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Cytotoxic T lymphocytes (CTLs) mediate host defense against viral and intracellular bacterial infections and tumors. However, the magnitude of CTL response and their function needed to confer heterosubtypic immunity against influenza virus infection are unknown. We addressed the role of CD8+ T cells in the absence of any cross-reactive antibody responses to influenza viral proteins using an adenoviral vector expressing a 9mer amino acid sequence recognized by CD8+ T cells. Our results indicate that both CD8+ T cell frequency and function are crucial for heterosubtypic immunity. Low morbidity, lower viral lung titers, low to minimal lung pathology, and better survival upon heterosubtypic virus challenge correlated with the increased frequency of NP-specific CTLs. NP-CD8+ T cells induced by differential infection doses displayed distinct RNA transcriptome profiles and functional properties. CD8+ T cells induced by a high dose of influenza virus secreted significantly higher levels of IFN-γ and exhibited higher levels of cytotoxic function. The mice that received NP-CD8+ T cells from the high-dose virus recipients through adoptive transfer had lower viral titers following viral challenge than those induced by the low dose of virus, suggesting differential cellular programming by antigen dose. Enhanced NP-CD8+ T-cell functions induced by a higher dose of influenza virus strongly correlated with the increased expression of cellular and metabolic genes, indicating a shift to a more glycolytic metabolic phenotype. These findings have implications for developing effective T cell vaccines against infectious diseases and cancer. IMPORTANCE: Cytotoxic T lymphocytes (CTLs) are an important component of the adaptive immune system that clears virus-infected cells or tumor cells. Hence, developing next-generation vaccines that induce or recall CTL responses against cancer and infectious diseases is crucial. However, it is not clear if the frequency, function, or both are essential in conferring protection, as in the case of influenza. In this study, we demonstrate that both CTL frequency and function are crucial for providing heterosubtypic immunity to influenza by utilizing an Ad-viral vector expressing a CD8 epitope only to rule out the role of antibodies, single-cell RNA-seq analysis, as well as adoptive transfer experiments. Our findings have implications for developing T cell vaccines against infectious diseases and cancer.
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BACKGROUND: Sexually transmitted infections (STIs) such as syphilis and HIV remain to be a significant public health issue worldwide. Dual rapid point-of-care tests (POCTs) have shown promise for detecting antibodies to HIV and syphilis but have not been fully evaluated in the field. Our study supported the WHO ProSPeRo study on Sexually Transmitted Infection Point-of-Care Testing (STI POCT) by providing external quality assessment (EQA) for HIV and syphilis testing in reference laboratories and their associated clinical sites in seven countries. METHODS: HIV/syphilis serum liquid and dried tube specimen (DTS) panels were prepared by CDC. Liquid panels were distributed to the reference laboratories for three rounds of testing using commercially and locally available laboratory-based serological tests. DTS panels were sent to the clinical testing sites for 8 rounds of POC testing using the Abbott SD BIOLINE HIV/Syphilis Duo test (hereafter referred to as SD BIOLINE) and the Chembio Dual Path Platform (DPP) HIV-Syphilis assay. EQA panels were tested at CDC using the Rapid Plasma Reagin (RPR) test and the Treponema pallidum Particle Agglutination assay (TP-PA) for syphilis antibodies. Genetic Systems HIV-1/HIV-2 Plus O EIA, Geenius HIV Supplemental Assay and the Oraquick Advance HIV test were used to detect HIV antibodies in the EQA panels. Results from the reference laboratories and POCT sites were compared to those obtained at the CDC and a percentage agreement was calculated. RESULTS: Qualitative RPR and TP-PA performed at the reference laboratories demonstrated 95.4-100% agreement with CDC results while quantitative RPR and TP-PA tests demonstrated 87.7% and 89.2% agreement, respectively. A 93.8% concordance rate was observed for qualitative HIV testing in laboratories. EQA testing at clinical sites using dual tests showed 98.7% and 99.1% agreement for detection of HIV antibodies and eight out of 10 sites had > 95.8% agreement for syphilis testing. However, two clinical sites showed only 65.0-66.7% agreement for SD BIOLINE and 84.0-86.7% for DPP, respectively, for syphilis testing. CONCLUSIONS: Overall, laboratories demonstrated high EQA performance in this study. Both HIV/syphilis POCTs gave expected results in the clinic-based evaluations using DTS. However, testing errors were identified in a few testing sites suggesting the necessity for continuous training and monitoring the quality of POC testing.
