The cellular localization and oncogenic or tumor suppressive effects of angiomiotin-like protein 2 in tumor and normal cells.

Angiomiotin (AMOT) family comprises three members: AMOT, AMOT-like protein 1 (AMOTL1), and AMOT-like protein 2 (AMOTL2). AMOTL2 is widely expressed in endothelial cells, epithelial cells, and various cancer cells. Specifically, AMOTL2 predominantly localizes in the cytoplasm and nucleus in human normal cells, whereas associates with cell-cell junctions and actin cytoskeleton in non-human cells, and locates at cell junctions or within the recycling endosomes in cancer cells. AMOTL2 is implicated in regulation of tube formation, cell polarity, and shape, although the specific impact on tumorigenesis remains to be conclusively determined. It has been shown that AMOTL2 enhances tumor growth and metastasis in pancreatic, breast, and colon cancer, however inhibits cell proliferation and migration in lung, hepatocellular cancer, and glioblastoma. In addition to its role in cell shape and cytoskeletal dynamics through co-localization with F-actin, AMOTL2 modulates the transcription of Yes-associated protein (YAP) by binding to it, thereby affecting its phosphorylation and cellular sequestration. Furthermore, the stability and cellular localization of AMOTL2, influenced by its phosphorylation and ubiquitination mediated by specific proteins, affects its cellular function. Additionally, we observe that AMOTL2 is predominantly downregulated in some tumors, but significantly elevated in colorectal adenocarcinoma (COAD). Moreover, overall analysis, GSEA and ROC curve analysis indicate that AMOTL2 exerts as an oncogenic protein in COAD by modulating Wnt pathway, participating in synthesis of collagen formation, and interacting with extracellular matrix receptor. In addition, AMOTL2 potentially regulates the distribution of immune cells infiltration in COAD. In summary, AMOTL2 probably functions as an oncogene in COAD. Consequently, further in-depth mechanistic research is required to elucidate the precise roles of AMOTL2 in various cancers.

Seco-cyclic phorbol derivatives and their anti-HIV-1 activities.

Phorbol esters are recognized for their dual role as anti-HIV-1 agents and as activators of protein kinase C (PKC). The efficacy of phorbol esters in binding with PKC is attributed to the presence of oxygen groups at positions C20, C3/C4, and C9 of phorbol. Concurrently, the lipids located at positions C12/C13 are essential for both the anti-HIV-1 activity and the formation of the PKC-ligand complex. The influence of the cyclopropane ring at positions C13 and C14 in phorbol derivatives on their anti-HIV-1 activity requires further exploration. This research entailed the hydrolysis of phorbol, producing seco-cyclic phorbol derivatives. The anti-HIV-1 efficacy of these derivatives was assessed, and the affinity constant (Kd) for PKC-δ protein of selected seco-cyclic phorbol derivatives was determined through isothermal titration calorimetry. The findings suggest that the chemical modification of cyclopropanols could affect both the anti-HIV-1 activity and the PKC binding affinity. Remarkably, compound S11, with an EC50 of 0.27 µmol·L-1 and a CC50 of 153.92 µmol·L-1, demonstrated a potent inhibitory effect on the intermediate products of HIV-1 reverse transcription (ssDNA and 2LTR), likely acting at the viral entry stage, yet showed no affinity for the PKC-δ protein. These results position compound S11 as a potential candidate for further preclinical investigation and for studies aimed at elucidating the pharmacological mechanism underlying its anti-HIV-1 activity.

Transmembrane protein 176B regulates amino acid metabolism through the PI3K-Akt-mTOR signaling pathway and promotes gastric cancer progression.

