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Toxoplasma gondii relies heavily on the de novo pyrimidine biosynthesis pathway for fueling the high uridine-5'-monophosphate (UMP) demand during parasite growth. The third step of de novo pyrimidine biosynthesis is catalyzed by dihydroorotase (DHO), a metalloenzyme that catalyzes the reversible condensation of carbamoyl aspartate to dihydroorotate. Here, functional analyses of TgDHO reveal that tachyzoites lacking DHO are impaired in overall growth due to decreased levels of UMP, and the noticeably growth restriction could be partially rescued after supplementation with uracil or high concentrations of L-dihydroorotate in vitro. When pyrimidine salvage pathway is disrupted, both DHOH35A and DHOD284E mutant strains proliferated much slower than DHO-expressing parasites, suggesting an essential role of both TgDHO His35 and Asp284 residues in parasite growth. Additionally, DHO deletion causes the limitation of bradyzoite growth under the condition of uracil supplementation or uracil deprivation. During the infection in mice, the DHO-deficient parasites are avirulent, despite the generation of smaller tissue cysts. The results reveal that TgDHO contributes to parasite growth both in vitro and in vivo. The significantly differences between TgDHO and mammalian DHO reflect that DHO can be exploited to produce specific inhibitors targeting apicomplexan parasites. Moreover, potential DHO inhibitors exert beneficial effects on enzymatic activity of TgDHO and T. gondii growth in vitro. In conclusion, these data highlight the important role of TgDHO in parasite growth and reveal that it is a promising anti-parasitic target for future control of toxoplasmosis.
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Parasitos , Toxoplasma , Animais , Camundongos , Di-Hidro-Orotase , Pirimidinas/farmacologia , Uracila , Uridina Monofosfato , MamíferosRESUMO
BACKGROUND: Depression is a heterogeneous disorder with high morbidity and disability rates that poses serious problems in regard to mental health care. It is now well established that N-methyl D-aspartate receptors (NMDARs) modulators are being increasingly explored as potential therapeutic options for treating depression, although relatively little is known about their mechanisms of action. NMDARs are glutamate-gated ion channels that are ubiquitously expressed in the central nervous system (CNS) and they have been shown to play key roles in excitatory synaptic transmission. GluN2A, the predominant Glu2N subunit of functional NMDARs in neurons, is involved in various physiological processes in the CNS and is associated with diseases such as anxiety, depression, and schizophrenia. However, the role of GluN2A in the pathophysiology of depression has not yet been elucidated. METHODS: We reviewed several past studies in order to better understand the function of GluN2A in depression. Additionally, we also summarized the pathogenesis of depression based on the regulation of GluN2A expression, particularly its interaction with neuroinflammation and neurogenesis, which has received considerable critical attention and is highly implicated in the onset of depression. RESULTS: These evidences suggest that GluN2A overexpression impairs structural and functional synaptic plasticity, which contributes to the development of depression. Consequently, this knowledge is vital for the development of selective antagonists targeting GluN2A subunits using pharmacological and molecular methods. CONCLUSIONS: Specific inhibition of GluN2A NMDAR subunit is resistant to chronic stress-induced depressive-like behaviors, making them promising targets for the development of novel antidepressants.
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Toxoplasma gondii is a widespread protozoan parasite approximately infecting one-third of the world population and can cause serious public health problems. In this study, we investigated the protective effect of the attenuated vaccine Pru:Δcdpk2 against acute toxoplasmosis and explored the underlying immune mechanisms of the protection in pigs. The systemic T-cell and natural killer (NK) cell responses were analyzed, including kinetics, phenotype, and multifunctionality (interferon [IFN]-γ, tumor necrosis factor [TNF]-α), and the IFN-γ levels were analyzed in PBMCs. Our results showed that T. gondii-specific antibodies were induced by Pru:Δcdpk2. After challenging with RH, the antibodies were able to respond quickly in the immunized group, and the expression level was significantly higher than that in the unimmunized group. The expression level of IFN-γ significantly increased after vaccination, and the CD3+ γδ-, NK, and CD3+ γδ+ cell subsets also significantly increased. At the same time, functional analysis indicated that these cells were polarized toward a Th1 phenotype, showing the ability to secrete IFN-γ and TNF-α. The CD4+CD8α-T cell population exhibited a higher frequency of IFN-γ+ producing cells compared with the CD4-CD8α+ and CD4+CD8α+ cell populations during the early days of vaccination. Our results indicated that the attenuated vaccine could induce the expression of NK, γδ, and CD3αß cells in pigs, and IFN-γ and TNF-α secreted by these cells are important for resistance to T. gondii infection.
