Triple negative breast cancer(TNBC)is an exceptionally aggressive subtype of breast cancer with a poor prognosis.TNBC patients have limited treatment options beyond conventional chemotherapy,and they face significant ...Triple negative breast cancer(TNBC)is an exceptionally aggressive subtype of breast cancer with a poor prognosis.TNBC patients have limited treatment options beyond conventional chemotherapy,and they face significant challenges associated with disease recurrence and resistance to chemotherapy.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)/mechanistic target of rapamycin(mTOR)signaling pathway plays a pivotal role in cell proliferation,growth,metabolism,and survival.Its aberrant activation is closely linked to the development and progression of TNBC,as well as treatment response and drug resistance.Currently,numerous targeted drugs specifically inhibiting this signaling pathway are being developed and undergoing clinical trials.These include inhibitors targeting PI3K,AKT,or mTOR individually,as well as dual-target or multi-target inhibitors simultaneously targeting different components of this pathway.Encouragingly,some inhibitors have demonstrated promising potential in clinical trials.This review delves into the therapeutic potential of the PI3K/AKT/mTOR signaling pathway for TNBC and explores prospects for drug discovery.展开更多
This article explores the association between salivary uric acid(UA)and periodontitis,systematically analyzing its dual roles and research progress.Studies indicate that UA acts as a primary antioxidant in saliva unde...This article explores the association between salivary uric acid(UA)and periodontitis,systematically analyzing its dual roles and research progress.Studies indicate that UA acts as a primary antioxidant in saliva under physiological conditions(accounting for 70%),protecting periodontal tissues by scavenging reactive oxygen species.However,when gum disease becomes severe,UA can switch roles and fuel inflammation,worsening tissue damage.Lorente et al’s research found an independent inverse correlation between salivary UA levels and periodontitis severity(odds ratio=6.14,P=0.001),establishing 111 nmol/mL as a diagnostic threshold(area under the curve=66%).Nevertheless,limitations include sample heterogeneity and failure to distinguish between gingivitis and periodontitis.Mechanistically,three hypotheses are proposed:The Antioxidant Depletion Hypothesis(UA oxidation consumption leading to feedback loops),the Microbial Metabolic Hijacking Hypothesis(pathogens utilizing UA as a carbon source to disrupt redox balance),and the Epithelial Barrier Dysfunction Hypothesis(UA deficiency causing downregulation of tight junction proteins).Future research should prioritize longitudinal cohorts to validate predictive value,integrate multi-omics to explore dysregulated signatures,and develop UA supplementation or targeted antioxidant therapies.This study provides novel insights into periodontitis diagnosis and mechanisms,advancing the application of salivary biomarkers in precision periodontics.展开更多
OBJECTIVE:To investigate the effects of Jiawei Huangqi Guizhi decoction(加味黄芪桂枝汤)on chronic atrophic gastritis(CAG)in rats and its modulation of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic tar...OBJECTIVE:To investigate the effects of Jiawei Huangqi Guizhi decoction(加味黄芪桂枝汤)on chronic atrophic gastritis(CAG)in rats and its modulation of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin complex 2(PI3K/Akt/m TORC2)signaling pathway.METHODS:CAG was induced in rats and treated with high-,medium-,or low-dose Jiawei Huangqi Guizhi decoction.Gastric histopathology was observed by hematoxylin and eosin staining.Serum levels of gastrin,PI3K,Akt,and m TORC2 were detected by enzyme-linked immunosorbent assay.Gene and protein expression levels were analyzed by reverse transcription polymerase chain reaction and western blot.RESULTS:The decoction alleviated gastric mucosal injury,reduced inflammation,and restored epithelial structure.It regulated PI3K,Akt,and m TORC2 expression at both m RNA and protein levels.CONCLUSION:Jiawei Huangqi Guizhi decoction may prevent CAG progression by improving gastric tissue and modulating the PI3K/Akt/m TORC2 signaling pathway.展开更多
Mechanistic studies of the cleavage and transformation of unactivated C_(sp3)-H bonds are a significant field of chemistry.Overcoming the inherent low acidity of C-H bonds to activate the inert substrates is challenge...Mechanistic studies of the cleavage and transformation of unactivated C_(sp3)-H bonds are a significant field of chemistry.Overcoming the inherent low acidity of C-H bonds to activate the inert substrates is challenge under mild conditions.And their complex multi-step transformations may also hinder mechanistic understanding.Herein,we perform theoretical calculations and experimental studies to explore the C_(sp3)-H bonds activation and acylation mechanisms of toluene/thioether using the relatively weak base LDA.A synergistic"main and auxiliary"model was revealed involving dual lithium metal by LDA dimers,and the aryl dilithium species as an intermediate base can facilitate C_(sp3)-H activation.This model not only aids in understanding the acidity of unactivated C_(sp3)-H bonds and the nucleophilicity of their conjugate bases for their kinetic control through cooperative interactions,but also predicts unusual kinetic isotope effects(KIE)for newly designed 2-(methylthio)naphthalene that are experimentally validated.This research is expected to provide a crucial scenario for the cleavage and transformation of unactivated C_(sp3)-H bonds and the development of new functionalities for alkali metal reagents.展开更多
Zinc-air batteries(ZABs)are promising energy storage systems because of high theoretical energy density,safety,low cost,and abundance of zinc.However,the slow multi-step reaction of oxygen and heavy reliance on noble-...Zinc-air batteries(ZABs)are promising energy storage systems because of high theoretical energy density,safety,low cost,and abundance of zinc.However,the slow multi-step reaction of oxygen and heavy reliance on noble-metal catalysts hinder the practical applications of ZABs.Therefore,feasible and advanced non-noble-metal elec-trocatalysts for air cathodes need to be identified to promote the oxygen catalytic reaction.In this review,we initially introduced the advancement of ZABs in the past two decades and provided an overview of key developments in this field.Then,we discussed the work-ing mechanism and the design of bifunctional electrocatalysts from the perspective of morphology design,crystal structure tuning,interface strategy,and atomic engineering.We also included theoretical studies,machine learning,and advanced characterization technologies to provide a comprehensive understanding of the structure-performance relationship of electrocatalysts and the reaction pathways of the oxygen redox reactions.Finally,we discussed the challenges and prospects related to designing advanced non-noble-metal bifunctional electrocatalysts for ZABs.展开更多
