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Stimulator of IFN genes (STING; also known as STING1) is an important adaptor protein for detecting cytosolic double-stranded DNA, which can come from HIV infection. Several HIV proteins, such as p6, Vpx and Vif, can influence STING-mediated innate immunity, but the function of p17 is still unknown. In this study, we find that HIV-1 p17, but not HIV-2 p17 or SIV p17, promotes STING signaling induced by cyclic GMP-AMP (cGAMP) treatment. Mechanistically, HIV-1 p17 binds to Obg-like ATPase 1 (OLA1) and inhibits the regulation of STING by OLA1. Here, OLA1 interacts with STING and inhibits the translocation and phosphorylation of STING upon cGAMP stimulation. Furthermore, compared with HIV-2 and SIV, the ATPase and GTPase activities of OLA1 are only promoted by HIV-1 p17. Our study shows that the p17 of HIV-1, but not HIV-2 or SIV, promotes STING-mediated innate immunity by interfering the interaction between OLA1 and STING, thus providing a new clue for specific immune activation of HIV-1.
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Infecções por HIV , HIV-1 , Interferon Tipo I , Humanos , HIV-1/metabolismo , Imunidade Inata/genética , Adenosina Trifosfatases/metabolismo , Nucleotidiltransferases/metabolismo , Proteínas de Ligação ao GTP/metabolismoRESUMO
OBJECTIVES: Pseudomonas aeruginosa and Acinetobacter baumannii are ranked as top-priority organisms by WHO. Antimicrobial peptides (AMPs) are promising antimicrobial agents that are highly effective against serious bacterial infections. METHODS: In our previous study, a series of α-helical AMPs were screened using a novel multiple-descriptor strategy. The current research suggested that S24 exhibited strong antimicrobial activity against major pathogenic bacteria, and displayed minimal haemolysis, good serum stability and maintained salt resistance. RESULTS: We found that S24 exerted an antimicrobial effect by destroying outer membrane permeability and producing a strong binding effect on bacterial genomic DNA that inhibits genomic DNA migration. Furthermore, S24 exerted a strong ability to promote healing in wound infected by P. aeruginosa, A. baumannii and mixed strains in a mouse model. CONCLUSIONS: Overall, S24 showed good stability under physiological conditions and excellent antimicrobial activity, suggesting it may be a potential candidate for the development of serious bacterial infection treatment.
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Infecções por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas , Pseudomonas aeruginosa , Infecção dos Ferimentos , Acinetobacter baumannii/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Animais , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologia , Camundongos , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Antibacterianos/farmacologia , Peptídeos Antimicrobianos/farmacologia , Peptídeos Antimicrobianos/química , Modelos Animais de Doenças , Permeabilidade da Membrana Celular/efeitos dos fármacos , Humanos , DNA Bacteriano/genéticaRESUMO
Salmonella enterica serovar Typhimurium, which is a common foodborne pathogen, causes both intestinal and systemic infections in hosts. Salmonella has a complex pathogenic mechanism that involves invasive capacity and intracellular survivability, which hampers research on virulence of Salmonella. The virulence of Salmonella is primarily studied through Salmonella pathogenicity islands (SPIs). However, there are also genes outside these SPIs that significantly impact virulence. Macrophage survival gene msgA is positioned at a region independent of the SPIs and conserved in Salmonella. However, there has been limited research on msgA to date. This study aims to investigate the virulent function of msgA to deepen our understanding of Salmonella virulence. Proteomic and RT-qPCR analyses reveal that MsgA influences multiple metabolic pathways and the expression of SPIs. The depletion of msgA led to the significantly reduced invasive capacity and intracellular survivability, and thus the decreased virulence of Salmonella. In conclusion, our study suggests that MsgA is an important regulator that mainly regulates virulence. Further research into the function of MsgA will enhance the understanding of Salmonella pathogenesis and promote the application of Salmonella for medical treatment. IMPORTANCE: Salmonella enterica serovar Typhimurium is a common foodborne pathogen, it has a complex pathogenic mechanism that involves invasive capacity and intracellular survivability. The virulence of Salmonella is primarily studied through its pathogenicity islands. In contrast, virulence genes located outside the Salmonella pathogenicity islands (SPIs) have received less attention. Macrophage survival gene (MsgA) is positioned at a region independent of the SPIs and conserved in Salmonella. Our research indicates that MsgA is a novel global regulator influencing the metabolic pathways and SPIs. Further research into the function of MsgA will enhance the understanding of Salmonella pathogenesis and promote the application of Salmonella for medical treatment.