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Background: Structural social determinants of health have an accumulated negative impact on physical and mental health. Evidence is needed to understand whether emerging health information technology and innovative payment models can help address such structural social determinants for patients with complex health needs, such as Alzheimer's disease and related dementias (ADRD). Objective: This study aimed to test whether telehealth for care coordination and Accountable Care Organization (ACO) enrollment for residents in the most disadvantaged areas, particularly those with ADRD, was associated with reduced Medicare payment. Methods: The study used the merged data set of 2020 Centers for Medicare and Medicaid Services Medicare inpatient claims data, the Medicare Beneficiary Summary File, the Medicare Shared Savings Program ACO, the Center for Medicare and Medicaid Service's Social Vulnerability Index (SVI), and the American Hospital Annual Survey. Our study focused on community-dwelling Medicare fee-for-service beneficiaries aged 65 years and up. Cross-sectional analyses and generalized linear models (GLM) were implemented. Analyses were implemented from November 2023 to February 2024. Results: Medicare fee-for-service beneficiaries residing in SVI Q4 (i.e., the most vulnerable areas) reported significantly higher total Medicare costs and were least likely to be treated in hospitals that provided telehealth post-discharge services or have ACO affiliation. Meanwhile, the proportion of the population with ADRD was the highest in SVI Q4 compared with other SVI levels. The GLM regression results showed that hospital telehealth post-discharge infrastructure, patient ACO affiliation, SVI Q4, and ADRD were significantly associated with higher Medicare payments. However, coefficients of interaction terms among these factors were significantly negative. For example, the average interaction effect of telehealth post-discharge and ACO, SVI Q4, and ADRD on Medicare payment was -$1,766.2 (95% confidence interval: -$2,576.4 to -$976). Conclusions: Our results suggested that the combination of telehealth post-discharge and ACO financial incentives that promote care coordination is promising to reduce the Medicare cost burden among patients with ADRD living in socially vulnerable areas.
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Organizações de Assistência Responsáveis , Doença de Alzheimer , Demência , Medicare , Telemedicina , Humanos , Estados Unidos , Organizações de Assistência Responsáveis/economia , Organizações de Assistência Responsáveis/estatística & dados numéricos , Medicare/economia , Doença de Alzheimer/economia , Doença de Alzheimer/terapia , Telemedicina/economia , Telemedicina/organização & administração , Idoso , Masculino , Feminino , Demência/terapia , Demência/economia , Estudos Transversais , Idoso de 80 Anos ou mais , Populações Vulneráveis , Planos de Pagamento por Serviço PrestadoRESUMO
Three new compounds, (8S)-2,2,7,7-tetramethyl-8-hydroxymethyl-6H-indanone-(2,3-b)-2H-pyran-9-O-ß-d-glucopyranoside (1), (7S,8S)-2,2,7-trimethyl-7-hydroxymethyl-8-hydroxy-2,7,8,9-tetrahydro-6H-naphtho-(2,3-b)-pyran-10-O-ß-d-glucopyranoside (2), 1-deoxy-1-(3,4-dihydro-7-methyl-2,3-dioxo-1(2H)-quinoxalinyl)pentitol-6-carboxylic acid (3), as well as six known compounds (4-9), were obtained. Their structures were determined by spectroscopy and comparison with NMR data of related compounds. Absolute configurations were determined by ECD spectroscopy. The hepatoprotective effects of these compounds were investigated on HepG2 and LO2 cells lines; compounds 1, 2, and 4 displayed moderate activity.
