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Abstract Multi-functional cysteine-targeting covalent warheads possess significant therapeutic potential in medicinal chemistry and chemical biology. Herein, we present novel unsaturated and asymmetric ketone (oxazolinosene) scaffolds that selectively conjugate cysteine residues of peptides and bovine serum albumin under normal physiological conditions. This unsaturated saccharide depletes GSH in NCI-H1299 cells, leading to anti-tumor effects in vitro. The acetyl group of the ketal moiety on the saccharide ring can be converted to other carboxylic acids in a one-pot synthesis. In this way, the loaded acid can be click-released during cysteine conjugation, making the oxazolinosene a potential multifunctional therapeutic agent. The reaction kinetic model for oxazolinosene conjugation to GSH is well established and was used to evaluate oxazolinosene reactivity. The aforementioned oxazolinosenes were stereoselectively synthesized via a one-step reaction of nitriles with saccharides and conveniently converted into a series of α, β-unsaturated ketone N-glycosides as prevalent synthetic building blocks. The reaction mechanisms of oxazolinosene synthesis were investigated through calculations and validated with control experiments. Overall, these oxazolinosenes can be easily synthesized and developed as cysteine-targeted covalent warheads carrying useful click-releasing groups.

The increase in installed PV capacity worldwide and the intermittent nature of solar resources highlight the importance of power prediction for grid integration of this technology. Therefore, there is an urgent need for an effective prediction model, but the choice of model hyperparameters greatly affects the prediction performance. In this paper, a multi-strategy improved snowmelt algorithm (MISAO) is proposed for optimizing intrinsic computing-expressive empirical mode decomposition with adaptive noise (ICEEMDAN) and weighted least squares support vector machine for PV power forecasting. Firstly, a cyclic chaotic mapping initialization strategy is used to generate a uniformly distributed high-quality population, which facilitates the algorithm to enter the appropriate search domain quickly. Secondly, the Gaussian diffusion strategy enhances the local exploration ability of the intelligences and extends their search in the solution space, effectively preventing them from falling into local optima. Finally, a stochastic follower search strategy is employed to reserve better candidate solutions for the next iteration, thus achieving a robust exploration–exploitation balance. With these strategies, the optimization performance of MISAO is comprehensively improved. In order to comprehensively evaluate the optimization performance of MISAO, a series of numerical optimization experiments were conducted using IEEE CEC2017 and test sets, and the effectiveness of each improvement strategy was verified. In terms of solution accuracy, convergence speed, robustness, and scalability, MISAO was compared with the basic SAO, various state-of-the-art optimizers, and some recently developed improved algorithms. The results showed that the overall optimization performance of MISAO is excellent, with Friedman average rankings of 1.80 and 1.82 in the two comparison experiments. In most of the test cases, MISAO delivered more accurate and reliable solutions than its competitors. In addition, the altered algorithm was applied to the selection of hyperparameters for the ICEEMDAN-WLSSVM PV prediction model, and seven neural network models, including WLSSVM, ICEEMDAN-WLSSVM, and MISAO-ICEEMDAN-WLSSVM, were used to predict the PV power under three different weather types. The results showed that the models have high prediction accuracy and stability. The MAPE, MAE and RMSE of the proposed model were reduced by at least 25.3%, 17.8% and 13.3%, respectively. This method is useful for predicting the output power, which is conducive to the economic dispatch of the grid and the stable operation of the power system.

Non-fluorinated chitosan-based proton exchange membranes (PEMs) have been attracting considerable interest due to their environmental friendliness and relatively low cost. However, low proton conductivity and poor physicochemical properties have limited their application in fuel cells. In this work, a reinforced nanofiller (sulfonated CS/GO, S-CS/GO) is accomplished, for the first time, via a facile amidation and sulfonation reaction. Novel chitosan-based composite PEMs are successfully constructed by the incorporation of the nanofiller into the chitosan matrix. Additionally, the effects of the type and amount of the nanofillers on physicochemical and electrochemical properties are further investigated. It is demonstrated that the chitosan-based composite PEMs incorporating an appropriate amount of the nanofillers (9 wt.%) exhibit good membrane-forming ability, physicochemical properties, improved proton conductivity, and low methanol permeability even under a high temperature and low humidity environment. When the incorporated amounts of S-CS/GO are 9 wt.%, the proton conductivity of the composite PEMs was up to 0.032 S/cm but methanol permeability was decreased to 1.42 × 10−7 cm2/s. Compared to a pristine CS membrane, the tensile strength of the composite membrane is improved by 98% and the methanol permeability is reduced by 51%.

The journal retracts the article “Inhibition of SDF-1α/CXCR4 Signalling in Subchondral Bone Attenuates Post-Traumatic Osteoarthritis” [...]

Abstract Organic solar cells (OSCs) have attracted extensive attention from both academia and industry in recent years due to their remarkable improvement in power conversion efficiency (PCE). However, the Golden Triangle (the balance of efficiency‐stability‐cost) required for large‐scale industrialization of OSCs still remains a great challenge. Here, a new nonfused‐ring electron acceptor (NFREA) BF and its polymerized counterpart PBF were designed and synthesized, and their photovoltaic performance, storage stability and material cost were systematically investigated. When blended with a widely‐used polymer donor PBDB‐T, the PBF‐based all‐polymer solar cell (all‐PSC) displayed a record high PCE of 12.61% for polymerized NFREAs (PNFREAs) with an excellent stability (95.2% of initial PCE after 800 h storage), superior to the BF counterpart. Impressively, PBF‐based all‐PSC possesses the highest industrial figure‐of‐merit (i‐FOM) value of 0.309 based on an efficiency‐stability‐cost evaluation, in comparison to several representative OSC systems (such as PM6:Y6 and PBDB‐T:PZ1). This work provides an insight into the balance of efficiency, stability, and cost, and also indicates that the PNFREAs are promising materials toward the commercial application of OSCs.

