Boosting Efficient Alkaline Hydrogen Evolution Reaction of CoFe-Layered Double Hydroxides Nanosheets via Co-Coordination Mechanism of W-Doping and Oxygen Defect Engineering.

While surface defects and heteroatom doping exhibit promising potential in augmenting the electrocatalytic hydrogen evolution reaction (HER), their performance remains unable to rival that of the costly Pt-based catalysts. Yet, the concurrent modification of catalysts by integrating both approaches stands as a promising strategy to effectively address the aforementioned limitation. In this work, tungsten dopants are introduced into self-supported CoFe-layered double hydroxides (LDH) on nickel foam using a hydrothermal method, and oxygen vacancies (Ov) are further introduced through calcination. The analysis results demonstrated that tungsten doping reduces the Ov formation energy of CoFeW-LDH. The Ov acted as oxophilic sites, facilitating water adsorption and dissociation, and reducing the barrier for cleaving HO─H bonds from 0.64 to 0.14 eV. Additionally, Ov regulated the electronic structure of CoFeW-LDH to endow optimized hydrogen binding ability on tungsten atoms, thereby accelerating alkaline Volmer and Heyrovsky reaction kinetics. Specifically, the abundance of Ov induced a transition of tungsten from a six-coordinated to highly active four-coordinated structure, which becomes the active site for HER. Consequently, an ultra-low overpotential of 41 mV at 10 mA cm-2, and a low Tafel slope of 35 mV dec-1 are achieved. These findings offer crucial insights for the design of efficient HER electrocatalysts.

KAT8/SIRT7-mediated Fascin-K41 acetylation/deacetylation regulates tumor metastasis in esophageal squamous cell carcinoma.

Fascin actin-bundling protein 1 (Fascin) is highly expressed in a variety of cancers, including esophageal squamous cell carcinoma (ESCC), working as an important oncogenic protein and promoting the migration and invasion of cancer cells by bundling F-actin to facilitate the formation of filopodia and invadopodia. However, it is not clear how exactly the function of Fascin is regulated by acetylation in cancer cells. Here, in ESCC cells, the histone acetyltransferase KAT8 catalyzed Fascin lysine 41 (K41) acetylation, to inhibit Fascin-mediated F-actin bundling and the formation of filopodia and invadopodia. Furthermore, NAD-dependent protein deacetylase sirtuin (SIRT) 7-mediated deacetylation of Fascin-K41 enhances the formation of filopodia and invadopodia, which promotes the migration and invasion of ESCC cells. Clinically, the analysis of cancer and adjacent tissue samples from patients with ESCC showed that Fascin-K41 acetylation was lower in the cancer tissue of patients with lymph node metastasis than in that of patients without lymph node metastasis, and low levels of Fascin-K41 acetylation were associated with a poorer prognosis in patients with ESCC. Importantly, K41 acetylation significantly blocked NP-G2-044, one of the Fascin inhibitors currently being clinically evaluated, suggesting that NP-G2-044 may be more suitable for patients with low levels of Fascin-K41 acetylation, but not suitable for patients with high levels of Fascin-K41 acetylation. © 2024 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Heme-Inducing Endothelial Pyroptosis Plays a Key Role in Radiofrequency Ablation of Hepatic Hemangioma Leading to Systemic Inflammatory Response Syndrome.