BACKGROUND: The present study aimed to investigate the expression level, biological function, and underlying mechanism of transmembrane protein 176B (TMEM176B) in gastric cancer (GC). METHODS: TMEM176B expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB). The function of TMEM176B was determined by various in vitro assays including colony formation, 5-ethynyl-2'-deoxyuridine (EdU), Transwell, and flow cytometry. Bioinformatics techniques were then used to elucidate the signaling pathways associated with TMEM176B activity. Tumor formation experiments were conducted on nude mice for in vivo validation of the preceding findings. TMEM176B expression was cross-referenced to clinicopathological parameters and survival outcomes. RESULTS: It was observed that TMEM176B was overexpressed in GC cells and tissues. Targeted TMEM176B abrogation inhibited colony formation, proliferation, migration, and invasion but promoted apoptosis in GC cell lines while TMEM176B overexpression had the opposite effects. Subsequent experimental validation disclosed an association between TMEM176B and the phosphatidylinositol 3-carboxykinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling axis. Moreover, TMEM176B affects GC cancer progression by regulating asparagine synthetase (ASNS). The in vivo assays confirmed that TMEM176B is oncogenic and the clinical data revealed a connection between TMEM176B expression and the clinicopathological determinants of GC. CONCLUSION: The foregoing results suggest that TMEM176B significantly promotes the development of gastric cancer and is an independent prognostic factor of it.

Synthesis and anti-HIV activities of phorbol derivatives.

In this study, 37 derivatives of phorbol esters were synthesized and their anti-HIV-1 activities evaluated, building upon our previous synthesis of 51 phorbol derivatives. 12-Para-electron-acceptor-trans-cinnamoyl-13-decanoyl phorbol derivatives stood out, demonstrating remarkable anti-HIV-1 activities and inhibitory effects on syncytia formation. These derivatives exhibited a higher safety index compared with the positive control drug. Among them, 12-(trans-4-fluorocinnamoyl)-13-decanoyl phorbol, designated as compound 3c, exhibited the most potent anti-HIV-1 activity (EC50 2.9 nmol·L-1, CC50/EC50 11 117.24) and significantly inhibited the formation of syncytium (EC50 7.0 nmol·L-1, CC50/EC50 4891.43). Moreover, compound 3c is hypothesized to act both as an HIV-1 entry inhibitor and as an HIV-1 reverse transcriptase inhibitor. Isothermal titration calorimetry and molecular docking studies indicated that compound 3c may also function as a natural activator of protein kinase C (PKC). Therefore, compound 3c emerges as a potential candidate for developing new anti-HIV drugs.

Novel Triazolopyridine-Based BRD4 Inhibitors as Potent HIV-1 Latency Reversing Agents.

Bromodomain-containing protein 4 (BRD4) inhibitors have been proven to be a promising option for anti-HIV-1 latency therapeutics. We herein describe the design, synthesis, and anti-HIV-1 latency bioevaluation of triazolopyridine derivatives as BRD4 inhibitors. Among them, compound 13d displayed favorable HIV-1 reactivation and prominent safety profile without triggering abnormal immune activation. It exerted strong synergism when combined with the PKC activator prostratin and has the same BRD4-targeting latency mechanism as observed with JQ1, by stimulating Tat-dependent HIV-1 elongation. Besides, it neither affected the antiviral efficacies of antiviral drugs nor caused secondary infections to uninfected cells and the latency reversing potency of 13d, in turn, was not affected by different classes of antiviral drugs.

Effects of Aquatic Plant Coverage on Diversity and Resource Use Efficiency of Phytoplankton in Urban Wetlands: A Case Study in Jinan, China.

With the acceleration of urbanization, biodiversity and ecosystem functions of urban wetlands are facing serious challenges. The loss of aquatic plants in urban wetlands is becoming more frequent and intense due to human activities; nevertheless, the effects of aquatic plants on wetland ecosystems have received less attention. Therefore, we conducted field investigations across 10 urban wetlands in Jinan, Shandong Province, as a case in North China to examine the relationships between aquatic plant coverage and phytoplankton diversity, as well as resource use efficiency (RUE) in urban wetlands. Multivariate regression and partial least squares structural equation modeling (PLS-SEM) were used to analyze the water quality, phytoplankton diversity, and RUE. The results demonstrate that the increase in aquatic plant coverage significantly reduced the concentration of total nitrogen and suspended solids' concentrations and significantly increased the phytoplankton diversity (e.g., species richness and functional diversity). The aquatic plant coverage significantly affected the composition of phytoplankton functional groups; for example, functional groups that had adapted to still-water and low-light conditions became dominant. Furthermore, the increase in phytoplankton diversity improved phytoplankton RUE, highlighting the importance of aquatic plants in maintaining wetland ecosystem functions. This study may provide a scientific basis for the management strategy of aquatic plants in urban wetlands, emphasizing the key role of appropriate aquatic plant cover in maintaining the ecological stability and ecosystem service functions of wetlands.

