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BACKGROUND: A novel approach known as intraosseous regional administration (IORA) has emerged as a technique for delivering prophylactic antibiotics, and it results in higher tissue concentrations around the knee. It is hypothesized that IORA of cefazolin for antibiotic prophylaxis during total knee arthroplasty will result in sustained effective levels for a longer duration. The aim of the current study was to investigate temporal changes in peri-knee cefazolin blood concentrations after IORA of cefazolin. METHODS: Twelve rabbits were randomly divided into two groups, with six rabbits in each group. In control group a single intravenous bolus injection of cefazolin (10 mL, 100 mg) was administered into the marginal ear vein. In experimental groupexperimental group the same dose of cefazolin was injected into the left tibial marrow cavity after tourniquet inflation at the base of the left thigh. Blood samples were collected periodically at different timepoints, and cefazolin concentrations were determined. RESULTS: The intraosseous treatment resulted in significant differences in plasma cefazolin concentrations at all timepoints. Experimental group exhibited higher plasma cefazolin concentrations than control group. CONCLUSIONS: Cefazolin in intraosseous regional prophylaxis exhibits effectiveness in intraoperative antibiotic prophylaxis by maintaining concentrations above the minimum inhibitory concentration for extended durations, rather than relying solely on high concentrations.
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Artroplastia do Joelho , Cefazolina , Animais , Coelhos , Cefazolina/uso terapêutico , Antibacterianos , Artroplastia do Joelho/efeitos adversos , Artroplastia do Joelho/métodos , Antibioticoprofilaxia/métodos , Administração IntravenosaRESUMO
BACKGROUND: Prophylactic antibiotics reduce the risk of periprosthetic joint infection. However, conventional systemic administration may not provide adequate tissue concentrations against more resistant organisms such as coagulase-negative staphylococci. Intraosseous regional administration is known to achieve significantly higher antibiotic tissue concentrations than systemic administration, but it is unclear how synovial fluid concentrations are affected. We aimed to compare synovial fluid cefazolin concentrations achieved by regional intraosseous versus systemic intravenous administration, and also to compare synovial fluid cefazolin concentrations with those in subcutaneous fat. METHODS: A total of 60 patients undergoing primary knee arthroplasty were randomized into 2 groups: group IO received 2 g interosseous cefazolin in 100 mL saline through a tibial cannula after tourniquet inflation and before skin incision; group IV received 2 g cefazolin in 100 mL saline via the median basilic or median cephalic vein 30 min before tourniquet inflation. Subcutaneous fat and synovial fluid samples were collected immediately after skin incision, and cefazolin concentrations were measured by high-performance liquid chromatography. RESULTS: The cefazolin concentration in synovial fluid was 391.3 ± 70.1 µg/ml in group IO and 17.6 ± 3.5 µg/ml in group IV. The cefazolin concentration in subcutaneous fat was 247.9 ± 64.9 µg/g in group IO and 11.4 ± 1.9 µg/g in group IV. CONCLUSION: Intraosseous regional administration results in several times higher tissue concentrations than systemic administration, especially in the synovial fluid.
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In nature, prenylation and geranylation are two important metabolic processes for the creation of hemiterpenoids and monoterpenoids under enzyme catalysis. Herein, we have demonstrated bioinspired unnatural prenylation and geranylation of oxindoles using the basic industrial feedstock isoprene through ligand regulation under Pd catalysis. Pentenylated oxindoles (with C5 added) were attained with high selectivity when using a bisphosphine ligand, whereas upon switching to a monophosphine ligand, selectivity toward geranylated oxindoles (with C10 added) was achieved. Moreover, the head-to-head product could be further isomerized to an internal skipped diene under Pd-H catalysis. No stoichiometric by-product was formed in the process.
