Peripheral nerve-derived Sema3A promotes osteogenic differentiation of mesenchymal stem cells through the Wnt/ß-catenin/Nrp1 positive feedback loop.

Sensory nerves play a crucial role in maintaining bone homeostasis by releasing Semaphorin 3A (Sema3A). However, the specific mechanism of Sema3A in regulation of bone marrow mesenchymal stem cells (BMMSCs) during bone remodelling remains unclear. The tibial denervation model was used and the denervated tibia exhibited significantly lower mass as compared to sham operated bones. In vitro, BMMSCs cocultured with dorsal root ganglion cells (DRGs) or stimulated by Sema3A could promote osteogenic differentiation through the Wnt/ß-catenin/Nrp1 positive feedback loop, and the enhancement of osteogenic activity could be inhibited by SM345431 (Sema3A-specific inhibitor). In addition, Sema3A-stimulated BMMSCs or intravenous injection of Sema3A could promote new bone formation in vivo. To sum up, the coregulation of bone remodelling is due to the ageing of BMMSCs and increased osteoclast activity. Furthermore, the sensory neurotransmitter Sema3A promotes osteogenic differentiation of BMMSCs via Wnt/ß-catenin/Nrp1 positive feedback loop, thus promoting osteogenesis in vivo and in vitro.

Absorption behavior of polycarboxylate superplasticizer with different molecular structures on montmorillonite.

Polycarboxylate (PCE) is a high performance superplasticizer for modern concrete. With the high quality sand becoming precious, more and more low quality sands are used in concrete. However, low quality sands generally contain a relatively high content of montmorillonite (MMT), which could seriously reduce the efficiency of PCE. In order to develop PCE suitable for concrete with low quality sands, the absorption behavior on MMT of PCE with different side chains and acid/ether ratio was investigated. In order to explore the effect of MMT on PCE, two macromonomers were selected, isoprene glycol ether 400(TPEG400) and isoprene glycol ether 2400 (TPEG2400), to synthesize six long and short side chain comb-type PCEs with acid-ether ratios of 1.5:1, 2.5:1 and 3.5:1, respectively. The MMT tolerance mechanism of comb-type PCE in MMT-containing cement slurry was examined by FT-IR, DLS, TOC and other analysis. The PCE with long side chain is much easier to be inserted into the layered structure of MMT, resulting in intercalation absorption. The absorption amount of two kinds of side chain PCE on the MMT particles decreased as the acid ether ratio increases. PCE with long side chains showed shear-thickening properties in MMT-containing cement slurry, on the contrary, short side chains showed shear-thinning properties.

Liver Injury Impaired 25-Hydroxylation of Vitamin D Suppresses Intestinal Paneth Cell defensins, leading to Gut Dysbiosis and Liver Fibrogenesis.

Vitamin D deficiency is co-prevalent with various liver diseases including cirrhosis, while the underlying mechanism remains elusive. Vitamin D receptor (VDR) is abundantly expressed in the distal region of small intestine, where the Paneth cells are enriched, suggesting that vitamin D signaling may modulates the intestinal Paneth cells and their production of defensins to restrain microbiome growth in the small intestine. In this study we found that in carbon tetrachloride-induced liver injury, hepatic 25-hydroxylation of vitamin D was impaired, leading to down regulated expression of Paneth cell fensins in the small intestine, gut dysbiosis, and endotoxinemia. While intraperitoneal injection of endotoxin (lipopolysaccharides) alone did not elicit liver fibrosis, it exacerbated the carbon tetrachloride initiated liver fibrogenesis. Oral gavage of synthetic Paneth cell alpha-defensin 5 (DEFA5) restored the homeostasis of gut microbiota, reduced endotoxemia, relieved liver inflammation, and ameliorated liver fibrosis. Likewise, Cholestyramine, cationic resin that can sequestrate endotoxin in the intestine, attenuated the liver fibrosis as well. Fecal transplant of the microbes derived from the DEFA5-treated donors improved liver fibrosis in the recipient mice. The intestinal Vdrconditional knockout mice exhibited reduction of Paneth cell defensins and lysozyme production, and worsened liver injury and fibrogenesis. Thus, liver injury impairs synthesis of 25(OH)VD3, which consequently impedes the Paneth cells functions in the small intestine, leading to gut dysbiosis for liver fibrogenesis.

Vitamin D signaling maintains intestinal innate immunity and gut microbiota: potential intervention for metabolic syndrome and NAFLD.