Celecoxib alleviates the DSS-induced ulcerative colitis in mice by enhancing intestinal barrier function, inhibiting ferroptosis and suppressing apoptosis.

INTRODUCTION: Ulcerative colitis (UC) is an inflammatory intestine disease characterized by dysfunction of the intestinal mucosal barrier, ferroptosis, and apoptosis. Previous researches suggest that celecoxib, a nonsteroidal anti-inflammatory drug, holds promise in alleviating inflammation in UC. Therefore, this study aims to investigate the effects and mechanisms of celecoxib in UC. METHODS: To identify ferroptosis-related drugs and genes associated with UC, we utilized the Gene Expression Omnibus (GEO), FerrDb databases, and DGIdb database. Subsequently, we established a 2.5% DSS (Dextran sulfate sodium)-induced colitis model in mice and treated them with 10 mg/kg of celecoxib to validate the bioinformatics results. We evaluated histological pathologies, inflammatory response, intestinal barrier function, ferroptosis markers, and apoptosis regulators. RESULTS: Celecoxib treatment significantly ameliorated DSS-induced UC in mice, as evidenced by the body weight change curve, colon length change curve, disease activity index (DAI) score, and histological index score. Celecoxib treatment reduced the level of pro-inflammatory factors and promoted the expressions of intestinal tight junction proteins such as Claudin-1 and Occludin, thereby restoring the integrity of the intestinal mucosal barrier. Furthermore, celecoxib treatment reversed the ferroptosis characteristics in DSS-induced mice by increasing glutathione (GSH), decreasing malondialdehyde (MDA), and increasing the expression of GPX-4 and xCT. Additionally, apoptosis was induced in mice with UC, as evidenced by increased Caspase3, BAD, P53, BAX, Caspase9 and Aifm1 production, and decreased expression of BCL-XL and BCL2. Celecoxib treatment significantly reversed the apoptotic changes in DSS-induced mice. CONCLUSION: Our findings suggest that celecoxib effectively treats DSS-induced UC in mice by inhibiting ferroptosis and apoptosis.

Celecoxib enhancing intestinal barrier functionCelecoxib alleviates ferroptosis in DSS-induces ulcerative colitisCelecoxib effectively alleviates apoptosis signaling pathway.

Direct writing concave structure on viscoelastic substrate for loading and releasing liquid on skin surface.

Droplet deposition on deformable matrix has a broad application prospect. Regular deposition and diffusion of droplet on the substrate is the key to prepare flexible concave structure. Direct writing technique is an advanced method for depositing ink droplet on various substrates, which could produce a variety of deposition forms. Meanwhile, direct writing technique has the characteristics of simplicity, convenience and strong controllability. In this work, patterned concave structure was fabricated with viscoelastic substrate by direct writing technology, depositing behavior of ink droplet, formation condition and shape control of concave structure were studied with viscoelastic substrate, and practical application of the patterned concave structure was explored in loading and releasing liquid on skin surface. This study provides an efficient method for the preparation and application of controllable concave surface.

Trajectories of depressive symptoms and their predictors in Chinese older population: Growth Mixture model.

