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The genetic recombination and antigenic variation of influenza viruses may decrease the efficacy of antiviral vaccines, highlighting the imperativeness of developing novel anti-influenza agents. Herein, a series of thiophene-based compounds were designed and synthesized as potent anti-influenza agents. Among them, ATV2301exhibited an excellent anti-influenza activity (EC50, H1N1 = 1.88 nM, H3N2 = 4.77 nM), a higher safety index (SI, H1N1 = 18218, H3N2 = 7180), and a remarkably improved oral bioavailability (F= 71.60%). The prodrug ATV2301Ademonstrated strong therapeutic efficacy and protection in H1N1-infected BALB/c mice, with low toxicity and broad tissue distribution. ATV2301also exhibited high stability in both human and mouse liver microsomes. Mechanistic studies indicated that ATV2301’s anti-influenza activity was due to its effects on polymerase acid protein (PA), nuclear protein (NP), and RNA-dependent RNA polymerase (RdRp). Additionally, ATV2301showed potent activities against clinical isolates of anti-influenza A virus (IAV) and anti-influenza B virus (IBV), positioning it as a promising cap-dependent endonuclease inhibitor for further clinical research.

Deep eutectic solvents (DESs) have emerged as promising green liquid lubricants for solving tribological problems due to their economic and excellent physicochemical and lubrication properties. However, a trace amount of water would affect their structure, physicochemical properties, and tribological properties. The effect of water on the tribological properties of DES is still unclear and needs further investigate. Herein, we carried out a systematic investigation into the chemical structure, rheological properties, and tribological performance of DES-water (DES-W) binary systems constructed by combining DES with varying contents of water. The results revealed that low levels of water in DES had a minimal impact on its chemical structure but affected its fluidity and viscosity. Frictional experiments demonstrated that DES-W binary systems displayed a reduced coefficient of friction from 0.094 to 0.025 compared to pure DESs and manifested outstanding antiwear properties under a high-load condition. This was attributed to the formation of hydration layers, adsorption layers, and tribochemical films at the tribointerface through physicochemical adsorption and tribochemical reactions. Our findings not only foster the design and development of green lubricating materials but also expand the engineering applications of DESs to solve wear-related mechanical failures in practical application.

English-medium Instruction (EMI), that is, the use of the English language to teach academic subjects apart from English, is a growing phenomenon around the world. In view of the facilitative role of language in content learning, scholars have stressed the need to incorporate a language focus into EMI classrooms. One practical question that arises from this discussion is “How?” This study, through a telling case, intends to reveal the classroom practices of an EMI teacher who explicitly addresses different language issues during her content teaching in a psychology course in a Macau university. Drawing on multiple sources of data including field observations and interviews, the authors unearth three forms of the teacher’s language-related teaching practices – (1) teaching language for content comprehension, (2) teaching language for classroom engagement, and (3) teaching language through feedback. Specific teaching techniques are further identified and discussed in relation to various personal and contextual factors surrounding the EMI classroom. Practical insights are offered to individual EMI teachers in embracing a language focus to facilitate content learning in EMI programs across geographical contexts.

ABSTRACTIntroductionSince the coronavirus disease 2019-mandated social distancing policy has been lifted worldwide, the circulation of influenza is expected to resume. Currently, oseltamivir is approved as the first-line agent for influenza prevention and treatment.Areas coveredThis paper reviews the updated evidence in the pharmacology, resistance mechanisms, clinical pharmacy management, and real-world data on oseltamivir for influenza.Expert opinionOseltamivir is an oral prodrug of oseltamivir carboxylate, an influenza A and B neuraminidase inhibitor. Recently, the therapeutic efficacy of oseltamivir has been demonstrated in several trials. Oseltamivir is generally well-tolerated but may lead to neuropsychiatric events and bleeding. Oseltamivir-resistant influenza virus has been associated with the H275Y mutation in the influenza A(H1N1)pdm09 virus, while most strains are still sensitive to oseltamivir. Dose adjustment for oseltamivir should be based on creatinine clearance and body weight in pediatric patients with renal failure. According to real-world data from Nanfang Hospital, the annual number of patients prescribed oseltamivir declined from 35,711 in 2019 to 8,971 in 2020, with marked increases in 2022 (20,213) and 2023 (18,071). Among the 206 inpatients, children aged < 6 years who were treated with oseltamivir had the shortest duration to defervescence.