Purpose: Systemic inflammatory response syndrome (SIRS) is a common complication of radiofrequency ablation (RFA) for hepatic hemangiomas. RFA can cause hemolytic reactions during hepatic hemangioma ablation. However, the mechanisms underlying RFA-induced SIRS remain unclear. Methods: We established an orthotopic liver hemangioma model and performed radiofrequency ablation. The levels of interleukin (IL)-1ß and IL-18 and the production of ROS were measured. The wet-to-dry lung ratio, inflammation score, and in vivo endothelial cell permeability were examined. GSDMD-/- mice were used to investigate the effect of heme-inducing SIRS. RNA sequencing (RNA-seq) was performed to identify the main pathways underlying heme-induced SIRS. Western blotting and immunoprecipitation were used to determine the changes and interactions of associated proteins. Results: The levels of heme, IL-1ß, and IL-18 were significantly increased after RFA. The wet-to-dry lung ratio increased in hepatic hemangiomas after RFA, indicating that SIRS occurred. Heme induced increased levels of IL-1ß and IL-18, cell death, wet-to-dry lung radio, and inflammation score in vitro and in vivo, indicating that heme induced SIRS and pyroptosis. Furthermore, GSDMD participates in heme-induced SIRS in mice, and GSDMD deletion in mice reverses the effect of heme. Heme regulates NLRP3 activation through the NOX4/ROS/TXNIP-TRX pathway, and an N-acetyl-L-cysteine (NAC) or NOX4 inhibitor (GLX351322) reverses heme-induced SIRS. Conclusion: Our findings suggest that heme induces endothelial cell pyroptosis and SIRS in mice and decreasing heme levels and ROS scavengers may prevent SIRS in hepatic hemangioma after RFA.

THBS1 promotes angiogenesis and accelerates ESCC malignant progression by the HIF-1/VEGF signaling pathway.

Previously, we demonstrated that the expression of THBS1 is increased in esophageal squamous cell carcinoma (ESCC) tissues and is correlated with lymph node metastasis and poor prognosis, indicating that THBS1 might be a candidate oncogene in ESCC. In this study, we future studied the specific role of THBS1 in ESCC and its molecular mechanism. Silencing THBS1 expression resulted in inhibition of cell migration and cell invasion of ESCC cells, the decrease of colony formation and proliferation. Tube formation of human umbilical vein endothelial cells (HUVECs) in vitro was decreased when cultured with conditioned medium from THBS1-silenced cells. The expression of CD31, a marker for blood vessel endothelial cells, was decreased in tumor tissues derived from THBS1-silenced tumors in vivo. Silencing THBS1 leaded the decreased of hypoxia-inducible factor-1α (HIF-1α), HIF-1ß, and VEGFA protein. The expression of p-ERK and p-AKT were declined in HUVECs following incubation with conditioned medium from THBS1-silenced ESCC cells compared conditioned medium from control cells. Furthermore, the treatment with bevacizumab boosted the decrease of the p-ERK and p-AKT levels in HUVECs incubated with the conditioned medium from THBS1-silenced ESCC cells. THBS1 silencing combined with bevacizumab blocked VEGF, inhibited to the tube formation, colony formation and migration of HUVECs, which were superior to that of bevacizumab alone. We presumed that THBS1 can enhance HIF-1/VEGF signaling and subsequently induce angiogenesis by activating the AKT and ERK pathways in HUVECs, resulting in bevacizumab resistance. THBS1 would be a potential target in tumor antiangiogenesis therapies.

A protein complex of LCN2, LOXL2 and MMP9 facilitates tumour metastasis in oesophageal cancer.

During malignant tumour development, the extracellular matrix (ECM) is usually abnormally regulated. Dysregulated expression of lysyl oxidase-like 2 (LOXL2), matrix metalloproteinase 9 (MMP9) and lipocalin 2 (LCN2) are associated with ECM remodelling. In this study, protein-protein interaction assays indicated that LCN2 and LOXL2 interactions and LCN2 and MMP9 interactions occurred both intracellularly and extracellularly, but interactions between LOXL2 and MMP9 only occurred intracellularly. The LCN2/LOXL2/MMP9 ternary complex promoted migration and invasion of oesophageal squamous cell carcinoma (ESCC) cells, as well as tumour growth and malignant progression in vivo, while the iron chelator deferoxamine mesylate (DFOM) inhibited ESCC tumour growth. Co-overexpression of LCN2, LOXL2 and MMP9 enhanced the ability of tumour cells to degrade fibronectin and Matrigel, increased the formation and extension of filopodia, and promoted the rearrangement of microfilaments through upregulation of profilin 1. In addition, the LCN2/LOXL2/MMP9 ternary complex promoted the expression of testican-1 (SPOCK1), and abnormally activated the FAK/AKT/GSK3ß signalling pathway. In summary, the LCN2/LOXL2/MMP9 ternary complex promoted the migration and invasion of cancer cells and malignant tumour progression through multiple mechanisms and could be a potential therapeutic target.

