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The activation of halogens (X = Cl, Br, I) by N2O5is linked to NOxsources, ozone concentrations, NO3reactivity, and the chemistry of halide-containing aerosol particles. However, a detailed chemical mechanism is still lacking. Herein, we explored the chemistry of the N2O5···X–systems at the air–water interface. Two different reaction pathways were identified for the reaction of N2O5with X–at the air–water interface: the formation of XNO2or XONO, along with NO3–. In the case of the Cl–system, the ClNO2generation pathway is more favorable, while for the Br–and I–systems, the formation of BrONO and IONO is barrierless, making them the predominant products. Furthermore, the mechanisms of formation of X2from XNO2and XONO were also investigated. The high energy barriers of reactions and the high free energies of the products compared to those of the reactants indicate that ClNO2is stable at the air–water interface. Contrary to the widely held belief regarding X2producing from the reaction of XNO2with X–, our calculations demonstrate that BrONO and IONO initially form stable BrONO···Br–and IONO···I–complexes, which then subsequently react with Br–and I–to form Br3–and I3–, respectively. Finally, Br3–and I3–decompose to form Br2and I2.These findings have significant implications for experimental interpretation and offer new insights into halogen cycling in the atmosphere.

The field of remote sensing (RS) image change detection (CD) has made significant progress, largely due to the powerful feature representation abilities of deep learning. However, traditional methods have not fully exploited the valuable information in differences. These methods often treat deep models as tools to extract features from individual images, which limits their ability to effectively describe differences. Additionally, many approaches tend to focus on spatial differences, while neglecting variations in the channel dimension. In this study, we introduce a novel Summator–Subtractor network for CD ( ${S}^{2}$ CD), which adeptly captures subtle differences within both the spatial and channel aspects of bi-temporal images. The initial spatial and channel differences are derived through summation and subtraction operations on the bi-temporal images. The summator computes initial channel variations, while the subtractor captures initial spatial disparities. Transformers are then used to pull out meaningful differences in both spatial and channel patterns, allowing for a more nuanced understanding than methods relying solely on features from individual images. Finally, a heterogeneous modulation block integrates channel and spatial difference features, thus amplifying overall differences. Through extensive experimentation on four widely acknowledged CD benchmark datasets, our proposed ${S}^{2}$ CD method outperforms existing techniques, showcasing its superior performance and promising potential. The codes of this work will be available for the sake of reproducibility at: https://github.com/qianday/SSCD-CD.

Proton Exchange Membrane Fuel Cell (PEMFC) is a multi-parameter and strongly coupled complex system, efficient and smooth operation is beneficial to the efficiency and stability of PEMFC. In this paper, aiming at improve the temperature and voltage management in PEMFC, a stack model is established, and a PEMFC temperature and voltage dynamic management controller based on Model Predict Control method (MPC) is proposed. The working temperature and output voltage are controlled by the mass flow rate of cooling water and hydrogen gas, respectively. The performances of PEMFC under different controller including MPC and traditional PID controllers are analyzed. Due to the optimization of future time step in MPC controller, the measured value will move close to the set value faster. The response time and overshoots of temperature and voltage are remarkably reduced. Compared with PID controller, MPC temperature control has smaller overshoot and faster response time, Moreover, with step current change, voltage overshoot of MPC controller is less than 1.2% which is better than other controllers.

During the operation of high-power proton exchange membrane (PEM) fuel cell, huge heat is generated in the chemical reaction, which need be removed by efficient cooling design. To solve the problem of local overheating during PEMFC, a novel multi-input and multi-output (MIMO) cooling flow field is proposed. The maximum temperature, temperature uniformity and pressure drop characteristics of the U-shaped and Z-shaped cooling flow fields with different MIMO channels configurations are researched by computational fluid dynamics (CFD) method. The results demonstrate that comparing with U-shaped cooling flow field, Z-shaped design can provide better temperature distribution with the same MIMO channel configuration. Moreover, the serpentine cooling flow field provides better cooling performance than parallel cooling flow field, but leads to higher pressure loss. Compared to other cases, Z-shaped serpentine MIMO channel presents the best cooling performance, reducing the maximum temperature value to 322.7 K.

The lack of funding is one of the most important challenges in achieving the 2030 Sustainable Development Goals (SDGs) in African countries. Can foreign direct investment (FDI) from China as an important source of external financing help African countries achieve their SDGs? This study used the panel data random effects model to analyze the influence of China’s direct investment on SDG scores. Then, the study conducted the ordered probit model to examine the influence of FDI from China on the trend of achieving each SDG in Africa, with the SDGs being grouped into social, economic, and environmental dimensions. Results showed that China’s direct investment contributed to the achievement of SDGs in Africa. FDI from China positively influenced the SDG score in general and some of the 17 SDG scores including SDG 7 (Affordable and Clean Energy), SDG 8 (Decent Work and Economic Growth), SDG 9 (Industry, Innovation, and Infrastructure), SDG 12 (Responsible Consumption and Production), SDG 13 (Climate Action), and SDG 15 (Life on Land). The relationship between FDI from China and the trends for SDG 7, 8, 9, 11 (Sustainable Cities and Communities), and 14 (Life below Water) was significantly positive. However, the SDG scores above belonged to the economic and environmental dimensions, whereas FDI from China had no significant influence on the social-dimension SDG scores and trends. To further expand the scale of China’s direct investment, more investment scopes, particularly those in the social dimension, should be developed. Moreover, China–Africa cooperation should be deepened to create a good investment environment for the achievement of African countries’ SDGs and to facilitate China’s implementation of promoting the development of developing countries as mentioned in the 2030 Agenda of Sustainable Development and building the China–Africa community with a shared future.

