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A simple and efficient heteroannulation reaction for the synthesis of 1-(quinolin-2-yl)naphthalen-2-ols has been developed, and the products can be transformed to axially chiral arylquinolines by dynamic kinetic resolution.

The accurate estimation of parameters is the premise for establishing a high-fidelity simulation model of a valve-controlled cylinder system. Although bench test data are convenient to obtain in model parameter estimation, there is a need for the load data to conform to the actual working conditions. Although the operating data include the actual load information, it is not easy to collect the control valve operating data. This paper proposes a model parameter estimation method based on bench test and operating data fusion to solve the above problems. The proposed method is based on Bayesian theory, and its core is a pool fusion of prior information from bench test and operating data. First, a system model is established, and the parameters in the model are analysed. Then, the bench test and operating data of the system are collected, and the model parameters and weight coefficients are estimated using the data fusion method. Finally, the estimated effects of the data fusion method, Bayesian method, and PSO algorithm on system model parameters are compared. The research shows that the parameter estimation result based on the data fusion method is accurate. The weight coefficient represents the contribution of different prior information to the parameter estimation result. The effect of parameter estimation based on the data fusion method is better than that of the Bayesian method and the PSO algorithm. The more complex the load is, the worse the model's accuracy, which verifies the influence of the load on the valve-controlled cylinder system model and proves that the data fusion method plays an essential role in parameter estimation studies.

BackgroundSelf-harm (SH) increases significantly in early adolescence with great variability, and childhood maltreatment (CM) contributes to this increase. Understanding the developmental pathway from CM to SH could provide clues for SH prevention. This study used latent class analysis (LCA) to detect the phenotype of SH and explored the role of psychological resilience in the pathway from the CM to SH phenotype.MethodsA cross-sectional study was conducted with 5724 early adolescents from three middle schools in Anhui Province, China. We categorized SH into five subtypes based on their severity and further explored SH phenotypes by LCA to detect the heterogeneity of SH. Moreover, a path model was performed to test the mediation of resilience in the CM-SH association.ResultsThe prevalence rates of highly lethal SH, less lethal SH with visible tissue damage, SH without visible tissue damage, self-harmful behaviours with latency damage and psychological SH were 10.2%, 25.8%, 35.5%, 20.8% and 28.2%, respectively. Three interpretable phenotypes of SH were identified: low SH (57.8%), medium SH (29.0%), and high SH (13.2%). Furthermore, CM was positively associated with the SH phenotype, psychological resilience mediated the association between CM and the SH phenotype (all ps < 0.01), and a larger mediating effect was observed in the medium SH (22.41%).ConclusionsOur findings offer new perspectives that improving psychological resilience can be used as an efficient intervention to reduce the risk of SH among early adolescents who have experienced CM.

Child sexual abuse (CSA) has been recognized as a risk factor for sexual dysfunction and has attracted increasing attention. However, controversies remain regarding related research. The aim is to calculate the pooled effect size estimate for the correlation between CSA and sexual dysfunction in adults by meta-analysis. Five bibliographic databases (PubMed, Cochrane Library, Web of Science, Embase, and PsycINFO) were comprehensively searched to clarify the association between CSA and sexual dysfunction in adults. We used a fixed-effects model to determine the total pooled effect size estimate and reported odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). Subgroup analysis, publication bias analysis, and sensitivity analysis were conducted. Adults who had a history of CSA experienced a higher proportion of sexual dysfunction than adults with no history of CSA (OR = 1.68, 95% CI [1.49, 1.87]). Subgroup analysis showed that women with a history of CSA reported a higher proportion of sexual dysfunction than men with a history of CSA (men: OR = 1.45, 95% CI [1.05, 1.84]; women: OR = 1.62, 95% CI [1.42, 1.83]). The estimates of the effect sizes differed substantially depending on the CSA and sexual dysfunction instruments that were used in each study and the region of each sample. This meta-analysis provides conclusive evidence of an association between CSA and sexual dysfunction in adults. Currently known interventions for the treatment of sexual dysfunction after CSA have only been evaluated in women, so specific interventions should be designed for men CSA survivors who experience sexual impairment.