Autumn phenology plays a critical role in shaping the carbon sequestration capacity of temperate forests. Notable local-scale variations in autumn phenology have drawn increasing attention recently, potentially introducing substantial uncertainty when predicting temperate forest productivity. Yet the underpinning mechanisms driving these variations remain inadequately elucidated. Here we observed significant and consistent relationships between canopy structure and autumn phenology across six temperate forest sites, induced by the regulation effect of canopy structure on microclimate conditions. Incorporating the identified ‘canopy structure–microclimate–autumn phenology’ pathway into existing autumn phenology models significantly improves the prediction accuracy and reduces the projected delay in the start of autumn over the remainder of the century. These findings offer a new perspective for interpreting the local variations of autumn phenology in temperate forests and emphasize the urgent need to integrate the identified pathway into the Earth system and vegetation models, especially considering the asynchronous changes of macroclimate and microclimate conditions.

Hybrid bonded-riveted joint has poor corrosion resistance under salt spray environment, especially for dissimilar materials. The study investigates the strength degradation mechanism of carbon fiber reinforced polymer and aluminium alloy (CFRP-Al) hybrid bonded-riveted joints under salt spray environment, and it proposes a method to improve corrosion resistance of CFRP-Al hybrid bonded-riveted joints. The study found that the strength degradation of CFRP-Al hybrid joints under salt spray environment was mainly attributed to the decrease in bonding strength at the aluminum/adhesive interface. Comparison results further showed that the diffusion of corrosive medium along the aluminum/adhesive bonding interface caused a 33.3% decrease in joint strength, while the accelerated electrochemical corrosion of the aluminum surface caused a 59.3% decrease in joint strength. Applying laser to modify the surface characteristics of aluminum resulted in a 46% increase in the maximum shear loads of CFRP-Al hybrid bonded-riveted joints before salt spray exposure and a 45% increase after salt spray exposure. It has been found that laser surface treatment produced rough microstructures on aluminum surface, which increases the bonding area between adhesive and aluminum alloy, effectively preventing the diffusion of corrosive medium along the bonding interface. Furthermore, a dense oxide layer was formed by laser surface treatment on aluminum surface, which contributed to slow down the galvanic corrosion between CFRP and aluminum. Consequently, an apparently improvement was observed in the bearing capacity and corrosion resistance of CFRP-Al hybrid bonded-riveted joints.

ABSTRACTColorectal cancer (CRC) is one of the most lethal cancers. Single-cell RNA sequencing (scRNA-seq) and protein-protein interactions (PPIs) have enabled the systematic study of CRC. In our research, the activation of the AKT pathway in CRC was analyzed by KEGG using single-cell sequencing data from the GSE144735 dataset. The correlation and PPIs of MDFI and ITGB4/LAMB3 were examined. The results were verified in the TCGA and CCLE and further tested by coimmunoprecipitation experiments. The effect of MDFI on the AKT pathway via ITGB4/LAMB3 was validated by knockdown and lentiviral overexpression experiments. The effect of MDFI on oxaliplatin/fluorouracil sensitivity was probed by colony formation assay and CCK8 assay. We discovered that MDFI was positively associated with ITGB4/LAMB3. In addition, MDFI was negatively associated with oxaliplatin/fluorouracil sensitivity. MDFI upregulated the AKT pathway by directly interacting with LAMB3 and ITGB4 in CRC cells, and enhanced the proliferation of CRC cells via the AKT pathway. Finally, MDFI reduced the sensitivity of CRC cells to oxaliplatin and fluorouracil. In conclusion, MDFI promotes the proliferation and tolerance to chemotherapy of colorectal cancer cells, partially through the activation of the AKT signaling pathway by the binding to ITGB4/LAMB3. Our findings provide a possible molecular target for CRC therapy.

