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During the progression of HIV-1 infection, macrophage tropic HIV-1 that use the CCR5 co-receptor undergoes a change in co-receptor use to CXCR4 that is predominately T cell tropic. This change in co-receptor preference makes the virus able to infect T cells. HIV-2 is known to infect MDMs and T cells and is dual tropic. The aim of this study was to elucidate the differential expression profiles of host miRNAs and their role in cells infected with HIV-1/HIV-2. To achieve this goal, a comparative global miRNA expression profile was determined in human PBMCs and MDMs infected with HIV-1/HIV-2. Differentially expressed miRNAs were identified in HIV-1/HIV-2 infected PBMCs and MDMs using the next-generation sequencing (NGS) technique. A comparative global miRNA expression profile in infected MDMs and PBMCs with HIV-1 and HIV-2 identified differential expression of several host miRNAs. These differentially expressed miRNAs are likely to be involved in many signaling pathways, like the p53 signaling pathway, PI3K-Akt signaling pathways, MAPK signaling pathways, FoxO signaling pathway, and viral carcinogenesis. Thus, a comparative study of the differential expression of host miRNAs in MDMs and T cell in response to HIV-1 and HIV-2 infection will help us to identify unique biomarkers that can differentiate HIV-1 and HIV-2 infection.
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Infecciones por VIH/metabolismo , VIH-1/metabolismo , VIH-2/metabolismo , Sistema de Señalización de MAP Quinasas , Macrófagos/metabolismo , MicroARNs/biosíntesis , Monocitos/metabolismo , Transcriptoma , Infecciones por VIH/patología , Humanos , Macrófagos/patología , Macrófagos/virología , Monocitos/patología , Monocitos/virologíaRESUMEN
Macrophages contribute to HIV-1 pathogenesis by forming a viral reservoir that serve as a viral source for the infection of CD4 T cells. The relationship between HIV-1 latent infection and superinfection in macrophages has not been well studied. Using susceptible U1 cells chronically infected with HIV-1, we studied the effects of HIV superinfection on latency and differences in superinfection with HIV-1 and HIV-2 in macrophages. We found that HIV-1 (MN) superinfection displayed increased HIV-1 replication in a time-dependent manner; while cells infected with HIV-2 (Rod) initially showed increased HIV-1 replication, followed by a decrease in HIV-1 RNA production. HIV-1 superinfection upregulated/activated NF-ĸB, NFAT, AP-1, SP-1, and MAPK Erk through expression/activation of molecules, CD4, CD3, TCRß, Zap-70, PLCγ1, and PKCΘ in T cell receptor-related signaling pathways; while HIV-2 superinfection initially increased expression/activation of these molecules followed by decreased protein expression/activation. HIV superinfection initially downregulated HDAC1 and upregulated acetyl-histone H3 and histone H3 (K4), while HIV-2 superinfection demonstrated an increase in HDAC1 and a decrease in acetyl-histone H3 and histone H3 (K4) relative to HIV-1 superinfection. U1 cells superinfected with HIV-1 or HIV-2 showed differential expression of proteins, IL-2, PARP-1, YB-1, and LysRS. These findings indicate that superinfection with HIV-1 or HIV-2 has different effects on reactivation of HIV-1 replication. HIV-1 superinfection with high load of viral replication may result in high levels of cytotoxicity relative to HIV-2 superinfection. Cells infected with HIV-2 showed lower level of HIV-1 replication, suggesting that co-infection with HIV-2 may result in slower progression toward AIDS. J. Cell. Physiol. 232: 1746-1753, 2017. © 2016 Wiley Periodicals, Inc.
