Targeting UBE2T Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Regulating Pyrimidine Metabolism and Replication Stress.

BACKGROUND & AIMS: Although small patient subsets benefit from current targeted strategies or immunotherapy, gemcitabine remains the first-line drug for pancreatic cancer (PC) treatment. However, gemcitabine resistance is widespread and compromises long-term survival. Here, we identified ubiquitin-conjugating enzyme E2T (UBE2T) as a potential therapeutic target to combat gemcitabine resistance in PC. METHODS: Proteomics and metabolomics were combined to examine the effect of UBE2T on pyrimidine metabolism remodeling. Spontaneous PC mice (LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre; KPC) with Ube2t-conditional knockout, organoids, and large-scale clinical samples were used to determine the effect of UBE2T on gemcitabine efficacy. Organoids, patient-derived xenografts (PDX), and KPC mice were used to examine the efficacy of the combination of a UBE2T inhibitor and gemcitabine. RESULTS: Spontaneous PC mice with Ube2t deletion had a marked survival advantage after gemcitabine treatment, and UBE2T levels were positively correlated with gemcitabine resistance in clinical patients. Mechanistically, UBE2T catalyzes ring finger protein 1 (RING1)-mediated ubiquitination of p53 and relieves the transcriptional repression of ribonucleotide reductase subunits M1 and M2, resulting in unrestrained pyrimidine biosynthesis and alleviation of replication stress. Additionally, high-throughput compound library screening using organoids identified pentagalloylglucose (PGG) as a potent UBE2T inhibitor and gemcitabine sensitizer. The combination of gemcitabine and PGG diminished tumor growth in PDX models and prolonged long-term survival in spontaneous PC mice. CONCLUSIONS: Collectively, UBE2T-mediated p53 degradation confers PC gemcitabine resistance by promoting pyrimidine biosynthesis and alleviating replication stress. This study offers an opportunity to improve PC survival by targeting UBE2T and develop a promising gemcitabine sensitizer in clinical translation setting.

Radiofrequency radiation reshapes tumor immune microenvironment into antitumor phenotype in pulmonary metastatic melanoma by inducing active transformation of tumor-infiltrating CD8+ T and NK cells.

Immunosuppression by the tumor microenvironment is a pivotal factor contributing to tumor progression and immunotherapy resistance. Priming the tumor immune microenvironment (TIME) has emerged as a promising strategy for improving the efficacy of cancer immunotherapy. In this study we investigated the effects of noninvasive radiofrequency radiation (RFR) exposure on tumor progression and TIME phenotype, as well as the antitumor potential of PD-1 blockage in a model of pulmonary metastatic melanoma (PMM). Mouse model of PMM was established by tail vein injection of B16F10 cells. From day 3 after injection, the mice were exposed to RFR at an average specific absorption rate of 9.7 W/kg for 1 h per day for 14 days. After RFR exposure, lung tissues were harvested and RNAs were extracted for transcriptome sequencing; PMM-infiltrating immune cells were isolated for single-cell RNA-seq analysis. We showed that RFR exposure significantly impeded PMM progression accompanied by remodeled TIME of PMM via altering the proportion and transcription profile of tumor-infiltrating immune cells. RFR exposure increased the activation and cytotoxicity signatures of tumor-infiltrating CD8+ T cells, particularly in the early activation subset with upregulated genes associated with T cell cytotoxicity. The PD-1 checkpoint pathway was upregulated by RFR exposure in CD8+ T cells. RFR exposure also augmented NK cell subsets with increased cytotoxic characteristics in PMM. RFR exposure enhanced the effector function of tumor-infiltrating CD8+ T cells and NK cells, evidenced by increased expression of cytotoxic molecules. RFR-induced inhibition of PMM growth was mediated by RFR-activated CD8+ T cells and NK cells. We conclude that noninvasive RFR exposure induces antitumor remodeling of the TIME, leading to inhibition of tumor progression, which provides a promising novel strategy for TIME priming and potential combination with cancer immunotherapy.

Life cycle assessment perspective on waste resource utilization and sustainable development: A case of glyphosate production.