BACKGROUND: Given the rapidly rising proportion of the older population in China and the relatively high prevalence of depressive symptoms among this population, this study aimed to identify the trajectories of depressive symptoms and the factors associated with the trajectory class to gain a better understanding of the long-term course of depressive symptoms in this population. METHODS: Data were obtained from four wave's survey of the China Health and Retirement Longitudinal Study (CHARLS). A total of 3646 participants who aged 60 years or older during baseline survey, and completed all follow-ups were retained in this study. Depressive symptoms were measured using the 10-item version of the Center for Epidemiologic Studies Depression Scale (CES-D-10). Growth mixture modelling (GMM) was adopted to identify the trajectory classes of depressive symptoms, and both linear and quadratic functions were considered. A multivariate logistic regression model was used to calculate the adjusted odds ratios (ORs) of the associated factors to predict the trajectory class of participants. RESULTS: A four-class quadratic function model was the best-fitting model for the trajectories of depressive symptoms in the older Chinese population. The four trajectories were labelled as increasing (16.70%), decreasing (12.31%), high and stable (7.30%), and low and stable (63.69%), according to their trends. Except for the low and stable trajectory, the other trajectories were almost above the threshold for depressive symptoms. The multivariate logistic regression model suggested that the trajectories of chronic depressive symptoms could be predicted by being female, living in a village (rural area), having a lower educational level, and having chronic diseases. CONCLUSIONS: This study identified four depressive symptom trajectories in the older Chinese population and analysed the factors associated with the trajectory class. These findings can provide references for prevention and intervention to reduce the chronic course of depressive symptoms in the older Chinese population.

Prognostic model for the prediction of cancer-specific survival in elderly patients with stage I-III gastric cancer.

Elderly patients with gastric cancer (GC) exhibit unique physiological conditions and population characteristics. However, no efficient predictive tools have been developed for this patient subgroup. We extracted data on elderly patients diagnosed with stage I-III GC between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database, and applied Cox regression analysis to examine factors associated with cancer-specific survival (CSS). A prognostic model was developed and validated to predict CSS. We assessed the performance of the prognostic model and stratified patients based on their prognostic scores. Notably, 11 independent prognostic factors, including age, race, grade, the tumor-node-metastasis (TNM) stage, T-stage, N-stage, operation, tumor size, regional nodes, radiation, and chemotherapy, associated with CSS were identified using multivariate Cox regression. A nomogram was constructed based on these predictors. The C-index score of the nomogram was 0.802 (95% (confidence interval) [CI]: 0.7939-0.8114), which is superior to the American Joint Commission on Cancer (AJCC) TNM staging prediction ability in the training cohort (C-index: 0.589; 95% CI: 0.5780-0.6017). Based on the receiver operating characteristic (ROC) and calibration curve, the predicted value of the nomogram demonstrated a satisfactory accuracy with the actual observation value. Additionally, decision curve analysis (DCA) showed that the nomogram had a more ideal clinical net benefit than TNM staging. Survival analysis of the different risk groups confirmed the noteworthy clinical and statistical utility of the nomogram in prognosis stratification. This retrospective study reports the successful creation and validation of a nomogram for predicting CSS at 1-, 3- and 5-years in elderly patients with stage I-III GC. This nomogram critically guides personalized prognostic assessments and may contribute to clinical decision-making and consultation for postoperative survival.

Long-term poor sleep quality is associated with adverse donor reactions in college students in Central China: A population-based cross-sectional study.

BACKGROUND AND OBJECTIVES: Adverse donor reaction (ADR) could adversely impact the recruitment and retention of blood donors, but the evidence of effect of sleep quality on ADR is limited and controversial. The goal of this study was to explore the association between the sleep quality and ADR among college students in Wuhan. MATERIALS AND METHODS: The college student blood donors in Wuhan from March to May 2022 were recruited. Self-compiled general information questionnaire and Pittsburgh sleep quality index (PSQI) were investigated by convenience sampling. Univariable and multivariable logistic regression analyses were used to estimate the association. RESULTS: Among 1014 participants included in this study, 63 were in the ADR group and 951 were in the non-ADR group. Compared with the non-ADR group, the PSQI scores of ADR group were higher (3.44 ± 1.81 vs. 2.78 ± 1.82, p < 0.01). The results of multivariable logistic regression analysis showed that after adjusting gender, body mass index, blood donation history and other potential confounding factors, higher PSQI scores were related to the occurrence of ADRs (odds ratio = 1.231, 95% confidence interval 1.075-1.405), that is, the worse the sleep quality, the more likely the ADRs will occur. CONCLUSION: The long-term poor sleep quality of college students is a risk factor for the occurrence of ADRs. It should be identified early before blood donation to reduce the incidence of ADRs and improve the safety and satisfaction of donors.