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VIH-1/fisiología , VIH-2/fisiología , Replicación Viral/fisiología , Antígenos CD4/metabolismo , Epigénesis Genética , Humanos , Interleucina-2/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , ARN Viral/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Sobreinfección/virología , Células U937 , Ensamble de VirusRESUMEN
BACKGROUND: Individuals with acute / early HIV-1 infection are often unaware that they are infected with HIV-1 and may be involved in high-risk behavior leading to transmission of HIV-1. Identifying individuals with acute / early HIV-1 infection is critical to prevent further HIV-1 transmission, as diagnosis can lead to several effective HIV-1 prevention strategies. Identification of disease-stage specific non-viral host biomarkers would be useful as surrogate markers to accurately identify new HIV-1 infections. The goal of this study was to identify a panel of host derived plasma long non-coding RNAs (lncRNAs) that could serve as prognostic and predictive biomarkers to detect early/acute HIV-1 infection. METHODS: A total of 84 lncRNAs were analyzed in sixteen plasma samples from HIV-1 infected individuals and four healthy controls using the lncRNA PCR-array. Twenty-one lncRNAs were selected and validated in 80 plasma samples from HIV-1 infected individuals [HIV-1 infected patients in the eclipse stage (n = 20), acute stage (n = 20), post-seroconversion p31 negative stage (n = 20), and post-seroconversion p31 positive stage (n = 20) of infection] and 20 healthy controls. The validation study results were used to develop a plasma lncRNA panel that was evaluated in the panel test phase to detect early/acute HIV-1 infection in 52 independent samples. RESULTS: We identified a lncRNA panel (Pmodel-I) containing eight lncRNAs (DISC2, H19, IPW, KRASP1, NEAT1, PRINS, WT1-AS and ZFAS1) that could distinguish HIV-1 infection from healthy controls with high AUC 0·990 (95% CI 0.972-1.000), sensitivity (98.75%), and specificity (95%). We also found that Pmodel-II and Pmodel-III demonstrates 100% sensitivity and specificity (AUC 1·00; 95%CI:1·00-1·00) and could distinguish eclipse stage and acute stage of HIV-1 infection from healthy controls respectively. Antiretroviral treatment (ART) cumulatively restored the levels of lncRNAs to healthy controls levels. CONCLUSION: lncRNA expression changes significantly in response to HIV-1 infection. Our findings also highlight the potential of using circulating lncRNAs to detect both the eclipse and acute stages of HIV-1 infection, which may help to shorten the window period and facilitate early detection and treatment initiation. Initiating ART treatment at this stage would significantly reduce HIV-1 transmission. The differentially expressed lncRNAs identified in this study could serve as potential prognostic and diagnostic biomarkers of HIV-1 infection, as well as new therapeutic targets.
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BACKGROUND: The CLASP IID randomized trial (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial) demonstrated the safety and effectiveness of the PASCAL system for mitral transcatheter edge-to-edge repair (M-TEER) in patients at prohibitive surgical risk with significant symptomatic degenerative mitral regurgitation (DMR). OBJECTIVES: This study describes the echocardiographic methods and outcomes from the CLASP IID trial and analyzes baseline variables associated with residual mitral regurgitation (MR) ≤1+. METHODS: An independent echocardiographic core laboratory assessed echocardiographic parameters based on American Society of Echocardiography guidelines focusing on MR mechanism, severity, and feasibility of M-TEER. Factors associated with residual MR ≤1+ were identified using logistic regression. RESULTS: In 180 randomized patients, baseline echocardiographic parameters were well matched between the PASCAL (n = 117) and MitraClip (n = 63) groups, with flail leaflets present in 79.2% of patients. Baseline MR was 4+ in 76.4% and 3+ in 23.6% of patients. All patients achieved MR ≤2+ at discharge. The proportion of patients with MR ≤1+ was similar in both groups at discharge but diverged at 6 months, favoring PASCAL (83.7% vs 71.2%). Overall, patients with a smaller flail gap were significantly more likely to achieve MR ≤1+ at discharge (adjusted OR: 0.70; 95% CI: 0.50-0.99). Patients treated with PASCAL and those with a smaller flail gap were significantly more likely to sustain MR ≤1+ to 6 months (adjusted OR: 2.72 and 0.76; 95% CI: 1.08-6.89 and 0.60-0.98, respectively). CONCLUSIONS: The study used DMR-specific echocardiographic methodology for M-TEER reflecting current guidelines and advances in 3-dimensional echocardiography. Treatment with PASCAL and a smaller flail gap were significant factors in sustaining MR ≤1+ to 6 months. Results demonstrate that MR ≤1+ is an achievable benchmark for successful M-TEER. (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial [CLASP IID]; NCT03706833).
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Cateterismo Cardíaco , Implantación de Prótesis de Válvulas Cardíacas , Insuficiencia de la Válvula Mitral , Válvula Mitral , Valor Predictivo de las Pruebas , Recuperación de la Función , Índice de Severidad de la Enfermedad , Humanos , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/cirugía , Insuficiencia de la Válvula Mitral/fisiopatología , Masculino , Femenino , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/cirugía , Válvula Mitral/fisiopatología , Resultado del Tratamiento , Cateterismo Cardíaco/instrumentación , Cateterismo Cardíaco/efectos adversos , Anciano , Factores de Riesgo , Implantación de Prótesis de Válvulas Cardíacas/instrumentación , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Factores de Tiempo , Anciano de 80 o más Años , Prótesis Valvulares Cardíacas , Estudios de Factibilidad , Medición de Riesgo , Diseño de Prótesis , Ecocardiografía TridimensionalRESUMEN
COVID-19 has threatened the existence of human life for more than the last 2 years. More than 460 million confirmed cases and 6 million deaths have been reported worldwide due to COVID-19. To measure the severity of the COVID-19, the mortality rate plays an important role. Understanding the nature of COVID-19 and forecasting the death cases of COVID-19 require more investigation of the real effect for different risk factors. In this work, various regression machine learning models are proposed to extract the relationship between different factors and the death rate of COVID-19. The optimal regression tree algorithm employed in this work estimates the impact of essential causal variables that significantly affect the mortality rates. We have generated a real-time forecast for the death case of COVID-19 using machine learning techniques. The analysis is evaluated with the well-known regression models XGBoost, Random Forest, and SVM on the data sets of the US, India, Italy, and three continents Asia, Europe, and North America. The results show that the models can be used to forecast the death cases for the near future in case of an epidemic like Novel Coronavirus.
