Microenvironment Responsive Hydrogel Exerting Inhibition of Cascade Immune Activation and Elimination of Synovial Fibroblasts for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a progressive autoimmune disease and drug therapy has been restricted due to poor therapeutic efficacy and adverse effects. In RA synovium, dendritic cells present self-antigens to activate cascade immune pathway. Furthermore, downstream macrophages secrete high levels of pro-inflammatory cytokines; Hyperplasia of activated synovial fibroblasts (FLS) is responsible for hypoxic synovium microenvironment, secretion of cytokines/chemokines and erosion of bone/cartilage tissues. Positive feedback loop of inflammation between macrophages and FLS independent of antigen-presentation is constructed. Herein, an injectable pH-sensitive peptide hydrogel encapsulating siRNA/Methotrexate-polyethyleneimine (siMP, including sip65MP, sip38MP, siCD86MP) and Bismuthene nanosheet/Methotrexate-polyethyleneimine (BiMP) is successfully developed. Among them, siCD86MP reduces protein level of co-stimulatory molecule CD86 while sip65MP and sip38MP separately inhibit NF-κB and MAPK-p38 pathways of macrophages and FLS to suppress secretion of cytokines and MMPs. Meanwhile, reduction in anti-apoptotic property of FLS induced by inhibition of NF-κB pathway has a synergistic effect with photodynamic therapy (PDT) and photothermal therapy (PTT) mediated by BiMP for FLS elimination, effectively ameliorating hypoxic synovium microenvironment. After being injected into synovium, hydrogel responds to acidic microenvironment and serves as a reservoir for sustained drug release and inherent retention capacity of which enables cationic nanoparticles to bypass tissue barrier for precise synovium targeting. This brand-new drug delivery system combines modulating cascade immune pathway from beginning to end by RNAi and eliminating FLS for improving synovium microenvironment by phototherapy together, providing a robust strategy for clinical RA treatment.

Electrophysiological techniques in marine microalgae study: A new perspective for harmful algal bloom (HAB) research.

Electrophysiological techniques, by measuring bioelectrical signals and ion channel activities in tissues and cells, are now widely utilized to study ion channel-related physiological functions and their underlying mechanisms. Electrophysiological techniques have been extensively employed in the investigation of animals, plants, and microorganisms; however, their application in marine algae lags behind that in other organisms. In this paper, we present an overview of current electrophysiological techniques applicable to algae while reviewing the historical usage of such techniques in this field. Furthermore, we explore the potential specific applications of electrophysiological technology in harmful algal bloom (HAB) research. The application prospects in the studies of stress tolerance, competitive advantage, nutrient absorption, toxin synthesis and secretion by HAB microalgae are discussed and anticipated herein with the aim of providing novel perspectives on HAB investigations.

Synovium microenvironment-responsive injectable hydrogel inducing modulation of macrophages and elimination of synovial fibroblasts for enhanced treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a progressive autoimmune disease accompanied by joint swelling, cartilage erosion and bone damage. Drug therapy for RA has been restricted due to poor therapeutic effect, recurrence and adverse effects. Macrophages and synovial fibroblasts both play important roles in the pathology of RA. Macrophages secrete large amount of pro-inflammatory cytokines, while synovial fibroblasts are tightly correlated with hypoxia synovium microenvironment, cytokine release, recruitment of pro-inflammatory cells, bone and cartilage erosion. Therefore, in this timely research, an injectable and pH-sensitive peptide hydrogel loading methotrexate (MTX) and bismuthene nanosheet/polyethyleneimine (BiNS/PEI) has been developed to reduce the activity of macrophages and eliminate over-proliferated synovial fibroblasts simultaneously. MTX can reduce the cytokine secretion of macrophages/anti-apoptosis property of synovial fibroblasts and BiNS/PEI can eliminate synovial fibroblasts via photodynamic therapy (PDT) and photothermal therapy (PTT) routes. The hydrogel was injected into the acidic inflammatory synovium for precise targeting and served as a drug reservoir for pH responsive and sustained drug release, while improving the bioavailability and reducing the toxicity of MTX. Excellent therapeutic efficacy has been achieved in both in vivo and in vitro studies, and this unique drug delivery system provides a new and robust strategy to eliminate synovial fibroblasts and modulate immune system for RA treatment in clinical.

Characterization of histone acetyltransferases and deacetylases and their roles in response to dehydration stress in Pyropia yezoensis (Rhodophyta).

