Diterpenoids from the Aerial Parts of Isodon serra with Selective Cytotoxic Activity.

Four new diterpenoids, isodosins A-D (1-4), together with nine known compounds (5-13) were isolated and identified from the aerial parts of Isodon serra (Maxim.) Hara. The structures of the new diterpenoids were elucidated based on the analysis of HR-ESI-MS data, 1D/2D-NMR-spectroscopic data, and electronic circular dichroism (ECD) calculations. Cytotoxicities of compounds 2, 3, 5, 6, and 9 against the HepG2 and H1975 cell lines were evaluated with the MTT assay. As a result, compounds 2, 3, and 6 revealed higher levels of cytotoxicity against HepG2 cells than against H1975 cells. Moreover, compund 6 demonstrated the most efficacy in inhibiting the proliferation of HepG2 cells, with an IC50 value of 41.13 ± 3.49 µM. This effect was achieved by inducing apoptosis in a dose-dependent manner. Furthermore, the relationships between the structures and activities of these compounds are briefly discussed.

SOSTDC1 Nuclear Translocation Facilitates BTIC Maintenance and CHD1-Mediated HR Repair to Promote Tumor Progression and Olaparib Resistance in TNBC.

Breast tumor-initiating cells (BTICs) of triple-negative breast cancer (TNBC) tissues actively repair DNA and are resistant to treatments including chemotherapy, radiotherapy, and targeted therapy. Herein, it is found that a previously reported secreted protein, sclerostin domain containing 1 (SOSTDC1), is abundantly expressed in BTICs of TNBC cells and positively correlated with a poor patient prognosis. SOSTDC1 knockdown impairs homologous recombination (HR) repair, BTIC maintenance, and sensitized bulk cells and BTICs to Olaparib. Mechanistically, following Olaparib treatment, SOSTDC1 translocates to the nucleus in an importin-α dependent manner. Nuclear SOSTDC1 interacts with the N-terminus of the nucleoprotein, chromatin helicase DNA-binding factor (CHD1), to promote HR repair and BTIC maintenance. Furthermore, nuclear SOSTDC1 bound to ß-transducin repeat-containing protein (ß-TrCP) binding motifs of CHD1 is found, thereby blocking the ß-TrCP-CHD1 interaction and inhibiting ß-TrCP-mediated CHD1 ubiquitination and degradation. Collectively, these findings identify a novel nuclear SOSTDC1 pathway in regulating HR repair and BTIC maintenance, providing insight into the TNBC therapeutic strategies.

IL1R2 Blockade Alleviates Immunosuppression and Potentiates Anti-PD-1 Efficacy in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options. IL1 receptor type 2 (IL1R2) promotes breast tumor-initiating cell (BTIC) self-renewal and tumor growth in TNBC, indicating that targeting it could improve patient treatment. In this study, we observed that IL1R2 blockade strongly attenuated macrophage recruitment and the polarization of tumor-associated macrophages (TAM) to inhibit BTIC self-renewal and CD8+ T-cell exhaustion, which resulted in reduced tumor burden and prolonged survival in TNBC mouse models. IL1R2 activation by TAM-derived IL1ß increased PD-L1 expression by interacting with the transcription factor Yin Yang 1 (YY1) and inducing YY1 ubiquitination and proteasomal degradation in both TAMs and TNBC cells. Loss of YY1 alleviated the transcriptional repression of c-Fos, which is a transcriptional activator of PDL-1. Combined treatment with an IL1R2-neutralizing antibodies and anti-PD-1 led to enhanced antitumor efficacy and reduced TAMs, BTICs, and exhausted CD8+ T cells. These results suggest that IL1R2 blockade might be a strategy to potentiate immune checkpoint blockade efficacy in TNBC to improve patient outcomes. Significance: IL1R2 in both macrophages and breast cancer cells orchestrates an immunosuppressive tumor microenvironment by upregulating PD-L1 expression and can be targeted to enhance the efficacy of anti-PD-1 in triple-negative breast cancer.

Enhanced dewaterability and triclosan removal of waste activated sludge with iron-rich mineral-activated peroxymonosulfate.