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Hemiterpenos , Paládio , Butadienos , Catálise , Ligantes , Oxindóis , PrenilaçãoRESUMO
BACKGROUND: Esophageal adenocarcinoma (EAC) is an aggressive malignancy with a poor prognosis. The immune-related genes (IRGs) are crucial to immunocytes tumor infiltration. This study aimed to construct a IRG-related prediction signature in EAC. METHODS: The related data of EAC patients and IRGs were obtained from the TCGA and ImmPort database, respectively. The cox regression analysis constructed the prediction signature and explored the transcription factors regulatory network through the Cistrome database. TIMER database and CIBERSORT analytical tool were utilized to explore the immunocytes infiltration analysis. RESULTS: The prediction signature with 12 IRGs (ADRM1, CXCL1, SEMG1, CCL26, CCL24, AREG, IL23A, UCN2, FGFR4, IL17RB, TNFRSF11A, and TNFRSF21) was constructed. Overall survival (OS) curves indicate that the survival rate of the high-risk group is significantly shorter than the low-risk group (P = 7.26e-07), and the AUC of 1-, 3- and 5- year survival prediction rates is 0.871, 0.924, and 0.961, respectively. Compared with traditional features, the ROC curve of the risk score in the EAC patients (0.967) is significant than T (0.57), N (0.738), M (0.568), and Stage (0.768). Moreover, multivariate Cox analysis and Nomogram of risk score are indicated that the 1-year and 3-year survival rates of patients are accurate by the combined analysis of the risk score, Sex, M stage, and Stage (The AUC of 1- and 3-years are 0.911, and 0.853). CONCLUSION: The 12 prognosis-related IRGs might be promising therapeutic targets for EAC.
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Adenocarcinoma , Regulação Neoplásica da Expressão Gênica , Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Esôfago , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , PrognósticoRESUMO
BACKGROUND: lncRNA may be involved in the occurrence, metastasis, and chemical reaction of hepatocellular carcinoma (HCC) through various pathways associated with autophagy. Therefore, it is urgent to reveal more autophagy-related lncRNAs, explore these lncRNAs' clinical significance, and find new targeted treatment strategies. METHODS: The corresponding data of HCC patients and autophagy genes were obtained from the TCGA database, and the human autophagy database respectively. Based on the co-expression and Cox regression analysis to construct prognostic prediction signature. RESULTS: Finally, a signature containing seven autophagy-related lncRNAs (PRRT3-AS1, RP11-479G22.8, RP11-73M18.8, LINC01138, CTD-2510F5.4, CTC-297N7.9, RP11-324I22.4) was constructed. Based on the risk score of signature, Overall survival (OS) curves show that the OS of high-risk patients is significantly lower than that of low-risk patients (P = 2.292e-10), and the prognostic prediction accuracy of risk score (AUC = 0.786) is significantly higher than that of ALBI (0.532), child_pugh (0.573), AFP (0.5751), and AJCC_stage (0.631). Moreover, multivariate Cox analysis and Nomogram of risk score are indicated that the 1-year and 3-year survival rates of patients are obviously accuracy by the combined analysis of the risk score, child_pugh, age, M_stage, and Grade (The AUC of 1- and 3-years are 0.87, and 0.855). Remarkably, the 7 autophagy-related lncRNAs may participate in Spliceosome, Cell cycle, RNA transport, DNA replication, and mRNA surveillance pathway and be related to the biological process of RNA splicing and mRNA splicing. CONCLUSION: In conclusion, the 7 autophagy-related lncRNAs might be promising prognostic and therapeutic targets for HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Autofagia , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Criança , Pré-Escolar , Humanos , Lactente , Neoplasias Hepáticas/genética , Prognóstico , RNA Longo não Codificante/genéticaRESUMO
Thiophene-based rings are one of the most widely used building blocks for the synthesis of sulfur-containing molecules. Inspired by the redox diversity of these features in nature, we demonstrate herein a redox-divergent construction of dihydrothiophenes, thiophenes, and bromothiophenes from the respective readily available allylic alcohols, dimethyl sulfoxide (DMSO), and HBr. The redox-divergent selectivity could be manipulated mainly by controlling the dosage of DMSO and HBr. Mechanistic studies suggest that DMSO simultaneously acts as an oxidant and a sulfur donor. The synthetic potentials of the products as platform molecules were also demonstrated by various derivatizations, including the preparation of bioactive and functional molecules.