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The devastating waves of covid-19 have wreaked havoc on the world, particularly India and US. The article aims to predict the real-time forecasts of covid-19 confirm cases for India and US. To serve the purpose, ARIMA and NNAR based models have been used to the daily new covid-19 confirm cases. The proposed hybrid models are: (i) ARIMA-NNAR model, (ii) NNAR-ARIMA model, (iii) ARIMA-Wavelet ARIMA model, (iv) ARIMA-Wavelet ANN model, (v) NNAR-Wavelet ANN model, and (vi) NNAR-Wavelet ARIMA model. The models are performed to predict the next 45 days of daily new cases. These forecasts can help Govt. to predict the behavior of covid -19 and aware people about the upcoming third wave of covid-19. Our results suggest that hybrid models perform better than single models. We have also proved that our wavelet-based hybrid models can outdated the performance of previously defined hybrid models in terms of accuracy assessments (MAE and RMSE). We have also estimated the time-dependent reproduction number for India and US to observe the present situation.
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The ability of the human immunodeficiency virus type 1 (HIV-1) to establish latent infections serves as a major barrier for its cure. This process could occur when its host cells undergo apoptosis, but it is uncertain whether the components of the apoptotic pathways affect viral latency. Using the susceptible Jurkat cell line, we investigated the relationship of apoptosis-associated components with HIV-1 DNA levels using the sensitive real-time PCR assay. Here, we found that the expression of proapoptotic proteins, including Fas ligand (FasL), FADD, and p53, significantly decreased HIV-1 viral DNA in cells. In contrast, the expression of antiapoptotic molecules, such as FLIP, Bcl2, and XIAP, increased the levels of viral DNA. Furthermore, promoting cellular antiapoptotic state via the knockdown of Bax with siRNA and FADD with antisense mRNA or the treatment with the Caspase-3 inhibitor, Z-DEVD, also raised viral DNA. We also simultaneously measured viral RNA from supernatants of these cell cultures and found that HIV-1 latency is inversely proportional to viral replication. Furthermore, we demonstrated that HIV-1-infected cells that underwent the transient expression of FLIP- or XIAP-induced viral latency would then produce an increased level of viral RNA upon the reversal of these antiapoptotic effects via PMA treatment compared to LacZ control cells. Taken together, these data suggest that HIV-1 infection could be adapted to employ or even manipulate the cellular apoptotic pathway to its advantage: when the host cell remains in a pro-apoptotic state, HIV-1 favors active replication, while when the host cell prefers an anti-apoptotic state, the virus establishes viral latency and promotes latent reservoir seeding in a way which would enhance viral replication and cytopathogenesis when the cellular conditions shift to encourage the productive infection phase.
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Infecciones por VIH , VIH-1 , Linfocitos T CD4-Positivos/metabolismo , ADN Viral/genética , VIH-1/genética , Humanos , Células Jurkat , ARN Viral/genética , Latencia del Virus , Replicación ViralRESUMEN
The impact of steroid hormones estrogen and progesterone on human immunodeficiency virus type 1 (HIV-1) replication is well documented. However, the exact mechanism involved in the regulation of HIV-1 replication by estrogen and progesterone is still unclear. In the present study, we wanted to elucidate the molecular mechanisms underlying the modulation of HIV-1 replication by estrogen and progesterone. To achieve this goal, we used real-time quantitative PCR arrays (PCR arrays) to identify differentially expressed host genes in response to hormone treatments that are involved in antiviral responses. Our in vitro results suggest that treatment with high doses of estrogen and progesterone promotes the expression of host antiviral factors Secretory leukocyte protease inhibitor (SLPI) and Serpin family C member 1 (SERPIN C1) among others produced in response to HIV-1 infection. SLPI is an enzyme that inhibits human leukocyte elastase, human cathepsin G, human trypsin, neutrophil elastase, and mast cell chymase. SERPIN C1 is a plasma protease inhibitor that regulates the blood coagulation cascade by the inhibition of thrombin and other activated serine proteases of the coagulation system. A dose dependent downmodulation of HIV-1 replication was observed in monocyte-derived macrophages (MDMs) pre-treated with the two proteins SLPI and SERPIN C1. Further investigations suggests that the host antiviral factors, SLPI and SERPIN C1 act at the pre-integration stage, inhibiting HIV-1 viral entry and leading to the observed downmodulation of HIV-1 replication. Our studies would help identify molecular mechanisms and pathways involved in HIV-1 pathogenesis.
