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The plant pathogen Pseudomonas syringae secretes multiple effectors that modulate plant defenses. Some effectors trigger defenses due to specific recognition by plant immune complexes, whereas others can suppress the resulting immune responses. The HopZ3 effector of P. syringae pv. syringae B728a (PsyB728a) is an acetyltransferase that modifies not only components of plant immune complexes, but also the Psy effectors that activate these complexes. In Arabidopsis, HopZ3 acetylates the host RPM1 complex and the Psy effectors AvrRpm1 and AvrB3. This study focuses on the role of HopZ3 during tomato infection. In Psy-resistant tomato, the main immune complex includes PRF and PTO, a RIPK-family kinase that recognizes the AvrPto effector. HopZ3 acts as a virulence factor on tomato by suppressing AvrPto1Psy-triggered immunity. HopZ3 acetylates AvrPto1Psy and the host proteins PTO, SlRIPK and SlRIN4s. Biochemical reconstruction and site-directed mutagenesis experiments suggest that acetylation acts in multiple ways to suppress immune signaling in tomato. First, acetylation disrupts the critical AvrPto1Psy-PTO interaction needed to initiate the immune response. Unmodified residues at the binding interface of both proteins and at other residues needed for binding are acetylated. Second, acetylation occurs at residues important for AvrPto1Psy function but not for binding to PTO. Finally, acetylation reduces specific phosphorylations needed for promoting the immune-inducing activity of HopZ3's targets such as AvrPto1Psy and PTO. In some cases, acetylation competes with phosphorylation. HopZ3-mediated acetylation suppresses the kinase activity of SlRIPK and the phosphorylation of its SlRIN4 substrate previously implicated in PTO-signaling. Thus, HopZ3 disrupts the functions of multiple immune components and the effectors that trigger them, leading to increased susceptibility to infection. Finally, mass spectrometry used to map specific acetylated residues confirmed HopZ3's unusual capacity to modify histidine in addition to serine, threonine and lysine residues.
Assuntos
Acetiltransferases/metabolismo , Complexo Antígeno-Anticorpo/imunologia , Proteínas de Bactérias/antagonistas & inibidores , Doenças das Plantas/imunologia , Proteínas de Plantas/metabolismo , Pseudomonas syringae/patogenicidade , Solanum lycopersicum/imunologia , Acetilação , Acetiltransferases/genética , Acetiltransferases/imunologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/metabolismo , Solanum lycopersicum/microbiologia , Doenças das Plantas/microbiologia , Proteínas de Plantas/genética , Proteínas de Plantas/imunologia , Virulência , Fatores de Virulência/genética , Fatores de Virulência/imunologia , Fatores de Virulência/metabolismoRESUMO
OBJECTIVE: URC102, a novel and potent inhibitor of human uric acid transporter 1 (hURAT1), is currently under clinical development to treat patients with gout. We performed a randomized, double-blind, placebo-controlled, phase I study to evaluate the safety, tolerability, pharmacodynamic, and pharmacokinetic profiles of URC102 after single and multiple oral administration in healthy male subjects. METHODS: Thirty-one Koreans and 23 Caucasians received a single dose of URC102 at 1-30 mg and 1-10 mg, respectively, while 44 Koreans received URC102 once-daily for 7 days at 1-20 mg. We evaluated safety and tolerability throughout the study, and serially determined serum uric acid, the fractional excretion of uric acid and URC102 concentrations. RESULTS: URC102 was well tolerated over the dose range of 1-10 mg after single and multiple administration. URC102 rapidly reduced serum uric acid, which was maintained over the entire treatment period. Furthermore, URC102 increased the area-under-the-effect curve over 168 h for fractional excretion of uric acid in a dose-dependent manner. The maximum plasma concentration and the area under the plasma concentration-time curve of URC102 increased dose-proportionally. The pharmacokinetic and pharmacodynamics characteristics of URC102 were similar in Koreans and Caucasians. CONCLUSION: URC102 was safe and effectively lowered serum uric acid, which should be tested and confirmed in patients with hyperuricaemia and/or gout through further studies. TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01953497 and NCT02524678.