Kidney disease is manifested in a wide variety of phenotypes, many of which have an important hereditary component. To delineate the genotypic and phenotypic spectrum of pediatric nephropathy, a multicenter registration system is being implemented based on the Chinese Children Genetic Kidney Disease Database (CCGKDD). In this study, all the patients with kidney and urological diseases were recruited from 2014 to 2020. Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features. The genetic diagnosis was confirmed in 883 of 2256 (39.1%) patients from 23 provinces in China. Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome (SRNS, 23.5%), glomerulonephritis (GN, 32.2%), congenital anomalies of the kidney and urinary tract (CAKUT, 21.2%), cystic renal disease (3.9%), renal calcinosis/stone (3.6%), tubulopathy (9.7%), and chronic kidney disease of unknown etiology (CKDu, 5.8%). The pathogenic variants of 105 monogenetic disorders were identified. Ten distinct genomic disorders were identified as pathogenic copy number variants (CNVs) in 11 patients. The diagnostic yield differed by subgroups, and was highest in those with cystic renal disease (66.3%), followed by tubulopathy (58.4%), GN (57.7%), CKDu (43.5%), SRNS (29.2%), renal calcinosis /stone (29.3%) and CAKUT (8.6%). Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions. We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed. Our data demonstrate the utility of family-based exome sequencing, and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease.

Constructing a three-dimensional (3D) network of fillers with high thermal conductivity is considered to be an effective strategy to obtain ideal thermal management materials (TMMs). However, 3D filler network is often disrupted by the subsequent processing and forming processes, and it is difficult to incorporate high levels of fillers into lyophilized aerogels, which is a key factor limiting their widespread use. In this work, boron nitride@polymethylacrylimide/epoxy (BN@PMI/EP) composites with a stable 3D BN network were prepared by freeze-drying and hot-pressing. A water-soluble copolymer quaternary ammonium salt has been synthesized by the solution polymerization. A BN@PMI aerogel was obtained by the freeze-drying of ammonium salt and BN solution and thermal imidization. The BN@PMI aerogel has a six-membered imine ring structure that can be loaded with a high content of BN, which ensures the stability of the 3D BN network structure and facilitates the subsequent impregnation of EP in vacuum, which is one of the innovations of this work. The stable and complete 3D BN network leads to the enhancement of thermal conductivity, and the out-of-plane and in-plane thermal conductivities of BN@PMI/EP reach 1.21 W·m−1·K−1and 2.76 W·m−1·K−1at a BN loading of 40% (mass), respectively. Meanwhile, the excellent mechanical properties and results of finite-element simulation and actual experiments confirm that BN@PMI/EP is a potential TMM.

Chlorine oxides play crucial roles in ozone depletion, and the final oxidation steps of chlorine oxide potentially result in the formation of chloric acid (HClO3) or perchloric acid (HClO4). Herein, the solvation and reactive uptake of three stable isomers of chlorine trioxide (Cl2O3), namely, ClOCl(O)O, ClClO3, and ClOOOCl, at the air–water interface were investigated using classical and hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) coupled with advanced free energy methods. Two distinct mechanisms were revealed for the hydrolysis of ClOCl(O)O and ClClO3: molecular and ionic mechanisms. A comparison of the computed free-energy profiles for the gaseous and air–water interfacial systems indicated that the air–water interface could markedly lower the free-energy barrier for ClO3−or HClO3formation while stabilizing the product state. In particular, the hydrolysis of ClClO3at the air–water interface was barrierless. In contrast, our calculations showed that the hydrolysis of ClOOOCl was very slow, indicating that ClOOOCl was inert to water at the air–water interface. This study provides theoretical evidence for the hypothesis that HClO3is a sink for chlorine oxides and for the widespread distributions of HClO3recently observed in the Arctic region.

Methyl salicylate (MS) as a subunit of larger salicylates found in commercial sunscreens has been shown to exhibit keto–enol tautomerization and dual fluorescence emission via excited-state intramolecular proton transfer (ESIPT) after the absorption of ultraviolet (UV) radiation. However, its excited-state relaxation mechanism is unclear. Herein, we have employed the quantum mechanics(CASPT2//CASSCF)/molecular mechanics method to explore the ESIPT and excited-state relaxation mechanism of MS in the lowest three electronic states, that is, S0, S1, and T1states, in a methanol solution. Based on the optimized geometric and electronic structures, conical intersections and crossing points, and minimum-energy paths combined with the computed linearly interpolated Cartesian coordinate paths, the photophysical mechanism of MS has been proposed. The S1state is a spectroscopically bright 1ππ* state in the Franck–Condon region. From the initially populated S1state, there exist three nonradiative relaxation paths to repopulate the S0state. In the first one, the S1system (i.e., ketoB form) first undergoes an ESIPT path to generate an S1tautomer (i.e., enol form) that exhibits a large Stokes shift in experiments. The generated S1enol tautomer further evolves toward the nearby S1/S0conical intersection and then hops to the S0state, followed by the backward ground-state intramolecular proton transfer (GSIPT) to the initial ketoB form S0state. In the second one, the S1system first hops through the S1→ T1intersystem crossing (ISC) to the T1state, which then further decays to the S0state via T1→ S0ISC at the T1/S0crossing point. In the third path, the T1system that stems from the S1→ T1ISC process via the S1/T1crossing point first takes place a T1ESIPT to generate a T1enol tautomer, which can further decay to the S0state via T1-to-S0ISC. Finally, the GSIPT occurs to back the system to the initial ketoB form S0state. Our present work could contribute to understanding the photophysics of MS and its derivatives.