High water and pharmaceutical and care products (PPCPs) bounded in sludge flocs limit its utilization and disposal. The advanced oxidation process of perxymonosulfate (PMS) catalyzed by iron salts has been widely used in sludge conditioning. In this study, two iron-rich minerals pyrite and siderite were proposed to enhance sludge dewatering performance and remove the target contaminant of triclosan (TCS). The permanent release of Fe2+ in the activation of PMS made siderite more effective in enhancing sludge dewater with capillary suction time (CST) diminishing by 60.5 %, specific resistance to filtration (SRF) decreasing by 79.2 %, and bound water content (BWC) dropping from 37.1 % to 2.6 % at siderite/PMS dosages of 0.36/0.20 mmol/g-TSS after 20 min of pretreatment. Pyrite/PMS performed slightly inferior under the same conditions and the corresponding CST and SRF decreased by 51.5 % and 71.8 % while the BWC only declined to 17.8 %. Rheological characterization was employed to elucidate the changes in sludge dewatering performance, with siderite/PMS treated sludge showing a 48.3 % reduction in thixotropy, higher than 28.4 % of pyrite/PMS. Oscillation and creep tests further demonstrated the significantly weakened viscoelastic behavior of the sludge by siderite/PMS pretreatment. For TCS mineralization removal, siderite/PMS achieved a high removal efficiency of 43.9 %, in comparison with 39.9 % for pyrite/PMS. The reduction in the sludge solids phase contributed the most to the TCS removal. Free radical quenching assays and EPR spectroscopy showed that both siderite/PMS and pyrite/PMS produced SO4-·  and ·OH, with the latter acting as the major radicals. Besides, the dosage of free radicals generated from siderite/PMS exhibited a lower time-dependence, which also allowed it to outperform in destroying EPS matrix, neutralizing the negative Zeta potential of sludge flocs, and mineralizing macromolecular organic matter.

Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1.

Tumor-resident microbiota in breast cancer promotes cancer initiation and malignant progression. However, targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail. Here, we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis (ETBF) was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy. ETBF, albeit at low biomass, secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance. Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein. NOD1 was highly expressed on ALDH+ breast cancer stem cells (BCSCs) and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation, thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs. NOD1 inhibition and ETBF clearance increase the chemosensitivity of breast cancer by impairing BCSCs.

Gradual conductance modulation by defect reorganization in amorphous oxide memristors.

Amorphous oxides show great prospects in revolutionizing memristors benefiting from their abundant non-stoichiometric composition. However, an in-depth investigation of the memristive characteristics in amorphous oxides is inadequate and the resistive switching mechanism is still controversial. In this study, aiming to clearly understand the gradual conductance modulation that is deeply bound to the evolution of defects-mainly oxygen vacancies, forming-free memristors based on amorphous ZnAlSnO are fabricated, which exhibit high reproducibility with an initial low-resistance state. Pulse depression reveals the logarithmic-exponential mixed relaxation during RESET owing to the diffusion of oxygen vacancies in orthogonal directions. The remnants of conductive filaments formed through aggregation of oxygen vacancies induced by high-electric-field are identified using ex situ TEM. Especially, the conductance of the filament, including the remnant filament, is larger than that of the hopping conductive channel derived from the diffusion of oxygen vacancies. The Fermi level in the conduction band rationalizes the decay of the high resistance state. Rare oxidation-migration of Au occurs upon device failure, resulting in numerous gold nanoclusters in the functional layer. These comprehensive revelations on the reorganization of oxygen vacancies could provide original ideas for the design of memristors.

Impact of sandwich-type composite anodic membrane on membrane fouling and methane recovery from sewage sludge and food waste via electrochemical anaerobic membrane bioreactor.

Membrane fouling presents a big challenge for the real-world implementation of anaerobic membrane bioreactors (AnMBRs) in digesting high-solid biowastes. In this study, an electrochemical anaerobic membrane bioreactor (EC-AnMBR) with a novel sandwich-type composite anodic membrane was designed and constructed for controlling membrane fouling whilst improving the energy recovery. The results showed that EC-AnMBR produced a higher methane yield of 358.5 ± 74.8 mL/d, rising by 12.8% compared to the AnMBR without applied voltage. Integration of composite anodic membrane induced a stable membrane flux and low transmembrane pressure through forming an anodic biofilm while total coliforms removal reached 97.9%. The microbial community analysis further provided compelling evidence that EC-AnMBR enriched the relative abundance of hydrolyzing (Chryseobacterium 2.6%) bacteria and methane-producing (Methanobacterium 32.8%) archaea. These findings offered new insights into anti-biofouling performance and provided significant implications for municipal organic waste treatment and energy recovery in the new EC-AnMBR.

Aldehyde dehydrogenase in solid tumors and other diseases: Potential biomarkers and therapeutic targets.