To establish a diatom database by analyzing the quatity, species distribution and differences of diatom in water samples of the whole navigable sections of the Beijing-Hangzhou Grand Canal, to provide a reference for the inference of the drowning site.Water samples were collected at 22 sites in the navigable sections of the Beijing-Hangzhou Grand Canal (Jining section to Yangzhou Section), and the diatoms at each site were qualitatively and quantitatively analyzed by using graphite digestion-scanning electron microscopy.Sampling site T (Laohuaijiang River Line, Gaoyou City, Yangzhou City, Jiangsu Province) had the highest number of diatoms, while sampling site O (Siyang County, Suqian City, Jiangsu Province) had the lowest number of diatoms, with a large gap of 68 times. At sampling site Q (Jiangpu District, Huaian city, Jiangsu Province), there were 19 species of diatoms. The sampling site O had the least diatoms, with 7 species. There were no significant differences in species evenness and species diversity at each sampling site (The species richness of diatoms gradually increased from north to south. Diatom species richness and species diversity might be higher in areas with complex environments and large population flow. Climate type has a certain influence on the distribution of diatoms.

CRISPR-based genome engineering tools are associated with off-target effects that constitutively active Cas9 protein may instigate. In the present study, we screened for irreversible small molecule off-switches of CRISPR-Cas9 and discovered that selective inhibitors of nuclear export (SINEs) could inhibit the cellular activity of CRISPR-Cas9 by interfering with the nuclear export of Cas9 mRNA. We subsequently found that SINEs, including an FDA-approved anticancer drug KPT330, could improve the specificities of CRISPR-Cas9-based genome and base editing tools in human cells.

CRISPR-based genome engineering tools are associated with off-target effects that constitutively active Cas9 protein may instigate. Previous studies have revealed the feasibility of modulating Cas9-based genome- and base-editing tools using protein or small-molecule CRISPR inhibitors. Here we screened a set of small molecule compounds with irreversible warhead, aiming to identifying small-molecule modulators of CRISPR-Cas9. It was found that selective inhibitors of nuclear export (SINEs) could efficiently inhibit the cellular activity of Cas9 in the form of genome-, base- and prime-editing tools. Interestingly, SINEs did not function as direct inhibitors to Cas9, but modulated Cas9 activities by interfering with the nuclear export process of Cas9 mRNA. Thus, to the best of our knowledge, SINEs represent the first reported indirect, irreversible inhibitors of CRISPR-Cas9. Most importantly, an FDA-approved anticancer drug KPT330, along with other examined SINEs, could improve the specificities of CRISPR-Cas9-based genome- and base editing tools in human cells. Our study expands the toolbox of CRISPR modulating elements and provides a feasible approach to improving the specificity of CRISPR-Cas9-based genome engineering tools.

Asymmetric synthesis of quinoline-naphthalene atropisomers with fully blocked ortho positions has been developed by a two-step strategy, which contains a chiral phosphoric acid-catalyzed Povarov reaction and a DDQ oxidation reaction. This method provides facile access to diverse functionalized quinoline-naphthalene atropisomers with one or two chiral axes in excellent yields (≤98%) and excellent enantioselectivities (≤99% ee).