Neural networks are often viewed as pure‘black box’models,lacking interpretability and extrapolation capabilities of pure mechanistic models.This work proposes a new approach that,with the help of neural networks,im...Neural networks are often viewed as pure‘black box’models,lacking interpretability and extrapolation capabilities of pure mechanistic models.This work proposes a new approach that,with the help of neural networks,improves the conformity of the first-principal model to the actual plant.The final result is still a first-principal model rather than a hybrid model,which maintains the advantage of the high interpretability of first-principal model.This work better simulates industrial batch distillation which separates four components:water,ethylene glycol,diethylene glycol,and triethylene glycol.GRU(gated recurrent neural network)and LSTM(long short-term memory)were used to obtain empirical parameters of mechanistic model that are difficult to measure directly.These were used to improve the empirical processes in mechanistic model,thus correcting unreasonable model assumptions and achieving better predictability for batch distillation.The proposed method was verified using a case study from one industrial plant case,and the results show its advancement in improving model predictions and the potential to extend to other similar systems.展开更多
The synthesis of phosphine compounds through the addition reaction of H-[P(O)]species to olefins and alkynes has been extensively studied.Two different mechanisms of the addition of H-[P(O)]species to non-activated al...The synthesis of phosphine compounds through the addition reaction of H-[P(O)]species to olefins and alkynes has been extensively studied.Two different mechanisms of the addition of H-[P(O)]species to non-activated alkyne are mainly summarized.One is the oxidative addition-migration insertion-reductive elimination mechanism,namely the Chalk-Harrod type mechanism,and the other is the proton transfer-reductive elimination mechanism.This review elaborates on the specific steps of each mechanism,and discusses experimental and computational evidence supporting these steps.Additionally,a few other types of mechanisms are briefly mentioned.The mechanism of H-[P(O)]reaction with relevant conjugated dienes was also involved when closely related.展开更多
A three dimensional finite element program incorporating actually measured vertical tire-pavement contact pressure(TPCP) was utilized for modeling the mechanistic responses in asphalt concrete(AC) layers by simulating...A three dimensional finite element program incorporating actually measured vertical tire-pavement contact pressure(TPCP) was utilized for modeling the mechanistic responses in asphalt concrete(AC) layers by simulating various vehicle motions:stationary and non-stationary(i.e.in acceleration or deceleration mode).Analysis of the results indicated the following items.1) It is critical to use the vertical TPCP as the design control criteria for the tensile strains at the bottom of the AC layer when the base layer modulus is lower in magnitude(e.g.≤400 MPa);however,when the base layer modulus is higher in magnitude(e.g.≥7 000 MPa),the horizontal TPCP and the tensile strains in the X-direction at the surface of the AC layer should also be considered as part of the design response criteria.2) The definition of "overload" needs to be revised to include tire pressure over-inflation,i.e.,a vehicle should be considered to be overloaded if the wheel load exceeds the specification and/or the tire inflation pressure is higher than the specification.3) Light trucks have more structural impact on the strain responses and pavement design when the thickness of the surfacing AC layer is thinner(e.g.≤50 mm).4) The acceleration of a vehicle does not significantly impact the AC surface distresses such as rutting at the top of the upgrade slopes or intersections;however,vehicle deceleration can dramatically induce horizontal shear strains and consequently,aggravate shoving and rutting problems at the highway intersections.Evidently,these factors should be taken into account during mechanistic stress-strain modeling and structural design of asphalt pavements.展开更多
An improved method to determine cutting force coefficients for bull-nose cutters is proposed based on the semi-mechanistic cutting force model. Due to variations of cutting speed along the tool axis in bull-nose milli...An improved method to determine cutting force coefficients for bull-nose cutters is proposed based on the semi-mechanistic cutting force model. Due to variations of cutting speed along the tool axis in bull-nose milling, they affect coefficients significantly and may bring remarkable discrepancies in the prediction of cutting forces. Firstly, the bull-nose cutter is regarded as a finite number of axial discs piled up along the tool axis, and the rigid cutting force model is exerted. Then through discretization along cutting edges, the cutting force related to each element is recalculated, which equals to differential force value between the current and previous elements. In addition, coefficient identification adopts the cubic polynomial fitting method with the slice elevation as its horizontal axis. By calculating relations of cutting speed and cutting depth, the influences of speed variations on cutting force can be derived. Thereby, several tests are conducted to calibrate the coefficients using the improved method, which are applied to later force predictions. Eventually, experimental evaluations are discussed to verify the effectiveness. Compared to the conventional method, the results are more accurate and show satisfactory consistency with the simulations. For further applications, the method is instructive to predict the cutting forces in bull-nose milling with lead or tilt angles and can be extended to the selection of cutting parameters.展开更多
BACKGROUND The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin(PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills(XHP) a...BACKGROUND The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin(PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills(XHP) are a traditional Chinese preparation with antitumour properties. They inhibit the growth of breast cancer, glioma, and other tumours by regulating the PI3K/Akt/mTOR signalling pathway. However, the effects and mechanisms of action of XHP in hepatocellular carcinoma(HCC) remain unclear. Regulation of the PI3K/Akt/mTOR signalling pathway effectively inhibits the progression of HCC. However, no study has focused on the XHPassociated PI3K/Akt/mTOR signalling pathway. Therefore, we hypothesized that XHP might play a role in inhibiting HCC through the PI3K/Akt/mTOR signalling pathway.AIM To confirm the effect of XHP on HCC and the possible mechanisms involved.METHODS The chemical constituents and active components of XHP were analysed using ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS). Cellbased experiments and in vivo xenograft tumour experiments were utilized to evaluate the effect of XHP on HCC tumorigenesis. First, SMMC-7721 cells were incubated with different concentrations of XHP(0, 0.3125, 0.625, 1.25, and 2.5 mg/mL) for 12 h, 24 h and 48 h. Cell viability was assessed using the CCK-8 assay, followed by an assessment of cell migration using a wound healing assay.Second, the effect of XHP on the apoptosis of SMMC-7721 cells was evaluated. SMMC-7721 cells were stained with fluorescein