A lack of sunlight exposure, residence in the northern latitudes, and dietary vitamin D insufficiency are coprevalent with metabolic syndrome (MetS), Type 2 diabetes (T2D), and nonalcoholic fatty liver diseases (NAFLD), implying a potential causality and underlying mechanism. Whether vitamin D supplementation or treatment can improve these disorders is controversial, in part, because of the absence of large-scale trials. Experimental investigations, on the other hand, have uncovered novel biological functions of vitamin D in development, tumor suppression, and immune regulation, far beyond its original role as a vitamin that maintained calcium homeostasis. While the large intestine harbors massive numbers of microbes, the small intestine has a minimal quantity of bacteria, indicating the existence of a gating system located in the distal region of the small intestine that may restrain bacterial translocation to the small intestine. Vitamin D receptor (VDR) was found to be highly expressed at the distal region of small intestine, where the vitamin D signaling promotes innate immunity, including the expression of α-defensins by Paneth cells, and maintains the intestinal tight junctions. Thus, a new hypothesis is emerging, indicating that vitamin D deficiency may impair the intestinal innate immunity, including downregulation of Paneth cell defensins, leading to bacterial translocation, endotoxemia, systemic inflammation, insulin resistance, and hepatic steatosis. Here, we review the studies for vitamin D for innate immunity and metabolic homeostasis, and we outline the clinical trials of vitamin D for mitigating MetS, T2D, and NAFLD.

Continuous preparation and antibacterial mechanisms of biodegradable polylactic acid/nano-zinc oxide/additives antibacterial non-wovens.

Biodegradable polylactic acid (PLA)/nano­zinc oxide (ZnO)/additives non-woven slices were prepared by melt blending method. The effects of antibacterial agent nano-ZnO, antioxidant pentaerythrityl tetrakis-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionate (1010), and chain extender multi-functional epoxy (ADR), on the melt flow rate, mechanical properties, thermal stabilities and micromorphology of the slices were investigated. The melt flow rate decreased from 26.94 g/10 min to 17.76 g/10 min, and the tensile strength increased from 10.518 MPa to 30.427 MPa with the increase of nano-ZnO and additives content. The slices were further spunbonded. The wettability and antibacterial properties of PLA/nano-ZnO/additives antibacterial non-wovens were studied, and the antibacterial action mechanism was clarified. The results showed that the biodegradable PLA/nano-ZnO/additives antibacterial non-wovens were prepared continuously successfully. The prepared non-woven fabrics exhibited good hydrophobicity and antibacterial properties. The mechanism study shows that zinc ion produced by nano-ZnO and photocatalytic reaction make the fabrics have good antibacterial activity at low nano-ZnO content. When nano-ZnO concentration reaches 1.5 wt%, the antibacterial rate against Escherichia coli and Staphylococcus aureus reaches 98.52 % and 98.13 %, respectively.

Prognostic value of neutrophil-to-lymphocyte ratio in gastric cancer patients treated with immune checkpoint inhibitors: A meta-analysis.

The neutrophil-to-lymphocyte ratio (NLR) has been extensively studied in patients with gastric cancer (GC) treated with immune checkpoint inhibitors (ICIs), although the results are controversial. Therefore, we performed the present meta-analysis to systematically assess the correlation between NLR and prognosis and clinicopathological factors in GC patients undergoing treatment with ICIs. Among the electronic databases, PubMed, Web of Science, Embase, and Cochrane Library were thoroughly searched. To estimate the prognostic value of NLR for progression-free survival (PFS) and overall survival (OS), hazard ratios (HRs) were calculated, and their 95% confidence intervals were calculated. This meta-analysis included 10 studies with 830 patients. Based on the pooled data, a high NLR was associated with poor OS in GC patients receiving ICIs (HR = 2.13, 95% confidence interval [CI] = 1.70-2.66, p < 0.001). Elevated NLR was a significant biomarker for worse PFS in GC patients treated with ICIs (HR = 1.74, 95% CI = 1.22-2.48, p = 0.002). There was, however, no significant correlation between NLR and sex, age, and Eastern Cooperative Oncology Group Performance Status (PS) of the ECOG, differentiation, human epidermal growth factor receptor 2 (HER2) status, or PD-L1 status in GC patients treated with ICIs. High NLR before treatment was associated with poor OS and PFS in GC patients treated with ICIs, according to our meta-analysis. NLR is an effective biomarker for evaluating the prognosis of GC patients receiving ICIs and provide more valuable information for treatment decisions in the era of immunotherapy for GC.

Multifunctionalized carbon-fiber-reinforced polyetheretherketone implant for rapid osseointegration under infected environment.