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OBJECTIVE: To investigate the association between sarcopenia, short-term efficacy, and long-term survival in patients with extensive small-cell lung cancer (SCLC) treated with standard first-line immunochemotherapy. METHODS: A total of 63 patients initially diagnosed with extensive-stage small cell lung cancer were enrolled in the prospective study from December 1, 2020 to December 31, 2022. The clinical characteristics, body composition, blood test results, and image data were obtained before treatment. Patients were divided into sarcopenia and non-sarcopenia groups according to the diagnostic criteria of the Asian Sarcopenia Working Group 2019. The primary outcome was overall survival (OS) and comprehensive survival analyses were performed. Secondary outcomes included short-term efficacy and adverse events associated with first-line immunochemotherapy. RESULTS: The median age of the 63 patients enrolled in our study was 63.0 years (40-80 years). The incidence of sarcopenia was 19.0% (12/63) in patients with extensive SCLC. Compared with non-sarcopenia patients, extensive-stage SCLC patients with sarcopenia were significantly older (69.0 vs. 62.0, P = 0.017), and had lower body mass index (BMI) (20.29 vs. 24.27, P < 0.001), hand grip strength (HGS) (20.42 vs. 30.75, P < 0.001), and albumin (35.9 vs. 41.40, P < 0.001). The objective response rate after two cycles of standard first-line immunochemotherapy in the sarcopenia group was lower than in the non-sarcopenia group (30.0 vs. 78.9%, P = 0.012). There was no significant difference in chemotherapy-related hematological toxicity between the two groups. During a median follow-up of 15 months (3-33 months), patients with extensive SCLC had a median OS of 24 months, with 1-year survival of 75% and 2-year survival of 52%, respectively. Compared to non-sarcopenia patients, the median OS in the sarcopenia group was significantly shorter (9 vs. 24 months, P = 0.0014). Multivariate Cox analysis showed that sarcopenia was an independent risk factor for OS in patients with extensive SCLC (HR = 4.993, 95%CI = 1.106-22.538, P = 0.037). CONCLUSIONS: Patients with Extensive SCLC and sarcopenia had worse clinical outcomes and shorter OS. Sarcopenia is a prognostic factor affecting first-line treatment efficacy and long-term survival of patients with SCLC in the era of immunotherapy.
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A novel Gram-stain-negative, rod-shaped, non-spore-forming, aerobic, motile bacterium with a single polar or subpolar flagellum, designated strain H3510T, was isolated from marine alga collected on sea shore of Yantai, PR China. The organism grew optimally at 28 °C and pH 7.0 and in presence of 3.0â% (w/v) NaCl. The strain exhibited positive catalase activity but negative oxidase and nitrate reduction activities. The predominant cellular fatty acids were C18â:â1 ω7c and/or C18â:â1 ω6c, 11-methyl C18â:â1 ω7c, and C16â:â0. Additionally, the major polar lipids were phosphatidylglycerol, phosphatidylmonomethylethanolamine, diphosphatidylglycerol, and phosphatidylethanolamine; the respiratory quinone was ubiquinone 10 (Q-10). The genomic DNA G+C content of strain H3510T was 54.2%. The novel strain showed the closest relationship with Roseibium polysiphoniae KMM 9699T with 98.2â% 16S rRNA gene sequence similarity. The calculated values for average nucleotide identity and DNA-DNA hybridization between strain H3510T and the phylogenetically related Roseibium species were in the range of 71.3-74.9â% and 13.7-19.9â%, respectively. Based on polyphasic analyses, strain H3510T was identified as representing a novel species of the genus Roseibium, for which the name Roseibium algae sp. nov. is proposed. The type strain is H3510T (=KCTC 8206T=MCCC 1K04325T). The heterologously expressed inositol 2-dehydrogenase gene from strain H3510T displayed high oxidation activity on myo-inositol and showed potential in the production of rare stereoisomers of inositol, such as scyllo-inositol.