isothiocyanate and annexin V/propidium iodide. The number of apoptotic cells and cell cycle distribution were measured using flow cytometry. The cleaved protein and mRNA expression levels of caspase-3 and caspase-9 were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction(RT-qPCR), respectively.Third, Western blotting and RT–qPCR were performed to confirm the effects of XHP on the protein and mRNA expression of components of the PI3K/Akt/mTOR signalling pathway.Finally, the effects of XHP on the tumorigenesis of subcutaneous hepatocellular tumours in nude mice were assessed.RESULTS The following 12 compounds were identified in XHP using high-resolution mass spectrometry:Valine, 4-gingerol, myrrhone, ricinoleic acid, glycocholic acid, curzerenone, 11-keto-β-boswellic acid, oleic acid, germacrone, 3-acetyl-9,11-dehydro-β-boswellic acid, 5β-androstane-3,17-dione, and 3-acetyl-11-keto-β-boswellic acid. The cell viability assay results showed that treatment with 0.625mg/mL XHP extract decreased HCC cell viability after 12 h, and the effects were dose-and timedependent. The results of the cell scratch assay showed that the migration of HCC cells was significantly inhibited in a time-dependent manner by the administration of XHP extract(0.625mg/mL). Moreover, XHP significantly inhibited cell migration and resulted in cell cycle arrest and apoptosis. Furthermore, XHP downregulated the PI3K/Akt/mTOR signalling pathway, which activated apoptosis executioner proteins(e.g., caspase-9 and caspase-3). The inhibitory effects of XHP on HCC cell growth were determined in vivo by analysing the tumour xenograft volumes and weights.CONCLUSION XHP inhibited HCC cell growth and migration by stimulating apoptosis via the downregulation of the PI3K/Akt/mTOR signalling pathway, followed by the activation of caspase-9 and caspase-3.Our findings clarified that the antitumour effects of XHP on HCC cells are mediated by the PI3K/Akt/mTOR signalling pathway, revealing that XHP may be a potential complementary therapy for HCC.展开更多
Mammalian target of rapamycin, also known as me-chanistic target of rapamycin(m TOR) is a protein kinase that belongs to the PI3K/AKT/m TOR signaling pathway, which is involved in several fundamental cellular function...Mammalian target of rapamycin, also known as me-chanistic target of rapamycin(m TOR) is a protein kinase that belongs to the PI3K/AKT/m TOR signaling pathway, which is involved in several fundamental cellular functions such as cell growth, proliferation, and survival. This protein and its associated pathway have been implicated in cancer development and the regulation of immune responses, including the rejection response generated following allograft transplantation. Inhibitors of m TOR(m TORi) such as rapamycin and its derivative everolimus are potent immunosuppressive drugs that both maintain similar rates of efficacy and could optimize the renal function and diminish the side effects compared with calcineurin inhibitors. These drugs are used in solid-organ transplantationtoinduceimmunosuppression while also promoting the expansion of CD4+CD25+FOXP3+ regulatory T-cells that could favor a scenery of immu-nological tolerance. In this review, we describe the mechanisms by which inhibitors of m TOR induce sup-pression by regulation of these pathways at different levels of the immune response. In addition, we par-ticularly emphasize about the main methods that are used to assess the potency of immunosuppressive drugs, highlighting the studies carried out about immunosuppressive potency of inhibitors of m TOR.展开更多
Understanding the drifting motion of a small semi-submersible drifter is of vital importance regarding monitoring surface currents and the floating pollutants in coastal regions. This work addresses this issue by esta...Understanding the drifting motion of a small semi-submersible drifter is of vital importance regarding monitoring surface currents and the floating pollutants in coastal regions. This work addresses this issue by establishing a mechanistic drifting forecast model based on kinetic analysis. Taking tide–wind–wave into consideration, the forecast model is validated against in situ drifting experiment in the Radial Sand Ridges. Model results show good performance with respect to the measured drifting features, characterized by migrating back and forth twice a day with daily downwind displacements. Trajectory models are used to evaluate the influence of the individual hydrodynamic forcing. The tidal current is the fundamental dynamic condition in the Radial Sand Ridges and has the greatest impact on the drifting distance. However, it loses its leading position in the field of the daily displacement of the used drifter. The simulations reveal that different hydrodynamic forces dominate the daily displacement of the used drifter at different wind scales. The wave-induced mass transport has the greatest influence on the daily displacement at Beaufort wind scale 5–6; while wind drag contributes mostly at wind scale 2–4.展开更多
Three sets of data from the field experiments with different wheat( Triticum L. ) varieties and sowing dates in China and USA were used to test the performance of the mechanistic model of wheat development. The result...Three sets of data from the field experiments with different wheat( Triticum L. ) varieties and sowing dates in China and USA were used to test the performance of the mechanistic model of wheat development. The results showed that the absolute prediction errors for most phasic and phenological stages ranged within 0 - 5 days, and the root mean square errors were generally less than 5 days. The model was of high accuracy and low error especially for emergence, tillering, stamen and pistil initiation, and heading stages, reflecting an enhanced level of mechanism and prediction.展开更多
The impact of lipophilicity as represented by the logarithm of octanol/water partition coefficient (logP), the combined steric/polarizability effect as represented by molar refractivity (MR) and bulk as represented by...The impact of lipophilicity as represented by the logarithm of octanol/water partition coefficient (logP), the combined steric/polarizability effect as represented by molar refractivity (MR) and bulk as represented by molar volume (MV) on the biological activity of 29 known aminopyrimidoisoquinolinequinones APIQ were analyzed using quantitative structure activity relationships methodology (QSAR). The activity data chosen was the inhibitory concentration (IC50) against human gastric adenocarcinoma (AGS) cell line. On running regression analysis, the physicochemical parameters and IC50 show very weak correlations as evident by the low values of Pearson Correlation R2 (0.1 to 0.2). Since the individual compounds show appreciable activity (ranging from 20 to 0.5 μM), classification was resorted to in order to expose mechanistic nesting subgroups. This was done by clustering data points around various trend lines extracted from the scattered plot relating parameters to activity using R2 as an index. The correlation of IC50 versus MV was chosen a base of classification owing to higher statistical metrics it yield. This gave five regression lines, each of which is believed to represent a separate mechanistic profile. Additional descriptors were used to consolidate the clustering approach and to give depth to the assumed mechanistic profiles of each cluster.展开更多