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Glicosídeos , Estrutura Molecular , Glicosídeos/química , Linhagem Celular , Espectroscopia de Ressonância MagnéticaRESUMO
Surface plasmon lithography breaks through the diffraction limit with surface plasmon effect and achieves high-resolution imaging below sub-wavelengths. The dynamic detection and control of the working distance between the mask and the substrate is particularly important for the quality of the lithography samples. In this paper, the mask-substrate gap sensing mechanism is analyzed, and a mask-substrate gap absolute distance measurement model is established based on the principle of white light interference. We design a Fizeau interferometer demodulation system based on a hardware optical correlation method, and focus on analyzing the influence of the sub-nanometer surface profile of the optical wedge on the resolution. Finally, we propose a data processing method for extracting the dynamic gap value by SSA (singular spectrum analysis). The experimental results show that the system shows high performance with a gap detection range of 3.0â¼6.0 µm, the stability of ±0.12 nm, and the resolution of better than 0.30 nm.
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OBJECTIVE: This study aimed to evaluate the efficacy and safety of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) versus standard-dose intensity-modulated radiotherapy (SD-IMRT) in the treatment of locally advanced esophageal squamous cell carcinoma. METHODS: From July 2003 to March 2014, 1748 patients in a single center who received definitive chemoradiotherapy were included in the analysis. A total of 109 patients who underwent SIB-IMRT and fulfilled all inclusion and exclusion criteria were identified as the study group. A total of 266 patients who underwent SD-IMRT (60â¯Gy/30 fractions, 2â¯Gy/fraction, 1 time/day, 5 times/week) during the same period were selected as the control group. Propensity score matching (PSM) was used to balance the baseline characteristics. Survival status, treatment failure mode, and the occurrence of adverse events were compared between the two groups. RESULTS: There were more women and more cervical and upper thoracic cancers (Pâ¯= 0.038, <â¯0.001, respectively) in the SIB-IMRT group before case matching. The median progression-free survival (PFS) in the SD-IMRT and SIB-IMRT groups was 22 and 19 months, respectively, and the median overall survival duration was 24 and 22 months, respectively, with χ2â¯= 0.244 and Pâ¯= 0.621. After PSM of 1:1, 138 patients entered the final analysis (69 cases from each group). The median PFS of the SD-IMRT group and the SIB-IMRT group was 13 and 18 months, respectively, with χ2â¯= 8.776 and Pâ¯= 0.003. The 1, 3, and 5year overall survival rates were 66.7, 21.7, and 8.7% and 65.2, 36.2, and 27.3%, respectively, and the median overall survival duration was 16 and 22 months, respectively, with χ2â¯= 5.362 and Pâ¯= 0.021. Treatment failure mode: 5year local regional recurrence rates of SD-IMRT and SIB-IMRT were 50.7 and 36.2%, respectively, with χ2â¯= 2.949 and Pâ¯= 0.086. The 5year distant metastasis rates of the two groups were 36.2 and 24.6%, respectively, with χ2â¯= 2.190 and Pâ¯= 0.139. ADVERSE EVENTS: 3 patients experienced grade 4-5 toxicity (2.2%), including one case of grade 4 radiation esophagitis and two cases of grade 5 radiation pneumonitis, all in the SD-IMRT group; 14 patients experienced grade 3 adverse events (10.1%), primarily including radiation esophagitis, radiation pneumonitis, and hematological toxicity. CONCLUSION: The technique of SIB-IMRT was safe and reliable compared with SD-IMRT. In addition, SIB-IMRT had locoregional control advantages and potential survival benefits.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Esofagite , Pneumonite por Radiação , Radioterapia de Intensidade Modulada , Quimiorradioterapia/efeitos adversos , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas do Esôfago/radioterapia , Esofagite/etiologia , Feminino , Humanos , Pneumonite por Radiação/etiologia , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Estudos RetrospectivosRESUMO