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Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano , Ácidos Graxos , Hibridização de Ácido Nucleico , Filogenia , RNA Ribossômico 16S , Rhodobacteraceae , Análise de Sequência de DNA , RNA Ribossômico 16S/genética , DNA Bacteriano/genética , China , Ácidos Graxos/química , Rhodobacteraceae/isolamento & purificação , Rhodobacteraceae/classificação , Rhodobacteraceae/genética , Ubiquinona/análogos & derivados , Água do Mar/microbiologia , Rodófitas/microbiologiaRESUMO
Cardiac fibrosis is a detrimental pathological process, which constitutes the key factor for adverse cardiac structural remodeling leading to heart failure and other critical conditions. Circular RNAs (circRNAs) have emerged as important regulators of various cardiovascular diseases. It is known that several circRNAs regulate gene expression and pathological processes by binding miRNAs. In this study we investigated whether a novel circRNA, named circNSD1, and miR-429-3p formed an axis that controls cardiac fibrosis. We established a mouse model of myocardial infarction (MI) for in vivo studies and a cellular model of cardiac fibrogenesis in primary cultured mouse cardiac fibroblasts treated with TGF-ß1. We showed that miR-429-3p was markedly downregulated in the cardiac fibrosis models. Through gain- and loss-of-function studies we confirmed miR-429-3p as a negative regulator of cardiac fibrosis. In searching for the upstream regulator of miR-429-3p, we identified circNSD1 that we subsequently demonstrated as an endogenous sponge of miR-429-3p. In MI mice, knockdown of circNSD1 alleviated cardiac fibrosis. Moreover, silence of human circNSD1 suppressed the proliferation and collagen production in human cardiac fibroblasts in vitro. We revealed that circNSD1 directly bound miR-429-3p, thereby upregulating SULF1 expression and activating the Wnt/ß-catenin pathway. Collectively, circNSD1 may be a novel target for the treatment of cardiac fibrosis and associated cardiac disease.
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BACKGROUND: Subjective well-being (SWB) is associated with social support in cross-sectional studies. However, it remains unclear whether and how social support predicts SWB longitudinally, especially during the COVID-19 contingency. METHODS: By adopting a prospective design, the current work addressed this research question in a sample of 594 participants from the U.K. The data were collected via the online platform, Prolific, at two time points (June, 2020 and August, 2021) with a 14-month interval. Descriptive analysis and a moderated mediation model were conducted to test the proposed hypotheses. RESULTS: Baseline social support was a significant predictor of subjective well-being (SWB) 14 months later, even after controlling for baseline SWB and other covariates such as personality traits. Additionally, affect balance (i.e., the affective component of SWB) fully mediated the link between baseline social support and subsequent life satisfaction (i.e., the cognitive component of SWB). Moreover, household income moderated this relationship, indicating a stronger mediation for individuals with lower monthly household income. CONCLUSION: The present work sheds light on the underlying mechanism and boundary condition of the association between social support and different components of SWB during the COVID-19 pandemic.
