Detoxified pneumolysin derivative ΔA146Ply inhibits autophagy and induces apoptosis in acute myeloid leukemia cells by activating mTOR signaling

Leukemia is caused by the malignant clonal expansion of hematopoietic stem cells, and in adults, the most common type of leukemia is acute myeloid leukemia (AML). Autophagy inhibitors are often used in preclinical and clinical models in leukemia therapy. However, clinically available autophagy inhibitors and their efficacy are very limited. More effective and safer autophagy inhibitors are urgently needed for leukemia therapy. In a previous study, we showed that ΔA146Ply, a mutant of pneumolysin that lacks hemolytic activity, inhibited autophagy of triple-negative breast cancer cells by activating mannose receptor (MR) and toll-like receptor 4 (TLR4) and that tumor-bearing mice tolerated ΔA146Ply well. Whether this agent affects AML cells expressing TLR4 and MR and the related mechanisms remain to be determined. In this study, we found that ΔA146Ply inhibited autophagy and induced apoptosis in AML cells. A mechanistic study showed that ΔA146Ply inhibited autophagy by activating mammalian target of rapamycin signaling and induced apoptosis by inhibiting autophagy. ΔA146Ply also inhibited autophagy and induced apoptosis in a mouse model of AML. Furthermore, the combination of ΔA146Ply and chloroquine synergistically inhibited autophagy and induced apoptosis in vitro and in vivo. Overall, this study provides an alternative effective autophagy inhibitor that may be used for leukemia therapy.Subject terms: Translational research, Acute myeloid leukaemia     

Natural Products in Preventing Tumor Drug Resistance and Related Signaling Pathways

Drug resistance is still an obstacle in cancer therapy, leading to the failure of tumor treatment. The emergence of tumor drug resistance has always been a main concern of oncologists. Therefore, overcoming tumor drug resistance and looking for new strategies for tumor treatment is a major focus in the field of tumor research. Natural products serve as effective substances against drug resistance because of their diverse chemical structures and pharmacological effects. We reviewed the signaling pathways involved in the development of tumor drug resistance, including Epidermal growth factor receptor (EGFR), Renin-angiotensin system (Ras), Phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), Wnt, Notch, Transforming growth factor-beta (TGF-β), and their specific signaling pathway inhibitors derived from natural products. This can provide new ideas for the prevention of drug resistance in cancer therapy.     

Dynamic Variation of Amino Acid Contents and Identification of Sterols in Xinyang Mao Jian Green Tea

As important biomolecules in Camellia sinensis L., amino acids (AAs) are considered to contribute to the overall green tea sensory quality and undergo dynamic changes during growth. However, limited by analytical capacity, detailed AAs composition in different growth stages remains unclear. To address this question, we analyzed the dynamic changes of 23 AAs during leaf growth in Xinyang Mao Jian (XYMJ) green tea. Using amino acid analyzer, we demonstrated that most AAs are abundant on Pure Brightness Day and Grain Rain Day. After Grain Rain, 23 AAs decreased significantly. Further analysis shows that theanine has a high level on the day before Spring Equinox and Grain Rain, accounting for 44–61% of the total free AAs content in tea leaves. Glu, Pro, and Asp are the second most abundant AAs. Additionally, spinasterol and 22,23-dihydrospinasterol are first purified and identified in ethanol extract of XYMJ by silica gel column chromatography method. This study reveals the relationship between plucking days and the dynamic changes of AAs during the growth stage and proves the rationality of the traditional plucking days of XYMJ green tea.     

An unexpected all-metal aromatic tetranuclear silver cluster in human copper chaperone Atox1

Metal clusters, such as iron–sulfur clusters, play key roles in sustaining life and are intimately involved in the functions of metalloproteins. Herein we report the formation and crystal structure of a planar square tetranuclear silver cluster when silver ions were mixed with human copper chaperone Atox1. Quantum chemical studies reveal that two Ag 5s¹ electrons in the tetranuclear silver cluster fully occupy the one bonding molecular orbital, with the assumption that this Ag₄ cluster is Ag₄²⁺, leading to extensive electron delocalization over the planar square and significant stabilization. This bonding pattern of the tetranuclear silver cluster represents an aromatic all-metal structure that follows a 4n + 2 electron counting rule (n = 0). This is the first time an all-metal aromatic silver cluster was observed in a protein.