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Antitrombina III/metabolismo , Estradiol/farmacología , VIH-1/fisiología , Macrófagos/virología , Progesterona/farmacología , Inhibidor Secretorio de Peptidasas Leucocitarias/metabolismo , Antitrombina III/genética , Antitrombina III/farmacología , VIH-1/efectos de los fármacos , Humanos , Inhibidor Secretorio de Peptidasas Leucocitarias/genética , Inhibidor Secretorio de Peptidasas Leucocitarias/farmacología , Regulación hacia Arriba , Integración Viral/efectos de los fármacos , Internalización del Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
"Oxidative stress" is initiated by reactive oxygen species (ROS), which are responsible for majority of the diseases. However, antioxidants with ROS scavenging ability may have great relevance in the prevention of oxidative stress. The present study was undertaken, using a 70% methanolic extract of Caesalpinia crista leaves, to examine different in vitro tests in diversified fields including total antioxidant activity, scavenging activities for various ROS, iron chelating activity and phenolic and flavonoid contents. Total antioxidant activity was evaluated as trolox equivalent antioxidant capacity value of 0.546 ± 0.014. The extract was investigated for different ROS scavenging activities and IC(50) values were found to be 0.44 ± 0.1 mg/ml, 24.9 ± 0.98 µg/ml, 33.72 ± 0.85 µg/ml, 61.13 ± 3.24 µg/mL and 170.51 ± 4.68 µg/mL for hydroxyl, superoxide, nitric oxide, singlet oxygen and hypochlorous acid, respectively; however, no significant results were obtained in scavenging of hydrogen peroxide and peroxynitrite anion. The extract was found to be a potent iron chelator with IC(50) = 279.85 ± 4.72 µg/mL. The plant extract (100 mg) yielded 50.23 ± 0.003 mg/mL gallic acid equivalent phenolic content and 106.83 ± 0.0003 mg/mL quercetin equivalent flavonoid content. In the in vivo experiments, the extract treatment showed significant increase in the level of superoxide dismutase, catalase, glutathione-S-transferase and reduced glutathione. In a word, it may be concluded that 70% methanol extract of C. crista leaves acts as an antioxidant and ROS scavenger; which may be due to the presence of phenolic and flavonoid compounds.
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The continued diversification of HIV poses potentially significant challenges to HIV diagnostics and therapeutics. The dynamic evolution of emerging variants is highlighted in countries such as Cameroon in West Central Africa, where all known subtypes and circulating recombinant forms (CRFs) have been shown to be prevalent. We obtained several hundred HIV-positive plasma and viruses from this region for characterization and identification of highly divergent HIV strains. A total of 163 viral strains were cultured to high titers and high volumes using donor peripheral blood mononuclear cells (PBMCs). Initially, 101 viruses representing 59 strains were well characterized and categorized. Results showed that the viral load (VL) range was 0.36-398.9 × 107 copies/mL, p24 values was 0.2-1134 ng/mL. Phylogenetic analysis of thirty-six near full-length HIV-1 genomic sequences demonstrated that most recombinants were highly diverse CRF02 containing unique recombinant forms (URFs). There were seven viral isolates identified as pure subtype/sub-subtypes (F2, A1, G, and D), six as CRFs (CRF06, CRF18, and CRF22), and ten as URFs. These extensively characterized reagents reflect the current dynamic and complex HIV epidemic in Cameroon and provide valuable insights into the potential phylogenetic evolutionary trend of global HIV molecular epidemiology in the future. These materials may be useful for development of HIV validation and reference panels to evaluate the performance of serologic antigen and nucleic acid assays for their ability to detect and quantitate highly divergent HIV strains.
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Variación Genética , VIH-1/clasificación , VIH-1/genética , Filogenia , Genoma Viral , Genotipo , Infecciones por VIH/virología , Humanos , Leucocitos Mononucleares/virología , Recombinación Genética , Estándares de Referencia , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Cellular damage caused by reactive oxygen species (ROS) has been implicated in several diseases, and hence natural antioxidants have significant importance in human health. The present study was carried out to evaluate the in vitro antioxidant and reactive oxygen species scavenging activities of Terminalia chebula, Terminalia belerica and Emblica officinalis fruit extracts. METHODS: The 70% methanol extracts were studied for in vitro total antioxidant activity along with phenolic and flavonoid contents and reducing power. Scavenging ability of the extracts for radicals like DPPH, hydroxyl, superoxide, nitric oxide, hydrogen peroxide, peroxynitrite, singlet oxygen, hypochlorous acid were also performed to determine the potential of the extracts. RESULTS: The ability of the extracts of the fruits in exhibiting their antioxative properties follow the order T. chebula >E. officinalis >T. belerica. The same order is followed in their flavonoid content, whereas in case of phenolic content it becomes E. officinalis >T. belerica >T. chebula. In the studies of free radicals' scavenging, where the activities of the plant extracts were inversely proportional to their IC50 values, T. chebula and E. officinalis were found to be taking leading role with the orders of T. chebula >E. officinalis >T. belerica for superoxide and nitric oxide, and E. officinalis >T. belerica >T. chebula for DPPH and peroxynitrite radicals. Miscellaneous results were observed in the scavenging of other radicals by the plant extracts, viz., T. chebula >T. belerica >E. officinalis for hydroxyl, T. belerica >T. chebula >E. officinalis for singlet oxygen and T. belerica >E. officinalis >T. chebula for hypochlorous acid. In a whole, the studied fruit extracts showed quite good efficacy in their antioxidant and radical scavenging abilities, compared to the standards. CONCLUSIONS: The evidences as can be concluded from the study of the 70% methanol extract of the fruits of Terminalia chebula, Terminalia belerica and Emblica officinalis, imposes the fact that they might be useful as potent sources of natural antioxidant.
