Systematic Identification of Synergistic Drug Pairs Targeting HIV

The systematic identification of effective drug combinations has been hindered by the unavailability of methods that can explore the large combinatorial search space of drug interactions. Here we present a multiplex screening method named MuSIC (Multiplex Screening for Interacting Compounds), which expedites the comprehensive assessment of pair-wise compound interactions. We examined ~500,000 drug pairs from 1000 FDA-approved or clinically tested drugs and identified drugs that synergize to inhibit HIV replication. Our analysis reveals an enrichment of anti-inflammatory drugs in drug combinations that synergize against HIV, indicating HIV benefits from inflammation that accompanies its infection. Multiple drug pairs identified in this study, including glucocorticoid and nitazoxanide, synergize by targeting different steps of the HIV life cycle. As inflammation accompanies HIV infection, our findings indicate that inhibiting inflammation could curb HIV propagation. MuSIC can be applied to a wide variety of disease-relevant screens to facilitate efficient identification of compound combinations

Comprehensive Identification of Host Modulators of HIV-1 Replication using Multiple Orthologous RNAi Reagents

SummaryRNAi screens have implicated hundreds of host proteins as HIV-1 dependency factors (HDFs). While informative, these early studies overlap poorly due to false positives and false negatives. To ameliorate these issues, we combined information from the existing HDF screens together with new screens performed with multiple orthologous RNAi reagents (MORR). In addition to being traditionally validated, the MORR screens and the historical HDF screens were quantitatively integrated by the adaptation of an established analysis program, RIGER, for the collective interpretation of each gene’s phenotypic significance. False positives were addressed by the removal of poorly expressed candidates through gene expression filtering, as well as with GESS, which identifies off-target effects. This workflow produced a quantitatively integrated network of genes that modulate HIV-1 replication. We further investigated the roles of GOLGI49, SEC13, and COG in HIV-1 replication. Collectively, the MORR-RIGER method minimized the caveats of RNAi screening and improved our understanding of HIV-1–host cell interactions

Impact of Tourists’ Perceived Value and Sense of Social Responsibility on the Low-Carbon Consumption Behavior Intention: A Case Study of Zhangjiajie National Forest Park

People’s increasing attention towards environmental issues and carbon emission level per capita of consumption has made the influencing factors of low-carbon consumption behavior a research hotspot. In this study, a random sample of tourists in Zhangjiajie National Forest Park in China were surveyed by questionnaire to examine the impact of tourists’ perceived value and sense of social responsibility on the low-carbon consumption behavior intention. Results suggest that tourists’ perceived value has a direct and significant positive effect on the sense of social responsibility and low-carbon consumption behavior intention. Tourists’ sense of social responsibility demonstrates a significant positive impact on consumption attitude, with the latter having a positive impact on tourists’ low-carbon consumption behavior intention. A sense of social responsibility and the consumption attitude are found to play an important intermediary role between perceived value and tourists’ low-carbon consumption behavior intention. Some suggestions for managing and promoting tourists’ low-carbon consumption behavior intention are also put forward in this paper

Impact of Tourists’ Perceived Value and Sense of Social Responsibility on the Low-Carbon Consumption Behavior Intention: A Case Study of Zhangjiajie National Forest Park

People’s increasing attention towards environmental issues and carbon emission level per capita of consumption has made the influencing factors of low-carbon consumption behavior a research hotspot. In this study, a random sample of tourists in Zhangjiajie National Forest Park in China were surveyed by questionnaire to examine the impact of tourists’ perceived value and sense of social responsibility on the low-carbon consumption behavior intention. Results suggest that tourists’ perceived value has a direct and significant positive effect on the sense of social responsibility and low-carbon consumption behavior intention. Tourists’ sense of social responsibility demonstrates a significant positive impact on consumption attitude, with the latter having a positive impact on tourists’ low-carbon consumption behavior intention. A sense of social responsibility and the consumption attitude are found to play an important intermediary role between perceived value and tourists’ low-carbon consumption behavior intention. Some suggestions for managing and promoting tourists’ low-carbon consumption behavior intention are also put forward in this paper

Fast Synthesis of Pt Nanocrystals and Pt/Microporous La2O3 Materials Using Acoustic Levitation

Abstract Usually, we must use an appropriate support material to keep the metal species stable and finely dispersed as supported metal nanoparticles for industry application. Therefore, the choice of support material is a key factor in determining the dispersion and particle size of the noble metal species. Here, we report the synthesis of a single-atom Pt material in the solution and supported Pt nanoclusters on microporous La2O3 by a one-step acoustic levitation method without any pretreatment/modification of raw oxide. We have strongly contributed to the synthetic methodology of the surface/interfacial heterogeneous catalysts in this study, and this finding could open another door for synthesis of supported metal nanoparticles on porous materials for environmental catalysis

Additional file 1: of Fast Synthesis of Pt Nanocrystals and Pt/Microporous La2O3 Materials Using Acoustic Levitation

HAADF-STEM and HRTEM images of Pt particles. (DOCX 2196 kb

Reactivation of Latent HIV-1 by Inhibition of BRD4

HIV-1 depends on many host factors for propagation. Other host factors, however, antagonize HIV-1 and may have profound effects on viral activation. Curing HIV-1 requires the reduction of latent viral reservoirs that remain in the face of antiretroviral therapy. Using orthologous genetic screens, we identified bromodomain containing 4 (BRD4) as a negative regulator of HIV-1 replication. Antagonism of BRD4, via RNA interference or with a small molecule inhibitor, JQ1, both increased proviral transcriptional elongation and alleviated HIV-1 latency in cell-line models. In multiple instances, JQ1, when used in combination with the NF-κB activators Prostratin or PHA, enhanced the in vitro reactivation of latent HIV-1 in primary T cells. These data are consistent with a model wherein BRD4 competes with the virus for HIV-1 dependency factors (HDFs) and suggests that combinatorial therapies that activate HDFs and antagonize HIV-1 competitive factors may be useful for curing HIV-1 infection

Pan-TGFβ inhibition by SAR439459 relieves immunosuppression and improves antitumor efficacy of PD-1 blockade

TGFβ is a pleiotropic cytokine that may have both tumor inhibiting and tumor promoting properties, depending on tissue and cellular context. Emerging data support a role for TGFβ in suppression of antitumor immunity. Here we show that SAR439459, a pan-TGFβ neutralizing antibody, inhibits all active isoforms of human and murine TGFβ, blocks TGFβ-mediated pSMAD signaling, and TGFβ-mediated suppression of T cells and NK cells. In vitro, SAR439459 synergized with anti-PD1 to enhance T cell responsiveness. In syngeneic tumor models, SAR439459 treatment impaired tumor growth, while the combination of SAR439459 with anti–PD-1 resulted in complete tumor regression and a prolonged antitumor immunity. Mechanistically, we found that TGFβ inhibition with PD-1 blockade augmented intratumoral CD8+ T cell proliferation, reduced exhaustion, evoked proinflammatory cytokines, and promoted tumor-specific CD8+ T cell responses. Together, these data support the hypothesis that TGFβ neutralization using SAR439459 synergizes with PD-1 blockade to promote antitumor immunity and formed the basis for the ongoing clinical investigation of SAR439459 in patients with cancer (NCT03192345)