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The prognosis of Achilles tendon rupture is often unsatisfactory. Proliferative fibrous tissues and disordered collagen bundles make it difficult to guarantee normal biomechanical properties. The present study aimed to investigate the role of fibroblast growth factor-2 (FGF-2) in promoting the ability of human tendon-derived stem cells (hTDSCs) to treat Achilles tendon injury. hTDSCs were isolated from fetal Achilles tendon tissue and verified using fluorescence activated cell sorting analysis and multi-directional differentiation. The cells were then transfected with a lentivirus carrying the FGF2 gene. In vitro, FGF2 overexpression increased the expression of Collagen Type III Alpha 1 Chain (collagen-III) and scleraxis BHLH transcription factor (SCXA) significantly. Additionally, FGF-2-hTDSCs were transplanted into a rat Achilles tendon defect model. The in vivo results showed that the Achilles tendon tissue in the FGF-2 group secreted more extracellular matrix and produced collagen fibers that showed a more orderly arrangement. The expression of collagen-I and III in the FGF-2 group was significantly increased at 4 weeks postoperatively compared with the control group. Moreover, biomechanical tests showed that the failure load of FGF-2 group was higher at 4 and 8 weeks postoperatively than that of the controls. FGF-2 group had the highest stiffness in the early postoperative period, but showed no significant difference in the middle and late postoperative periods compared with that of the controls. In conclusion, FGF2 gene-modified hTDSCs promoted healing of Achilles tendon injury more effectively than hTDSCs alone.
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Tendão do Calcâneo/metabolismo , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/metabolismo , Células-Tronco/metabolismo , Traumatismos dos Tendões/metabolismo , Tendão do Calcâneo/patologia , Animais , Células Cultivadas , Feminino , Fatores de Crescimento de Fibroblastos/genética , Humanos , Ratos , Ratos Sprague-Dawley , Células-Tronco/patologia , Traumatismos dos Tendões/patologiaRESUMO
In this paper, we report the anisotropic optical and catalytic properties of wurtzite-type hexagonal CoO (h-CoO) nanocrystals, an unusual nanosized indirect semiconductor material. h-CoO nanoplates and nanorods with a divided morphology have been synthesized via facile solution methods. The employment of flash-heating and surfactant tri-n-octylphosphine favors the formation of plate-like morphology, whereas the utilization of cobalt stearate as a precursor is critical for the synthesis of nanorods. Structural analyses indicate that the basal plane of the nanoplates is (001) face and the growth direction of the nanorods is along the c axis. Moreover, the UVvis absorption spectra, the corresponding energy gap and the catalytic properties are found to vary with the crystal shape and the dimensions of the as-prepared h-CoO nanocrystals. Furthermore, remarkable catalytic activities for H2 generation from the hydrolysis of alkaline NaBH4 solutions have been observed for the as-prepared h-CoO nanocrystals. The calculated Arrhenius activation energies show a decreasing trend with increasing extension degree along the <001> direction, which is in agreement with the variation of the charge-transfer energy gap. Finally the maximum hydrogen generation rate of the h-CoO nanoplates exceeds most of the reported values of transition metal or noble metal containing catalysts performing in the same reaction system, which makes them a low-cost alternative to commonly used noble metal catalysts in H2 generation from the hydrolysis of borohydrides, and might find potential applications in the field of green energy.