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Antioxidantes/farmacología , Flavonoides/farmacología , Depuradores de Radicales Libres/farmacología , Fenoles/farmacología , Phyllanthus emblica/química , Extractos Vegetales/farmacología , Terminalia/química , Antioxidantes/aislamiento & purificación , Flavonoides/análisis , Frutas , Concentración 50 Inhibidora , Fenoles/análisis , Especies Reactivas de OxígenoRESUMEN
Atherosclerotic cardiovascular disease (ASCVD) is the most important cause of morbidity and mortality nationally and internationally. Improving ASCVD risk prediction is a high clinical priority. We sought to determine which of 3 ASCVD risk scores best predicts the need for revascularization and incident major adverse coronary events (MACE) in symptomatic patients at low-to-intermediate primary ASCVD risk referred for regadenoson-stress positron emission tomography (PET). Risk scores included the standard ASCVD pooled cohort equation (PCE), the multiethnic study of atherosclerosis (MESA) risk equation, and the coronary artery calcium score (CACS), obtained by PET. All qualifying patients in our institution at primary ASCVD risk referred for PET-stress tests in whom PCE, MESA, and CAC scores could be calculated were studied. CACS categories were: 0, 1 to 10, 11 to 299, 300 to 999, and 1000+. MESA and PCE scores were divided into quartiles. Logistic regression modeling was used to predict clinical/PET-driven early revascularization (within 90 days) and 1-year MACE (death, myocardial infarction, or any-time revascularization). A total of 981 patients (54% men, age 67 ± 10 years) qualified and were studied. Scores including CAC (MESA, CACS) performed better than PCE for predicting overall 1-year MACE (MESA p <0.001, CACS pâ¯=â¯0.012 vs PCE), which was driven by early revascularization. In conclusion, in a large population of patients at primary ASCVD risk referred for PET-stress testing, risk scores including CAC (CACS, MESA), which better predicted early revascularization and 1-year MACE, may be particularly useful in primary coronary risk assessment when considering whom to refer for PET-stress testing.
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Aterosclerosis/epidemiología , Calcio/metabolismo , Enfermedad de la Arteria Coronaria/epidemiología , Vasos Coronarios/diagnóstico por imagen , Revascularización Miocárdica , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Calcificación Vascular/epidemiología , Anciano , Aterosclerosis/diagnóstico , Aterosclerosis/cirugía , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/cirugía , Vasos Coronarios/metabolismo , Prueba de Esfuerzo/métodos , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Medición de Riesgo/métodos , Factores de Riesgo , Factores de Tiempo , Calcificación Vascular/diagnóstico , Calcificación Vascular/cirugíaRESUMEN
BACKGROUND: Accurate laboratory diagnosis of HIV is essential to reduce the risk of HIV-positive individuals transmitting HIV-1 infection. The goal of this study was to identify and assess a panel of host derived plasma miRNAs that could to serve as a prognostic and predictive biomarker to detect early/acute HIV-1 infection. METHODS: A total of 372 microRNAs were analyzed in nine plasma samples from HIV-1 infected individuals in the early phase of infection and three healthy controls using the miRNA PCR-array. Seventeen microRNAs were selected and validated in 80 plasma samples from HIV-1 infected individuals in the early phase of infection (20 each of eclipse stage, RNA+ stage, Agâ¯+â¯stage, and Agâ¯+â¯Ab+ stage of HIV-1 patients) and 25 healthy controls. Using the validation study results a plasma miRNA panel was developed and evaluated to detect early/acute HIV-1 infection in 49 blinded samples. FINDING: We identified an miRNA panel (PeHIV-1) containing four differentially expressed miRNAs (miR-16-5p, miR-20b-5p, miR-195-5p, and miR-223-3p) that could distinguish early HIV-1 infection from healthy controls with high AUC (1·000[1·00-1·00]), sensitivity (100%), and specificity (100%).We also found that miR-223-3p demonstrates 100% sensitivity and specificity (AUC 1·00[1·00-1·00]) and could distinguish eclipse stage of HIV-1 infection from healthy controls. To detect eclipse stage of HIV-1 infection we also developed a four-miRNA based (miR-16-5p, miR-206, let-7â¯g-3p, and miR-181c-3p) panel (PE) with AUC 0·999 (0·995-1·000), 100% sensitivity and 95·8% specificity. INTERPRETATION: The miRNA panel, PeHIV-1 is a potential biomarker for detecting early/acute stage of HIV-1infection and could help initiate early antiretroviral treatment, thus preventing the spread of HIV-1 infection.
