Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism.

Recent investigations into heterochronic parabiosis have unveiled robust rejuvenating effects of young blood on aged tissues. However, the specific rejuvenating mechanisms remain incompletely elucidated. Here we demonstrate that small extracellular vesicles (sEVs) from the plasma of young mice counteract pre-existing aging at molecular, mitochondrial, cellular and physiological levels. Intravenous injection of young sEVs into aged mice extends their lifespan, mitigates senescent phenotypes and ameliorates age-associated functional declines in multiple tissues. Quantitative proteomic analyses identified substantial alterations in the proteomes of aged tissues after young sEV treatment, and these changes are closely associated with metabolic processes. Mechanistic investigations reveal that young sEVs stimulate PGC-1α expression in vitro and in vivo through their miRNA cargoes, thereby improving mitochondrial functions and mitigating mitochondrial deficits in aged tissues. Overall, this study demonstrates that young sEVs reverse degenerative changes and age-related dysfunction, at least in part, by stimulating PGC-1α expression and enhancing mitochondrial energy metabolism.

Palladium-Catalyzed Cyclization/Alkenylation of Ynone Oximes with Vinylsilanes for the Assembly of Isoxazolyl Vinylsilanes.

A palladium-catalyzed cascade cyclization/alkenylation for the assembly of synthetically valuable isoxazolyl vinylsilane derivative has been accomplished. Easily accessible ynone oximes, and available vinylsilane agents were used as the reaction starting materials This protocol features broad substrate scope, good functional group tolerance, and good step- and atom-economy. Remarkably, this approach provides a new approach for the construction of structurally diverse isoxazolyl-containing vinylsilanes with high molecular complexity, showing a promising application in synthetic and pharmaceutical chemistry.

Rapid assembly of structurally diverse cyanamides and disulfanes via base-mediated aminoalkylation of aryl thiourea.

A general method for the preparation of cyanamides and disulfanes from aryl thiourea and halide through a base-mediated strategy is described. Mercaptan and N-aryl cyanamide are the key intermediates in the reaction. The current method is convenient, eco-friendly, and has high yields for the synthesis of substituted cyanamide and functional disulfanes in a one-pot procedure from readily available starting materials.

Whole-exome sequencing analysis identifies novel variants associated with Kawasaki disease susceptibility.

BACKGROUND: Kawasaki disease (KD) is an acute pediatric vasculitis affecting genetically susceptible infants and children. Although the pathogenesis of KD remains unclear, growing evidence links genetic susceptibility to the disease. METHODS: To explore the genes associated with susceptibility in KD, we applied whole-exome sequencing to KD and control subjects from Yunnan province, China. We conducted association study analysis on the two groups. RESULTS: In this study, we successfully identified 11 significant rare variants in two genes (MYH14 and RBP3) through the genotype/allele frequency analysis. A heterozygous variant (c.2650G > A, p.V884M) of the RBP3 gene was identified in 12 KD cases, while eight heterozygous variants (c.566G > A, p.R189H; c.1109 C > T, p.S370L; c.3917T > G, p.L1306R; c.4301G > A, p.R1434Q; c.5026 C > T, p.R1676W; c.5329 C > T, p.R1777C; c.5393 C > A, p.A1798D and c.5476 C > T, p.R1826C) of the MYH14 gene were identified in 8 KD cases respectively. CONCLUSION: This study suggested that nine variants in MYH14 and RBP3 gene may be associated with KD susceptibility in the population from Yunnan province.

Synthesis of gem-Difluorinated Isoxazoles via Palladium-Catalyzed Oxylallylation of Alkynone Oxime Ethers.

A novel and reliable palladium-catalyzed oxylallylation of alkynone oxime ethers with fluorine-containing alkenes was accomplished. Using the bulk industrial chemical 3-bromo-3,3-difluoroprop-1-ene as the coupling partner, this synthetic methodology offers the first example for the assembly of structurally diverse gem-difluorinated isoxazole derivatives in moderate to good yields with high atom- and step-economy and excellent functional group compatibility. More importantly, this strategy allows for the direct combination of the isoxazole motifs and gem-difluoroalkene unit, which is not easy to obtain through a general synthetic strategy.