We propose CanaryExp, an exploitability evaluation solution for vulnerabilities among binary programs protected by StackGuard. CanaryExp devises three novel techniques, namely canary leakage proof of concept generation, canary leaking analysis time exploitation, and dynamic canary-relocation-based exploitability evaluation. The canary leakage proof of concept input generation mechanism first traces the target program’s execution, transforming the execution state into some canary leaking state, from which some canary leaking input is derived. This input can be deemed as proof that some vulnerability that can lead to canary leakage exists. The canary leaking analysis time exploit generation then performs incremental analysis based on the canary leaking input, crafting analysis time exploit that can complete vulnerability exploitation in the analysis time environment. Based on the analysis time exploit, the dynamic canary-relocation-based exploitability evaluation component collects the necessary metadata, on which an exploitation session is automatically constructed that can not only leak the runtime canary and relocate it in the input stream but also evaluate the exploitability of the desired vulnerability. Using a benchmark containing six test programs, eight challenges from some network challenging events and four real-world applications, we demonstrate that CanaryExp can generate canary leaking samples more effectively than existing test case generation methods and automatically evaluate the exploitability for vulnerabilities among programs where the StackGuard protection mechanism is deployed.

Static analysis is popular for detecting SQL injection vulnerabilities. However, due to the lack of accurate modeling of object-oriented database extensions, current methods fail to accurately detect SQL injection vulnerabilities in applications that use object-oriented database extensions. We propose a program transformation-based SQL injection vulnerability detection method to address this issue. This method consists of two stages: program transformation and vulnerability detection. In the first stage, object-oriented database extensions are automatically transformed into semantically equivalent procedural database extensions through the identification of key statements, call relation verification, and program transformation. In the second stage, application programs are automatically scanned using a combination of control flow graph construction and taint analysis techniques to detect SQL injection vulnerabilities. Based on the proposed method, we have implemented the OODBE-SCAN prototype system and performed experimental analysis on eight modern PHP applications. We compare OODBE-SCAN with two related static analysis tools, RIPS and Seay. The results show that OODBE-SCAN can detect more real-world vulnerabilities and has higher accuracy than existing methods.

Black-box web application scanning has been a popular technique to detect Cross-Site Scripting (XSS) vulnerabilities without prior knowledge of the application. However, several limitations lead to low efficiency of current black-box scanners, including (1) the scanners waste time by repetitively visiting similar states, such as similar HTML forms of two different products, and (2) using a First-In-First-Out (FIFO) fuzzing order for the collected forms has led to low efficiency in detecting XSS vulnerabilities, as different forms have different potential possibilities of XSS vulnerability. In this paper, we present a state-sensitive black-box web application scanning method, including a filtering method for excluding similar states and a heuristic ranking method for optimizing the fuzzing order of forms. The filtering method excludes similar states by comparing readily available characteristic information that does not require visiting the states. The ranking method sorts forms based on the number of injection points since it is commonly observed that forms with a greater number of injection points have a higher probability of containing XSS vulnerabilities. To demonstrate the effectiveness of our scanning method, we implement it in our black-box web scanner and conduct experimental evaluations on eight real-world web applications within a limited scanning time. Experimental results demonstrate that the filtering method improves the code coverage about 17% on average and the ranking method helps detect 53 more XSS vulnerabilities. The combination of the filtering and ranking methods helps detect 81 more XSS vulnerabilities.

Exploiting cost-effective and durable non-platinum electrocatalysts for oxygen reduction reaction (ORR) is of great significance for the development of abundant renewable energy conversion and storage technologies. Herein, a series of Co3O4 supported on graphene-like carbon (Co3O4/C) samples were firstly effectively synthesized by one-step calcination of cobalt phthalocyanine and their electrocatalytic performances were measured for ORR under an alkaline medium. By systematically adjusting the calcination temperature of cobalt phthalocyanine, we found that the material pyrolyzed at 750 °C (Co3O4/C−750) shows the best ORR electrocatalytic performance (half-wave potentials of 0.77 V (vs. RHE) in 0.1 M KOH) among all the control samples. Moreover, it displays better stability and superior methanol tolerance than commercial 20% Pt/C. The further electrochemical test results reveal that the process is close in characteristics to the four-electron ORR process on Co3O4/C−750. In addition, Co3O4/C−750 applied in the zinc–air battery presents 1.34 V of open circuit potential. Based on all the characterizations, the enhanced electrocatalytic performances of Co3O4/C−750 composite should be ascribed to the synergistic effect between Co3O4 and the graphene-like carbon layer structure produced by pyrolysis of cobalt phthalocyanine, as well as its high specific surface area.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and has complicated pathobiology, leading to irreversible memory loss and severe cognitive dysfunction. For patients with AD, the advent of the disease usually occurs after years of pathological changes. The early diagnosis and monitoring of AD are of great significance as the early-stage intervention and treatment may be the most effective. Biomarkers, such as beta-amyloid and tau levels in cerebrospinal fluid (CSF) and brain, offer one of the most promising paths and are combined with neuroimaging and immunological detection for AD diagnosis. However, high expense and radiation of neuroimaging and low sensitivity of immunosorbent assay limited their applications. Meanwhile, the relevance of Aβ peptides and tau proteins to the development of AD remains highly debatable, meaning that detecting one specific biomarker holds limited prospects in achieving early and accurate detection of AD. Optical sensor arrays based on pattern recognition enable the discrimination of multiple analytes in complicated environments and are thus highly advantageous for the detection of AD with multi-biomarkers. In this review, we survey the recent advances of optical sensor arrays for the diagnosis of AD, as well as the remaining challenges.