The excited-state properties and relaxation mechanisms after light irradiation of 6-selenoguanine (6SeG) in water and in DNA have been investigated using a quantum mechanics/molecular mechanics (QM/MM) approach with the multistate complete active space second-order perturbation theory (MS-CASPT2) method. In both environments, the S11(nSeπ5*) and S21(πSeπ5*) states are predicted to be the spectroscopically dark and bright states, respectively. Two triplet states, T13(πSeπ5*) and T23(nSeπ5*), are found energetically below the S2state. Extending the QM region to include the 6SeG-Cyt base pair slightly stabilizes the S2state and destabilizes the S1, due to hydrogen-bonding interactions, but it does not affect the order of the states. The optimized minima, conical intersections, and singlet–triplet crossings are very similar in water and in DNA, so that the same general mechanism is found. Additionally, for each excited state geometry optimization in DNA, three kind of structures (“up”, “down”, and “central”) are optimized which differ from each other by the orientation of the C═Se group with respect to the surrounding guanine and thymine nucleobases. After irradiation to the S2state, 6SeG evolves to the S2minimum, near to a S2/S1conical intersection that allows for internal conversion to the S1state. Linear interpolation in internal coordinates indicate that the “central” orientation is less favorable since extra energy is needed to surmount the high barrier in order to reach the S2/S1conical intersection. From the S1state, 6SeG can further decay to the T13(πSeπ5*) state via intersystem crossing, where it will be trapped due to the existence of a sizable energy barrier between the T1minimum and the T1/S0crossing point. Although this general S2→ T1mechanism takes place in both media, the presence of DNA induces a steeper S2potential energy surface, that it is expected to accelerate the S2→ S1internal conversion.

ABSTRACTHepatocellular carcinoma (HCC) is a leading cause of mortality in cancer patients, but the association between miR-125b-2-3p and the onset and prognosis of HCC has not been reported in previous studies; thus, the clinicopathological implications of miR-125b-2-3p in HCC require elaboration. To examine the expression of miR-125b-2-3p in HCC, both in-house RT-qPCR and public datasets were used to calculate the standard mean difference (SMD) and the summary receiver operating characteristic (sROC). MiR-125b-2-3p was markedly lower in HCC than in non-tumor tissue as assessed by the in-house RT-qPCR which was confirmed by the integrative analysis showing the SMD being −0.69 and the area under the curve (AUC) being 0.84 based on 1,233 cases of HCC and 630 cases of non-HCC controls. To gain a overview of the clinical value of miR-125b-2-3p in HCC, all possible datasets were integrated, and lower miR-125b-2-3p levels could lead to poorer differentiation and a more advanced clinical stage of HCC. The hazard ratio (HR) of miR-125b-2-3p was also calculated using a Cox proportional hazards model, and the miR-125b-2-3p level could act as an protective indication for the survival with the HR being 0.74 based on 586 cases of HCC. Furthermore, the effect of nitidine chloride (NC), a natural bioactive phytochemical alkaloid, on the regulation of miR-125b-2-3p and its potential targets was also investigated. The miR-125b-2-3p level was increased after NC treatment, while the expression of its potential target PRKCA was reduced. Above all, a low-expressed level of miR-125b-2-3p plays a tumor suppressive role in HCC.

Hexagonal boron nitride (hBN) films were epitaxially grown on (100)-Oriented silicon and c-plane sapphire (α-Al2O3) substrates via a low-pressure chemical vapor deposition (LPCVD) method with boron trichloride (BCl3) and ammonia (NH3) as the boron source and nitrogen source. Crystalline quality differences between hBN films grown on different substrates are studied and discussed by XPS, Raman spectroscopy, XRD and SEM characterizations. All the characterization results indicate that the sapphire substrate is more suitable for epitaxial growth of hBN films than silicon substrates.

Communication is a fundamental feature of life, and all living organisms interact actively with their surroundings to better their chance of survival through the coordination of group behavior. To develop mutual interactions between an artificial cell and living organism, we constructed a positively charged thermo-sensitive proteinosome with loaded l-arginine modified chitosan oligosaccharide as an antimicrobial in the hydrogel-based core domain, and then by controlling the temperature and ionic strength we demonstrate that changes in both the hydrophobicity and the electrostatic attraction allowed the constructed proteinosomes to show a programmed interaction with the living organism E. coli, including capture, aggregation induced self-suicide, release, and then the renewal of the proteinosomes. It is anticipated that our results will contribute to the development of the communication behaviours within artificial cell and living organism hybrid microsystems, and lay a foundation for further engineering artificial cell models towards biology inspired materials.