Colorectal cancer(CRC)is a common cancer with high morbidity and mortality rates.Its occurrence and development are determined by many factors,including genetics,the environment,lifestyle,and so on.The occurrence of C...Colorectal cancer(CRC)is a common cancer with high morbidity and mortality rates.Its occurrence and development are determined by many factors,including genetics,the environment,lifestyle,and so on.The occurrence of CRC is often accompanied by changes in the intestinal microenvironment.Numerous studies have focused on the association between dietary patterns,dietary components,and CRC now.This article reviews five different dietary patterns:the Western diet,the Mediterranean diet,the ketogenic diet,the Dietary Approaches to Stop Hypertension diet,and fasting,and themechanistic associations between their food components and CRC.The finding can provide a reference for further studies on the association between different dietary patterns and CRC and will help clinicians formulate reasonable and feasible dietary interventions.展开更多
Some mechanistic models have been proposed to predict the No3- concentrations in the soil solution at root surface and the NO3-N uptake by plants, but all these relatively effective non-steady state models have not ye...Some mechanistic models have been proposed to predict the No3- concentrations in the soil solution at root surface and the NO3-N uptake by plants, but all these relatively effective non-steady state models have not yet been verified by any soil culture experiment. In the present study, a mathematical model based on the nutrient transport to the roots, root length and root uptake kinetics as well as taking account of the inter-root competition was used for calculation, and soil culture experiments with rice, wheat and rape plants grown on alkali, neutral and acid soils in rhizoboxes with nylon screen as a isolator were carried out to evaluate the prediction ability of the model through comparing the measured NO3-concentrations at root surface and N uptake with the calculated values. Whether the inter-root competition for nutrients was accounted for in the model was of less importance to the calculated N uptake but could induce significant changes in the relative concentrations of NO3- at root surface. For the three soils and crops, the measured NO3-N uptake agreed well with the calculated one, and the calculated relative concentrations at root surface were approximate to the measured values. But an appropriate rectification for some conditions is necessary when the plant uptake parameter obtained in solution culture experiment is applied to soil culture. In contrast with the present non-steady state model, the predicted relative concentrations, which show an accumulation, by the Phillips' steady-state model were distinct from the measured values which show a depletion, indicating that the present model has a better prediction ability than the steady-state model.展开更多
Over past decades,takotsubo cardiomyopathy(TTC)has drawn a substantial interest as a unique form of acute and reversible cardiomyopathy that usually emerges in response to adrenergic hyperactivation associated with a ...Over past decades,takotsubo cardiomyopathy(TTC)has drawn a substantial interest as a unique form of acute and reversible cardiomyopathy that usually emerges in response to adrenergic hyperactivation associated with a variety of emotional and physical triggers.[1,2]Even though,this phenomenon is generally characterized by an apical balloning pattern(classical variant),it might occasionally present with atypical morphological variants including mid-ventricular,inverted and focal forms of myocardial involvement.展开更多
In the paper entitled"Efficient adsorption of Mn(Ⅱ)by layered double hydroxides intercalated with di ethylenetriaminepentaacetic acid and the mechanistic study"in Journal of Environmental Sciences,volume 85...In the paper entitled"Efficient adsorption of Mn(Ⅱ)by layered double hydroxides intercalated with di ethylenetriaminepentaacetic acid and the mechanistic study"in Journal of Environmental Sciences,volume 85,page 56-65,there were problems with mathematical notation and dimensional errors in the calculation for Giibbs free energy.In Section 2.5:Adsorption isotherms and thermodynamics studies,authors calculated the Gibbs free energy change(△G°)展开更多
This research aimed to combine 3 cell and tissue culture technologies to obtain mechanistic insights of cells in porous scaffolds. When cultivated on 2D （2-dimensional） surfaces, HDFs （human dermal fibroblasts） be...This research aimed to combine 3 cell and tissue culture technologies to obtain mechanistic insights of cells in porous scaffolds. When cultivated on 2D （2-dimensional） surfaces, HDFs （human dermal fibroblasts） behaved individually and had no strict requirement on seeding density for proliferation; while HaCat cells relied heavily on initial densities for proliferation and colony formation, which was facilitated when co-cultured with HDFs. Experiments using a 3D CCIS （3-dimensional cell culture and imaging system） indicated that HDFs colonised openpores of varying sizes （125-420 ~tm） on modular substrates via bridge structures; while HaCat cells formed aperture structures and only colonised small pores （125 txm）. When co-cultured, HDFs not only facilitated HaCat attachment on the substrates, but also coordinated with HaCat cells to colonise open pores of varying sizes via bridge and aperture structures. Based on these observations, a 2-stage strategy for the culture of HDFs and HaCat cells on porous scaffolds was proposed and applied successfully on a cellulosic scaffold. This research demonstrated that cell colonisation in scaffolds was dependent on multiple factors; while the integrated 2D＆3D culture technologies and the 3D CCIS was an effective and efficient approach to obtain mechanistic insights of their influences on tissue regeneration.展开更多
Model-based controllers can significantly improve the performance of Proton Exchange Membrane Fuel Cell (PEMFC) systems. However, the complexity of these strategies constraints large scale implementation. In this work...Model-based controllers can significantly improve the performance of Proton Exchange Membrane Fuel Cell (PEMFC) systems. However, the complexity of these strategies constraints large scale implementation. In this work, with a view to reduce complexity without affecting performance, two different modeling approaches of a single-cell PEMFC are investigated. A mechanistic model, describing all internal phenomena in a single-cell, and an artificial neural network (ANN) model are tested. To perform this work, databases are measured on a pilot plant. The identification of the two models involves the optimization of the operating conditions in order to build rich databases. The two different models benefits and drawbacks are pointed out using statistical error criteria. Regarding model-based control approach, the computational time of these models is compared during the validation step.展开更多
基金Supported by the Scientific Research Fund of Tai’an Science and Technology Agency,No.2019NS180.