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BACKGROUND: Brachydactyly type E (BDE) is a general term characterized by variable shortening of metacarpals and metatarsals, with phalanges affected frequently. It can occur as an isolated form or part of syndromes and manifest a high degree of phenotypic variability. In this study, we have identified the clinical characteristics and pathogenic causes of a four-generation pedigree with 10 members affected by BDE and short stature. METHODS: After the informed consent was signed, clinical data and peripheral blood samples were collected from available family members. Karyotype analysis, array-CGH, next-generation sequencing, and Sanger sequencing were employed to identity the pathogenic candidate gene. RESULTS: No translocation or microdeletion/duplication was found in karyotype analysis and array-CGH; hence, a novel heterozygous mutation, c.146dupA. p.S50Vfs*22, was detected by next-generation sequencing in PTHLH gene, leading to a premature stop codon. Subsequently, the mutation was confirmed by Sanger sequencing and co-segregation analysis. CONCLUSION: In this study, we described a novel heterozygous mutation (c.146dupA. p.S50Vfs*22) of gene PTHLH in a Chinese family. The mutation could induce a premature stop codon leading to a truncation of the protein. Our study broadened the mutation spectrum of PTHLH in BDE.
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Braquidactilia , Nanismo , Humanos , Braquidactilia/genética , Códon sem Sentido , Mutação , Proteína Relacionada ao Hormônio Paratireóideo/genéticaRESUMO
Acetaldehyde dehydrogenase 2 (ALDH2) mutations are commonly found in a subgroup of the Asian population. However, the role of ALDH2 in septic acute respiratory distress syndrome (ARDS) remains unknown. Here, we showed that human subjects carrying the ALDH2rs671 mutation were highly susceptible to developing septic ARDS. Intriguingly, ALDH2rs671-ARDS patients showed higher levels of blood cell-free DNA (cfDNA) and myeloperoxidase (MPO)-DNA than ALDH2WT-ARDS patients. To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS, we utilized Aldh2 gene knockout mice and Aldh2rs671 gene knock-in mice. In clinically relevant mouse sepsis models, Aldh2-/- mice and Aldh2rs671 mice exhibited pulmonary and circulating NETosis, a specific process that releases neutrophil extracellular traps (NETs) from neutrophils. Furthermore, we discovered that NETosis strongly promoted endothelial destruction, accelerated vascular leakage, and exacerbated septic ARDS. At the molecular level, ALDH2 increased K48-linked polyubiquitination and degradation of peptidylarginine deiminase 4 (PAD4) to inhibit NETosis, which was achieved by promoting PAD4 binding to the E3 ubiquitin ligase CHIP. Pharmacological administration of the ALDH2-specific activator Alda-1 substantially alleviated septic ARDS by inhibiting NETosis. Together, our data reveal a novel ALDH2-based protective mechanism against septic ARDS, and the activation of ALDH2 may be an effective treatment strategy for sepsis.
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Aldeído-Desidrogenase Mitocondrial , Armadilhas Extracelulares , Camundongos Knockout , Neutrófilos , Síndrome do Desconforto Respiratório , Sepse , Animais , Sepse/complicações , Humanos , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/patologia , Camundongos , Armadilhas Extracelulares/metabolismo , Masculino , Modelos Animais de Doenças , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Camundongos Endogâmicos C57BL , Ubiquitinação , Feminino , Peroxidase/metabolismo , MutaçãoRESUMO
For rechargeable aqueous zinc-ion batteries (ZIBs), manganese dioxide is one of the most promising candidates as a cathode material because of its cost effectiveness, eco-friendliness, and high specific capacities. However, the ZIBs suffer from poor rate performance and low cycle life due to the weak intrinsic electronic conductivity of manganese dioxide, poor ion diffusion of lump manganese dioxide, and its volumetric expansion during the cycle. Herein, we prepare MnO2@carbon composites (MnO2@IPHCSs) by in situ growing MnO2 nanoflowers on an interconnected porous hollow carbon spheres (IPHCSs) template. IPHCSs, as excellent conductors, significantly improve the conductivity of the manganese dioxide cathode. The hollow porous carbon framework of IPHCSs can offer more ion diffusion paths to internal MnO2@IPHCS carbon composites and acts as a buffer room to cope with the drastic volume contraction and expansion during charge/discharge cycling. The rate performance tests show that MnO2@IPHCSs with high conductivity have a specific capacity of 147 mA h g-1 at 3 C. MnO2@IPHCSs with hollow and nanoflower structures are shown to have excellent ion diffusion performance (ion diffusion coefficient = 10-11 to 10-10 cm2 s-1) in the electrochemical kinetics of the galvanostatic intermittent titration technique. Long cycle performance testing and in situ Raman characterization reveal that MnO2@IPHCSs have high cycling stability (85.5% capacity retention after 800 cycles) and reversibility due to the enhanced structure and increased conductivity. The excellently conductive manganese dioxide supported by IPHCSs has good rate and cycling performance, which can be used to produce superior-performance ZIBs.