BACKGROUND AND PURPOSE: The complications of radical surgery for cervical cancer can increase patient suffering and affect their quality of life. This retrospective study assessed the safety of radical hysterectomy (RH) with pelvic lymph node dissection (PLND) by observing the complications of patients with cervical cancer who underwent this procedure in a single centre over 10 years. Our findings may provide experience and evidence for preventing and reducing complications. METHODS: A total of 2226 cervical cancer patients who met the inclusion criteria were enrolled. All patients underwent RH + PLND. Intraoperative injury to adjacent tissues and short-term and long-term complications were recorded to analyze factors associated with the occurrence of complications. RESULTS: Postoperative complications occurred in 34.41% (766/2226) of patients, including 7.68% of patients with injury to adjacent tissues, 31.45% with short-term complications, and 2.96% with long-term complications. Age, tumor size, invasion depth, parametrial invasion, lymph vascular space invasion (LVSI), lymph node metastasis, International Federation of Gynaecology and Obstetrics (FIGO) stage, and surgical procedure were closely associated with the postoperative complications of RH + PLND (P < 0.05). CONCLUSIONS: The results of this study showed that RH + PLND for cervical cancer is safe and practical. Patients aged 40-60 years, with tumors ≥ 4 cm, invasion depth ≥ 2/3, parametrial invasion, LVSI, lymph node metastasis, FIGO stage > IB2, and who underwent open surgery were more prone to complications.
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Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/cirurgia , Metástase Linfática , Estudos Retrospectivos , Qualidade de Vida , Excisão de Linfonodo/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
Protein phosphorylation plays key roles in a variety of essential cellular processes. Fasciola gigantica is a tropical liver fluke causing hepatobiliary disease fascioliasis, leading to human health threats and heavy economic losses. Although the genome and protein kinases of F. gigantica provided new insights to understand the molecular biology and etiology of this parasite, there is scant knowledge of protein phosphorylation events in F. gigantica. In this study, we characterized the global phosphoproteomics of adult F. gigantica by phosphopeptide enrichment-based LC-MS/MS, a high-throughput analysis to maximize the detection of a large repertoire of phosphoproteins and phosphosites. A total of 1030 phosphopeptides with 1244 phosphosites representing 635 F. gigantica phosphoproteins were identified. The phosphoproteins were involved in a wide variety of biological processes including cellular, metabolic, and single-organism processes. Meanwhile, these proteins were found predominantly in cellular components like membranes and organelles with molecular functions of binding (51.3%) and catalytic activity (40.6%). The KEGG annotation inferred that the most enriched pathways of the phosphoproteins included tight junction, spliceosome, and RNA transport (each one contains 15 identified proteins). Combining the reports in other protozoa and helminths, the phosphoproteins identified in this work play roles in metabolic regulation and signal transduction. To our knowledge, this work performed the first global phosphoproteomics analysis of adult F. gigantica, which provides valuable information for development of intervention strategies for fascioliasis.
