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BACKGROUND AND PURPOSE: Multiple system atrophy (MSA) is a progressive, adult-onset neurodegenerative disorder clinically characterized by combinations of autonomic failure, parkinsonism, cerebellar ataxia and pyramidal signs. Although a few genetic factors have been reported to contribute to the disease, its mutational profiles have not been systemically studied. METHODS: To address the genetic profiles of clinically diagnosed MSA patients, exome sequencing and triplet repeat detection was conducted in 205 MSA patients, including one familial case. The pathogenicity of variants was determined according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. RESULTS: In the familial patient, a novel heterozygous COQ2 pathogenic variant (p.Ala351Thr) was identified in the MSA pedigree. In the sporadic patients, 29 pathogenic variants were revealed in 21 genes, and the PARK7 p.Ala104Thr variant was significantly associated with MSA (p = 0.0018). Moreover, burden tests demonstrated that the pathogenic variants were enriched in cerebellar ataxia-related genes in patients. Furthermore, repeat expansion analyses revealed that two patients carried the pathogenic CAG repeat expansion in the CACNA1A gene (SCA6), one patient carried the (ACAGG)exp/(ACAGG)exp expansion in RFC1 and one carried the GAA-pure expansion in FGF14 gene. CONCLUSION: In conclusion, a novel COQ2 pathogenic variant was identified in a familial MSA patient, and repeat expansions in CACNA1A, RFC1 and FGF14 gene were detected in four sporadic patients. Moreover, a PARK7 variant and the burden of pathogenic variants in cerebellar ataxia-related genes were associated with MSA.
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Hydrolysis, alcoholysis and ammonolysis are viable routes for the efficient degradation and recycling of polyethylene naphthalate (PEN) plastic waste. Various possible hydrolysis/alcoholysis/ammonolysis reaction pathways for the degradation mechanism of the ethylene naphthalate dimer were investigated using the density functional theory (DFT) B3P86/6-31++G(d,p). To determine the thermodynamic and kinetic parameters, geometric structure optimization and frequency calculation were performed on a range of intermediates, transition states, and products associated with the reaction. The calculation results show that the highest energy barrier of the main element reaction step in hydrolysis is about 169.0 kJ/mol, the lowest is about 151.0 kJ/mol for ammonolysis, and the second is about 155.0 kJ/mol for alcoholysis. The main hydrolysis products of the ethylene naphthalate dimer are 2,6-naphthalenedicarboxylic acid and ethylene glycol; the main products of alcoholysis are dimethyl naphthalene-2,6-dicarboxylate and ethylene glycol, and the main products of ammonolysis are naphthalene-2,6-dicarboxamide and ethylene glycol. Furthermore, in the process of ethylene naphthalate dimer hydrolysis/alcoholysis/ammonolysis, the decomposition reaction in the NH3 atmosphere is better than that in methanol, and the reaction in CH3OH is better than that in the H2O molecular environment, and the increase in reaction temperature can increase its spontaneity. Our study presents the molecular mechanism of PEN hydrolysis/alcoholysis/ammonolysis and provides a reference for studying the degradation of other plastic wastes.
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Teoria da Densidade Funcional , Hidrólise , Naftalenos/química , Cinética , Etilenos/química , Plásticos/química , Termodinâmica , Modelos QuímicosRESUMO
BACKGROUND: Kinesin family member 26B (KIF26B) has been closely linked to the occurrence and progression of various tumors. However, there is limited research on its role in oral squamous cell carcinoma (OSCC). This article aims to investigate the expression levels and mechanisms of KIF26B in OSCC. METHODS: Real time quantity polymerase chain reaction (RT-qPCR) and Western blot analyses were conducted to assess the expression levels of KIF26B in 35 OSCC specimens and their corresponding non-cancerous tissues. Overexpression and silencing of KIF26B were achieved in HSC6 and SCC25 cells, respectively, resulting in the establishment of KIF26B-overexpressing and si-KIF26B cell lines, designated as the KIF26B group and si-KIF26B group. Proliferation assays using 5-Ethynyl-2'-deoxyuridine (EdU) labeling and clone formation were performed to evaluate the proliferative capacity of cells in these groups. The invasive and migratory abilities of cells in the KIF26B and si-KIF26B groups were assessed using Transwell assay. Additionally, the influence of KIF26B on the glycogen synthase kinase (GSK)-3ß/ß-catenin pathway was investigated through Western blot analysis. RESULTS: According to the results of RT-qPCR and Western blot analyses, the expression of KIF26B was predominantly higher in OSCC tissues compared to normal tissues (p < 0.01). Overexpression of KIF26B notably accelerated cell migration, invasion, and proliferation (p < 0.01), whereas knockdown of KIF26B significantly inhibited these processes (p < 0.01). Additionally, KIF26B overexpression led to increased levels of active ß-catenin, p-GSK-3, and c-myc (p < 0.01), while KIF26B silencing decreased the levels of these proteins (p < 0.01). CONCLUSION: Our findings suggest that KIF26B may play a role in the pathogenesis and progression of OSCC as an oncogene. This study establishes a foundation for the identification of potential therapeutic targets for OSCC.
