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Genetic studies have elucidated mechanisms that regulate aging; however, there has been little progress in identifying drugs that retard ageing. Caenorhabditis elegans is among the classical model organisms in ageing research. Methyl 3,4-dihydroxybenzoate (MDHB) can prolong the life-span of C. elegans, but the underlying molecular mechanisms are not yet fully understood. Here, we report that MDHB prolongs the life-span of C. elegans and delays age-associated declines of physiological processes. Besides, MDHB can lengthen the life-span of eat-2 (ad1113) mutations, revealing that MDHB does not work via caloric restriction (CR). Surprisingly, the life-span–extending activity of MDHB is completely abolished in daf-2 (e1370) mutations, which suggests that daf-2 is crucial for a MDHB-induced pro-longevity effect in C. elegans. Moreover, MDHB enhances the nuclear localization of daf-16/FoxO, and then modulates the expressions of genes that positively correlate with defenses against stress and longevity in C. elegans. Therefore, our results indicate that MDHB at least partially acts as a modulator of the daf-2/daf-16 pathway to extend the lifespan of C. elegans, and MDHB might be a promising therapeutic agent for age-related diseases.

Neural stem cells (NSCs) have been shown as a potential source for replacing degenerated neurons in neurodegenerative diseases. However, the therapeutic potential of these cells is limited by the lack of effective methodologies for controlling their differentiation. Inducing endogenous pools of NSCs by small molecule can be considered as a potential approach of generating the desired cell types in large numbers. Here, we reported the characterization of a small molecule (Methyl 3,4-dihydroxybenzoate; MDHB) that selectively induces hippocampal NSCs to differentiate into cholinergic motor neurons which expressed synapsin 1 (SYN1) and postsynaptic density protein 95 (PSD-95). Studies on the mechanisms revealed that MDHB induced the hippocampal NSCs differentiation into cholinergic motor neurons by inhibiting AKT phosphorylation and activating autophosphorylation of GSK3β at tyrosine 216. Furthermore, we found that MDHB enhanced β-catenin degradation and abolished its entering into the nucleus. Collectively, this report provides the strong evidence that MDHB promotes NSCs differentiation into cholinergic motor neurons by enhancing gene expression and inhibiting cell cycle progression. It may provide a basis for pharmacological effects of MDHB directed on NSCs.

Although lipopolysaccharides (LPS) have been used to establish animal models of memory loss akin to what is observed in Alzheimer's disease (AD), the exact mechanisms involved have not been substantiated. In this study, we established an animal model of learning and memory impairment induced by LPS and explored the biological processes and pathways involved. Mice were continuously intraperitoneally injected with LPS for 7 days. Learning- and memory-related behavioral performance and the pathological processes involved were assessed using the Morris water maze test and immunostaining, respectively. We detected comprehensive expression of C1q, C3, microglia, and their regulatory cytokines in the hippocampus. After 7 days of LPS administration, we were able to observe LPS-induced learning and memory impairment in the mice, which was attributed to neural impairment and synapse loss in the hippocampus. We elucidated that the immune system was activated, with the classical complement pathway and microglial phagocytosis being involved in the synapse loss. This study demonstrates that an LPS-injected mouse can serve as an early memory impairment model for studies on anti-AD drugs.