The family of aldehyde dehydrogenases (ALDHs) contains 19 isozymes and is involved in the oxidation of endogenous and exogenous aldehydes to carboxylic acids, which contributes to cellular and tissue homeostasis. ALDHs play essential parts in detoxification, biosynthesis, and antioxidants, which are of important value for cell proliferation, differentiation, and survival in normal body tissues. However, ALDHs are frequently dysregulated and associated with various diseases like Alzheimer's disease, Parkinson's disease, and especially solid tumors. Notably, the involvement of the ALDHs in tumor progression is responsible for the maintenance of the stem-cell-like phenotype, triggering rapid and aggressive clinical progressions. ALDHs have captured increasing attention as biomarkers for disease diagnosis and prognosis. Nevertheless, these require further longitudinal clinical studies in large populations for broad application. This review summarizes our current knowledge regarding ALDHs as potential biomarkers in tumors and several non-tumor diseases, as well as recent advances in our understanding of the functions and underlying molecular mechanisms of ALDHs in disease development. Finally, we discuss the therapeutic potential of ALDHs in diseases, especially in tumor therapy with an emphasis on their clinical implications.

Optoelectronic Artificial Synaptic Device Based on Amorphous InAlZnO Films for Learning Simulations.

Neuromorphic computing, which mimics brain function, can address the shortcomings of the "von Neumann" system and is one of the critical components of next-generation computing. The use of light to stimulate artificial synapses has the advantages of low power consumption, low latency, and high stability. We demonstrate amorphous InAlZnO-based light-stimulated artificial synaptic devices with a thin-film transistor structure. The devices exhibit fundamental synaptic properties, including excitatory postsynaptic current, paired-pulse facilitation (PPF), and short-term plasticity to long-term plasticity conversion under light stimulation. The PPF index stimulated by 375 nm light is 155.9% when the time interval is 0.1 s. The energy consumption of each synaptic event is 2.3 pJ, much lower than that of ordinary MOS devices and other optical-controlled synaptic devices. The relaxation time constant reaches 277 s after only 10 light spikes, which shows the great synaptic plasticity of the device. In addition, we simulated the learning-forgetting-relearning-forgetting behavior and learning efficiency of human beings under different moods by changing the gate voltage. This work is expected to promote the development of high-performance optoelectronic synaptic devices for neuromorphic computing.

Prognostic analysis and validation of diagnostic marker genes in patients with osteoporosis.

Backgrounds: As a systemic skeletal dysfunction, osteoporosis (OP) is characterized by low bone mass and bone microarchitectural damage. The global incidences of OP are high. Methods: Data were retrieved from databases like Gene Expression Omnibus (GEO), GeneCards, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Gene Expression Profiling Interactive Analysis (GEPIA2), and other databases. R software (version 4.1.1) was used to identify differentially expressed genes (DEGs) and perform functional analysis. The Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression and random forest algorithm were combined and used for screening diagnostic markers for OP. The diagnostic value was assessed by the receiver operating characteristic (ROC) curve. Molecular signature subtypes were identified using a consensus clustering approach, and prognostic analysis was performed. The level of immune cell infiltration was assessed by the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm. The hub gene was identified using the CytoHubba algorithm. Real-time fluorescence quantitative PCR (RT-qPCR) was performed on the plasma of osteoporosis patients and control samples. The interaction network was constructed between the hub genes and miRNAs, transcription factors, RNA binding proteins, and drugs. Results: A total of 40 DEGs, eight OP-related differential genes, six OP diagnostic marker genes, four OP key diagnostic marker genes, and ten hub genes (TNF, RARRES2, FLNA, STXBP2, EGR2, MAP4K2, NFKBIA, JUNB, SPI1, CTSD) were identified. RT-qPCR results revealed a total of eight genes had significant differential expression between osteoporosis patients and control samples. Enrichment analysis showed these genes were mainly related to MAPK signaling pathways, TNF signaling pathway, apoptosis, and Salmonella infection. RT-qPCR also revealed that the MAPK signaling pathway (p38, TRAF6) and NF-kappa B signaling pathway (c-FLIP, MIP1ß) were significantly different between osteoporosis patients and control samples. The analysis of immune cell infiltration revealed that monocytes, activated CD4 memory T cells, and memory and naïve B cells may be related to the occurrence and development of OP. Conclusions: We identified six novel OP diagnostic marker genes and ten OP-hub genes. These genes can be used to improve the prognostic of OP and to identify potential relationships between the immune microenvironment and OP. Our research will provide insights into the potential therapeutic targets and pathogenesis of osteoporosis.

miR-27b attenuates dexamethasone-inhibited proliferation and osteoblastic differentiation in MC3T3-E1 cells by targeting PPARγ2.