Endothelial nitric oxide synthase (eNOS) encoded by nitric oxide synthase 3 (NOS3), can generate nitric oxide (NO) which serves as an important deterrent to the pathogenesis of thrombosis by modulating the activation, adhesion and aggregate formation of platelets. Three serum miRNAs (miR-195, miR-532 and miR-582) have been suggested as biomarkers for the diagnosis of deep vein thrombosis (DVT), however their potential roles in DVT is not clear. The effect of miRNAs inhibiting the expression of NOS3 was evaluated in vitro. miR-195, miR-532 and miR-582 mimic, inhibitor, and control miRNAs were transfected into endothelial cells. The roles of miR-195, miR-532 and miR-582 regulating the expression of eNOS were evaluated by real-time quantitative PCR, Western Blotting and luciferase reporter assays. NO release was measured by Griess method. We confirmed NOS3 as a direct target of miR-195 and miR-582, which binds to the 3'-UTR of NOS3 mRNA in endothelial cells. A significantly inverse correlation between these two miRNAs and eNOS expression was detected. NO release from endothelial cells was decreased when the expression level of miR-195 and miR-582 was up-regulated. These findings indicated that miR-195 and miR-582 regulated NO release by targeting 3'-UTR of NOS3 post-transcriptionally in endothelial cells. Therefore, miR-195 and miR-582 might play an important role in maintaining endothelial NO bioavailability and could be a novel target for treatment of thrombotic diseases.

Meniscal allograft transplantation yields good and excellent results but is limited by donor availability. The purpose of the study was to evaluate the effectiveness of radiated deep-frozen xenogenic meniscal tissue (RDF-X) as an alternative graft choice in meniscal transplantation. The xenogenic meniscal tissues were harvested from the inner 1/3 part of the porcine meniscus and then irradiated and deeply frozen. The medial menisci of rabbits were replaced by the RDF-X. Meniscal allograft transplantation, meniscectomy and sham operation served as controls. Only a particular kind of rabbit-anti-pig antibody (molecular ranging 60–80 kD) was detected in the blood serum at week 2. The menisci of the group RDF-X grossly resembled the native tissue and the allograft meniscus with fibrocartilage regeneration at postoperative 1 year. Cell incorporation and the extracellular matrix were mostly observed at the surface and the inner 1/3 part of the newly regenerated RDF-X, which was different from the allograft. The biomechanical properties of the group RDF-X were also approximate to those of the native meniscus except for the compressive creep. In addition, chondroprotection was achieved after the RDF-X transplantation although the joint degeneration was not completely prevented. To conclude, the RDF-X could be a promising alternative for meniscal transplantation with similar tissue regeneration capacity to allograft transplantation and superior chondroprotection. The potential minor immunological rejection should be further studied before its clinical application.

Background CRISPR-Cas9 has been developed as a therapeutic agent for various infectious and genetic diseases. In many clinically relevant applications, constitutively active CRISPR-Cas9 is delivered into human cells without a temporal control system. Excessive and prolonged expression of CRISPR-Cas9 can lead to elevated off-target cleavage. The need for modulating CRISPR-Cas9 activity over time and dose has created the demand of developing CRISPR-Cas off switches. Protein and small molecule-based CRISPR-Cas inhibitors have been reported in previous studies. Results We report the discovery of Cas9-inhibiting peptides from inoviridae bacteriophages. These peptides, derived from the periplasmic domain of phage major coat protein G8P (G8PPD), can inhibit the in vitro activity of Streptococcus pyogenes Cas9 (SpCas9) proteins in an allosteric manner. Importantly, the inhibitory activity of G8PPD on SpCas9 is dependent on the order of guide RNA addition. Ectopic expression of full-length G8P (G8PFL) or G8PPD in human cells can inactivate the genome-editing activity of SpyCas9 with minimum alterations of the mutation patterns. Furthermore, unlike the anti-CRISPR protein AcrII4A that completely abolishes the cellular activity of CRISPR-Cas9, G8P co-transfection can reduce the off-target activity of co-transfected SpCas9 while retaining its on-target activity. Conclusion G8Ps discovered in the current study represent the first anti-CRISPR peptides that can allosterically inactivate CRISPR-Cas9. This finding may provide insights into developing next-generation CRISPR-Cas inhibitors for precision genome engineering.