Assuntos
Hidrocarbonetos Bromados/farmacologia , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Ácido Úrico/sangue , Uricosúricos/farmacologia , Administração Oral , Adulto , Povo Asiático , Método Duplo-Cego , Gota/sangue , Gota/tratamento farmacológico , Voluntários Saudáveis , Humanos , Hidrocarbonetos Bromados/administração & dosagem , Hiperuricemia/sangue , Hiperuricemia/tratamento farmacológico , Masculino , Uricosúricos/administração & dosagem , População BrancaRESUMO
Increased awareness of negative psychological symptoms and the negative impact of the pandemic has led to a rising demand for wellness-related travel experiences. There is a need for research on tourists' experiential and reflective engagement in order to maximize positive outcomes such as overall satisfaction, positive WOM, and recommendations. These positive outcomes are crucial for attracting tourists and strengthening destinations' brands. As there are few empirical studies, research on the effects of engagement on satisfaction and behavioral intentions is necessary. This study aimed to examine the relationships between wellness motivation, engagement, satisfaction, and destination loyalty among wellness tourists. It also aimed to examine the mediating effects of two engagement factors, experiential and reflective engagement, between wellness motivation and positive outcomes. A total of 319 respondents were used for the analysis, and structural equation modeling (SEM) was conducted. The results found that wellness motivation is composed of six wellness motivation components, namely physical motivation, transcendence, relaxation, social motivation, self-esteem, and escape, each representing first-order factors. Wellness motivation is positively associated with reflective and experiential engagement. Engagement positively affects satisfaction and destination loyalty. This study provides several implications, theoretically and practically.
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This study explores the relationships among social capital, community festival participation, and subjective well-being (SWB). It examines the mediating role of festival participation between social capital and SWB. The dataset Social Well-being Survey in Asia from the Philippines and Thailand was collected using nationwide surveys in 2016. The total number of respondents was 1057 in the Philippines and 982 in Thailand. The results affirm several determinants related to SWB, which is composed of happiness and overall life satisfaction. The models show significant relationships among festival participation, social capital, and SWB. The results indicate strong associations among social capital with family and relatives, festival participation, and SWB. The interaction effects between the two countries are included. Structural and cognitive social capital with kinship groups were important determinants in facilitating festival participation, and positively associated with SWB. Moreover, the results identify the mediating effect of festival participation between social capital with family and relatives and SWB. The results can provide similarities and differences in the relationships among social capital and kinship groups, community festival participation, and SWB between the Philippines and Thailand. This study offers important empirical evidence of a cross-cultural study in the context of the Philippines and Thailand.
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The purpose of this study is to examine the relationships among CSR activities, brand trust, supportive communication intention, and brand loyalty in a halal restaurant franchise. This study attempts to understand the brand loyalty formation among foreigners visiting a halal ethnic restaurant franchise in South Korea. This study can contribute to the body of empirical evidence showing that CSR activities for different stakeholders can increase brand loyalty mediated by trust. Data were collected from an online survey platform, and visitors were recruited in one of the largest halal franchise restaurants in Korea. This study used a convenience sampling technique, and 225 questionnaires were used for final analysis. Structural equation modeling was likewise used in this research. The results reveal that CSR activities include four constructs: for communities, employees, the environment, and customers. These four dimensions reflect voluntary activities for core stakeholders and are positively associated with enhancement of trustful relationships between customers and restaurants. Among four CSR dimensions, CSR activities to employee are the most influential dimension, followed by CSR to community and to environment. However, the insignificant effect of CSR activities to customers on trust is found. Furthermore, trust positively influences supportive communication intention and brand loyalty. The proposed model of this present study can shed light on how to enhance brand loyalty and sustain trustful and emotional value of an ethnic restaurant franchise. The results can provide important implications for planning CSR engagement from a practical and managerial perspective in the restaurant industry.
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We report glyco-pseudopolyrotaxanes composed of cucurbit[6]uril-based mannose wheels (ManCB[6]) threaded on polyviologen (PV), which not only effectively induce bacterial aggregation, but also exhibit high inhibitory activity against bacterial binding to host cells. Three glyco-pseudopolyrotaxanes (1-3), which have 10, 5, and 3 ManCB[6] wheels, respectively, on a PV string, were prepared and characterized. Bacterial aggregation assays and hemagglutination inhibition assays illustrated the specific and multivalent interaction between the glyco-pseudopolyrotaxanes and E. coli ORN178. Compound 3 was especially effective at inducing bacterial aggregation and showed 300 times higher inhibitory potency than monomeric methyl-α-mannoside (Me-αMan) for ORN178-induced hemagglutination. Furthermore, we demonstrated their inhibitory activities for the adhesion of ORN178 bacteria to urinary epithelial cells as a model of urinary tract infection. Our findings suggest that these supramolecular carbohydrate clusters are potentially useful in antiadhesion therapy.