Three-dimensional (3D) graphene/SiBCN composites (GF/SiBCN) were prepared by depositing SiBCN ceramics in 3D graphene foam via the chemical vapor infiltration technique. The effect of the heat treatment temperature on the microstructure, phase composition, and electromagnetic properties of the GF/SiBCN composite was investigated. The SiBCN ceramics maintained an amorphous structure in the composite below 1400 °C above which the crystallinity of the free carbon phase gradually increased. While the Si 3 N 4 and B 4 C phases started to crystallize at 1500 °C and their crystallinity increased with temperature, SiC was observed at 1700 °C. The electromagnetic shielding effectiveness of GF/SiBCN increased with the heat treatment temperature. [ABSTRACT FROM AUTHOR]

Methyl 2-cyano-3,3-diphenylacrylate (MCDPA) shares the same molecular skeleton with octocrylene (OCR) that is one of the most common molecules used in commercially available sunscreens. However, its excited-state relaxation mechanism is unclear. Herein, we have used the QM(CASPT2//CASSCF)/MM method to explore spectroscopic properties, geometric and electronic structures, relevant conical intersections and crossing points, and excited-state relaxation paths of MCDPA in methanol solution. We found that in the Franck–Condon (FC) region, the V(1ππ*) state is energetically lower than the V′(1ππ*) state only by 2.8 kcal/mol and is assigned to experimentally observed maximum absorption band. From these two initially populated singlet states, there exist three nonradiative relaxation paths to repopulate the S0state. In the first one, when the V(1ππ*) state is populated in the FC region, the system diabatically evolves along the V(1ππ*) state into its minimum where the internal conversion to S0occurs. In the second one, the V′(1ππ*) state is populated in the FC region and the system adiabatically overcomes a barrier of ca. 3.0 kcal/mol to approach the V(1ππ*) minimum eventually leading to a V(1ππ*)-to-S0internal conversion. In the third one, the V′(1ππ*) state first hops via the intersystem crossing to the T2state, which then decays through the internal conversion to the T1state. The T1state is finally converted to the S0state via the T1/S0crossing point. Our present work contributes to understanding the photophysics of OCR and its variants.

Vortex-ring cavitation occurs when the pressure inside a torus-shaped core of a vortex ring falls below the vapor pressure of the ambient liquid. By generating a vapor bubble in a rigid tube, a toroidal cavity can be produced outside the tube. The pulsation and propagation behaviors of vortex-ring cavitation are studied using a high-speed video camera and a hydrophone. The experimental results show that the cavity continues to oscillate with a period that depends heavily on the maximal cross-section radius of the cavity and circulation of the vortex flow, under the influence of the surrounding vortex flow field. It is also shown that the cross-radial oscillation of the toroidal cavity can be measured both by a high-speed camera and hydrophone. Moreover, three different methods for estimating the circulation are compared to propose an accurate model of toroidal cavity oscillation. The phenomenon of a toroidal cavity impinging on a fixed wall is also investigated.

The past decades have witnessed significant efforts toward the development of three-dimensional (3D) cell cultures as systems that better mimic in vivo physiology. Today, 3D cell cultures are emerging, not only as a new tool in early drug discovery but also as potential therapeutics to treat disease. In this review, we assess leading 3D cell culture technologies and their impact on drug discovery, including spheroids, organoids, scaffolds, hydrogels, organs-on-chips, and 3D bioprinting. We also discuss the implementation of these technologies in compound identification, screening, and development, ranging from disease modeling to assessment of efficacy and safety profiles.

The past decades have witnessed significant efforts toward the development of three-dimensional (3D) cell cultures as systems that better mimic in vivo physiology. Today, 3D cell cultures are emerging, not only as a new tool in early drug discovery but also as potential therapeutics to treat disease. In this review, we assess leading 3D cell culture technologies and their impact on drug discovery, including spheroids, organoids, scaffolds, hydrogels, organs-on-chips, and 3D bioprinting. We also discuss the implementation of these technologies in compound identification, screening, and development, ranging from disease modeling to assessment of efficacy and safety profiles.

Photochemical homolysis of hydrogen peroxide (H2O2) occurs widely in nature and is a key source of hydroxyl radicals (·OH). The kinetics of H2O2photolysis play a pivotal role in determining the efficiency of ·OH production, which is currently mainly investigated in bulk systems. Here, we report considerably accelerated H2O2photolysis at the air–water interface of microdroplets, with a rate 1.9 × 103times faster than that in bulk water. Our simulations show that due to the transquasiplanar conformational preference of H2O2at the air–water interface compared to the bulk or gas phase, the absorption peak in the spectrum of H2O2is significantly redshifted by 45 nm, corresponding to greater absorbance of photons in the sunlight spectrum and faster photolysis of H2O2. This discovery has great potential to solve current problems associated with ·OH-centered heterogeneous photochemical processes in aerosols. For instance, we show that accelerated H2O2photolysis in microdroplets could lead to markedly enhanced oxidation of SO2and volatile organic compounds.

The transport of dissolved organic sulfur, including thiols and thioethers, from the ocean surface to the atmosphere through sea spray aerosol (SSA) is of great importance for the global sulfur cycle. Thiol/thioether in SSA undergoes rapid oxidation that is historically linked to photochemical processes. Here, we report the discovery of a non-photochemical, spontaneous path of thiol/thioether oxidation in SSA. Among 10 investigated naturally abundant thiol/thioether, seven species displayed rapid oxidation in SSA, with disulfide, sulfoxide, and sulfone comprising the major products. We suggest that such spontaneous oxidation of thiol/thioether was mainly fueled by thiol/thioether enrichment at the air–water interface and generation of highly reactive radicals by the loss of an electron from ions (e.g., glutathionyl radical produced from ionization of deprotonated glutathione) at or near the surface of the water microdroplet. Our work sheds light on a ubiquitous but previously overlooked pathway of thiol/thioether oxidation, which could contribute to an accelerated sulfur cycle as well as related metal transformation (e.g., mercury) at ocean–atmosphere interfaces.