To provide a vehicle for sustained release of cartilage-protective agent for the potential application of osteoarthritis (OA) treatment, we developed a kartogenin (KGN)-incorporated thermogel for intra-articular injection. We fabricated a poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PLGA–PEG–PLGA) thermogel as a KGN carrier for IA injection. OA chondrocytes were cultured in thermogel with or with no KGN to investigate the effect of KGN thermogel on cartilage matrix. The in vivo effect of KGN thermogel on OA was examined in a rabbit OA model. The KGN thermogel showed a sustained in vitro release of KGN for 3 weeks. OA chondrocytes proliferated well both in thermogel and KGN thermogel. In addition, OA chondrocytes produced higher amount of [type 2 collagen (COL-2) and glycosaminoglycan (GAG)], as well as lower level of matrix metalloproteinase 13 (MMP-13) in KGN thermogel that those in thermogel with no addition of KGN. The gene analysis supported that KGN thermogel enhanced expression of hyaline-cartilage specific genes Col 2 and AGC, and inhibited the expression of MMP-13. Compared with intra-articular injection of saline or thermogel containing no KGN, KGN thermogel can enhance cartilage regeneration and inhibit joint inflammation of arthritic knees in a rabbit ACLT-induced OA model at 3 weeks after the injection. Therefore, the KGN-incorporated PLGA–PEG–PLGA thermogel may provide a novel treatment modality for OA treatment with IA injection.

To observe the effects of AdipoRon orally on the functions of spleen and pancreas in type 2 diabetic mice, in order to present data for clinical application.Forty C57/BL6 male mice were randomly divided into 2 groups: normal control group (n=10) and model group (n=30), the former group was fed normally, while the later group was fed with high fat and sugar for 4 weeks.After that, type 2 diabetes model was established in DM group induced by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg).As type 2 diabetes model established successfully, the model mice were randomly divided into three groups (n=10): diabetes mellitus (DM) group, high dose of AdipoRon group (DM + H) and low dose of adiponRon group (DM + L).All the four groups were treated with saline, saline, AdipoRon at the doses of 20 mg/kg and 50 mg/kg by gavages respectively, once a day for 10 days.And then put them to death for collecting blood, pancreas and spleen.Pathological changes of pancreas were observed with a light microscope after HE staining.Protein contents of insulin receptor (INSR), insulin receptor substrate 1( IRS-1) and tumor necrosis factor-α(TNF-α) in pancreatic and spleen tissues were detected by ELISA.The protein level of phosphorylation insulin receptor substrate 1(p-IRS-1) in pancreas was determined by Western blot, and the expression of insulin mRNA in pancreas was tested by RT-PCR.Under the light microscope, it was visible that the pancreatic tissue in NC group was full and closely packed, and the islet was big.Pancreatic tissue of DM mice was incompact and the islet of DM mice was smaller than that of normal mice.As for the mice treated with AdipoRon orally, the pancreatic tissue was full and closely arranged, and the islet was slightly smaller.Compared with NC group, the levels of TNF-α in pancreas and spleen of DM group were increased markedly, the levels of INSR and IRS-1 were decreased, the spleen coefficient, p-IR-1 protein level and insulin mRNA expression in pancreas were decreased, all were significant statistically (P＜0.05).Compared with DM group, the levels of TNF-α in pancreas and spleen of AdipoRon groups were decreased, the levels of INSR and IRS-1 in pancreas and spleen of AdipoRon groups were increased, while the spleen coefficient was increased (P＜0.05).The p-IRS-1 protein level and insulin mRNA expression in pancreas in DM+H group were increased (P＜0.05).Compared with DM + L group, the level of TNF-α was decreased, and the levels of INSR and IRS-1 were significantly increased (P＜0.05) in DM + H group (P＜0.05).Oral administration of AdipoRon can protect the spleen and pancreas of diabetic mice by decreasing the inflammatory response, up-regulating the expression of INSR, and increasing p-IRS-1 level in diabetic mice.