Lithium-ion batteries (LIBs) are widely used in portable electronic devices, electric vehicles and large scale energy storage, due to their considerable energy density, low cost and long cycle life. However, traditional liquid batteries suffer from safety problems such as leakage, thermal runaway and even explosion. Part of the issues are caused by lithium dendrites puncturing the liquid electrolyte during cycling. In order to achieve the objective of higher safety and energy density, a rigid solid-state electrolyte (SSE) is proposed instead of liquid electrolyte (LE). Thereinto, sulfide SSEs have received of the most attention due to their high ionic conductivity. Among all the sulfide SSEs, argyrodite SSEs are considered to be one of the most promising solid-state electrolytes due to their high ionic conductivity, high thermal stability and good processablity. On the other hand, lithium metal is an ideal material for anode because of its high specific energy, low potential and large storage capacity. However, interfacial problems between argyrodite SSEs and the anode (interfacial reactions, lithium dendrites, etc.) are considered to be important factors affecting their availability. In this mini review, we summarize the behavior, properties and problems arising at the interface between argyrodite SSEs and anode. Strategies to solve interface problems and stabilize interfaces in recent years are also discussed. Finally, a brief outlook about argyrodite SSEs is presented.

The alloying of noble metals with Cu is one of the most effective strategies for improving catalytic performance and reducing cost in electrocatalytic carbon dioxide reduction reactions (CO2RR). Previous works usually focused on the influence of morphology and composition on the catalytic activity, but lacked the study of the valence state ratio of metals and the electron transfer behavior on alloys. In this work, PdCu−2 alloy (Pd/Cu molar ratio is 1:2) was obtained by a simple one-step solvothermal method, which can effectively convert CO2 to CO with a maximum Faradaic efficiency (FE) of 85% at −0.9 V (vs. RHE). Then, the effect of the chemical state of Pd and Cu on the catalytic performance was investigated. The X-ray photoelectron spectroscopy (XPS) shows that the binding energy of Pd in PdCu alloy has a negative shift, which has affected the adsorption of key intermediates. When the proportion of oxidized state and zero-valent metal in the alloy is about 1:2, the PdCu alloy shows the best catalytic activity. In addition, the transient photovoltage (TPV) measurements further demonstrate that due to the introduction of Cu, the electron transfer rate of PdCu−2 becomes the slowest, which helps the accumulation of electrons on PdCu−2 and leads to the improvement of catalytic performance for electrocatalytic CO2RR. This work can provide more insights into the alloy catalysts of electrocatalytic CO2RR.

Selenium-sulfur solid solutions (Se1-xSx) are considered to be a new class of promising cathodic materials for high-performance rechargeable lithium batteries owing to their superior electric conductivity than S and higher theoretical specific capacity than Se. In this work, high-performance Li-Se1-xSx batteries employed freestanding cathodes by encapsulating Se1-xSx in a N-doped carbon framework with three-dimensional (3D) interconnected porous structure (NC@SWCNTs) are proposed. Se1-xSx is uniformly dispersed in 3D porous carbon matrix with the assistance of supercritical CO2 (SC-CO2) technique. Impressively, NC@SWCNTs host not only provides spatial confinement for Se1-xSx and efficient physical/chemical adsorption of intermediates, but also offers a highly conductive framework to facilitate ion/electron transport. More importantly, the Se/S ratio of Se1-xSx plays an important role on the electrochemical performance of Li- Se1-xSx batteries. Benefiting from the rationally designed structure and chemical composition, NC@SWCNTs@Se0.2S0.8 cathode exhibits excellent cyclic stability (632 mA h g−1 at 200 cycle at 0.2 A g−1) and superior rate capability (415 mA h g−1 at 2.0 A g−1) in carbonate-based electrolyte. This novel NC@SWCNTs@Se0.2S0.8 cathode not only introduces a new strategy to design high-performance cathodes, but also provides a new approach to fabricate freestanding cathodes towards practical applications of high-energy-density rechargeable batteries.

In this work, a freestanding layer-structure Se cathode, composed of alternant barrier layers and active layers, is synthesized via a facile syringe-filtration strategy. With employing the barrier layers simultaneously acting as polyselenide-interception barriers and as highly conductive current collectors, the active layers with 3D porous architecture are endowed with strong polyselenide-trapping capability and fast redox-conversion capability. Such novel Se cathode readily achieves a high Se loading up to 13.5 mg cm−2. The optimized Se cathode with a high Se loading of 4.5 mg cm−2 exhibits high specific capacity/areal capacity (794 mA h g−1/3.6 mA h cm−2), excellent cycling stability (508 mA h g−1@300 cycles), and remarkable rate capability (389 mA h g−1@800 mA g−1), which is superior to conventional Se cathodes. Keywords: Lithium-selenium batteries, Se cathode, Alternant layer structure, Syringe-filtration method, Areal capacity

Fluoride is widely distributed, and excessive intake will lead to dental fluorosis. In this study, six offspring rats administrated 100 mg/L sodium fluoride were defined as the dental fluorosis group, and eight offspring rats who received pure water were defined as the control group. Differentially expressed proteins and metabolites extracted from peripheral blood were identified using the liquid chromatography tandem mass spectrometry and gas chromatography mass spectrometry, with the judgment criteria of fold change >1.2 or p < 0.05. A coexpression enrichment analysis using OmicsBean was conducted on the identified proteins and metabolites, and a false discovery rate (FDR) < 0.05 was considered significant. Human Protein Atlas was used to determine the subcellular distribution of hub proteins. The Gene Cards was used to verify results. A total of 123 up-regulated and 46 down-regulated proteins, and 12 up-regulated and 2 down-regulated metabolites were identified. The significant coexpression pathways were the HIF-1 (FDR = 1.86 × 10−3) and glycolysis/gluconeogenesis (FDR = 1.14 × 10−10). The results of validation analysis showed the proteins related to fluorine were mainly enriched in the cytoplasm and extrinsic component of the cytoplasmic side of the plasma membrane. The HIF-1 pathway (FDR = 1.01 × 10−7) was also identified. Therefore, the HIF-1 and glycolysis/gluconeogenesis pathways were significantly correlated with dental fluorosis.