Carbon fiber reinforced polyetheretherketone (CFRPEEK) possesses a similar elastic modulus to that of human cortical bone and is considered as a promising candidate to replace metallic implants. However, the bioinertness and deficiency of antibacterial activities impede its application in orthopedic and dentistry. In this work, titanium plasma immersion ion implantation (Ti-PIII) is applied to modify CFRPEEK, achieving unique multi-hierarchical nanostructures and active sites on the surface. Then, hybrid polydopamine (PDA)@ZnO-EDN1 nanoparticles (NPs) are introduced to construct versatile surfaces with improved osteogenic and angiogenic properties and excellent antibacterial properties. Our study established that the modified CFRPEEK presented favorable stability and cytocompatibility. Compared with bare CFRPEEK, improved osteogenic differentiation of rat mesenchymal stem cells (BMSCs) and vascularization of human umbilical vein endothelial cells (HUVECs) are found on the functionalized surface due to the zinc ions and EDN1 releasing. In vitro bacteriostasis assay confirms that hybrid PDA@ZnO NPs on the functionalized surface provided an effective antibacterial effect. Moreover, the rat infected model corroborates the enhanced antibiosis and osteointegration of the functionalized CFRPEEK. Our findings indicate that the multilevel nanostructured PDA@ZnO-EDN1 coated CFRPEEK with enhanced antibacterial, angiogenic, and osteogenic capacity has great potential as an orthopedic/dental implant material for clinical application.

Influence of a Multiple Epoxy Chain Extender on the Rheological Behavior, Crystallization, and Mechanical Properties of Polyglycolic Acid.

This study investigated the impact of a multiple epoxy chain extender (ADR) on the rheological behavior, crystallization, and mechanical properties of polyglycolic acid (PGA). Tests of the torque and melt mass flow rate and dynamic rheological analysis were conducted to study the rheological behavior of PGA modified with ADR. The rheological results of the modified PGA showed a significantly increased viscosity and storage modulus with an increase in the ADR amount, which could be attributed to the chain extension/branching reactions between PGA and ADR. It was proved that ADR could be used as an efficient chain extender for tailoring the rheological performance of PGA. The Han plot of the modified PGA showed a transition of viscous behavior to elastic behavior, while the ADR content was increased from 0 to 0.9 phr. The formation of long-chain branches (LCBs) was confirmed via the Cole-Cole plot and weighted relaxation spectrum, wherein the LCBs substantially changed the rheological behavior of the modified PGA. The vGP plots predicted a star-type topological structure for the LCBs. The results of non-isothermal crystallization kinetics suggested that the crystallization of the modified PGA was predominantly homogeneous nucleation and three-dimensional growth. The crystallinity decreased slightly with the increase in the ADR amount. Compared to neat PGA, the modified PGA samples exhibited better tensile and flexural performances.

Frontiers of Hydroxyapatite Composites in Bionic Bone Tissue Engineering.

Bone defects caused by various factors may cause morphological and functional disorders that can seriously affect patient's quality of life. Autologous bone grafting is morbid, involves numerous complications, and provides limited volume at donor site. Hence, tissue-engineered bone is a better alternative for repair of bone defects and for promoting a patient's functional recovery. Besides good biocompatibility, scaffolding materials represented by hydroxyapatite (HA) composites in tissue-engineered bone also have strong ability to guide bone regeneration. The development of manufacturing technology and advances in material science have made HA composite scaffolding more closely related to the composition and mechanical properties of natural bone. The surface morphology and pore diameter of the scaffold material are more important for cell proliferation, differentiation, and nutrient exchange. The degradation rate of the composite scaffold should match the rate of osteogenesis, and the loading of cells/cytokine is beneficial to promote the formation of new bone. In conclusion, there is no doubt that a breakthrough has been made in composition, mechanical properties, and degradation of HA composites. Biomimetic tissue-engineered bone based on vascularization and innervation show a promising future.

Immune marker signature helps to predict survival in uveal melanoma.

The detailed molecular function of tumor microenvironment (TEM) in uveal melanoma (UVM) remains unclear. This study generated the immune index and the stromal index scores by ESTIMATE algorithm based on RNA-sequencing data with 80 UVM patients. There was no correlation between the immune stromal index and clinical parameters. The differentially expressed genes related to the immune stromal index were calculated and were described by functional annotations and protein-protein interaction network diagrams. After univariate and multivariate Cox regression analyses, there were four genes (HLA-J, MMP12, HES6, and ADAMDEC1) with significant prognostic significance. The prognostic model was constructed using these four characteristic genes, and the KM curve and tROC curve were described to show that the model had a better ability to predict survival outcomes and prognosis. The verification results in GSE62075 showed that HLA-J and HES6 were expressed differently in the cancer group than in the non-cancer group. This study indicates that the risk signature based on the immune index can be used as an indicator to evaluate the prognosis of patients with UVM.