Reconstruction of the anisotropic structure and proper function of the knee meniscus remains an important challenge to overcome, because the complexity of the zonal tissue organization in the meniscus has important roles in load bearing and shock absorption. Current tissue engineering solutions for meniscus reconstruction have failed to achieve and maintain the proper function in vivo because they have generated homogeneous tissues, leading to long-term joint degeneration. To address this challenge, we applied biomechanical and biochemical stimuli to mesenchymal stem cells seeded into a biomimetic scaffold to induce spatial regulation of fibrochondrocyte differentiation, resulting in physiological anisotropy in the engineered meniscus. Using a customized dynamic tension-compression loading system in conjunction with two growth factors, we induced zonal, layer-specific expression of type I and type II collagens with similar structure and function to those present in the native meniscus tissue. Engineered meniscus demonstrated long-term chondroprotection of the knee joint in a rabbit model. This study simultaneously applied biomechanical, biochemical, and structural cues to achieve anisotropic reconstruction of the meniscus, demonstrating the utility of anisotropic engineered meniscus for long-term knee chondroprotection in vivo.

An increasing number of studies have detected mesenchymal stromal cells (MSCs) and mesenchymal progenitor cells (MPCs) in the peripheral blood (PB). This study aimed to systematically review the possibility of using the PB as a source for chondrogenic progenitors. PubMed, the Web of Science, and Embase were searched for relevant articles. The findings of the studies were reviewed to evaluate the biological characteristics of PB-derived MSCs, chondrogenic MPCs, and their applications in cartilage repair. Thirty-six articles were included in the final analysis, 29 of which indicated that PB is a potential source for chondrogenic progenitor cells. Thirty-two studies reporting in vitro data, including 79.2% (19/24) of studies on PB MSCs and 75% (6/8) of studies on chondrogenic PB MPCs, confirmed the existence of PB MSCs and PB MPCs, respectively; all in vivo investigations showed that using PB as a cell source enhanced cartilage repair. PB MSCs were found in most of the animal studies (12/13), whereas 7 of 11 human studies described the presence of PB MSCs. This systematic review strongly indicates the existence of MSCs in the PB of animals, whereas the presence of MSCs in human PB is less clear. Although the presence of both MSCs and chondrogenic MPCs in the PB, as well as a few favorable outcomes associated with the use of PB-derived progenitors for cartilage repair in vivo, suggests that the PB is a potential alternative source of chondrogenic progenitor cells for cartilage repair, the efficacy of these cells has not been compared to those from other sources, such as bone marrow or adipose tissue in controlled studies.

A vertical flow constructed wetland was combined with a biological aerated filter to develop an ecological filter, and to obtain the optimal operating parameters: The hydraulic loading was 1.55 m 3 /(m 2 ·d), carbon–nitrogen ratio was 10, and gas–water ratio was 6. The experimental results demonstrated considerable removal efficiency of chemical oxygen demand (COD), ammonia nitrogen (NH 4 + -N), total nitrogen (TN), and total phosphorus (TP) in wastewater by the ecological filter, with average removal rates of 83.79%, 93.10%, 52.90%, and 79.07%, respectively. Concentration of NH 4 + -N after treatment met the level-A discharge standard of GB18918-2002. Compared with non-plant filter, the ecological filter improved average removal efficiency of COD, NH 4 + -N, TN, and TP by 13.03%, 25.30%, 14.80%, and 2.32%, respectively: thus, plants significantly contribute to the removal of organic pollutants and nitrogen. Through microporous aeration and O 2 secretion of plants, the ecological filter formed an aerobic–anaerobic–aerobic alternating environment; thus aerobic and anaerobic microbes were active and effectively removed organic pollutants. Meanwhile, nitrogen and phosphorus were directly assimilated by plants and as nutrients of microorganisms. Meanwhile, pollutants were removed through nitrification, denitrification, filtration, adsorption, and interception by the filler. High removal rates of pollutants on the ecological filter proved that it is an effective wastewater-treatment technology for decentralized wastewater of mountainous towns.

