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V2O5, which has multicolor and energy storage properties, is a promising electrochromic material for multifunctional electrochromic devices, but its practical application is limited by its poor lifespan and long switching time. In this work, high-performance V2O5/TiO2films were fabricated by spraying a V2O5solution on in situ-grown TiO2nanorods. Due to the porous structure formed between the TiO2nanorods and the remarkable electron transfer performance of TiO2, the switching time of the V2O5/TiO2films decreased. Moreover, the strong adhesion between the TiO2nanorods and F-doped tin oxide (FTO) glass and the increased surface roughness of the substrates significantly improved the cycling stability of the V2O5/TiO2films. With a large transmittance modulation (47.8% at 668 nm), fast response speed (τc= 5.1 s, τb= 4.2 s), and long lifespan, V2O5/TiO2films were used as electrodes for the electrochromic energy storage device (EESD), which switched in six colors through color overlay: dark orange, sandy yellow, green-yellow, yellow-green, dark green, and dark brown. Inspired by pixel displays, EESDs were designed by segmenting V2O5films to stagger the display of the electrochromic and ion storage layers, which presented 11 types of information based on different combinations of colors. This work provides inspiration for developing multifunctional electrochromic devices, especially for camouflage and information displays.

ABSTRACTIn modern industry, deep learning algorithms have increasingly replaced manual sorting for detecting workpieces and enabling sorting by robots or robotic arms. However, the detection of stacked workpieces presents a challenge to automated detection. In this paper, the YOLOv5-RES algorithm is proposed to solve the problem of detecting stacked workpieces based on the YOLOv5 algorithm. The receptive field block (RFB) replaces the original fast pyramid pooling layer (SPPF) of YOLOv5 to enable the network to better acquire feature information of stacked workpieces. The EIOU loss is introduced to improve the network’s accuracy in regression, and a flexible prediction box selection algorithm (Soft-NMS) is utilized to reduce the possibility of incorrectly removing stacked workpiece targets. The effectiveness of YOLOv5-RES is verified on a homemade workpiece dataset. On the test set, the precision for all classes is 93.3%, the mAP@.5 is 91.4%, and the detection speed is 65.4 FPS (Frames Per Second), which meets the real-time requirement. And the detection results show that YOLOv5-RES greatly avoids the problems of incorrect detection and missed detection of YOLOv5. Moreover, YOLOv5-RES achieves the optimal effect in both the comparison experiment and the ablation experiment, indicating its effectiveness and potential for application.

Here, we report the first catalytic enantioselective 1,4-addition of diarylphosphine oxides to α,β-unsaturated thioesters. Importantly, the most common and commercial oxazaborolidine (CBS) was employed as a catalyst for its new application without being activated by strong protonic acids or Lewis acids and led to the chiral thioesters in excellent yields and enantioselectivities. Furthermore, this method features mild reaction conditions (room temperature and air-insensitive), good substrate tolerance, and easy scalability.

The photovoltaic thermochromic smart window, which combines perovskite with thermochromic and photovoltaic properties, can not only control the solar transmittance at different temperatures, but also convert the absorbed light energy into usable electric energy. Herein, we designed a fluoride-doped tin oxide (FTO)/SnO2/CsPbIBr2/NiOx/indium tin oxide (ITO) semitransparent solar cell structure by using the optimized post-annealing process and obtained an average visible transmittance (AVT) of 33.2% and a power conversion efficiency of 3.89% under the optimal conditions. Meanwhile, based on the thermochromic properties of CsPbIBr2, it was found that the AVT of the device improved from 33.2% to 73.5% when CsPbIBr2converted from the colored high-temperature phase to the transparent low-temperature phase. Besides, the transition from high-temperature phase to low-temperature phase is humidity-dominated. When the relative humidity rises from 50% to 90%, the phase transition time of perovskite decreases substantially from 1005 to 17 min. However, the excessively fast phase transition caused by high humidity will destroy the thin film morphology and crystal structure of perovskite, causing irreversible damage to CsPbIBr2perovskite. This work is promising for the application of semitransparent photovoltaic and thermochromic smart window, which represents an attractive prospect in further reducing the energy consumption of buildings and automobiles.

