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Doxorubicin (Dox), a chemotherapeutic agent frequently used to treat cancer, elicits cardiotoxicity, a condition referred to as Dox-induced cardiotoxicity (DIC), and ferroptosis plays a contributory role in its pathophysiology. Fucoidan, a polysaccharide with various biological activities and safety profile, has potential therapeutic and pharmaceutical applications. This study aimed to investigate the protective effects and underlying mechanisms of fucoidan in DIC. Echocardiography, biomarkers of cardiomyocyte injury, serum creatine kinase, creatine kinase isoenzyme and lactate dehydrogenase, as well as histological staining results, revealed that fucoidan significantly reduced myocardial damage and improved cardiac function in DIC mice. Transmission electron microscopy; levels of lipid reactive oxygen species, glutathione, and malondialdehyde; ferroptosis-related markers; and regulatory factors such as glutathione peroxidase 4 (GPX4), transferrin receptor protein-1, ferritin heavy chain-1, heme oxygenase-1 in the heart tissue were measured to explore the effect of fucoidan on Dox-induced ferroptosis. These results suggested that fucoidan could inhibit cardiomyocyte ferroptosis caused by Dox. In vitro experiments revealed that silencing nuclear factor-erythroid 2-related factor 2 (Nrf2) in cardiomyocytes reduced the inhibitory effect of fucoidan on ferroptosis. Hence, fucoidan has the potential to ameliorate DIC by inhibiting ferroptosis via the Nrf2/GPX4 pathway.
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Cardiotoxicidade , Doxorrubicina , Ferroptose , Miócitos Cardíacos , Fator 2 Relacionado a NF-E2 , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Polissacarídeos , Transdução de Sinais , Animais , Polissacarídeos/farmacologia , Polissacarídeos/química , Ferroptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Camundongos , Cardiotoxicidade/tratamento farmacológico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , MasculinoRESUMO
Adherent-invasive Escherichia coli (AIEC) strain LF82, isolated from patients with Crohn's disease, invades gut epithelial cells, and replicates in macrophages contributing to chronic inflammation. In this study, we found that RstAB contributing to the colonization of LF82 in a mouse model of chronic colitis by promoting bacterial replication in macrophages. By comparing the transcriptomes of rstAB mutant- and wild-type when infected macrophages, 83 significant differentially expressed genes in LF82 were identified. And we identified two possible RstA target genes (csgD and asr) among the differentially expressed genes. The electrophoretic mobility shift assay and quantitative real-time PCR confirmed that RstA binds to the promoters of csgD and asr and activates their expression. csgD deletion attenuated LF82 intracellular biofilm formation, and asr deletion reduced acid tolerance compared with the wild-type. Acidic pH was shown by quantitative real-time PCR to be the signal sensed by RstAB to activate the expression of csgD and asr. We uncovered a signal transduction pathway whereby LF82, in response to the acidic environment within macrophages, activates transcription of the csgD to promote biofilm formation, and activates transcription of the asr to promote acid tolerance, promoting its replication within macrophages and colonization of the intestine. This finding deepens our understanding of the LF82 replication regulation mechanism in macrophages and offers new perspectives for further studies on AIEC virulence mechanisms.
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Aderência Bacteriana , Biofilmes , Infecções por Escherichia coli , Proteínas de Escherichia coli , Escherichia coli , Regulação Bacteriana da Expressão Gênica , Macrófagos , Macrófagos/microbiologia , Animais , Camundongos , Escherichia coli/genética , Escherichia coli/patogenicidade , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Biofilmes/crescimento & desenvolvimento , Infecções por Escherichia coli/microbiologia , Humanos , Concentração de Íons de Hidrogênio , Virulência , Colite/microbiologia , Doença de Crohn/microbiologia , Modelos Animais de Doenças , Transdução de Sinais , Ácidos/metabolismoRESUMO
Uropathogenic Escherichia coli (UPEC) is the most common causative agent of urinary tract infection (UTI). UPEC invades bladder epithelial cells (BECs) via fusiform vesicles, escapes into the cytosol, and establishes biofilm-like intracellular bacterial communities (IBCs). Nucleoside-diphosphate kinase (NDK) is secreted by pathogenic bacteria to enhance virulence. However, whether NDK is involved in UPEC pathogenesis remains unclear. Here, we find that the lack of ndk impairs the colonization of UPEC CFT073 in mouse bladders and kidneys owing to the impaired ability of UPEC to form IBCs. Furthermore, we demonstrate that NDK inhibits caspase-1-dependent pyroptosis by consuming extracellular ATP, preventing superficial BEC exfoliation, and promoting IBC formation. UPEC utilizes the reactive oxygen species (ROS) sensor OxyR to indirectly activate the regulator integration host factor, which then directly activates ndk expression in response to intracellular ROS. Here, we reveal a signaling transduction pathway that UPEC employs to inhibit superficial BEC exfoliation, thus facilitating acute UTI.