文摘Triple negative breast cancer(TNBC)is an exceptionally aggressive subtype of breast cancer with a poor prognosis.TNBC patients have limited treatment options beyond conventional chemotherapy,and they face significant challenges associated with disease recurrence and resistance to chemotherapy.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)/mechanistic target of rapamycin(mTOR)signaling pathway plays a pivotal role in cell proliferation,growth,metabolism,and survival.Its aberrant activation is closely linked to the development and progression of TNBC,as well as treatment response and drug resistance.Currently,numerous targeted drugs specifically inhibiting this signaling pathway are being developed and undergoing clinical trials.These include inhibitors targeting PI3K,AKT,or mTOR individually,as well as dual-target or multi-target inhibitors simultaneously targeting different components of this pathway.Encouragingly,some inhibitors have demonstrated promising potential in clinical trials.This review delves into the therapeutic potential of the PI3K/AKT/mTOR signaling pathway for TNBC and explores prospects for drug discovery.
文摘This article explores the association between salivary uric acid(UA)and periodontitis,systematically analyzing its dual roles and research progress.Studies indicate that UA acts as a primary antioxidant in saliva under physiological conditions(accounting for 70%),protecting periodontal tissues by scavenging reactive oxygen species.However,when gum disease becomes severe,UA can switch roles and fuel inflammation,worsening tissue damage.Lorente et al’s research found an independent inverse correlation between salivary UA levels and periodontitis severity(odds ratio=6.14,P=0.001),establishing 111 nmol/mL as a diagnostic threshold(area under the curve=66%).Nevertheless,limitations include sample heterogeneity and failure to distinguish between gingivitis and periodontitis.Mechanistically,three hypotheses are proposed:The Antioxidant Depletion Hypothesis(UA oxidation consumption leading to feedback loops),the Microbial Metabolic Hijacking Hypothesis(pathogens utilizing UA as a carbon source to disrupt redox balance),and the Epithelial Barrier Dysfunction Hypothesis(UA deficiency causing downregulation of tight junction proteins).Future research should prioritize longitudinal cohorts to validate predictive value,integrate multi-omics to explore dysregulated signatures,and develop UA supplementation or targeted antioxidant therapies.This study provides novel insights into periodontitis diagnosis and mechanisms,advancing the application of salivary biomarkers in precision periodontics.
基金Supported by Guangzhou Science and Technology Bureau Research Fund:the Mechanism of Action of Huangqi Guizhi Decoction on Precancerous Lesions in Cag Rats was Studied based on the Phosphatidylinositol 3-Kinase-Protein Kinase B-Mechanistic Target of Rapamycin Complex 2 Pathway(No.202102080643)Guangzhou Traditional Chinese Medicine and Integrative Medicine Research Project:Observation on the Therapeutic Effect of Wenyang Jianpi Ointment on Chronic Atrophic Gastritis of Spleen and Stomach Weakness Type and Study on its Regulatory Effect on Transforming Growth Factor Beta 3(No.20222A010079)Panyu District Science and Technology Project:the Mechanism by which the Modified Huangqi Guizhi Decoction Regulates the Transforming Growth Factor-β3 Signaling Pathway to Improve Precancerous Lesions in Rats with Chronic Atrophic Gastritis(No.2020-Z04-025)。
文摘OBJECTIVE:To investigate the effects of Jiawei Huangqi Guizhi decoction(加味黄芪桂枝汤)on chronic atrophic gastritis(CAG)in rats and its modulation of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin complex 2(PI3K/Akt/m TORC2)signaling pathway.METHODS:CAG was induced in rats and treated with high-,medium-,or low-dose Jiawei Huangqi Guizhi decoction.Gastric histopathology was observed by hematoxylin and eosin staining.Serum levels of gastrin,PI3K,Akt,and m TORC2 were detected by enzyme-linked immunosorbent assay.Gene and protein expression levels were analyzed by reverse transcription polymerase chain reaction and western blot.RESULTS:The decoction alleviated gastric mucosal injury,reduced inflammation,and restored epithelial structure.It regulated PI3K,Akt,and m TORC2 expression at both m RNA and protein levels.CONCLUSION:Jiawei Huangqi Guizhi decoction may prevent CAG progression by improving gastric tissue and modulating the PI3K/Akt/m TORC2 signaling pathway.
基金the National Key Research and Development Program of China(No.2021YFA1500100)the National Natural Science Foundation of China(Nos.92156017 and 21890722)+1 种基金“Frontiers Science Center for New Organic Matter”,Nankai University(No.63181206)Haihe Laboratory of Sustainable Chemical Transformation of Tianjin(No.24HHWCSS00019)for generous financial support。
文摘Mechanistic studies of the cleavage and transformation of unactivated C_(sp3)-H bonds are a significant field of chemistry.Overcoming the inherent low acidity of C-H bonds to activate the inert substrates is challenge under mild conditions.And their complex multi-step transformations may also hinder mechanistic understanding.Herein,we perform theoretical calculations and experimental studies to explore the C_(sp3)-H bonds activation and acylation mechanisms of toluene/thioether using the relatively weak base LDA.A synergistic"main and auxiliary"model was revealed involving dual lithium metal by LDA dimers,and the aryl dilithium species as an intermediate base can facilitate C_(sp3)-H activation.This model not only aids in understanding the acidity of unactivated C_(sp3)-H bonds and the nucleophilicity of their conjugate bases for their kinetic control through cooperative interactions,but also predicts unusual kinetic isotope effects(KIE)for newly designed 2-(methylthio)naphthalene that are experimentally validated.This research is expected to provide a crucial scenario for the cleavage and transformation of unactivated C_(sp3)-H bonds and the development of new functionalities for alkali metal reagents.
基金the Natural Science Foundation of China(Grant No:22309180)Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No:XDB0600000,XDB0600400)+3 种基金Liaoning Binhai Laboratory,(Grant No:LILBLB-2023-04)Dalian Revitalization Talents Program(Grant No:2022RG01)Youth Science and Technology Foundation of Dalian(Grant No:2023RQ015)the University of Waterloo.
