EIN2-directed translational regulation of ethylene signaling in Arabidopsis.

Ethylene is a gaseous phytohormone that plays vital roles in plant growth and development. Previous studies uncovered EIN2 as an essential signal transducer linking ethylene perception on ER to transcriptional regulation in the nucleus through a "cleave and shuttle" model. In this study, we report another mechanism of EIN2-mediated ethylene signaling, whereby EIN2 imposes the translational repression of EBF1 and EBF2 mRNA. We find that the EBF1/2 3' UTRs mediate EIN2-directed translational repression and identify multiple poly-uridylates (PolyU) motifs as functional cis elements of 3' UTRs. Furthermore, we demonstrate that ethylene induces EIN2 to associate with 3' UTRs and target EBF1/2 mRNA to cytoplasmic processing-body (P-body) through interacting with multiple P-body factors, including EIN5 and PABs. Our study illustrates translational regulation as a key step in ethylene signaling and presents mRNA 3' UTR functioning as a "signal transducer" to sense and relay cellular signaling in plants. VIDEO ABSTRACT.

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.

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.

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.

Transcription Factors FHY3 and FAR1 Regulate Light-Induced CIRCADIAN CLOCK ASSOCIATED1 Gene Expression in Arabidopsis.

The circadian clock provides a time-keeping mechanism that synchronizes various biological activities with the surrounding environment. Arabidopsis (Arabidopsis thaliana) CIRCADIAN CLOCK ASSOCIATED1 (CCA1), encoding a MYB-related transcription factor, is a key component of the core oscillator of the circadian clock, with peak expression in the morning. The molecular mechanisms regulating the light induction and rhythmic expression of CCA1 remain elusive. In this study, we show that two phytochrome signaling proteins, FAR-RED ELONGATED HYPOCOTYL3 (FHY3) and its paralog FAR-RED IMPAIRED RESPONSE1 (FAR1), are essential for the light-induced expression of CCA1 FHY3 and FAR1 directly bind to the CCA1 promoter and activate its expression, whereas PHYTOCHROME INTERACTING FACTOR5 (PIF5) directly binds to its promoter and represses its expression. Furthermore, PIF5 and TIMING OF CAB EXPRESSION1 physically interact with FHY3 and FAR1 to repress their transcriptional activation activity on CCA1 expression. These findings demonstrate that the photosensory-signaling pathway integrates with circadian oscillators to orchestrate clock gene expression. This mechanism might form the molecular basis of the regulation of the clock system by light in response to daily changes in the light environment, thus increasing plant fitness.

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.

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.

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.

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.

Arabidopsis FHY3 and FAR1 Regulate the Balance between Growth and Defense Responses under Shade Conditions.

Increasing crop yield per unit of area can be achieved by increasing planting density. However, high-density planting could trigger shade avoidance responses, which cause exaggerated growth and increased susceptibility to various diseases. Previous studies have shown that the rapid elongation of plants under shade (i.e., reduced red to far-red ratios) is regulated by phytochromes and various phytohormones. However, the detailed molecular mechanisms governing the interaction among these signaling pathways are not well understood. Here, we report that loss-of-function mutants of FAR-RED ELONGATED HYPOCOTYL3 (FHY3) and FAR-RED-IMPAIRED RESPONSE1 (FAR1), which encode two homologous transcription factors essential for phytochrome signaling, exhibit an exaggerated shade avoidance phenotype. We show that FHY3 and FAR1 repress plant growth through directly activating the expression of two atypical basic helix-loop-helix transcriptional cofactors, PHYTOCHROME RAPIDLY REGULATED1 (PAR1) and PAR2, and that this process is antagonized by a group of JASMONATE ZIM-DOMAIN proteins, key repressors of the jasmonic acid (JA) signaling pathway, through physical interactions. Furthermore, we show that FHY3 interacts with MYC2, a key transcriptional regulator of JA responses, coordinately regulating JA-responsive defense gene expression. Our results unveil a previously unrecognized mechanism whereby plants balance their growth and defense responses through convergence of the phytochrome signaling pathway and JA signaling pathway under shade conditions.