To determine the beneficial effects of intraoperative high-field magnetic resonance imaging (MRI), multimodal neuronavigation, and intraoperative electrophysiological monitoring-guided surgery for treating supratentorial cavernomas.

Background: Most drugs exert their biological and physiological effects via binding to protein targets. Although drugs are traditionally optimized against a single protein, most marketed drugs exhibit clinically relevant polypharmacology – the activity of drugs at multiple targets. The wide-spread presence of polypharmacology makes it challenging to assess the mechanisms of action of multi-target drugs. Methods: This paper first reviews approaches for discovering multi-targets of drug molecules, then discusses key characteristics of label-free cell phenotypic assays, and finally focuses on how to use these assays to assess drug polypharmacology. Results: labelfree cell phenotypic assays have ability to provide a holistic view of drug action in living cells with wide phenotype/ target/pathway coverage, and permit effective deconvolution of the action of multi-target drugs at the whole cell level. Conclusion: Label-free cell phenotypic assays hold great potential in assessing drug polypharmacology.

Benefits of high-throughput screening technology (HTS) in drug discovery are presented. Applications of HTS technologies in cell-based screening and research are also discussed.

Introduction:Drug discovery is a long and costly process. Innovations and paradigm shifts are essential for continuous improvement in the productivity of pharmaceutical R&D.Areas covered:The author reviews the progress of label-free cell phenotypic and computational approaches in early drug discovery since 2004 and proposes a novel paradigm, which combines both approaches.Expert opinion:Label-free cell phenotypic profiling techniques offer an unprecedented and integrated approach to comprehend drug–target interactions in their native environments. However, these approaches have disadvantages associated with the lack of molecular details. Computational approaches, including ligand-, structure- and phenotype-based virtual screens, have become versatile tools in the early drug discovery process. However, these approaches mostly predict the binding of drug molecules to targets of interest and are limited to targets that are either well annotated for ligands or that are structurally resolved. Thus, combining label-free cell phenotypic profiling with computational approaches can provide a potential paradigm to accelerate novel drug discovery by taking advantages of the best of both approaches.

Phenotypic screen holds great potential in the discovery of new small molecule probes and drugs, as it permits interrogating small molecules with native targets and pathways in model organisms and disease relevant cells. In recent years, label-free cell phenotypic profiling has emerged as an alternative for drug discovery. This paper provides the rationale for phenotypic screens, discusses the basics of label-free cell phenotypic profiling technologies, and provides some guidelines as to how to use these techniques to facilitate drug discovery.

Introducing the background of domestic park cloud platform. Comparing the Platform construction operations of Suzhou Software park, Hangzhou east software park, Beijing Zhongguan Village software park, Chengdu Tianfu software park and Dalian software park platform construction operation comparison. Through the study, we concluded that park's cloud platform was more than just an IT service platform. It was also a park assets and service of integrated management platform and learning and employment platform. Cloud platform will support park characteristic industry and provide information for the development of the park’s industry.

An orthogonal frequency division multiplexing (OFDM) is one of the effective techniques used in wireless communications. In OFDM systems, channel impairments due to multipath dispersive wireless channels can cause deep fades in wireless channels. The OFDM receiver also requires an accurate and computationally efficient channel state information when coherent detection is involved. Therefore, it needs a good robust estimation method of the channel in wireless communication for OFDM systems. And one of these channel estimation methods is minimum mean square error (MMSE) channel estimation. MMSE channel estimation one most used method in OFDM systems. In this work we enhanced robustness of MMSE channel estimation by using it in base of quasi-cyclic low density parity check (QC-LDPC) coded OFDM system.

Spatial organization of metabolic enzymes may represent a general cellular mechanism to regulate metabolic flux. One recent example of this type of cellular phenomenon is the purinosome, a newly discovered multi-enzyme metabolic assembly that includes all of the enzymes within the de novopurine biosynthetic pathway. Our understanding of the components and regulation of purinosomes has significantly grown in recent years. This paper reviews the purine de novobiosynthesis pathway and its regulation, and presents the evidence supporting the purinosome assembly and disassembly processes under the control of G-protein-coupled receptor (GPCR) signaling. This paper also discusses the implications of purinosome and GPCR regulation in drug discovery.

Mixed reactive disperse dyes is adopted to dye wool yarn by supercritical CO2 dyeing equipment, and the influencing factors on the wool yarn uptake are analyzed including dyeing temperature, dyeing time, dyeing pressure. The results reveal the interaction relationship between single dyes dyeing on the wool yarn: the total uptake of mixed reactive disperse dyes and the uptake of single reactive disperse dyes increase with the increasing of temperature and pressure, it also increase by the extension of time. In the same conditions, the total uptake of mixed reactive disperse dyes is more than the uptake of single reactive disperse dyes. The uptake of single reactive disperse dyes in the mixed dyes is less than the uptake of single reactive disperse dyes. In the dyeing process of mixed dyes, the wool yarn dyeing of two dyes has selective and competitive. Both color fastness to rubbing and color fastness to washing of dyed wool yarn are in line with national institute of standards.