Dynamic System Stability Modeling Approach with Sparrow-Inspired Meta-Heuristic Optimization Algorithm.

Aiming at the accurate prediction of the inception of instability in a compressor, a dynamic system stability model is proposed based on a sparrow-inspired meta-heuristic optimization algorithm in this article. To achieve this goal, a spatial mode is employed for flow field feature extraction and modeling object acquisition. The nonlinear characteristic presented in the system is addressed using fuzzy entropy as the identification strategy to provide a basis for instability determination. Using Sparrow Search Algorithm (SSA) optimization, a Radial Basis Function Neural Network (RBFNN) is achieved for the performance prediction of system status. A Logistic SSA solution is first established to seek the optimal parameters of the RBFNN to enhance prediction accuracy and stability. On the basis of the RBFNN-LSSA hybrid model, the stall inception is detected about 35.8 revolutions in advance using fuzzy entropy identification. To further improve the multi-step network model, a Tent SSA is introduced to promote the accuracy and robustness of the model. A wider range of potential solutions within the TSSA are explored by incorporating the Tent mapping function. The TSSA-based optimization method proves a suitable adaptation for complex nonlinear dynamic modeling. And this method demonstrates superior performance, achieving 42 revolutions of advance warning with multi-step prediction. This RBFNN-TSSA model represents a novel and promising approach to the application of system modeling. These findings contribute to enhancing the abnormal warning capability of dynamic systems in compressors.

GNA13 inhibits glioblastoma metastasis via the ERKs/FOXO3 signaling pathway.

Glioblastoma (GBM) is a malignant tumor characterized by poor prognosis and low overall survival (OS) rate. Identification of novel biological markers for the diagnosis and treatment of GBM is crucial to developing interventions to improve patient survival. GNA13, a member of the G12 family, has been reported to play important roles in a variety of biological processes involved in tumorigenesis and development. However, its role in GBM is currently unknown. Here, we explored the expression patterns and functions of GNA13 in GBM, as wells its impact on metastasis process. Results showed that GNA13 was downregulated in GBM tissues and correlated with poor prognosis of GBM. Downregulation of GNA13 promoted the migration, invasion and proliferation of GBM cells; whereas its overexpression abolished these effects. Western blots revealed that GNA13 knockdown and overexpression upregulated and inhibited the phosphorylation of ERKs, respectively. Moreover, GNA13 was the upstream of ERKs signaling to regulating ERKs phosphorylation level. Furthermore, U0126 alleviated the metastasis effect induced by GNA13 knockdown. Bioinformatics analyses and qRT-PCR experiments demonstrated that GNA13 could regulate FOXO3, a downstream signaling molecule of ERKs pathway. Overall, our results demonstrate that GNA13 expression is negatively correlated with GBM and can suppress tumor metastasis by inhibiting the ERKs signaling pathway and upregulating FOXO3 expression.

Spatial analysis of stromal signatures identifies invasive front carcinoma-associated fibroblasts as suppressors of anti-tumor immune response in esophageal cancer.

