Latent HIV reservoirs are the primary hurdle to eradication of infection. Identification of agents, pathways and molecular mechanisms that activate latent provirus may, in the presence of highly ...active antiretroviral therapy, permit clearance of infected cells by the immune system. Promoter-proximal pausing of RNA polymerase (Pol) II is a major rate-limiting step in HIV gene expression. The viral Tat protein recruits human Super Elongation Complex (SEC) to paused Pol II to overcome this limitation. Here, we identify the bromodomain protein Brd4 and its inhibition of Tat-transactivation as a major impediment to latency reactivation. Brd4 competitively blocks the Tat-SEC interaction on HIV promoter. The BET bromodomain inhibitor JQ1 dissociates Brd4 from the HIV promoter to allow Tat recruitment of SEC to stimulate HIV elongation. JQ1 synergizes with another latency activator prostratin, which promotes Pol II loading onto the viral promoter. Because JQ1 activates viral latency without inducing global T cell activation, this and other closely related compounds and their antagonization of Brd4 to promote Tat-SEC interaction merit further investigations as effective agents/strategies for eliminating latent HIV.
•A new SVR model to forecast the demand response baseline for office buildings.•Take temperature two hours before DR event can improve the forecasting accuracy.•The forecasting accuracy is better ...than other seven existing methods in DR programs.•The model is very generic and can be applied to a wide variety of office buildings.
Demand Response (DR) aims at improving the operation efficiency of power plants and grids, and it constitutes an effective means of reducing grid risk during peak periods to ensure the safety of power supplies. One key challenge related to DR is the calculation of load baselines. A fair and accurate baseline serves as useful information for resource planners and system operators who wish to implement DR programs. In the meantime, baseline calculation cannot be too complex, and in most cases, only weather data input is permitted. Inspired by the strong non-linear capabilities of Support Vector Regression (SVR), this paper proposes a new SVR forecasting model with the ambient temperature of two hours before DR event as input variables. We use electricity loads for four typical office buildings as sample data to test the method. After analyzing the model prediction results, we find that the SVR model offers a higher degree of prediction accuracy and stability in short-term load forecasting compared to the other seven traditional forecasting models.
Previous studies has shown a significant relationship between baseline triglyceride-glucose (TyG) index and cardiovascular disease (CVD). However, the long-term effect of TyG index and incident CVD ...remains uncertain. This study aimed to investigate the association between cumulative TyG index and the risk of CVD.
In this study, we recruited individuals participating in Kailuan Study from 2006 to 2013 without stroke, myocardial infarction, and cancer in the four consecutive examinations. Cumulative TyG index was calculated by multiplying the average TyG index and the time between the two consecutive examinations. Cumulative TyG index levels were categorized into four quartile groups: Q1 group, ≤ 50.65 (as reference group), Q2 group, 50.65-53.86, Q3 group, 53.86-57.44, Q4 group, > 57.44. The association between cumulative TyG index and the risk of CVD was estimated by multivariable Cox proportional hazard models.
A total of 44,064 individuals participated in the final analysis. After a mean follow-up of 6.52 ± 1.14 years, incident CVD, MI and stroke occurred in 2057, 395 and 1695, respectively. The risk of developing CVD increased with the quartile of cumulative in TyG index, after adjustment for multiple potential confounders, the HR for CVD events were 1.25 (1.08-1.44) in Q2, 1.22 (1.05-1.40) in Q3 and 1.39 (1.21-1.61) in Q4, compared to Q1 group. The longer duration of higher TyG index exposure was significantly associated with increased CVD risk. Similar results were obtained in the subgroup and sensitivity analysis.
Cumulative TyG index was associated with increased risk of CVD. Maintaining an appropriate level of TG and FBG within the desirable range and better control of cumulative TyG index are important for prevention of CVD.
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•Ecological civilization pilot promotes industrial structural rationalization.•Good central-local relationships enhance industrial structure rationalization.•Positive spatial ...spillover effect exists in industrial structure rationalization.•Nuanced policy design becomes imperative due to the potential negative impact.•Key mechanisms are disclosed with actionable strategies.
Industrial structure transformation is important for realizing Chinese modernization, and ecological civilization is necessary for building a beautiful China. How to use the construction of ecological civilization to realize industrial structure transformation is a major issue for the economic development of China and other developing countries. The difference-in-differences method was used to evaluate the impact of the ecological civilization pilot policy (ECPP) on industrial structure transformation. The three-stage mediating effect method is used to explore the mechanism channel. Through heterogeneity discussion and spatial spillover analysis method, the effects of ECPP were further understood. The study reveals the following: Overall, the ECPP has promoted the transformation of the industrial structure. Specifically, the ECPP has a significant positive impact on industrial structure rationalization but a negative impact on industrial structure advancement. Several robustness checks support this finding. Second, the mechanism channels are primarily achieved through environmental investment, green finance infusion, and congestion alleviation. Third, good central-local relationships can enhance the trend toward industrial structure rationalization, while unfavorable relationships may pose hindrances to industrial structure advancement. In addition, the effect of the ECPP varies depending on the population density and environmental pollution. Lastly, the ECPP has a spatial positive spillover effect promoting industrial structure rationalization. The results above provide additional information about the effects of ECPPs on industrial structure transformation, both positive and negative, and help the ecological civilization strategy system be adjusted promptly.