Aiming at the problem of valve port erosion caused by contaminated particles, a three-dimensional prediction model of valve orifice erosion was established based on computational fluid dynamics (CFD) and erosion theory, considering the influence of the valve port eddy current on the oil flow. The discrete phase model (DPM) of fluent is used to obtain the orifice erosion location and erosion rate, and the causes of erosion of the high-speed on/off valve are analyzed. On this basis, several factors influencing valve port erosion are simulated to investigate the relationship between particle collision behavior and valve port erosion morphology under different factors, and the change rule of valve port erosion under different factors is analyzed. The results show that the high-speed on/off valve service life decreases with a larger cone angle of the spool, a larger pressure difference at the valve port, a larger proportion of large particle contaminants in the oil, a higher oil contamination level, and a larger filter aperture. In addition, the grey relational analysis method is used to clarify the pressure difference at the valve port, the particle size, and the filter aperture as the three most important factors affecting the erosion of the valve port of a high-speed on/off valve.

Current automatic exploit generation solutions generally adopt an 1-step exploit generation philosophy and neglect the potential difference between analysis-time environment and runtime environment. Therefore, they usually fail in evaluating exploitability for vulnerable programs running in an ASLR environment. We propose ExpGen, a 2-step vulnerability-exploitability evaluation solution for binary programs running in an ASLR environment, with three novel techniques introduced, separately partial-exploit sensitive-POC generation, exploitation context sensitive analysis-time exploit generation, and runtime exploit relocation. ExpGen firstly generates an analysis-time exploit that can carry out all the desired exploitation steps through applying the first two techniques in an iterative manner, then dynamically gaps the address-space layout differences between the analysis-time environment and runtime environment by adopting the runtime exploit-relocation technique, making the analysis-time exploit dynamically adaptable to the runtime exploitation session. Using a benchmark containing six test programs, 10 CTF&RHG programs and four real-world applications with known vulnerabilities, we demonstrate that ExpGen can effectively generate partial exploit input that carries out some address-leakage event and provide a complete automated exploitability evaluation workflow on vulnerable programs running in the ASLR environment.

With the approaching exhaustion of shallow-ground gas and oil, heat-resistant explosives are in highly demand in oil/gas ultra-deep and ocean well development. However, the prediction method on decomposition temperatures of heat-resistant explosives is still yet to be determined. In this paper, based on the decomposition reaction of “trinitrotoluene mechanism”, the influences of the enthalpy changes, entropies, Gibbs free energies, conversion temperatures and resonance energies on corresponding decomposition temperatures were studied. A theoretical relation was proposed after a genetic-algorithm optimization. Based on this relation, the decomposition temperatures of LLM-105 derivatives and its isomers were discussed. The results showed that the proposed relation coincided well with the decomposition temperatures of typical aromatic explosives. Furthermore, the decomposition temperatures of LLM-105, LLM-105I2 and ANPZ,TANPyO were predicted high and can be taken as new heat-resistant explosive candidates.

In this work, an innovative nano-carbon material (N-CM) adsorbent was reported for exploring its adsorption behaviors toward cationic methylene blue (MB) and anionic reactive blue 19 (RB19) pollutants. The proposed N-CM was synthesized by a one-step solvothermal treatment of citric acid and zinc gluconate small precursors. N-CM consists of nanosheets that have an advantageous specific surface area, large sp2/sp3 hybridized domains, and abundant nitrogen/oxygen-containing surface functional groups. The synergistic effects of these features are conducive to the MB and RB19 adsorption. Different from anionic RB19 adsorption (79.54 mg/g) by the cooperative π-π stacking and hydrogen bonding, cationic MB adsorbed onto N-CM mainly by the electrostatic attraction at the natural pH solution (> pHpzc), with an adsorption capacity up to 118.98 mg/g. Interestingly, both MB and RB19 adsorption conformed to the pseudo-second order kinetic (R2 ≥ 0.995) and Langmuir isothermal (R2 ≥ 0.990) models, accompanied by similar maximum monolayer adsorption capacities of 120.77 and 116.01 mg/g, respectively. Their adsorption processes exhibited spontaneously endothermic characteristics. Moreover, N-CM showed superior selective capability toward MB in different mixed dye systems, with high removal efficiencies of 73–89%. These results demonstrate that the high-performance carbon adsorbent prepared from small precursors via low-temperature carbonization shows great potentials in wastewater treatment.

A depolarizer, a kind of optical element that converts polarized light to unpolarized light, has been found massive applications in classical optics. However, depolarizers based on metasurface which can be applied in integrated optics have rarely been proposed. In this paper, an electronically controlled metasurface depolarizer is demonstrated based on the time-domain integral average method and nano-material barium titanate. It obtains emergent light with a degree of polarization reduced to 2.5% when hit by linearly polarized light at 633 nm, and has a transmission efficiency greater than 72%. This depolarizing metasurface can be designed on-demand, immunizing the degree of the emergent light from its size, and has the simple electronic control with high-speed response.