Introduction:The study of drug–target interactions is essential for the understanding of biological processes and for the efforts to develop new therapeutic molecules. Increased ligand-binding assays have coincided with the advances in reagents, detection and instrumentation technologies, the expansion in therapeutic targets of interest, and the increasingly recognized importance of biochemical aspects of drug–target interactions in determining the clinical performance of drug molecules. Nowadays, ligand-binding assays can determine every aspect of many drug–target interactions.Areas covered:Given that ligand–target interactions are very diverse, the author has decided to focus on the binding of small molecules to protein targets. This article first reviews the key biochemical aspects of drug–target interactions, and then discusses the detection principles of various ligand-binding techniques in the context of their primary applications for drug discovery and development.Expert opinion:Equilibrium-binding affinity should not be used as a solo indicator for the in vivopharmacology of drugs. The clinical relevance of drug-binding kinetics demands high throughput kinetics early in drug discovery. The dependence of ligand binding and function on the conformation of targets necessitates solution-based and whole cell-based ligand-binding assays. The increasing need to examine ligand binding at the proteome level, driven by the clinical importance of the polypharmacology of ligands, has started to make the structure-based in silicobinding screen an indispensable technique for drug discovery and development. Integration of different ligand-binding assays is important to improve the efficiency of the drug discovery and development process.

Stem cells hold great potential in drug discovery and development. However, challenges remain to quantitatively measure the functions of stem cells and their differentiated products. Here, we applied fluorescent imaging, quantitative real-time PCR, and label-free dynamic mass redistribution (DMR) assays to characterize the differentiation process of the ReNcell VM human neural progenitor stem cell. Immunofluorescence imaging showed that after growth factor withdrawal, the neuroprogenitor stem cell was differentiated into dopaminergic neurons, astrocytes, and oligodendrocytes, thus creating a neuronal cell system. High-performance liquid chromatography analysis showed that the differentiated cell system released dopamine upon depolarization with KCl. In conjunction with quantitative real-time PCR, DMR assays using a G-protein-coupled receptor agonist library revealed that a subset of receptors, including dopamine D1and D4receptors, underwent marked alterations in both receptor expression and signaling pathway during the differentiation process. These findings suggest that DMR assays can decode the differentiation process of stem cells at the cell system level.

Objective:The drug-loaded PEGylated nanomaterials have shown effective cell-killing in vitro,but to the best of authors' knowledge there have been no reports of successful drug delivery in vitroand in vivousing polyethyleneglycol-2000-distearoyl phosphatidyl ethanolamine (PEG2000-DSPE) nanomaterials loaded with unmodified drug molecules, such as quercetin (QUE). In this study, it remained an open question as to whether such formulations could prove effective in vitroand in vivo,and to study the distribution and clearance of PEG-DPSE-ylated lipid-based quercetin nanoliposomes (PEG2000-DPSE-QUE-NLs) as delivery vehicles for the anticancer drug in vitroand in vivo.Research design and methods:PEG-DPSE layers were attached to QUE-NLs, dispersed in aqueous media and characterized using TEM and HPLC/UV spectroscopy. Tumor cell killing efficacy was assessed in vitrousing MTT and trypan blue exclusion assays, and the distribution and clearance pathways, as well as repeated administration in rats, were studied by HPLC spectroscopy.Results:PEG2000-DPSE-QUE-NLs were efficiently dispersed in aqueous media compared with controls, and PEGylated (PEG2000-DPSE) NLs were found to be effective drug delivery vehicles when simply loaded with QUE. The plasma QUE concentration decreased significantly (p < 0.05) after repeated administration of PEG2000-DSPE liposomal QUE. There was a slight ABC phenomenon with the PEG2000-DSPE-modified QUE liposomes.Conclusion:The QUE/PEG2000-DPSE formulation was more effective than QUE in vitroon inhibiting the growth of glioma cancer cells. This work demonstrates that nanomaterials (PEG2000-DPSE) are effective drug delivery vehicles in vivoas tumor-targeted drug carriers.

A high-throughput label-free cell assay for modulating cell-cell communication is demonstrated with the Epic® system, a resonant waveguide grating sensor platform. Natural killer (NK) cells are known to be able to recognize abnormal cells (e.g., cancer cells and cells presenting intercellular adhesion molecule 1 [ICAM1] through cell surface receptors) and kill them. In this study, the effect of effecter cells NK92MI on two kinds of target cells, cervical cancer cells (HeLa) and Chinese hamster ovarian cells overexpressing ICAM1 (CHO-ICAM1), was examined. Living target cells’ response to NK92MI cells was monitored in real time and measured as wavelength shift in picometers. The authors showed that the detectability of target cell response is affected by multiple factors: the ratio of effecter cells to target cells (E/T), the interaction time of the two types of cells, and the target cell type. For example, with the effecter cells NK92MI and the same incubation time of 16 h, a minimal E/T ratio of 1 is required to detect HeLa cell response, whereas an E/T of 0.5 is sufficient to detect CHO-ICAM1 cell response. The authors confirmed that NK92MI cell–mediated target cell cytotoxicity results in negative optical signals and is associated with apoptosis mainly through caspase pathways. Distinct optical signals could be generated with the pretreatment of the target cells with various known pharmaceutical reagents, making the assay useful for discovering new chemicals that may affect cell-cell communications.

Introduction:The need to improve drug research and development productivity continues to drive innovation in pharmacological assays. Technologies that can leverage the advantages of both molecular and phenotypic assays would hold great promise for discovery of new medicines.Areas covered:This article briefly reviews current label-free platforms for cell-based assays and is primarily focused on fundamental aspects of these assays using dynamic mass redistribution technology as an example. The article also presents strategies for relating label-free profiles to molecular modes of actions of drugs.Expert opinion:Emerging evidence suggests that label-free cellular assays are phenotypic in nature, yet permit molecular mechanistic deconvolution. Together with unique competency in throughput, sensitivity and pathway coverages, label-free cellular assays allow users to screen drugs against endogenous receptors in native cells (including disease relevant primary cells) and determine the molecular modes of action of drug molecules. However, there are challenges for label-free in both basic research and drug discovery: the deconvolution of the cellular and molecular mechanisms for the biosensor signatures of receptor–drug interactions, new methodologies for data analysis and the development of new biosensor technologies. These challenges will need to be met for the wide adoption of these assays in drug discovery.