BACKGROUND: Increasing evidence indicates that the tumor microenvironment (TME) is a crucial determinant of cancer progression. However, the clinical and pathobiological significance of stromal signatures in the TME, as a complex dynamic entity, is still unclear in esophageal squamous cell carcinoma (ESCC). METHODS: Herein, we used single-cell transcriptome sequencing data, imaging mass cytometry (IMC) and multiplex immunofluorescence staining to characterize the stromal signatures in ESCC and evaluate their prognostic values in this aggressive disease. An automated quantitative pathology imaging system determined the locations of the lamina propria, stroma, and invasive front. Subsequently, IMC spatial analyses further uncovered spatial interaction and distribution. Additionally, bioinformatics analysis was performed to explore the TME remodeling mechanism in ESCC. To define a new molecular prognostic model, we calculated the risk score of each patient based on their TME signatures and pTNM stages. RESULTS: We demonstrate that the presence of fibroblasts at the tumor invasive front was associated with the invasive depth and poor prognosis. Furthermore, the amount of α-smooth muscle actin (α-SMA)+ fibroblasts at the tumor invasive front positively correlated with the number of macrophages (MØs), but negatively correlated with that of tumor-infiltrating granzyme B+ immune cells, and CD4+ and CD8+ T cells. Spatial analyses uncovered a significant spatial interaction between α-SMA+ fibroblasts and CD163+ MØs in the TME, which resulted in spatially exclusive interactions to anti-tumor immune cells. We further validated the laminin and collagen signaling network contributions to TME remodeling. Moreover, compared with pTNM staging, a molecular prognostic model, based on expression of α-SMA+ fibroblasts at the invasive front, and CD163+ MØs, showed higher accuracy in predicting survival or recurrence in ESCC patients. Regression analysis confirmed this model is an independent predictor for survival, which also identifies a high-risk group of ESCC patients that can benefit from adjuvant therapy. CONCLUSIONS: Our newly defined biomarker signature may serve as a complement for current clinical risk stratification approaches and provide potential therapeutic targets for reversing the fibroblast-mediated immunosuppressive microenvironment.

Aerodynamic System Machine Learning Modeling with Gray Wolf Optimization Support Vector Regression and Instability Identification Strategy of Wavelet Singular Spectrum.

The prediction of a stall precursor in an axial compressor is the basic guarantee to the stable operation of an aeroengine. How to predict and intelligently identify the instability of the system in advance is of great significance to the safety performance and active control of the aeroengine. In this paper, an aerodynamic system modeling method combination with the wavelet transform and gray wolf algorithm optimized support vector regression (WT-GWO-SVR) is proposed, which breaks through the fusion technology based on the feature correlation of chaotic data. Because of the chaotic characteristic represented by the sequence, the correlation-correlation (C-C) algorithm is adopted to reconstruct the phase space of the spatial modal. On the premise of finding out the local law of the dynamic system variety, the machine learning method is applied to model the reconstructed low-frequency components and high-frequency components, respectively. As the key part, the parameters of the SVR model are optimized by the gray wolf optimization algorithm (GWO) from the biological view inspired by the predatory behavior of gray wolves. In the definition of the hunting behaviors of gray wolves by mathematical equations, it is superior to algorithms such as differential evolution and particle swarm optimization. In order to further improve the prediction accuracy of the model, the multi-resolution and equivalent frequency distribution of the wavelet transform (WT) are used to train support vector regression. It is shown that the proposed WT-GWO-SVR hybrid model has a better prediction accuracy and reliability with the wavelet reconstruction coefficients as the inputs. In order to effectively identify the sign of the instability in the modeling system, a wavelet singular information entropy algorithm is proposed to detect the stall inception. By using the three sigma criteria as the identification strategy, the instability early warning can be given about 102r in advance, which is helpful for the active control.

Regulating the concentration of dissolved oxygen to achieve the directional transformation of reactive oxygen species: A controllable oxidation process for ciprofloxacin degradation by calcined CuCoFe-LDH.