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MicroARN Circulante , Infecciones por VIH/diagnóstico , Infecciones por VIH/genética , VIH-1 , Interacciones Huésped-Patógeno/genética , MicroARNs/genética , Biomarcadores , Estudios de Casos y Controles , Diagnóstico Precoz , Perfilación de la Expresión Génica , Infecciones por VIH/virología , Humanos , MicroARNs/sangre , Pronóstico , Curva ROC , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
BACKGROUND: Many diseases are associated with oxidative stress caused by free radicals. Current research is directed towards finding naturally-occurring antioxidants of plant origin. The aim of the present study was to evaluate the in vitro antioxidant activities of Spondias pinnata stem bark extract. METHODS: A 70% methanol extract of Spondias pinnata stem bark was studied in vitro for total antioxidant activity, for scavenging of hydroxyl radicals, superoxide anions, nitric oxide, hydrogen peroxide, peroxynitrite, singlet oxygen and hypochlorous acid, and for iron chelating capacity, reducing power, and phenolic and flavonoid contents. RESULTS: The extract showed total antioxidant activity with a trolox equivalent antioxidant concentration (TEAC) value of 0.78 +/- 0.02. The IC50 values for scavenging of free radicals were 112.18 +/- 3.27 microg/ml, 13.46 +/- 0.66 microg/ml and 24.48 +/- 2.31 microg/ml for hydroxyl, superoxide and nitric oxide, respectively. The IC50 for hydrogen peroxide scavenging was 44.74 +/- 25.61 mg/ml. For the peroxynitrite, singlet oxygen and hypochlorous acid scavenging activities the IC50 values were 716.32 +/- 32.25 microg/ml, 58.07 +/- 5.36 microg/ml and 127.99 +/- 6.26 microg/ml, respectively. The extract was found to be a potent iron chelator with IC50 = 66.54 +/- 0.84 microg/ml. The reducing power was increased with increasing amounts of extract. The plant extract (100 mg) yielded 91.47 +/- 0.004 mg/ml gallic acid-equivalent phenolic content and 350.5 +/- 0.004 mg/ml quercetin-equivalent flavonoid content. CONCLUSION: The present study provides evidence that a 70% methanol extract of Spondias pinnata stem bark is a potential source of natural antioxidants.
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Anacardiaceae/química , Antioxidantes/farmacología , Quelantes/farmacología , Depuradores de Radicales Libres/farmacología , Radicales Libres/metabolismo , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Antioxidantes/aislamiento & purificación , Quelantes/aislamiento & purificación , Flavonoides/aislamiento & purificación , Depuradores de Radicales Libres/aislamiento & purificación , Hierro/metabolismo , Quelantes del Hierro/aislamiento & purificación , Quelantes del Hierro/farmacología , Fenoles/aislamiento & purificación , Corteza de la Planta/química , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Tallos de la Planta/químicaRESUMEN
Significant sex specific differences in the progression of HIV/AIDS have been reported. Several studies have implicated steroid hormones in regulating host factor expression and modulating HIV transmission and replication. However, the exact mechanism exerted by steroid hormones estrogen and progesterone in the regulation of HIV-1 replication is still unclear. Results from the current study indicated a dose dependent down regulation of HIV-1 replication in monocyte derived macrophages pre-treated with high concentrations of estrogen or progesterone. To elucidate the molecular mechanisms associated with the down regulation of HIV-1 replication by estrogen and progesterone we used PCR arrays to analyze the expression profile of host genes involved in antiviral responses. Several chemokines, cytokines, transcription factors, interferon stimulated genes and genes involved in type-1 interferon signaling were down regulated in cells infected with HIV-1 pre-treated with high concentrations of estrogen or progesterone compared to untreated HIV-1 infected cells or HIV-1 infected cells treated with low concentrations of estrogen or progesterone. The down regulation of CXCL9, CXCL10 and CXCL11 chemokines and IL-1ß, IL-6 cytokines in response to high concentrations of estrogen and progesterone pre-treatment in HIV-1 infected cells was confirmed at the protein level by quantitating chemokine and cytokine concentrations in the culture supernatant. These results demonstrate that a potent anti-inflammatory response is mediated by pre-treatment with high concentrations of estrogen and progesterone. Thus, our study suggests a strong correlation between the down-modulation of anti-viral and pro-inflammatory responses mediated by estrogen and progesterone pre-treatment and the down regulation of HIV-1 replication. These findings may be relevant to clinical observations of sex specific differences in patient populations and point to the need for further investigation.