Wood I-joists is a kind of wood-based engineering material which was widely used in wood construction. As it is in fact, the property of I-joists are influenced not only by normal stress but also by a part of shear stress when they are taking into application. In this study, the effects of different factors were evaluated on the tensile property of the wood I-joists. The factors include the depth of the tanks on the flanges, the length of joint and different kinds of flanges. The method of control test was used in the process of the experiment design, and tensile shear test were taken during the experiment at the aim of testing the bonding property of the I-joists using a universal mechanical testing machine. Ultimately, it has been discovered that the factor of depth of the tanks and the length of the joint influence the bonding property mostly. So this paper offers the optimal fabrication technology of the I-joists to make it is possible for the increase of reliability when wood I-joists are taken into application.

Importance of the field:Cancer is a collection of diseases that arise from the progressive accumulation of genetic alterations in somatic cells. Genomic approaches have identified a great variety of genetic abnormalities associated with tumorigenesis, and molecular imaging and quantification assays have further elucidated the complex interactions within or between pathways. It is acknowledged that proteins, rather than genes, fulfill most cellular functions and signaling proteins largely operate through a large and complex network. To this end, cancer is mostly a pathway dysregulated disease: a small number of core pathways are dominant in aberrant cell growth leading to cancer. Thus, understanding the functional consequences of dysregulated and/or mutant signaling proteins in the context of native signaling networks is the frontier in cancer research.Areas covered in this review:This article reviews why resonant waveguide grating (RWG) biosensor cellular assays are considered to be integrative in nature, and how RWG biosensor can be used for mining the surface markers of cancer cells and discovering core pathway(s) of cancer receptor signaling.What the reader will gain:The reader will gain an overview of cancer biology from pathway perspective and have a glimpse of potential implications of integrative cellular assays, as promised by RWG biosensor, in cancer research and diagnosis.Take home message:Successful approaches for developing next-generation anticancer therapies and diagnostic protocols should take into account that the dysregulation of oncogenic pathways is central to tumorigenesis. The biosensor cellular assays offer unprecedented advantage in characterizing cancer biology. However, significant challenges are also presented in deconvoluting and validating cellular mechanisms identified in cancer receptor signaling using these assays.

This article describes duplexed label-free optical biosensor cellular assays for simultaneously assaying 2 endogenous receptors, the Gq-coupled histamine receptor (H1) and the Gs-coupled β2-adrenergic receptor (β2AR), in A431 cells. The biosensor cellular assays consist of 2 sequential steps—an initial agonist screening using Sigma LOPAC (Library of Pharmaceutically Active Compounds) and a subsequent antagonist screening using a solution mixture containing the H1agonist histamine and the β2AR agonist epinephrine. Results showed that costimulating A431 cells with histamine and epinephrine led to an optical response additive to individual responses. The agonist screening not only identified all full agonists for both the H1and β2receptors, but also detected pathway-biased ligands for the β2AR. Furthermore, the succeeding antagonist screening documented all known antagonists in the library for either the H1or β2receptors. This is the 1st demonstration of a single cellular assay that is capable of screening ligands against 2 GPCRs coupled to distinct G proteins, and highlights the power of pathway-unbiased and label-free biosensor cellular assays for GPCR screens.

G protein-coupled receptors (GPCRs) have been proven to be the largest family of druggable targets in the human genome. Given the importance of GPCRs as drug targets and the de-orphanization of novel targets, GPCRs are likely to remain the frequent targets of many drug discovery programs. With recent advances in instrumentation and understanding of cellular mechanisms for the signals measured, biosensor-centered label-free cell assay technologies become a very active area for GPCR screening. This article reviews the principles and potential of current label-free cell assay technologies in GPCR drug discovery.

Once viewed solely as a tool for low throughput and kinetic analysis of biomolecular interactions, optical biosensors are gaining widespread uses in drug discovery because of recent advances in instrumentation and experimental design. These advances have expanded the capabilities of optical biosensors to meet the needs at many points in the drug discovery process. Concurrent shifts in drug discovery paradigms have seen the growing use of whole cell systems for drug screens, thus creating both a need in drug discovery and a solution in optical biosensors. This article reviews important advances in optical biosensor instrumentation, and highlights the potential of optical biosensors for drug discovery with an emphasis on whole cell sensing in both high throughput and high content fashions.

This article presents theoretical analysis and experimental data for the use of resonant waveguide grating (RWG) biosensors to characterize stimulation-mediated cell responses including signaling. The biosensor is capable of detecting redistribution of cellular contents in both directions that are perpendicular and parallel to the sensor surface. This capability relies on online monitoring cell responses with multiple optical output parameters, including the changes in incident angle and the shape of the resonant peaks. Although the changes in peak shape are mainly contributed to stimulation-modulated inhomogeneous redistribution of cellular contents parallel to the sensor surface, the shift in incident angle primarily reflects the stimulation-triggered dynamic mass redistribution (DMR) perpendicular to the sensor surface. The optical signatures are obtained and used to characterize several cellular processes including cell adhesion and spreading, detachment and signaling by trypsinization, and signaling through either epidermal growth factor receptor or bradykinin B2receptor. A mathematical model is developed to link the bradykinin-mediated DMR signals to the dynamic relocation of intracellular proteins and the receptor internalization during B2receptor signaling cycle. This model takes the form of a set of nonlinear, ordinary differential equations that describe the changes in four different states of B2receptors, diffusion of proteins and receptor-protein complexes, and the DMR responses. Classical analysis shows that the system converges to a unique optical signature, whose dynamics (amplitudes, transition time, and kinetics) is dependent on the bradykinin signal input, and consistent with those observed using the RWG biosensors. This study provides fundamentals for probing living cells with the RWG biosensors, in general, optical biosensors.