Different reactive oxygen species (ROS) tend to attack specific sites on pollutants, leading to the formation of intermediates with different toxic effects. Therefore, regulating the directional transformation of ROS is a new effective approach for safe degradation of refractory organic compounds in wastewater. However, the regulation mechanism and transformation path of ROS remain unclear. In this work, the dissolved oxygen (DO) content was controlled by aeration to generate different ROS through the activation of O2 on the calcined CuCoFe-LDH (CuCoFe-300). ROS quantitative experiments and electron paramagnetic resonance proved that O2 was mainly activated to superoxide radical (•O2-) and singlet oxygen (1O2) under low DO concentration (0.231 mmol/L) (O2 â†’ â€¢O2- â†’ 1O2). With the increasing of DO concentration (0.606 mmol/L), O2 was inclined to convert into hydroxyl radicals (•OH) (O2 â†’ â€¢O2- â†’ H2O2 â†’ â€¢OH). The density functional theory and function model of active sites utilization and DO concentration built a solid proof for ROS conversion mechanism that increasing the DO concentration promotes the increase of active sites utilization on the CuCoFe-300 system. That is, the •O2- was more prone to convert to •OH, not 1O2 in thermodynamics under high active sites utilization condition. Hence, the ROS generation was controlled by regulating DO concentration, and the nontoxic degradation pathway of ciprofloxacin was well-designed. This work is dedicated to the in-depth exploration of the mechanism between DO concentration and ROS conversion, which provides an extremely flexible, low energy consumption, and environmentally friendly wastewater treatment method in a new perspective.

MTHFD2 suppresses glioblastoma progression via the inhibition of ERK1/2 phosphorylation.

Glioblastoma (GBM) is a WHO grade 4 tumor and is the most malignant form of glioma. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial enzyme involved in folate metabolism, has been reported to be highly expressed in several human tumors. However, little is known about the role of MTHFD2 in GBM. In this study, we aimed to explore the biological functions of MTHFD2 in GBM and identify the associated mechanisms. We performed experiments such as immunohistochemistry, Western blot, and transwell assays and found that MTHFD2 expression was lower in high-grade glioma than in low-grade glioma. Furthermore, a high expression of MTHFD2 was associated with a favorable prognosis, and MTHFD2 levels showed good prognostic accuracy for glioma patients. The overexpression of MTHFD2 could inhibit the migration, invasion, and proliferation of GBM cells, whereas its knockdown induced the opposite effect. Mechanistically, our findings revealed that MTHFD2 suppressed GBM progression independent of its enzymatic activity, likely by inducing cytoskeletal remodeling through the regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, thereby influencing GBM malignance. Collectively, these findings uncover a potential tumor-suppressor role of MTHFD2 in GBM cells. MTHFD2 may act as a promising diagnostic and therapeutic target for GBM treatment.

Targeting USP10 induces degradation of oncogenic ANLN in esophageal squamous cell carcinoma.

Anillin (ANLN) is a mitosis-related protein that promotes contractile ring formation and cytokinesis, but its cell cycle-dependent degradation mechanisms in cancer cells remain unclear. Here, we show that high expression of ANLN promotes cytokinesis and proliferation in esophageal squamous cell carcinoma (ESCC) cells and is associated with poor prognosis in ESCC patients. Furthermore, the findings of the study showed that the deubiquitinating enzyme USP10 interacts with ANLN and positively regulates ANLN protein levels. USP10 removes the K11- and K63-linked ubiquitin chains of ANLN through its deubiquitinase activity and prevents ANLN ubiquitin-mediated degradation. Importantly, USP10 promotes contractile ring assembly at the cytokinetic furrow as well as cytokinesis by stabilizing ANLN. Interestingly, USP10 and the E3 ubiquitin ligase APC/C co-activator Cdh1 formed a functional complex with ANLN in a non-competitive manner to balance ANLN protein levels. In addition, the macrolide compound FW-04-806 (F806), a natural compound with potential for treating ESCC, inhibited the mitosis of ESCC cells by targeting USP10 and promoting ANLN degradation. F806 selectively targeted USP10 and inhibited its catalytic activity but did not affect the binding of Cdh1 to ANLN and alters the balance of the USP10-Cdh1-ANLN complex. Additionally, USP10 expression was positively correlated with ANLN level and poor prognosis of ESCC patients. Overall, targeting the USP10-ANLN axis can effectively inhibit ESCC cell-cycle progression.

Progression of hepatocellular carcinoma after radiofrequency ablation: Current status of research.