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Caspase 1 , Infecções por Escherichia coli , Núcleosídeo-Difosfato Quinase , Piroptose , Infecções Urinárias , Escherichia coli Uropatogênica , Escherichia coli Uropatogênica/patogenicidade , Animais , Infecções Urinárias/microbiologia , Infecções Urinárias/patologia , Camundongos , Caspase 1/metabolismo , Núcleosídeo-Difosfato Quinase/metabolismo , Núcleosídeo-Difosfato Quinase/genética , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/patologia , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL , Humanos , Feminino , Bexiga Urinária/microbiologia , Bexiga Urinária/patologia , Células Epiteliais/microbiologia , Células Epiteliais/metabolismo , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Transdução de SinaisRESUMO
BACKGROUND: The global spread of COVID-19 has brought immense physiological and psychological distress to students, such as test anxiety and poor sleep quality. This study aims to explore the relationship between COVID-19 stress and test anxiety and the mediating roles of intolerance of uncertainty and sleep quality between them. METHODS: A study was conducted in China during the late stage of the pandemic. A total of 936 Chinese art students (age M = 18.51, SD = 2.11, 46.6% female) completed the Coronavirus Stress Measure (CSM), the 12-item Intolerance of Uncertainty (IUS-12), the Brief Version of the Pittsburgh Sleep Quality Index (B-PSQI), and the Test Anxiety Inventory (TAI). A chain mediation model analysis was conducted to examine the mediating effects of intolerance of uncertainty and sleep quality on the association with COVID-19 stress and test anxiety. RESULTS: COVID-19 stress was positively associated with test anxiety (ß = 0.50, p < 0.001). The intolerance of uncertainty and sleep quality partially and serially mediated the relationship between COVID-19 stress and test anxiety (ß = 0.01, 95% CI = 0.01 to 0.02). CONCLUSION: These findings suggest that art students' intolerance of uncertainty and sleep quality partially and serially mediate the relation between COVID-19 stress and test anxiety. The results have significant implications for the intervention and prevention of test anxiety, providing additional evidence for the relationship between COVID-19 stress and test anxiety.
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COVID-19 , Qualidade do Sono , Estresse Psicológico , Estudantes , Humanos , Feminino , COVID-19/psicologia , COVID-19/epidemiologia , Incerteza , Masculino , China/epidemiologia , Estudantes/psicologia , Estudantes/estatística & dados numéricos , Adulto Jovem , Adolescente , Estresse Psicológico/psicologia , Estresse Psicológico/epidemiologia , Ansiedade aos Exames/psicologia , Ansiedade aos Exames/epidemiologia , AdultoRESUMO
Objective: Multiple observational studies have demonstrated an association between type 2 diabetes mellitus (T2DM) and chronic liver diseases (CLDs). However, the causality of T2DM on CLDs remained unknown in various ethnic groups. Methods: We obtained instrumental variables for T2DM and conducted a two-sample mendelian randomization (MR) study to examine the causal effect on nonalcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), viral hepatitis, hepatitis B virus (HBV) infection, and hepatitis C virus (HCV) infection risk in Europeans and East Asians. The primary analysis utilized the inverse variance weighting (IVW) technique to evaluate the causal relationship between T2DM and CLDs. In addition, we conducted a series of rigorous analyses to bolster the reliability of our MR results. Results: In Europeans, we found that genetic liability to T2DM has been linked with increased risk of NAFLD (IVW : OR =1.3654, 95% confidence interval [CI], 1.2250-1.5219, p=1.85e-8), viral hepatitis (IVW : OR =1.1173, 95%CI, 1.0271-1.2154, p=0.0098), and a suggestive positive association between T2DM and HCC (IVW : OR=1.2671, 95%CI, 1.0471-1.5333, p=0.0150), HBV (IVW : OR=1.1908, 95% CI, 1.0368-1.3677, p=0.0134). No causal association between T2DM and HCV was discovered. Among East Asians, however, there was a significant inverse association between T2DM and the proxies of NAFLD (ALT: IVW OR=0.9752, 95%CI 0.9597-0.9909, p=0.0021; AST: IVW OR=0.9673, 95%CI, 0.9528-0.9821, p=1.67e-5), and HCV (IVW: OR=0.9289, 95%CI, 0.8852-0.9747, p=0.0027). Notably, no causal association was found between T2DM and HCC, viral hepatitis, or HBV. Conclusion: Our MR analysis revealed varying causal associations between T2DM and CLDs in East Asians and Europeans. Further research is required to investigate the potential mechanisms in various ethnic groups, which could yield new insights into early screening and prevention strategies for CLDs in T2DM patients.