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Estrógenos/fisiología , VIH/fisiología , Macrófagos/virología , Progesterona/fisiología , Replicación Viral , Humanos , Reacción en Cadena de la PolimerasaRESUMEN
Non-coding RNAs and mRNAs have been implicated in replication, pathogenesis and host response in HIV infection. However, the impact of long intergenic non-coding RNAs (lincRNAs) on HIV-1 and HIV-2 infection is not known. In this study, we have analyzed expression profiles of lincRNAs and mRNAs in monocyte derived macrophages (MDMs) infected with HIV-1/HIV-2 using microarrays. Our study identified many differentially expressed lincRNAs and mRNAs in MDMs infected with HIV-1/HIV-2 compared to uninfected MDMs. Genes involved in glutathione metabolism and lysine degradation were differentially regulated only in HIV-1 infected MDMs. In HIV-2 infected MDMs, CUL 2, SFRS9, and RBBP4 genes were differentially expressed. Furthermore, we found that plasma levels of lincRNA: chr2: 165509129-165519404 and lincRNA: chr12: 57761837-57762303 were better indicators of HIV-1 infection while lincRNA: chr10:128586385-128592960, XLOC_001148 and lincRNA: chr5:87580664-87583451, were better indicators of HIV-2 infection. In summary, our study has demonstrated that there is substantial alteration in lincRNA and mRNA expression in response to HIV-1/HIV-2 infection. These differentially expressed lincRNAs and mRNAs could serve as prognostic and diagnostic biomarkers of HIV infection and help in the identification of new targets for therapy.
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Perfilación de la Expresión Génica , Infecciones por VIH , VIH-1/inmunología , VIH-2/inmunología , Macrófagos/virología , ARN Largo no Codificante/genética , ARN Mensajero/genética , Proteínas Cullin/genética , Proteínas Cullin/metabolismo , Glutatión/genética , Glutatión/metabolismo , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , Humanos , Lisina/genética , Lisina/metabolismo , Proteína 4 de Unión a Retinoblastoma/genética , Proteína 4 de Unión a Retinoblastoma/metabolismo , Factores de Empalme Serina-Arginina/genética , Factores de Empalme Serina-Arginina/metabolismoRESUMEN
BACKGROUND: Cardiac positron emission testing (PET) is more accurate than single photon emission computed tomography (SPECT) at identifying coronary artery disease (CAD); however, the 2 modalities have not been thoroughly compared in a real-world setting. We conducted a retrospective analysis of 60-day catheterization outcomes and 1-year major adverse cardiovascular events (MACE) after the transition from a SPECT- to a PET-based myocardial perfusion imaging (MPI) program. METHODS: MPI patients at Intermountain Medical Center from January 2011-December 2012 (the SPECT era, n = 6,777) and January 2014-December 2015 (the PET era, n = 7,817) were studied. Outcomes studied were 60-day coronary angiography, high-grade obstructive CAD, left main/severe 3-vessel disease, revascularization, and 1-year MACE-revascularization (MACE-revasc; death, myocardial infarction [MI], or revascularization >60 days). RESULTS: Patients were 64 ± 13 years old; 54% were male and 90% were of European descent; and 57% represented a screening population (no prior MI, revascularization, or CAD). During the PET era, compared with the SPECT era, a higher percentage of patients underwent coronary angiography (13.2% vs. 9.7%, P < 0.0001), had high-grade obstructive CAD (10.5% vs. 6.9%, P < 0.0001), had left main or severe 3-vessel disease (3.0% vs. 2.3%, P = 0.012), and had coronary revascularization (56.7% vs. 47.1%, P = 0.0001). Similar catheterization outcomes were seen when restricted to the screening population. There was no difference in 1-year MACE-revasc (PET [5.8%] vs. SPECT [5.3%], P = 0.31). CONCLUSIONS: The PET-based MPI program resulted in improved identification of patients with high-grade obstructive CAD, as well as a larger percentage of revascularization, thus resulting in fewer patients undergoing coronary angiography without revascularization. FUNDING: This observational study was funded using internal departmental funds.