Histone acetylation is one of the most pivotal epigenetic mechanisms in eukaryotes and has been tightly linked to the regulation of various genes controlling growth, development and response to environmental stresses in both animals and plants. Till date, the association of histone acetylation to dehydration stress in red algae and genes encoding the enzymes responsible for histone acetylation: histone acetyltransferases (HATs) or histone deacetylases (HDACs), remains largely unknown. In this study, in silico analysis of the red seaweed Pyropia yezoensis identified 6 HAT genes and 10 HDAC genes. These genes displayed good synteny in genome loci with their Pyropia haitanensis orthologs except for a putative gene duplication event in HDAC and a loss of one HAT gene in P. yezoensis. According to the conserved domains and phylogenetic analysis, they encoded three GCNA5-, one TAFII250- and one MYST-HAT, as well as five HDA1-and five SIRT-HDACs. The sirtuin-domain of Py06502 harbored a ~100 aa insert and interestingly, this insertion was specifically observed in Bangiales species. Two nuclear-localized HATs were transcriptionally up-regulated at the early stage of dehydration and so were two nuclear HDA1s when moderate dehydration started, suggesting their potential roles in modulating downstream gene expression to facilitate dehydration adaptation by changing histone acetylation patterns on relevant regulatory elements. This was experimentally confirmed by the increased decline in photosynthesis efficiency during dehydration when HAT and HDAC activities were inhibited by SAHA and MB-3, respectively. Transcriptional patterns of multiple dehydration-responsive genes after water loss were strongly affected by MB-3 or SAHA treatment. This study provides the first insight into the regulation and function of HAT/HDAC during stress adaptation in red algae.

Sustained and Targeted Delivery of Self-Assembled Doxorubicin Nonapeptides Using pH-Responsive Hydrogels for Osteosarcoma Chemotherapy.

While chemotherapeutic agents have particularly potent effects in many types of cancer, their clinical applications are still far from satisfactory due to off-target drug exposure, chemotherapy resistance, and adverse effects, especially in osteosarcoma. Therefore, it is clinically promising to construct a novel tumor-targeted drug delivery system to control drug release and alleviate side effects. In this study, a pH-responsive nonapeptide hydrogel was designed and fabricated for the tumor-targeted drug delivery of doxorubicin (DOX). Using a solid-phase synthesis method, a nonapeptide named P1 peptide that is structurally akin to surfactant-like peptides (SLPs) due to its hydrophobic tail and hydrophilic head was synthesized. The physicochemical properties of the P1 hydrogel were characterized via encapsulation capacity, transmission electron microscopy (TEM), circular dichroism (CD), zeta potential, rheological analysis, and drug release studies. We also used in vitro and in vivo experiments to investigate the cytocompatibility and tumor inhibitory efficacy of the drug-loaded peptide hydrogel. The P1 peptide could self-assemble into biodegradable hydrogels under neutral conditions, and the prepared drug-loaded hydrogels exhibited good injectability and biocompatibility. The in vitro drug release studies showed that DOX-P1 hydrogels had high sensitivity to acidic conditions (pH 5.8 versus 7.4, up to 3.6-fold). Furthermore, the in vivo experiments demonstrated that the DOX-P1 hydrogel could not only amplify the therapeutic effect but also increase DOX accumulation at the tumor site. Our study proposes a promising approach to designing a pH-responsive hydrogel with controlled doxorubicin-release action based on self-assembled nonapeptides for targeted chemotherapy.

Robust finite-time adaptive control for high performance voice coil motor-actuated fast steering mirror.

Fast steering mirror (FSM) is an efficient and reliable mechanical device in aerial optical image systems for controlling the beam direction with high precision. With the advantages of compact size, high speed, simple structure, and long linear stroke, voice coil motors are ideal actuators for FSM systems. However, model uncertainty can lead to poor performance or even system divergence, especially in environments with temperature variations, electromagnetic environment changes, etc. This paper proposes a novel finite-time adaptive control (FAC) algorithm for an FSM system to obtain high performance, i.e., positioning accuracy, dynamic performance, and robustness. In addition, the finite-time convergence of the controller is analyzed. In the experiments, the controller is implemented in a DSP-based microprocessor. The step response results show that the proposed algorithm has a shorter setting time, smaller overshoot, and smaller steady-state error compared to classical sliding mode control (SMC). The sinusoidal signal tracking accuracy of FAC + SMC has been improved by 19.8%. In addition, as the model uncertainty increases 10%, the root mean square errors (RMSEs) are 1.73″ and 1.18″ for SMC and FAC + SMC, respectively. With 20% model uncertainty, the RMSEs increase to 2.56″ and 1.85″, respectively. Extensive experiments demonstrate the general effectiveness of the proposed algorithm.

Establishment and preliminary study of electrophysiological techniques in a typical red tide species.