Metal clusters, such as iron–sulfur clusters, play key roles in sustaining life and are intimately involved in the functions of metalloproteins.     

High-performance potassium poly(heptazine imide) films for photoelectrochemical water splitting

Photoelectrochemical (PEC) water splitting is an appealing approach by which to convert solar energy into hydrogen fuel. Polymeric semiconductors have recently attracted intense interest of many scientists for PEC water splitting. The crystallinity of polymer films is regarded as the main factor that determines the conversion efficiency. Herein, potassium poly(heptazine) imide (K-PHI) films with improved crystallinity were in situ prepared on a conductive substrate as a photoanode for solar-driven water splitting. A remarkable photocurrent density of ca. 0.80 mA cm⁻² was achieved under air mass 1.5 global illumination without the use of any sacrificial agent, a performance that is ca. 20 times higher than that of the photoanode in an amorphous state, and higher than those of other related polymeric photoanodes. The boosted performance can be attributed to improved charge transfer, which has been investigated using steady state and operando approaches. This work elucidates the pivotal importance of the crystallinity of conjugated polymer semiconductors for PEC water splitting and other advanced photocatalytic applications.

Potassium poly(heptazine imide) photoanode is synthesized, and owing to the improved crystallinity, it has presented a remarkable performance for solar-driven water splitting.     

Metabolic Engineering of Shikimic Acid Biosynthesis Pathway for the Production of Shikimic Acid and Its Branched Products in Microorganisms: Advances and Prospects

The shikimate pathway is a necessary pathway for the synthesis of aromatic compounds. The intermediate products of the shikimate pathway and its branching pathway have promising properties in many fields, especially in the pharmaceutical industry. Many important compounds, such as shikimic acid, quinic acid, chlorogenic acid, gallic acid, pyrogallol, catechol and so on, can be synthesized by the shikimate pathway. Among them, shikimic acid is the key raw material for the synthesis of GS4104 (Tamiflu^®), an inhibitor of neuraminidase against avian influenza virus. Quininic acid is an important intermediate for synthesis of a variety of raw chemical materials and drugs. Gallic acid and catechol receive widespread attention as pharmaceutical intermediates. It is one of the hotspots to accumulate many kinds of target products by rationally modifying the shikimate pathway and its branches in recombinant strains by means of metabolic engineering. This review considers the effects of classical metabolic engineering methods, such as central carbon metabolism (CCM) pathway modification, key enzyme gene modification, blocking the downstream pathway on the shikimate pathway, as well as several expansion pathways and metabolic engineering strategies of the shikimate pathway, and expounds the synthetic biology in recent years in the application of the shikimate pathway and the future development direction.     

Activation of Stimulation of Interferon Genes (STING) Signal and Cancer Immunotherapy

Stimulator of interferon gene (STING), an intracellular receptor in the endoplasmic reticulum, could induce the production of cytokines such as type I interferon (IFN) by activating the cGAS-STING signal pathway. In recent years, activation of STING has shown great potential to enhance anti-tumor immunity and reshape the tumor microenvironment, which is expected to be used in tumor immunotherapy. A number of STING agonists have demonstrated promising biological activity and showed excellent synergistic anti-tumor effects in combination with other cancer therapies in preclinical studies and some clinical trials. The combination of STING agonists and ICI also showed a potent effect in improving anti-tumor immunity. In this review, we introduce the cGAS-STING signaling pathway and its effect in tumor immunity and discuss the recent strategies of activation of the STING signaling pathway and its research progress in tumor immunotherapy.     