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Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Hepatite B , Hepatite C , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/genética , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Reprodutibilidade dos Testes , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/genética , HepacivirusRESUMO
Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a common food-borne pathogen that can cause acute diseases. Lysine acetylation is a post-translational modification (PTM) that occurs in various prokaryotes and is regulated by CobB, the only deacetylase found in bacteria. Here, we demonstrated that CobB plays an important role in the virulence of EHEC O157:H7 and that deletion of cobB significantly decreased the intestinal colonization ability of bacteria. Using acetylation proteomic studies, we systematically identified several proteins that could be regulated by CobB in EHEC O157:H7. Among these CobB substrates, we found that acetylation at the K44 site of CesA, a chaperone for the type-III secretion system (T3SS) translocator protein EspA, weakens its binding to EspA, thereby reducing the stability of this virulence factor; this PTM ultimately attenuating the virulence of EHEC O157:H7. Furthermore, we showed that deacetylation of the K44 site, which is deacetylated by CobB, promotes the interaction between CesA and EspA, thereby increasing bacterial virulence in vitro and in animal experiments. In summary, we showed that acetylation influences the virulence of EHEC O157:H7, and uncovered the mechanism by which CobB contributes to bacterial virulence based on the regulation of CesA deacetylation.
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Infecções por Escherichia coli , Escherichia coli O157 , Proteínas de Escherichia coli , Microbioma Gastrointestinal , Animais , Escherichia coli O157/metabolismo , Virulência , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Proteômica , Infecções por Escherichia coli/microbiologiaRESUMO
Mitochondrial dynamics are critical in cellular energy production, metabolism, apoptosis, and immune responses. Pathogenic bacteria have evolved sophisticated mechanisms to manipulate host cells' mitochondrial functions, facilitating their proliferation and dissemination. Salmonella enterica serovar Typhimurium (S. Tm), an intracellular foodborne pathogen, causes diarrhea and exploits host macrophages for survival and replication. However, S. Tm-associated mitochondrial dynamics during macrophage infection remain poorly understood. In this study, we showed that within macrophages, S. Tm remodeled mitochondrial fragmentation to facilitate intracellular proliferation mediated by Salmonella invasion protein A (SipA), a type III secretion system effector encoded by Salmonella pathogenicity island 1. SipA directly targeted mitochondria via its N-terminal mitochondrial targeting sequence, preventing excessive fragmentation and the associated increase in mitochondrial reactive oxygen species, loss of mitochondrial membrane potential, and release of mitochondrial DNA and cytochrome c into the cytosol. Macrophage replication assays and animal experiments showed that mitochondria and SipA interact to facilitate intracellular replication and pathogenicity of S. Tm. Furthermore, we showed that SipA delayed mitochondrial fragmentation by indirectly inhibiting the recruitment of cytosolic dynamin-related protein 1, which mediates mitochondrial fragmentation. This study revealed a novel mechanism through which S. Tm manipulates host mitochondrial dynamics, providing insights into the molecular interplay that facilitates S. Tm adaptation within host macrophages.