Hepatocellular carcinoma (HCC) remains an important disease for health care systems in view of its high morbidity, mortality, and increasing incidence worldwide. Radiofrequency ablation (RFA) is preferred to surgery as a local treatment for HCC because it is safer, less traumatic, less painful, better tolerated, causes fewer adverse reactions, and allows more rapid postoperative recovery. The biggest shortcoming of RFA when used to treat HCC is the high incidence of residual tumor, which is often attributed to the vascular thermal deposition effect, the wide infiltration zone of peripheral venules, and the distance between satellite foci and the main focus of the cancer. Recurrence and progression of the residual tumor is the most important determinant of the prognosis. Therefore, it is important to be aware of the risk of recurrence and to improve the efficacy of RFA. This review summarizes the relevant literature and the possible mechanisms involved in progression of HCC after RFA. Current studies have demonstrated that multimodal treatments which RFA combined with other anti-cancer approaches can prevent progression of HCC after RFA.

Anatomic resection versus radiofrequency ablation with an ablative margin ≥ 1.0 cm for solitary small hepatocellular carcinoma measuring ≤ 3 cm: Comparison of long-term outcomes using propensity score matching analysis.

PURPOSE: To compare the long-term outcomes of anatomic resection (AR) and radiofrequency ablation (RFA) with an ablative margin (AM) of ≥ 1.0 cm as first-line treatment for solitary hepatocellular carcinoma measuring ≤ 3 cm. METHODS: Two hundred and fifty-one patients who underwent AR (n = 156) or RFA (ablative margin ≥ 1.0 cm, n = 95) at any of 6 tertiary hospitals from 2009 to 2018 were enrolled. Propensity score matched analysis (PSM) were used to compare overall survival (OS), recurrence-free survival (RFS), and perioperative outcomes. Univariate and multivariate analyses were performed to identify prognostic factors associated with RFS and OS. RESULTS: PSM created 67 patient-pairs. After 96 months of follow-up, RFA with an ablative margin ≥ 1.0 cm and AR showed comparable 1-year, 3-year, 5-year, and 8-year OS rates before (P = 0.580) and after (P = 0.640) PSM. However, RFS was better at 1, 3, 5, and 8 years after AR before (P = 0.0036) and after (P = 0.017) PSM. The operation time and postoperative hospital stay were significantly longer in the AR group than in the RFA group before and after PSM (P < 0.05). Multivariate analysis identified age and type of treatment to be independent prognostic factors for RFS and age and hepatitis C to be associated with OS. CONCLUSIONS: Long-term OS was not significantly different between AR and RFA with an AM ≥ 1.0 cm in patients with a solitary hepatocellular carcinoma measuring ≤ 3 cm; but, RFS appeared to be better after AR than after RFA. However, RFA was associated with fewer perioperative complications and a shorter postoperative hospital stay.

Valence-Inverted States of Nickel(II) Complexes Perform Facile C-H Bond Activation.

Valence-inverted reactivity (VIR) is discovered here through high-level computations of excited states of Ni(II) complexes that are generated by triplet energy transfer. For example, the so-generated 3[(Ar)(bpy)NiII(Br)] species possesses a valence-inverted occupancy, dxy1dxz1dx2-y22, wherein the uppermost dx2-y2 orbital is metal-ligand antibonding. This state promotes C-H bond activation of THF and its cross-coupling to the aryl ligand. Thus, due to the metal-ligand antibonding character of dx2-y2, the dxy1dx2-y22 subshell opens a Ni-coordination site by shifting the bidentate bipyridine ligand to monodentate plus a dangling pyridine. The tricoordinate Ni(II) intermediate inserts into a C-H bond of THF, transfers a proton to the dangling pyridine moiety, and eventually generates an arylated THF by reductive-coupling. The calculated high kinetic isotope effect is in accord with experiment, both revealing C-H activation. The VIR pattern is novel, its cross-coupling reaction is highly useful, and it is generally expected to occur in other d8 complexes.

