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A cell membrane-derived vesicle (MV) that has cell-mimicking features with characteristic functionalities holds vast appeal for biomimetic nanomedicine and drug delivery but suffers from a major limitation of innate fragility and poor stability. Herein, we report a lipid-anchoring strategy for stabilizing MV for enhanced drug delivery. An array of amphiphilic mono-acyl phosphatidylcholines (MPCs) with specific hydrophobic moieties are synthesized and readily engineered on MV based on their commendable aqueous solubility and efficient membrane insertability. Incorporation of MPCs containing rigid ring structures in the hydrophobic segment demonstrates the potency of stabilizing MV by the combined ordering and condensing effects. The optimized MPC-stabilized MV exhibits prolonged circulation in the bloodstream, elevated accumulation within a tumor, and enhanced therapeutic effects of chemotherapeutic and photothermal drugs. Moreover, doxorubicin-loaded MV, engineered with mono-all-transretinoyl phosphatidylcholine as an MV stabilizer and a therapeutic prodrug, potently suppresses growth and metastasis of high-stemness tumors.

In this paper, the finite-time control and bumpless transfer control are investigated for switched systems under asynchronously switching. First, a class of dynamic output feedback controllers are designed to stabilize the switched system with measurable system outputs. Considering the improvement of transient performance, the bumpless transfer control and finite-time control are further studied in the controller design. To avoid the control bumps, a practical filter is introduced to make the control signal smoother and continuous. Furthermore, to derive a finite-time bounded system state over short-time intervals, the finite-time analysis is considered in managing the switching process with the average dwell time. New criteria are proposed to analyze the finite-time stability and finite-time boundedness for the closed-loop system and solvable conditions are newly proposed to optimize the controller gain. Finally, the superiorities of the proposed method are validated through an application to a boost converter. [ABSTRACT FROM AUTHOR]

This brief proposes the fuzzy switched active disturbance rejection controller (FSADRC) for generators with load switchings. First, to better reflect the working dynamics of generators, the switched Takagi-Sugeno (T-S) fuzzy models are established. Then, the FSADRC is designed, which can eliminate the load-switching effect on the system performance. By constructing the mode-dependent Lyapunov function, the stability is analyzed for the closed-loop system with the persistent dwell-time restriction. Subsequently, a new criterion is proposed to optimize the controller gains and ensure the $L_{\infty}$ performance. Finally, superiorities are validated through the DC-link voltage control experiments.

Aero-engine fault prediction aims to accurately predict the development trend of the future state of aero-engines, so as to diagnose faults in advance. Traditional aero-engine parameter prediction methods mainly use the nonlinear mapping relationship of time series data but generally ignore the adequate spatiotemporal features contained in aero-engine data. To this end, we propose a brain-inspired spike echo state network (Spike-ESN) model for aero-engine intelligent fault prediction, which is used to effectively capture the evolution process of aero-engine time series data in the framework of spatiotemporal dynamics. In the proposed approach, we design a spike input layer based on Poisson distribution inspired by the spike neural encoding mechanism of biological neurons, which can extract the useful temporal characteristics in aero-engine sequence data. Then, the temporal characteristics are input into a spike reservoir through the current calculation method of spike accumulation in neurons, which projects the data into a high-dimensional sparse space. In addition, we use the ridge regression method to read out the internal state of the spike reservoir. Finally, the experimental results of aero-engine states prediction demonstrate the superiority and potential of the proposed method.

Architectural Technical Debt (ATD) refers to sub-optimal architectural design in a software system that incurs high maintenance “interest” over time. Previous research revealed that ATD has significant negative impact on daily development. This paper contributes an approach to enable an architect to precisely locate ATDs, as well as capture the trajectory of maintenance cost on each debt, based on which, predict the cost of the debt in a future release. The ATDs are expressed in four typical patterns, which entail the core of each debt. Furthermore, we aggregate compound ATDs to capture the complicated relationship among multiple ATD instances, which should be examined together for effective refactoring solutions. We evaluate our approach on 18 real-world projects. We identified ATDs that persistently incur significant (up to 95 percent of) maintenance costs in most projects. The maintenance costs on the majority of debts fit into a linear regression model—indicating stable “interest” rate. In five projects, 12.1 to 27.6 percent of debts fit into an exponential model, indicating increasing “interest” rate, which deserve higher priority from architects. The regression models can accurately predict the costs of the majority of (82 to 100 percent) debts in the next release of a system. By aggregating related ATDs, architects can focus on a small number of cost-effective compound debts, which contain a relatively small number of source files, but account for a large portion of maintenance costs in their projects. With these capabilities, our approach can help architects make informed decisions regarding whether, where, and how to refactor for eliminating ATDs in their systems.