The growing demand for pesticide manufacturing and increasing public awareness of sustainable development, have let to urgent requirements for a refined environmental management framework. It is imperative to conduct process-based life cycle assessments (LCAs) to promote clean and environment-friendly technologies. Herein, the cradle-to-gate LCA of glyphosate production was executed as an example to investigate crucial production factors (materials or energy) and multiple environmental impacts during the production processes. Results showed that methanol caused the highest environmental damage in terms of toxicity, with a normalized value of 85.7 × 10-8, followed by coal-fired electricity in 6.00 × 10-8. Furthermore, optimized schemes were proposed, including energy improvement (electricity generated by switching from coal-fired power to solar power) and wastewater targeted conversion. Regarding the normalization results before and after optimization, the latter showed more significant results with the normalized value decreasing by 21.10 × 10-8, while that of the former only decreased by 6.50 × 10-8. This study provides an integrated LCA framework for organophosphorus pesticides (OPs) from upstream control and offers an important supplement to managing the key pollution factors and control links of the OP industry. Moreover, it reveals the positive influence of optimized schemes in facilitating cleaner production technologies, thus ultimately promoting new methodologies for resource recycling.

Wound infection and healing in minimally invasive plate osteosynthesis compared with intramedullary nail for distal tibial fractures: A meta-analysis.

To systematically explore the effects of minimally invasive plate osteosynthesis (MIPO) versus intramedullary nail (IMN) on wound infection and wound healing in patients with distal tibia fractures. A computerised search of PubMed, Web of Science, Cochrane Library, Embase, Wanfang, China Biomedical Literature Database (CBM) and China National Knowledge Infrastructure databases was performed, from their inception to October 2023, to identify relevant studies on the application of MIPO and IMN in patients with distal tibial fractures. The quality of the included literature was evaluated by two researchers based on inclusion and exclusion criteria, and basic information of the literature was collected, with wound infection, postoperative complications and wound healing time as the main indicators for analysis. Stata 17.0 software was applied for analysis. Overall, 23 papers and 2099 patients were included, including 1026 patients in the MIPO group and 1073 patients in the IMN group. The results revealed, when compared with IMN treatment, patients with distal tibia fractures who underwent MIPO treatment had a lower incidence of postoperative complications (OR = 0.33, 95% CI: 0.25-0.42, p < 0.001) and a shorter wound healing time (SMD = -1.00, 95% CI: -1.51 to -0.49, p < 0.001), but the incidence of postoperative wound infection was higher (OR = 2.01, 95% CI: 1.35-3.01, p = 0.001). Both MIPO and IMN are excellent treatments for distal tibia fractures. MIPO is effective in reducing the incidence of complications as well as shortening the time of wound healing time but increases the risk of wound infection. In clinical practice, surgeons can make individual choices based on the patient's wishes and proficiency in both techniques.

Visible-Light-Promoted Cyanoalkylation/Cyclization Cascade Reaction to Assemble Polyheterocycles in Continuous Flow.

This study describes a visible-light-induced cascade reaction for preparing cyanoalkyl-containing polyheterocycles initiated by the photoinduced radical cascade addition of N-arylacrylamide derivatives using cyclic oxime esters as radical sources followed by cyanoalkyl-mediated cyclization. This protocol features outstanding functional group compatibility, providing a variety of desired phenanthridine derivatives in moderate to good yields. Moreover, the application of a microflow technique enhanced these reactions compared with the equivalent batch reaction, significantly reducing reaction times to 10 min.

Exploring the role of PMEPA1 in gastric cancer.

Although there are several treatments available for gastric cancer (GC), the prognosis of the disease is still poor due to many factors, such as late diagnosis and tumor heterogeneity. To identify potential therapeutic targets, bioinformatics techniques and clinical sample validation were employed and prostate transmembrane protein androgen induced 1 (PMEPA1) was selected for further study. In the present study, we found that elevated PMEPA1 expression correlates with a worse prognosis and weaker anti-tumor immunity in GC patients. Moreover, our study showed that PMEPA1 not only influences cell proliferation, clone formation, invasion, and migration in vitro, but also plays an important role in GC progression in vivo. Mechanically, PMEPA1 exerts its oncogenic effects through activating the Wnt/ß-catenin signaling pathway. Therefore, PMEPA1 is a potential target for treating GC effectively.

