obtain 15 modules, among which the red module was chosen for the downstream analysis. We chose 10 hub genes that satisfied ∣log2Fold Change | >2 and had a higher degree of connectivity within the module. These candidate genes were subsequently confirmed to have higher gene significance and module membership in the red module. Coexpression networks were established for the hub genes to unfold the connection between the genes in the red module and PE. Finally, ceRNA networks were constructed to further clarify the underlying molecular mechanism involved in the occurrence of PE. 56 circRNAs, 17 lncRNAs, and 20 miRNAs participated in the regulation of the hub genes. Coagulation factor II thrombin receptor (F2R) and lumican (LUM) were considered the most relevant genes, and ceRNA networks of them were constructed. CONCLUSION: The microarray data mining process based on bioinformatics methods constructed lncRNA and miRNA networks for ten hub genes that were closely related to PE and focused on ceRNAs of F2R and LUM finally. The results of our study may provide insight into the mechanisms underlying PE occurrence.

Superlithiation Performance of Covalent Triazine Frameworks as Anodes in Lithium-Ion Batteries.

Organics with the merit of renewability have been viewed as the promising alternative of inorganic electrode materials in lithium-ion batteries, but most of them display inferior performance due to the sluggish ion/electron diffusion and the potential dissolution in aprotic electrolytes. Here, covalent triazine frameworks (CTFs-1), full of vertical pores and layered spaces for Li+ transfer, have been synthesized with p-dicyanobenzene as the monomer by a facile two-step method including a prepolymerization with CF3SO3H as the catalyst and deep polymerization in molten ZnCl2. CTFs-1-400, obtained at the deep polymerization temperature of 400 °C, exhibits the superlithiation property with the specific capacities of 1626 mA h g-1 at 25 °C and 1913 mA h g-1 at 45 °C at 100 mA g-1, indicating the formation of Li6C6/Li6C3N3 in the reduction process. Electrochemical analysis and density functional theory calculation indicate that the ultrahigh capacity is mainly contributed by the capacitance of micropores and the redox capacity of benzene and triazine rings. Moreover, CTFs-1-400 displays the specific capacity of 740 mA h g-1 for 1000 cycles at 1 A g-1 with almost no capacity fading.

Biosynthesis of Chuangxinmycin Featuring a Deubiquitinase-like Sulfurtransferase.

The knowledge on sulfur incorporation mechanism involved in sulfur-containing molecule biosynthesis remains limited. Chuangxinmycin is a sulfur-containing antibiotic with a unique thiopyrano[4,3,2-cd]indole (TPI) skeleton and selective inhibitory activity against bacterial tryptophanyl-tRNA synthetase. Despite the previously reported biosynthetic gene clusters and the recent functional characterization of a P450 enzyme responsible for C-S bond formation, the enzymatic mechanism for sulfur incorporation remains unknown. Here, we resolve this central biosynthetic problem by in vitro biochemical characterization of the key enzymes and reconstitute the TPI skeleton in a one-pot enzymatic reaction. We reveal that the JAMM/MPN+ protein Cxm3 functions as a deubiquitinase-like sulfurtransferase to catalyze a non-classical sulfur-transfer reaction by interacting with the ubiquitin-like sulfur carrier protein Cxm4GG. This finding adds a new mechanism for sulfurtransferase in nature.

Matching sensor ontologies through siamese neural networks without using reference alignment.

Sensors have been growingly used in a variety of applications. The lack of semantic information of obtained sensor data will bring about the heterogeneity problem of sensor data in semantic, schema, and syntax levels. To solve the heterogeneity problem of sensor data, it is necessary to carry out the sensor ontology matching process to determine correspondences among heterogeneous sensor concepts. In this paper, we propose a Siamese Neural Network based Ontology Matching technique (SNN-OM) to align the sensor ontologies, which does not require the utilization of reference alignment to train the network model. In particular, a representative concepts extraction method is presented to enhance the model's performance and reduce the time of the training process, and an alignment refining method is proposed to enhance the alignments' quality by removing the logically conflict correspondences. The experimental results show that SNN-OM is capable of efficiently determining high-quality sensor ontology alignments.

Nitrogen Doped γ-Graphyne: A Novel Anode for High-Capacity Rechargeable Alkali-Ion Batteries.

High energy density is the major demand for next-generation rechargeable batteries, while the intrinsic low alkali metal adsorption of traditional carbon-based electrode remains the main challenge. Here, the mechanochemical route is proposed to prepare nitrogen doped γ-graphyne (NGY) and its high capacity is demonstrated in lithium (LIBs)/sodium (SIBs) ion batteries. The sample delivers large reversible Li (1037 mAh g-1 ) and Na (570.4 mAh g-1 ) storage capacities at 100 mA g-1 and presents excellent rate capabilities (526 mAh g-1 for LIBs and 180.2 mAh g-1 for SIBs) at 5 A g-1 . The superior Li/Na storage mechanisms of NGY are revealed by its 2D morphology evolution, quantitative kinetics, and theoretical calculations. The effects on the diffusion barriers (Eb ) and adsorption energies (Ead ) of Li/Na atoms in NGY are also studied and imine-N is demonstrated to be the ideal doping format to enhance the Li/Na storage performance. Besides, the Li/Na adsorption routes in NGY are optimized according to the experimental and the first-principles calculation results. This work provides a facile way to fabricate high capacity electrodes in LIBs/SIBs, which is also instructive for the design of other heteroatomic doped electrodes.