Hepatitis B represents a major global public health burden, which is caused by the hepatitis B virus (HBV) with a high infection rate. Although several anti-HBV drugs have been developed for clinical treatment of hepatitis B, the current therapeutic strategies still suffer from undeniable adverse effects, insufficient efficacy after systemic administration and chronic inflammation. Here, we develop a carrier-free metal–organic hybrid nanoassembly that is co-loaded with tenofovir (TFV), an anti-viral agent and phosphorylated glycyrrhetinic acid (GAP), an anti-inflammatory compound (TFV/GAP/NA) to enhance the anti-HBV effect and alleviate the inflammatory response for hepatitis B treatment. The nanoassembly is easily prepared through the ionic interactions between the anionic phosphonate/phosphate groups from TFV/GAP and the zirconium cation, which has a stable nanostructure and a high drug-loading capacity. The nanoassembly prolongs the circulation time with reduced drug leakage in the blood and elevates drug accumulation in the liver after intravascular administration. After internalization mediated by the GAP ligand–GA receptor interaction, TFV/GAP/NA disassembles by the phosphatase-triggered degradation of the phosphate ester bonds in GAP and releases TFV, GAP and GA within the HBV-positive hepatocytes. The released TFV interferes with the HBV polymerase to inhibit the viral DNA replication, while the released GAP and GA suppress the pro-inflammatory protein expression. In mouse models, treatment with TFV/GAP/NA inhibits HBV production and alleviates inflammation-mediated liver injury.

High-speed railway systems face frequent cybersecurity threats targeting their information networks. Continuous operation of protection mechanisms on wireless sensors results in persistent energy consumption, which is undesirable. To address this, we propose an optimal defense strategy selection approach for High-speed Railway Wireless Sensor Networks (HSR-WSNs) using an enhanced signaling game model. We first establish the basic elements and overall structure of the model, considering the presence of incomplete information and dynamic interactions between players. This paper provides background on signaling games, including theoretical concepts of equilibrium strategies and locations. We then develop a system to quantify payoffs for offensive and defensive tactics, incorporating distance and usage frequency weights. Finally, Long Short-Term Memory (LSTM) and the public UNSW-NB15 dataset are leveraged to augment assumptions and reduce human subjectivity in results. Experiments demonstrate the model effectively identifies energy balance points for HSR-WSNs and determines appropriate protection strategies. The work contributes to enhancing the selection of effective defense techniques against network attacks in wireless sensor systems. This has significant practical implications in enabling optimized energy usage and functionality of secured sensor nodes. [ABSTRACT FROM AUTHOR]

Monolithic systems increasingly suffer from maintainability and scalability issues as they grow in functionality, size, and complexity. It is widely believed that (micro)service-based architectures can alleviate these problems as each service is supposed to have the following characteristics: clearly defined functionality, sufficient modularity, and the ability to evolve independently. Industrial practices show that service extraction from a legacy monolithic system is labor-intensive and complex. Existing work on service candidate identification aims to group entities of a monolithic system into potential service candidates, but this process has two major challenges: first, it is difficult to extract service candidates with consistent quality; second, it is hard to evaluate the identified service candidates regarding the above three characteristics. To address these challenges, this paper proposes the Functionality-oriented Service Candidate Identification (FoSCI) framework to identify service candidates from a monolithic system. Our approach is to record the monolith's execution traces, and extract services candidates using a search-based functional atom grouping algorithm. We also contribute a comprehensive service candidate evaluation suite that uses interface information, structural/conceptual dependency, and commit history. This evaluation system consists of 8 metrics, measuring functionality, modularity, and evolvability respectively of identified service candidates. We compare FoSCI with three existing methods, using 6 widely-used open-source projects as our evaluation subjects. Our results show that FoSCI outperforms existing methods in most measures.

In large-scale software systems, error-prone or change-prone files rarely stand alone. They are typically architecturally connected and their connections usually exhibit architecture problems causing the propagation of error-proneness or change-proneness. In this paper, we propose and empirically validate a suite of architecture anti-patterns that occur in all large-scale software systems and are involved in high maintenance costs. We define these architecture anti-patterns based on fundamental design principles and Baldwin and Clark’s design rule theory. We can automatically detect these anti-patterns by analyzing a project’s structural relationships and revision history. Through our analyses of 19 large-scale software projects, we demonstrate that these architecture anti-patterns have significant impact on files’ bug-proneness and change-proneness. In particular, we show that 1) files involved in these architecture anti-patterns are more error-prone and change-prone; 2) the more anti-patterns a file is involved in, the more error-prone and change-prone it is; and 3) while all of our defined architecture anti-patterns contribute to file’s error-proneness and change-proneness, Unstable Interface and Crossing contribute the most by far.

Tumour heterogeneity remains a major challenge in cancer therapy owing to the different susceptibility of cells to chemotherapy within a solid tumour. Cancer stem-like cells (CSCs), which reside in hypoxic tumour regions, are characterized by high tumourigenicity and chemoresistance and are often responsible for tumour progression and recurrence. Here we report a nanotherapeutic strategy to kill CSCs in tumours using nanoparticles that are co-loaded with the differentiation-inducing agent, all-transretinoic acid, and the chemotherapeutic drug, camptothecin. All-transretinoic acid is released under hypoxic conditions, leading to CSC differentiation in the hypoxic niche. In differentiating CSC, the reactive oxygen species levels increase, which then causes the release of camptothecin and subsequent cell death. This dual strategy enables controlled drug release in CSCs and reduces stemness-related drug resistance, enhancing the chemotherapeutic response. In breast tumour mouse models, treatment with the nanoparticles suppresses tumour growth and prevents post-surgical tumour relapse and metastasis.