Introduction: The association between diabetes mellitus (DM) and risk of osteoarthritis (OA) is inconsistent based on published observational studies. This study aimed to conduct a two-sample Mendelian randomization (MR) analysis to explore the causal link between glycated hemoglobin (HbA1c) level and OA risk. Methods: Genome-wide association studies (GWAS) summary statistics were obtained from the publicly available Integrative Epidemiology Unit (IEU) OpenGWAS database. A series of screening processes were performed to select qualified instrumental single-nucleotide polymorphisms (SNPs) strongly related to exposure. The inverse-variance-weighted method, weighted-median method, and MR–Egger method were performed to ensure robust and reliable results. The MR–Egger intercept test, Cochran’s Qtest, and the leave-one-out sensitivity analysis were utilized to assess the horizontal pleiotropy, heterogeneities, and stability of these genetic variants for OA. Odds ratio (OR) and 95% confidence interval (CI) were calculated. Results: MR analyses found a robust causal association of genetically determined HbA1c with knee OA (OR = 1.561; 95% CI 1.110–2.197; P= 0.011), but not with hip OA (OR = 1.073; 95% CI 0.674–1.710; P= 0.766) or overall OA (OR = 1.141; 95% CI 0.904–1.441; P= 0.804). Sensitivity analyses showed that there was a strong association between SNPs and HbA1c (F= 21.138), no evidence of heterogeneity (Q= 150.625, P= 0.402), and no potential SNPs affecting the causal link. Conclusion: Our MR study supported a causal effect of genetically increased HbA1c on knee OA risk.

Efficient peptide and protein identifications from data-independent acquisition mass spectrometric (DIA-MS) data typically rely on a project-specific spectral library with a suitable size. Here, we describe subLib, a computational strategy for optimizing the spectral library for a specific DIA data set based on a comprehensive spectral library, requiring the preliminary analysis of the DIA data set. Compared with the pan-human library strategy, subLib achieved a 41.2% increase in peptide precursor identifications and a 35.6% increase in protein group identifications in a test data set of six colorectal tumor samples. We also applied this strategy to 389 carcinoma samples from 15 tumor data sets: up to a 39.2% increase in peptide precursor identifications and a 19.0% increase in protein group identifications were observed. Our strategy for spectral library size optimization thus successfully proved to deepen the proteome coverages of DIA-MS data.

Ciraparantag, an anticoagulant reversal agent, is a small molecule specifically designed to bind noncovalently by charge-charge interaction to unfractionated heparin and low-molecular-weight heparin. It shows binding characteristics that are similar to those of direct oral anticoagulants (DOACs). A dynamic light-scattering methodology was used to demonstrate ciraparantag’s binding to the heparins and DOACs and its lack of binding to a variety of proteins including coagulation factors and commonly used drugs. Ciraparantag reaches maximum concentration within minutes after IV administration with a half-life of 12 to 19 minutes. It is primarily hydrolyzed by serum peptidases into 2 metabolites, neither of which has substantial activity. Ciraparantag and its metabolites are recovered almost entirely in the urine. In animal models of bleeding (rat tail transection and liver laceration), a single IV dose of ciraparantag given at peak concentrations of the anticoagulant, but before the bleeding injury, significantly reduced the blood loss. Ciraparantag, given after the bleeding injury, also significantly reduced blood loss. It appears to have substantial ability to reduce blood loss in animal models in which a variety of anticoagulants are used and has potential as a useful DOAC reversal agent.

We reported and evaluated a microflow, single-shot, short gradient SWATH MS method intended to accelerate the discovery and verification of protein biomarkers in preclassified clinical specimens. The method uses a 15 min gradient microflow-LC peptide separation, an optimized SWATH MS window configuration, and OpenSWATH software for data analysis. We applied the method to a cohort containing 204 FFPE tissue samples from 58 prostate cancer patients and 10 benign prostatic hyperplasia patients. Altogether we identified 27,975 proteotypic peptides and 4037 SwissProt proteins from these 204 samples. Compared to a reference SWATH method with a 2 h gradient, we found 3800 proteins were quantified by the two methods on two different instruments with relatively high consistency (r= 0.77). The accelerated method consumed only 17% instrument time, while quantifying 80% of proteins compared to the 2 h gradient SWATH. Although the missing value rate increased by 20%, batch effects reduced by 21%. 75 deregulated proteins measured by the accelerated method were selected for further validation. A shortlist of 134 selected peptide precursors from the 75 proteins were analyzed using MRM-HR, and the results exhibited high quantitative consistency with the 15 min SWATH method (r= 0.89) in the same sample set. We further verified the applicability of these 75 proteins in separating benign and malignant tissues (AUC = 0.99) in an independent prostate cancer cohort (n= 154). Altogether, the results showed that the 15 min gradient microflow SWATH accelerated large-scale data acquisition by 6 times, reduced batch effect by 21%, introduced 20% more missing values, and exhibited comparable ability to separate disease groups.