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Biomarcadores Tumorais , Carcinoma de Células Escamosas , Proliferação de Células , Cinesinas , Neoplasias Bucais , Humanos , Cinesinas/genética , Cinesinas/metabolismo , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Neoplasias Bucais/metabolismo , Linhagem Celular Tumoral , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Proliferação de Células/genética , Feminino , Masculino , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Movimento Celular/genética , Idoso , Via de Sinalização Wnt/genética , beta Catenina/metabolismo , beta Catenina/genéticaRESUMO
Alopecia areata affects over 140 million people worldwide and causes severe psychological distress. The Janus kinase (JAK) inhibitor, tofacitinib, shows significant potential in therapeutic applications for treating alopecia areata; however, the systemic adverse effects of oral administration and low absorption rate at the target site limit its application. Hence, to address this issue, we designed topical formulations of tofacitinib-loaded cationic lipid nanoparticles (TFB-cNLPs) with particle sizes of approximately 200 nm. TFB-cNLPs promoted percutaneous absorption and hair follicle targeting in an ex vivo pig ear model. TFB-cNLP decreased IFN-γ-induced alopecia areata symptoms in an in vitro follicle model by blocking the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. It also reduced the number of CD8+NKG2D+T cells in a C3H mouse model of alopecia areata in vivo, thereby inhibiting the progression of alopecia areata and reversing hair loss. These findings suggest that TFB-cNLP enhanced hair follicle targeting and has the potential for topical treatment or prevention of alopecia areata.
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Alopecia em Áreas , Portadores de Fármacos , Folículo Piloso , Lipídeos , Piperidinas , Pirimidinas , Absorção Cutânea , Animais , Alopecia em Áreas/tratamento farmacológico , Folículo Piloso/metabolismo , Folículo Piloso/efeitos dos fármacos , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Suínos , Lipídeos/química , Lipídeos/administração & dosagem , Portadores de Fármacos/química , Camundongos Endogâmicos C3H , Nanopartículas/administração & dosagem , Camundongos , Nanoestruturas/administração & dosagem , Feminino , LipossomosRESUMO
Semi-aerobic aged refuse biofilters (SAARB) are commonly-used biotechnologies for treating landfill leachate. In actual operation, SAARB often faces harsh conditions characterized by high concentrations of chemical oxygen demand (COD) and Cl-, as well as a low carbon-to-nitrogen ratio (C/N), which can disrupt the microbial community within SAARB, leading to operational instability. Maintaining the stable operation of SAARB is crucial for the efficient treatment of landfill leachate. However, the destabilization mechanism of SAARB under harsh conditions remains unclear. To address this, the study simulated the operation of SAARB under three harsh conditions, namely, high COD loading (H-COD), high chloride ion (Cl-) concentration environment (H-Cl-), and low C/N ratio environment (L-C/N). The aim is to reveal the destabilization mechanism of SAARB under harsh conditions by analyzing the fluorescence characteristics of effluent DOM and the microbial community in aged refuse. The results indicate that three harsh conditions have different effects on SAARB. H-COD leads to the accumulation of proteins; H-Cl- impedes the reduction of nitrite nitrogen; L-C/N inhibits the degradation of humic substances. These outcomes are attributed to the specific effects of different factors on the microbial communities in different zones of SAARB. H-COD and L-C/N mainly affect the degradation of organic matter in aerobic zone, while H-Cl- primarily impedes the denitrification process in the anaerobic zone. The abnormal enrichment of Corynebacterium, Castellaniella, and Sporosarcina can indicate the instability of SAARB under three harsh conditions, respectively. To maintain the steady operation of SAARB, targeted acclimation of the microbial community in SAARB should be carried out to cope with potentially harsh operating conditions. Besides, timely mitigation of loads should be implemented when instability characteristics emerge, and carbon sources and electron donors should be provided to restore treatment performance effectively.