Background: Lupus nephritis (LN) is the most common complication of systemic lupus erythematosus (SLE). The limited treatment options for LN increase the economic burdens on patients. Because fibrotic progression leads to irreversible renal damage in LN patients and further progresses to chronic kidney disease (CKD) and the end stage of renal disease (ESRD), developing new targets to prevent LN fibrotic progression could lead to a feasible treatment strategy for LN patients. Methods: In this study, we examined YAP activation and LATS2 downregulation in LN kidney biopsy samples (LN: n= 8, normal: n= 2) and lupus-prone MRL/lpr mice (n= 8 for each disease stage). The function of LATS2 was further investigated by in situ injection of Ad-LATS2 into mice with LN (n= 6 mice per group). We examined the role of SIAH2-LATS2 regulation by IP-MS and co-IP, and the protective effect of the SIAH2 inhibitor was investigated in mice with LN. Results: Restoring LATS2 by an adenovirus in vivo alleviated renal fibrotic damage in mice with LN. Moreover, we found that LATS2 was degraded by a K48 ubiquitination-proteasome pathway mediated by SIAH2 and promoted YAP activation to worsen fibrosis progression in LN. The H150 region of the substrate binding domain (SBD) is an important site for SIAH2-LATS2 binding. The SIAH2-specific inhibitor vitamin K3 protected against LN-associated fibrotic damage in vivo. Conclusion: In summary, we identified the SIAH2-LATS2 axis as an attractive intervention target in LN to alter the resistance to fibrosis.

ABSTRACTObjectiveThe aim of the study was to understand Chinese university students’ psychological development during the COVID-19 outbreak.MethodFour online surveys, i.e., emotional adjustment, perceived social support, self-efficacy belief, and anxiety in English learning, were administered to 585 university students in China. The data were analyzed through a latent profile analysis.ResultsThree profiles were identified: high adaptation, moderate adaptation, and low adaptation. The students with high adaptation (n = 276, 47.1%) possessed a more positive self-efficacy belief and demonstrated lower levels of anxiety. In contrast, the students with low adaptation (n = 82, 14%) possessed a less positive self-efficacy belief and demonstrated higher levels of anxiety.ConclusionThe findings highlight the need of psychological interventions to support the psychological development of vulnerable groups of learners within and beyond the COVID-19 pandemic.KEY POINTSWhat is already known about this topic:(1) Anxiety is an important factor that influences the learning of foreign languages.(2) Self-efficacy and perceived social support help students cope with stress.(3) Emotional adjustment helps to reduce foreign language anxiety.What this paper adds:(1) Students with low adaptation possessed lower levels of self-efficacy belief and demonstrated higher levels of anxiety.(2) Teachers need to pay special attention to the psychological development of vulnerable groups of learners within and beyond the COVID-19 pandemic.(3) Teachers are advised to develop interventions that enhance students’ self-efficacy beliefs and offer tailored interventions on emotional adjustment strategies.

In this era characterized by fast development of urbanization, public transportation problem is one of the main obstacles for people to promote their life satisfaction in China. This paper aims at discussing problems on mass customization public transportation, providing suggestions and consults for its sustainable development and improvement. A mass customization model for public transportation is constructed based on client requirement and cost analysis, and case studies are made to validate route planning results. Results show that mass customization public transportation can make high profit for bus companies and relieve traffic congestion and air contamination.