A nationwide survey exploring physicians' and pharmacists' knowledge, awareness and perceptions regarding generic medicines in China.

BACKGROUND: Generic medicines substitution is an important means to control rapid growth of pharmaceutical expenditures for the healthcare system in China. Acceptance and utilization of generic medicines is highly influenced by healthcare providers' perceptions. This study aimed to compare the knowledge, awareness and perceptions of generic medicines between physicians and pharmacists in China. METHODS: We used an online, cross-sectional survey across China. The questionnaire explored four sections: demographic characteristics, assessment of the participants' knowledge and awareness of generic medicines, perceptions of generic medicines and generic substitution practices. Chi-square or Mann-Whitney-U tests were applied to compare differences between physicians and pharmacists. P-values < 0.05 were considered significant. RESULTS: A total of 1644 physicians and 4187 pharmacists participated. Most physicians (82.8%, n = 1362) and pharmacists (89.8%, n = 3760) correctly identified the definition of generic medicines. A similar percentage of physicians and pharmacists agreed that approved generic medicines are as effective (64.1% vs 68.2%) or safe (63.8% vs 69.1%) as brand-name medicines. Most physicians and pharmacists (67.6% vs 71.0%) supported the policy of generic substitution. In practice, 79.4% (n = 1305) of physicians reported that they had prescribed generic medicines. More than 78% of respondents reported an obvious increase in the number of generic medicines prescribed in their medical institutions. The majority of physicians and pharmacists identified lack of trust regarding efficacy and safety of generic medicines and the difficulty of changing patients' preference as top challenges in generic substitution. CONCLUSIONS: Both physicians and pharmacists surveyed had adequate knowledge of generic medicines, and hold positive attitude towards generics and generic substitution. Efficacy and safety are key factors related to prescribing or dispensing generic medicines. Various policies and regulations should be taken to encourage successful generic substitution.

Study on Intrinsic Influence Law of Specimen Size and Loading Speed on Charpy Impact Test.

Charpy impact energy/impact toughness is closely related to external factors such as specimen size. However, when the sample size is small, the linear conversion relationship between the Charpy impact energy of the sub-size and full-size Charpy specimens does not hold; the Charpy impact toughness varies with the size of the specimen and other factors. This indicates that studying the internal influence of external factors on impact energy or impact toughness is the key to accurately understanding and evaluating the toughness and brittleness of materials. In this paper, the effects of strain rate on the flow behavior and the effects of stress triaxiality on the fracture behavior of 30CrMnSiNi2A high-strength steel were investigated using quasi-static smooth bar and notched bar uniaxial tensile tests and Split Hopkinson Tensile Bar (SHTP). Based on the flow behavior and strain rate dependences of the yield behavior, a modified JC model was established to describe the flow behavior and strain rate behavior. Charpy impact tests were simulated using the modified JC model and JC failure model with the determined parameters. Reasonable agreements between the simulation and experimental results have been achieved, and the validity of the model was proved. According to the simulation results, the impact energy was divided into crack initiation energy, crack stability propagation energy and crack instability propagation energy. On this basis, the effects of striker velocity and specimen width on the energy and characteristic load of each part were studied. The results show that each part of the impact energy has a negligible dependence on the hammer velocity, but there is a significantly different positive linear relationship with the width of the sample. The energy increment of each part also showed an inverse correlation with the increase in the sample width. The findings reveal that the internal mechanism of Charpy impact toughness decreases with the increase in sample width; to a certain extent, it also reveals the internal reason why the linear transformation relationship of Charpy impact energy between sub-size specimens and standard specimens is not established when the specimens are small. The analytical method and results presented in this paper can provide a reference for the study of the dynamic behavior of high-strength steel, the relationship between material properties and sample size, and the elastic-plastic impact dynamic design.

Oxygen Vacancy-Mediated CuCoFe/Tartrate-LDH Catalyst Directly Activates Oxygen to Produce Superoxide Radicals: Transformation of Active Species and Implication for Nitrobenzene Degradation.