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Infecções por HIV , HIV-1 , Sífilis , Humanos , Treponema pallidum , Anticorpos Anti-HIV , Infecções por HIV/diagnóstico , Sensibilidade e Especificidade , Anticorpos Antibacterianos , Testes Imediatos , Sorodiagnóstico da Sífilis/métodos , HIV-2 , Organização Mundial da Saúde , Sistemas Automatizados de Assistência Junto ao LeitoRESUMO
BACKGROUND: Antibody responses to non-egg-based standard-dose cell-culture influenza vaccine (containing 15 µg hemagglutinin [HA]/component) and recombinant vaccine (containing 45 µg HA/component) during consecutive seasons have not been studied in the United States. METHODS: In a randomized trial of immunogenicity of quadrivalent influenza vaccines among healthcare personnel (HCP) aged 18-64 years over 2 consecutive seasons, HCP who received recombinant-HA influenza vaccine (RIV) or cell culture-based inactivated influenza vaccine (ccIIV) during the first season (year 1) were re-randomized the second season of 2019-2020 (year 2 [Y2]) to receive ccIIV or RIV, resulting in 4 ccIIV/RIV combinations. In Y2, hemagglutination inhibition antibody titers against reference cell-grown vaccine viruses were compared in each ccIIV/RIV group with titers among HCP randomized both seasons to receive egg-based, standard-dose inactivated influenza vaccine (IIV) using geometric mean titer (GMT) ratios of Y2 post-vaccination titers. RESULTS: Y2 data from 414 HCP were analyzed per protocol. Compared with 60 IIV/IIV recipients, 74 RIV/RIV and 106 ccIIV/RIV recipients showed significantly elevated GMT ratios (Bonferroni corrected P < .007) against all components except A(H3N2). Post-vaccination GMT ratios for ccIIV/ccIIV and RIV/ccIIV were not significantly elevated compared with IIV/IIV except for RIV/ccIIV against A(H1N1)pdm09. CONCLUSIONS: In adult HCP, receipt of RIV in 2 consecutive seasons or the second season was more immunogenic than consecutive egg-based IIV for 3 of the 4 components of quadrivalent vaccine. Immunogenicity of ccIIV/ccIIV was similar to that of IIV/IIV. Differences in HA antigen content may play a role in immunogenicity of influenza vaccination in consecutive seasons. CLINICAL TRIALS REGISTRATION: NCT03722589.
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Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza , Influenza Humana , Vacina Antivariólica , Adulto , Humanos , Anticorpos Antivirais , Técnicas de Cultura de Células , Atenção à Saúde , Testes de Inibição da Hemaglutinação , Vírus da Influenza A Subtipo H3N2 , Estados Unidos , Vacinação , Vacinas Combinadas , Vacinas de Produtos Inativados , Vacinas SintéticasRESUMO
Automated nontreponemal rapid plasma reagin (RPR) tests were recently introduced in the United States for syphilis testing and limited performance data are available. In collaboration with the Association of Public Health Laboratories, three public health laboratories (PHL) were chosen through a competitive selection process to evaluate the performance of three FDA-cleared automated RPR test systems: BioPlex 2200 Syphilis Total & RPR assay (Bio-Rad Laboratories), AIX 1000 (Gold Standard Diagnostics), and ASI Evolution (Arlington Scientific). Panels prepared at the CDC included: a qualitative panel comprised of 734 syphilis reactive/nonreactive sera; a quantitative panel of 50 syphilis reactive sera (RPR titer 1:64 to 1:1,024); and a reproducibility panel of 15 nonreactive and reactive sera (RPR titer 1:1 to 1:64). Panels were shipped frozen to the PHL and tested on the automated RPR systems following manufacturers' instructions. Prior test results were blinded to all laboratories. When compared to manual RPR (Arlington Scientific) performed at the CDC as a reference test, the qualitative panel results demonstrated an overall concordance of 95.9% for AIX 1000, 94.6% for ASI Evolution, and 92.6% for Bioplex RPR; quantitative panel showed within range titer of 2-fold for 94% of specimens for AIX 1000, 68% for ASI Evolution, and 64% for BioPlex RPR, and the reproducibility testing panel demonstrated point estimates ranging from 69 to 95%. Automated RPR instruments could reduce turnaround time and minimize interpretation errors. However, additional evaluations with more specimens could assist laboratories with implementing automated RPR tests and understanding their limitations.