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Microbioma Gastrointestinal , Salmonella typhimurium , Animais , Salmonella typhimurium/metabolismo , Proteína Estafilocócica A/genética , Proteína Estafilocócica A/metabolismo , Sorogrupo , Dinâmica Mitocondrial , Proteínas de Bactérias/metabolismo , Macrófagos/metabolismo , Proliferação de CélulasRESUMO
Enterohemorrhagic Escherichia coli (EHEC) is an important foodborne pathogen that infects humans by colonizing the large intestine. The genome of EHEC O157:H7 contains 177 unique O islands (OIs). Certain OIs significantly contribute to the heightened virulence and pathogenicity exhibited by EHEC O157:H7. However, the function of most OI genes remains unknown. We demonstrated here that EHEC O157:H7 adherence to and colonization of the mouse large intestine are both dependent on OI-97. Z3495, which is annotated as a LysR-type transcriptional regulator and encoded in OI-97, contributes to this phenotype. Z3495 activated the locus of enterocyte effacement (LEE) gene expression, promoting bacterial adherence. Deletion of z3495 significantly decreased the transcription of ler and other LEE genes, the ability to adhere to the host cells, and colonization in the mouse large intestine. Furthermore, the ChIP-seq results confirmed that Z3495 can directly bind to the promoter region of rcsF, which is a well-known activator of Ler, and increase LEE gene expression. Finally, phylogenetic analysis revealed that Z3495 is a widespread transcriptional regulator in enterohemorrhagic and enteropathogenic Escherichia coli. As a result of this study, we have gained a deeper understanding of how bacteria control their virulence and provide another example of a laterally acquired regulator that regulates LEE gene expression in bacteria.
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BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver cirrhosis and cancer. Lonicerae flos polysaccharides (LPs) have been shown to be effective in treating metabolic diseases; however, the therapeutic effects and underlying molecular mechanisms of LPs in NAFLD remain unclear. PURPOSE: The objective of this study was to investigate the morphological characterization of Lonicerae flos polysaccharides (LPs) and the mechanism of LPs in relieving NAFLD. METHODS: The morphology of LPs was observed using atomic force microscopy (AFM), X-ray diffraction (XRD), thermal weight (TG), and thermal weight derivative (DTG); NAFLD mice were treated with LPs at the same time as they were induced with a Western diet, and then the indexes related to glycolipid metabolism, fibrosis, inflammation, and autophagy in the serum and liver of the mice were detected. RESULTS: The atomic force microscope analysis results indicated that the LPs displayed sugar-chain aggregates, exhibited an amorphous structure, and were relatively stable in thermal cracking at 150 °C. It was also found that LPs exerted therapeutic effects in NAFLD. The LPs prevented high-fat and -cholesterol diet-induced NAFLD progression by regulating glucose metabolism dysregulation, insulin resistance, lipid accumulation, inflammation, fibrosis, and autophagy. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) inhibitor compound C abrogated LP-induced hepatoprotection in mice with NAFLD. The LPs further treated NAFLD by reshaping the structure of the gut microbiota, in which Desulfovibrio bacteria plays a key roles. CONCLUSION: Lonicerae flos polysaccharides exert protective effects against NAFLD in mice by improving the structure of the intestinal flora and activating the AMPK signaling pathway. © 2023 Society of Chemical Industry.
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Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Lipopolissacarídeos , Proteínas Quinases Ativadas por AMP/metabolismo , Fígado/metabolismo , Metabolismo dos Lipídeos , Inflamação/metabolismo , Polissacarídeos/farmacologia , Polissacarídeos/metabolismo , Fibrose , Adenosina/metabolismo , Adenosina/farmacologia , Adenosina/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BLRESUMO
Compact, lightweight, and on-chip spectrometers are required to develop portable and handheld sensing and analysis applications. However, the performance of these miniaturized systems is usually much lower than their benchtop laboratory counterparts due to oversimplified optical architectures. Here, we develop a compact plasmonic "rainbow" chip for rapid, accurate dual-functional spectroscopic sensing that can surpass conventional portable spectrometers under selected conditions. The nanostructure consists of one-dimensional or two-dimensional graded metallic gratings. By using a single image obtained by an ordinary camera, this compact system can accurately and precisely determine the spectroscopic and polarimetric information of the illumination spectrum. Assisted by suitably trained deep learning algorithms, we demonstrate the characterization of optical rotatory dispersion of glucose solutions at two-peak and three-peak narrowband illumination across the visible spectrum using just a single image. This system holds the potential for integration with smartphones and lab-on-a-chip systems to develop applications for in situ analysis.