Neuroinflammation plays a pivotal part in the pathogenesis of stroke. Orphan nuclear receptor NR4A1 is involved in the inflammatory response of microglia and macrophages. In this study, we discovered an old drug, 9-aminoacridine (9-AA), as a novel NR4A1 activator from our in-house FDA-approved drug library, which exhibited anti-inflammatory activities through an NR4A1/IL-10/SOCS3 signaling pathway and modulated the microglia activation. To improve the druggability of 9-AA, different liposomal formulations were screened and investigated. 9-AA-loaded liposome (9-AA/L) was prepared to reduce the adverse effect of 9-AA. Furthermore, 9-AA-loaded PEG/cRGD dual-modified liposome (9-AA/L-PEG-cRGD) was obtained, which displayed prolonged circulation, improved biodistribution, and increased brain accumulation. In the transient middle cerebral artery occlusion (tMCAO) rat model, 9-AA/L-PEG-cRGD significantly reduced brain infarct area, ameliorated ischemic brain injury, and promoted long-term neurological function recovery. This “from drug discovery to drug delivery” methodology provides a potential therapeutic strategy using the liposomal 9-AA, the NR4A1 activator to suppress neuroinflammation for treatment of ischemic stroke.

Nanomedicine has huge potential in cancer therapy due to its advantages of improving the solubility, increasing the bioavailability and reducing the side effects of anticancer drugs. However, the intratumoral accumulation of anticancer nanomedicine is still extremely low owing to multiple physiological barriers to drug delivery; thus, it is inefficient for cancer treatments. Inspired by the communication between natural cells and the body environment, living cell-based anticancer therapeutics have been developed as promising drug carriers or active drugs for cancer therapy. In this review, we will survey recent advances in living cell-based anticancer therapeutics by leveraging their physiological characteristics, from long circulating properties to tumor-homing capacity and anticancer immune responses. In addition, future prospects of this field will be discussed.

Nagashima-type palmoplantar keratoderma is an autosomal recessive genodermatosis caused by loss-of-function variants in SERPINB7and is the most prevalent form of inherited palmoplantar keratodermas among Asians. However, there is currently no effective therapy for Nagashima-type palmoplantar keratoderma because its pathogenesis remains unclear. In this study, Serpinb7−/−mice were generated and spontaneously developed a disrupted skin barrier, which was further exacerbated by acetone–ether–water treatment. The skin of these Serpinb7−/−mice showed weakened cytoskeletal proteins. In addition, SERPINB7 deficiency consistently led to decreased epidermal differentiation in a 3-dimensional human epidermal model. We also demonstrated that SERPINB7 was an inhibitory serpin that mainly inhibited the protease legumain. SERPINB7 bound directly with legumain and inhibited legumain activity both in vitro and in vivo. Furthermore, we found that SERPINB7 inhibited legumain in a protease-substrate manner and identified the cleavage sites of SERPINB7 as Asn71and Asn343. Overall, we found that SERPINB7 showed the nature of a cysteine protease inhibitor and identified legumain as a key target protease of SERPINB7. Loss of SERPINB7 function led to overactivation of legumain, which might disrupt cytoskeletal proteins, contributing to the impaired skin barrier in Nagashima-type palmoplantar keratoderma. These findings may lead to the development of therapeutic strategies for Nagashima-type palmoplantar keratoderma.

TRPV3 is a temperature-sensitive calcium-permeable channel. In previous studies, we noticed prominent TUNEL-positive keratinocytes in patients with Olmsted syndrome and Trpv3+/G568Vmice, both of which carry gain-of-function mutations in the TRPV3gene. However, it remains unclear how the keratinocytes die and whether this process contributes to more skin disorders. Herein, we showed that gain-of-function mutation or pharmacological activation of TRPV3 resulted in PARP1/AIFM1/MIF axis-mediated parthanatos, which is an underestimated form of cell death in skin diseases. Chelating calcium, scavenging reactive oxygen species or inhibiting nitric oxide synthase effectively rescued the parthanatos, indicating that TRPV3 regulates parthanatos through calcium-mediated oxidative stress. Furthermore, inhibiting PARP1 downregulated TSLPand IL33induced by TRPV3 activation in HaCaT cells, reduced immune cell infiltration, and ameliorated epidermal thickening in Trpv3+/G568Vmice. Marked parthanatos was also detected in the skin of MC903-treated mice and patients with atopic dermatitis (AD), while inhibiting PARP1 largely alleviated the MC903-induced dermatitis. Additionally, stimulating parthanatos in mouse skin with methylnitronitrosoguanidine recapitulated many features of AD. These data demonstrate that the TRPV3-regulated parthanatos-associated PARP1/AIFM1/MIF axis is a critical contributor to the pathogenesis of Olmsted syndrome and AD, suggesting that modulating the PARP1/AIFM1/MIF axis is a promising therapy for these conditions.

The direct recycling process shows excellent flexibility and potential for the regeneration of spent lithium-ion battery cathodes. However, conventional direct recycling methods involve high temperatures or potential secondary pollution. Herein, the green restoration of spent LiFePO4(LFP) cathodes is achieved via a polymerization of dopamine (POD)-assisted process in water at room temperature. A unique mechanism is proposed based on DFT calculations: Some intermediates, rather than dopamine or polydopamine, restore the crystal structure of spent LFP. Furthermore, a short annealing treatment could not only increase the structural stability, but also avoid the potential secondary pollution caused by the reductants by converting the Polydopamine (PDA) layer to an N-doped carbon layer and improve the electrochemical performance of the regenerated LFP. A subsequent techno-economic analysis suggests that the present strategy promises great potential in practical application.