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BACKGROUND: The optimal tibial component rotational alignment in unicompartmental knee arthroplasty has not been defined. This study aimed to explore the effect of tibial component rotational alignment on the clinical outcomes of UKA. METHODS: Clinical and follow-up data from 269 patients were retrospectively analysed. They were assigned into Groups A (- 5° to 0°), B (0°-3°), C (3°-6°) and D (> 6°) according to the external rotation of the tibial component to Akagi's line. The Knee Society Score clinical (KSS-c), Knee Society Score function (KSS-f), Forgotten Joint Score (FJS) and postoperative complications at 2 years postsurgically were analysed. RESULTS: The mean rotation of the tibial component relative to Akagi's line in 269 patients was 4.56 ± 3.79°. There were 15, 84, 89 and 81 patients in Groups A, B, C and D, respectively. The postoperative KSS-c and KSS-f in Groups B and C were significantly higher than those in Group D. No significant differences in KSS-c and KSS-f were detected between Groups B and C. The postoperative FJS in Group B was significantly higher than that in Group C, which was significantly higher in Group C than in Group D. There were 5, 8 and 15 cases of postoperative knee pain in Groups B, C and D, respectively, and the difference was statistically significant. CONCLUSION: Tibial component rotational alignment is of significance to Oxford Phase III UKA in patients. External rotation of the tibial component by 0°-3° is optimal to achieve satisfactory clinical outcomes.
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Artroplastia do Joelho , Prótese do Joelho , Osteoartrite do Joelho , Humanos , Artroplastia do Joelho/efeitos adversos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/cirurgia , Tíbia/diagnóstico por imagem , Tíbia/cirurgia , Dor Pós-Operatória/cirurgia , Osteoartrite do Joelho/cirurgiaRESUMO
INTRODUCTION: Small cell lung cancer (SCLC) is a special type of lung cancer sensitive to radiotherapy and chemotherapy but is prone to drug resistance and recurrence and has a very poor prognosis. This study aimed to explore the potential biomarkers and therapeutic targets for SCLC. METHODS: After batch normalization of GSE40275, GSE1037, and GSE44447 datasets, R was used to screen SCLC's differentially expressed genes (DEGs) and hub genes. We used immunohistochemistry (IHC) to assess the tissue's expression level of the hub gene. The clinical value of the hub gene was further evaluated based on the collected clinical-pathological data. RESULTS: In this study, a total of 230 DEGs (133 upregulated and 97 downregulated) were screened by the R package. The IHC showed that the expression of CCNA2 and CCNE2 in SCLC tissues was significantly higher than that in normal tissues (p < 0.01). Overexpression of CCNA2 was closely associated with the extensive period of NCCN (p = 0.004), tumor position (p = 0.046), and clinical stage (p = 0.002). The high expression levels of CCNE2 were related to high survival in chemotherapy patients (p = 0.019). CONCLUSION: CCNA2 and CCNE2 may serve as potential biomarkers of diagnosis and treatment for SCLC.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Ciclina A2/genética , Ciclina A2/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Ciclinas/genética , Ciclinas/metabolismo , Prognóstico , Biomarcadores Tumorais/genética , Perfilação da Expressão GênicaRESUMO