Due to the ever-growing demand for high-density energy storage devices, lithium-ion batteries with a high-capacity cathode and anode are thought to be the next-generation batteries for their high energy density. Lithium sulfide (Li2S) is considered the promising cathode material for its high theoretical capacity, high melting point, affordable volume expansion, and lithium composition. This review summarizes the activation and lithium storage mechanism of Li2S cathodes. The design strategies in improving the electrochemical performance are highlighted. The application of the Li2S cathode in full cells of lithium-ion batteries is discussed. The challenges and new directions in commercial applications of Li2S cathodes are also pointed out.

Conventional lithium-ion batteries with a limited energy density are unable to assume the responsibility of energy-structure innovation. Lithium-selenium (Li-Se) batteries are considered to be the next generation energy storage devices since Se cathodes have high volumetric energy density. However, the shuttle effect and volume expansion of Se cathodes severely restrict the commercialization of Li-Se batteries. Herein, a facile solid-phase synthesis method is successfully developed to fabricate novel pre-lithiated Li2Se-LiTiO2 composite cathode materials. Impressively, the rationally designed Li2Se-LiTiO2 composites demonstrate significantly enhanced electrochemical performance. On the one hand, the overpotential of Li2Se-LiTiO2 cathode extremely decreases from 2.93 V to 2.15 V. On the other hand, the specific discharge capacity of Li2Se-LiTiO2 cathode is two times higher than that of Li2Se. Such enhancement is mainly accounted to the emergence of oxygen vacancies during the conversion of Ti4+ into Ti3+, as well as the strong chemisorption of LiTiO2 particles for polyselenides. This facile pre-lithiated strategy underscores the potential importance of embedding Li into Se for boosting electrochemical performance of Se cathode, which is highly expected for high-performance Li-Se batteries to cover a wide range of practical applications.

The multifocal metalens with an adjustable intensity has great potential in many applications such as the multi-imaging system, but it is less studied. In this paper, by combining the electro-optic material barium titanate (BTO) with the Pancharatnam-Berry phase, an electrically modulated bifocal metalens in a visible light band is innovatively proposed. Due to the electro-optic effect, we can control the refractive index of the BTO nanofins to vary between 2.4 and 3.07 by applying different voltages (0–60 V). Thus, the method of modulating the intensity ratio of the two focal points is applying an electric field. It is different from using phase change materials or changing the ellipticity of incident light, the strategies proposed in previous studies. Moreover, when the applied voltage is 0 V or 60 V, the bifocal metalens becomes a single focal metalens with different focal lengths, and the full width at half maximum of each focal point is close to the diffraction limit. It has great potential in applications of optical storage, communication and imaging systems.

The zoom metalens has been a research hotspot for metasurfaces in recent years. There are currently a variety of zoom methods, including dual metalenses, micro-electromechanical system metalenses, polydimethylsiloxane metalenses and Alvarez metalenses. However, for most metalenses, zooming is achieved by manipulating the relative displacement of two or more metasurfaces. Therefore, these methods seem inadequate when faced with more precise zooming requirements, and the precise control of the phase distribution cannot be achieved. In this paper, we innovatively propose an electrically-driven zoom metalens (EZM) of one-dimensional based on dynamically controlling barium titanate (BaTiO3, BTO) antennas. Using the electro-optic effect of BTO crystals, we can apply a voltage to change the refractive index of BTO nanopillars (n = 2.4–3.6), thereby accurately controlling the phase distribution of column antennas. The proposed EZM can achieve 5× zoom (f = 10–50 μm), with advantages, such as high-speed optical amplitude modulation, ultra-compactness, flexibility and replicability. It can be applied in fields that require ultra-compact beam focusing, zoom imaging, and microscopic measuring.

Dynamic remodeling of the actin cytoskeleton plays a central role in the elongation of cotton fibers, which are the most important natural fibers in the global textile industry. Here, a high-resolution mapping approach combined with comparative sequencing and a transgenic method revealed that a G65V substitution in the cotton actin Gh_D04G0865 (GhACT17D in the wild-type) is responsible for the Gossypium hirsutum Ligon lintless-1 (Li1) mutant (GhACT17DM). In the mutant GhACT17DM from Li1 plant, Gly65 is substituted with valine on the lip of the nucleotide-binding domain of GhACT17D, which probably affects the polymerization of F-actin. Over-expression of GhACT17DM, but not GhACT17D, driven by either a CaMV35 promoter or a fiber-specific promoter in cotton produced a Li1-like phenotype. Compared with the wild-type control, actin filaments in Li1 fibers showed higher growth and shrinkage rates, decreased filament skewness and parallelness, and increased filament density. Taken together, our results indicate that the incorporation of GhACT17DM during actin polymerization disrupts the establishment and dynamics of the actin cytoskeleton, resulting in defective fiber elongation and the overall dwarf and twisted phenotype of the Li1 mutant.

Control Flow Graphs (CFGs) provide fundamental data for many program analyses, such as malware analysis, vulnerability detection, code similarity analysis, etc. Existing techniques for constructing control flow graphs include static, dynamic, and hybrid analysis, which each having their own advantages and disadvantages. However, due to the difficulty of resolving indirect jump relations, the existing techniques are limited in completeness. In this paper, we propose a practical technique that applies static analysis and dynamic analysis to construct more complete control flow graphs. The main innovation of our approach is to adopt directed gray-box fuzzing (DGF) instead of coverage-based gray-box fuzzing (CGF) used in the existing approach to generate test cases that can exercise indirect jumps. We first employ a static analysis to construct the static CFGs without indirect jump relations. Then, we utilize directed gray-box fuzzing to generate test cases and resolve indirect jump relations by monitoring the execution traces of these test cases. Finally, we combine the static CFGs with indirect jump relations to construct more complete CFGs. In addition, we also propose an iterative feedback mechanism to further improve the completeness of CFGs. We have implemented our technique in a prototype and evaluated it through comparing with the existing approaches on eight benchmarks. The results show that our prototype can resolve more indirect jump relations and construct more complete CFGs than existing approaches.