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Fasciola hepatica , Fasciola , Fasciolíase , Animais , Cromatografia Líquida , Humanos , Espectrometria de Massas em TandemRESUMO
OBJECTIVE: This study aimed to evaluate the clinical outcomes for patients with stage IB2/IIA2 cervical squamous cell carcinoma treated with neoadjuvant chemotherapy combined with radical surgery. METHODS: A total of 68 patients with cervical squamous cell carcinoma were randomly divided into the experimental group (n = 35) and the control group (n = 33). The patients in the experimental group received paclitaxel plus cisplatin neoadjuvant chemotherapy for two cycles, then underwent radical hysterectomy and bilateral adnexectomy at 2 weeks post-chemotherapy. The control group only underwent radical hysterectomy and bilateral adnexectomy after the diagnosis of cervical squamous cell carcinoma. The toxic and side effects of chemotherapy in the experimental group were observed. Also, the operation method, operation time, blood loss, grade of wound healing, complications, and postoperative pathology were noted in the two groups. Primary foci and pelvic lymph node recurrence and distant metastasis were observed, and 3-year and 5-year survival rates were calculated. RESULTS: Only one patient in the experiment had grade III bone marrow suppression; no other grade III and IV chemotherapy toxic reactions were observed. The operation was successfully completed in all patients. The operation time, intraoperative blood loss, placement of the ureteral catheter, bladder injury, ureteric injury, postoperative urinary tub, pelvic drainage tube indwelling time, anal exhaust time, postoperative complications, and metastatic ratio of lymph nodes were not significantly different between the two groups (P > 0.05). The number of dissected lymph nodes, deep myometrial invasion, and vascular tumor emboli showed a significant difference in the experimental group compared with the control group (P < 0.05). The 3-year disease-free survival (82.9% vs 81.9%), 5-year disease-free survival (71.4% vs 60.6%), 3-year overall survival (91.4% vs 87.8%), and 5-year overall survival (82.9% vs 75.6%) were not statistically significantly different between the experimental group and the control group (P > 0.05). CONCLUSIONS: Neoadjuvant chemotherapy in IB2/IIA2 stage cervical squamous cell carcinoma showed low toxic side effects. Radical surgery after chemotherapy is safe and feasible. It plays a coordinating role in reducing the tumor infiltration depth of the deep muscle layer and the incidence of vascular tumor emboli, reducing the use of postoperative adjuvant therapy, and improving the quality of life of patients, but does not improve the 3-year/5-year survival rate.
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Carcinoma de Células Escamosas , Neoplasias do Colo do Útero , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Quimioterapia Adjuvante , Feminino , Humanos , Histerectomia , Terapia Neoadjuvante , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Qualidade de Vida , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgiaRESUMO
Migration and release of sediment pollutants has become one of the important causes of water pollution, but the contribution of different forms of nitrogen in different water layers to the water quality of the overlying water is unclear. In this study, the main stream of Liaohe River with heavy nitrogen pollution was taken as an example. The static simulation method and related analysis techniques were used to explore the release characteristics of different forms of inorganic nitrogen and its effect on TN and Chla in overlying water from the different water layers. The results showed that the release rates of TN, NH4+-N and NO3--N from upstream, midstream and downstream sections were different, but the release characteristics of them in different water layers were the same basically. Generally, the inorganic nitrogen in the pore water of the sediment was released to the water body rapidly in the early 0-8 days. The contribution rate of NH4+-N and NO3--N to the change of TNo was 76.85% for the upstream section, and the contribution rate of NO3--N to the change of TNo was 65.02% for the midstream section. NH4+-N and NO3--N in the different water layers from downstream did not showed a significant correlation with TN of overlying water. NO3--N in sediments was the main contributor of TN and Chla changes in the overlying water and its content can reflect the nitrogen pollution trend of the water body to a certain extent. When the water retention time was 4-16 days, the TLI in the water body was relatively high. After effective control of exogenous pollution, the release of endogenous nutrients in Liaohe River should be paid more attention.
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Nitrogênio , Poluentes Químicos da Água , China , Monitoramento Ambiental , Sedimentos Geológicos , Lagos , Nitrogênio/análise , Fósforo/análise , Água , Poluentes Químicos da Água/análiseRESUMO
Long-term outcomes of 530 esophageal squamous cell carcinoma patients with minimally invasive Ivor Lewis esophagectomy. J Surg Oncol. 2018; 117:957-969. https://doi.org/10.1002/jso.24997 The above article, published online on May 30, 2018 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors and the Journal Editor in Chief Dr. Stephen Sener and Wiley Periodicals, Inc. The retraction has been agreed following concerns raised that the number of patients operated on was considerably lower than the number of patients reported in the article. When asked to provide documentary evidence of the operations performed, the authors confirmed the reported discrepancy and requested to retract their article.