Osteoporosis is a metabolic bone illness characterized by low bone density and a high risk of fracture. It is estimated that there are >60 million individuals in China suffering from this disease, which highlights an urgent requirement for the development of novel and safe drugs for the long-term treatment of osteoporosis. MicroRNAs (miRNAs/miRs) have previously been identified as critical regulators in the progression of osteoporosis. As an intronic miRNA, miR-27b enhances the osteoblastic differentiation of stem cells from the bone marrow and the maxillary sinus membrane. However, the mechanism underlying miR-27b in osteoporosis remains to be elucidated. In the present study, MC3T3-E1 pre-osteoblasts were treated with dexamethasone (DEX) to establish an in vitro model of osteoporosis. The results of the present study demonstrated that DEX treatment markedly inhibited the viability of MC3T3-E1 cells, and downregulated the expression level of miR-27b. The results of reverse transcription-quantitative PCR, western blotting and dual-luciferase assays revealed that miR-27b directly regulated and suppressed the expression of peroxisome proliferator-activated receptor γ2 (PPARγ2) in MC3T3-E1 cells. Furthermore, overexpression of miR-27b by transfection of cells with miR-27b mimic attenuated DEX-mediated inhibition of cell viability, alkaline phosphatase (ALP) activity and the expression levels of bone morphogenetic protein-2 (BMP2), runt-related protein 2 (Runx2) and osteocalcin (OCN). The results of the present study indicated that miR-27b alleviated DEX-inhibited proliferation and osteoblastic differentiation. Moreover, miR-27b knockdown repressed MC3T3-E1 cell viability, ALP activity and protein levels of BMP2, Runx2 and OCN. However, these effects were abrogated by small interfering RNA-mediated PPARγ2 silencing. In conclusion, the results of the present study demonstrated that miR-27b attenuated DEX-inhibited proliferation and osteoblastic differentiation in MC3T3-E1 pre-osteoblasts by targeting PPARγ2.

Supervised Learning Achieves Human-Level Performance in MOBA Games: A Case Study of Honor of Kings.

We present JueWu-SL, the first supervised-learning-based artificial intelligence (AI) program that achieves human-level performance in playing multiplayer online battle arena (MOBA) games. Unlike prior attempts, we integrate the macro-strategy and the micromanagement of MOBA-game-playing into neural networks in a supervised and end-to-end manner. Tested on Honor of Kings, the most popular MOBA at present, our AI performs competitively at the level of High King players in standard 5v5 games.

A longitudinal observational retrospective study on risk factors and predictive model of PICC associated thrombosis in cancer patients.

To analyze the incidence of PICC associated venous thrombosis. To predict the risk factors of thrombosis. To validate the best predictive model in predicting PICC associated thrombosis. Consecutive oncology cases in 341 who initially naive intended to be inserted central catheter for chemotherapy, were recruited to our dedicated intravenous lab. All patients used the same gauge catheter, Primary endpoint was thrombosis formation, the secondary endpoint was infusion termination without thrombosis. Two patients were excluded. 339 patients were divided into thrombosis group in 59 (17.4%) and non-thrombosis Group in 280 (82.6%), retrospectively. Tumor, Sex, Age, Weight, Height, BMI, BSA, PS, WBC, BPC, PT, D-dimer, APTT, FIB, Smoking history, Location, Catheter length, Ratio and Number as independent variables were analyzed by Fisher's scoring, then Logistic risk regression, ROC analysis and nomogram was introduced. Total incidence was 17.4%. Venous mural thrombosis in 2 (3.4%), "fibrin sleeves" in 55 (93.2%), mixed thrombus in 2 (3.4%), symptomatic thrombosis in 2 (3.4%), asymptomatic thrombosis in 57 (96.6%), respectively. Height (χ² = 4.48, P = 0.03), D-dimer (χ² = 37.81, P < 0.001), Location (χ² = 7.56, P = 0.006), Number (χ² = 43.64, P < 0.001), Ratio (χ² = 4.38, P = 0.04), and PS (χ² = 58.78, P < 0.001), were statistical differences between the two groups analyzed by Fisher's scoring. Logistic risk regression revealed that Height (ß = -0.05, HR = 0.95, 95%CI: 0.911-0.997, P = 0.038), PS (ß = 1.07, HR = 2.91, 95%CI: 1.98-4.27, P < 0.001), D-dimer (ß0.11, HR = 1.12, 95%CI: 1.045-1.200, P < 0.001), Number (ß = 0.87, HR = 2.38, 95% CI: 1.619-3.512, P < 0.001) was independently associated with PICC associated thrombosis. The best prediction model, D-dimer + Number as a novel co-variable was validated in diagnosing PICC associated thrombosis before PICC. Our research revealed that variables PS, Number, D-dimer and Height were risk factors for PICC associated thrombosis, which were slightly associated with PICC related thrombosis, in which, PS was the relatively strongest independent risk factor of PICC related thrombosis.