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Sífilis , Humanos , Sífilis/diagnóstico , Reaginas , Reprodutibilidade dos Testes , Anticorpos Antibacterianos , Sorodiagnóstico da Sífilis/métodos , Treponema pallidumAssuntos
Autoteste , Sífilis , Humanos , Sífilis/diagnóstico , Sífilis/epidemiologia , Fatores de Tempo , Estados Unidos/epidemiologiaRESUMO
The Internet of Things (IoT) is an advanced technology that comprises numerous devices with carrying sensors to collect, send, and receive data. Due to its vast popularity and efficiency, it is employed in collecting crucial data for the health sector. As the sensors generate huge amounts of data, it is better for the data to be aggregated before being transmitting the data further. These sensors generate redundant data frequently and transmit the same values again and again unless there is no variation in the data. The base scheme has no mechanism to comprehend duplicate data. This problem has a negative effect on the performance of heterogeneous networks.It increases energy consumption; and requires high control overhead, and additional transmission slots are required to send data. To address the above-mentioned challenges posed by duplicate data in the IoT-based health sector, this paper presents a fuzzy data aggregation system (FDAS) that aggregates data proficiently and reduces the same range of normal data sizes to increase network performance and decrease energy consumption. The appropriate parent node is selected by implementing fuzzy logic, considering important input parameters that are crucial from the parent node selection perspective and share Boolean digit 0 for the redundant values to store in a repository for future use. This increases the network lifespan by reducing the energy consumption of sensors in heterogeneous environments. Therefore, when the complexity of the environment surges, the efficiency of FDAS remains stable. The performance of the proposed scheme has been validated using the network simulator and compared with base schemes. According to the findings, the proposed technique (FDAS) dominates in terms of reducing energy consumption in both phases, achieves better aggregation, reduces control overhead, and requires the fewest transmission slots.
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Antibacterianos , Azitromicina , Farmacorresistência Bacteriana , Macrolídeos , Sífilis , Treponema pallidum , Humanos , Antibacterianos/farmacologia , Antibacterianos/provisão & distribuição , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana/genética , Macrolídeos/farmacologia , Macrolídeos/uso terapêutico , América do Norte , Sífilis/tratamento farmacológico , Sífilis/genética , Sífilis/microbiologia , Treponema pallidum/efeitos dos fármacos , Treponema pallidum/genética , Treponema pallidum/isolamento & purificação , Azitromicina/farmacologia , Azitromicina/uso terapêutico , Estados Unidos , Canadá , Penicilina G Benzatina/farmacologia , Penicilina G Benzatina/provisão & distribuição , Penicilina G Benzatina/uso terapêutico , Doxiciclina/farmacologia , Doxiciclina/provisão & distribuição , Doxiciclina/uso terapêuticoRESUMO
The mechanisms that initiate T helper type 2 (T(H)2) responses are poorly understood. Here we demonstrate that cysteine protease-induced T(H)2 responses occur via 'cooperation' between migratory dermal dendritic cells (DCs) and basophils positive for interleukin 4 (IL-4). Subcutaneous immunization with papain plus antigen induced reactive oxygen species (ROS) in lymph node DCs and in dermal DCs and epithelial cells of the skin. ROS orchestrated T(H)2 responses by inducing oxidized lipids that triggered the induction of thymic stromal lymphopoietin (TSLP) by epithelial cells mediated by Toll-like receptor 4 (TLR4) and the adaptor protein TRIF; by suppressing production of the T(H)1-inducing molecules IL-12 and CD70 in lymph node DCs; and by inducing the DC-derived chemokine CCL7, which mediated recruitment of IL-4(+) basophils to the lymph node. Thus, the T(H)2 response to cysteine proteases requires DC-basophil cooperation via ROS-mediated signaling.