Prediabetes is a high-risk condition for type 2 diabetes (T2D). Pancreatic β-cells adapt to impaired glucose regulation in prediabetes by increasing insulin secretion and β-cell mass expansion. In people with prediabetes, metformin has been shown to prevent prediabetes conversion to diabetes. However, emerging evidence indicates that metformin has negative effects on β-cell function and survival. Our previous study established the Nile rat (NR) as a model for prediabetes, recapitulating characteristics of human β-cell compensation in function and mass expansion. In this study, we investigated the action of metformin on β-cells in vivo and in vitro. A 7-week metformin treatment improved glucose tolerance by reducing hepatic glucose output and enhancing insulin secretion. Although high-dose metformin inhibited β-cell glucose-stimulated insulin secretion in vitro, stimulation of β-cell insulin secretion was preserved in metformin-treated NRs via an indirect mechanism. Moreover, β-cells in NRs receiving metformin exhibited increased endoplasmic reticulum (ER) chaperones and alleviated apoptotic unfold protein response (UPR) without changes in the expression of cell identity genes. Additionally, metformin did not suppress β-cell mass compensation or proliferation. Taken together, despite the conflicting role indicated by in vitro studies, administration of metformin does not exert a negative effect on β-cell function or cell mass and, instead, early metformin treatment may help protect β-cells from exhaustion and decompensation.

Amorphous structures may play important roles in achieving highly efficient microwave absorption performance due to the polarization losses induced by the disorders, vacancies and other functional groups existed in them. Herein, a kind of amorphous TiO2/rGO composite (a-TiO2/rGO) was successfully fabricated via a facile one-step solvothermal method. The complex permittivity of the composites can be regulated by adjusting the addition of precursor solution. The minimum reflection loss of a-TiO2/rGO composites reached −42.8 dB at 8.72 GHz with a thickness of 3.25 mm, and the widest efficient absorption bandwidth (EAB) was up to 6.2 GHz (11.8 to 18 GHz) with a thickness of only 2.15 mm, which achieved the full absorption in Ku band (12 to 18 GHz). Furthermore, the EAB was achieved ranging from 3.97 to 18 GHz by adjusting the thickness of the absorber, covering 87.7% of the whole radar frequency band. It is considered that the well-matched impedance, various polarization processes, capacitor-like structure and conductive networks all contributed to the excellent microwave absorption of a-TiO2/rGO. This study provides reference on constructing amorphous structures for future microwave absorber researches and the as-prepared a-TiO2/rGO composites also have great potential owing to its facile synthesis and highly efficient microwave absorption.

Diabetes is one of the leading causes of death globally. Currently, the donor pancreas is the only source of human islets, placing extreme constraints on supply. Hence, it is imperative to develop renewable islets for diabetes research and treatment. To date, extensive efforts have been made to derive insulin-secreting cells from human pluripotent stem cells with substantial success. However, the in vitro generation of functional islet organoids remains a challenge due in part to our poor understanding of the signaling molecules indispensable for controlling differentiation pathways towards the self-assembly of functional islets from stem cells. Since this process relies on a variety of signaling molecules to guide the differentiation pathways, as well as the culture microenvironments that mimic in vivo physiological conditions, this review highlights extracellular matrix proteins, growth factors, signaling molecules, and microenvironments facilitating the generation of biologically functional pancreatic endocrine cells from human pluripotent stem cells. Signaling pathways involved in stepwise differentiation that guide the progression of stem cells into the endocrine lineage are also discussed. The development of protocols enabling the generation of islet organoids with hormone release capacities equivalent to native adult islets for clinical applications, disease modeling, and diabetes research are anticipated.

Epidemiological results revealed that there is an inverse correlation between high-density lipoprotein (HDL) cholesterol levels and risks of atherosclerotic cardiovascular disease (ASCVD). Mounting evidence supports that HDLs are atheroprotective, therefore, many therapeutic approaches have been developed to increase HDL cholesterol (HDL-C) levels. Nevertheless, HDL-raising therapies, such as cholesteryl ester transfer protein (CETP) inhibitors, failed to ameliorate cardiovascular outcomes in clinical trials, thereby casting doubt on the treatment of cardiovascular disease (CVD) by increasing HDL-C levels. Therefore, HDL-targeted interventional studies were shifted to increasing the number of HDL particles capable of promoting ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux. One such approach was the development of reconstituted HDL (rHDL) particles that promote ABCA1-mediated cholesterol efflux from lipid-enriched macrophages. Here, we explore the manipulation of rHDL nanoparticles as a strategy for the treatment of CVD. In addition, we discuss technological capabilities and the challenge of relating preclinical in vivo mice research to clinical studies. Finally, by drawing lessons from developing rHDL nanoparticles, we also incorporate the viabilities and advantages of the development of a molecular imaging probe with HDL nanoparticles when applied to ASCVD, as well as gaps in technology and knowledge required for putting the HDL-targeted therapeutics into full gear.