Factors associated with depressive symptoms among the elderly in China: structural equation model.

OBJECTIVES: To establish a structural equation model for exploring the direct and indirect relationships of depressive symptoms and their associated factors among the Chinese elderly population. DESIGN: A cross-sectional research. The 2015 data from the China Health and Retirement Longitudinal Study (CHARLS) were adopted. SETTING: CHARLS is an ongoing longitudinal study assessing the social, economic, and health status of nationally representative samples of middle-aged and elderly Chinese residents. PARTICIPANTS: A total of 5791 participants aged 60 years and above were included. MEASUREMENTS: Depressive symptoms were used as the study outcome. Sociodemographic characteristics, poor health status, unhealthy habits, and sleep duration were used as predictors. Confirmatory factor analysis was first conducted to test the latent variables. Structural equation model was then utilized to examine the associations among latent variables and depressive symptoms. RESULTS: The mean age of the participants was 68.82 ± 6.86 years, with 55.53% being males. The total prevalence of depressive symptoms was 37.52%. The model paths indicated that sociodemographic characteristics, poor health status, unhealthy habits, and sleep duration were directly associated with depressive symptoms, and the effects were 0.281, 0.509, -0.067, and -0.162, respectively. Sociodemographic characteristics, unhealthy habits, and sleep duration were indirectly associated with depressive symptoms, mediating by poor health status. Their effects on poor health status were -0.093, 0.180, and -0.279, respectively. All paths of the model were significant (P < 0.001). The model could explain 40.9% of the variance in the depressive symptoms of the Chinese elderly population. CONCLUSIONS: Depressive symptoms were significantly associated with sociodemographic characteristics, poor health status, unhealthy habits, and sleep duration among Chinese elderly population. The dominant predictor of depressive symptoms was poor health status. Targeting these results might be helpful in rationally allocating health resources during screening or other mental health promotion activities for the elderly.

Dose-response relationship between intergenerational contact frequency and depressive symptoms amongst elderly Chinese parents: a cross-sectional study.

BACKGROUND: Given the high prevalence of depressive symptoms amongst the elderly Chinese population and the significance of intergenerational contact in this demographic group, the purpose of this study was to examine the association and dose-response relationship between the frequency of intergenerational contact and depressive symptoms. METHODS: Data were obtained from the third wave of the China Health and Retirement Longitudinal Study. A total of 5791 participants at age 60 or older were included in this study. Depressive symptoms were defined by the 10-item version of the Centre for Epidemiologic Studies Depression Scale. Intergenerational contact included in-person meeting and remote connecting, and they were analysed separately. Intergenerational contact frequency was classified into ten categories and then treated as a continuous variable for analysis. We performed univariate and multivariate logistic regressions to identify risk covariables. Restrictive cubic spline analysis was used to examine the dose-response relationship between intergenerational contact frequency and the outcome of depressive symptoms. RESULTS: Both the frequency of meeting and the frequency of connecting with children were independently associated with depressive symptoms in the elderly, and the odds ratios for depressive symptoms increased with decreasing frequencies (P < 0.01). There was a negative dose-response relationship between intergenerational contact frequency and depressive symptoms. The odds of depressive symptoms steadily decreased with increasing frequency of meeting with their children. Following an initial increase, the odds rapidly decreased as the frequency of connecting with children increased with an inflection point at once a monthly. Both associations were nonlinear (P < 0.001). CONCLUSIONS: Our findings revealed a negative dose-response relationship between intergenerational contact frequency and depressive symptoms in the elderly Chinese population. Thus, future health interventions should consider cultural norms in shaping the mental well-being of Chinese elderly persons.

Factors associated with health literacy in rural areas of Central China: structural equation model.