Mechanochemical Synthesis of γ-Graphyne with Enhanced Lithium Storage Performance.

γ-Graphyne is a new nanostructured carbon material with large theoretical Li+ storage due to its unique large conjugate rings, which makes it a potential anode for high-capacity lithium-ion batteries (LIBs). In this work, γ-graphyne-based high-capacity LIBs are demonstrated experimentally. γ-Graphyne is synthesized through mechanochemical and calcination processes by using CaC2 and C6 Br6 . Brunauer-Emmett-Teller, atomic force microscopy, X-ray photoelectron spectroscopy, solid-state 13 C NMR and Raman spectra are conducted to confirm its morphology and chemical structure. The sample presents 2D mesoporous structure and is exactly composed of sp and sp2 -hybridized carbon atoms as the γ-graphyne structure. The electrode shows high Li+ storage (1104.5 mAh g-1 at 100 mA g-1 ) and rate capability (435.1 mAh g-1 at 5 A g-1 ). The capacity retention can be up to 948.6 (200 mA g-1 for 350 cycles) and 730.4 mAh g-1 (1 A g-1 for 600 cycles), respectively. These excellent electrochemical performances are ascribed to the mesoporous architecture, large conjugate rings, enlarged interplanar distance, and high structural integrity for fast Li+ diffusion and improved cycling stability in γ-graphyne. This work provides an environmentally benign and cost-effective mechanochemical method to synthesize γ-graphyne and demonstrates its superior Li+ storage experimentally.

Preparation and Rate Capability of Carbon Coated LiNi1/3Co1/3Mn1/3O2 as Cathode Material in Lithium Ion Batteries.

LiNi1/3Co1/3Mn1/3O2 (NCM) is regarded as a promising material for next-generation lithium ion batteries due to the high capacity, but its practical applications are limited by the poor electronic conductivity. Here, a one-step method is used to prepare carbon coated LiNi1/3Co1/3Mn1/3O2 (NCM/C) by applying active carbon as reaction matrix. TEM shows LiNi1/3Co1/3Mn1/3O2 particles are homogeneously coated by carbon with a thickness about 10 nm. NCM/C delivers the discharge capacity of 191.2 mAh g-1 at 0.5 C (85 mA g-1) with a columbic efficiency of 91.1%. At 40 C (6800 mA g-1), the discharge capacity of NCM/C is 54.6 mAh g-1, whereas NCM prepared through sol-gel route only delivers 13.2 mAh g-1. After 100 charge and discharge cycles at 1 C (170 mA g-1) the capacity retention is 90.3% for NCM/C, whereas it is only 72.4% for NCM. The superior charge/discharge performance of NCM/C owes much to the carbon coating layer, which is not only helpful to increase the electronic conductivity but also contributive to inhibit the side reactions between LiNi1/3Co1/3Mn1/3O2 and the liquid electrolyte.

[Application of shortened replantation combined with limb lengthening in treatment of severe amputation of middle and distal lower leg].

Objective: To investigate the effectiveness and technical points of shortened replantation combined with limb lengthening in the treatment of severe amputation of middle and distal lower leg. Methods: Twelve cases of severe amputation of middle and distal lower leg were treated with shortened replantation at the 1st stage and limb lengthening at the 2nd stage between April 2009 and May 2016. There were 9 males and 3 females with an average age of 28 years (range, 16-32 years). The injury causes included traffic accident injury in 4 cases, heavy pound injury in 6 cases, and machine crush injury in 2 cases. The interval from injuries to treatment ranged from 30 minuts to 6 hours (mean, 3 hours and 12 minutes). All of 12 cases, 6 cases were completely amputated in the right middle and distal lower leg, 4 were not completely amputated in the left middle and distal lower leg, and 2 were ankle amputations. The limbs were 4.0-12.5 cm shorter than the contralateral sides, with an average of 7.3 cm. Limb lengthening was performed at 1.5-8.0 months after replantation and the time of extension was 1.7-5.3 months (mean, 3.1 months). Results: All 12 patients recovered the same lengths of both lower extremities after shortened replantation and limb lengthening. The lengthened segments gained good bone mineralization, bony union was achieved at lengthened segments and broken end of fracture at 7-16 months (mean, 11.3 months). All patients were followed up 6 months to 5 years (mean, 2 years and 5 months). The range of motion of the knee joint were 0-5° (mean, 3°) in hyperextension and 110-140° (mean, 120°) in flexion. Except for 2 cases of ankle arthrodesis, plantar flexion angles were 15-45° (mean, 26°) and dorsiflexion angles were 10-25° (mean, 15°) in the other cases. The plantar sensation was restored to the S 3 + level in 4 cases, S 3 level in 6 cases, and S 2 level in 2 cases. At last follow-up, the affected limb function were excellent in 7 cases, good in 3 cases, fair in 2 cases according to Kofoed functional evaluation criteria. Conclusion: It expanded indications for replantation of lower limb amputation, reduced the operation difficulty and trauma with shortened replantation combined with limb lengthening in the treatment of severe amputation of middle and distal lower leg.