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COVID-19 , Humanos , COVID-19/epidemiologia , Estudos Prospectivos , Estudos Transversais , Pandemias , Apoio SocialRESUMO
Prenatal environmental exposure could be an essential health risk factor associated with neurodevelopmental disorders in offspring. However, the exact mechanisms underlying the impact of prenatal PM2.5 exposure on offspring cognition remain unclear. In our recent study using a PM2.5 exposed pregnant mouse model, we observed significant synaptic dysfunction in the hippocampi of the offspring. Concurrently, the epigenetic regulator of KDM5A and the Shh signaling pathway exhibited decreased activities. Significantly, changes in hippocampal KDM5A and Shh levels directly correlated with PM2.5 exposure intensity. Subsequent experiments revealed a marked reduction in the expression of Shh signaling and related synaptic proteins when KDM5A was silenced in cells. Notably, the effects of KDM5A deficiency were reversed significantly with the supplementation of a Shh activator. Furthermore, our findings indicate that Shh activation significantly attenuates PM2.5-induced synaptic impairments in hippocampal neurons. We further demonstrated that EGR1, a transcriptional inhibitor, plays a direct role in KDM5A's regulation of the Shh pathway under conditions of PM2.5 exposure. Our results suggest that the KDM5A's inhibitory regulation on the Shh pathway through the EGR1 gene is a crucial epigenetic mechanism underlying the synaptic dysfunction in hippocampal neurons caused by maternal PM2.5 exposure. This emphasizes the role of epigenetic regulations in neurodevelopmental disorders caused by environmental factors.
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Epigênese Genética , Proteínas Hedgehog , Hipocampo , Material Particulado , Efeitos Tardios da Exposição Pré-Natal , Transdução de Sinais , Hipocampo/efeitos dos fármacos , Animais , Feminino , Gravidez , Transdução de Sinais/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Camundongos , Material Particulado/toxicidade , Proteína 2 de Ligação ao Retinoblastoma/genética , Exposição Materna/efeitos adversos , Sinapses/efeitos dos fármacos , Poluentes Atmosféricos/toxicidadeRESUMO
Food-derived oligopeptides (FOPs) exhibit various bioactivities. However, little was known about their sequence changes in the gastrointestinal tract and the effect of changes on bioactivities. FOPs' sequence features, changes and effects on bioactivities have been summarised. The sequence length of FOPs decreases with increased exposure of hydrophobic and basic amino acids at the terminal during simulated gastrointestinal digestion. A decrease in bioactivities after simulated intestinal absorption has correlated with a decrease of Leu, Ile, Arg, Tyr, Gln and Pro. The sequence of FOPs that pass readily through the intestinal epithelium corresponds to transport modes, and FOPs whose sequences remain unchanged after transport are the most bioactive. These include mainly dipeptides to tetrapeptides, consisting of numerous hydrophobic and basic amino acids, found mostly at the end of the peptide chain, especially at the C-terminal. This review aims to provide a foundation for applications of FOPs in nutritional supplements and functional foods.
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Oligopeptídeos , Peptídeos , Sequência de Aminoácidos , Oligopeptídeos/metabolismo , Aminoácidos Básicos , DigestãoRESUMO
α-Amylase inhibitory peptides are used to treat diabetes, but few studies have statistically characterized their interaction with α-amylase. This study performed the molecular docking of α-amylase with inhibitory peptides from published papers. The key sites, side chain chargeability, and hydrogen bond distribution characteristics were analyzed. Molecular dynamics simulated the role of key sites in complex stability. Moreover, partial least squares regression (PLSR) was used to analyze the contribution of different amino acids in the peptides to inhibition. The results showed that, for the α-amylase molecule, His201 and Gln63, with the highest interaction numbers (INs, 15, 15) and hydrogen bond values (HBVs, 11.50, 10.33), are the key sites on α-amylase, and amino acids with positively charged side chains were important for inhibitory activity. For the inhibitory peptides, Asp and Arg had the highest HBVs, and amino acids with charged side chains were more likely to form hydrogen bonds and exert inhibitory activity. In molecular dynamics simulations, peptides involving key binding sites formed more stable complexes with α-amylase than α-amylase alone, suggesting enhanced inhibitory effects. Further, PLSR results showed that amino acids close to the N-terminus of the inhibitory peptide, located in the third and fifth positions, were significantly correlated with its inhibitory activity. In conclusion, this study provides a new approach to developing and screening α-amylase inhibitors.