Direct-Writing Flexible Metal Circuit with Polymer/Metal Precursor Ink and Interfacial Reaction.

In this study, flexible metal circuits are fabricated with polymer/metal precursor ink and an interfacial reaction by direct-writing technology. Poly(vinyl alcohol) (PVA) is selected as one component of ink, which could be a flexible composite in a metal circuit and an adhesive layer to connect the flexible metal circuit with the flexible substrate. Silver nitrate (AgNO3) is added to the ink as a source of metal. After the direct-writing structure was placed in contact with an ascorbic acid (VC) aqueous solution with an adjustable process, silver nanoparticles (AgNPs) with 100-400 nm uniform size could be generated on the direct-writing PVA skeleton. The resistivity of the composite silver layer could reach 10-6 Ω·m without any postprocessing. Meanwhile, the resistance change could keep within 20% with 180° bending after 10 000 repeat times. Patterned flexible metal circuits could be facilely fabricated by direct-writing technology, which presented excellent electrical conductivity and flexibility.

The association of energy and macronutrient intake at breakfast and cardiovascular disease in Chinese adults: From a 14-year follow-up cohort study.

Background: We aimed to examine the associations between energy and macronutrient intakes at breakfast and the incidence of cardiovascular events among Chinese adults. Methods: There were 12,937 participants from the China Health and Nutrition Survey who met the study criteria and completed six rounds of questionnaires in 1997, 2000, 2004, 2006, 2009, and 2011. Combined weighing methods with 24-h dietary recall were used to measure dietary intake throughout the day. Intakes of macronutrients at breakfast were calculated using energy provided by nutrients as a percentage of breakfast energy. We calculated hazard ratios using a multivariable Cox frailty model with random intercepts to account for household clustering. Results: During follow-up, we documented 453 (3.6 per 1,000 person-years) major cardiovascular events, 195 (1.5 per 1,000 person-years) myocardial infarctions, and 293 (2.3 per 1,000 person-years) strokes. In Chinese adults, more breakfast carbohydrates or less proteins intake was associated with the reduced risk of cardiovascular diseases. Especially for women, higher intake of breakfast carbohydrates was associated with a lower risk of major cardiovascular events (quintile 5 vs. quintile 1, HR 0.47 [95%CI 0.30-0.74]; p trend = 0.0008) and stroke (quintile 5 vs. quintile 1, HR 0.48 [95%CI 0.26-0.88]; p trend = 0.0006). Higher intake of breakfast proteins was associated with a higher risk of major cardiovascular events (quintile 5 vs. quintile 1, HR 1.77 [95%CI 1.12-2.79]; p trend = 0.1162), myocardial infarction (quintile 5 vs. quintile 1, HR 2.49 [95%CI 1.21-5.11]; p trend = 0.2641). There was a significant association between breakfast fat intake and cardiovascular diseases in the adult population, but less significant correlation was found in Chinese men or women. Breakfast fat intake was positively associated with the risk of major cardiovascular events (quintile 5 vs. quintile 1, HR 1.74 [95%CI 1.27-2.36]; p trend = 0.0070), myocardial infarction (quintile 5 vs. quintile 1, HR 2.03 [95%CI 1.23-3.37]; p trend = 0.0168), and stroke (quintile 5 vs. quintile 1, HR 1.64 [95%CI 1.12-2.41]; p trend = 0.0732). There was a significant reduction in major cardiovascular events and stroke when breakfast energy intake was moderated, even if the independence of skipping breakfast. Conclusion: High carbohydrate intake and low protein and fat intake at breakfast may contribute to cardiovascular health while maintaining a moderate energy intake.

Synthesis and anti-HIV activity of non-nucleoside reverse-transcriptase inhibitor DB02 phosphate derivatives based on water-soluble optimization.