Optimized Selection of Water Resource Allocation Schemes Based on Improved Connection Entropy in Beijing’s Southern Plain

Increased urbanization has caused problems such as increasing water consumption and the continuous deterioration of the groundwater environment. It is necessary to consider the groundwater quality in the water resource optimization system and increase the rate of reclaimed water development to reduce the amount of groundwater exploitation and achieve sustainable development of water resources. This study used the Daxing District, a region of Beijing’s southern plain, as an example to evaluate water quality by analyzing water quality data of surface and groundwater from 2012 to 2016 and actual water-use schemes from 2006 to 2016. Three groundwater extraction modes were set up based on NO₃–N concentrations, water resources were optimized under three extraction modes, and water resource optimization schemes were determined based on the improved connection entropy. The results show that (1) the surface water quality was poor, and the proportion of V₄ type water in the indexes of NH₃–N and chemical oxygen demand (COD) was the largest. The surface water can only be used for agricultural irrigation. The pollution sources contributing most to NH₃–N and COD were domestic and agricultural pollution sources. (2) The groundwater quality was good. The NO₃–N index was primarily type I–III water, accounting for 95.20% of the total samples. Severe NH₃–N pollution areas were mainly in the northern region, and most regional groundwater can be used for various purposes. (3) Taking 2016 as an example, three groundwater exploitation modes were set to optimize water resource allocation, and the results showed that the rate of groundwater development and NO₃–N pollution decreased significantly after optimization. (4) Connection entropy is an evaluation method that combines connection numbers and entropy, including identify, difference, and opposition entropy. As connection entropy being a kind of complete entropy, which can reflect the difference of the system in different states, based on the improved connection entropy, the connection entropies of optimal water resource allocation and actual water-use schemes were calculated. The connection entropy of groundwater exploitation mode 3 was less than that of groundwater exploitation modes 1 and 2 and actual water-use schemes from 2006 to 2016. Therefore, exploitation mode 3’s water resource optimization scheme was recommended. In the paper, satisfactory results have been obtained. As a kind of complete entropy, connection entropy has great research value in dealing with complex hydrological problems. This study’s research methods and outcomes can provide methodological and theoretical lessons for water management in freshwater-deficient areas.     

Electrochemical Immunoassay for Tumor Marker CA19-9 Detection Based on Self-Assembled Monolayer

A CA19-9 electrochemical immunosensor was constructed using a hybrid self-assembled membrane modified with a gold electrode and applied to detect real samples. Hybrid self-assembled membranes were selected for electrode modification and used to detect antigens. First, the pretreated working electrodes were placed in a 3-mercaptopropionic acid (MPA)/β-mercaptoethanol (ME) mixture for 24 h for self-assembly. The electrodes were then placed in an EDC/NHS mixture for 1 h. Layer modification was performed by stepwise dropwise addition of CA19-9 antibody, BSA, and antigen. Differential pulse voltammetry was used to characterize this immunosensor preparation process. The assembled electrochemical immunosensor enables linear detection in the concentration range of 0.05–500 U/mL of CA19-9, and the detection limit was calculated as 0.01 U/mL. The results of the specificity measurement test showed that the signal change of the interfering substance was much lower than the response value of the detected antigen, indicating that the sensor has good specificity and strong anti-interference ability. The repeatability test results showed that the relative standard deviations were less than 5%, showing good accuracy and precision. The CA19-9 electrochemical immunosensor was used for the actual sample detection, and the experimental results of the standard serum addition method showed that the RSD values of the test concentrations were all less than 10%. The recoveries were 102.4–115.0%, indicating that the assay has high precision, good accuracy, and high potential application value.     

Deep Multilabel Multilingual Document Learning for Cross-Lingual Document Retrieval

Cross-lingual document retrieval, which aims to take a query in one language to retrieve relevant documents in another, has attracted strong research interest in the last decades. Most studies on this task start with cross-lingual comparisons at the word level and then represent documents via word embeddings, which leads to insufficient structure information. In this work, the cross-lingual comparison at the document level is achieved through the cross-lingual semantic space. Our method, MDL (deep multilabel multilingual document learning), leverages a six-layer fully connected network to project cross-lingual documents into a shared semantic space. The semantic distances can be calculated when the cross-lingual documents are transformed into embeddings in semantic space. The supervision signals are automatically extracted from the data and then used to construct the semantic space via a linear classifier. The ambiguity of manual labels could be avoided and the multilabel supervision signals can be acquired instead of a single label. The representation of the semantic space is enriched by multilabel supervision signals, which improves the discriminative ability of the embeddings. The MDL is easy to extend to other fields since it does not depend on specific data. Furthermore, MDL is more efficient than the models training all languages jointly, since each language is trained individually. Experiments on Wikipedia data showed that the proposed method outperforms the state-of-the-art cross-lingual document retrieval methods.