A novel electrochemical biosensor for ultrasensitive Hg2+ detection via a triple signal amplification strategy.

We developed a novel electrochemical biosensor for ultrasensitive Hg2+ detection via a triple signal amplification strategy of a DNA dual cycle, organic-inorganic hybrid nanoflowers (Cu3(PO4)2 HNFs) and gold nanoparticle (AuNP) probe. The DNA dual cycle was triggered by exonuclease III (Exo III) in the presence of Hg2+, and Cu3(PO4)2 HNFs were synthesized as an AuNP probe carrier. The electrochemical biosensor displayed high stability, high sensitivity and excellent specificity, which was improved by up to seven orders of magnitude compared to the World Health Organization (WHO) allowed Hg2+ levels in drinking water. This signal amplification strategy could be easily modified and extended to detect other hazardous heavy metals and nucleic acids.

Effects of vitamin D deficiency on the improvement of metabolic disorders in obese mice after vertical sleeve gastrectomy.

Vertical sleeve gastrectomy (VSG) is one of the most commonly performed clinical bariatric surgeries for the remission of obesity and diabetes. Its effects include weight loss, improved insulin resistance, and the improvement of hepatic steatosis. Epidemiologic studies demonstrated that vitamin D deficiency (VDD) is associated with many diseases, including obesity. To explore the role of vitamin D in metabolic disorders for patients with obesity after VSG. We established a murine model of diet-induced obesity + VDD, and we performed VSGs to investigate VDD's effects on the improvement of metabolic disorders present in post-VSG obese mice. We observed that in HFD mice, the concentration of VitD3 is four fold of HFD + VDD one. In the post-VSG obese mice, VDD attenuated the improvements of hepatic steatosis, insulin resistance, intestinal inflammation and permeability, the maintenance of weight loss, the reduction of fat loss, and the restoration of intestinal flora that were weakened. Our results suggest that in post-VSG obese mice, maintaining a normal level of vitamin D plays an important role in maintaining the improvement of metabolic disorders.

Effects of Organic Montmorillonite (OMMT) and Pre-Orientation on Property of Poly(l-lactic acid) (PLLA)/Ethylene Propylene Diene Monomer (EPDM) Blends.

Poly(l-lactic acid)/ethylene propylene diene monomer/organic montmorillonite (PLLA/EPDM/OMMT) samples were melt-compounded and then processed into sheets via two routes, namely, compression-molding and calendering. Tensile performance, morphology, and thermal property of the samples were investigated. Tensile test showed that the incorporation of OMMT resulted in significant enhancement in the tensile ductility of the PLLA/EPDM samples. SEM observation revealed that EPDM domain size decreased largely with increasing OMMT loading, indicating the compatibility of OMMT with PLLA/EPDM blends. Moreover, the elongation at break, tensile yield strength, and modulus of the calendered samples were found to be much higher than those of the compression-molded samples. It can be attributed to the pre-oriented rigid amorphous fraction of PLLA matrix and pre-stretched EPDM phases in the calendered samples produced by the stretching/shearing effect of calendering. Compared to the spherical/ellipsoidal EPDM particles in the compression-molded samples, these stretched EPDM phases with higher aspect ratio in the calendered samples can be more effective to initiate craze, and terminate the craze growing to a crack along transversal direction. Therefore, the calendered samples show a better tensile ductility than the compression-molded ones. Moreover, annealing was carried out to increase the crystallinity of the samples. Tensile performance, morphology, and thermal property of the annealed samples were also systematically investigated.

Liver Transcriptome and miRNA Analysis of Silver Carp (Hypophthalmichthys molitrix) Intraperitoneally Injected With Microcystin-LR.