Chaperone-mediated autophagy (CMA) is involved in wild-type α-synuclein degradation in Parkinson’s disease (PD), and LAMP2A and Hsc 70 have recently been indicated to be deregulated by microRNAs. To recognize the regularory role of miR-320a in CMA and the possible role in α-synuclein degradation, in the present study, we examined the targeting and regulating role of miR-320 in Hsc 70 expression. We first constructed an α-synuclein-overexpressed human neuroblastoma cell line, SH-SY5Y-Syn(+), stably over-expressing wild-type α-synuclein and sensitive to an autophagy inhibitor, which exerted no effect on the expression of LAMP2A and Hsc 70. Then we evaluated the influence on the CMA by miR-320a in the SH-SY5Y-Syn(+) cells. It was shown that miR-320a mimics transfection of specifically targeted Hsc 70 and reduced its expression at both mRNA and protein levels, however, the other key CMA molecule, LAMP2A was not regulated by miR-320a. Further, the reduced Hsc 70 attenuated the α-synuclein degradation in the SH-SY5Y-Syn(+) cells, and induced a significantly high level of α-synuclein accumulation. In conclusion, we demonstrate that miR-320a specifically targeted the 3' UTR of Hsc 70, decreased Hsc 70 expression at both protein and mRNA levels in α-synuclein-over-expressed SH-SY5Y cells, and resulted in significant α-synuclein intracellular accumulation. These results imply that miR-320a might be implicated in the α-synuclein aggravation in PD.

Lysine propionylation is a reversible and widely distributed post-translational modification that is known to play a regulatory role in both eukaryotes and prokaryotes. However, the extent and function of lysine propionylation in photosynthetic organisms remains unclear. Cyanobacteria are the most ancient group of Gram-negative bacteria capable of oxygenic photosynthesis, and are of great importance to global carbon and nitrogen cycles. Here, we carried out a systematic study of lysine propionylaiton in cyanobacteria where we used Synechocystis sp. PCC 6803 (Synechocystis) as a model. Combining high-affinity anti-propionyllysine pan antibodies with high-accuracy mass spectrometry (MS) analysis, we identified 111 unique lysine propionylation sites on 69 proteins in Synechocystis. Further bioinformatic analysis showed that a large fraction of the propionylated proteins were involved in photosynthesis and metabolism. The functional significance of lysine propionylation on the enzymatic activity of fructose-1,6-bisphosphatase (FbpI) was studied by site-directed mutagenesis and biochemical studies. Further functional studies revealed that the propionylation level of subunit II of photosystem I (PsaD) was obviously increased after high light (HL) treatment, suggesting that propionylation may be involved in high light adaption in Synechocystis. Thus, our findings provide novel insights into the range of functions regulated by propionylation and reveal that reversible propionylation is a functional modification with the potential to regulate photosynthesis and carbon metabolism in Synechocystis, as well as in other photosynthetic organisms.

Sarcoidosis is a systemic granulomatous disease, which is thought to result from an aberrant immune response. CD4+ T lymphocytes play an important role in the development of granulomas. Previously, the immunopathogenesis of sarcoidosis was focused on Th1/Th2 disturbances. The aim of this study was to evaluate the balance between newer CD4+ T lymphocytes, i.e., Treg and Th17 cells. In our studies, a decrease in Treg cells and an increase in Th17 cells were observed in the peripheral blood and BALF of sarcoidosis patients. A significant increase in the Th17/Treg cell ratio was observed in sarcoidosis patients. After treatment with prednisone, the expression of Foxp3 mRNA was elevated in the peripheral blood, and expression of (ROR)γt mRNA showed a downward trend. These findings suggest that sarcoidosis is associated with an imbalance between Th17 and Treg cells in peripheral blood and BALF. Therefore, targeting the cytokines that affect the Th17/Treg ratio could provide a new promising therapy for pulmonary sarcoidosis.

The mechanisms underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF) involve multiple pathways, such as inflammation, epithelial mesenchymal transition, coagulation, oxidative stress, and developmental processes. The small GTPase, RhoA, and its target protein, Rho-kinase (ROCK), may interact with other signaling pathways known to contribute to pulmonary fibrosis. This study aimed to determine the beneficial effects and mechanisms of fasudil, a selective ROCK inhibitor, on bleomycin-induced pulmonary fibrosis in mice. Our results showed that the Aschcroft score and hydroxyproline content of the bleomycin-treated mouse lung decreased in response to fasudil treatment. The number of infiltrated inflammatory cells in the bronchoalveolar lavage fluid (BALF) was attenuated by fasudil. In addition, fasudil reduced the production of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA), and plasminogen activator inhibitor-1 (PAI-1) mRNA and protein expression in bleomycin-induced pulmonary fibrosis. These findings suggest that fasudil may be a potential therapeutic candidate for the treatment of pulmonary fibrosis.

Cancer is one of the leading causes of death worldwide and a major global health problem. In recent decades, the rates of both mortality and morbidity of cancer have rapidly increased for a variety of reasons. Despite treatment options, there are serious side effects associated with chemotherapy drugs and multiple forms of drug resistance that significantly reduce their effects. There is an accumulating amount of evidence on the pharmacological activities of baicalein (e.g., anti-inflammatory, antioxidant, antiviral, and antitumor effects). Furthermore, there has been great progress in elucidating the target mechanisms and signaling pathways of baicalein’s anti-cancer potential. The anti-tumor functions of baicalein are mainly due to its capacities to inhibit complexes of cyclins to regulate the cell cycle, to scavenge oxidative radicals, to attenuate mitogen activated protein kinase (MAPK), protein kinase B (Akt) or mammalian target of rapamycin (mTOR) activities, to induce apoptosis by activating caspase-9/-3 and to inhibit tumorinvasion and metastasis by reducing the expression of matrix metalloproteinase-2/-9 (MMP-2/-9). In this review, we focused on the relevant biological mechanisms of baicalein involved in inhibiting various cancers, such as bladder cancer, breast cancer, and ovarian cancer. Moreover, we also summarized the specific mechanisms by which baicalein inhibited the growth of various tumors in vivo. Taken together, baicalein may be developed as a potential, novel anticancer drug to treat tumors.