This article reports the use of Corning Epic system— a label-free and noninvasive optical system that is centered on resonant waveguide grating biosensors—to profile endogenous G protein-coupled receptors (GPCRs) in living cells under physiologically relevant conditions. The endogenous GPCRs examined were bradykinin B2receptor in A431 cells and protease-activated receptor subtype 1 (PAR1) in Chinese hamster ovary (CHO) cells. The activation of either receptor led to Gq-mediated signaling in the respective cells, as confirmed by Fluo-3 assays. Stimulation of CHO cells with thrombin, a PAR1natural agonist, resulted in an optical response relating to dynamic mass redistribution that is similar to that induced by bradykinin in A431 cells. Based on the kinetics of agonist-mediated optical signatures, two time points, one before and another 5 min after the stimulation, were chosen to develop high-throughput (HT) screening assays. Results showed that such endpoint measurements enable not only HT screening of compounds using endogenous GPCRs, but also determining the efficacies of agonists. Those results suggested that the Corning Epic label-free system is an easily scaleable biosensor, amenable as an HTS platform for GPCR drug discovery and deorphanization. (JALA 2006;11:181–7)

Conventional assay methods for discovering and profiling drug-target interactions are typically developed on a target-by-target basis and hence can be cumbersome to enable and orchestrate. Herein the authors report a solid-state ligand-binding assay that operates in a multiplexed mode to report compound activity against a micorarray-configured panel of G-protein-coupled receptor (GPCR) targets. The pharmacological fidelity of the system is high, and its miniaturized “plug-and-play” format provides improved efficiency both in terms of execution time and reagent consumption. Taken together, these features make the system ideally suited to explore the structure-activity relationship of compounds across a broad region of target class space.

Membrane-bound proteins represent the single most important class of drug targets. This article discusses the issues surrounding fabrication of membrane–protein microarrays by conventional robotic pin printing techniques. Ligand binding selectivity and specificity to G protein-coupled receptor (GPCR) microarrays are presented. The potential applications of these arrays for drug screening are discussed.

This report describes the fabrication of lipid arrays on gold-coated substrates presenting self-assembled monolayers (SAMs) of 16-mercaptohexadecanoic acid (MHA) derivatized with Brij®-76 (C18H37(OCH2CH2)n∼10X) (X=OH (1), NH2(2)). The oligo(ethylene glycol)-stearyl moiety was chosen to act as an anchor lipid, and to provide a hydrophilic spacer between the surface and the adsorbed lipid. Infrared spectroscopy and ellipsometry indicated that 2 was coupled to the MHA surface through the formation of peptide bonds with ∼25%of the —COOH groups being converted to —CONH-Brij-76 groups; the reaction with 1 was much less efficient (∼60% less than 2). The fabrication of arrays of supported lipids was investigated using two approaches. In the first method, arrays were made by incubating patterned surfaces in solutions of lipid; these patterns consisted of lipid binding regions made of gold that were derivatized with Brij, and lipid non-binding regions made of titanium oxide. In the second approach, arrays were made by robotic pin-printing of lipids on unpatterned Brij-derivatized gold surfaces. Biospecific binding of streptavidin to lipid arrays presenting biotin groups was observed using fluorescence microscopy and surface plasmon resonance imaging. The convenient fabrication of lipid arrays described here should enable the development of these tools for high-throughput screening of ligands against membrane bound proteins.

Atomic force microscopy has been used to study self‐assembled structures of two α‐hemolysin mutants. For a mutant (αHL‐H5) that was locked into the prepore state on fluid phase egg‐PC membranes, we visualized, for the first time, heptameric prepores and showed that the 7‐fold axis in the prepore lies perpendicular to the membrane surface. For another mutant (TCM) with the transmembrane domain, the self‐assembled oligomer that assumes the conformation of the fully assembled pore is also a heptamer. These results show that heptamers are the preferred oligomerization state of α‐hemolysin. Microsc. Res. Tech. 44:353–356, 1999. © 1999 Wiley‐Liss, Inc.

The effect of ethanol on the structure of DNA confined to mica in the presence of Mg2+ was examined by varying the ethanol concentration and imaging the DNA by atomic force microscopy. Contour length measurements of the DNA show a transition from all‐B‐form at 0% ethanol to all‐A‐form at >25% ethanol. At intermediate ethanol concentrations, contour lengths suggest that individual molecules of air‐dried DNA are trapped with mixed compositions of A‐form and B‐form. The relative composition depends on the ethanol concentration. Fitting the length distributions at intermediate ethanol concentrations to a simple binomial model results in an upper bound estimate for the A‐form and B‐form domains of ∼54 bp in the individual molecules. In addition to length changes, the apparent persistence length of DNA decreases with increasing ethanol concentration. At high concen‐trations of ethanol (>20%), DNA formed several higher order structures, including flower shaped condensates and toroids.