Facile synthesis of isoquinolines and isoquinoline N-oxides via a copper-catalyzed intramolecular cyclization in water.

A highly efficient method for the facile access of isoquinolines and isoquinoline N-oxides via a Cu(i)-catalyzed intramolecular cyclization of (E)-2-alkynylaryl oxime derivatives in water has been developed. This protocol was performed under simple and mild conditions without organic solvent, additives or ligands. By switching on/off a hydroxyl protecting group of oximes, the selective N-O/O-H cleavage could be triggered, delivering a series of isoquinolines and isoquinoline N-oxides, respectively, in moderate to high yields with good functional group tolerance and high atom economy. Moreover, the practicality of this method was further demonstrated by the total synthesis of moxaverine in five steps.

Palladium-Catalyzed Cascade Cyclization/Alkylation of Oxime Ethers: Assembly of 4-Alkylisoxazoles by "Chain-Walking" Strategy.

A reliable and efficient palladium-catalyzed cascade cyclization/alkylation of oxime ethers with unactivated alkenes is described, affording a whole variety of structurally diverse isoxazole derivatives in moderate to good yields with excellent functional group compatibility. Ionic liquid [Aeim]Br not only acts as an environmentally friendly solvent but also acts as an accelerating agent to provide excess bromine source to eliminate bromomethane from oxime ethers. More importantly, the use of "chain-walking" strategy provides a novel methodology in organic synthesis to rapid generation of molecular complexity from readily available starting materials.

Comparison of the Outcomes between AO Type B2 Thoracolumbar Fracture with and without Disc Injury after Posterior Surgery.

OBJECTIVE: The type AO B2 thoracolumbar fracture is a kind of flexion-distraction injury and the effect of disc injury on treatment results of patients with B2 fracture remains unclear. The objective of the current study was to compare and analyze the outcomes in AO Type B2 thoracolumbar fracture patients with and without disc injuries in terms of the Cobb angle of kyphosis, the incidence of complication, and the rate of implant failure. METHODS: This is a retrospective study. Of the 486 patients with thoracolumbar fractures who underwent posterior fixation, 38 patients with AO type B2 injuries were included. All the patients were divided into two groups according to changes in the adjoining discs. Disc injury group A included 17 patients and no disc injury group included 21 patients. Clinical and radiologic parameters were evaluated before surgery, after surgery, and at follow-up. Clinical outcomes included visual analogue scale (VAS) scores, incidence of complications, and incidence of implant failure. Radiologic assessment was accomplished with the Cobb angle (CA), local kyphosis (LK), percentage of anterior vertebral height (AVBH%), intervertebral disc height, and intervertebral disc angle. Fisher's precision probability tests were employed and chi square test were used to compare categorical variables. Paired sample t tests and independent-sample t tests were used to compare continuous data. RESULTS: Disc injury mainly involved the cranial disc (15/19, 78.9%). The mean follow-up period for the patients was 30.2 ± 20.1 months. No neurologic deterioration was reported in the patients at the last follow-up. Radiological outcomes at the last follow-up showed significant differences in the CA (18.59° ± 13.74° vs 8.16° ± 9.99°, P = 0.008), LK (12.74° ± 8.00° vs 6.55° ± 4.89°, P = 0.006), and %AVBH (77.16% vs 90.83%, P = 0.01) between the two groups.Implant failure occurred after posterior fixation in five patients with disc injury who did not undergo interbody fusion during the initial surgery. Additionally, in the subgroup analysis, interbody fusion in the implant failure group were significantly different than in the no implant failure group (0% vs 75%, P = 0.009). CONCLUSIONS: AO B2 fracture patients with disc injury have higher risk of complications, especially implant failure after posterior surgery. Interbody fusion should be considered in AO type B2 fracture patients with disc injury.

Enhancement of the bone-implant interface by applying a plasma-sprayed titanium coating on nanohydroxyapatite/polyamide66 implants in a rabbit model.

