The exonuclease activity of Apurinic/apyrimidinic endonuclease 1 (APE1) is responsible for processing matched/mismatched terminus in various DNA repair pathways and for removing nucleoside analogs ...associated with drug resistance. To fill in the gap of structural basis for exonucleolytic cleavage, we determine the APE1-dsDNA complex structures displaying end-binding. As an exonuclease, APE1 does not show base preference but can distinguish dsDNAs with different structural features. Integration with assaying enzyme activity and binding affinity for a variety of substrates reveals for the first time that both endonucleolytic and exonucleolytic cleavage can be understood by an induced space-filling model. Binding dsDNA induces RM (Arg176 and Met269) bridge that defines a long and narrow product pocket for exquisite machinery of substrate selection. Our study paves the way to comprehend end-processing of dsDNA in the cell and the drug resistance relating to APE1.
This article reports our study on a reduced adaptive fuzzy decoupling control for our lower limb exoskeleton system which typically is a multi-input-multi-output (MIMO) uncertain nonlinear system. To ...show the applicability and generality of the proposed control methods, a more general MIMO uncertain nonlinear system model is considered. By decoupling control, the entire MIMO system is separated into several MISO subsystems. In our experiments, such a system may have problems (even unstable) if a traditional fuzzy approximator is used to estimate the complicated coupling terms. In this article, to overcome this problem, a reduced adaptive fuzzy system together with a compensation term is proposed. Compared to traditional approaches, the proposed fuzzy control approach can reduce possible chattering phenomena and achieve better control performance. By employing the proposed control scheme to an actual 2-DOF lower limb exoskeleton rehabilitation robot system, it can be seen from the experimental results that, as expected, it has good performance to track the model trajectory of a human walking gait. Therefore, it can be concluded that the developed approach is effective for the control of a lower limb exoskeleton system.
Adipose-derived stem cells (ASCs) secrete several angiogenic growth factors and can be applied to treat ischemic tissue. However, transplantation of dissociated ASCs has frequently resulted in rapid ...cell death. Therefore, we aimed to develop a thermosensitive chitosan/gelatin hydrogel that is capable of ASC sustained release for therapeutic angiogenesis. By blending gelatin in the chitosan thermosensitive hydrogel, we significantly enhanced the viability of the encapsulated ASCs. During in vitro culturing, the gradual degradation of gelatin led to sustained release of ASCs from the chitosan/gelatin hydrogel. In vitro wound healing assays revealed significantly faster cell migration by co-culturing fibroblasts with ASCs encapsulated in chitosan/gelatin hydrogel compared to pure chitosan hydrogels. Additionally, significantly higher concentrations of vascular endothelial growth factor were found in the supernatant of ASC-encapsulated chitosan/gelatin hydrogels. Co-culturing SVEC4-10 endothelial cells with ASC-encapsulated chitosan/gelatin hydrogels resulted in significantly more tube-like structures, indicating the hydrogel's potential in promoting angiogenesis. Chick embryo chorioallantoic membrane assay and mice wound healing model showed significantly higher capillary density after applying ASC-encapsulated chitosan/gelatin hydrogel. Relative to ASC alone or ASC-encapsulated chitosan hydrogel, more ASCs were also found in the wound tissue on post-wounding day 5 after applying ASC-encapsulated chitosan/gelatin hydrogel. Therefore, chitosan/gelatin thermosensitive hydrogels not only maintain ASC survival, they also enable sustained release of ASCs for therapeutic angiogenesis applications, thereby exhibiting great clinical potential in treating ischemic diseases.
Adipose-derived stem cells (ASCs) exhibit great potential to treat ischemic diseases. However, poor delivery methods lead to low cellular survival or dispersal of cells from target sites. In this study, we developed a thermosensitive chitosan/gelatin hydrogel that not only enhances the viability of the encapsulated ASCs, the gradual degradation of gelatin also result in a more porous architecture, leading to sustained release of ASCs from the hydrogel. ASC-encapsulated hydrogel enhanced in vitro wound healing of fibroblasts and tube formation of endothelial cells. It also promoted in vivo angiogenesis in a chick embryo chorioallantoic membrane assay and a mice wound model. Therefore, chitosan/gelatin hydrogel represents an effective delivery system that allows for controlled release of viable ASCs for therapeutic angiogenesis.
Abstract
Interest in bringing p- and n-type monolayer semiconducting transition metal dichalcogenides (TMD) into contact to form rectifying pn diode has thrived since it is crucial to control the ...electrical properties in two-dimensional (2D) electronic and optoelectronic devices. Usually this involves vertically stacking different TMDs with pn heterojunction or, laterally manipulating carrier density by gate biasing. Here, by utilizing a locally reversed ferroelectric polarization, we laterally manipulate the carrier density and created a WSe
2
pn homojunction on the supporting ferroelectric BiFeO
3
substrate. This non-volatile WSe
2
pn homojunction is demonstrated with optical and scanning probe methods and scanning photoelectron micro-spectroscopy. A homo-interface is a direct manifestation of our WSe
2
pn diode, which can be quantitatively understood as a clear rectifying behavior. The non-volatile confinement of carriers and associated gate-free pn homojunction can be an addition to the 2D electron–photon toolbox and pave the way to develop laterally 2D electronics and photonics.