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Antifibrinolíticos , alfa-Amilases , Simulação de Acoplamento Molecular , Análise dos Mínimos Quadrados , Simulação de Dinâmica Molecular , Aminoácidos , PeptídeosRESUMO
BACKGROUND: Extrusion is the main method for the preparation of plant-based meat. Current studies have focused on the effect of different extrusion parameters on the texture and quality of plant-based meat, but there has been less research on their digestibility. This study determined the textural properties of extruded soybean protein (ESPro) for different extrusion parameters and the digestibility after in vitro simulated digestion experiments. The effect of extrusion on the structure and digestibility of ESPro and the relationship between them were elucidated. RESULTS: The results demonstrated a significant improvement in the digestibility of ESPro through extrusion, with the highest values for cohesiveness, springiness, chewiness, fibrous degree, digestibility, and proportion of digested peptides with <1 kDa molecular weight at an extrusion temperature of 160 °C and a screw speed of 30 rpm (ESPro1). In addition, ß-sheet content in the secondary structure of the ESPro showed a significant negative association with ESPro digestibility. CONCLUSION: In this study, extrusion could improve the digestibility of ESPro by altering the protein structure. This advancement holds the potential for more effective applications in plant-based meats. © 2023 Society of Chemical Industry.
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Carne , Proteínas de Soja , Animais , Fenômenos Fisiológicos da Nutrição Animal , DigestãoRESUMO
Stimulator of IFN genes (STING), an endoplasmic reticulum (ER) signaling adaptor, is essential for the type I interferon response to cytosolic double-stranded DNA. Translocation from the ER to perinuclear vesicles following cyclic GMP-AMP (cGAMP) binding is a critical step for STING to activate downstream signaling molecules, which leads to the production of interferon and pro-inflammatory cytokines. Here, we found that apoptosis-linked gene 2 (ALG2, also known as PDCD6) suppressed STING signaling induced by herpes simplex virus-1 (HSV-1) infection or cGAMP presence. Knockout of ALG2 markedly increased the expression of type I interferons upon cGAMP treatment or HSV-1 infection in THP-1 monocytes. Mechanistically, ALG2 associated with the C-terminal tail of STING and inhibited its trafficking from the ER to the perinuclear region. Furthermore, the ability of ALG2 to coordinate Ca2+ was crucial for its regulation of STING trafficking and DNA-induced innate immune responses. This work suggests that ALG2 is involved in DNA-induced innate immune responses by regulating STING trafficking.
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Herpes Simples , Herpesvirus Humano 1 , Interferon Tipo I , Proteínas de Membrana , Proteínas Reguladoras de Apoptose , Proteínas de Ligação ao Cálcio , Herpesvirus Humano 1/metabolismo , Humanos , Imunidade Inata , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismoRESUMO
BACKGROUND: Age-related macular degeneration (AMD), characterized by the degeneration of retinal pigment epithelium (RPE) and photoreceptors, is the leading cause of irreversible vision impairment among the elderly. RPE senescence is an important contributor to AMD and has become a potential target for AMD therapy. HTRA1 is one of the most significant susceptibility genes in AMD, however, the correlation between HTRA1 and RPE senescence hasn't been investigated in the pathogenesis of AMD. METHODS: Western blotting and immunohistochemistry were used to detect HTRA1 expression in WT and transgenic mice overexpressing human HTRA1 (hHTRA1-Tg mice). RT-qPCR was used to detect the SASP in hHTRA1-Tg mice and ARPE-19 cells infected with HTRA1. TEM, SA-ß-gal was used to detect the mitochondria and senescence in RPE. Retinal degeneration of mice was investigated by fundus photography, FFA, SD-OCT and ERG. The RNA-Seq dataset of ARPE-19 cells treated with adv-HTRA1 versus adv-NC were analyzed. Mitochondrial respiration and glycolytic capacity in ARPE-19 cells were measured using OCR and ECAR. Hypoxia of ARPE-19 cells was