Solid fusion at the bone-implant interface (BII) is considered one of the indicators of a satisfactory clinical outcome for spine surgery. Although the mechanical and physical properties of nanohydroxyapatite/polyamide66 (n-HA/PA66) offers many advantages, the results of long-term follow-up for BIIs remain limited. This study aimed to improve the BII of n-HA/PA66 by applying plasma-sprayed titanium (PST) and assessing the mechanical and histological properties. After the PST coating was applied to n-HA/PA66 implants, the coating had uneven, porous surfaces. The compression results were not significantly different between the two groups. The micro-CT results demonstrated that at 6 weeks and 12 weeks, the bone volume (BV), BV/tissue volume (TV) and trabecular number (Tb.N) values of the n-HA/PA66-PST group were significantly higher than those of the n-HA/PA66 group. The results of undecalcified bone slicing showed that more new bone appeared to form around n-HA/PA66-PST implant than around n-HA/PA66 implant. The bone-implant contact (BIC) and push-out test results of the n-HA/PA66-PST group were better than those of the n-HA/PA66 group. In conclusion, after PST coating, direct and additional new bone-to-implant bonding could be achieved, improving the BII of n-HA/PA66 implants. The n-HA/PA66-PST implants could be promising for repair purposes.

Pd-Catalyzed Sequential Formation of C-C Bonds: A New Strategy for the Synthesis of (E)-α,ß-Unsaturated Carbonyl Compounds from Sulfoxonium Ylides and 1-Iodo-2-((2-methylallyl)oxy)benzene Compounds.

α,ß-Unsaturated carbonyl compounds are significant moieties in many biological molecules and have attracted considerable attention in organic synthetic chemistry. A Pd-catalyzed cascade cyclization for the synthesis of (E)-α,ß-unsaturated carbonyl compounds with the sequential formation of C-C bonds was developed. This method offers high efficiency, good functional group tolerance, and moderate to excellent yields and generally displays high stereoselectivity.

Synthesis of medicinally relevant oxalylamines via copper/Lewis acid synergistic catalysis.

Allylamines have long been recognized as valuable synthons because of their excellent reactivity in organic synthesis. Here, an efficient amination reaction of allenyl ethers via copper/Lewis acid synergistic catalysis has been established, providing straightforward access to diverse functionalized Z-oxalylamines and E -halogenated oxalylamines in good to excellent yields with high regio- and stereoselectivities. The developed method tolerates more than 100 examples that include late-stage functionalization of bioactive molecules, and features gram-scale synthesis of oxalylamines with high turnover number (TON > 1000) under mild and simple conditions. The applicability of the protocol is further demonstrated with the construction of drug molecules.

[Detect 15 pesticides fungicide in edible fungi by multiplug filtration clean-up pretreatment technology with ultra-high performance liquid chromatography-tandem mass spectrometry].

OBJECTIVE: To establish a method for determination of 15 pesticides residue in edible fungi by multiplug filtration clean-up(m-PFC) pretreatment technique with ultra-high performance liquid chromatography-tandem triple quadruple mass spectrometry(UPLC-MS/MS). METHODS: The interferences of edible fungus samples were removed by extracting with acetonitrile and filtration type extraction column, which were fat, carbohydrates, water-soluble vitamins. Samples were separated with column of Waters ACQUITY UPLC®HSS T3(2.1 mm×100 mm, 1.8 µm), and were scanned by multiple reaction monitoring mode(MRM). Samples were quantified with matrix matching standard curve external standard method. RESULTS: The recoveries of 15 target compounds at the spiked levels of 10, 20, 50 µg/kg were 82.5%-118.5%, and the relative standard deviations were between 6.1% and 23.1%(n=6). The detection limit of 15 target compounds was 1-3 µg/kg, and the limit of quantification was 3-10 µg/kg. CONCLUSION: This method improves the efficiency of pretreatment, has good stability and high sensitivity, and could be used for the detection of 15 pesticides in edible fungi.

Palladium-catalyzed aerobic oxyarylthiolation of alkynone O-methyloximes with arylhydrazines and elemental sulfur.

A novel and practical palladium-catalyzed aerobic oxyarylthiolation of alkynone O-methyloximes for the assembly of 4-sulfenylisoxazole derivatives using S8 and arylhydrazines as the S-aryl sources is accomplished. In the presence of 0.1 mol% of IPr-Pd-allyl-Cl as the catalyst and O2 (1 atm) as the sole oxidant, both alkynone O-methyloximes and arylhydrazines are suitable substrates, delivering diverse 4-sulfenyl isoxazoles in moderate to good yields with good functional group tolerance. Notably, the phenyl diazonium salt and sodium phenyl sulfinate are also suitable arylation reagents, providing an alternative synthetic strategy to access structurally diverse 4-sulfenyl isoxazoles.