A tumour microenvironment imposes barriers to the passive diffusion of molecules, which renders tumour penetration an unresolved obstacle to an effective anticancer drug delivery. Here, we present a γ-glutamyl transpeptidase-responsive camptothecin–polymer conjugate that actively infiltrates throughout the tumour tissue through transcytosis. When the conjugate passes on the luminal endothelial cells of the tumour blood vessels or extravasates into the tumour interstitium, the overexpressed γ-glutamyl transpeptidase on the cell membrane cleaves the γ-glutamyl moieties of the conjugate to generate positively charged primary amines. The resulting cationic conjugate undergoes caveolae-mediated endocytosis and transcytosis, which enables transendothelial and transcellular transport and a relatively uniform distribution throughout the tumour. The conjugate showed a potent antitumour activity in mouse models that led to the eradication of small solid tumours (~100 mm3) and regression of large established tumours with clinically relevant sizes (~500 mm3), and significantly extended the survival of orthotopic pancreatic tumour-bearing mice compared to that with the first-line chemotherapeutic drug gemcitabine. A zwitterionic camptothecin–polymer conjugate that is enzymatically transformed in a cationic molecule at the tumour periphery penetrates deep into tumours via caveolae-mediated endocytosis and transcytosis, resulting in high anticancer efficiency in vivo.

New families of materials that may potentially replace dominant carbon electrodes have emerged as a major research hotspot in the field of capacitive deionization (CDI). Here, we report a metal–organic framework (MOF)/polypyrrole (PPy) hybrid, in which conductive PPy nanotubes that are running through each MOF particle have the potential to increase the overall bulk electrical conductivity, thus promoting such a system as a good CDI electrode material. Consequently, the MOF/PPy hybrid shows a high desalination capacity of 11.34 mg g−1, which is amongst those of state-of-the-art CDI electrodes. Moreover, the MOF/PPy hybrid also shows a superior desalination performance for brackish water and good cycling stability, far exceeding typical carbon-based benchmarks. This is the first example of CDI electrodes derived from direct MOF-based materials, highlighting the potential of these hybrid systems as promising materials beyond traditional carbon electrodes.

In this paper, we propose an architecture model called Design Rule Space (DRSpace). We model the architecture of a software system as multiple overlapping DRSpaces, reflecting the fact that any complex software system must contain multiple aspects, features, patterns, etc. We show that this model provides new ways to analyze software quality. In particular, we introduce an Architecture Root detection algorithm that captures DRSpaces containing large numbers of a project's bug-prone files, which are called Architecture Roots (ArchRoots). After investigating ArchRoots calculated from 15 open source projects, the following observations become clear: from 35 to 91 percent of a project's most bug-prone files can be captured by just 5 ArchRoots, meaning that bug-prone files are likely to be architecturally connected. Furthermore, these ArchRoots tend to live in the system for significant periods of time, serving as the major source of bug-proneness and high maintainability costs. Moreover, each ArchRoot reveals multiple architectural flaws that propagate bugs among files and this will incur high maintenance costs over time. The implication of our study is that the quality, in terms of bug-proneness, of a large, complex software project cannot be fundamentally improved without first fixing its architectural flaws.

Topical administration of anticancer drugs provides a potential chemotherapeutic modality with high patient compliance for cutaneous melanoma. However, the drug delivery efficiency is highly limited by physiological barriers from the skin to the tumor, which cannot acquire desired therapeutic efficacy. Herein, we propose a paintable oligopeptide hydrogel containing paclitaxel (PTX)-encapsulated cell-penetrating-peptide (CPP)-modified transfersomes (PTX-CTs) to enhance transdermal PTX delivery for topical melanoma treatment. After being plastered on the skin above the melanoma tumor, the PTX-CTs-embedded hydrogel (PTX-CTs/Gel) as a patch provided prolonged retention capacity of the PTX-CTs on the skin. The PTX-CTs with superior deformability could efficiently squeeze through the channels in the stratum coreum, and the surfactant components improved the fluidity of the lipid molecules in the stratum corneum to further enhance the skin permeation. Moreover, the CPP modification rendered the PTX-CT-enhanced penetration in the skin and tumor stroma as well as efficient transportation in the tumor cells. The PTX-CTs were shown to effectively slow the tumor growth in combination with the systemic chemotherapy using Taxol, the commercial PTX formulation on the xenograft B10F16 melanoma mouse model.