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This study aimed to explore the optimal indications and mechanism of Uncariae Ramulus cum Uncis(UR)-Eucommiae Cortex(EC) in lowering blood pressure based on network pharmacology and molecular docking. Chemical constituents were collected and screened by TCMSP database. Swiss Target Prediction platform was used to predict the related targets of the drug. OMIM, TCMIP and GeneCards databases were used to collect hypertension-related genes, and the intersections were taken to obtain potential targets for anti-hypertensive treatment of UR-EC. FunRich software was used to enrich the clinical phenotype and expression site of potential target of lowering blood pressure to analyze and predict the optimal indications of UR-EC. STRING database was used for KEGG pathway enrichment analysis, and Cytoscape 3.7.2 was used to construct the network of "composition-target-pathway". The key targets and their corresponding components in the network were analyzed and obtained, and then molecular docking was applied for preliminary verification. Twenty potential active components of UR and 24 potential active components of EC were respectively collected, and 92 anti-hypertensive potential targets of UR-EC were obtained. According to FunRich enrichment results, the optimal indication of UR-EC was pregnancy hypertension, which involved calcium signaling pathway, HIF-1 signaling pathway, neuroactive ligand receptor interaction, renin vascular tightening, VEGF signaling pathway, etc. In addition, AKT1, NOS2, ADRB2, F2, NOS3, SCN5 A, HTR2 A and JAK2 were considered as the key targets in the network. The molecular docking results showed that the screened potential active components had high binding activity with the key targets. This study preliminarily revealed that UR-EC may have therapeutic effects on pregnancy hypertension in terms of sedation, anti-hypertension, anti-inflammatory, anti-oxidation, improvement of vascular endothelial function and so on.
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Medicamentos de Ervas Chinesas , Hipertensão , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , GravidezRESUMO
Autophagy is a highly conservative and multi-component activated energy metabolism and self-renewal mechanism, which plays a crucial regulatory role in maintaining the normal physiological state of cells and is involved in various pathological processes. In recent years, the mechanism study has made great progress in regulating autophagy with effective components of Chinese materia medica(CMM),which are reported to prevent and treat cancers, neurodegenerative diseases, cardiovascular diseases and metabolic and immune-related diseases. This review outlines the molecular regulation mechanisms of cell autophagy with CMM components in controlling the above-mentioned diseases. There are many relevant reports on the regulatory mechanisms of autophagy in tumor and cardiovascular cells with CMM monomers. The main chemical structural types are alkaloids, saponins, polyphenols, flavonoids and terpenes. And m-TOR pathway is the main mechanism relating to the regulatory mechanisms of autophagy with CMM. Therefore, the regulatory mec-hanisms of cell autophagy become a new research targeting strategy of therapies with CMM. This review provides evidences for the effectiveness and scientificity of CMM in regulating autophagy, in the expectation of providing references for the in-depth studies of CMM in the field of autophagy and the development of natural autophagy regulators.
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Medicamentos de Ervas Chinesas , Materia Medica , Saponinas , Povo Asiático , Autofagia , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Medicina Tradicional ChinesaRESUMO
BACKGROUND AND OBJECTIVES: The short-term benefits of minimally invasive esophagectomy (MIE) Ivor Lewis were proved, but 6-year outcomes in esophageal squamous cell carcinoma (ESCC) patients remain unclear. We sought to investigate perioperative outcomes, quality of life (QOL), survival and impact of adjuvant therapy in ESCC patients who underwent MIE Ivor Lewis. METHODS: We conducted a retrospective review of 530 ESCC patients treated with MIE Ivor Lewis from 2011 to 2016. Relevant variables were collected and assessed. Overall survival (OS) and disease-free survival (DFS) was analyzed by Kaplan-Meier or Cox proportional hazards modeling. RESULTS: Median operation duration was 266 min. The median number of lymph nodes was 28. The 30-day postoperative mortality was 1.7%. At a median follow-up of 41 months, the 6-year OS and DFS were 44.7% and 46.1%. Adjuvant chemoradiotherapy offered survival advantages in advanced stage patients. Pathological tumor-node-metastasis stage, postoperative complications, and recurrent laryngeal nerve lymphadenectomy were independent prognostic factors based on multivariate analysis. Generalized estimating equation analysis showed a rapid postoperative QOL improvement. CONCLUSIONS: MIE Ivor Lewis is a safe and feasible procedure in ESCC patients. It offers satisfactory perioperative outcomes, rapid QOL improvement, and acceptable long-term oncologic survival. Adjuvant chemoradiotherapy may improve OS and DFS in advanced stage patients.