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Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Prueba de Esfuerzo/métodos , Imagen de Perfusión Miocárdica/métodos , Tomografía de Emisión de Positrones , Tomografía Computarizada de Emisión de Fotón Único , Anciano , Cateterismo Cardíaco , Angiografía Coronaria/estadística & datos numéricos , Enfermedad de la Arteria Coronaria/complicaciones , Muerte , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/etiología , Revascularización Miocárdica/estadística & datos numéricos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
Visceral leishmaniasis (VL) is a deadly neglected tropical disease that poses a serious problem in various countries all over the world. Implementation of various intervention strategies fail in controlling the spread of this disease due to issues of parasite drug resistance and resistance of sandfly vectors to insecticide sprays. Due to this, policy makers need to develop novel strategies or resort to a combination of multiple intervention strategies to control the spread of the disease. To address this issue, we propose an extensive SIR-type model for anthroponotic visceral leishmaniasis transmission with seasonal fluctuations modeled in the form of periodic sandfly biting rate. Fitting the model for real data reported in South Sudan, we estimate the model parameters and compare the model predictions with known VL cases. Using optimal control theory, we study the effects of popular control strategies namely, drug-based treatment of symptomatic and PKDL-infected individuals, insecticide treated bednets and spray of insecticides on the dynamics of infected human and vector populations. We propose that the strategies remain ineffective in curbing the disease individually, as opposed to the use of optimal combinations of the mentioned strategies. Testing the model for different optimal combinations while considering periodic seasonal fluctuations, we find that the optimal combination of treatment of individuals and insecticide sprays perform well in controlling the disease for the time period of intervention introduced. Performing a cost-effective analysis we identify that the same strategy also proves to be efficacious and cost-effective. Finally, we suggest that our model would be helpful for policy makers to predict the best intervention strategies for specific time periods and their appropriate implementation for elimination of visceral leishmaniasis.
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Simulación por Computador , Control de Insectos/métodos , Insectos Vectores/parasitología , Leishmania , Leishmaniasis Visceral/prevención & control , Modelos Teóricos , Psychodidae/parasitología , Animales , Antiprotozoarios/economía , Antiprotozoarios/uso terapéutico , Análisis Costo-Beneficio , Reservorios de Enfermedades , Costos de los Medicamentos , Humanos , India/epidemiología , Mordeduras y Picaduras de Insectos/epidemiología , Mordeduras y Picaduras de Insectos/parasitología , Control de Insectos/economía , Mosquiteros Tratados con Insecticida/economía , Insecticidas/economía , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/epidemiología , Leishmaniasis Visceral/economía , Leishmaniasis Visceral/epidemiología , Leishmaniasis Visceral/transmisión , Estaciones del AñoRESUMEN
Despite significant advancement in vaccine and virus research, influenza continues to be a major public health concern. Each year in the United States of America, influenza viruses are responsible for seasonal epidemics resulting in over 200,000 hospitalizations and 30,000-50,000 deaths. Accurate and early diagnosis of influenza viral infections are critical for rapid initiation of antiviral therapy to reduce influenza related morbidity and mortality both during seasonal epidemics and pandemics. Several different approaches are currently available for diagnosis of influenza infections in humans. These include viral isolation in cell culture, immunofluorescence assays, nucleic acid amplification tests, immunochromatography-based rapid diagnostic tests, etc. Newer diagnostic approaches are being developed to overcome the limitations associated with some of the conventional detection methods. This review discusses diagnostic approaches currently available for detection of influenza viruses in humans.
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Gripe Humana/diagnóstico , Gripe Humana/virología , Orthomyxoviridae/genética , Orthomyxoviridae/inmunología , Animales , Técnicas de Cultivo de Célula , Técnica del Anticuerpo Fluorescente Directa , Humanos , Inmunoensayo , Dispositivos Laboratorio en un Chip , Técnicas de Diagnóstico Molecular , Orthomyxoviridae/aislamiento & purificación , Análisis de Secuencia de ADN , Pruebas SerológicasRESUMEN
While human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2) share many similar traits, major differences in pathogenesis and clinical outcomes exist between the two viruses. The differential expression of host factors like microRNAs (miRNAs) in response to HIV-1 and HIV-2 infections are thought to influence the clinical outcomes presented by the two viruses. MicroRNAs are small non-coding RNA molecules which function in transcriptional and post-transcriptional regulation of gene expression. MiRNAs play a critical role in many key biological processes and could serve as putative biomarker(s) for infection. Identification of miRNAs that modulate viral life cycle, disease progression, and cellular responses to infection with HIV-1 and HIV-2 could reveal important insights into viral pathogenesis and provide new tools that could serve as prognostic markers and targets for therapeutic intervention. The aim of this study was to elucidate the differential expression profiles of host miRNAs in cells infected with HIV-1 and HIV-2 in order to identify potential differences in virus-host interactions between HIV-1 and HIV-2. Differential expression of host miRNA expression profiles was analyzed using the miRNA profiling polymerase chain reaction (PCR) arrays. Differentially expressed miRNAs were identified and their putative functional targets identified. The results indicate that hsa-miR 541-3p, hsa-miR 518f-3p, and hsa-miR 195-3p were consistently up-regulated only in HIV-1 infected cells. The expression of hsa-miR 1225-5p, hsa-miR 18a* and hsa-miR 335 were down modulated in HIV-1 and HIV-2 infected cells. Putative functional targets of these miRNAs include genes involved in signal transduction, metabolism, development and cell death.