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Aderência Bacteriana/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/química , Carboidratos/química , Carboidratos/farmacologia , Ciclodextrinas/química , Ciclodextrinas/farmacologia , Células Epiteliais/efeitos dos fármacos , Hemaglutinação/efeitos dos fármacos , Imidazóis/química , Manose/química , Manose/farmacologia , Poloxâmero/química , Poloxâmero/farmacologia , Polímeros/química , Polímeros/farmacologia , Rotaxanos/química , Rotaxanos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Imidazóis/farmacologia , Estrutura Molecular , Infecções Urinárias/tratamento farmacológicoRESUMO
The present study examined the relationship between social capital, local festival participation, and subjective well-being. Moreover, this study examined whether the effect of social capital on subjective well-being can be mediated by festival participation. In addition, it examined the decomposition effect of festival participation and control of models for demographic characteristics. Data used are from the International Comparative Survey on Lifestyle and Values (ICSLV) SWB South Korea Survey. The total number of respondents for the analysis is 1694. The findings indicate that trustful relationships with family and relatives, friends, and neighbors are considerably related to subjective well-being than structural social capital. Moreover, the trust of informal social ties shows considerable potential in facilitating individuals' local festival participation, which is associated with subjective well-being. Individuals who often participate in traditional local festivals in their communities show higher subjective well-being than those who never attend any festivals. Local festivals in communities can play an important role in strengthening links with individuals in these communities and affect community residents' well-being. Lastly, the findings can suggest beneficial theoretical and practical implications, and enrich the previous literature on social capital and festival participation.
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Férias e Feriados , Relações Interpessoais , Capital Social , Participação Social , Apoio Social , Adulto , Idoso , Família , Feminino , Amigos , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia , Confiança , Adulto JovemRESUMO
Cucurbituril-based nanoparticles (CB[6]NPs) serve as new efficient vehicles for delivery of hydrophobic drugs, which have unique features including (1) a high drug loading capacity and efficiency, (2) noncovalently tunable surfaces, (3) efficient delivery of hydrophobic drugs into a cancer cell by receptor-mediated endocytosis, and (4) facile release of drugs into cytoplasm, which enhances the pharmaceutical effects of the drugs.
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Sistemas de Liberação de Medicamentos , Nanopartículas/química , Preparações Farmacêuticas/química , Veículos Farmacêuticos/química , Corantes , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Células HeLa , Humanos , Compostos Macrocíclicos/química , Microscopia Confocal , Oxazinas , Tamanho da Partícula , Fotoquímica , Solubilidade , ÁguaRESUMO
BACKGROUND: JX-594 is a targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell-cycle abnormalities and epidermal growth factor receptor (EGFR)-ras pathway activation. Direct oncolysis plus granulocyte-macrophage colony-stimulating factor (GM-CSF) expression also stimulates shutdown of tumour vasculature and antitumoral immunity. We aimed to assess intratumoral injection of JX-594 in patients with refractory primary or metastatic liver cancer. METHODS: Between Jan 4, 2006, and July 4, 2007, 14 patients with histologically confirmed refractory primary or metastatic liver tumours (up to 10.9 cm total diameter) that were amenable to image-guided intratumoral injections were enrolled into this non-comparative, open-label, phase I dose-escalation trial (standard 3x3 design; two to six patients for each dose with 12-18 estimated total patients). Patients received one of four doses of intratumoral JX-594 (10(8) plaque-forming units [pfu], 3x10(8) pfu, 10(9) pfu, or 3x10(9) pfu) every 3 weeks at Dong-A University Hospital (Busan, South Korea). Patients were monitored after treatment for at least 48 h in hospital and for at least 4 weeks as out-patients. Adverse event-monitoring according to the National Cancer Institute Common Toxicity Criteria (version 3) and standard laboratory toxicity grading for haematology, liver and renal function, coagulation studies, serum chemistry, and urinalysis were done. The primary aims were to ascertain the maximum-tolerated dose (MTD) and safety