Background: BAG3 is an essential regulator of cell survival and has been investigated in the context of heart disease and cancer. Our previous study used immunoprecipitation-liquid chromatography-tandem mass spectrometry to show that BAG3 might directly interact with INTS7 and regulate bone marrow mesenchymal stem cell (BMMSCs) proliferation. However, whether BAG3 bound INTS7 directly and how it regulated BMMSCs expansion was unclear. Methods: BAG3 expression was detected by quantitative real-time PCR in BMMSCs after siRNA-mediated BAG3 knockdown. BMMSC proliferation was determined using the CCK-8 and colony formation assays. The transwell migration, flow cytometry and TUNEL assays were performed to measure BMMSC migration, cell cycle and apoptosis, respectively. Moreover, co-immunoprecipitation, protein half-life assay and western blotting analyses were used to determine the regulatory mechanism underlying the BAG3-mediated increase in BMMSC proliferation. Results: The results showed that knocking down BAG3 in BMMSCs markedly decreased their proliferative activity, colony formation and migratory capacity, and induced cell apoptosis as well as cell cycle arrest. Meanwhile, overexpression of BAG3 had the opposite effect. Bioinformatics and BAG3-INTS7 co-immunoprecipitation analyses revealed that BAG3 directly interacted with INTS7. Moreover, the downregulation of BAG3 inhibited the expression of INTS7 and promoted its ubiquitination. We also observed that BAG3 knockdown increased the levels of reactive oxygen species and the extent of DNA damage in BMMSCs. Notably, the upregulation of INTS7 or the addition of an antioxidant scavenger could rescue the BMMSC phenotype induced by BAG3 downregulation. Conclusions: BAG3 directly interacts with INTS7 and promotes BMMSC expansion by reducing oxidative stress.
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Células-Tronco Mesenquimais , Apoptose/genética , Regulação para Cima , Estresse Oxidativo , Proliferação de Células/genéticaRESUMO
Developing efficient strategies to realize divergent arylation of dienes has been a long-standing synthetic challenge. Herein, a nickel catalyzed divergent Mizoroki-Heck reaction of 1,3-dienes has been demonstrated through the regulation of ligands and additives. In the presence of Mn/NEt3, the Mizoroki-Heck reaction of dienes delivers linear products under Ni(dppe)Cl2 catalysis in high regio- and stereoselectivities. With the help of catalytic amount of organoboron and NaF, the use of bulky ligand IPr diverts the selectivity from linear products to branched products. Highly aryl-substituted compounds can be transformed from dispersive Mizoroki-Heck products programmatically. Preliminary experimental studies are carried out to elucidate the role of additives.
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For lithium metal batteries (LMBs), the elevated operating temperature results in severe capacity fading and safety issues due to unstable electrode-electrolyte interphases and electrolyte solvation structures. Therefore, it is crucial to construct advanced electrolytes capable of tolerating harsh environments to ensure stable LMBs. Here, we proposed a stable localized high-concentration electrolyte (LHCE) by introducing the highly solvating power solvent diethylene glycol dimethyl ether (DGDME). Computational and experimental evidence discloses that the original DGDME-LHCE shows favorable features for high-temperature LMBs, including high Li+-binding stability, electro-oxidation resistance, thermal stability, and nonflammability. The tailored solvated sheath structure achieves the preferred decomposition of anions, inducing the stable (cathode and Li anode)/interphases simultaneously, which enables a homogeneous Li plating-stripping behavior on the anode side and a high-voltage tolerance on the cathode side. For the Li||Li cells coupled with DGDME-LHCE, they showcase outstanding reversibility (a long lifespan of exceeding 1900 h). We demonstrate exceptional cyclic stability (â¼95.59%, 250 cycles), high Coulombic efficiency (>99.88%), and impressive high-voltage (4.5 V) and high-temperature (60 °C) performances in Li||NCM523 cells using DGDME-LHCE. Our advances shed light on an encouraging ether electrolyte tactic for the Li-metal batteries confronted with stringent high-temperature challenges.