Background/AimsTo develop a deep learning system (DLS) that can automatically detect malignant melanoma (MM) in the eyelid from histopathological sections with colossal information density.MethodsSetting: Double institutional study.Study population: We retrospectively reviewed 225 230 pathological patches (small section cut from pathologist-labelled area from an H&E image), cut from 155 H&E-stained whole-slide images (WSI).Observation procedures: Labelled gigapixel pathological WSIs were used to train and test a model designed to assign patch-level classification. Using malignant probability from a convolutional neural network, the patches were embedded back into each WSI to generate a visualisation heatmap and leveraged a random forest model to establish a WSI-level diagnosis.Main outcome measure(s): For classification, the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity and specificity were used to evaluate the efficacy of the DLS in detecting MM.ResultsFor patch diagnosis, the model achieved an AUC of 0.989 (95% CI 0.989 to 0.991), with an accuracy, sensitivity and specificity of 94.9%, 94.7% and 95.3%, respectively. We displayed the lesion area on the WSIs as graded by malignant potential. For WSI, the obtained sensitivity, specificity and accuracy were 100%, 96.5% and 98.2%, respectively, with an AUC of 0.998 (95% CI 0.994 to 1.000).ConclusionOur DLS, which uses artificial intelligence, can automatically detect MM in histopathological slides and highlight the lesion area on WSIs using a probabilistic heatmap. In addition, our approach has the potential to be applied to the histopathological sections of other tumour types.

Ganoderma lucidumpolysaccharide (GLP) is a prebiotic with immunomodulatory effects. However, the therapeutic potential of GLP in tumor immunotherapy has not been fully explored, especially in T cell-mediated antitumor immunity. In this study, we found that GLP significantly inhibited tumor growth and activated antitumor immunity in colorectal cancer (CRC). In the spleens and tumor tissues, the proportion of cytotoxic CD8+T cells and Th1 helper cells increased, while immunosuppressive Tregs decreased. Additionally, microbiota dysbiosis was alleviated by GLP, and short-chain fatty acid production was increased. Meanwhile, GLP decreased the ratio of kynurenine and tryptophan (Kyn/Trp) in the serum, which contributed to antitumor immunity of T cells. More importantly, the combination of GLP and the immune checkpoint inhibitor anti-PD-1 monoclonal antibody further enhanced the efficacy of anti-PD-1 immunotherapy. Thus, GLP as a prebiotic has the potential to be used in tumor immunotherapy.

Objective: To observe the clinical features and efficacy of immunosuppressive therapy in patients with primary Sjögren's syndrome (PSS) combined with peripheral neuropathy (PN) syndrome and to explore the risk factors for PN in patients with PSS. Methods: Sixty consecutive patients with PSS admitted to the Department of Rheumatology and Immunology, Wuhan No. 1 Hospital, from January 2014 to June 2020 were analysed retrospectively. Patients were divided into a PN group (N= 15) and a non-PN group (N= 45). The clinical characteristics of the two groups were compared, and the independent risk factors for PN combined with PSS were analysed by multivariate logistic regression. The patients with PSS combined with PN were followed up to observe the effect of immunosuppressive therapy. Results: The patients with PN had a longer course of disease than those without PN (z= − 3.225, P= 0.001), and the incidence of Raynaud's phenomenon, anti-SSB antibody, rheumatoid factor and hyperglobulinaemia was higher (all P< 0.05) in patients with PN than in those without PN. Multivariate logistic regression analysis showed that hyperglobulinaemia, RF and anti-SSB antibodies were independent risk factors for PN with PSS (P< 0.05). Fourteen patients with PSS-PN were treated with immunosuppressants. The clinical symptoms of 10 patients were relieved, and mRS scores of 10 patients were decreased. Conclusion: PN is a common complication in PSS patients. Patients with PSS combined with PN have a longer course of disease and a significantly higher percentage of Raynaud's phenomenon, positive anti-SSB antibody, positive RF and hyperglobulinaemia. Immunosuppressive therapy was effective for partial remission of PN with PSS.