文摘Zinc-air batteries(ZABs)are promising energy storage systems because of high theoretical energy density,safety,low cost,and abundance of zinc.However,the slow multi-step reaction of oxygen and heavy reliance on noble-metal catalysts hinder the practical applications of ZABs.Therefore,feasible and advanced non-noble-metal elec-trocatalysts for air cathodes need to be identified to promote the oxygen catalytic reaction.In this review,we initially introduced the advancement of ZABs in the past two decades and provided an overview of key developments in this field.Then,we discussed the work-ing mechanism and the design of bifunctional electrocatalysts from the perspective of morphology design,crystal structure tuning,interface strategy,and atomic engineering.We also included theoretical studies,machine learning,and advanced characterization technologies to provide a comprehensive understanding of the structure-performance relationship of electrocatalysts and the reaction pathways of the oxygen redox reactions.Finally,we discussed the challenges and prospects related to designing advanced non-noble-metal bifunctional electrocatalysts for ZABs.
基金supported by Beijing Natural Science Foundation(2222037)by the Fundamental Research Funds for the Central Universities.
文摘Neural networks are often viewed as pure‘black box’models,lacking interpretability and extrapolation capabilities of pure mechanistic models.This work proposes a new approach that,with the help of neural networks,improves the conformity of the first-principal model to the actual plant.The final result is still a first-principal model rather than a hybrid model,which maintains the advantage of the high interpretability of first-principal model.This work better simulates industrial batch distillation which separates four components:water,ethylene glycol,diethylene glycol,and triethylene glycol.GRU(gated recurrent neural network)and LSTM(long short-term memory)were used to obtain empirical parameters of mechanistic model that are difficult to measure directly.These were used to improve the empirical processes in mechanistic model,thus correcting unreasonable model assumptions and achieving better predictability for batch distillation.The proposed method was verified using a case study from one industrial plant case,and the results show its advancement in improving model predictions and the potential to extend to other similar systems.
文摘The synthesis of phosphine compounds through the addition reaction of H-[P(O)]species to olefins and alkynes has been extensively studied.Two different mechanisms of the addition of H-[P(O)]species to non-activated alkyne are mainly summarized.One is the oxidative addition-migration insertion-reductive elimination mechanism,namely the Chalk-Harrod type mechanism,and the other is the proton transfer-reductive elimination mechanism.This review elaborates on the specific steps of each mechanism,and discusses experimental and computational evidence supporting these steps.Additionally,a few other types of mechanisms are briefly mentioned.The mechanism of H-[P(O)]reaction with relevant conjugated dienes was also involved when closely related.
文摘A three dimensional finite element program incorporating actually measured vertical tire-pavement contact pressure(TPCP) was utilized for modeling the mechanistic responses in asphalt concrete(AC) layers by simulating various vehicle motions:stationary and non-stationary(i.e.in acceleration or deceleration mode).Analysis of the results indicated the following items.1) It is critical to use the vertical TPCP as the design control criteria for the tensile strains at the bottom of the AC layer when the base layer modulus is lower in magnitude(e.g.≤400 MPa);however,when the base layer modulus is higher in magnitude(e.g.≥7 000 MPa),the horizontal TPCP and the tensile strains in the X-direction at the surface of the AC layer should also be considered as part of the design response criteria.2) The definition of "overload" needs to be revised to include tire pressure over-inflation,i.e.,a vehicle should be considered to be overloaded if the wheel load exceeds the specification and/or the tire inflation pressure is higher than the specification.3) Light trucks have more structural impact on the strain responses and pavement design when the thickness of the surfacing AC layer is thinner(e.g.≤50 mm).4) The acceleration of a vehicle does not significantly impact the AC surface distresses such as rutting at the top of the upgrade slopes or intersections;however,vehicle deceleration can dramatically induce horizontal shear strains and consequently,aggravate shoving and rutting problems at the highway intersections.Evidently,these factors should be taken into account during mechanistic stress-strain modeling and structural design of asphalt pavements.
基金the Postgraduate Seed Fund of Northwestern Polytechnical University(No.Z2012038)National Natural Science Foundation of China(No.51005183)National Key S&T Special Projects(No.2011X04016-031)
文摘An improved method to determine cutting force coefficients for bull-nose cutters is proposed based on the semi-mechanistic cutting force model. Due to variations of cutting speed along the tool axis in bull-nose milling, they affect coefficients significantly and may bring remarkable discrepancies in the prediction of cutting forces. Firstly, the bull-nose cutter is regarded as a finite number of axial discs piled up along the tool axis, and the rigid cutting force model is exerted. Then through discretization along cutting edges, the cutting force related to each element is recalculated, which equals to differential force value between the current and previous elements. In addition, coefficient identification adopts the cubic polynomial fitting method with the slice elevation as its horizontal axis. By calculating relations of cutting speed and cutting depth, the influences of speed variations on cutting force can be derived. Thereby, several tests are conducted to calibrate the coefficients using the improved method, which are applied to later force predictions. Eventually, experimental evaluations are discussed to verify the effectiveness. Compared to the conventional method, the results are more accurate and show satisfactory consistency with the simulations. For further applications, the method is instructive to predict the cutting forces in bull-nose milling with lead or tilt angles and can be extended to the selection of cutting parameters.