To improve the water solubility of anti-human immunodeficiency virus (HIV) agent DB02, an excellent non-nucleoside reverse-transcriptase inhibitor (NNRTI) obtained in our previous efforts, we designed and synthesized four phosphate derivatives of DB02 based on the molecular model of DB02 with RT. Here, the antiviral activity of these four derivatives was detected, leading to the discovery of compound P-2, which possessed a superior potency to the lead compound DB02 against wild-type HIV-1 and a variety of HIV-resistant mutant viruses significantly. Furthermore, the water solubility of P-2 was nearly 17 times higher than that of DB02, and the pharmacokinetic test in rats showed that P-2 demonstrate significantly improved oral bioavailablity of 14.6%. Our study showed that the introduction of a phosphate ester group at the end of the C-2 side chain of DB02 was beneficial to the improvement of its antiviral activity and pharmacokinetic properties, which provided a promising lead for the further development of S-DACOs type of NNRTIs.

Predator-mediated diversity of stream fish assemblages in a boreal river basin, China.

Predator-prey interactions are critical for understanding species composition and community assembly; however, there is still limited research on whether and how the prey species composition or community assembly in natural communities are mediated by predators. To address this question, we performed a field investigation to examine the influence of the presence of Lutra lutra on the diversity of fish communities of the Hunchun River Basin, Jilin Province, China. Our results indicate that L. lutra, as a potential umbrella species and generalist predator in the stream ecosystem, promotes the coexistence of a vast variety of fish taxa, which emphasizes the importance of top-down control in the ecological community. We suggest that L. lutra regulates the fish community assembly likely through the stochastic process. Although this was a pilot study regarding predator-prey interactions, the results highlight the effects of predators on the prey community assembly, and emphasize the role of predators on the maintenance of biodiversity and ecosystem function. Future conservation decisions involving ecosystem biodiversity should require the inclusion of predation intensity. The inclusion of scientific research and protection of umbrella species would thus constitute an additional and important step in biodiversity conservation.

Structure-Based Discovery and Characterization of a Preclinical Drug Candidate for the Treatment of HIV-1 Infection.

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) area key component of the current HIV-1 combination drug regimens. Although they exhibit potent anti-HIV-1 activity and modest toxicity, the emergence of mutant strains limits their application in clinical. Our previous research efforts contributed to the identification of compound K-5a2, which exhibits nanomolar activity in HIV-1-infected MT-4 cells. In this study, K-5a2 was shown to have a high level of anti-HIV-1 activity against various lab-adapted strains and clinical isolate strains, being comparable to ETR. Moreover, we showed the feasibility of K-5a2 as a preclinical anti-HIV-1 candidate by establishing its synergistic or additive anti-HIV-1 activity in combination with other representative anti-HIV-1 drugs and candidates. In addition, K-5a2 exhibited no inhibitory activity to the primary CYP isoforms and favorable pharmacokinetics. Taken together, its robust anti-HIV-1 potency, synergistic or additive effects with other anti-HIV drugs, and favorable pharmacokinetic and safety profiles make K-5a2 a potent alternative drug for HIV/AIDS treatment.

Broadened optical absorption, enhanced photoelectric conversion and ultrafast carrier dynamics of N, P co-doped carbon dots.

Carbon dots (CDs) have attracted extensive attention for their unique properties and promising applications in many fields. Many efforts have been made to improve the optical and physicochemical properties of CDs using an atomic doping strategy; however, the photoelectric properties of CD-based devices have been less studied and the photocurrent density is far from satisfactory for practical operation. Deep understanding of the doping effects on the electronic structure and photophysical properties of CDs is fundamental and essential for effectively improving the optical and photoelectrical performance of CD-based devices. Here, we have synthesized nitrogen (N) and phosphorus (P) co-doped CDs (N, P-CDs) through a one-step hydrothermal approach, and systematically investigated the effects of P-dopants on the improved optical and photoelectric properties of N, P-CDs. The introduction of P atoms into N-CDs significantly changes the electronic structure and extends the absorption spectral region, enhancing the light-harvesting ability of N, P-CDs. Meanwhile, the regulated carrier dynamics have been investigated using time-resolved fluorescence and transient absorption spectroscopy. We found that the carrier recombination was decreased with introducing P atoms, and the photogenerated electrons in the higher excited states could be efficiently transferred to the lowest excited state. Moreover, the photocurrent density of N, P-CDs was increased by twelve times compared with that of N-CDs. Therefore, the effective doping of P atoms can significantly regulate the electronic structure, optical properties, carrier dynamics and photoelectric conversion of N, P-CDs. The achieved broadband light-harvesting, good photoelectric properties and photostability of the as-prepared N, P-CDs demonstrate an important example of P-doping to improve the optical and photoelectrical properties of CD-based devices.