Oxygen vacancies play a vital role in the catalytic activity of layered double hydroxide (LDH) catalysts in wastewater treatment. However, the mechanism of oxygen vacancy-mediated LDH-activated oxygen to produce reactive oxygen species (ROS) still lacks a reasonable explanation. In this work, a tartrate-modified CuCoFe-LDH (CuCoFe/Tar-LDH) with abundant oxygen vacancies was designed, which can efficiently degrade nitrobenzene (NB) under room conditions. The technical energy consumption is 0.011 kW h L-1. According to the characterization and calculation results, it is proposed that oxygen vacancies are formed because of the oxygen deficiency which is caused by the reduction of the energy between the metal ion and oxygen, and the metal ion transitions to a lower state. Compared with CuCoFe-LDH, the oxygen vacancy formation energy of CuCoFe/Tar-LDH decreased from 1.98 to 1.13 eV. The O2 bond length adsorbed on the oxygen vacancy is 1.27 Å, close to the theoretical length of superoxide radicals (•O2-) (1.26 Å). Radical trapping experiments and electron spin-resonance spectroscopy spectrum prove that •O2- is an important precursor of •OH. This work is dedicated to the in-depth exploration of the oxygen vacancy-mediated CuCoFe/Tar-LDH catalyst activation mechanism for molecular oxygen and the conversion relationship between ROS.

Blocking STAT3 signaling augments MEK/ERK inhibitor efficacy in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the world's leading causes of death, and its primary clinical therapy relies on surgical resection, chemotherapy, radiotherapy, and chemoradiotherapy. Although the genomic features and clinical significance of ESCC have been identified, the outcomes of targeted therapies are still unsatisfactory. Here, we demonstrate that mitogen-activated protein kinase (MAPK) signaling is highly activated and associated with poor prognosis in patients with ESCC. Mitogen-activated protein kinase kinase (MEK) inhibitors efficiently blocked the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in ESCC, while signal transducer and activator of transcription 3 (STAT3) signaling was rapidly activated. Combined STAT3 inhibition prevented the emergence of resistance and enhanced MEK inhibitor-induced cell cycle arrest and senescence in vitro and in vivo. Mechanistic studies revealed that the suppressor of cytokine signaling 3 (SOCS3) was downregulated, resulting in an increase in STAT3 phosphorylation in MEK-inhibited cells. Furthermore, chromatin immunoprecipitation showed that ELK1, which was activated by MEK/ERK signaling, induced SOCS3 transcription. These data suggest that the development of combined MEK and STAT3 inhibition could be a useful strategy in ESCC targeted therapy.

[Research on gait recognition and prediction based on optimized machine learning algorithm].

Aiming at the problems of individual differences in the asynchrony process of human lower limbs and random changes in stride during walking, this paper proposes a method for gait recognition and prediction using motion posture signals. The research adopts an optimized gated recurrent unit (GRU) network algorithm based on immune particle swarm optimization (IPSO) to establish a network model that takes human body posture change data as the input, and the posture change data and accuracy of the next stage as the output, to realize the prediction of human body posture changes. This paper first clearly outlines the process of IPSO's optimization of the GRU algorithm. It collects human body posture change data of multiple subjects performing flat-land walking, squatting, and sitting leg flexion and extension movements. Then, through comparative analysis of IPSO optimized recurrent neural network (RNN), long short-term memory (LSTM) network, GRU network classification and prediction, the effectiveness of the built model is verified. The test results show that the optimized algorithm can better predict the changes in human posture. Among them, the root mean square error (RMSE) of flat-land walking and squatting can reach the accuracy of 10 -3, and the RMSE of sitting leg flexion and extension can reach the accuracy of 10 -2. The R 2 value of various actions can reach above 0.966. The above research results show that the optimized algorithm can be applied to realize human gait movement evaluation and gait trend prediction in rehabilitation treatment, as well as in the design of artificial limbs and lower limb rehabilitation equipment, which provide a reference for future research to improve patients' limb function, activity level, and life independence ability.