基金Supported by National Natural Science Foundation of China, No. U20A20408 and No. 82074450Natural Science Foundation of Hunan Province, No. 2020JJ4066+4 种基金Hunan Province"Domestic First-class Cultivation Discipline"Integrated Traditional Chinese and Western Medicine Open Fund Project, No. 2020ZXYJH34 and No. 2020ZXYJH35Hunan Graduate Scientific Research Innovation Project, No. QL20210173 and No. CX20210730Hunan Province Science and Technology Innovation Talents Plan College Students Science and Technology Innovation and Entrepreneurship Project, No. 2020RC1004Guangzhou Health Science and Technology Project, No. 20221A011102Hunan Traditional Chinese Medicine Scientific Research Project, No. 202101
文摘BACKGROUND The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin(PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills(XHP) are a traditional Chinese preparation with antitumour properties. They inhibit the growth of breast cancer, glioma, and other tumours by regulating the PI3K/Akt/mTOR signalling pathway. However, the effects and mechanisms of action of XHP in hepatocellular carcinoma(HCC) remain unclear. Regulation of the PI3K/Akt/mTOR signalling pathway effectively inhibits the progression of HCC. However, no study has focused on the XHPassociated PI3K/Akt/mTOR signalling pathway. Therefore, we hypothesized that XHP might play a role in inhibiting HCC through the PI3K/Akt/mTOR signalling pathway.AIM To confirm the effect of XHP on HCC and the possible mechanisms involved.METHODS The chemical constituents and active components of XHP were analysed using ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS). Cellbased experiments and in vivo xenograft tumour experiments were utilized to evaluate the effect of XHP on HCC tumorigenesis. First, SMMC-7721 cells were incubated with different concentrations of XHP(0, 0.3125, 0.625, 1.25, and 2.5 mg/mL) for 12 h, 24 h and 48 h. Cell viability was assessed using the CCK-8 assay, followed by an assessment of cell migration using a wound healing assay.Second, the effect of XHP on the apoptosis of SMMC-7721 cells was evaluated. SMMC-7721 cells were stained with fluorescein isothiocyanate and annexin V/propidium iodide. The number of apoptotic cells and cell cycle distribution were measured using flow cytometry. The cleaved protein and mRNA expression levels of caspase-3 and caspase-9 were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction(RT-qPCR), respectively.Third, Western blotting and RT–qPCR were performed to confirm the effects of XHP on the protein and mRNA expression of components of the PI3K/Akt/mTOR signalling pathway.Finally, the effects of XHP on the tumorigenesis of subcutaneous hepatocellular tumours in nude mice were assessed.RESULTS The following 12 compounds were identified in XHP using high-resolution mass spectrometry:Valine, 4-gingerol, myrrhone, ricinoleic acid, glycocholic acid, curzerenone, 11-keto-β-boswellic acid, oleic acid, germacrone, 3-acetyl-9,11-dehydro-β-boswellic acid, 5β-androstane-3,17-dione, and 3-acetyl-11-keto-β-boswellic acid. The cell viability assay results showed that treatment with 0.625mg/mL XHP extract decreased HCC cell viability after 12 h, and the effects were dose-and timedependent. The results of the cell scratch assay showed that the migration of HCC cells was significantly inhibited in a time-dependent manner by the administration of XHP extract(0.625mg/mL). Moreover, XHP significantly inhibited cell migration and resulted in cell cycle arrest and apoptosis. Furthermore, XHP downregulated the PI3K/Akt/mTOR signalling pathway, which activated apoptosis executioner proteins(e.g., caspase-9 and caspase-3). The inhibitory effects of XHP on HCC cell growth were determined in vivo by analysing the tumour xenograft volumes and weights.CONCLUSION XHP inhibited HCC cell growth and migration by stimulating apoptosis via the downregulation of the PI3K/Akt/mTOR signalling pathway, followed by the activation of caspase-9 and caspase-3.Our findings clarified that the antitumour effects of XHP on HCC cells are mediated by the PI3K/Akt/mTOR signalling pathway, revealing that XHP may be a potential complementary therapy for HCC.
基金Supported by Novartis Espana and by grant to Pons JA as Principal Investigator from Instituto Salud Carlos III,No.PI12/02042
文摘Mammalian target of rapamycin, also known as me-chanistic target of rapamycin(m TOR) is a protein kinase that belongs to the PI3K/AKT/m TOR signaling pathway, which is involved in several fundamental cellular functions such as cell growth, proliferation, and survival. This protein and its associated pathway have been implicated in cancer development and the regulation of immune responses, including the rejection response generated following allograft transplantation. Inhibitors of m TOR(m TORi) such as rapamycin and its derivative everolimus are potent immunosuppressive drugs that both maintain similar rates of efficacy and could optimize the renal function and diminish the side effects compared with calcineurin inhibitors. These drugs are used in solid-organ transplantationtoinduceimmunosuppression while also promoting the expansion of CD4+CD25+FOXP3+ regulatory T-cells that could favor a scenery of immu-nological tolerance. In this review, we describe the mechanisms by which inhibitors of m TOR induce sup-pression by regulation of these pathways at different levels of the immune response. In addition, we par-ticularly emphasize about the main methods that are used to assess the potency of immunosuppressive drugs, highlighting the studies carried out about immunosuppressive potency of inhibitors of m TOR.
基金supported by the National Key Research and Development Program of China(Grant No.2017YFC0405401)the National Science&Technology Pillar Program(Grant No.2012BAB03B01)+1 种基金the Fundamental Research Funds for the Central Universities,Hohai University(Grant No.2014B30914)the Natural Science Foundation of Jiangsu Province(Grant No.BK2012411)
文摘Understanding the drifting motion of a small semi-submersible drifter is of vital importance regarding monitoring surface currents and the floating pollutants in coastal regions. This work addresses this issue by establishing a mechanistic drifting forecast model based on kinetic analysis. Taking tide–wind–wave into consideration, the forecast model is validated against in situ drifting experiment in the Radial Sand Ridges. Model results show good performance with respect to the measured drifting features, characterized by migrating back and forth twice a day with daily downwind displacements. Trajectory models are used to evaluate the influence of the individual hydrodynamic forcing. The tidal current is the fundamental dynamic condition in the Radial Sand Ridges and has the greatest impact on the drifting distance. However, it loses its leading position in the field of the daily displacement of the used drifter. The simulations reveal that different hydrodynamic forces dominate the daily displacement of the used drifter at different wind scales. The wave-induced mass transport has the greatest influence on the daily displacement at Beaufort wind scale 5–6; while wind drag contributes mostly at wind scale 2–4.
文摘Three sets of data from the field experiments with different wheat( Triticum L. ) varieties and sowing dates in China and USA were used to test the performance of the mechanistic model of wheat development. The results showed that the absolute prediction errors for most phasic and phenological stages ranged within 0 - 5 days, and the root mean square errors were generally less than 5 days. The model was of high accuracy and low error especially for emergence, tillering, stamen and pistil initiation, and heading stages, reflecting an enhanced level of mechanism and prediction.