Next-generation sequencing was used to analyze the effects of toxic microcystin-LR (MC-LR) on silver carp (Hypophthalmichthys molitrix). Silver carps were intraperitoneally injected with MC-LR, and RNA-seq and miRNA-seq in the liver were analyzed at 0.25, 0.5, and 1 h. The expression of glutathione S-transferase (GST), which acts as a marker gene for MC-LR, was tested to determine the earliest time point at which GST transcription was initiated in the liver tissues of the MC-LR-treated silver carps. Hepatic RNA-seq/miRNA-seq analysis and data integration analysis were conducted with reference to the identified time point. Quantitative PCR (qPCR) was performed to detect the expression of the following genes at the three time points: heme oxygenase 1 (HO-1), interleukin-10 receptor 1 (IL-10R1), apolipoprotein A-I (apoA-I), and heme binding protein 2 (HBP2). Results showed that the liver GST expression was remarkably decreased at 0.25 h (P < 0.05). RNA-seq at this time point revealed that the liver tissue contained 97,505 unigenes, including 184 significantly different unigenes and 75 unknown genes. Gene Ontology (GO) term enrichment analysis suggested that 35 of the 145 enriched GO terms were significantly enriched and mainly related to the immune system regulation network. KEGG pathway enrichment analysis showed that 18 of the 189 pathways were significantly enriched, and the most significant was a ribosome pathway containing 77 differentially expressed genes. miRNA-seq analysis indicated that the longest miRNA had 22 nucleotides (nt), followed by 21 and 23 nt. A total of 286 known miRNAs, 332 known miRNA precursor sequences, and 438 new miRNAs were predicted. A total of 1,048,575 mRNA-miRNA interaction sites were obtained, and 21,252 and 21,241 target genes were respectively predicted in known and new miRNAs. qPCR revealed that HO-1, IL-10R1, apoA-I, and HBP2 were significantly differentially expressed and might play important roles in the toxicity and liver detoxification of MC-LR in fish. These results were consistent with those of high-throughput sequencing, thereby verifying the accuracy of our sequencing data. RNA-seq and miRNA-seq analyses of silver carp liver injected with MC-LR provided valuable and new insights into the toxic effects of MC-LR and the antitoxic mechanisms of MC-LR in fish. The RNA/miRNA data are available from the NCBI database Registration No. : SRP075165.

Effects of toxic Microcystis aeruginosa on the silver carp Hypophthalmichtys molitrix revealed by hepatic RNA-seq and miRNA-seq.

High-throughput sequencing was applied to analyze the effects of toxic Microcystis aeruginosa on the silver carp Hypophthalmichthys molitrix. Silver carps were exposed to two cyanobacteria species (toxic and non-toxic) for RNA-seq and miRNA-seq analysis. RNA-seq revealed that the liver tissue contained 105,379 unigenes. Of these genes, 143 were significantly differentiated, 82 were markedly up-regulated, and 61 were remarkably down-regulated. GO term enrichment analysis indicated that 35 of the 154 enriched GO terms were significantly enriched. KEGG pathway enrichment analysis demonstrated that 17 of the 118 enriched KEGG pathways were significantly enriched. A considerable number of disease/immune-associated GO terms and significantly enriched KEGG pathways were also observed. The sequence length determined by miRNA-seq was mainly distributed in 20-23 bp and composed of 882,620 unique small RNAs, and 53% of these RNAs were annotated to miRNAs. As confirmed, 272 known miRNAs were differentially expressed, 453 novel miRNAs were predicted, 112 miRNAs were well matched with 7,623 target genes, and 203 novel miRNAs were matched with 15,453 target genes. qPCR also indicated that Steap4, Cyp7a1, CABZ01088134.1, and PPP1R3G were significantly differentially expressed and might play major roles in the toxic, detoxifying, and antitoxic mechanisms of microcystin in fish.

Isothermal Cold Crystallization, Heat Resistance, and Tensile Performance of Polylactide/Thermoplastic Polyester Elastomer (PLA/TPEE) Blends: Effects of Annealing and Reactive Compatibilizer.

The combined influences of crystallinity and reactive compatibilizer-a multifunctional epoxide (ADR)-on morphology, tensile performance, and heat resistance of polylactide/thermoplastic polyester elastomer (PLA/TPEE) (80/20) blends were investigated. Annealing involved an isothermal cold crystallization of PLA matrix was performed to increase crystallinity of the samples. First, isothermal cold crystallization kinetics were investigated using differential scanning calorimetry measurement. It was found that the addition of ADR decreased the crystallization rate of the samples. The maximum crystallinity of the annealed samples also decreased from 40% to 34% while ADR loading increased from zero to 1.0 phr. Furthermore, influence of crystallinity on mechanical performances of the PLA/TPEE sample was researched. The heat resistance of the sample showed a significant enhancement while increasing its crystallinity. Meanwhile, the tensile ductility of the crystallized PLA/TPEE sample became very poor due to the embrittlement with increased crystallinity and the incompatibility between PLA and TPEE. However, the annealed PLA/TPEE/ADR samples with high crystallinity kept a higher tensile ductility because ADR greatly improved the interfacial compatibility. Differences in tensile fracture behaviors of the quenched and annealed PLA/TPEE samples with and without ADR were discussed in detail. At last, crystallized PLA/TPEE/ADR blends with excellent heat resistance and high tensile ductility were obtained by annealing and reactive compatibilization.