Bromodomain and Extra-Terminal Inhibitor BMS-986158 Reverses Latent HIV-1 Infection In Vitro and Ex Vivo by Increasing CDK9 Phosphorylation and Recruitment.

Latent reservoir persistence remains a major obstacle for curing human immunodeficiency virus type 1 (HIV-1) infection. Thus, strategies for the elimination of latent HIV-1 are urgently needed. As a bromodomain and extra-terminal (BET) inhibitor, BMS-986158 has been used in clinical trials for advanced solid tumors and hematological malignancies. Here, we found that BMS-986158 reactivated latent HIV-1 in three types of HIV-1 latency cells in vitro, and in combination antiretroviral therapy (cART)-treated patient-derived peripheral blood mononuclear cells ex vivo, without influencing global immune cell activation. BMS-986158 reactivated latent HIV-1 by increasing phosphorylation of CDK9 at Thr186 and promoting recruitment of CDK9 and RNA polymerase II to the HIV-1 long terminal repeat in J-Lat cells. Furthermore, BMS-986158 exerted strong synergism in reactivating latent HIV-1 when combined with prostratin and vorinostat and enhanced the antiviral activity of anti-HIV-1 drugs. Finally, BMS-986158 showed antiviral activity in an HIV-1 acute infection model, possibly by arresting the cell cycle in infected cells. Thus, these results suggest that BMS-986158 is a potential candidate for AIDS/HIV-1 therapy.

The effect of spacers in dual drug-polymer conjugates toward combination therapeutic efficacy.

Recently, a great effort has been made to perfect the therapeutic effect of solid tumor, from single-agent therapy to combined therapy and many other polymer-drug conjugations with dual or more anticancer agents due to their promising synergistic effect and higher drug level accumulation towards tumor tissues. Different polymer-drug spacers present diverse therapeutic efficacy, therefore, finding an appropriate spacer is desirable. In this study, dual drugs that are doxorubicin (DOX) and mitomycin C (MMC) were conjugated onto a polymer carrier (xyloglucan) via various peptide or amide bonds, and a series of polymers drug conjugates were synthesized with different spacers and their effect on tumor treatment efficacy was studied both in vitro and in vivo. The result shows that the synergistic effect is better when using different linker to conjugate different drugs rather than using the same spacer to conjugate different drugs on the carrier. Particularly, the finding of this works suggested that, using peptide bond for MMC and amide bond for DOX to conjugate dual drugs onto single XG carrier could improve therapeutic effect and synergy effect. Therefore, in polymer-pharmaceutical formulations, the use of different spacers to optimize the design of existing drugs to enhance therapeutic effects is a promising strategy.

Arabidopsis FHY3 and FAR1 Function in Age Gating of Leaf Senescence.

Leaf senescence is the terminal stage of leaf development. Both light and the plant hormone ethylene play important roles in regulating leaf senescence. However, how they coordinately regulate leaf senescence during leaf development remains largely unclear. In this study, we show that FHY3 and FAR1, two homologous proteins essential for phytochrome A-mediated light signaling, physically interact with and repress the DNA binding activity of EIN3 (a key transcription factor essential for ethylene signaling) and PIF5 (a bHLH transcription factor negatively regulating light signaling), and interfere with their DNA binding to the promoter of ORE1, which encodes a key NAC transcription factor promoting leaf senescence. In addition, we show that FHY3, PIF5, and EIN3 form a tri-protein complex(es) and that they coordinately regulate the progression of leaf senescence. We show that during aging or under dark conditions, accumulation of FHY3 protein decreases, thus lifting its repression on DNA binding of EIN3 and PIF5, leading to the increase of ORE1 expression and onset of leaf senescence. Our combined results suggest that FHY3 and FAR1 act in an age gating mechanism to prevent precocious leaf senescence by integrating light and ethylene signaling with developmental aging.