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Alkaline membrane water electrolysis is a promising production technology, and advanced electrocatalyst and membrane electrode design have always been the core technology. Herein, an ion-exchange method and an environmentally friendly in situ green phosphating strategy are successively employed to fabricate Ru-Ru2 P heterogeneous nanoparticles by using hydroxyapatite (HAP) as a phosphorus source, which is an exceptionally active electrocatalyst for hydrogen evolution reaction (HER). Density functional theory calculation results reveal that strong electronic redistribution occurs at the heterointerface of Ru-Ru2 P, which modulates the electronic structure to achieve an optimized hydrogen adsorption strength. The obtained Ru-Ru2 P possesses excellent HER performance (24 mV at 10 mA cm-2 ) and robust stability (1000 mA cm-2 for 120 h) in alkaline media. Furthermore, an environmentally friendly membrane electrode with a sandwich structure is assembled by HAP nanowires as an alkaline membrane, Ru-Ru2 P as a cathodic catalyst, and NiFe-LDH as an anodic catalyst, respectively. The voltage of (-) Ru-Ru2 P || NiFe-LDH/CNTs (+) (1.53 V at 10 mA cm-2 ) is lower than that of (-) 20 wt% Pt/C || RuO2 (+) (1.60 V at 10 mA cm-2 ) for overall water splitting. Overall, the studies not only design an efficient catalyst but also provide a new route to achieve a high-stability electrolyzer for industrial H2 production.
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KEY MESSAGE: We identified and fine-mapped S58, a selfish genetic locus from Asian rice that confers hybrid male sterility in crosses between Asian and African cultivated rice, and found a natural neutral allele in Asian rice lines that will be useful for overcoming S58-mediated hybrid sterility. Hybrids between Asian cultivated rice (Oryza sativa L.) and African cultivated rice (Oryza glaberrima Steud) display severe hybrid sterility (HS), hindering the utilization of strong heterosis in hybrids between these species. Several African rice selfish loci causing HS in Asian-African cultivated rice hybrids have been identified, but few such Asian rice selfish loci have been found. In this study, we identified an Asian rice selfish locus, S58, which causes hybrid male sterility (HMS) in hybrids between the Asian rice variety 02428 and the African rice line CG14. Genetic analysis confirmed that S58 causes a transmission advantage for the Asian rice S58 allele in the hybrid offspring. Genetic mapping with near-isogenic lines and DNA markers delimited S58 to 186 kb and 131 kb regions of chromosome 1 in 02428 and CG14, respectively, and revealed complex genomic structural variation over these mapped regions. Gene annotation analysis and expression profiling analyses identified eight anther-expressed candidate genes potentially responsible for S58-mediated HMS. Comparative genomic analysis determined that some Asian cultivated rice varieties harbor a 140 kb fragment deletion in this region. Hybrid compatibility analysis showed that this large deletion allele in some Asian cultivated rice varieties can serve as a natural neutral allele, S58-n, that can overcome S58-mediated interspecific HMS. Our study demonstrates that this selfish genetic element from Asian rice is important for HMS between Asian and African cultivated rice, broadening our understanding of interspecific HS. This study also provides an effective strategy for overcoming HS in future interspecific rice breeding.
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Infertilidade Masculina , Oryza , Masculino , Humanos , Oryza/genética , Melhoramento Vegetal , Mapeamento Cromossômico , Loci Gênicos , Infertilidade Masculina/genéticaRESUMO
BACKGROUND: Hyperlipidemia is regarded as a public health matter, and its effective prevention and treatment are urgently required. However, the treatment of hyperlipidemia is still relatively scarce. RESULTS: Fermented Cerasus humilis fruit (FCHF) had higher total flavonoid, total phenolic, procyanidin, and organic and free amino acid content, and lower total sugar content, than non-fermented C. humilis fruit (NFCHF). Both FCHF and NFCHF treatment significantly prevent putting on weight. Furthermore, FCHF administration ameliorated hyperlipidemia and cholesterol over-accumulation. In addition, FCHF administration activated the antioxidase system and decreased the malondialdehyde content to relieve oxidative stress, and showed more efficaciously than NFCHF administration. FCHF treatments significantly reverse the fat deposition in high-fat diet rat liver. FCHF supplementation can relieve the dysbacteriosis induced by hyperlipidemia, and regulate the composition of rat gut microbiota by increasing the abundance of Prevotella and norank_f_Muribaculaceae. CONCLUSION: Lactobacillus plantarum and Saccharomyces cerevisiae fermentation enhanced the antihyperlipidemic property of C. humilis fruits by promoting gut microbiota regulation. © 2022 Society of Chemical Industry.