Abstract Based on the classical Nix-Gao model of indentation size effect (ISE), a new model incorporating the role of elastic deformation is proposed for modeling ISE at indentation depths below 100 nm. We show that, while elastic deformation is generally not associated with the generation of geometrically necessary dislocations (GNDs), neglecting it can lead to severe overestimation of both the nanoindentation hardness and GND density at small indentation depths, particularly below 100 nm, and the reverse ISE is also described. In this sense, elastic deformation can play an essential role in estimating nanoindentation hardness at small indentation depths. It is shown that our model predictions are in good agreement with experimental results on nanoindentation of single Cu and MgO crystals. A similar model applied to ISE in ion-irradiated metallic materials, where the irradiation hardening effect and ISE are successfully separated, enables analysis of irradiation hardening in ion-irradiated metallic materials without the interference of ISE. [ABSTRACT FROM AUTHOR]

Ultrafine-grained tungsten (UFG W) produced by severe plastic deformation technology has many potential applications due to its high strength and ductility. To reveal the mechanism for the high ductility of UFG W, the deformation and failure behaviors of coarse-grained tungsten (CG W) and UFG W have been compared based on a three-dimensional crystal plastic finite element method (CPFEM) simulation. Cohesive element method has been utilized to model the behavior of grain boundaries (GBs). Both plastic deformation in grain interiors and grain boundary opening have been observed in different periods of deformation in UFG W. It is concluded that the high GB density and elongated microstructure in the UFG W suppress crack propagation, decrease the stress concentration and impurity concentration on GBs, therefore enhance the ductility of the material.

Among all‐inorganic perovskites, CsPbIBr2has become a potential candidate in semitransparent perovskite solar cells (ST‐PSCs) due to its excellent thermal stability and suitable bandgap. Herein, by optimizing the ambient temperature in an N2‐filled glovebox, the growth process of CsPbIBr2crystals is regulated to avoid the generation of pinholes and improve the photoelectric conversion capacity of perovskite cells. When the ambient temperature is around 25 °C, the champion power conversion efficiency (PCE) of 10.82% with opaque n–i–p structure is achieved. Based on MoOx/Ag/MoOx(20/12/20 nm) multilayer top electrode, the ST‐PSC device achieves a maximum PCE of 7.06% at the fluorine‐doped tin oxide side under the simulated 1 sun illumination condition and a PCE of 23.96% at MoOx/Ag/MoOxelectrode side under the intensity of 1000 lux (≈350 μW cm−2) provided by a white light‐emitting diode lamp, along with an average visible transmittance of 29.25%. The resulting perovskite solar cell is the first bifacial inorganic ST‐PSC that could be used under both sunlight and indoor light, which is an important step toward all‐day power generation of inorganic ST‐PSCs and building‐integrated photovoltaics. CsPbIBr2is a potential candidate in semitransparent perovskite solar cells (ST‐PSCs) due to its excellent thermal stability and suitable bandgap. Herein, the CsPbIBr2‐based ST‐PSC is the first bifacial inorganic ST‐PSC that could be used under both sunlight and indoor light, which is an important step toward all‐day power generation of inorganic ST‐PSCs and building‐integrated photovoltaics.

CsPbIBr2has shown great potential in the optoelectronics field due to its well‐balanced relationship between bandgap and durability among all‐inorganic perovskites materials. However, the CsPbIBr2thin films prepared by the traditional one‐step spin coating method suffer from unsatisfactory morphology, poor crystallinity, and high defect density, which lead to the degradation of device performance. Herein, a simple preannealing method is used to form unstable transition films which are then annealed at high temperature to obtain CsPbIBr2perovskite films with uniform morphology, free pinholes, and strong crystallinity. The performance of the device can be effectively improved due to the reduction of defects and the optimization of the contact between functional layers. Therefore, the power conversion efficiency of 9.6% is obtained, which is nearly 100% improvement compared with that of the control device. A simple preannealing method is used to obtain CsPbIBr2perovskite films with uniform morphology, strong crystallinity, and free pinholes. The performance of the device can be effectively improved due to the reduction of defects and the optimization of the contact between functional layers. Therefore, a power conversion efficiency of 9.6% is obtained, which is nearly 100% improvement compared with that of the controlled device.