Electrophysiology studies the electrical properties of cells and tissues including bioelectrical signals and membrane ion channel activities. As an important means to reveal ion channel related physiological functions and the underlying mechanisms, electrophysiological techniques have been widely used in studies of animals, higher plants and algae that are closely related to higher plants. However, few electrophysiological studies have been carried out in red tide organisms, especially in dinoflagellates, which is mainly due to the complex surface structure of dinoflagellate amphiesma. In this study, the surface amphiesma of Alexandrium pacificum, a typical red tide species, was removed by centrifugation, low-temperature treatment and enzymatic treatment. In all three treatments, low-temperature treatment with 4 °C for 2 h had high ecdysis rate and high fixation rate, and the treated cells were easy to puncture, so low-temperature treatment was used as a preprocessing treatment for subsequent current recording. Acquired protoplasts of A. pacificum were identified by calcofluor fluorescence and immobilized by poly-lysine. A modified "puncture" single-electrode voltage-clamp recording was first applied to dinoflagellates, and voltage-gated currents, which had the characteristics of outward K+ current and inward Cl- current, were recorded and confirmed by ion replacement, indicating the voltage-gated currents were mixed. This method can be used as a technical basis for the electrophysiological study of dinoflagellates and provides a new perspective for the study of stress tolerance, red tide succession, and the regulation of physiological function of dinoflagellates.

Titanium nanosheet as robust and biosafe drug carrier for combined photochemo cancer therapy.

Two-dimensional (2D) Titanium nanosheets (Ti NSs) have shown many excellent properties, such as nontoxicity, satisfactory photothermal conversion efficacy, etc. However, the biomedical applications of Ti NSs have not been intensively investigated. Herein, we synthesized a multifunctional Ti NS drug delivery system modified with polydopamine/polyethylene glycol (Ti@PDA-PEG) and applied simultaneously for photothermal therapy and chemotherapy. Doxorubicin (DOX) was utilized as a model drug. Ti@PDA-PEG NS shows an ultrahigh antitumor drug DOX loading (Ti@PDA-PEG-DOX). The prepared Ti@PDA-PEG-DOX NS as robust drug delivery system demonstrates great stability and excellent multi-response drug-release capabilities, including pH-responsive and near-infrared -responsive behavior and obviously high photothermal efficiency. Both in vitro and in vivo experimental results have shown high biosafety and outstanding antitumor effects. Therefore, this work exhibits the enormous potential of a multifunctional platform in the treatment of tumors and may stimulate interest in the exploration of other new 2D nanomaterials for biomedical applications.

Finite-time adaptive sliding mode control for high-precision tracking of piezo-actuated stages.

Piezo-actuated stages are widely used in nanopositioning applications. However, they not only have inherent static hysteresis characteristics but also have dynamic rate-dependent hysteresis nonlinearity. Therefore, to address dynamic hysteresis nonlinearity and uncertainty in the model parameters, an adaptive switching-gain sliding mode controller with a proportional-integral-derivative surface is designed. In particular, the combination of Bouc-Wen model and second-order linear system is used to describe the dynamic hysteresis process. To improve the robustness and reduce chattering in the sliding mode control method, an adaptive switching-gain is added to the controller without knowing in advance the upper bound of uncertainties. Finite-time convergence conditions of the closed-loop system are also analyzed. Finally, the proposed control method is implemented in real time on an ARM experimental platform. Comparative experimental results demonstrate excellent tracking performance and robustness. The dynamic hysteresis characteristics are suppressed effectively, and this result provides a powerful reference for engineering applications.

Adaptive Tracking Control for the Piezoelectric Actuated Stage Using the Krasnosel'skii-Pokrovskii Operator.

In this paper, a discrete second order linear equation with the Krasnosel'skii-Pokrovskii (KP) operator is used to describe the piezoelectric actuated stage. The weights of the KP operators are identified by the gradient descent algorithm. To suppress the hysteresis nonlinearity of the piezoelectric actuated stage, this paper proposes an adaptive tracking control with the hysteresis decomposition on the designed error surface. The proposed adaptive tracking controller dispenses with any form of the feed-forward hysteresis compensation and the unknown parameters of the discrete second order linear equation are adaptively adjusted. Some simulations are implemented to verify the effectiveness of the KP operators, then a series of modeling and control experiments are carried out on the piezoelectric actuated stages experimental systems. The comparative experimental results verify the feasibility of the KP operators modeling method and the adaptive tracking control method.

The Histone Chaperone FACT Contributes to DNA Replication-Coupled Nucleosome Assembly.

DNA replication-coupled (RC) nucleosome assembly is mediated by histone chaperones and is fundamental for epigenetic inheritance and maintenance of genomic integrity. The mechanisms that promote this process are only partially understood. Here, we show that the histone chaperone FACT (facilitates chromatin transactions), consisting of Spt16 and Pob3, promotes newly synthesized histone H3-H4 deposition. We describe an allele of Spt16 (spt16-m) that has a defect in binding to H3-H4 and impairs their deposition onto DNA. Consistent with a direct role for FACT in RC nucleosome assembly, spt16-m displays synthetic defects with other histone chaperones associated with this process, CAF-1 and Rtt106. Importantly, we show that FACT physically associates with Rtt106 and that the acetylation of H3K56, a mark on newly synthesized H3, modulates this interaction. Therefore, FACT collaborates with CAF-1 and Rtt106 in RC nucleosome assembly.