Aim： 7,8-Dihydroxy-4-（3-hydroxy-4-methoxyphenyl）-2H-chromen-2-one （DW532） is one of simplified analogues of hematoxylin that has shown broad-spectrum inhibition on tyrosine kinases and in vitro anti-cancer activities. The aim of this study was to identify DW532 as a agent targeting both kinases and tubulin, and to investigate its anti-cancer and anti-angiogenesis activities. Methods： In vitro tyrosine kinases activity was examined with ELISA, and tyrosine kinases activity in cells was evaluated with Western blot analysis. Tubulin turbidity assay, surface plasmon resonance and immunofluorescence technique were used to characterize the tubulin inhibitory activity. Cell proliferation was examined with SRB assay, and cell apoptosis and cell cycle distribution were analyzed with Annexin-V/PI staining and flow cytometry. Tube formation, aortic ring and chick chorioallantoic membrane assays were used to evaluate the anti-angiogenesis efficacy. Results： DW532 inhibited EGFR and VEGFR2 in vitro kinase activity （the ICso values were 4.9 and 5.5 pmol/L, respectively）, and suppressed their downstream signaling. DW532 dose-dependently inhibited tubulin polymerization via direct binding to tubulin, thus disrupting the mitotic spindle assembly and leading to abnormal cell division. In a panel of human cancer cells, DW532 （1 and 10 pmol/L） induced G2/M phase arrest and cell apoptosis, which subsequently resulted in cytotoxicity. Knockdown of BubR1 or Mpsl, the two core proteins of the spindle assembly checkpoint dramatically decreased DW532-induced cell cycle arrest in MDA-MB-468 cells. Moreover, treatment with DW532 potently and dose-dependently suppressed angiogenesis in vitro and in vivo. Conclusion： DW532 is a dual inhibitor against tubulin and tyrosine kinases, and deserves further development as a novel anti-cancer agent.

Nowadays, many e-commerce websites allow users to login with their existing social networking accounts.When a new user comes to an e-commerce website, it is interesting to study whether the information from external socialmedia platforms can be utilized to alleviate the cold-start problem. In this paper, we focus on a specific task on cross-siteinformation sharing, i.e., leveraging the text posted by a user on the social media platform （termed as social text） to inferhis/her purchase preference of product categories on an e-commerce platform. To solve the task, a key problem is how toeffectively represent the social text in a way that its information call be utilized on the ecommerce platform. We studytwo major kinds of text representation methods for predicting cross-site purchase preference, including shallow textualfeatures and deep textual features learned by deep neural network models. We conduct extensive experiments on a largelinked dataset, and our experimental results indicate that it is promising to utilize the social text for predicting purchasepreference. Specially, the deep neural network approach has shown a more powerful predictive ability when the number ofcategories becomes large.

To investigate the significance and impact of molecular subtyping stratification on metastatic breast cancer patients, we identified 159,344 female breast cancer patients in the Surveillance, Epidemiology and End Results (SEER) database with known hormone receptor (HoR) and human epidermal growth factor receptor 2 (HER2) status. 4.8% of patients were identified as having stage IV disease, and were more likely to be HER2+/HoR−, HER2+/HoR+, or HER2−/HoR−. Stage IV breast cancer patients with a HER2+/HoR+ status exhibited the highest median overall survival (OS) (44.0 months) and those with a HER2−/HoR− status exhibited the lowest median OS (13.0 months). Patients with a HER2−/HoR+ status had more bone metastasis, whereas patients with a HER2+/HoR− status had an increased incidence of liver metastasis. Brain and lung metastasis were more likely to occur in women with a HER2−/HoR− status. The multivariable analysis revealed a significant interaction between single metastasis and molecular subtype. No matter which molecular subtype, women who did not undergo primary tumour surgery had worse survival than those who experienced primary tumour surgery. Collectively, our findings advanced the understanding that molecular subtype might lead to more tailored and effective therapies in metastatic breast cancer patients.