Direct polymerization of allyl alcohol generally results in low molar mass oligomers or highly branched or cross-linked structures, and the properties and applications of linear, high molar mass poly(allyl alcohol) (PAA) are relatively unexplored. Such macromolecular materials that cannot otherwise be obtained directly can be accessed by postpolymerization modification strategies. Herein we describe the synthesis and characterization of linear, high molar mass PAA by borohydride reduction of a new activated polyacrylamide. The facile polymerization and mild reduction conditions enable the preparation of PAA of targeted molar masses and low dispersity, as well as PAA block polymers via chemoselective reduction of the activated amide moiety.

To measure and manage plant growth in arid and semi-arid sandlands, improved understanding of the spatial patterns of desert soil resources and the role of soil microbes is required. The rhizosphere soils of

Therapeutic proteins have shown great potential in treating life-threatening diseases, but the hydrophilicity and high molecular weight hamper their passing through the cell membrane. Cell-penetrating peptide (CPP)-assisted protein delivery is a simple and efficacious strategy to promote the cellular uptake of therapeutic proteins. We recently demonstrated that the engineered Cys2-His2 zinc-finger domains possess intrinsic cell permeability, which could be leveraged for intracellular protein delivery. Here we applied this method to deliver superoxide dismutase (SOD), a therapeutic protein widely used in preclinical and clinical studies. We present a protocol for the production and delivery of zinc-finger domain-fused SOD. This protocol can be extended for delivering other therapeutic proteins.

Tissue-engineered meniscus offers a possible solution to the regeneration and replacement problem of meniscectomy. However, the nonuniform distribution and declined proliferation of seeded cells on scaffolds hinder the application of tissue-engineered meniscus as a new generation of meniscus graft. This study systematically investigated the performances of different seeding techniques by using the demineralized cancellous bone (DCB) as the scaffold. Static seeding, injection seeding, centrifugal seeding, and vacuum seeding methods were used to seed the meniscal fibrochondrocytes (MFCs) and mesenchymal stem cells (MSCs) to scaffolds. Cell-binding efficiency, survival rate, distribution ability, and long-term proliferation effects on scaffolds were quantitatively evaluated. Cell adhesion was compared via cell-binding kinetics. Cell viability and morphology were assessed by using fluorescence staining. Combined with the reconstructed three-dimensional image, the distribution of seeded cells was investigated. The Cell Counting Kit-8 assay and DNA assay were employed to assess cell proliferation. Cell-binding kinetics and cell survival of the MFCs were improved via centrifugal seeding compared to injection or vacuum seeding methods. Seeded MFCs by centrifugation showed a more homogeneous distribution throughout the scaffold than cells seeded by other methods. Moreover, the penetration depth in the scaffold of seeded MFCs by centrifugation was 300-500 μm, much higher than the value of 100-300 μm by the surface static and injection seeding. The long-term proliferation of the MFCs in the centrifugal group was also significantly higher than that in the other groups. The results of the MSCs were similar to those of the MFCs. The centrifugal seeding method could significantly improve MFCs or MSCs distribution and proliferation on the DCB scaffolds, thus providing a simple, cost-effective, and effective cell-seeding protocol for tissue-engineered meniscus.

Meniscus injury is a common sports injury. The removal of the injured meniscus predisposes the development of osteoarthritis. Tissue engineering provides a promising approach for the treatment of meniscus injury. Over the past few decades, researchers have put a lot of effort in developing various kinds of scaffolds for preventing osteoarthritis and relieving clinical symptoms. The scaffolds for meniscus tissue engineering (MTE) can be categorized into four classes: hydrogels, three-dimensional (3D) porous polymeric scaffolds, extracellular matrix (ECM) macromolecule-based 3D matrices, and tissue-derived platforms. Although the expected efficacies in tissue integration and chondro-protective function have not yet emerged, several scaffolds have been exploited to provide new substitutes for native meniscus, suggesting their great potential in promoting tissue engineered meniscus (TEM). In the current review, we provide and discuss evidences on different scaffolds in order to make recommendations for the further development of MTE.