文摘The impact of lipophilicity as represented by the logarithm of octanol/water partition coefficient (logP), the combined steric/polarizability effect as represented by molar refractivity (MR) and bulk as represented by molar volume (MV) on the biological activity of 29 known aminopyrimidoisoquinolinequinones APIQ were analyzed using quantitative structure activity relationships methodology (QSAR). The activity data chosen was the inhibitory concentration (IC50) against human gastric adenocarcinoma (AGS) cell line. On running regression analysis, the physicochemical parameters and IC50 show very weak correlations as evident by the low values of Pearson Correlation R2 (0.1 to 0.2). Since the individual compounds show appreciable activity (ranging from 20 to 0.5 μM), classification was resorted to in order to expose mechanistic nesting subgroups. This was done by clustering data points around various trend lines extracted from the scattered plot relating parameters to activity using R2 as an index. The correlation of IC50 versus MV was chosen a base of classification owing to higher statistical metrics it yield. This gave five regression lines, each of which is believed to represent a separate mechanistic profile. Additional descriptors were used to consolidate the clustering approach and to give depth to the assumed mechanistic profiles of each cluster.
文摘Colorectal cancer(CRC)is a common cancer with high morbidity and mortality rates.Its occurrence and development are determined by many factors,including genetics,the environment,lifestyle,and so on.The occurrence of CRC is often accompanied by changes in the intestinal microenvironment.Numerous studies have focused on the association between dietary patterns,dietary components,and CRC now.This article reviews five different dietary patterns:the Western diet,the Mediterranean diet,the ketogenic diet,the Dietary Approaches to Stop Hypertension diet,and fasting,and themechanistic associations between their food components and CRC.The finding can provide a reference for further studies on the association between different dietary patterns and CRC and will help clinicians formulate reasonable and feasible dietary interventions.
文摘Some mechanistic models have been proposed to predict the No3- concentrations in the soil solution at root surface and the NO3-N uptake by plants, but all these relatively effective non-steady state models have not yet been verified by any soil culture experiment. In the present study, a mathematical model based on the nutrient transport to the roots, root length and root uptake kinetics as well as taking account of the inter-root competition was used for calculation, and soil culture experiments with rice, wheat and rape plants grown on alkali, neutral and acid soils in rhizoboxes with nylon screen as a isolator were carried out to evaluate the prediction ability of the model through comparing the measured NO3-concentrations at root surface and N uptake with the calculated values. Whether the inter-root competition for nutrients was accounted for in the model was of less importance to the calculated N uptake but could induce significant changes in the relative concentrations of NO3- at root surface. For the three soils and crops, the measured NO3-N uptake agreed well with the calculated one, and the calculated relative concentrations at root surface were approximate to the measured values. But an appropriate rectification for some conditions is necessary when the plant uptake parameter obtained in solution culture experiment is applied to soil culture. In contrast with the present non-steady state model, the predicted relative concentrations, which show an accumulation, by the Phillips' steady-state model were distinct from the measured values which show a depletion, indicating that the present model has a better prediction ability than the steady-state model.
文摘Over past decades,takotsubo cardiomyopathy(TTC)has drawn a substantial interest as a unique form of acute and reversible cardiomyopathy that usually emerges in response to adrenergic hyperactivation associated with a variety of emotional and physical triggers.[1,2]Even though,this phenomenon is generally characterized by an apical balloning pattern(classical variant),it might occasionally present with atypical morphological variants including mid-ventricular,inverted and focal forms of myocardial involvement.
基金funded by the National Natural Science Foundation of China(Nos.31971551,31470573 and 31070478)the Tianjin Key Projects of Scientific and Technological Support(Nos.17YFZCNC00220 and 18YFZCNC01270)
文摘In the paper entitled"Efficient adsorption of Mn(Ⅱ)by layered double hydroxides intercalated with di ethylenetriaminepentaacetic acid and the mechanistic study"in Journal of Environmental Sciences,volume 85,page 56-65,there were problems with mathematical notation and dimensional errors in the calculation for Giibbs free energy.In Section 2.5:Adsorption isotherms and thermodynamics studies,authors calculated the Gibbs free energy change(△G°)
文摘This research aimed to combine 3 cell and tissue culture technologies to obtain mechanistic insights of cells in porous scaffolds. When cultivated on 2D （2-dimensional） surfaces, HDFs （human dermal fibroblasts） behaved individually and had no strict requirement on seeding density for proliferation; while HaCat cells relied heavily on initial densities for proliferation and colony formation, which was facilitated when co-cultured with HDFs. Experiments using a 3D CCIS （3-dimensional cell culture and imaging system） indicated that HDFs colonised openpores of varying sizes （125-420 ~tm） on modular substrates via bridge structures; while HaCat cells formed aperture structures and only colonised small pores （125 txm）. When co-cultured, HDFs not only facilitated HaCat attachment on the substrates, but also coordinated with HaCat cells to colonise open pores of varying sizes via bridge and aperture structures. Based on these observations, a 2-stage strategy for the culture of HDFs and HaCat cells on porous scaffolds was proposed and applied successfully on a cellulosic scaffold. This research demonstrated that cell colonisation in scaffolds was dependent on multiple factors; while the integrated 2D＆3D culture technologies and the 3D CCIS was an effective and efficient approach to obtain mechanistic insights of their influences on tissue regeneration.
文摘Model-based controllers can significantly improve the performance of Proton Exchange Membrane Fuel Cell (PEMFC) systems. However, the complexity of these strategies constraints large scale implementation. In this work, with a view to reduce complexity without affecting performance, two different modeling approaches of a single-cell PEMFC are investigated. A mechanistic model, describing all internal phenomena in a single-cell, and an artificial neural network (ANN) model are tested. To perform this work, databases are measured on a pilot plant. The identification of the two models involves the optimization of the operating conditions in order to build rich databases. The two different models benefits and drawbacks are pointed out using statistical error criteria. Regarding model-based control approach, the computational time of these models is compared during the validation step.