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Basófilos/metabolismo , Citocinas/biossíntese , Células de Langerhans/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Th2/imunologia , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Antígenos/imunologia , Basófilos/imunologia , Basófilos/patologia , Comunicação Celular , Citocinas/genética , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Interleucina-4/biossíntese , Células de Langerhans/imunologia , Células de Langerhans/patologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Papaína/imunologia , Espécies Reativas de Oxigênio/imunologia , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Linfopoietina do Estroma do TimoRESUMO
Beam splitters play important roles in several optical systems. Due to the growing demand for the miniaturization of optical systems, it is necessary to design beam splitters with nanoscale dimensions to miniaturize the essential components for integrated optical circuits. In this work, we propose and numerically demonstrate a broadband, high efficient, and four-channel beam splitter based on a fishnet-shaped metasurface. The proposed structure is constructed of cruciform AlSb nanoantennas on the PDMS substrate. The simple design can split a beam of light into four beams with equal intensity, it achieves a conversion efficiency above 83%, and an anomalous transmission intensity exceeding 0.8 for the wavelength range of 761-835 nm. In this wavelength range, the beam splitting angle changes from 46.45° to 53.68°. Moreover, the four-channel beam splitter is tunable when the metasurface is designed as a discrete structure. At the wavelength of 874 nm, the beam splitting angle can be adjusted from 56.34° to 46.39° as the period increases from 1050 nm to 1207 nm by stretching the substrate. The presented metasurface might enable promising applications in integrated optical devices, owing to its advantages of multi-channel, wide broadband, high efficiency, and large beam split angle.
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OBJECTIVE: To evaluate the field performance of a multiplex PCR (M-PCR) assay for detection of herpes simplex virus (HSV)-1 and HSV-2, Treponema pallidum (T. pallidum) and Haemophilus ducreyi (H. ducreyi) in genital ulcer disease (GUD) specimens. METHODS: GUD M-PCR was performed on 186 remnant specimens, previously collected for HSV testing, by four public health laboratories (PHLs) and the Laboratory Reference and Research Branch (LRRB) at the Centers for Disease Control and Prevention. The results from the PHLs were compared with those of LRRB, which served as the reference testing method, and percentage agreement was calculated. RESULTS: HSV was detected in 31 of 52 (59.6%), 20 of 40 (50%), 43 of 44 (97.7%) and 19 of 50 (38.0%) specimens from PHL1, PHL2, PHL3 and PHL4, respectively. There were seven discrepant results for HSV, and the overall percent agreement between the PHLs and the LRRB was 94%-100%, with a kappa value of 0.922, which demonstrates high agreement. T. pallidum was identified in 7 of 51 (13.7%) specimens from PHL1 with 94.1% agreement and in 2 of 40 (5.0%) specimens from PHL2 with 100% agreement. The LRRB identified three additional T. pallidum-positive specimens from PHL1. The kappa value (0.849) for T. pallidum testing suggests good agreement. Consistent with the LRRB results, no T. pallidum was detected in specimens from PHL3 and PHL4, and H. ducreyi was not detected at any of the study sites. CONCLUSIONS: The GUD M-PCR assay performed well in four independent PHLs and 12 suspected syphilis cases were identified in this study. The M-PCR assay could provide improved diagnostic options for GUD infections in state and local PHLs.