Under the constraints of distribution transformer capacity and customer charging needs, a UML model for EMS of EV Charging Station is proposed to analyze energy dispatching functions and integrate control strategies of Charging Station. Due to the fact that EV charging system is a complex adaptive system, Multi-Agent System method is utilized in this model. The UML development process provides an extensible and integrated framework, which lays the foundations for the further development on EMS of EV Charging station.

Synthetic polymeric scaffolds are commonly used in bone tissue engineering (BTE) due to their biocompatibility and adequate mechanical properties. However, their hydrophobicity and the lack of specific cell recognition sites confined their practical application. In this study, to improve the cell seeding efficiency and osteoinductivity, an injectable thermo-sensitive chitosan hydrogel (CSG) was incorporated into a 3D-printed poly(ε-caprolactone) (PCL) scaffold to form a hybrid scaffold. To demonstrate the feasibility of this hybrid system for BTE application, rabbit bone marrow mesenchymal stem cells (BMMSCs) and bone morphogenetic protein-2 (BMP-2) were encapsulated in CSG. Pure PCL scaffolds were used as controls. Cell proliferation and viability were investigated. Osteogenic gene expressions of BMMSCs in various scaffolds were determined with reverse transcription polymerase chain reaction (RT-PCR). Growth factor releasing profile and mechanical tests were performed. CCK-8 assay confirmed greater cell retention and proliferation in chitosan and hybrid groups. Confocal microscopy showed even distribution of cells in the hybrid system. After 2-week osteogenic culture in vitro, BMMSCs in hybrid and chitosan scaffolds showed stronger osteogenesis and bone-matrix formation. To conclude, chitosan/PCL hybrid scaffolds are a favorable platform for BTE due to its capacity to carry cells and drugs, and excellent mechanical strength.

Sarsasapogenin, extracted from Anemarrhena asphodeloides Bunge., has been reported to protect neurons from H 2 O 2 -induced damage. In the current study, four series of 26-amino acid methyl ester substituted sarsasapogenin derivatives ( 5a – 5e , 5f – 5j , 6a – 6e and 7a – 7e ) were synthesized and tested for neuroprotective activity by evaluating their neuroprotective ratio against SH-SHY5Y cell lines. Studies showed that most of the target compounds displayed better neuroprotective effects than that of sarsasapogenin. Structure-activity relationship analysis suggested that 3-methoxy derivatives ( 5f – 5j ) were more potent than other series and the phenylalanine methyl ester moiety at C-26 was important for exhibiting apparent neuroprotective activity. It was worth noting that compound 5h exhibited optimal neuroprotective activity (102.2%) compared with sarsasapogenin (27.3%) and trolox (40.5%), and this encouraged us to investigate the cellular mechanism of 5h further. Our investigation revealed that 5h could attenuate H 2 O 2 -induced cell damage by inhibiting the expression of cleaved poly (ADP-ribose) polymerase (PARP) and cleaved caspase-3 as well as rescuing the downregulation of brain-derived neurotrophic factor (BDNF) and its tyrosine receptor kinase B (TrkB). Taken together, these results suggest that the representative compound 5h is a profound lead compound for further investigation and the sarsasapogenin skeleton could be a promising structural template for the development of new anti-Alzheimer drug candidates.