Fine-Tuning Tridentate Ligands for the Construction of Nanotube-Based Boron Imidazolate Frameworks with High Chemical Stability.

Two unusual nanotube-based boron imidazolate frameworks (BIF-134 and BIF-135) were synthesized by a dual-ligand synthetic strategy under solvothermal conditions. In the structure of BIF-134 ([Co(BH(2-mim)3)(BTC)1/3](HBH(2-mim)3)1/3(NMA); 2-mim = 2-methylimidazole, NMA = N-methylacetamide, and BTC = 1,3,5-benzene tricarboxylate), one part of boron imidazolate ligands participate in the structural skeleton coordination, while another part of boron imidazolate ligands act as guest molecules that are located between adjacent nanotubes, which enhance the stability of the framework by the host-guest interaction and the pore space partition effects. It was found to be highly stable in air, water, organic solvents, and a wide pH range (pH 0-12). However, in the structure of BIF-135 ([Zn(BH(2-mim)3)(CHTC)1/3]; CHTC = 1,3,5-cyclohexanetricarboxylate), all boron imidazolate ligands participate in the structural skeleton coordination; there is no boron imidazolate guest molecule in the pores. The topology of BIF-135 is similar to that of BIF-134 by replacing BTC with CHTC and replacing Co with Zn. Furthermore, the obtained BIFs exhibited third-order nonlinear optical properties and potential optical limiting applications demonstrated by reverse saturable absorption.

Mussel-Inspired Multicomponent Codeposition Strategy toward Antibacterial and Lubricating Multifunctional Coatings on Bioimplants.

Bacterial infections and limited surface lubrication are the two key challenges for bioimplants in dynamic contact with tissues. However, the simultaneous lubricating and antibacterial properties of the bioimplants have rarely been investigated. In this work, we successfully developed a multifunctional coating with simultaneous antibacterial and lubricating properties for surface functionalization of bioimplant materials. The multifunctional coating was fabricated on a polyurethane (PU) substrate via polydopamine (PDA)-assisted multicomponent codeposition, containing polyethyleneimine (PEI) and trace amounts of copper (Cu) as synergistic antibacterial components and zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) as the lubricating component. The obtained PDA(Cu)/PEI/PMPC coating showed excellent antibacterial activity (antibacterial efficiency: ∼99%) to both Escherichia coli and Staphylococcus aureus compared with bare PU. The excellent antibacterial properties were attributed to the combined effect of anti-adhesion capability of hydrophilic PMPC and PEI and bactericidal activity of Cu in the coating. Meanwhile, the coefficient of friction of the coating was significantly decreased by ∼52% compared with bare PU owing to the high hydration feature of PMPC, suggesting the superior lubricating property. Furthermore, the PDA(Cu)/PEI/PMPC coating was highly biocompatible toward human umbilical vein endothelial cells demonstrated by in vitro cytotoxicity tests. This study not only contributes to the chemistry of PDA-assisted multicomponent codeposition but also provides a facile and practical way for rational design of multifunctional coatings for medical devices.

Induction of Chirality in Boron Imidazolate Frameworks: The Structure-Directing Effects of Substituents.

By enhancing steric hindrance of substituents on the imidazole ring, the fan-shaped molecule of a tridentate boron imidazolate ligand (KBH(2-ipim)3, 2-ipim = 2-isopropylimidazolate) with racemic chirality was obtained. Then, seven novel boron imidazolate frameworks (BIFs) were prepared by mixing KBH(2-ipim)3 ligands with various derivatives of benzene carboxylic acid under solvothermal conditions. All of these seven materials contain a ladder-like zinc-boron-imidazolate chain as a basic building block, and the ligand BH(2-ipim)3- exists in the same handedness in one chain. The structural variations are associated with the position of substituents of the auxiliary ligand. Of particular interest is the spontaneous resolution of BH(2-ipim)3- ligands into two independent enantiomorphous homochiral structures, BIF-131-S and BIF-131-R, which contain both a chiral chain and an absolute helix embedded in the nets.