ABSTRACTIntroductionBoth vaccines and antiviral drugs represent the mainstay for preventing and treating influenza. However, approved M2 ion channel inhibitors, neuraminidase inhibitors, polymerase inhibitors, and various vaccines cannot meet therapeutic needs because of viral resistance. Thus, the discovery of new targets for the virus or host and the development of more effective inhibitors are essential to protect humans from the influenza virus.Areas coveredThis review summarizes the latest progress in vaccines and antiviral drug research to prevent and treat influenza, providing the foothold for developing novel antiviral inhibitors.Expert opinionVaccines embody the most effective approach to preventing influenza virus infection, and recombinant protein vaccines show promising prospects in developing next-generation vaccines. Compounds targeting the viral components of RNA polymerase, hemagglutinin and nucleoprotein, and the modification of trusted neuraminidase inhibitors are future research directions for anti-influenza virus drugs. In addition, some host factors affect the replication of virus in vivo, which can be used to develop antiviral drugs.

Purpose: The study explores how pre-service teachers engage in Tong Ke Yi Gou(“Same lesson and different design”) as a Chinese version of lesson study in a language teacher education course. Design/methodology/approach: Data were collected from multiple sources, including semi-structured interviews, field observations, as well as individual reflections constructed by the participants. The different data sources served to triangulate and enrich each other, shedding light on the student teachers’ learning experiences through lesson study. Findings: The findings of the study reveal the participants’ enhanced motivation and participation through a process-oriented, collaborative design (i.e. joint lesson planning, micro-teaching, collaborative debrief and individual reflections). In addition, the participants engaged in constant comparisons at multiple levels, which collectively refined and expanded their pedagogical knowledge about language teaching. Such rich and collaborative experiences further contributed to their reflections on and for practice as future language teachers. On the other hand, the study also reveals the emotional challenges faced by some participants due to the competitive atmosphere brought by the comparative element embedded in the process of Tong Ke Yi Gou. Originality/value: This study incorporates the mode of Tong Ke Yi Gou into a pre-service teacher education course in order to examine how it can benefit student teachers’ learning to teach. The findings highlight the power of “comparison” in promoting student teachers’ reflective and analytical thinking at multiple levels with practical implications for current pre-service teacher education programs.

•This study successfully established the regorafenib-resistant cell line MHCC-97H/REGO and discovered that the activation of the ERK pathway promotes the epithelial-mesenchymal transition (EMT) process, resulting in resistance to regorafenib.•This study provides the first evidence for considering the use of drugs targeting the inhibition of the ERK pathway to potentially reverse regorafenib resistance in HCC within a clinical setting.•The study also observed that CuET can reverse regorafenib resistance by inhibiting EMT through the suppression of the ERK pathway.

The carbon fibre reinforced polymer (CFRP)-strengthened concrete structures are faced with the great threat of fire due to the vulnerability of the epoxy organic adhesive to high temperature. The traditional epoxy organic adhesives are thus urgently needed to be replaced by the alternatives with high-temperature resistance. This paper explored the feasibility of using magnesium phosphate inorganic adhesive (MPIA) to serve as the bonding material for the CFRP-strengthened concrete structures. To this end, the high-temperature resistance modification of MPIA was conducted through the addition of glass powder (GP) in this study. The effects of the GP content ranging from 0% to 15% on the temperature development, mechanical property degradation, phase evolution and microstructural characteristics of the MPIA after exposure to different temperatures were investigated. The results showed that the glass powder could effectively fill the pores caused by the decomposition of the hydration products and the cracks caused by the shrinkage of MPIA matrix at elevated temperatures, which improved the microstructure of MPIA significantly and thus alleviated its strength degradation under high temperature. In terms of the mechanical properties, the MPIA with 10% GP (hereinafter referred to as TRMPIA) yielded the best high-temperature resistance. In addition, the interfacial bond property test after high temperature was also conducted on the concrete members strengthened with the CFRP sheets pasted by TRMPIA, and the test results were also compared with the specimens with epoxy served as the bonding material. The results showed that even after exposure to 600°C, the in-plane shear strength of TRMPIA still remained 14.0% of that at room temperature, while the bond strength of epoxy had been completely lost, which highlighted the advantage of high-temperature resistance of the modified MPIA served as the bonding material of CFRP-strengthened concrete structures.