of JX-594 treatment. Data were also collected on pharmacokinetics, pharmacodynamics, and efficacy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00629759. FINDINGS: Of 22 patients with liver tumours who were assessed for eligibility, eight patients did not meet inclusion criteria. Therefore, 14 patients, including those with hepatocellular, colorectal, melanoma, and lung cancer, were enrolled. Patients were heavily pretreated (5.6 previous treatments, SD 2.8, range 2.0-12.0) and had large tumours (7.0 cm diameter, SD 2.7, range 1.8-10.9). Patients received a mean of 3.4 (SD 2.2, range 1.0-8.0) cycles of JX-594. All patients were evaluable for toxicity. All patients experienced grade I-III flu-like symptoms, and four had transient grade I-III dose-related thrombocytopenia. Grade III hyperbilirubinaemia was dose-limiting in both patients at the highest dose; the MTD was therefore 1x10(9) pfu. JX-594 replication-dependent dissemination in blood was shown, with resultant infection of non-injected tumour sites. GM-CSF expression resulted in grade I-III increases in neutrophil counts in four of six patients at the MTD. Tumour responses were shown in injected and non-injected tumours. Ten patients were radiographically evaluable for objective responses; non-evaluable patients had contraindications to contrast medium (n=2) or no post-treatment scans (n=2). According to Response Evaluation Criteria in Solid Tumors (RECIST), three patients had partial response, six had stable disease, and one had progressive disease. INTERPRETATION: Intratumoral injection of JX-594 into primary or metastatic liver tumours was generally well-tolerated. Direct hyperbilirubinaemia was the dose-limiting toxicity. Safety was acceptable in the context of JX-594 replication, GM-CSF expression, systemic dissemination, and JX-594 had anti-tumoral effects against several refractory carcinomas. Phase II trials are now underway.
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Neoplasias Hepáticas/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos , Vaccinia virus , Adulto , Idoso , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Hiperbilirrubinemia/etiologia , Imuno-Histoquímica , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos/genética , Vírus Oncolíticos/crescimento & desenvolvimento , Vírus Oncolíticos/metabolismo , Tomografia por Emissão de Pósitrons , Infecções por Poxviridae/etiologia , Fatores de Tempo , Tomografia Computadorizada por Raios X , Falha de Tratamento , Resultado do Tratamento , Vaccinia virus/genética , Vaccinia virus/crescimento & desenvolvimento , Vaccinia virus/metabolismo , Replicação ViralRESUMO
The work demonstrates a judicious approach to achieve hepatocyte cell-targeted highly efficient gene delivery by utilizing a supramolecular complex of galactosylated cucurbituril and dextran-spermine conjugates.
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Sistemas de Liberação de Medicamentos , Galactose/metabolismo , Terapia Genética/métodos , Vetores Genéticos/metabolismo , Hepatócitos/metabolismo , Compostos Macrocíclicos/metabolismo , Dextranos/química , Dextranos/metabolismo , Galactose/química , Vetores Genéticos/síntese química , Vetores Genéticos/química , Hepatócitos/química , Hepatócitos/citologia , Humanos , Compostos Macrocíclicos/química , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Substâncias Macromoleculares/metabolismo , Espermina/química , Espermina/metabolismoRESUMO
This study was conducted to determine the immunogenicity and safety of an inactivated split-virus influenza A/H1N1 vaccine in healthy Korean children from 6 months to <18 years of age. The immunization schedule consisted of two vaccinations, 21 days apart. The unadjuvanted vaccine contained 7.5microg (subjects 6 months to <3 years of age) or 15microg (subjects 3 to <18 years of age) of hemagglutinin antigen per dose. A total of 251 subjects were enrolled and 248 and 242 subjects, respectively, were included in the post-first dose and post-second dose immunogenicity evaluations conducted on a per protocol basis. By day 21, after the first dose, hemagglutination-inhibition titers of 1:40 or more were observed in 5.9% of subjects 6 months to <3 years of age, 34.9% of subjects 3 to <9 years of age and 81.4% of subjects 9-18 years of age. By day 21 after the second dose, the titer had been achieved 55.9%, 69.5% and 90.5%, respectively. No vaccination-related serious adverse events were observed. A single 15-microg dose of vaccine was highly immunogenic in subjects equal to or more than 9 years of age. However, a two-dose regimen is needed to produce potentially protective antibody titers in younger children.