NCAPH regulates gastric cancer progression through DNA damage response.

Gastric cancer (GC) is one of the most common devastating and deadly malignancies of the gastrointestinal tract in the world. GLOBOCAN data analysis showed that GC accounted for approximately 1,033,000 new cases of cancer and 78,200 deaths in 2018. Nonstructural maintenance of chromosomes (non-SMC) condensin I complex subunit H (NCAPH) is a regulatory subunit that encodes the non-SMC condensin I complex. Previous studies have demonstrated that NCAPH is highly expressed in multiple cancers. This study aimed to explore the function and potential mechanism of NCAPH in GC. Our study showed that NCAPH expression was significantly upregulated in The Cancer Genome Atlas (TCGA) and Oncomine datasets. Quantitative real-time polymerase chain reaction and western blotting were used to detect NCAPH expression in GC and paracarcinoma tissues. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to examine cell proliferation. Cell scratch and Transwell invasion assays were performed to assess cell migration. In addition, western blotting was used to detect the expression of proteins related to the cell cycle, DNA damage repair, and epithelial-mesenchymal transition (EMT). Flow cytometry was applied for cell cycle and apoptosis detection. A xenograft model was employed to assess the effect of NCAPH in vivo. The results demonstrated that NCAPH expression was significantly increased in GC tissue samples and cell lines. Knockout of NCAPH notably inhibited cell proliferation, cell migration, cell invasion, cell cycle progression, and tumor growth in vitro and in vivo, and induced the G1-phase cell cycle arrest by regulating the DNA damage response. In addition, knockout of NCAPH promoted cell apoptosis and regulated the expression of EMT-related proteins. The results indicate that the knockout of NCAPH in GC cells inhibits proliferation and metastasis via the DNA damage response in vitro and in vivo. NCAPH plays an important role in GC and may be a potential therapeutic target for GC treatment.

Separation and Purification of Two Saponins from Paris polyphylla var. yunnanensis by a Macroporous Resin.

An effective method for separating and purifying critical saponins (polyphyllin II and polyphyllin VII) from a Paris polyphylla var. yunnanensis extract was developed in this study which was environmentally friendly and economical. Static adsorption kinetics, thermodynamics, and the dynamic adsorption-desorption of macroporous resins were investigated, and then the conditions of purification and separation were optimized by fitting with an adsorption thermodynamics equation and a kinetic equation. Effective NKA-9 resin from seven macroporous resins was screened out to separate and purify the two saponins. The static adsorption and dynamic adsorption were chemical and physical adsorption dual-processes on the NKA-9 resin. Under the optimum parameters, the contents of polyphyllin II and polyphyllin VII in the product were 17.3-fold and 28.6-fold those in plant extracts, respectively. The total yields of the two saponins were 93.16%. This research thus provides a theoretical foundation for the large-scale industrial production of the natural drugs polyphyllin II and polyphyllin VII.

Electrochemical Tri- and Difluoromethylation-Triggered Cyclization Accompanied by the Oxidative Cleavage of Indole Derivatives.

Considering their unique roles in organic synthesis, and pharmaceutical and agrochemical applications, the development of fluoroalkylation, cyclization, and indole oxidative cleavage are important topics. Herein, an unprecedented electrochemical tri- and difluoromethylation/cyclization/indole oxidative cleavage process occurring in an undivided cell is presented. The protocol employs a readily prepared Langlois reagent as the fluoroalkyl source, affording a series of tri- or difluoromethylated 2-(2-acetylphenyl)isoquinoline-1,3-diones in good yields with excellent stereoselectivity. It is worth noting that this new methodology merges the fluoroalkylation/cyclization of N-substituted acrylamide alkenes with the oxidative cleavage of an indole C(2)=C(3) bond under external oxidant-free conditions.