Operator exposures to pesticides of mixer/loaders (M&L) and pilots during drone application in a typical paddy rice field were measured using a tracer formulation. Median potential dermal exposures to M&L and pilot operators were 9.886 and 0.400 mg substance/kg substance handled, respectively, indicating that operator exposure was mainly during M&L (with 73% detected on the operator’s hands). M&L operator exposure was reduced by 21% by wearing one layer of certified clothing (to 7.817 mg/kg), and by a further 98% by also using Tyvec gloves (to 0.173 mg/kg). Potential and actual exposures of drone pilots were 0.400 and 0.012 mg/kg, respectively. When 75th percentiles were compared to those from publicly available handheld exposure models recommended for regulatory purposes, the use of drones for application resulted in an exposure reduction of 90–99%. In conclusion, compared to handheld spray equipment, the use of drones for pesticide application significantly reduces the operator exposure.

AbstractWater-quenched blast furnace slag (WBFS) has been assessed regarding its capacity to remove Cu2+, Cd2+, and Zn2+from aqueous solutions. The physicochemical properties of the slag were characterized by ICP, SEM, and XRD. Batch experiments were conducted to study the effects of the adsorbent dosage, pH, initial concentration of heavy metal ions, temperature, and contact time on the removal of Cu2+, Cd2+, and Zn2+. The results showed that the removal efficiency increased with increasing adsorbent dosage and the optimum conditions for the removal of Cu2+, Cd2+, and Zn2+were obtained in the dosage of 12, 16, and 16 g/L, respectively. The removal efficiency and adsorption amount of Cu2+, Cd2+, and Zn2+onto WBFS increased on increasing the solution pH from 1 to 9, while the values decreased slightly as the pH further increased above 9. The adsorption process could fit the pseudo-second-order kinetic and Langmuir isotherm models. Various thermodynamic parameters were calculated and the results indicated the adsorption of Cu2+, Cd2+, and Zn2+onto WBFS was feasible and endothermic in nature. These results have significant implications for the treatment of heavy metal wastewater using low-cost adsorbents.

Microbe-soil combined treatment is a newly developed technology in view of the defects of the curing process and waste drilling mud slag properties. In particular, 0.3%–0.5% bioremediation reagents were fully mixed with the waste drilling sludge according to its wet and dry degree, and 1.5 folds to twice weight of more finely ground soil was added in the mix, which was covered by soil of 5–15 cm thick and thereby grasses or greeneries were planted on the soil. The process was successfully applied to some fields of Well Danqian 001-8, Well Lianhua 000-X8, etc. After three months of such treatment, the main indexes of the drilling solid waste such as the degradation of COD and the oil-degrading ratio reached more than 90%, the index of leaching solution met the requirement of the first grade in the national “Integrated Wastewater Discharge Standard”; heavy metal ion concentration in soil did not change significantly with the indicators meeting the requirement of the third grade in the national “Soil Environmental Quality Standard” (Dry Land); and no harmful effects of heavy metals have ever been found on the planted grasses and greeneries. In conclusion, with this microbe-soil technology, the soil property will recover its background values without any other chemical additives, realizing the ecological restoration and reuse of land covered by wellsite wastes, so it is in line with the energy-saving and environmentally-friendly treatment way.

The influenza virus matrix protein 2 (M2) assembles into a tetramer in the host membrane during viral uncoating and maturation. It has been used as a model system to understand the relative contributions of protein-lipid and protein-protein interactions to membrane protein structure and association. Here we investigate the effect of lipid chain length on the association of the M2 transmembrane domain into tetramers using Förster resonance energy transfer. We observe that the interactions between the M2 helices are much stronger in 1,2-dilauroyl-sn-glycero-3-phosphocholine than in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayers. Thus, lipid chain length and bilayer thickness not only modulate peptide interactions, but could also be a major determinant of the association of transmembrane helices into functional membrane protein oligomers.