Abstract
Mesothelin (MSLN) is an attractive candidate of targeted therapy for several cancers, and hence there are increasing needs to develop MSLN-targeting strategies for cancer therapeutics. ...Antibody–drug conjugates (ADCs) targeting MSLN have been demonstrated to be a viable strategy in treating MSLN-positive cancers. However, developing antibodies as targeting modules in ADCs for toxic payload delivery to the tumor site but not to normal tissues is not a straightforward task with many potential hurdles. In this work, we established a high throughput engineering platform to develop and optimize anti-MSLN ADCs by characterizing more than 300 scFv CDR-variants and more than 50 IgG CDR-variants of a parent anti-MSLN antibody as candidates for ADCs. The results indicate that only a small portion of the complementarity determining region (CDR) residues are indispensable in the MSLN-specific targeting. Also, the enhancement of the hydrophilicity of the rest of the CDR residues could drastically increase the overall solubility of the optimized anti-MSLN antibodies, and thus substantially improve the efficacies of the ADCs in treating human gastric and pancreatic tumor xenograft models in mice. We demonstrated that the in vivo treatments with the optimized ADCs resulted in almost complete eradication of the xenograft tumors at the treatment endpoints, without detectable off-target toxicity because of the ADCs’ high specificity targeting the cell surface tumor-associated MSLN. The technological platform can be applied to optimize the antibody sequences for more effective targeting modules of ADCs, even when the candidate antibodies are not necessarily feasible for the ADC development due to the antibodies’ inferior solubility or affinity/specificity to the target antigen.
•The study is the first to explore the method of correcting the stress wave velocity in the case of incomplete anchoring to deal with the problem of excessive detection errors.•To design rockbolts ...specimens with various anchoring ratios that will be able to simulate possible defects in construction.•Generally, for rock bolts anchored by grouting, the wave velocity of the anchoring layer material must be obtained first, and then the reasonable and the correct rockbolt length can be obtained by the method.
This study examines the spectral responses resulting from the use of the impact-echo method for rockbolt length detection. A rockbolt is a thin long member that is often used in tunnels or slope protection works to fasten structures and soil/rock mass tightly together. It involves embedding a long steel bolt fully anchored to the original structure to resist strong pulling forces and stabilize the original structure or serve as a connecting member between two materials. Inadequate embedment length or poor grouting can prevent rockbolts from serving the function they were designed for and result in rockbolt failure. This study employed finite element analysis to conduct numerical simulation analyses of the stress wave signals in rockbolts and then used the impact-echo method to measure rockbolt length and grout integrity. Our results indicate that the impact-echo method can be used to determine rockbolt length but requires prior knowledge of whether the rockbolt is grouted. If not, then its detection signals will be similar to those of a bare steel bar. The rockbolt length can then be calculated using the theoretical wave velocity in a steel bar and the fundamental frequency derived from measurements. If the rockbolt is grouted, then the wave velocity in the grout material must be known so that the accurate length of the rockbolt can be derived.
Peripheral neuropathy (PN) is a dose-limiting, painful adverse reaction associated with the use of paclitaxel. This common side effect was often partially attributed to the solvent used for ...solubilization of the highly hydrophobic drug substance. Therefore, the development of alternative formulations thrived, which included that of Abraxane® containing nanoparticle albumin-bound paclitaxel (nab-paclitaxel). However, studies demonstrated inconsistent conclusions regarding the mitigation of PN in comparison with the traditional formulation. The mass spectrometry-based cell metabolomics approach was used in the present study to explore the potentially associated mechanisms. Although no significant difference in the effects on cell viability was observed, fold changes in carnitine, several acylcarnitines and long-chain fatty acid(s) were significantly different between treatment groups in differentiated and undifferentiated SH-SY5Y cells. The most prominent difference observed was the significant increase of octanoylcarnitine in cells treated with solvent-based paclitaxel, which was found to be associated with significant decrease of medium-chain acyl-CoA dehydrogenase (MCAD). The findings suggested the potential role of altered fatty acid oxidation in the different neurotoxicity patterns observed, which may be a possible target for therapeutic interventions worth further investigation.
Self‐assembled vertical heterostructure with a high interface‐to‐volume ratio offers tremendous opportunities to realize intriguing properties and advanced modulation of functionalities. Here, a ...heterostructure composed of two visible‐light photocatalysts, BiFeO3 (BFO) and ε‐Fe2O3 (ε‐FO), is designed to investigate its photoelectrochemical performance. The structural characterization of the BFO‐FO heterostructures confirms the phase separation with BFO nanopillars embedded in the ε‐FO matrix. The investigation of band structure of the heterojunction suggests the assistance of photoexcited carrier separation, leading to an enhanced photoelectrochemical performance. The insights into the charge separation are further revealed by means of ultrafast dynamics and electrochemical impedance spectroscopies. This work shows a delicate design of the self‐assembled vertical heteroepitaxy by taking advantage of the intimate contact between two phases that can lead to a tunable charge interaction, providing a new configuration for the optimization of photoelectrochemical cell.
A novel heterostructure composed of two multiferroic–photocatalytic materials, BiFeO3 and ε‐Fe2O3, is fabricated to investigate its photoelectrochemical performance. A delicate design of the self‐assembled vertical heteroepitaxy by taking advantage of the intimate contact between two phases that can lead to a tunable charge interaction is shown, providing a new configuration for the optimization of photoelectrochemical water splitting devices.
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