We evaluated the role of the CXCL12/CXCR4 (C-X-C motif chemokine ligand 12/C-X-C chemokine receptor type 4) axis in aggrecanase-mediated cartilage degradation, and explored the underlying mechanism in a post-traumatic osteoarthritis rat model. Expression of CXCL12/CXCR4 and ADAMTS-5 was analyzed in the knees of osteoarthritic and non-arthritic rats using Western blot, ELISA, immunohistochemistry and immunofluorescence. Rodent studies were performed using Sprague-Dawley rats, with animals divided into three groups: Destabilization of the medial meniscus/AMD3100-treated (DMM/AMD3100-treated), DMM/PBS-treated, and sham controls. Rats were sacrificed after eight weeks, and samples were collected for histology and immunohistochemistry analyses. IL-1-pretreated primary chondrocytes were cultured with untreated control, CXCL12a, siNC + CXCL12a, or siRNA CXCR4 + CXCL12a, and analyzed for expression of relevant markers and cellular pathways. Higher levels of CXCL12 were detected in the knee fluid of osteoarthritic subjects, with strong staining for CXCR4 in chondrocytes and CXCL12 in synoviocytes together with enhanced expression of ADAMTS-5. DMM/AMD3100-treated rats showed a significantly reduced immunological response, with minimal evidence of pathology in both histological and immunohistochemical analyses. Treatment with CXCL12a increased the expression of ACAN, RUNX-2, and ADAMTS-4/5 in IL-1-pretreated primary chondrocytes, together with a decrease in the expression of SOX-9. Molecular analyses revealed strong induction of NF-κB activation, along with phosphorylation of MAPKs, and activation of canonical Wnt/β-catenin signaling. In conclusion, inhibition of SDF-1α/CXCR4 signaling axis was able to inhibit aggrecanase expression and lessen cartilage degeneration in post-traumatic osteoarthritis rats.

Previous studies showed that SDF-1α is a catabolic factor that can infiltrate cartilage, decrease proteoglycan content, and increase MMP-13 activity. Inhibiting the SDF-1α/CXCR4 signalling pathway can attenuate the pathogenesis of osteoarthritis (OA). Recent studies have also shown that SDF-1α enhances chondrocyte proliferation and maturation. These results appear to be contradictory. In the current study, we used a destabilisation OA animal model to investigate the effects of SDF-1α/CXCR4 signalling in the tibial subchondral bone and the OA pathological process. Post-traumatic osteoarthritis (PTOA) mice models were prepared by transecting the anterior cruciate ligament (ACLT), or a sham surgery was performed, in a total of 30 mice. Mice were treated with phosphate buffer saline (PBS) or AMD3100 (an inhibitor of CXCR4) and sacrificed at 30 days post ACLT or sham surgery. Tibial subchondral bone status was quantified by micro-computed tomography (μCT). Knee-joint histology was analysed to examine the articular cartilage and joint degeneration. The levels of SDF-1α and collagen type I c-telopeptidefragments (CTX-I) were quantified by ELISA. Bone marrow mononuclear cells (BMMCs) were used to clarify the effects of SDF-1α on osteoclast formation and activity in vivo. μCT analysis revealed significant loss of trabecular bone from tibial subchondral bone post-ACLT, which was effectively prevented by AMD3100. AMD3100 could partially prevent bone loss and articular cartilage degeneration. Serum biomarkers revealed an increase in SDF-1α and bone resorption, which were also reduced by AMD3100. SDF-1α can promote osteoclast formation and the expression oftartrate resistant acid phosphatase (TRAP), cathepsin K (CK), and matrix metalloproteinase (MMP)-9 in osteoclasts by activating the MAPK pathway, including ERK and p38, but not JNK. In conclusion, inhibition of SDF-1α/CXCR4signalling was able to prevent trabecular bone loss and attenuated cartilage degeneration in PTOA mice.

Human epidermal growth factor receptor 2 (HER2) is one of the most studied tumor-associated antigens for cancer immunotherapy. An engineered anti-HER-2 chimeric A21 antibody (chA21) is a chimeric antibody targeted to subdomain I of the HER2 extracellular domain. Here, we report the anti-tumor activity of the novel engineered monoclonal antibody humanized chA21 (HuA21) that targets HER2 on the basis of chA21, and we describe the underlying mechanisms. Our results reveal that HuA21 markedly inhibits the proliferation and migration of HER2-overexpressing breast cancer cells and causes enhanced antibody-dependent cell-mediated cytotoxicity potency against HER2-overexpressing tumor cells. In particular, HuA21, but not trastuzumab (Tra), markedly suppresses growth and enhances the internalization of the antibody in Tra-resistant BT-474 breast cancer cells. These characteristics are highly associated with the intrinsic ability of HuA21 to down-regulate HER2 activation and inhibit the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) signaling pathways. Furthermore, the combination of HuA21 with Tra synergistically enhances the anti-tumor effects in vitro and in vivo and inhibits HER2 activation and the ERK1/2 and Akt signaling pathways. Altogether, our results suggest that HuA21 may represent a unique anti-HER2 antibody with potential as a therapeutic candidate alone or in combination with other anti-HER2 reagents in cancer therapy.