detected using EF5 Hypoxia Detection Kit. KC7F2 was used to reduce the HIF1α expression both in vitro and in vivo. RESULTS: In our study, we found that RPE senescence was facilitated in hHTRA1-Tg mice. And hHTRA1-Tg mice became more susceptible to NaIO3 in the development of oxidative stress-induced retinal degeneration. Similarly, overexpression of HTRA1 in ARPE-19 cells accelerated cellular senescence. Our RNA-seq revealed an overlap between HTRA1-induced differentially expressed genes associated with aging and those involved in mitochondrial function and hypoxia response in ARPE-19 cells. HTRA1 overexpression in ARPE-19 cells impaired mitochondrial function and augmented glycolytic capacity. Importantly, upregulation of HTRA1 remarkably activated HIF-1 signaling, shown as promoting HIF1α expression which mainly located in the nucleus. HIF1α translation inhibitor KC7F2 significantly prevented HTRA1-induced cellular senescence in ARPE-19 cells, as well as improved the visual function in hHTRA1-Tg mice treated with NaIO3. CONCLUSIONS: Our study showed elevated HTRA1 contributes to the pathogenesis of AMD by promoting cellular senescence in RPE through damaging mitochondrial function and activating HIF-1 signaling. It also pointed out that inhibition of HIF-1 signaling might serve as a potential therapeutic strategy for AMD. Video Abstract.
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Degeneração Retiniana , Idoso , Humanos , Animais , Camundongos , Epitélio Pigmentado da Retina , Transdução de Sinais , Mitocôndrias , Núcleo CelularRESUMO
Studies have shown that probiotics can effectively inhibit pathogens in the presence of proteins, protein hydrolysates and peptides (protein derivates). However, it is still unclear the modes of probiotics to inhibit pathogens regulated by protein derivates. Therefore, we summarized the possible effects of protein derivates from different sources on probiotics and pathogens. There is abundant evidence that proteins and peptides from different sources can significantly promote the proliferation of probiotics and increase their secretion of antibacterial substances. Such proteins and peptides can also stimulate the adhesion of probiotics to intestinal epithelial cells and contribute to regulating intestinal immunity, but they seem to have the negative effects on pathogens. Moreover, a direct effect of proteins on intestinal cells is summarized. Whether or not they can cooperate with probiotics to inhibit pathogens using above possible mechanisms were discussed. Furthermore, there seems to be no consistent conclusions that protein derivates have synergistic effects with probiotics, and there is still limited evidence on the inhibiting patterns. Therefore, the existing problems and shortcomings are noted, and future research direction is proposed.
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Two Gram-stain-negative, rod-shaped, non-spore-forming, strictly aerobic, motile bacteria with a single polar flagellum, designated strains C1424T and C2222T, were isolated from marine alga collected from the sea shore at Yantai, PR China. Strain C1424T grew at 4-37 °C and in the presence of 1-9â% (w/v) NaCl, while strain C2222T grew at 4-32 °C with 1-6â% (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences and concatenated amino acid sequences of 120 ubiquitous single-copy proteins showed that both strains C1424T and C2222T belonged to the genus Marinomonas, showing highest 16S rRNA gene sequence similarities to the type strains of Marinomonas primoryensis (98.1â%) and Marinomonas dokdonensis (98.1â%), respectively. The major fatty acids of the two strains were C18â:â1 ω6c and/or C18â:â1 ω7c, C16â:â1 ω6c and/or C16â:â1 ω7c and C16â:â0, their predominant polar lipids were phosphatidylethanolamine and phosphatidylglycerol, and their sole respiratory quinone was Q8. On the basis of polyphasic analyses, strains C1424T and C2222T are considered to represent two novel species within the genus Marinomonas, for which the names Marinomonas transparens sp. nov. and Marinomonas sargassi sp. nov. are proposed. The type strains are C1424T (=KCTC 72119T=MCCC 1K03601T) and C2222T (=KCTC 72120T=MCCC 1K03602T), respectively.