Hypochlorite (OCl–), an essential part of reactive oxygen species (ROS), plays a crucial role in cellular redox balance. OCl–has been shown to be implicated in many physiological and pathological processes, including liver injury and cancer. Exploitation of fluorescent probes for the OCl–helps to reveal its function in the genesis and progression of the aforementioned diseases. Here we propose an easy-to-fabricate coumarin-based fluorescent probe incorporated with an aryl dihydrazide linker for highly specific detection and biological imaging of OCl–in living cells and tissues. The p-nitrophenyl-modified dihydrazide-linked coumarin derivative (Cou-dhz-Ph-NO2) was screened from a series of candidate molecules and served as a “turn-on” probe with a low background fluorescence interference due to the nitro-group-based quenching on the coumarin fluorescence. The Cou-dhz-Ph-NO2probe showed high selectivity and fast response with excellent linear relationship for detection of OCl–. A specific OCl–-responsive mechanism that the dihydrazide linker could be oxidatively cleaved by OCl–was deduced. The exogenous OCl–and endogenous OCl–were successfully visualized using the Cou-dhz-Ph-NO2probe in living cells, such as MDA-MB-231 cells, RAW 264.7 cells and neutrophils, and the pathologic tissues, including the tumor tissue and the acutely injured liver tissue. This study paves the way for utilizing the aryl dihydrazide linker as OCl–-responsive module, which can aid the evolution of increasingly specific probes for detection of OCl–and diagnosis of OCl–-coupled diseases.

In this paper, the small signal stability issue of a dual-active-bridge (DAB) converter enabled dc microgrid is addressed. The derived impedance characteristic of the source DAB converter reveal that the stability of this dc grid is decided by the low-frequency terminal behaviors of integrated units, which is different from that of dc microgrids powered by other types of source converters. At this low-frequency range, the tightly regulated load converter exhibits constant power load behavior even with a low control bandwidth, which degrades system stability by exacerbating interactions among power converters. Moreover, the deployed power management strategy requires operating mode transitions of energy storage units to achieve intelligent power flow, which further complicates system impedance characteristics. To analyze and solve these issues, the systematic impedance models of this dc grid under different operation modes are derived and analyzed. Reduced-order low-frequency models are simplified from the systematic impedance model to unravel the resonance mechanism. In addition, an impedance shaping technique is proposed to eliminate the resonant path in the reduced-order low-frequency models, therefore the dc grid stability has been improved. Finally, a hardware-in-the-loop application with OPAL-RT real-time simulators is used to validate proposed methods.

Cell-mediated drug-delivery systems have received considerable attention for their enhanced therapeutic specificity and efficacy in cancer treatment. Neutrophils (NEs), the most abundant type of immune cells, are known to penetrate inflamed brain tumours. Here we show that NEs carrying liposomes that contain paclitaxel (PTX) can penetrate the brain and suppress the recurrence of glioma in mice whose tumour has been resected surgically. Inflammatory factors released after tumour resection guide the movement of the NEs into the inflamed brain. The highly concentrated inflammatory signals in the brain trigger the release of liposomal PTX from the NEs, which allows delivery of PTX into the remaining invading tumour cells. We show that this NE-mediated delivery of drugs efficiently slows the recurrent growth of tumours, with significantly improved survival rates, but does not completely inhibit the regrowth of tumours.

This paper proposes an isolated modular multilevel dc/dc converter (iM2DC)-based hybrid energy storage system (ESS) for shipboard MVDC grid application. The cell capacitors of the iM2DC are applied to implement the dc active power filter capability, which improves the MVDC bus power quality without auxiliary devices or sacrificing the battery lifetime. In addition, the proposed ESS achieves superior fault response with fault current limiting function, which benefits the fault localization and fast recovery. The operation principle of the proposed system is introduced first and the converter equivalent averaged model is derived. Then the multifunctional control method is presented, including the virtual-impedance-based ripple distribution strategy. Both offline simulation and controller hardware-in-the-loop test results are provided to validate the control strategy as well as the ESS performance.

Combination cancer therapy possesses considerable appeal due to its many merits such as enhancing efficacy by synergistic effects and overcoming drug resistance as compared to monotherapy. Nanomedicine-mediated co-delivery of multiple anticancer agents is more effective than conventional cocktail-based physical mixture of free drugs. A strategy is required to differentiate their unique targets for maximizing the synergistic effects based on individual sites of action of different drugs. This review summarizes the recent progresses in nanomedicine-based combination cancer therapies using site-specific co-delivery strategies, which have been classified by different target sites at the anatomical scales such as tissue, cellular and subcellular levels. In particular, the design of materials and formulations functionalized with tumor-associated signal-responsive elements has been highlighted. The potential and perspective of future developments have also been discussed.

The serious electron leakage and poor transport of hole injection layers in deep‐ultraviolet (DUV) light‐emitting diodes (LEDs) lead to an imbalance between the hole and electron currents, which reduces the device's performance. Herein, a new DUV LED structure is designed. The aluminum composition of the p‐type electron‐blocking layer (p‐EBL) gradually decreases from 0.95 to 0.75 along the growth direction, replacing the traditional bulk p‐EBL. When the injection current is 100 mA, the optical power of this structure is about 32% higher than that of the traditional structure. In addition, when the p‐EBL adopts the opposite gradient (the Al composition gradually increases from 0.75 to 0.95), the device performance suddenly drops dramatically. The related devices are simulated by Silvaco TCAD software. The results show that the performance outputs of the two opposite aluminum gradient growth modes are completely opposite. The proposed p‐EBL with a gradual step‐down Al composition along the growth direction helps to improve the efficiency of hole injection into multiple quantum wells (MQWs) and reduce the level of electron leakage. This work provides an effective solution for increasing the light output power of high‐performance DUV LEDs. Herein, the Al composition of the p‐type electron‐blocking layer (p‐EBL) of DUV LED gradually decreases from 0.95 to 0.75 along the growth direction. When the injection current is 100 mA, the optical power of this structure is about 32% higher than that of the traditional structure. When the p‐EBL adopts the opposite gradient, the device performance suddenly drops dramatically.