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A catalyst-free photosensitized strategy has been developed for regioselective imino functionalizations of alkenes via the formation of an EDA complex. This photo-induced protocol facilitates the construction of structurally diverse ß-imino sulfones and vinyl sulfones in moderate to high yields. Mechanistic studies reveal that the reaction is initiated with an intermolecular charge transfer between oximes and sulfinates, followed by fragmentation to generate a persistent iminyl radical and transient sulfonyl radical. This catalyst-free protocol also features excellent regioselectivity, broad functional group tolerance and mild reaction conditions. The late stage functionalization of natural product derived compounds and total synthesis of some bioactive molecules have been demonstrated to highlight the utility of this protocol. Meanwhile, the compatibility of different donors has proved the generality of this strategy.
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Cell survival or death is critical for cardiac function. Myocardial pyroptosis, as a newly recognized programmed cell death, remains poorly understood in sepsis. In this study, we evaluated the effect of aldehyde dehydrogenase (ALDH2) on myocardial pyroptosis and revealed the underlying mechanisms in sepsis. We established a septic shock mice model by intraperitoneal injection of Lipopolysaccharide (LPS, 15 mg/kg) 12 h before sacrifice. It was found that aldehyde dehydrogenase significantly inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation and Caspase-1/GSDMD-dependent pyroptosis, which remarkably improved survival rate and septic shock-induced cardiac dysfunction, relative to the control group. While aldehyde dehydrogenase knockout or knockdown significantly aggravated these phenomena. Intriguingly, we found that aldehyde dehydrogenase inhibited LPS-induced deacetylation of Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex α subunit (HADHA) by suppressing the translocation of Histone deacetylase 3 (HDAC3) from nuclei to mitochondria. Acetylated HADHA is essential for mitochondrial fatty acid ß-oxidation, and its interruption can result in accumulation of toxic lipids, induce mROS and cause mtDNA and ox-mtDNA release. Our results confirmed the role of Histone deacetylase 3 and HADHA in NOD-like receptor protein 3 inflammasome activation. Hdac3 knockdown remarkedly suppressed NOD-like receptor protein 3 inflammasome and pyroptosis, but Hadha knockdown eliminated the effect. aldehyde dehydrogenase inhibited the translocation of Histone deacetylase 3, protected ac-HADHA from deacetylation, and significantly reduced the accumulation of toxic aldehyde, and inhibited mROS and ox-mtDNA, thereby avoided NOD-like receptor protein 3 inflammasome activation and pyroptosis. This study provided a novel mechanism of myocardial pyroptosis through mitochondrial Histone deacetylase 3/HADHA- NOD-like receptor protein 3 inflammasome pathway and demonstrated a significant role of aldehyde dehydrogenase as a therapeutic target for myocardial pyroptosis in sepsis.
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BACKGROUND: The optimal treatment for unstable intertrochanteric fractures in elderly patients remains controversial. We aimed to compare internal fixation and bipolar hemiarthroplasty for the treatment of unstable intertrochanteric fractures in elderly patients. METHODS: 124 patients aged over 70 years were enrolled into this study (64 internal fixations, 60 bipolar hemiarthroplasties). Patients were followed for two years, and had a clinical, radiological, and functional review at three, six, and twelve months as well as two years. RESULTS: In the internal fixation group, the fracture reduction and internal fixation were regarded as satisfactory in 44 cases and unsatisfactory in 20 cases. Five patients in the internal fixation group (two with satisfactory results and three with unsatisfactory results) and three patients in the arthroplasty group died before the final two-year follow-up. Five patients in the internal fixation group who had unsatisfactory results suffered complications. At 24 months post-operation, patients who were treated satisfactorily with internal fixation had higher Harris scores, less pain, and better walking ability than those treated with hemiarthroplasty and unsatisfactory internal fixation. CONCLUSIONS: Internal fixation with good reduction and fixation quality should be the preferred therapeutic method for elderly unstable intertrochanteric fractures, even when severe osteoporosis is present.