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Ácidos Graxos , Marinomonas , Ácidos Graxos/química , Fosfolipídeos/química , Filogenia , RNA Ribossômico 16S/genética , Cloreto de Sódio , Ubiquinona/química , Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano/genética , Análise de Sequência de DNA , Hibridização de Ácido NucleicoRESUMO
Underactive bladder (UAB) is a prevalent but under-researched lower urinary tract symptom that typically occurs alongside detrusor underactivity (DU). Unlike UAB, DU is a urodynamic diagnosis which the International Continence Society (ICS) defines as "a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal time span". Despite the widespread prevalence of UAB/DU, there are significant gaps in our understanding of its pathophysiological mechanisms, diagnosis, and treatment compared with overactive bladder (OAB) and detrusor overactivity (DO). These gaps are such that clinicians regard UAB/DU as an incurable condition. In recent years, the understanding of UAB has increased. The definition of UAB has been clarified, and the diagnostic criteria for DU have been considered more comprehensively. Meanwhile, a number of non-invasive diagnostic methods have also been reported. Clinical trials involving novel drugs, electrical stimulation, and stem cell therapy have shown promising results. Therefore, this review summarizes recent reports on UAB and DU and highlights the latest advances in their diagnosis and treatment.
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Sintomas do Trato Urinário Inferior , Doenças da Bexiga Urinária , Bexiga Urinária Hiperativa , Bexiga Inativa , Humanos , Bexiga Inativa/diagnóstico , Bexiga Inativa/etiologia , Bexiga Inativa/terapia , Estudos Prospectivos , Doenças da Bexiga Urinária/diagnóstico , Doenças da Bexiga Urinária/terapia , Bexiga Urinária Hiperativa/diagnóstico , Bexiga Urinária Hiperativa/terapia , Urodinâmica/fisiologiaRESUMO
Exposure of mucosal epithelial cells to the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 is known to disrupt epithelial cell junctions by impairing stathmin-mediated microtubule depolymerization. However, the pathological significance of this process and its underlying molecular mechanism remain unclear. Here we show that treatment of epithelial cells with pseudotyped HIV-1 viral particles or recombinant gp120 protein results in the activation of protein kinase G 1 (PKG1). Examination of epithelial cells by immunofluorescence microscopy reveals that PKG1 activation mediates the epithelial barrier damage upon HIV-1 exposure. Immunoprecipitation experiments show that PKG1 interacts with stathmin and phosphorylates stathmin at serine 63 in the presence of gp120. Immunoprecipitation and immunofluorescence microscopy further demonstrate that PKG1-mediated phosphorylation of stathmin promotes its autophagic degradation by enhancing the interaction between stathmin and the autophagy adaptor protein p62. Collectively, these results suggest that HIV-1 exposure exploits the PKG1/stathmin axis to affect the microtubule cytoskeleton and thereby perturbs epithelial cell junctions. Our findings reveal a novel molecular mechanism by which exposure to HIV-1 increases epithelial permeability, which has implications for the development of effective strategies to prevent mucosal HIV-1 transmission.