Recent advances in aminative difunctionalization of alkenes.

Alkenes are versatile building blocks in modern organic synthesis. In the difunctionalization reactions of alkenes, two functional groups can be simultaneously introduced into the π system. This is an efficient strategy for the synthesis of multifunctional compounds with complex structures and has the advantages of atom and step economy. Nitrogen-containing organic compounds are widely found in natural products and synthetic compounds, such as dyes, pesticides, medicines, artificial resins, and so on. Many natural products with high biological activity and a broad range of drugs have nitrogen-containing functional groups. The research on the construction methods of C-N bonds has always been one of the most important tasks in organic synthesis, especially in drug synthesis, and the synthetic methods starting from simple and easily available raw materials have been a topic of interest to chemists. The aminative difunctionalization of alkenes can efficiently construct C-N bonds, and at the same time, prepare some compounds that usually require multiple steps of reaction. It is one of the most effective strategies for the simple and efficient synthesis of functionalized nitrogen-containing compounds. This review outlines the major developments focusing on the transition metal-catalyzed or metal-free diamination, aminohalogenation, aminocarbonation, amino-oxidation and aminoboronation reactions of alkenes from 2015-2020.

Palladium-catalyzed bisthiolation of terminal alkynes for the assembly of diverse (Z)-1,2-bis(arylthio)alkene derivatives.

An efficient and straightforward palladium-catalyzed three-component cascade bisthiolation of terminal alkynes and arylhydrazines with sodium thiosulfate (Na2S2O3) as the sulfur source for the assembly of functionalized (Z)-1,2-bis(arylthio)alkene derivatives is described. Using 0.5 mol% IPr-Pd-Im-Cl2 as the catalyst, a wide range of terminal alkynes and arylhydrazines are well tolerated, thus producing the desired products in good yields with good functional group tolerance and excellent regioselectivity. Moreover, this protocol could be readily scaled up, showing potential applications in organic synthesis and material science.

Clinical efficacy of three types of autogenous bone grafts in treatment of single-segment thoracic tuberculosis: A retrospective cohort study.

A retrospective study investigated and compared the results of lamina with spinous process (LSP), transverse process strut (TPS) and iliac graft (IG) as bone graft in thoracic single-segment spinal tuberculosis(TB) with the one-stage posterior approach of debridement, fusion and internal instrumentation. 99 patients treated from January 2012 to December 2015 were reviewed. LSP was performed in 35 patients (group A), TPS was undertaken in 33 patients (group B), and IG was carried out in 31 patients (group C). Surgical time, blood loss, hospitalization time, drainage volume, and follow-up (FU) duration were recorded. The visual analog scale (VAS), Oswestry Disability Index (ODI), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), American Spinal Injury Association (ASIA) grade, segmental angle, intervertebral height and bone fusion time were compared between preoperative and final FU. All the patients were followed up for a mean 43.90±10.39 months in group A, 45.30±6.20 months in group B, 44.32±7.17 months in group C without difference(P>0.05). The mean age was younger, the blood loss was less, the hospitalization time and the surgical time were shorter in group A than those in group B and C (P<0.05). The drainage volume was less in group A than that in group B and group C. The CRP, ESR, VAS, and ODI were significantly decreased and there were no significant difference among the groups at the final FU. The neurological function after surgery was improved compared with preoperation among the groups. The bony fusion at a mean time 12.90±3.91 months in group A was longer than that in group B (6.75±1.55 months) and group C (5.52±1.64 months) (P<0.05). No significant difference was found at the mean segmental angle, mean intervetebral height of preoperation and final FU among the groups (P>0.05). In conclusion, the LSP and TPS as bone graft are reliable, safe, and effective for single-segment stability reconstruction for surgical management of thoracic TB and TPS could be new bone graft methods.

Palladium-catalyzed three-component cascade arylthiolation with aryldiazonium salts as S-arylation sources.