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Carcinoma de Células Escamosas/mortalidade , Neoplasias Esofágicas/mortalidade , Esofagectomia/mortalidade , Laparoscopia/mortalidade , Procedimentos Cirúrgicos Minimamente Invasivos/mortalidade , Complicações Pós-Operatórias , Idoso , Anastomose Cirúrgica , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Feminino , Seguimentos , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaAssuntos
Educação/normas , Universidades/normas , China , Educação/economia , Objetivos , Universidades/economiaRESUMO
Marburg virus (MARV), which is one of the most virulent agents in the world, causes lethal haemorrhagic fever in humans and nonhuman primates (NHPs) with a mortality rate of up to 90%. Currently, there is no effective treatment or approved vaccine for MARV for human use to control disease outbreak and spread. Virus-like particles (VLPs), which are morphologically identical to the native infectious virus particle, are efficacious as vaccines against many viruses, including human papilloma virus (HPV), porcine circovirus (PCV) type 2 and hepatitis B virus (HBV). In this study, we generated MARV virus-like particles (VLPs) by co-expressing a glycoprotein (GP) and matrix protein (VP40) using the baculovirus expression system. Rhesus macaques vaccinated with MARV VLPs mixed with adjuvant Poria cocos polysaccharides (PCP-II) produced a GP-specific IgG titer of up to 1:1280 and virus-neutralizing antibody titers that reached 1:320. MARV VLPs also elicited interferon-γ (IFN-γ) and interleukin-4 (IL-4) secretion associated with T-helper 1 cell (Th1)- and T-helper 2 cell (Th2)-mediated immunity, as detected using enzyme-linked immunospot (ELISpot) assays. These data indicate that MARV VLPs mixed with adjuvant PCP-II have excellent immunogenicity in rhesus macaques and may be a promising candidate vaccine against MARV.
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Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Marburgvirus/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , ELISPOT , Humanos , Interferon gama/metabolismo , Interleucina-4/metabolismo , Macaca mulatta , Doença do Vírus de Marburg/imunologia , Doença do Vírus de Marburg/virologia , Marburgvirus/genética , Marburgvirus/isolamento & purificação , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Células Sf9 , Vacinas de Partículas Semelhantes a Vírus/biossíntese , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/imunologiaRESUMO
Pathogenic bacteria utilize type 3 secretion systems to inject type 3 effectors (T3Es) into host cells, thereby subverting host defense reactions. Similarly, T3Es of symbiotic nitrogen-fixing rhizobia can affect nodule formation on roots of legumes. Previous work showed that NopL (nodulation outer protein L) of Sinorhizobium(Ensifer) sp. strain NGR234 is multiply phosphorylated in eukaryotic cells and that this T3E suppresses responses mediated by mitogen-activated protein (MAP) kinase signaling in yeast (mating pheromone signaling) and plant cells (expression of pathogenesis-related defense proteins). Here, we show that NopL is a MAP kinase substrate. Microscopic observations of fluorescent fusion proteins and bimolecular fluorescence complementation analysis in onion cells indicated that NopL is targeted to the nucleus and forms a complex with SIPK (salicylic acid-induced protein kinase), a MAP kinase of tobacco. In vitro experiments demonstrated that NopL is phosphorylatyed by SIPK. At least nine distinct spots were observed after two-dimensional gel electrophoresis, indicating that NopL can be hyperphosphorylated by MAP kinases. Senescence symptoms in nodules of beans (Phaseolus vulgaris cv. Tendergreen) were analyzed to determine the symbiotic effector activity of different NopL variants with serine to alanine substitutions at identified and predicted phosphorylation sites (serine-proline motif). NopL variants with six or eight serine to alanine substitutions were partially active, whereas NopL forms with 10 or 12 substituted serine residues were inactive. In conclusion, our findings provide evidence that NopL interacts with MAP kinases and reveals the importance of serine-proline motifs for effector activity during symbiosis.