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Cancroide , Haemophilus ducreyi , Herpes Simples , Herpesvirus Humano 1 , Sífilis , Cancroide/diagnóstico , Genitália , Haemophilus ducreyi/genética , Herpes Simples/diagnóstico , Humanos , Laboratórios , Saúde Pública , Reação em Cadeia da Polimerase em Tempo Real , Sífilis/diagnóstico , Treponema pallidum/genética , Úlcera/diagnósticoRESUMO
Influenza is a highly contagious respiratory virus that causes mild to severe respiratory illness, as well as death, and remains a serious threat to human health. Annual vaccination is the most cost-effective way to control influenza; however, the vaccine does not provide protection against emerging strains with epidemic and pandemic potential. Several antivirals have been developed to treat influenza but there is a rapid emergence of antiviral resistant strains. Therefore, there is an urgent need to understand the virus and its interactions with the host immune system so that novel strategies can be developed for prophylactic and therapeutic interventions. Innate lymphoid cells (ILCs), a family of immune cells present in the peripheral circulation and in mucosal tissues, play an important role in regulation of tissue homeostasis, inflammation, and immunity. This review examines the current understanding and therapeutic potential of ILCs during influenza virus infection in humans.
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Vacinas contra Influenza , Influenza Humana , Humanos , Imunidade Inata , Vacinas contra Influenza/uso terapêutico , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Linfócitos , VacinaçãoRESUMO
BACKGROUND: RIV4 and cell-culture based inactivated influenza vaccine (ccIIV4) have not been compared to egg-based IIV4 in healthcare personnel, a population with frequent influenza vaccination that may blunt vaccine immune responses over time. We conducted a randomized trial among healthcare personnel (HCP) aged 18-64 years to compare humoral immune responses to ccIIV4 and RIV4 to IIV4. METHODS: During the 2018-2019 season, participants were randomized to receive ccIIV4, RIV4, or IIV4 and had serum samples collected prevaccination, 1 and 6 months postvaccination. Serum samples were tested by hemagglutination inhibition (HI) for influenza A/H1N1, B/Yamagata, and B/Victoria and microneutralization (MN) for A/H3N2 against cell-grown vaccine reference viruses. Primary outcomes at 1 month were seroconversion rate (SCR), geometric mean titers (GMT), GMT ratio, and mean fold rise (MFR) in the intention-to-treat population. RESULTS: In total, 727 participants were included (283 ccIIV4, 202 RIV4, and 242 IIV4). At 1 month, responses to ccIIV4 were similar to IIV4 by SCR, GMT, GMT ratio, and MFR. RIV4 induced higher SCRs, GMTs, and MFRs than IIV4 against A/H1N1, A/H3N2, and B/Yamagata. The GMT ratio of RIV4 to egg-based vaccines was 1.5 (95% confidence interval [CI] 1.2-1.9) for A/H1N1, 3.0 (95% CI: 2.4-3.7) for A/H3N2, 1.1 (95% CI: .9-1.4) for B/Yamagata, and 1.1 (95% CI: .9-1.3) for B/Victoria. At 6 months, ccIIV4 recipients had similar GMTs to IIV4, whereas RIV4 recipients had higher GMTs against A/H3N2 and B/Yamagata. CONCLUSIONS: RIV4 resulted in improved antibody responses by HI and MN compared to egg-based vaccines against 3 of 4 cell-grown vaccine strains 1 month postvaccination, suggesting a possible additional benefit from RIV4. CLINICAL TRIALS REGISTRATION: NCT03722589.