One of the most extensively studied receptor tyrosine kinases is EGFR/ErbB1. Although our knowledge of the role of the extracellular domains and ligands in ErbB1 activation has increased dramatically based on solved domain structures, the exact mechanism of signal transduction across the membrane remains unknown. The transmembrane domains are expected to play an important role in the dimerization process, but the contribution of ErbB1 TM domain to dimer stability is not known, with published results contradicting one another. We address this controversy by showing that ErbB1 TM domain dimerizes in lipid bilayers and by calculating its contribution to stability as −2.5 kcal/mol. The stability calculations use two different methods based on Förster resonance energy transfer, which give the same result. The ErbB1 TM domain contribution to stability exceeds the change in receptor tyrosine kinases dimerization propensities that can convert normal signaling processes into pathogenic processes, and is thus likely important for biological function.

A facile synthesis is described for [3,4,1′‐13C3]genistein for use as an internal standard in isoflavone analysis by mass spectrometric methods. Ethyl 4‐hydroxy[1‐13C]benzoate was first prepared from the reaction of diethyl [2‐13C]malonate and 4H‐pyran‐4‐one. Two further 13C atoms were incorporated using potassium [13C]cyanide as the source to give 4′‐benzyloxy‐[1,2,1′‐13C3]phenylacetonitrile. [3,4,1′‐13C3]Genistein was then constructed through coupling of the isotopically labelled phenylacetonitrile with phloroglucinol under Hoesch conditions, followed by formylation and cyclization. Copyright © 2007 John Wiley & Sons, Ltd.

In the current work, three-dimensional QSAR studies for one large set of quinazoline type epidermal growth factor receptor (EGF-R) inhibitors were conducted using two types of molecular field analysis techniques:  comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). These compounds belonging to six different structural classes were randomly divided into a training set of 122 compounds and a test set of 13 compounds. The statistical results showed that the 3D-QSAR models derived from CoMFA were superior to those generated from CoMSIA. The most optimal CoMFA model after region focusing bears significant cross-validated r2cvof 0.60 and conventional r2of 0.92. The predictive power of the best CoMFA model was further validated by the accurate estimation to these compounds in the external test set, and the mean agreement of experimental and predicted log(IC50) values of the inhibitors is 0.6 log unit. Separate CoMFA models were conducted to evaluate the influence of different partial charges (Gasteiger−Marsili, Gasteiger−Hückel, MMFF94, ESP-AM1, and MPA-AM1) on the statistical quality of the models. The resulting CoMFA field map provides information on the geometry of the binding site cavity and the relative weights of various properties in different site pockets for each of the substrates considered. Moreover, in the current work, we applied MD simulations combined with MM/PBSA (Molecular mechanics/Possion-Boltzmann Surface Area) to determine the correct binding mode of the best inhibitor for which no ligand−protein crystal structure was present. To proceed, we define the following procedure:  three hundred picosecond molecular dynamics simulations were first performed for the four binding modes suggested by DOCK 4.0 and manual docking, and then MM/PBSA was carried out for the collected snapshots. The most favorable binding mode identified by MM/PBSA has a binding free energy about 10 kcal/mol more favorable than the second best one. The most favorable binding mode identified by MM/PBSA can give satisfactory explanation of the SAR data of the studied molecules and is in good agreement with the contour maps of CoMFA. The most favorable binding mode suggests that with the quinazoline-based inhibitor, the N3 atom is hydrogen-bonded to a water molecule which, in turn, interacts with Thr 766, not Thr 830 as proposed by Wissner et al. (J. Med. Chem.2000, 43, 3244). The predicted complex structure of quinazoline type inhibitor with EGF-R as well as the pharmacophore mapping from CoMFA can interpret the structure activities of the inhibitors well and afford us important information for structure-based drug design.

Objective: To investigate the gene regulation of taxol-induced apoptosis. Methods: Northern blot hybridization, enzyme activity assay of S-AdoMet synthetase and flow cytometry were performed in the investigation of expression in the mRNA level and biological action of S-AdoMet synthetase in taxol-induced apoptosis in human breast cancer cell line (BCap 37). Results: Up-regulation of S-AdoMet synthetase expression was resulted by taxol treatment and the expression peaked at 48 hours.Moreover,the up-regulation of S-AdoMet synthetase was associated with cytotoxicity of antimicrotubule agents including taxol and colchicine. Inhibition rate of S-AdoMet synthetase activity by 1% DMSO was 34% in taxol-treated cells and 14% in taxol-untreated cells compared to control groups, respectively. Posttreatment with 1% DMSO following pretreatment with individual antitumor agent for 3 hrs promoted apoptotic cell death of taxol-,colchicine-,and adriamycintreated Bcap37 cells. Conclusion : The induction of apoptosis enhanced by post-treatment with DMSO in taxol-treated cells is probably linked to its inhibition on enzyme activity of S-AdoMet synthetase, suggesting that the increased expression of S-AdoMet synthetase possibly plays an important role in protecting cells from DNA fragmentation in taxol-induced apoptosis.