Background: Total meniscectomy leads to knee osteoarthritis in the long term. The poly(ε-caprolactone) (PCL) scaffold is a promising material for meniscal tissue regeneration, but cell-free scaffolds result in relatively poor tissue regeneration and lead to joint degeneration. Hypothesis: A novel, 3-dimensional (3D)–printed PCL scaffold augmented with mesenchymal stem cells (MSCs) would offer benefits in meniscal regeneration and cartilage protection. Study Design: Controlled laboratory study. Methods: PCL meniscal scaffolds were 3D printed and seeded with bone marrow–derived MSCs. Seventy-two New Zealand White rabbits were included and were divided into 4 groups: cell-seeded scaffold, cell-free scaffold, sham operation, and total meniscectomy alone. The regeneration of the implanted tissue and the degeneration of articular cartilage were assessed by gross and microscopic (histological and scanning electron microscope) analysis at 12 and 24 weeks postoperatively. The mechanical properties of implants were also evaluated (tensile and compressive testing). Results: Compared with the cell-free group, the cell-seeded scaffold showed notably better gross appearance, with a shiny white color and a smooth surface. Fibrochondrocytes with extracellular collagen type I, II, and III and proteoglycans were found in both seeded and cell-free scaffold implants at 12 and 24 weeks, while the results were significantly better for the cell-seeded group at week 24. Furthermore, the cell-seeded group presented notably lower cartilage degeneration in both femur and tibia compared with the cell-free or meniscectomy group. Both the tensile and compressive properties of the implants in the cell-seeded group were significantly increased compared with those of the cell-free group. Conclusion: Seeding MSCs in the PCL scaffold increased its fibrocartilaginous tissue regeneration and mechanical strength, providing a functional replacement to protect articular cartilage from damage after total meniscectomy. Clinical Relevance: The study suggests the potential of the novel 3D PCL scaffold augmented with MSCs as an alternative meniscal substitution, although this approach requires further improvement before being used in clinical practice.

Background and aims: We aimed to evaluate the association between famine exposure during early life and obesity and obesity(max) (obese at the highest weight) in adulthood. Methods and results: Data were from two population-based cross-sectional surveys conducted in 2006 and 2009 in Qingdao, China. A total of 8185 subjects born between 1/1/1941 and 12/31/1971 were categorized into unexposed (born between 01/01/1962 and 12/31/1971), fetal/ infant exposed (born between 01/01/1959 and 12/31/1961), childhood exposed (born between 01/01/1949 and 12/31/1958) and adolescence exposed (born between 01/01/1941 and 12/31/1948) according to their age when exposed to the Chinese famine from 1959 to 1961. Obesity was defined as BMI (body mass index) >= 28.0 and obesitymax was defined as BMImax (BMI at the highest weight) >= 28.0. We compared fetal/ infant exposed, childhood exposed and adolescence exposed to the unexposed using logistic regression models to assess the effect of famine exposure on later obesity and obesitymax. Fetal/infant exposed (OR = 1.59, P

A novel vacuum cleaner was designed and tested. The testing results showed that the PM2.5 of new cleaner was130μg/m3, compared to the traditional one was 440μg/m3when they were working in a same condition. After being used 4 months, the resistance of the new cleaner remained about 50Pa, while the traditional one was more than 200Pa. The filters replacement cycle of the novel cleaner was changed from 3 times a year to 1 time a year. The relative humidity and temperature were improved from 21% and 18oC to 25oC and 45% in the winter respectively. The amount of average bacterial content was changed from 3560 cfu/m3to 1790 cfu/m3in a closed ward of a hospital.

Current approaches to fabrication of nSC composites for bone tissue engineering (BTE) have limited capacity to achieve uniform surface functionalization while replicating the complex architecture and bioactivity of native bone, compromising application of these nanocomposites for in situ bone regeneration. A robust biosilicification strategy is reported to impart a uniform and stable osteoinductive surface to porous collagen scaffolds. The resultant nSC composites possess a native-bone-like porous structure and a nanosilica coating. The osteoinductivity of the nSC scaffolds is strongly dependent on the surface roughness and silicon content in the silica coating. Notably, without the use of exogenous cells and growth factors (GFs), the nSC scaffolds induce successful repair of a critical-sized calvarium defect in a rabbit model. It is revealed that topographic and chemical cues presented by nSC scaffolds could synergistically activate multiple signaling pathways related to mesenchymal stem cell recruitment and bone regeneration. Thus, this facile surface biosilicification approach could be valuable by enabling production of BTE scaffolds with large sizes, complex porous structures, and varied osteoinductivity. The nanosilica-functionalized scaffolds can be implanted via a cell/GF-free, one-step surgery for in situ bone regeneration, thus demonstrating high potential for clinical translation in treatment of massive bone defects.