Under these rules, a newly emerged virus is normally assigned to a species based on phylogeny and taxonomy.4 Through DivErsity pArtitioning by hieRarchical Clustering-based analyses,5 the newly ...emerged coronavirus was deemed not sufficiently novel but is a sister virus to SARS-CoV, the primary viral isolate defining the species. For various reasons, the name of a disease and its causative viral pathogen can be different, as exemplified by acquired immunodeficiency syndrome (AIDS) and human immunodeficiency virus (HIV). Given that SARS-CoV-2 is already being used in the scientific literature, a name change at this stage would cause confusion in the scientific community.
Binding of the HIV-1 envelope to its chemokine coreceptors mediates two major biological events: membrane fusion and signaling transduction. The fusion process has been well studied, yet the role of ...chemokine coreceptor signaling in viral infection has remained elusive through the past decade. With the recent demonstration of the signaling requirement for HIV latent infection of resting CD4 T cells, the issue of coreceptor signaling needs to be thoroughly revisited. It is likely that virus-mediated signaling events may facilitate infection in various immunologic settings in vivo where cellular conditions need to be primed; in other words, HIV may exploit the chemokine signaling network shared among immune cells to gain access to downstream cellular components, which can then serve as effective tools to break cellular barriers. This virus-hijacked aberrant signaling process may in turn facilitate pathogenesis. In this review, we summarize past and present studies on HIV coreceptor signaling. We also discuss possible roles of coreceptor signaling in facilitating viral infection and pathogenesis.
To examine the change in fasting blood glucose (FBG) during repeated assessments over time and its potential impact on the risk of developing myocardial infarction (MI).
This prospective cohort study ...included 68,297 participants without diabetes (mean age 49 years) who were free of MI, stroke, and cancer prior to or in 2010 (baseline of the current analysis). FBG concentrations were measured in 2006, 2008, and 2010. The FBG trajectories during 2006-2010, the primary exposure of the current study, were identified by latent mixture modeling. Incident MI cases were confirmed via review of medical records by cardiologists.
We identified five discrete FBG trajectories according to FBG range and changing pattern over time: elevated-stable (
= 3,877), elevated-decreasing (
= 7,060), moderate-increasing (
= 10,298), moderate-stable (
= 40,352), and low-stable (
= 6,710). During 4 years of follow-up, we documented 283 incident MI cases. Relative to the moderate-stable pattern (FBG ranged from 4.9 to 5.1 mmol/L), adjusted hazard ratios (HRs) were 1.53 (95% CI 1.04, 2.26) for the elevated-stable pattern (FBG ranged from 6.1 to 6.3 mmol/L) and HR 0.61 (95% CI 0.38, 0.98) for the elevated-decreasing pattern (FBG decreased from 6.0 to 5.4 mmol/L), after adjustment for potential confounders such as age, sex, lifestyle factors, obesity, medical history, blood pressure, blood lipids, and C-reactive protein. Consistently, cumulative average and increasing rate of FBG during 2006-2010, but not a single baseline FBG, predicted future risk of MI.
We found that discrete FBG trajectories were significantly associated with subsequent risk of MI in individuals without diabetes. These observations suggest that long-term trajectories of FBG may be important for risk prediction of MI and possibly other macrovascular diseases.
This study aims to the function of miR-22 original mesenchymal stem cells (MSC) on osteosarcoma (OS) proliferation, migration and invasion. Bio-informatics analysis including GEO2R analysis, Gene ...Ontology analysis, integration analysis were used to confirmed the target genes (miR-22, Twist1, CADM1) in OS. RT-qPCR and western blotting confirmed the different expression of miR-22, Twist1, CADM1 in OS tissues, MG63 and Saos cell lines. MTS assay, CCK8 assay, colony forming assay, EdU assay were performed to detect the proliferation effect of miR-22 on MG63. Transwell migration assay, transwell invasion assay, wound healing assay were used to verify the migration and invasion effect of miR-22 on MG63. Luciferase reporter assay confirm the binding sites between miR-22 and Twist1. RT-qPCR confirmed miR-22 and CADM1 downregulated and Twist1 upregulated in OS tissues, MG63 and Saos. Exosome original MSC labeled with PKH-26 could be uptake by MG63, which upregulated the expression of miR-22 in MG63. High expression of miR-22 in MG63 inhibited proliferation, migration and invasion, which could be rescued by Twist1. Dual luciferase reporter analysis confirmed Twist1 was a target of miR-22. Exosome modified with miR-22 mimic inhibit proliferation, migration and invasion more efficient than exosome original MSC. miR-22 cargo in exo-MSC could uptake by MG63 and supply MG63 with miR-22, which inhibit MG63 proliferation, migration and invasion through targeting Twist1.
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