A genetic algorithm (GA) combined with a tabu search (TA) has been applied as a minimization method to rake the appropriate associated sites for some biomolecular systems. In our docking procedure, surface complementarity and energetic complementarity of a ligand with its receptor have been considered separately in a two-stage docking method. The first stage was to find a set of potential associated sites mainly based on surface complementarity using a genetic algorithm combined with a tabu search. This step corresponds with the process of finding the potential binding sites where pharmacophores will bind. In the second stage, several hundreds of GA minimization steps were performed for each associated site derived from the first stage mainly based on the energetic complementarity. After calculations for both of the two stages, we can offer several solutions of associated sites for every complex. In this paper, seven biomolecular systems, including five bound complexes and two unbound complexes, were chosen from the Protein Data Bank (PDB) to test our method. The calculated results were very encouraging—the hybrid minimization algorithm successfully reaches the correct solutions near the best binded modes for these protein complexes. The docking results not only predict the bound complexes very well, but also get a relatively accurate complexed conformation for unbound systems. For the five bound complexes, the results show that surface complementarity is enough to find the precise binding modes, the top solution from the tabu list generally corresponds to the correct binding mode. For the two unbound complexes, due to the conformational changes upon binding, it seems more difficult to get their correct binding conformations. The predicted results show that the correct binding mode also corresponds to a relatively large surface complementarity score. In these two test cases, the correct solution can be found in the top several solutions from the tabu list. For unbound complexes, the interaction energy from energetic complementarity is very important, it can be used to filter these solutions from the surface complementarity. After the evaluation of the energetic complementarity, the conformations and orientations close to the crystallographically determined structures are resolved. In most cases, the smallest root mean square distance (r.m.s.d.) from the GA combined with TA solutions is in a relatively small region. Our program of automatic docking is really a universal one among the procedures used for the theoretical study of molecular recognition.

Site-directed mutagenesis of an amino acid residue in the substrate binding site of porcine fructose-1,6-bisphosphatase was carried out based on the crystal structure of the enzyme (Zhang, Y., Liang, J.-Y., Huang, S., Ke, H., and Lipscomb, W. N.(1993) Biochemistry32, 1844-1857). A mutant enzyme form of fructose-1,6-bisphosphatase, G122A, was purified and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, circular dichroism spectrometry (CD), and initial rate kinetics. There were no discernible differences between the secondary structures of the wild-type and the mutant enzyme on the basis of CD data. Altering Gly-122 to alanine caused a significant decrease in the enzyme's activity and affinity for Mg2+. The kcatfor this mutant enzyme was only about 5% of that of wild-type fructose-1,6-bisphosphatase, and the Kafor Mg2+was about 20-fold higher than that of the wild-type enzyme. The Kifor AMP was increased 77-fold in the case of the mutant enzyme; however, the Hill coefficient was unaltered. Most importantly, it was observed that replacement of Gly-122 with alanine caused the total loss of cooperativity for Mg2+. It is concluded that Gly-122 is essential for Mg2+cooperativity and important for binding of Mg2+and AMP as well as for enzyme activity.

Objective: To investigate the mechanism by which taxol induces apoptosis in human breast cancer cells. Methods: Cell morphology, agarose gel electrophoresis, flow cytometry, video time-lapse monitor and Western blot were performed for investigating taxol-induced apoptosis in human breast cancer cells (BCap 37). Results: BCap 37 cells treated with taxol (100 nm) underwent the arrests of cell mitosis at metaphase of mitosis and induction of apoptosis. Apoptotic cells demonstrated cell shrinkage, condensation or fragmentation of chromosomes. Nuclear DNA of apoptotic cells displayed ladder bands characteristic of internucleosomal DNA fragmentation. The expression ofbcl-2, inhibitor of apotosis, was decreased with modification, while that of bax, inducer of apoptosis, increased only at early stage of the apoptotic pathway and decreased later. Conclusion: In human breast cancer cells the induction of apoptosis by taxol was closely associated with mitotic arrest of cell cycle, and altered expressions ofbcl-2 and bax gene possibly played an important role in regulating taxol-induced apoptosis.