Synthesis of a Boron-Imidazolate Framework Nanosheet with Dimer Copper Units for CO2 Electroreduction to Ethylene.

Fundamental understanding of the dependence between the structure and composition on the electrochemical CO2 reduction reaction (CO2 RR) would guide the rational design of highly efficient and selective electrocatalysts. A major impediment to the deep reduction CO2 to multi-carbon products is the complexity of carbon-carbon bond coupling. The chemically well-defined catalysts with atomically dispersed dual-metal sites are required for these C-C coupling involved processes. Here, we developed a catalyst (BIF-102NSs) that features Cl- bridged dimer copper (Cu2 ) units, which delivers high catalytic activity and selectivity for C2 H4 . Mechanistic investigation verifies that neighboring Cu monomers not only perform as regulator for varying the reaction barrier, but also afford distinct reaction paths compared with isolated monomers, resulting in greatly improved electroreduction performance for CO2 .

Supramolecular Co-assembly of the Ti8L12 Cube with [Ti(DMF)6] Species and Ti12-Oxo Cluster.

Titanium-based coordination cages are fascinating in the field of supramolecular and photophysical chemistry. Herein, we address the unprecedented supramolecular co-assembly arrangement of a cubic Ti8L12 cage with [Ti(DMF)6] species and Ti12-oxo cluster, contributing to the cocrystals of {Ti8L12 + Ti(DMF)6} (PTC-116) and {Ti8L12 + Ti12-oxo} (PTC-117). The ESI-MS and 1H NMR measurements reveal their stability in solution. The photophysical properties of these supramolecular complexes in solution, including light absorption and photoluminescent behaviors, were further investigated.

Synthesis of Supramolecular Boron Imidazolate Frameworks for CO2 Photoreduction.

Presented here are two novel porous supramolecular boron imidazolate frameworks (BIF-106 and BIF-107), which are stabilized through relatively weak interactions between two-dimensional boron imidazolate layers. Moreover, BIF-107 exhibits efficient CO2 photoreduction to CO with a remarkable rate of 1186.0 µmol·g-1·h-1 under visible-light irradiation.

Occurrence and human exposure assessment of organophosphate esters in atmospheric PM2.5 in the Beijing-Tianjin-Hebei region, China.

Organophosphate esters (OPEs) in atmospheric fine particles (PM2.5) were comprehensively investigated in the Beijing-Tianjin-Hebei (BTH) region from April 2016 to March 2017. The concentrations of Σ8OPEs in all the five sampling sites ranged from 90 to 8291 pg/m3 (mean 1148 ± 1239 pg/m3; median 756 pg/m3). The highest level (median 1067 pg/m3) was found at one of the urban sites in Beijing, followed by Tianjin (746 pg/m3) and Shijiazhuang (724 pg/m3). Tris(2-chloroethyl) phosphate (TCEP) and tri[(2R)-1-chloro-2-propyl] phosphate (TCPP) were the dominant compounds across the five sampling locations. Generally, the concentrations of chlorinated OPEs were relatively higher in summer than in winter (p < 0.05), but no significant seasonal difference was discovered for non-chlorinated individual OPEs. The concentrations of tri-n-butyl phosphate (TBP), TCEP, TCPP and triphenyl phosphate (TPP) were positively correlated with the meteorological parameters (i.e. temperature and relative humidity) (p < 0.05), indicating an evident influence of meteorological condition on OPE distribution. We observed a negative correlation (p < 0.05) between octanol-air partition coefficients (logKoa) and the ratio of PM2.5-bound OPE concentrations to total suspended particulates-bound OPE concentrations, suggesting that physicochemical properties affect the particle-size distribution of OPEs. Furthermore, the median value of cancer hazard quotients (HQs) of TCEP was higher than TBP and tris(2-ethylhexyl) phosphate (TEHP). The health risk assessment showed that HQ values for children were ~1.6 times higher than those for adults. Relatively higher health risk induced by PM2.5-bound OPEs via inhalation was found during severe hazy days than in clear days.

Single Real Goal, Magnitude-Based Deceptive Path-Planning.