Despite medical advances, there remains an unmet need for better treatment of obesity. Itaconate, a product of the decarboxylation of the tricarboxylic acid cycle intermediate cis-aconitate, plays a regulatory role in both metabolism and immunity. Here, we show that itaconate, as an endogenous compound, counteracts high-fat-diet (HFD)-induced obesity through leptin-independent mechanisms in three mouse models. Specifically, itaconate reduces weight gain, reverses hyperlipidemia, and improves glucose tolerance in HFD-fed mice. Additionally, itaconate enhances energy expenditure and the thermogenic capacity of brown adipose tissue (BAT). Unbiased proteomic analysis reveals that itaconate upregulates key proteins involved in fatty acid oxidation and represses the expression of lipogenic genes. Itaconate may provoke a major metabolic reprogramming by inducing fatty acid oxidation and suppression of fatty acid synthesis in BAT. These findings highlight itaconate as a potential activator of BAT-mediated thermogenesis and a promising candidate for anti-obesity therapy.

In orthotopic mouse tumor models, tumor progression is a complex process, involving interactions among tumor cells, host cell-derived stromal cells, and immune cells. Much attention has been focused on the tumor and its tumor microenvironment, while the host’s macroenvironment including immune organs in response to tumorigenesis is poorly understood. Here, we report a temporal proteomic analysis on a subcutaneous tumor and three immune organs (LN, MLN, and spleen) collected on Days 0, 3, 7, 10, 14, and 21 after inoculation of mouse forestomach cancer cells in a syngeneic mouse model. Bioinformatics analysis identified key biological processes during distinct tumor development phases, including an initial acute immune response, the attack by the host immune system, followed by the adaptive immune activation, and the build-up of extracellular matrix. Proteomic changes in LN and spleen largely recapitulated the dynamics of the immune response in the tumor, consistent with an acute defense response on D3, adaptive immune response on D10, and immune evasion by D21. In contrast, the immune response in MLN showed a gradual and sustained activation, suggesting a delayed response from a distal immune organ. Combined analyses of tumors and host immune organs allowed the identification of potential therapeutic targets. A proof-of-concept experiment demonstrated that significant growth reduction can be achieved by dual inhibition of MEK and DDR2. Together, our temporal proteomic dataset of tumors and immune organs provides a useful resource for understanding the interaction between tumors and the immune system and has the potential for identifying new therapeutic targets for cancer treatment.

The previous virtual screening of ten million compounds yielded two novel nonlipopeptide-like chemotypes as TLR2 agonists. Herein, we present the chemical optimization of our initial hit, 1-phenyl-3-(thiophen-2-yl)urea, which resulted in the identification of SMU-C80 (EC50= 31.02 ± 1.01 nM) as a TLR2-specific agonist with a 370-fold improvement in bioactivity. Mechanistic studies revealed that SMU-C80, through TLR1/2, recruits the adaptor protein MyD88 and triggers the NF-κB pathway to release cytokines such as TNF-α and IL-1β from human, but not murine, cells. To the best of our knowledge, it is the first species-specific TLR1/2 agonist reported until now. Moreover, SMU-C80 increased the percentage of T, B, and NK cells ex vivoand activated the immune cells, which suppressed cancer cell growth in vitro. In summary, we obtained a highly efficient and specific human TLR1/2 agonist that acts through the MyD88 and NF-κB pathway, facilitating cytokine release and the simultaneous activation of immune cells that in turn affects the apoptosis of cancer cells.