The insulin-like androgenic gland-specific peptide is a known primary regulator of sexual differentiation in crustaceans. However, the knowledge of the crucial elements involved in the insulin-like signaling cascade remains fragmented. Here, we characterized a novel insulin-like receptor gene in the white shrimp Penaeus vannameiand named as Pv-IR. The deduced amino acid sequence of Pv-IR contained conserved domains of IRs, including two ligand-binding domains, a furin-like domain, three fibronectin-3 domains, and an intracellular tyrosine kinase domain in order. Multiple sequence alignment of the first ligand-binding domain and the tyrosine kinase domain in Pv-IR revealed a high degree of similarity in all representative IRs. The phylogenetic analysis presented that Pv-IR was clustered into a separate branch with IRs from decapods. The tissue distribution analysis showed that Pv-IR was predominantly expressed in the sperm duct and terminal ampullae of the male reproductive system in P. vannamei. Meanwhile, Pv-IR knockdown was carried out in postlarvae. Although the sex reversal phenotype was not observed, the effects of Pv-IR silencing on the expressions of related-genes were analyzed by the comparative transcriptomic sequencing. Significantly, two down-regulated transcripts (clottable protein and insulin-like peptide) and two up-regulated transcripts (flotillin and thyroid stimulating hormone receptor) were focused as gonad-related differentially expressed unigenes in Pv-IR knockdown. The data provided a more theoretical basis for elucidating the mechanism of sexual differentiation in crustaceans.

A multistimuli responsive drug delivery system (DDS) based on sulfhydryl and amino-cofunctionalized mesoporous silica nanoparticles (SH/NH2-MSNs) has been developed, in which the multifunctional hyaluronic acid (HA) derivatives were grafted onto the SH/NH2-MSNs by disulfide bonds for targeting delivery, controlling drug release and reversing multidrug resistance (MDR). The doxorubicin (Dox) loaded multifunctional HA derivatives modified mesoporous silica nanoparticles (Dox/HHS-MSNs) were enzyme and redox sensitive, which could respond to the intracellular stimuli of hyaluronidase (HAase) and glutathione (GSH) successively and prevent drug leakage before reaching the tumor tissues. The cellular uptake experiments showed that Dox/HHS-MSNs were vulnerable to be endocytosed into the Dox-resistant human breast adenocarcinoma (MCF-7/ADR) cells, efficiently realized the endolysosomal escape and remained in the cytoplasm. Because of orchestrating multiple actions above including active targeting, endolysosomal escape and efficient multilevel drug release, Dox/HHS-MSNs could induce the strongest apoptosis and cytotoxicity of MCF-7/ADR cells. Furthermore, a series of in vivo studies on MCF-7/ADR tumor-bearing xenograft mouse models demonstrated that Dox/HHS-MSNs possessed the enhanced tumor-targeting capacity and the best therapeutic efficacy to reverse cancer MDR.

To summarize the use rate, safety, efficacy of antithrombotics in stroke/transient ischemic attack (TIA) prevention, and reasons for not using dabigatran etexilate (DE) in Shanghai, China.

Mycobacterium tuberculosis(Mtb), the causative agent of human tuberculosis, remains one of the most prevalent human pathogens and a major cause of mortality worldwide. Metabolic network is a central mediator and defining feature of the pathogenicity of Mtb. Increasing evidence suggests that lysine succinylation dynamically regulates enzymes in carbon metabolism in both bacteria and human cells; however, its extent and function in Mtbremain unexplored. Here, we performed a global succinylome analysis of the virulent Mtbstrain H37Rv by using high accuracy nano-LC-MS/MS in combination with the enrichment of succinylated peptides from digested cell lysates and subsequent peptide identification. In total, 1545 lysine succinylation sites on 626 proteins were identified in this pathogen. The identified succinylated proteins are involved in various biological processes and a large proportion of the succinylation sites are present on proteins in the central metabolism pathway. Site-specific mutations showed that succinylation is a negative regulatory modification on the enzymatic activity of acetyl-CoA synthetase. Molecular dynamics simulations demonstrated that succinylation affects the conformational stability of acetyl-CoA synthetase, which is critical for its enzymatic activity. Further functional studies showed that CobB, a sirtuin-like deacetylase in Mtb, functions as a desuccinylase of acetyl-CoA synthetase in in vitroassays. Together, our findings reveal widespread roles for lysine succinylation in regulating metabolism and diverse processes in Mtb. Our data provide a rich resource for functional analyses of lysine succinylation and facilitate the dissection of metabolic networks in this life-threatening pathogen.