A novel and efficient palladium-catalyzed three-component cascade cyclization/arylthiolation has been developed for the assembly of diverse 3-sulfenylindole and 3-sulfenylbenzofuran derivatives from 2-alkynylamines and 2-alkynylphenols, aryldiazonium salts, and Na2S2O3 under aerobic conditions with PEG-200 as an environmentally benign medium. The current study features exceptional functional group tolerance without additional ligands, oxidants or silver salts, and eco-friendly mild reaction conditions. The ionic liquid [C2OHmim]Cl plays a crucial role in this protocol as an environmentally friendly additive. Notably, this procedure represents the first example of the use of aryldiazonium salts as direct S-arylation sources in this type of chemical transformation.

Antitumor effects and mechanisms of pyropheophorbide­α methyl ester­mediated photodynamic therapy on the human osteosarcoma cell line MG­63.

Photodynamic therapy (PDT) is a promising treatment for osteosarcoma, and pyropheophorbide­α methyl ester (MPPa) is a second­generation photosensitizer for tumor treatment. The present study aimed to determine the efficacy and possible mechanisms of MPPa­PDT in the treatment of osteosarcoma MG­63 cells. Flow cytometry and western blotting were used to detect cell cycle­related indicators Cyclin D1, Cyclin E, Cyclin A and Cyclin B1. Cell migration and invasion abilities were detected using wound­healing and Transwell chamber assays. Cellular endoplasmic reticulum stress (ERS), autophagy and apoptosis­related indicators were detected by flow cytometry and western blotting. The results demonstrated that MPPa­PDT blocked the MG­63 cell cycle and inhibited cell migration and invasion. Additionally, MPPa­PDT inhibited the activation of the Akt/mammalian target of rapamycin (mTOR) pathway. MG­63 cells underwent ERS­induced apoptosis following MPPa­PDT treatment. Pretreatment with the mTOR phosphorylation inhibitor rapamycin affected the autophagy of MPPa­PDT­induced osteosarcoma MG­63 cells and enhanced apoptosis through targeting mTOR.

3D-printed titanium implant-coated polydopamine for repairing femoral condyle defects in rabbits.

BACKGROUND: Large segmental bone defects are still one of the challenges for orthopaedic surgeons. Although 3D-printed porous titanium is a potential bone substitute material because of its porous structure simulating natural bone, the titanium surface has low bioactivity, integrates with bone tissue through the simple mechanical interlock. The study aims to investigate the capability and osteogenesis of 3D-printed porous titanium (3D PPT)-coated polydopamine (PDA) for repairing bone defects. METHODS: Fifteen 6-month New Zealand white rabbits were implanted with PDA-3D PPT to repair 6 mm × 10 mm defects on the femoral condyle compared with the group of 3D PPT and comparing with the blank group. After 6 weeks and 12 weeks, micro-CT and histological examination were performed to observe bone growth. RESULTS: All the PDA-3D PPT group, the 3D PPT group and the blank group recovered in good condition. The images showed that the boundaries between the implant area and the surrounding area were obscure in the three groups. The results of micro-CT demonstrated that at 6 weeks and 12 weeks, the bone volume (BV) values of PDA-3D PPT implants group were significantly higher than those of the 3D PPT implants group and blank group (P < 0.05), the BV/tissue volume (TV) and the trabecular number (Tb.N) of PDA-3D PPT implants were significantly higher than those of the 3D PPT group and blank group (P < 0.05). The results of un-decalcified bone slicing showed that ore new bone appeared to form around the PDA-3D PPT than that of 3D PPT and blank group. The bone-implant contact (BIC) of PDA-3D PPT was better (P < 0.05) than that of 3D PPT group. CONCLUSION: PDA-3D PPT could improve the bioactivity and promote the growth and healing of bone tissue and can be a promising repairing material.

Direct Sulfenylation of the Purine C8-H Bond with Thiophenols.

The one-step copper-mediated regioselective formation of the C8-S bond for purine derivatives with arylthiols was achieved using air as the green oxidant in the presence of 1.0 equiv of Na2CO3 and stoichiometric CuCl and 1,10-phenanthroline monohydrate. This method provides an economical, easy-to-handle, and effective method for the synthesis of 8-sulfenylpurine derivatives in moderate to excellent yields. The reaction is selective for C8 over C2 and C6. It also tolerates a free amine on the purine, and it has a wide substrate scope.