ABSTRACTIntroduction: Seasonal influenza vaccination, together with FDA-approved neuraminidase (NA) and polymerase acidic (PA) inhibitors, is the most effective way for prophylaxis and treatment of influenza infections. However, the low efficacy of prevailing vaccines to newly emerging influenza strains and increasing resistance to available drugs drives intense research to explore more effective inhibitors. Hemagglutinin (HA), one of the major surface proteins of influenza strains, represents an attractive therapeutic target to develop such new inhibitors.Areas covered: This review summarizes the current progress of HA-based influenza virus inhibitors and their mechanisms of action, which may facilitate further research in developing novel antiviral inhibitors for controlling influenza infections.Expert opinion: HA-mediated entry of influenza virus is an essential step for successful infection of the host, which makes HA a promising target for the development of antiviral drugs. Recent progress in delineating the crystal structures of HA, especially HA-inhibitors complexes, has revealed a number of key residues and conserved binding pockets within HA. This has opened up important insights for developing HA-based antiviral inhibitors that have a high resistance barrier and broad-spectrum activities.

A new axial chiral binaphtoquinone, hypocrellone (1), and a new perylenequinone, hypomycin F (2), were isolated from the stromata of Hypocrella bambusae, together with five known compounds, 3–7. The structures of 1and 2were assigned by spectroscopic and HRESIMS data analyses. The axial chirality of 1was determined by electronic circular dichroism data analysis, and the absolute configurations of 2and 3were determined by X-ray crystallography. The axial chirality of 7was determined by UV-induced photooxidation from 4. Compounds 1, 4, and 5showed inhibitory activity against pseudotyped SARS-CoV-2 infection in 293T-ACE2 cells with IC50values of 0.17, 0.038, and 0.12 μM. Compounds 4and 5were also active against live SARS-CoV-2 infection with EC50values of 0.22 and 0.21 μM, respectively. Further cell–cell fusion assays, surface plasmon resonance assays, and molecular docking studies revealed that 4and 5could bind with the receptor-binding domain of SARS-CoV-2 S protein to prevent its interaction with human angiotensin-converting enzyme II receptor. Our results revealed that 4and 5are potential SARS-CoV-2 entry inhibitors.

Cancer vaccines play a key role in the prevention and treatment of early and recurrent tumors. Although they have been widely studied during the past few decades, designing an efficient and economical cancer vaccine is still challenging. Here, we propose an injectable live cell cancer vaccine (InLCCV) using live tumor cells as immunogenic sources for cancer immunoprophylaxis and immunotherapy. InLCCV is fabricated by loading live mouse breast cancer cells (4T1 cells), gold nanorods (GNRs), and super-low-dose lipopolysaccharide (LPS) into a biocompatible Pluronic F127 in situhydrogel matrix. After in situinactivation by the photothermal effect of GNRs upon near-infrared (NIR) laser irradiation, immunogenic cell death (ICD) of 4T1 cells is induced and tumor-associated antigens (TAAs) together with loaded LPS are released subsequently. Therefore, dendritic cells and macrophages are activated accordingly, further stimulating the systemic anti-tumor immune response. After vaccinating with InLCCV, the tumor-free percentage of the mice is 60% and the survival rate during the observation period reaches up to 80%. For lung metastasis, the metastatic foci are 3.9-fold less than those of the control group. The as-developed InLCCV shows much promise as a potential platform for breast cancer immunoprophylaxis and immunotherapy.

The rapid development of information technology and e-business has promoted financial development but has not addressed chronic asset shortages. Asset shortages are an important factor that affects enterprise operating systems and consequently influences economic growth. Using China's provincial panel data from 2001 to 2014 as sample, we use the overlapping generations model, fixed effect model, two-stage least-squares regression, and quantile regression model to explore the impact of asset shortages on economic growth. Empirical results show that asset shortages have been a perennial problem in China's provinces, thus having a significantly positive correlation with economic growth. In addition, the moderating effect of asset shortages positively influences the relationship between financial development and economic growth. These findings bear the practical implication that the government should develop information technology to increase the effective supply of sound assets.