Cyanobacteria are the oldest known life form inhabiting Earth and the only prokaryotes capable of performing oxygenic photosynthesis. Synechocystissp. PCC 6803 (Synechocystis) is a model cyanobacterium used extensively in research on photosynthesis and environmental adaptation. Posttranslational protein modification by lysine acetylation plays a critical regulatory role in both eukaryotes and prokaryotes; however, its extent and function in cyanobacteria remain unexplored. Herein, we performed a global acetylome analysis on Synechocystisthrough peptide prefractionation, antibody enrichment, and high accuracy LC–MS/MS analysis; identified 776 acetylation sites on 513 acetylated proteins; and functionally categorized them into an interaction map showing their involvement in various biological processes. Consistent with previous reports, a large fraction of the acetylation sites are present on proteins involved in cellular metabolism. Interestingly, for the first time, many proteins involved in photosynthesis, including the subunits of phycocyanin (CpcA, CpcB, CpcC, and CpcG) and allophycocyanin (ApcA, ApcB, ApcD, ApcE, and ApcF), were found to be lysine acetylated, suggesting that lysine acetylation may play regulatory roles in the photosynthesis process. Six identified acetylated proteins associated with photosynthesis and carbon metabolism were further validated by immunoprecipitation and Western blotting. Our data provide the first global survey of lysine acetylation in cyanobacteria and reveal previously unappreciated roles of lysine acetylation in the regulation of photosynthesis. The provided data set may serve as an important resource for the functional analysis of lysine acetylation in cyanobacteria and facilitate the elucidation of the entire metabolic networks and photosynthesis process in this model cyanobacterium.

The nanoparticle-based drug delivery system holds great attraction to overcome or circumvent multidrug resistance (MDR) in cancer to date. In this work, a synthesized amphiphilic graft copolymer, N-octyl-O-sulfate chitosan (NOSC), and its paclitaxel (PTX)-encapsulated micelles (PTX-M) have been systematically investigated on the MDR reversal effect in vitroand in vivoas well as the mechanism of P-glycoprotein (P-gp) inhibition. NOSC in a wide concentration range even above the critical micelle concentration showed an effective effect on inhibiting P-gp-mediated PTX efflux, which was remarkably different from the surfactants and the Pluronic copolymers. Multiple mechanisms were involved in this effect of NOSC, such as stimulating P-gp ATPase, competitively impeding the binding of PTX with P-gp and reducing the fluidity of the cell membrane. PTX-M presented the highest cellular uptake and the lowest efflux rate of PTX, thereby yielding the optimal cytotoxicity on both the human hepatocellular liver carcinoma (HepG2) cells and the multidrug resistance HepG2 (HepG2-P) cells, which resulted from a combination of the inhibiting P-gp effect of NOSC and the bypassing P-gp action of the intact PTX-M. Additionally, PTX-M had superior blood persistence, tumor accumulation, and therapeutic efficacy after intravenous injection into the tumor-bearing mice. Furthermore, it was demonstrated that most of PTX-M as an intact form was delivered at the tumor site, which ensures the synergetic effect of NOSC micelles on drug delivery and P-gp inhibition. The aforementioned results suggested that NOSC micelles presented promising potential as an anticancer drug carrier for enhanced MDR cancer therapy.

Bcl2-associated athanogene 3 (BAG3), a member of the BAG family of co-chaperones, plays a critical role in regulating apoptosis, development, cell motility, autophagy, and tumor metastasis and in mediating cell adaptive responses to stressful stimuli. BAG3 carries a BAG domain, a WW domain, and a proline-rich repeat (PXXP), all of which mediate binding to different partners. To elucidate BAG3's interaction network at the molecular level, we employed quantitative immunoprecipitation combined with knockdown and human proteome microarrays to comprehensively profile the BAG3 interactome in humans. We identified a total of 382 BAG3-interacting proteins with diverse functions, including transferase activity, nucleic acid binding, transcription factors, proteases, and chaperones, suggesting that BAG3 is a critical regulator of diverse cellular functions. In addition, we characterized interactions between BAG3 and some of its newly identified partners in greater detail. In particular, bioinformatic analysis revealed that the BAG3 interactome is strongly enriched in proteins functioning within the proteasome-ubiquitination process and that compose the proteasome complex itself, suggesting that a critical biological function of BAG3 is associated with the proteasome. Functional studies demonstrated that BAG3 indeed interacts with the proteasome and modulates its activity, sustaining cell survival and underlying resistance to therapy through the down-modulation of apoptosis. Taken as a whole, this study expands our knowledge of the BAG3 interactome, provides a valuable resource for understanding how BAG3 affects different cellular functions, and demonstrates that biologically relevant data can be harvested using this kind of integrated approach.

Li1-xLaxV3O8 cathode materials has been synthesized by pechini sol-gel method. The electrochemical performances of Li1-xLaxV3O8(x=0-0.05) have been studied by X-ray diffraction (XRD), galvanostatic charge-discharge, and cyclic voltammetric (CV). The results showed that the optimal content of the La3+ doping in LiV3O8 was x=0.01, and the first discharge capacity of Li0.99La0.01V3O8 sample in the voltage range of 2.0-4.0V was 230mAhg-1, which was much higher than that of LiV3O8 (200mAhg-1). The Li0.99La0.01V3O8 cathode also showed higher discharge voltage plateau than LiV3O8 cathode from the CV curves.

The thermal aging experiments on nitrile rubber (NBR) and modified NBR were carried out in 25# transformer oil. Both of the content of CH4, microstructure, morphology and mechanics characterization was analyzed by Gas Chromatography (GC), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS) and Servo Control material testing machine, respectively. The results shows that the amount of CH4 released from the modified NBR is less than original NBR, and the mechanics characterization of the modified NBR is also satisfied with the application requirements.