BACKGROUND: Health literacy is a strong predictor of health status. This study develops and tests a structural equation model to explore the factors that are associated with the health literacy level of rural residents in Central China. METHODS: The participants were recruited from a county-level city in Central China (N = 1164). Face-to-face interviews were conducted to complete the self-designed questionnaire of each participant. The questionnaire included items for the (1) demographic information, (2) socioeconomic status, and (3) health literacy of the participants. Mplus analyses were performed to evaluate the proposed model. RESULTS: The final model showed good fit for the data, and both demographic characteristics (i.e., age, BMI, and residence) and socioeconomic status (i.e., monthly income, occupation, and education level) were significantly associated with health literacy level. The effects of these two variables were - 0.277 (P < 0.05) and 0.615 (P < 0.001), respectively, and the model explained 70.2% of the variance in health literacy. CONCLUSIONS: Health literacy was significantly associated with age, BMI, distance between residence and nearest medical institution, monthly income, occupation, and education level, whereas socioeconomic status was a dominant predictor of health literacy level. Targeting these factors might be helpful in allocating health resources rationally when performing health promotion work.

Prehypertension and its optimal indicator among adults in Hubei Province, Central China, 2013-2015.

BACKGROUND: Hypertension accounts for 7% of the annual global disease burden, despite great efforts to counter this trend. Thus, interventions targeted at prehypertension might lead to a breakthrough for hypertension prevention. This study focused on the prevalence of prehypertension among adults in Central China and the best indicator of prehypertension, which would provide the basis for future interventions. METHODS: This cross-sectional study was conducted using multistage stratified random sampling in seven counties in Hubei Province. Data from 30,634 survey respondents were analyzed using logistic regression and receiver operating characteristic (ROC) curve statistical tests, for the prevalence of prehypertension and the predictive ability of body mass index (BMI), waist-to-height ratio (WHtR), and waist circumference (WC) for prehypertension. RESULTS: The prevalence of prehypertension in adults was 42.2%. The following factors contributed to the risk of prehypertension: male sex, elder age, divorce/separation, drinking, heavy labor intensity, and high BMI (p < 0.05). Being a farmer and exercise exhibited positive associations with prehypertension (p < 0.05). Compared with BMI and WHtR, WC had a higher predictive value for prehypertension (area under ROC curve, AUC = 0.630, 95% confidence interval: 0.623-0.637, p < 0.0001), especially for men. The optimal cutoffs of WC for prehypertension were 79.95 cm in men and 76.85 cm in women. CONCLUSIONS: The prehypertension rate in adults was high in Central China. Significant factors related to hypertension were identified. More interventions targeting individuals with WC above the cutoff level are needed for timely awareness of prehypertension and early prevention of hypertension.

DELLA proteins interact with FLC to repress flowering transition.

Flowering is a highly orchestrated and extremely critical process in a plant's life cycle. Previous study has demonstrated that SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1) and FLOWERING LOCUS T (FT) integrate the gibberellic acid (GA) signaling pathway and vernalization pathway in regulating flowering time, but detailed molecular mechanisms remain largely unclear. In GA signaling pathway, DELLA proteins are a group of master transcriptional regulators, while in vernalization pathway FLOWERING LOCUS C (FLC) is a core transcriptional repressor that down-regulates the expression of SOC1 and FT. Here, we report that DELLA proteins interact with FLC in vitro and in vivo, and the LHRI domains of DELLAs and the C-terminus of MADS domain of FLC are required for these interactions. Phenotypic and gene expression analysis showed that mutation of FLC reduces while over-expression of FLC enhances the GA response in the flowering process. Further, DELLA-FLC interactions promote the repression ability of FLC on its target genes. In summary, these findings report that the interaction between MADS box transcription factor FLC and GRAS domain regulator DELLAs may integrate various signaling inputs in flowering time control, and shed new light on the regulatory mechanism both for FLC and DELLAs in regulating gene expression.

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.

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.

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.

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.