Co-pyrolysis of microalgae with low-density polyethylene (LDPE) for deoxygenation and denitrification.

To upgrade the algae pyrolytic oil, the influence of algae components on co-pyrolysis with LDPE were studied, with Spirulina platensis (SP), Nannochloropsis sp. (NS) and Enteromorpha Prolifera (EP) as typical algae samples, as they are enriched with proteins, lipids and carbohydrate, respectively, especially, the N and O transformation behavior during the co-pyrolysis was studied in depth. During co-pyrolysis, the interaction on products depended on the components of algae. EP and SP were prior to form CO2, rather than CO. For pyrolytic oil, co-pyrolysis effectively inhibited the formation of N- and O-compounds, but promoted the generation of long-chain alcohol and formic/acetic ester. And the obvious decrease of N and O content in co-pyrolytic oil was observed. However, the rich lipids in NS resulted in the improvement of N yield in pyrolytic oil during co-pyrolysis.

SIRT 1 Overexpression is Associated with Metastasis of Pancreatic Ductal Adenocarcinoma (PDAC) and Promotes Migration and Growth of PDAC Cells.

BACKGROUND SIRT 1, as a class III histone deacetylase (HDAC), is implicated in the initiation and progression of malignancies. However, the association of SIRT 1 with tumorigenesis or progression of pancreatic ductal adenocarcinoma (PDAC) is not clear. MATERIAL AND METHODS In our study we investigated SIRT 1 expression in PDAC samples and evaluated the association of SIRT 1 level with the clinical and pathological characteristics of PDAC patients. We investigated the role of SIRT 1 in the migration and growth of PDAC PANC-1 or BxPC-3 cells using gain-of-function and loss-of-function approach. RESULTS We demonstrated that SIRT 1 mRNA level was significantly promoted in intra-tumor tissues compared to peri-tumor tissues of PDAC; and SIRT 1 overexpression was markedly associated with distant or lymph node (LN) metastasis of these PDAC tissues. Moreover, the in vitro wound healing assay demonstrated that SIRT 1 overexpression with lentivirus vector markedly promoted the migration of PANC-1 or BxPC-3 cells, whereas SIRT 1 knockdown using SIRT 1 specific siRNA transfection significantly inhibited the migration of PDAC cells. The colony forming assay confirmed SIRT 1 promotion of the growth of PANC-1 or BxPC-3 cells. CONCLUSIONS In summary, SIRT 1 overexpression is significantly associated with metastasis of PDAC, and overexpressed SIRT 1 plays an important role in pancreatic cancer cell migration and growth. Our data warrants further studies on SIRT 1 as a novel chemotherapeutic target in PDAC.

miR-155 inhibitor reduces the proliferation and migration in osteosarcoma MG-63 cells.

As the most common malignant primary bone tumor in childhood, osteosarcoma (OS) maintains a high recurrence, despite the significant improvements in the overall survival rate of high-grade OS patients during the recent decades. Therefore, a novel therapy strategy is required for OS treatment. Recently, various microRNAs (miRNAs or miRs) have been confirmed as deregulated in OS, and the miR-155 dysregulation in OS has been discovered by the microarray analysis. In the present study, the regulation of miR-155 on the OS cell proliferation, migration and invasion on the MG-63 cells was explored in vitro. The miR-155 mimics were found to promote cell proliferation, colony formation, migration and invasion significantly, compared to the control miRNA. An miR-155 inhibitor was also used to evaluate whether miR-155 served as a therapeutic target for OS. The results demonstrated that the miR-155 inhibitor significantly reduced the proliferation, colony formation, migration and invasion of the MG-63 OS cells. Thus, the study confirmed the oncogenic regulation on the OS progression of miR-155, which could serve as a therapeutic target with an miR-155 inhibitor.