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Poluentes Químicos da Água , Poluentes Químicos da Água/análise , Filtração , Eliminação de Resíduos Líquidos/métodos , Análise da Demanda Biológica de Oxigênio , Nitrogênio , Aerobiose , Eliminação de Resíduos/métodos , Reatores Biológicos , Fluorescência , MicrobiotaRESUMO
Multi-functional packaging materials are an important development for food preservation. Emulsion electrospinning is a novel and simple method that can be used to prepare multi-functional packaging materials, which can effectively protect the loaded active substances during the preparation process. In this study, PCL/lecithin/bacteriocin CAMT6 nanofiber films with antimicrobial and antioxidant activity were prepared by emulsion electrostatic spinning. The morphology and homogeneity of the prepared nanofibrous membranes could be improved by optimising the formulation of the emulsion for electrospinning. Analytical testing of the prepared nanofiber films revealed that the nanofibers had a core-shell structure, with bacteriocin CAMT6 effectively encapsulated in the core layer and the PCL and phospholipids homogeneously mixed to form the shell layer. Additionally, the nanofiber films had acceptable tensile properties and water absorption capacity. In chilled salmon meat, the nanofiber film effectively inhibited the growth of bacteria, slowed the oxidation of oil and slowed water loss, which was a good protective effect. This study provides a reference for the encapsulation application of food-active packaging materials and bacteriocins.
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Anti-Infecciosos , Bacteriocinas , Nanofibras , Animais , Bacteriocinas/farmacologia , Antioxidantes/farmacologia , Nanofibras/química , Lecitinas , Emulsões , Salmão , ÁguaRESUMO
The encapsulation efficiency (EE%) reflects the amount of bioactive components that can be loaded into nanoliposomes. Obtaining a suitable nanoliposome stabiliser may be the key to improving their EE%. In this study, three polyphenols were screened as stabilisers of nanoliposomes with high nisin EE%, with curcumin nanoliposomes (Cu-NLs) exhibiting the best performance (EE% = 95.94%). Characterizations of particle size, PDI and zeta potential indicate that the Cu-NLs had good uniformity and stability. TEM found that nisin accumulated at the edges of the Cu-NLs' phospholipid layer. DSC and FT-IR revealed that curcumin was involved in the formation of the phospholipid layer and altered its structure. FT-IR and molecular docking simulations indicate that the interactions between curcumin and nisin are mainly hydrogen bonding and hydrophobic. In whole milk, Cu-NLs effectively protected nisin activity. This study provides an effective strategy for improving the EE% of nanoliposomes loaded with nisin and other bacteriocins.
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Lipossomos , Nanopartículas , Nisina , Tamanho da Partícula , Nisina/química , Lipossomos/química , Nanopartículas/química , Simulação de Acoplamento Molecular , Antibacterianos/química , Antibacterianos/farmacologia , Animais , Curcumina/química , Polifenóis/química , Leite/química , Composição de Medicamentos , Estabilidade de Medicamentos , Interações Hidrofóbicas e HidrofílicasRESUMO
Current sprayable hydrogel masks lack the stepwise protection, cleansing, and nourishment of extensive wounds, leading to delayed healing with scarring. Here, we develop a sprayable biomimetic double wound mask (BDM) with rapid autophasing and hierarchical programming for scarless wound healing. The BDMs comprise hydrophobic poly (lactide-co-propylene glycol-co-lactide) dimethacrylate (PLD) as top layer and hydrophilic gelatin methacrylate (GelMA) hydrogel as bottom layer, enabling swift autophasing into bilayered structure. After photocrosslinking, BDMs rapidly solidify with strong interfacial bonding, robust tissue adhesion, and excellent joint adaptiveness. Upon implementation, the bottom GelMA layer could immediately release calcium ion for rapid hemostasis, while the top PLD layer could maintain a moist, breathable, and sterile environment. These traits synergistically suppress the inflammatory tumor necrosis factor-α pathway while coordinating the cyclic guanosine monophosphate/protein kinase G-Wnt/calcium ion signaling pathways to nourish angiogenesis. Collectively, our BDMs with self-regulated construction of bilayered structure could hierarchically program the healing progression with transformative potential for scarless wound healing.
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Cicatrização , Cicatrização/efeitos dos fármacos , Animais , Hidrogéis/química , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Cicatriz/metabolismo , Humanos , Biomimética/métodos , Camundongos , Gelatina/química , Cálcio/metabolismoRESUMO
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. To identify additional genetic factors, we analyzed exome sequences in a large cohort of Chinese ALS patients and found a homozygous variant (p.L700P) in PCDHA9 in three unrelated patients. We generated Pcdhα9 mutant mice harboring either orthologous point mutation or deletion mutation. These mice develop progressive spinal motor loss, muscle atrophy, and structural/functional abnormalities of the neuromuscular junction, leading to paralysis and early lethality. TDP-43 pathology is detected in the spinal motor neurons of aged mutant mice. Mechanistically, we demonstrate that Pcdha9 mutation causes aberrant activation of FAK and PYK2 in aging spinal cord, and dramatically reduced NKA-α1 expression in motor neurons. Our single nucleus multi-omics analysis reveals disturbed signaling involved in cell adhesion, ion transport, synapse organization, and neuronal survival in aged mutant mice. Together, our results present PCDHA9 as a potential ALS gene and provide insights into its pathogenesis.