We propose a probabilistic model coupling with the temperature dependent constitutive relationship to describe the competition between the cleavage and ductile void failure of ferritic/martensitic steels with irradiation effects. It is found that both the material deformation and failure modes exhibit significant temperature dependence. Regarding the material deformation, two regimes have been found for the ductile-to-brittle transition (DBT). At low temperature, the flow stress is controlled by the mobility of screw dislocations. The high-temperature regime is about the thermally activated jog drag of dislocations. The failure modes depend on the carbide precipitate and temperature. Cleavage micro-cracks initiate at the carbide sites at low temperature giving rise to brittle behaviors. At high temperature, void nucleation evolving from the carbide precipitate suppresses the cleavage nucleation and propagation, and leads to good ductility. It is demonstrated that the competition between the cleavage fracture and ductile void failure is the major mechanism for the DBT. Our probabilistic model successfully predicts the temperature-dependent fracture toughness and ductile-to-brittle transition temperature (DBTT). Besides temperature, irradiation has a significant effect on the DBT of steels. Upon irradiation, the steels exhibit both irradiation hardening and irradiation embrittlement, i.e., rise in yield and flow stresses, and increase on DBTT. The main reason for these irradiation effects is that the irradiation-induced hardening increases the flow stress, and the plasticity localization weakens the overall hindering effect from ductile void growth on the cleavage nucleation and propagation, promoting the development of cleavage. Our probabilistic model takes into account the cleavage nucleation-propagation process and the influence of ductile void growth simultaneously, and it gives a sound explanation for the fundamental relation between the DBTT and mechanical properties of metallic materials. [ABSTRACT FROM AUTHOR]

In this paper, a theoretical framework including the micro-mechanical method and crystal plasticity model is developed to characterize the macroscopic mechanical behaviors of irradiated metallic materials. At the microscale, a rate-dependent crystal plasticity model is applied to capture the effects of irradiation-induced defects and helium (He) bubbles for individual grains. Then, the micro-mechanical method is adopted to establish the relationship between microscopic individual grains and macroscopic polycrystals. The developed theoretical framework is applied to simulate the mechanical behaviors of neutron irradiated polycrystalline Cu and He implanted Cu/Nb nano-metallic-multilayers (NMMs), and the numerical results match well with corresponding experimental data.

The extracellular domain of a receptor tyrosine kinase has opposing effects on dimerization depending on whether ligand is present.

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Dislocation transmission across grain boundary (GB) and activation of dislocation source in adjacent grains are considered common features of dislocation-GB interactions in regulating mechanical properties and behaviors of metallic materials and structures. However, it is currently unclear which of dislocation transmission and dislocation source activation plays the dominant role in regulating dislocation-GB interaction. To study the competition between dislocation transmission and dislocation source activation, a theoretical framework is established based on a dislocation pile-up model. It is found that both dislocation transmission and dislocation source activation exhibit strong dependence on the GB misorientation angle. The critical transmission stress derived based on an energy method also depends on the grain size in a scaling form similar to the Hall-Petch relation. The outgoing slip systems during dislocation transmission are successfully predicted and agree with experimental observations. Regarding the dislocation source activation, the critical activation stress is investigated by examining the local stress fields generated by single and multiple slip dislocation pile-ups. It is found that compared with single slip dislocation pile-up, the result of multiple slip dislocation pile-ups displays lower critical activation stresses and exhibits feature of sensitivity to loading direction, interpreting the reported results of dislocation source activation in polycrystals. Further comparison between dislocation transmission and dislocation source activation for ⟨100⟩ tilt GBs indicates that the dislocation transmission prevails at low angle GB, while dislocation source activation is prone to occur at high angle GB. Our theoretical studies quantify the dislocation-GB interaction induced by dislocation pile-ups, shed light on the competition between dislocation transmission and dislocation source activation, and might provide essential guidance for high-performance metallic material design. [ABSTRACT FROM AUTHOR]