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Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza , Influenza Humana , Anticorpos Antivirais , Técnicas de Cultura de Células , Atenção à Saúde , Testes de Inibição da Hemaglutinação , Humanos , Imunogenicidade da Vacina , Vírus da Influenza A Subtipo H3N2 , Vírus da Influenza B , Influenza Humana/prevenção & controle , Vacinas de Produtos InativadosRESUMO
A major challenge in vaccinology is to prospectively determine vaccine efficacy. Here we have used a systems biology approach to identify early gene 'signatures' that predicted immune responses in humans vaccinated with yellow fever vaccine YF-17D. Vaccination induced genes that regulate virus innate sensing and type I interferon production. Computational analyses identified a gene signature, including complement protein C1qB and eukaryotic translation initiation factor 2 alpha kinase 4-an orchestrator of the integrated stress response-that correlated with and predicted YF-17D CD8(+) T cell responses with up to 90% accuracy in an independent, blinded trial. A distinct signature, including B cell growth factor TNFRS17, predicted the neutralizing antibody response with up to 100% accuracy. These data highlight the utility of systems biology approaches in predicting vaccine efficacy.
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Perfilação da Expressão Gênica/métodos , Imunidade Inata/genética , Biologia de Sistemas/métodos , Vacina contra Febre Amarela/imunologia , Febre Amarela/prevenção & controle , Vírus da Febre Amarela/imunologia , Adolescente , Adulto , Anticorpos Antivirais/sangue , Linfócitos T CD8-Positivos/imunologia , Proteínas de Transporte/genética , Células Cultivadas , Ensaios Clínicos Controlados como Assunto , Humanos , Imunidade Ativa/genética , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Análise Multivariada , Testes de Neutralização , Proteínas Serina-Treonina Quinases/genética , Fator de Necrose Tumoral alfa/genética , Vacinação , Vacina contra Febre Amarela/uso terapêutico , Adulto JovemRESUMO
The external voltage-driven polymer translocation through a conical pore (with a large opening at the entry and a small tip at the exit) is studied by using the Langevin dynamics simulation in this paper. The entire translocation process is divided into an approaching stage and a threading stage. First, the approaching stage starts from the polymer entering the large opening and ends up at a terminal monomer reaching the pore tip. In this stage, the polymer will undergo the conformation adjustment to fit the narrowed cross-sectional area of the pore, leading to three approaching modes: the non-stuck mode with a terminal monomer arriving at the pore tip smoothly, the weak-stuck mode for the polymer stuck inside the pore for a short duration with minor conformational adjustments, and the strong-stuck mode with major conformational changes and a long duration. The approaching times (the duration of the approaching stage) of the three approaching modes show different behavior as a function of the pore apex angle. Second, the threading stage describes that the polymer threads through the pore tip with a linear fashion. In this stage, an increase in the apex angle causes the reduction of the threading time (the duration of the threading stage) due to the increase in the driving force with the apex angle at the tip. Moreover, we also find that with the increase in the apex angle or the polymer length, the polymer threading dynamics will change from the quasi-equilibrium state to the non-equilibrium state.
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Bacterial contamination has caused a major public health problem worldwide. Bacillus cereus is a conditional environmental pathogenic bacteria that can cause food poisoning. Whether environmental pathogens can cause widespread transmission in the insect kingdom is unclear. In this study, a Bacillus cereus ZJ-4 was isolated from the hospital environment of Zhenjiang City, Jiangsu Province, China. It was fatal by injection into the silkworm hemolymph. To investigated the potential toxic factors of ZJ-4 and clarified the toxicity response mechanism of silkworm by the ZJ-4 infection. Then, the whole genome of ZJ-4 was sequenced, and the immune mechanism of silkworm fat body to ZJ-4 pathogen was studied by HE pathological section and proteomics. Bacterial genome sequencing indicated that ZJ-4 had 352 drug resistance genes and 6 virulence genes. After 36 h of subcutaneous puncture with ZJ-4 suspension, the pathological changes were obviously found in HE pathological sections of fat body tissue. Comparative proteomic results indicated that differentially expressed proteins are mainly involved in stress reactions, biological regulation, and innate immunity. The qRT-PCR analysis showed that the expressions of ß-GRP, Spaetzle, MyD88, Tube and Dorsal genes in Toll pathway were up-regulated, while Pell and Cactus genes were down-regulated; in the antimicrobial peptide pathway, Glv2, Lzm, Mor, and Leb3 genes were up-regulated, while attacin1 and defensin genes were down-regulated; Sod gene was up-regulated, while Cat gene was down-regulated in the antioxidant pathway; Ldh, Sdh, and Mdh genes were down-regulated in glucose metabolism pathway. These results indicated that ZJ-4 can damage the innate immune pathway of silkworm, and also affect the normal immune function of fat body cells.