The enamel powder was preseted on the Ti alloy by electrophoresis, and the enamel coatings were obtained through sintering. Friction and abrasion performance of the enamel coatings and RE enamel coatings were compared. The results show that the RE element improved the inner organizational structure of the enamel coating, decreased the friction coefficient of the coating and consequently improved the friction-resistant character of the enamel coatings. By adding RE, the viscidity, suspension and fluidity of the enamel coatings are improved, and that the microstructure of the enamel coating are more dense and the horniness grain phase was more small in uniform during sintering.

Abstract. The thermal aging experiments on nitrile rubber and rubber additives were carried out for different time in 25# transformer oil at 70℃. The amount of CH4 released from non-rubber group, nitrile rubber group and rubber additives group were measured by Gas Chromatography (GC). The molecular structure of NBR matrix and liquid extracted from NBR were analyzed with fourier transform infrared analysis (FTIR), respectively. At last, the formation mechanism of CH4 in nitrile rubber were investigated. The results illustrated that the rubber additive RD released methyl radicals and hydrogen radicals, and generated CH4 by reacted with each other.

Protein drugs have attracted more attentions due to their high specificity and efficacy. However, the poor stability, plasma degradation, inferior cell membrane permeability, and immunogenicity severely limit the in vivo application of protein drugs. Nanogels are the nanosized crosslinked gels with high water‐loading capacities and large cavities for protein loading, which are able to increase the stability and decrease the immunogenicity for protein delivery. The bioresponsive nanogels possess the capability of programmatically releasing the protein drugs in an on‐demand manner at the target sites with distinct biosignals, which show considerable potential to increase the therapeutic efficacies and decrease the adverse effects of the protein drugs. In this review, we outline the recent advance in the bioresponsive nanogels for delivery of protein drugs, and survey the design of new materials and formulations that can respond typical biosignals, such as temperature, pH, reductive potential, and enzyme expression. The prospects and challenges are also discussed. The bioresponsive nanogels show considerable potential to enhance the therapeutic efficacies and reduce the adverse effects of the protein drugs. This mini‐review summarizes recent advance in the applications of the bioresponsive nanogels for protein delivery and disease treatment.

Antibody-based therapeutics, which induce apoptosis of malignant cells by selectively binding to their receptors, hold tremendous promise for clinical cancer therapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received considerable interest due to its favorable capability of activating apoptosis in cancer cells by interacting with death receptors (DRs). However, cancer stem-like cells (CSCs) show deficient or lower DR and are highly resistant to TRAIL-mediated apoptosis limiting the therapeutic efficacy. Here, we report a liposome-mediated acclimatization strategy to overcome the CSC-emanated TRAIL resistance. The liposomal assemblies coencapsulating plasmid DNA encoding TRAIL and salinomycin enable cancer cells as protein generators to express TRAIL, and more importantly, can acclimatize resistant CSCs to be sensitized to the TRAIL-triggered apoptosis by salinomycin-induced upregulation of DR expression on CSCs. This programmable liposome-based drug codelivery system shows the potential to efficiently eliminate CSCs and inhibit CSC-enriched tumor growth in the orthotopic colon tumor mouse model.

A novel and facile method for the synthesis of 4H-cyclopenta[c]pyrrolo[1,2-b] isoquinolin-2(3H)-one has been developed by employing the [2, 3] Stevens rearrangement of methyl N-allyl-N-benzylpyrrolidine 2-carboxylate to methyl 2-allyl-l-benzyl-pyrrolidine 2-carboxylate and acid-lactonisation as key transformations. The synthetic strategy from readily available materials provided a model skeletal analogue of cephalotaxine and should have general applicability in the synthesis of Cephalotaxusalkaloids.

The Women's Empowerment in Agriculture Index (WEAI) has been in use since 2012 and is widely recognized as one of the most rigorous tools to measure women's empowerment as a direct or indirect result of interventions from development projects. Changes to the WEAI have been ongoing and recent adaptations include measuring effects of interventions to improve livestock value chains on women's empowerment, as well as livestock related research. A multidisciplinary team of researchers at ILRI and Emory University developed the Women's Empowerment in Livestock Index (WELI), a new index to assess the empowerment of women in the livestock sector. While the WELI has been piloted in both Honduras and Tanzania, this article provides details on the latter case only. Currently, the Feed the Future Innovation Lab for Livestock Systems has employed the Abbreviated-Women's Empowerment in Agriculture Index (A-WEAI) to examine female decision-making in various projects from animal care knowledge and practices to feeding practices for children. Additionally, the development of the Project-Women Empowerment in Agriculture Index, currently in pilot testing, may allow for more insight into scaling existing projects. This article will discuss the adaptation and use of the WEAI for livestock research in Tanzania and Uganda, as well as future uses for contextually measuring women livestock producers' empowerment.

Reports on the decision of the Bank of China and the China Construction Bank to transfer non-performing loans to the Cinda Asset Management Co. in a deal in China. Amount of bailout received by the banks from the government; Aim of improving corporate governance; Effort of both banks to complete their share holding restructuring. INSET: Subordinated Debt..

Reports on the increase in agricultural production in China. Profit generated by the grain business; Benefits of using modern techniques in farming; Government initiative to stabilize grain prices and protect farmers' interests. INSET: World Gain Reserves..

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