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Proteínas de Bactérias/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Sinorhizobium/metabolismo , Núcleo Celular/metabolismo , Sistema de Sinalização das MAP Quinases , Mutação/genética , Phaseolus/fisiologia , Fosforilação , Nodulação , Ligação Proteica , Saccharomyces cerevisiae/metabolismo , Serina/metabolismo , Sinorhizobium/enzimologia , Especificidade por Substrato , Simbiose , NicotianaRESUMO
A Gram-stain-positive, strictly aerobic and rod-shaped bacterium, designated strain XAT, was isolated from the moss, Physcomitrella patens, and characterized by using a polyphasic taxonomic approach. The novel strain was non-spore-forming, non-motile, catalase-positive and oxidase-negative. Its optimal temperature for growth occurred at 28-30 °C and the optimum pH for growth was 7.0-7.5. The major fatty acids comprised anteiso-C15 : 0, iso-C16 : 0, ω-cyclohexyl-C17 : 0 and anteiso-C17 : 0. The polar lipids contained diphosphatidylglycerol, phosphatidylglycerol, seven unidentified glycolipids, one unidentified phospholipid and one unidentified lipid. The major menaquinone was MK-11, followed by MK-10 and MK-12. The peptidoglycan type was B2γ and contained the amino acids 2,4-diaminobutyric acid, alanine, glycine, 3-hydroxy-glutamic acid and small amounts of glutamic acid. The genomic DNA G+C content of strain XAT was 68.2âmol%. Strain XAT exhibited highest 16S rRNA gene sequence similarity with Leifsonia lichenia 2SbT (96.3 %) and Humibacter antri D7-27T (96.2 %). However, phylogenetic analyses showed that strain XAT did not cluster with any species of the genera Leifsonia, Humibacter or other genera of the family Microbacteriaceae and the phylum Actinobacteria. Based on 16S rRNA gene sequence analyses, and the phenotypic and chemotaxonomic data, strain XAT is considered to represent a novel species of a novel genus, for which the name Cnuibacter physcomitrellae gen. nov., sp. nov. is proposed. The type strain is XAT ( = CGMCC 1.15041T = DSM 29843T).
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OBJECTIVE: To investigate the action mechanisms of the FZD5 gene in prostate cancer bone metastasis and search for some new treatments for this disease. METHODS: We determined the expression level of the FZD5 gene in prostate cancer PC3 cells and, after transfection of siRNA into the PC3 cells and silence of the FZD5 gene, observed the changes in the migration and proliferation of the cells. We established the model of prostate cancer bone metastasis by tibial injection of prostate cancer cells in the nude mice. Then we injected control siRNA and FZD5-silenced siRNA into the tibia of the mice followed by evaluation of tumor-induced bone destruction by X-ray imaging at 0, 1, and 3 weeks and by HE staining at 3 weeks after injection. RESULTS: After transfection of FZD5-silenced siRNA into the prostate cancer PC3 cells, the expression of the FZD5 gene was decreased about 70%. The rate of cell proliferation was significantly lower in the gene silencing group than in the control (P < 0.05), and that of cell migration dropped by 30% in the former as compared with the latter group at 48 hours after FZD5 silencing (P < 0.05). At 3 weeks after injection of control siRNA or FZD5-silenced siRNA into the tibia of the mice, osteolytic damage was observed in both groups, though less in the FZD5 silencing group, with only a few remaining bone trabeculae visible. CONCLUSION: Silencing the FZD5 gene can reduce the migration and proliferation of prostate cancer cells, help to suppress bone metastasis and destruction, and thereby improve the survival rate and quality of life of the patients.