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Bombyx , Animais , Bacillus cereus/genética , Bombyx/genética , Genômica , Hemolinfa , ProteômicaRESUMO
Adaptive beamforming is sensitive to steering vector (SV) and covariance matrix mismatches, especially when the signal of interest (SOI) component exists in the training sequence. In this paper, we present a low-complexity robust adaptive beamforming (RAB) method based on an interference-noise covariance matrix (INCM) reconstruction and SOI SV estimation. First, the proposed method employs the minimum mean square error criterion to construct the blocking matrix. Then, the projection matrix is obtained by projecting the blocking matrix onto the signal subspace of the sample covariance matrix (SCM). The INCM is reconstructed by replacing part of the eigenvector columns of the SCM with the corresponding eigenvectors of the projection matrix. On the other hand, the SOI SV is estimated via the iterative mismatch approximation method. The proposed method only needs to know the priori-knowledge of the array geometry and angular region where the SOI is located. The simulation results showed that the proposed method can deal with multiple types of mismatches, while taking into account both low complexity and high robustness.
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Processamento de Sinais Assistido por Computador , Simulação por Computador , Imagens de Fantasmas , UltrassonografiaRESUMO
Robust production of type I interferon (IFN-alpha/beta) in plasmacytoid dendritic cells (pDCs) is crucial for antiviral immunity. Here we show involvement of the mammalian target of rapamycin (mTOR) pathway in regulating interferon production by pDCs. Inhibition of mTOR or its 'downstream' mediators, the p70 ribosomal S6 protein kinases p70S6K1 and p70S6K2, during pDC activation by Toll-like receptor 9 (TLR9) blocked the interaction of TLR9 with the adaptor MyD88 and subsequent activation of the interferon-regulatory factor IRF7, which resulted in impaired IFN-alpha/beta production. Microarray analysis confirmed that inhibition of mTOR by the immunosuppressive drug rapamycin suppressed antiviral and anti-inflammatory gene expression. Consistent with this, targeting rapamycin-encapsulated microparticles to antigen-presenting cells in vivo resulted in less IFN-alpha/beta production in response to CpG DNA or the yellow fever vaccine virus strain 17D. Thus, mTOR signaling is crucial in TLR-mediated IFN-alpha/beta responses by pDCs.
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Células Dendríticas/metabolismo , Interferon Tipo I/metabolismo , Proteínas Quinases/metabolismo , Transdução de Sinais/imunologia , Receptor Toll-Like 9/metabolismo , Animais , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Eletroforese em Gel de Poliacrilamida , Citometria de Fluxo , Regulação da Expressão Gênica/imunologia , Humanos , Immunoblotting , Imunossupressores/farmacologia , Interferon Tipo I/imunologia , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Fosfatidilinositol 3-Quinases/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Quinases/imunologia , Proteínas Quinases S6 Ribossômicas 70-kDa/imunologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR , Receptor Toll-Like 9/imunologia , TransfecçãoRESUMO
BACKGROUND: Human immunodeficiency virus (HIV)-infected persons are at a higher risk of severe influenza. Although we have shown that a standard-dose intradermal influenza vaccine versus a standard-dose intramuscular influenza vaccine does not result in differences in hemagglutination-inhibition titers in this population, a comprehensive examination of cell-mediated immune responses remains lacking. METHODS: Serological, antigen-specific B-cell, and interleukin 2-, interferon γ-, and tumor necrosis factor α-secreting T-cell responses were assessed in 79 HIV-infected men and 79 HIV-uninfected men. RESULTS: The route of vaccination did not affect the immunoglobulin A and immunoglobulin G (IgG) plasmablast or memory B-cell response, although these were severely impaired in the group with a CD4+ T-cell count of <200 cells/µL. The frequencies of IgG memory B cells measured on day 28 after vaccination were highest in the HIV-uninfected group, followed by the group with a CD4+ T-cell count of ≥200 cells/µL and the group with a CD4+ T-cell count of <200 cells/µL. The route of vaccination did not affect the CD4+ or CD8+ T-cell responses measured at various times after vaccination. CONCLUSIONS: The route of vaccination had no effect on antibody responses, antibody avidity, T-cell responses, or B-cell responses in HIV-infected or HIV-uninfected subjects. With the serological and cellular immune responses to influenza vaccination being impaired in HIV-infected individuals with a CD4+ T-cell count of <200 cells/µL, passive immunization strategies need to be explored to protect this population. CLINICAL TRIALS REGISTRATION: NCT01538940.