Aim： The aim of the present study was to further improve the therapeutic effects for human hepatocellular carcinoma （HCC） and reduce the damage in normal cells using a novel chemo-gene-virotherapeutic strategy. Methods： An oncolytic adenoviral vector （ZD55） similar to the typical oncolytic adenovirus ONYX-015, with a deletion of E1B-55K gene, was employed to express the second mitochon- dria-derived activator of caspases （Smac） protein by constructing a recombinant virus ZD55-Smac. The enhanced cytotoxicity of the combined treatment of ZD55- Smac with cisplatin or 5-fluorouracil （5-FU） was evaluated in several HCC cell lines. Moreover, the negative effects on normal cells have been tested in human normal liver cell lines L-02 and QSG-7701 cell lines by 3-（4,5-dimethylthiazol-2-yl）- 2,5-diphenyltetrazolium bromide assay and apoptotic cell staining. Results： According to our observation, ZD55-Smac is superior to ONYX-015 in sensitizing chemotherapy, ZD55-Smac used in conjunction with chemotherapy was found to exhibit obviously enhanced cytotoxicity in HCC cells, yet significantly abolished the negative toxicity in normal cells by utilizing the tumor selective replication vector and reducing the dosage. Conclusion： This chemo-gene-virotherapeutic （cisplatin or 5-FU＋ZD55-Smac） strategy is superior to the conventional chemo- gene or chemo-viro approach.

Chemicals of emerging concern (CECs) pose critical threats to both public health and the environment, emphasizing the urgent need for effective water treatment measures. Yet, the implementation of such intervention technologies often results in increased energy consumption and adverse environmental consequences. Here, we employ a comprehensive methodology that integrates multiple datasets, assumptions, and calculations to assess the human health and environmental implications of removing various CECs from source water. Our analysis of two treatment alternatives reveals that the integration of riverbank filtration with reverse osmosis offers a promising solution, yielding healthier and more environmentally favorable outcomes than conventional sequential technologies. By incorporating context-specific practices, such as utilizing renewable energy sources and clean energy technologies, we can mitigate the adverse impacts associated with energy-intensive water treatment services. This research advances our understanding of the water-health-environment nexus and proposes strategies to align drinking water provision with public health and environmental sustainability objectives. Chemicals of emerging concern threaten health and the environment, necessitating effective water treatment. This study clarifies the water-health-environment nexus and suggests approaches to align drinking water with health and sustainability goals.

The shotgun proteomic analysis is currently the most promising single-cell protein sequencing technology, however its identification level of ~1000 proteins per cell is still insufficient for practical applications. Here, we develop a pick-up single-cell proteomic analysis (PiSPA) workflow to achieve a deep identification capable of quantifying up to 3000 protein groups in a mammalian cell using the label-free quantitative method. The PiSPA workflow is specially established for single-cell samples mainly based on a nanoliter-scale microfluidic liquid handling robot, capable of achieving single-cell capture, pretreatment and injection under the pick-up operation strategy. Using this customized workflow with remarkable improvement in protein identification, 2449–3500, 2278–3257 and 1621–2904 protein groups are quantified in single A549 cells ( n  = 37), HeLa cells ( n  = 44) and U2OS cells ( n  = 27) under the DIA (MBR) mode, respectively. Benefiting from the flexible cell picking-up ability, we study HeLa cell migration at the single cell proteome level, demonstrating the potential in practical biological research from single-cell insight. Single-cell proteomics is of fundamental importance to capture biological heterogeneity, while limited in proteome depth. Here, the authors develop a pick-up single-cell proteomic analysis (PiSPA) workflow to achieve a deep coverage of quantifying up to 3000 protein groups in a mammalian cell.

Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. Here, we determine that somatic mutations in PIK3CA (44%), PIK3R1 (17%), AKT3 (15%), and PTEN (12%) are prevalent and diverse in Chinese breast cancer patients, with 60 novel mutations identified. A high proportion of tumors harbors multiple mutations, especially PIK3CA plus PIK3R1 mutations (9.0%). Next, we develop a recombination-based mutation barcoding (ReMB) library for impactful mutations conferring clonal advantage in proliferation and drug responses. The highest-ranking PIK3CA and PIK3R1 mutations include previously reported deleterious mutations, as well as mutations with unknown significance. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity. Collectively, these findings advance our understanding of PI3K impactful mutations in breast cancer and have important implications for PI3K-targeted therapy in precision oncology. The PI3K pathway is altered across various cancer types. Here the authors use amplicon exon sequencing to analyze the landscape of somatic mutations affecting the PI3K pathway specifically in breast cancer patients in China.