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Microbioma Gastrointestinal , Hiperlipidemias , Ratos , Animais , Frutas/química , Hiperlipidemias/metabolismo , Dieta Hiperlipídica , Estresse OxidativoRESUMO
PURPOSE: To develop an ultrafast and robust MR parameter mapping network using deep learning. THEORY AND METHODS: We design a deep learning framework called SuperMAP that directly converts a series of undersampled (both in k-space and parameter-space) parameter-weighted images into several quantitative maps, bypassing the conventional exponential fitting procedure. We also present a novel technique to simultaneously reconstruct T1rho and T2 relaxation maps within a single scan. Full data were acquired and retrospectively undersampled for training and testing using traditional and state-of-the-art techniques for comparison. Prospective data were also collected to evaluate the trained network. The performance of all methods is evaluated using the parameter qualification errors and other metrics in the segmented regions of interest. RESULTS: SuperMAP achieved accurate T1rho and T2 mapping with high acceleration factors (R = 24 and R = 32). It exploited both spatial and temporal information and yielded low error (normalized mean square error of 2.7% at R = 24 and 2.8% at R = 32) and high resemblance (structural similarity of 97% at R = 24 and 96% at R = 32) to the gold standard. The network trained with retrospectively undersampled data also works well for the prospective data (with a slightly lower acceleration factor). SuperMAP is also superior to conventional methods. CONCLUSION: Our results demonstrate the feasibility of generating superfast MR parameter maps through very few undersampled parameter-weighted images. SuperMAP can simultaneously generate T1rho and T2 relaxation maps in a short scan time.
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Aceleração , Imageamento por Ressonância Magnética , Imageamento por Ressonância Magnética/métodos , Estudos Retrospectivos , Estudos Prospectivos , Processamento de Imagem Assistida por Computador/métodos , AlgoritmosRESUMO
Vibrio cholerae (V. cholerae), one of the most important bacterial pathogens in history, is a gram-negative motile bacterium that causes fatal pandemic disease in humans via oral ingestion of contaminated water or food. This process involves the coordinated actions of numerous regulatory factors. The MerR family regulators, which are widespread in prokaryotes, have been reported to be associated with pathogenicity. However, the role of the MerR family regulators in V. cholerae virulence remains unknown. Our study systematically investigated the influence of MerR family regulators on intestinal colonization of V. cholerae within the host. Among the five MerR family regulators, MlrA was found to significantly promote the colonization capacity of V. cholerae in infant mice. Furthermore, we revealed that MlrA increases bacterial intestinal colonization by directly enhancing the expression of tcpA, which encodes one of the most important virulence factors in V. cholerae, by binding to its promoter region. In addition, we revealed that during infection, mlrA is activated by anaerobic signals in the small intestine of the host through Fnr. In summary, our findings reveal a MlrA-mediated virulence regulation pathway that enables V. cholerae to sense environmental signals at the infection site to precisely activate virulence gene expression, thus providing useful insights into the pathogenic mechanisms of V. cholerae.