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Permeabilidade da Membrana Celular , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Células Epiteliais/patologia , HIV-1/fisiologia , Microtúbulos/metabolismo , Estatmina/metabolismo , Movimento Celular , Proteínas Quinases Dependentes de GMP Cíclico/genética , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Infecções por HIV/virologia , Humanos , Microtúbulos/virologia , Fosforilação , Estatmina/genéticaRESUMO
How plants balance growth and stress adaptation is a long-standing topic in plant biology. Abscisic acid (ABA) induces the expression of the stress-responsive Asparagine Rich Protein (NRP), which promotes the vacuolar degradation of PP6 phosphatase FyPP3, releasing ABI5 transcription factor to initiate transcription. Whether NRP is required for growth remains unknown. We generated an nrp1 nrp2 double mutant, which had a dwarf phenotype that can be rescued by inhibiting auxin transport. Insufficient auxin in the transition zone and over-accumulation of auxin at the root tip was responsible for the short elongation zone and short-root phenotype of nrp1 nrp2. The auxin efflux carrier PIN2 over-accumulated in nrp1 nrp2 and became de-polarized at the plasma membrane, leading to slower root basipetal auxin transport. Knock-out of PIN2 suppressed the dwarf phenotype of nrp1 nrp2. Furthermore, ABA can induce NRP-dependent vacuolar degradation of PIN2 to inhibit primary root elongation. FyPP3 also is required for NRP-mediated PIN2 turnover. In summary, in growth condition, NRP promotes PIN2 vacuolar degradation to help maintain PIN2 protein concentration and polarity, facilitating the establishment of the elongation zone and primary root elongation. When stressed, ABA employs this pathway to inhibit root elongation for stress adaptation.
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Proteínas de Arabidopsis , Arabidopsis , Ácido Abscísico/farmacologia , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Ácidos Indolacéticos , Raízes de Plantas/metabolismoRESUMO
Chiral sulfoxides are versatile synthons and have gained a particular interest in asymmetric synthesis of active pharmaceutical and agrochemical ingredients. Herein, a linear oxidation-reduction bienzymatic cascade to synthesize chiral sulfoxides is reported. The extraordinarily stable and active vanadium-dependent chloroperoxidase from Curvularia inaequalis (CiVCPO) was used to oxidize sulfides into racemic sulfoxides, which were then converted to chiral sulfoxides by highly enantioselective methionine sulfoxide reductase A (MsrA) and B (MsrB) by kinetic resolution, respectively. The combinatorial cascade gave a broad range of structurally diverse sulfoxides with excellent optical purity (>99 %â ee) with complementary chirality. The enzymatic cascade requires no NAD(P)H recycling, representing a facile method for chiral sulfoxide synthesis. Particularly, the envisioned enzymatic cascade not only allows CiVCPO to gain relevance in chiral sulfoxide synthesis, but also provides a powerful approach for (S)-sulfoxide synthesis; the latter case is significantly unexplored for heme-dependent peroxidases and peroxygenases.
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Metionina Sulfóxido Redutases , Sulfóxidos , Oxirredução , SafrolRESUMO
Diabetic retinopathy (DR) is one of the most common blindness in working-age adults. Transcription factor 7 like 2 (TCF7L2) is a susceptibility gene of DR, however, its roles in the pathogenesis of DR are still largely unknown. In this study, we found that TCF7L2 was mainly located in the cell nucleus of retinal ganglion cell layer (GCL) and inner nuclear layer (INL), while it was not expressed in the cell nucleus of retinal outer nuclear layer (ONL). Expression of TCF7L2 was significantly elevated in the retinas of db/db diabetic mice and oxygen-induced retinopathy (OIR) mice. Also, in Ad-hTCF7L2 treated hiPSCs-derived retinal progenitor cells (RPCs), activating transcription factor 6 (ATF6)-related endoplasmic reticulum (ER) stress signaling was remarkably activated. Moreover, knockdown of TCF7L2 significantly inhibited ATF6-related ER stress signaling. Furthermore, the data of endothelial permeability assay showed that RPCs pretreated with Ad-hTCF7L2 lead to enhanced monolayer permeability of human umbilical vein endothelial cells (HUVECs), and knockdown of TCF7L2 or ATF6 in RPCs could alleviate the monolayer permeability of HUVECs. Thus, our results showed that TCF7L2 could trigger ATF6-related ER stress signaling and promote vein endothelial cell permeability, which will provide important insight into the role of TCF7L2 in the pathogenesis of DR and contribute to designing potential therapies.