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Infecções por HIV/imunologia , Imunidade Celular/imunologia , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/normas , Influenza Humana/prevenção & controle , Adulto , Anticorpos Antivirais/imunologia , Formação de Anticorpos , Linfócitos B/imunologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Infecções por HIV/complicações , Testes de Inibição da Hemaglutinação , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Imunoglobulina A , Imunoglobulina G , Vírus da Influenza A Subtipo H1N1/imunologia , Interferon gama/metabolismo , Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Tailândia , Fator de Necrose Tumoral alfa/metabolismo , VacinaçãoRESUMO
BACKGROUND: MicroRNAs are small RNAs (~ 22 nt) that modulate the expression of thousands of genes in tumors and play important roles in the formation of multidrug resistance. In this study, we firstly investigated that miR-4532 involved in the multidrug resistance formation of breast cancer by targeting hypermethylated in cancer 1 (HIC-1), a tumor-suppressor gene. METHODS: To identify and characterize the possible miRNAs in regulating multidrug resistance, we employed the transcriptome sequencing approach to profile the changes in the expression of miRNAs and their target mRNAs were obtained by bioinformatics prediction. Then the molecular biology experiments were conducted to confirm miR-4532 involved in multidrug resistance formation of breast cancer. RESULTS: The luciferase reporter assay experiment was employed to confirm that HIC-1 was the target of miR-4532. Transfection with an miR-4532 mimic indicated miR-4532 mimic significantly increased breast cancer cell resistance to adriamycin. Cell proliferation and invasion assay experiments showed overexpression of HIC-1 inhibited the invasion and metastasis of breast cancer cells. Meanwhile, the interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway was confirmed to be involving in multidrug resistance by western blotting experiments. CONCLUSIONS: These results suggest that downregulation of hypermethylated in cancer-1 by miR-4532 could promote adriamycin resistance in breast cancer cells, in which the IL-6/STAT3 pathway was regulated by the HIC-1. This finding might contribute to new therapeutic target for reversal of tumor resistance.
RESUMO
We report a non-sampling model, combining the blob method with the standard lattice-based approximation, to calculate the free energy for the polymer translocation into an attractive sphere (i.e., spherical confined trans side) through a small pore. The translocation time is then calculated by the Fokker-Planck equation based on the free energy profile. There is a competition between the confinement effect of the sphere and the polymer-sphere attraction. The translocation time is increased due to the confinement effect of the sphere, whereas it is reduced by the polymer-sphere attraction. The two effects offset each other at a special polymer-sphere attraction which is dependent on the sphere size, the polymer length, and the driving force. Moreover, the entire translocation process can be divided into an uncrowded stage where the polymer does not experience the confinement effect of the sphere and a crowded stage where the polymer is confined by the sphere. At the critical sphere radius, the durations of the two (uncrowded and crowded) stages are the same. The critical sphere radius R* has a scaling relation with the polymer length N as R* â¼ Nß. The calculation results show that the current model can effectively treat the translocation of a three-dimensional self-avoiding polymer into the spherical confined trans side.