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Cólera , Microbioma Gastrointestinal , Vibrio cholerae , Humanos , Camundongos , Animais , Vibrio cholerae/metabolismo , Regulação Bacteriana da Expressão Gênica , Anaerobiose , Proteínas de Bactérias/metabolismo , Intestino Delgado/metabolismo , Cólera/microbiologiaRESUMO
Vibrio cholerae (V. cholerae) is an aquatic bacterium responsible for acute and fatal cholera outbreaks worldwide. When V. cholerae is ingested, the bacteria colonize the epithelium of the small intestine and stimulate the Paneth cells to produce large amounts of cationic antimicrobial peptides (CAMPs). Human defensin 5 (HD-5) is the most abundant CAMPs in the small intestine. However, the role of the V. cholerae response to HD-5 remains unclear. Here we show that HD-5 significantly upregulates virulence gene expression. Moreover, a two-component system, CarSR (or RstAB), is essential for V. cholerae virulence gene expression in the presence of HD-5. Finally, phosphorylated CarR can directly bind to the promoter region of TcpP, activating transcription of tcpP, which in turn activates downstream virulence genes to promote V. cholerae colonization. In conclusion, this study reveals a virulence-regulating pathway, in which the CarSR two-component regulatory system senses HD-5 to activate virulence genes expression in V. cholerae.
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Vibrio cholerae , alfa-Defensinas , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Humanos , Intestino Delgado , Fatores de Transcrição/metabolismo , Virulência/genética , alfa-Defensinas/genética , alfa-Defensinas/metabolismoRESUMO
This study aimed to investigate the structure characteristics Lonicera flos polysaccharides (LP) and the protective effects of LP on cyclophosphamide-induced immunosuppression in mice. The results showed the yield and purity of LP was 1.41% and 94.15%, the molecular weight was 53 kDa, and composed of arabinose, rhamnose, ribose, xylose, mannose, fructose, galactose and glucose; and LP had typical polysaccharide structural characteristics via ultraviolet and Fourier transform infrared (FTIR) spectroscopy, 1H NMR and 13C NMR spectra, and scanning electron microscopy (SEM) analyses. Furthermore, LP obviously alleviated the injury of spleen and thymus; significantly promoted Interleukin-2 (IL-2), IL-6, tumor necrosis factor α (TNF-α), immunoglobulin (IgA, IgG and IgM) secretion; and improved the richness of gut microbiota and the contents of short-chain fatty acids (SCFAs) in immunosuppressive mice. Taken together, these results suggested that LP possessed strong protective effect on cyclophosphamide-induced immunosuppression in mice via modulating gut microbiota.
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The aim of the present study was to examine whether adiponectin could inhibit cardiomyocyte senescence induced by Dgalactose (Dgal), and whether it functioned via the adiponectin receptor 1 (AdipoR1)/adaptor protein phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) signaling pathway. For this purpose, the expression levels of adiponectin, AdipoR1 and APPL1 in mouse plasma and myocardial tissues were detected via reverse transcriptionquantitative PCR (RTqPCR) and western blotting. An adiponectinoverexpression plasmid was transfected into Dgaltreated H9c2 cells prior to the detection of AdipoR1 and APPL1 expression by RTqPCR. Senescenceassociated ßgalactose staining was then performed to observe cellular senescence following the transfection of small interfering RNAs (si) targeting AdipoR1 and APPL1 into Dgaltreated H9c2 cells overexpressing adiponectin. Commercial kits were used to detect reactive oxygen species (ROS) production and malondialdehyde (MDA) content in the different groups. The expression levels of heme oxygenase (HO)1 and high mobility group box 1 (HMGB1) were examined by western blot analysis. The results revealed that the expression levels of adiponectin, AdipoR1 and APPL1 were downregulated in aged mouse plasma, myocardial tissues and Dgaltreated cardiomyocytes. It was also observed that AdipoR1 and APPL1 expression levels were significantly upregulated following the overexpression of adiponectin into Dgaltreated cardiomyocytes. Moreover, adiponectin overexpression reduced cellular senescence induced by Dgal and the expression of p16 and p21; these effects were reversed following transfection with siAdipoR1 and siAPPL1. Adiponectin also downregulated the levels of ROS and MDA in Dgaltreated H9c2 cells via AdipoR1/APPL1. Additionally, the release of HO11/HMGB1 was affected by adiponectin via AdipoR1/APPL1, and adiponectin/AdipoR1/APPL1 suppressed ROS production via HO1/HMGB1. On the whole, the present study demonstrated that adiponectin played an inhibitory role in cardiomyocyte senescence via the AdioR1/APPL1 signaling pathway and inhibited the levels of oxidative stress in senescent cardiomyocytes via the HO1/HMGB1 signaling pathway.