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

Hyperoxalemia Leads to Oxidative Stress in Endothelial Cells and Mice with Chronic Kidney Disease

Introduction: Cardiovascular disease is the most common cause of morbidity and mortality in patients with ESRD. In addition to phosphate overload, oxalate, a common uremic toxin, is also involved in vascular calcification in patients with ESRD. The present study investigated the role and mechanism of hyperoxalemia in vascular calcification in mice with uremia. Methods: A uremic atherosclerosis (UA) model was established by left renal excision and right renal electrocoagulation in apoE−/− mice to investigate the relationship between oxalate loading and vascular calcification. After 12 weeks, serum and vascular levels of oxalate, vascular calcification, inflammatory factors (TNF-α and IL-6), oxidative stress markers (malondialdehyde [MDA], and advanced oxidation protein products [AOPP]) were assessed in UA mice. The oral oxalate-degrading microbe Oxalobacter formigenes (O. formigenes) was used to evaluate the effect of a reduction in oxalate levels on vascular calcification. The mechanism underlying the effect of oxalate loading on vascular calcification was assessed in cultured human aortic endothelial cells (HAECs) and human aortic smooth muscle cells (HASMCs). Results: Serum oxalate levels were significantly increased in UA mice. Compared to the control mice, UA mice developed more areas of aortic calcification and showed significant increases in aortic oxalate levels and serum levels of oxidative stress markers and inflammatory factors. The correlation analysis showed that serum oxalate levels were positively correlated with the vascular oxalate levels and serum MDA, AOPP, and TNF-α levels, and negatively correlated with superoxide dismutase activity. The O. formigenes intervention decreased serum and vascular oxalate levels, while did not improve vascular calcification significantly. In addition, systemic inflammation and oxidative stress were also improved in the O. formigenes group. In vitro, high concentrations of oxalate dose-dependently increased oxidative stress and inflammatory factor expression in HAECs, but not in HASMCs. Conclusions: Our results indicated that hyperoxalemia led to the systemic inflammation and the activation of oxidative stress. The reduction in oxalate levels by O. formigenes might be a promising treatment for the prevention of oxalate deposition in calcified areas of patients with ESRD

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

Signature Movements Lead to Efficient Search for Threatening Actions

The ability to find and evade fighting persons in a crowd is potentially life-saving. To investigate how the visual system processes threatening actions, we employed a visual search paradigm with threatening boxer targets among emotionally-neutral walker distractors, and vice versa. We found that a boxer popped out for both intact and scrambled actions, whereas walkers did not. A reverse correlation analysis revealed that observers' responses clustered around the time of the “punch", a signature movement of boxing actions, but not around specific movements of the walker. These findings support the existence of a detector for signature movements in action perception. This detector helps in rapidly detecting aggressive behavior in a crowd, potentially through an expedited (sub)cortical threat-detection mechanism

Strategies using recent feedback lead to matching or maximising behaviours

One challenge facing humans (and nonhuman animal) is that some options that appear attractive locally may not turn out best in the long run. To analyse this human learning problem, we explore human performance in a dynamic decision-making task that places local and global rewards in conflict. We found that experiences that included previous choices and rewards are not easily incorporated into people’s strategy to enhance their performance. Our results suggest that humans are easily driven by concerns about recent feedback, and that choice of a suboptimal behaviour option may be overcome by providing informative cues that indicate a clear immediate outcome for a better option

Review of regulating Zn2+ solvation structures in aqueous zinc-ion batteries

Aqueous zinc-ion batteries, due to their high power density, intrinsic safety, low cost, and environmental benign, have attracted tremendous attentions recently. However, their application is severely plagued by the inferior energy density and short cycling life, which was mainly ascribed to zinc dendrites, and interfacial side reactions, narrow potential window induced by water decomposition, all of which are highly related with the Zn ^2+ solvation structures in the aqueous electrolytes. Therefore, in this review, we comprehensively summarized the recent development of strategies of regulating Zn ^2+ solvation structures, specially, the effect of zinc salts, nonaqueous co-solvents, and functional additives on the Zn ^2+ solvation structures and the corresponding electrochemical performance of aqueous zinc-ion batteries. Moreover, future perspectives focused on the challenges and possible solutions for design and commercialization of aqueous electrolytes with unique solvation structures are provided

Effects of letrozole co-treatment on the cumulative live-birth rate among normal responders in gonadotropin-releasing hormone antagonist cycles

Studies have shown that letrozole cotreatment can improve clinical outcomes in high and poor responders in GnRH-antagonist protocol. However, whether letrozole is also beneficial to normal responders is not known. To investigate the clinical value of letrozole cotreatment during ovarian stimulation in vitro fertilization for normal ovarian reserve patients who were treated with the GnRH antagonist protocol, we conducted a retrospective study that based data from 1 January to 31 December 2017 for all IVF–ICSI GnRH-antagonist protocols. A total of 252 women who aged <40 years, FSH <10 IU/L on day 3 and antral follicle counting (AFC) >6 were included in the analysis (96 in the letrozole group and 156 in the no-letrozole group). The cumulative live-birth rate was calculated as the first live birth achieved after all cycles having an embryo transfer (cycles using fresh embryos and frozen–thawed embryos) among both groups. The initial gonadotropin (Gn) dosage and total Gn dosage were significantly lower and the number of days of Gn treatment was significantly fewer in the letrozole group than the non-letrozole group (p < 0.05). There were also significant between-group differences in luteinizing hormone, estradiol, and progesterone concentrations; and the number of metaphase II oocytes on the day of human chorionic gonadotropin treatment (p < 0.05). There was a significant difference in the implantation rate between the two groups that the letrozole group higher than the non-letrozole group (39.79 vs. 27.96%, p = 0.006), but there was no significant difference in the cumulative live-birth rate. The combination of letrozole with a GnRH antagonist may have no effect on the clinical pregnancy rate or cumulative live-birth rate in patients with a normal ovarian reserve. However, letrozole may increase the rate of embryo implantation and may reduce the requirement for exogenous gonadotrophins and, consequently, the cost of an IVF treatment cycle. In addition, the decreased estradiol level in the ovarian simulation by letrozole supports letrozole can be a safe solution for fertility preservation in estrogen-related cancer patients

Quality Inspection Methods and Case Studies on Thematic Natural Resources Survey and Monitoring Results

The thematic survey and monitoring results of natural resources (TMR) provide scientific, detailed and reliable data support for government management departments to grasp the overall situation, reflect the society and people’s lives. Therefore, product quality for TMR is a major concern of outcome producers and users. This paper discusses the quality evaluation model and test method of TMR, and summarizes and proposes methods to improve the quality of the results by examining the quality of different TMR