Deceptive path-planning is the task of finding a path so as to minimize the probability of an observer (or a defender) identifying the observed agent's final goal before the goal has been reached. It is one of the important approaches to solving real-world challenges, such as public security, strategic transportation, and logistics. Existing methods either cannot make full use of the entire environments' information, or lack enough flexibility for balancing the path's deceptivity and available moving resource. In this work, building on recent developments in probabilistic goal recognition, we formalized a single real goal magnitude-based deceptive path-planning problem followed by a mixed-integer programming based deceptive path maximization and generation method. The model helps to establish a computable foundation for any further imposition of different deception concepts or strategies, and broadens its applicability in many scenarios. Experimental results showed the effectiveness of our methods in deceptive path-planning compared to the existing one.

Navigation in Unknown Dynamic Environments Based on Deep Reinforcement Learning.

In this paper, we propose a novel Deep Reinforcement Learning (DRL) algorithm which can navigate non-holonomic robots with continuous control in an unknown dynamic environment with moving obstacles. We call the approach MK-A3C (Memory and Knowledge-based Asynchronous Advantage Actor-Critic) for short. As its first component, MK-A3C builds a GRU-based memory neural network to enhance the robot's capability for temporal reasoning. Robots without it tend to suffer from a lack of rationality in face of incomplete and noisy estimations for complex environments. Additionally, robots with certain memory ability endowed by MK-A3C can avoid local minima traps by estimating the environmental model. Secondly, MK-A3C combines the domain knowledge-based reward function and the transfer learning-based training task architecture, which can solve the non-convergence policies problems caused by sparse reward. These improvements of MK-A3C can efficiently navigate robots in unknown dynamic environments, and satisfy kinetic constraints while handling moving objects. Simulation experiments show that compared with existing methods, MK-A3C can realize successful robotic navigation in unknown and challenging environments by outputting continuous acceleration commands.

[Hidden Markov models for human interactive behavior].

In order to meet the requirements in the cooperation and competition experiments for an individual patient in clinical application, two human interactive behavior key-press models based on hidden Markov model (HMM) were proposed. To validate the cooperative and competitive models, a verification experimental task was designed and the data were collected. The correlation of the score and subjects' participation level has been used to analyze the reasonability verification. Behavior verification was conducted by comparing the statistical difference in response time for subjects between human-human and human-computer experiment. In order to verify the physiological validity of the models, we have utilized the coherence analysis to analyze the deep information of prefrontal brain area. Reasonability verification shows that the correlation coefficient for the training data and the testing data is 0.883 1 and 0.578 6 respectively based on cooperation model, and 0.813 1 and 0.617 8 respectively based on the competition model. The behavioral verification result shows that the cooperation and competition models have an accuracy of 71.43% respectively. The results of physiological validity show that the deep information of prefrontal brain area could been extracted based on the cooperation and competition models, and reveal the consistency of coherence between the double key-press cooperative and competitive experiments, respectively. Above all, the high consistency is obtained between the cooperatio/competition model and the double key-press experiment by the behavioral and physiological evaluation results. Consequently, the cooperation and competition models could be applied to clinical trials.

Isolated Square-Planar Copper Center in Boron Imidazolate Nanocages for Photocatalytic Reduction of CO2 to CO.

Photocatalytic reduction of CO2 to value-added fuel has been considered to be a promising strategy to reduce global warming and shortage of energy. Rational design and synthesis of catalysts to maximumly expose the active sites is the key to activate CO2 molecules and determine the reaction selectivity. Herein, we synthesize a well-defined copper-based boron imidazolate cage (BIF-29) with six exposed mononuclear copper centers for the photocatalytic reduction of CO2 . Theoretical calculations show a single Cu site including weak coordinated water delivers a new state in the conduction band near the Fermi level and stabilizes the *COOH intermediate. Steady-state and time-resolved fluorescence spectra show these Cu sites promote the separation of electron-hole pairs and electron transfer. As a result, the cage achieves solar-driven reduction of CO2 to CO with an evolution rate of 3334 µmol g-1 h-1 and a high selectivity of 82.6 %.