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Background: Chimeric antigen receptor T (CAR-T) cell therapy has achieved marked therapeutic success in ameliorating hematological malignancies. However, there is an extant void in the clinical guidelines concerning the most effective chemotherapy regimen prior to chimeric antigen receptor T (CAR-T) cell therapy, as well as the optimal timing for CAR-T cell infusion post-chemotherapy. Materials and Methods: We employed cell-derived tumor xenograft (CDX) murine models to delineate the optimal pre-conditioning chemotherapy regimen and timing for CAR-T cell treatment. Furthermore, transcriptome sequencing was implemented to identify the therapeutic targets and elucidate the underlying mechanisms governing the treatment regimen. Results: Our preclinical in vivo evaluation determined that a combination of cyclophosphamide and fludarabine, followed by the infusion of CD19 CAR-T cells five days subsequent to the chemotherapy, exerts the most efficacious therapeutic effect in B-cell hematological malignancies. Concurrently, RNA-seq data indicated that the therapeutic efficacy predominantly perturbs tumor cell metabolism, primarily through the inhibition of key mitochondrial targets, such as C-Jun Kinase enzyme (C-JUN). Conclusion: In summary, the present study offers critical clinical guidance and serves as an authoritative reference for the deployment of CD19 CAR-T cell therapy in the treatment of B-cell hematological malignancies.
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Antígenos CD19 , Ciclofosfamida , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Vidarabina , Ensayos Antitumor por Modelo de Xenoinjerto , Vidarabina/análogos & derivados , Vidarabina/farmacología , Ciclofosfamida/uso terapéutico , Ciclofosfamida/farmacología , Animales , Ratones , Humanos , Inmunoterapia Adoptiva/métodos , Antígenos CD19/inmunología , Receptores Quiméricos de Antígenos/inmunología , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/tratamiento farmacológico , Línea Celular Tumoral , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Terapia CombinadaRESUMEN
Class switch recombination (CSR) diversifies the effector functions of antibodies and involves complex regulation of transcription and DNA damage repair. Here, we show that the deubiquitinase USP7 promotes CSR to immunoglobulin A (IgA) and suppresses unscheduled IgG switching in mature B cells independent of its role in DNA damage repair, but through modulating switch region germline transcription. USP7 depletion impairs Sα transcription, leading to abnormal activation of Sγ germline transcription and increased interaction with the CSR center via loop extrusion for unscheduled IgG switching. Rescue of Sα transcription by transforming growth factor ß (TGF-ß) in USP7-deleted cells suppresses Sγ germline transcription and prevents loop extrusion toward IgG CSR. Mechanistically, USP7 protects transcription factor RUNX3 from ubiquitination-mediated degradation to promote Sα germline transcription. Our study provides evidence for active transcription serving as an anchor to impede loop extrusion and reveals a functional interplay between USP7 and TGF-ß signaling in promoting RUNX3 expression for efficient IgA CSR.
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Subunidad alfa 3 del Factor de Unión al Sitio Principal , Inmunoglobulina A , Cambio de Clase de Inmunoglobulina , Activación Transcripcional , Peptidasa Específica de Ubiquitina 7 , Subunidad alfa 3 del Factor de Unión al Sitio Principal/metabolismo , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Animales , Inmunoglobulina A/metabolismo , Peptidasa Específica de Ubiquitina 7/metabolismo , Peptidasa Específica de Ubiquitina 7/genética , Ratones , Factor de Crecimiento Transformador beta/metabolismo , Ratones Endogámicos C57BL , Humanos , Ubiquitinación , Linfocitos B/metabolismo , Linfocitos B/inmunología , Inmunoglobulina G/metabolismo , Inmunoglobulina G/inmunología , Estabilidad ProteicaRESUMEN
Recently, a variety of piezoelectric motors with remarkable performance have appeared. However, due to the hysteresis effect of piezoelectrics and stress return errors within the mechanical structures, the existing piezoelectric motors still face some challenges, such as inconsistent step size, high working voltage, and considerable speed variances during upward vs downward movements even under identical driving voltage signals. Here, we introduce a novel low-voltage piezoelectric motor with a dual-channel force loop based on piezoelectric stacks, in which each slider has two force loops connected with other sliders and the internal elastic preload element is installed, which can effectively address these issues. This new type of piezoelectric motor has low working voltage (starting voltage is only 0.8 V, significantly lower than that of conventional piezoelectric motors), large driving force, uniform step size, and excellent linearity.
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Aerogels are of a popular choice for oil-water separation and water purification due to their attractive properties, such as lightweight, large surface area, and high porosity. Developing robust aerogels with multifunctional characteristics is highly desirable but remains challenging nowadays. Herein, we develop a facile one-pot condensation strategy for the fabrication of superhydrophilic-oleophobic (SHI-OP) composite aerogels using cellulose nanofibers (CNF), 3-glycidy-loxypropyl trimethoxysilane (GPTMS), polyethyleneimine (PEI) and fluorine-contained compound (FS-60). The resulted aerogels exhibit a directional lamellar structure with interconnected macropores, super-lightweight with high porosity of 98.30 % and low density of 0.0256 g·cm-3. Also, the aerogels are mechanically durable against repeated compression. Meanwhile, the amphibious SHI-OP feature of the composite aerogels in both air and water states enables them to not only absorb trace amount of water from contaminated oils, but also separate oil-water mixtures with separation efficiency of over 99 % and high permeation flux of over 9060 L/m2·h. Moreover, the aerogels also show excellent dye adsorption capability and reusability toward anionic dyes with a maximum adsorption capacity of 1245.68 mg/g. Such robust and multifunctional aerogels with special surface wettability provide good opportunity for liquid purification and dye-containing wastewater treatment.
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High actuation performance of a moisture actuator highly depends on the presence of a large property difference between the two layers, which may cause interfacial delamination. Improving interfacial adhesion strength while increasing the difference between the layers is a challenge. In this study, a moisture-driven tri-layer actuator with a Yin-Yang-interface (YYI) design is investigated in which a moisture-responsive polyacrylamide (PAM) hydrogel layer (Yang) is combined with a moisture-inert polyethylene terephthalate (PET) layer (Yin) using an interfacial poly(2-ethylhexyl acrylate) (PEA) adhesion layer. Fast and large reversible bending, oscillation, and programmable morphing motions in response to moisture are realized. The response time, bending curvature, and response speed normalized by thickness are among the best compared with those of previously reported moisture-driven actuators. The excellent actuation performance of the actuator has potential multifunctional applications in moisture-controlled switches, mechanical grippers, and crawling and jumping motions. The Yin-Yang-interface design proposed in this work provides a new design strategy for high-performance intelligent materials and devices.
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Background: Observational studies suggest that inflammatory markers may increase the risk of idiopathic sudden sensorineural hearing loss (ISSHL). However, the causal relationship between the two has not been established. We sought to assess the possible causal effect between several genetically predicted inflammatory markers and ISSHL by Mendelian random (MR) analysis. Methods: We extracted single nucleotide polymorphisms (SNPs) associated with C-reactive protein (CRP), Tumor necrosis factor-α (TNF-α), and fibrinogen from abstract data from the European Individual Large genome-wide association studies (GWAS). Genetic data for ISSHL were obtained from the FinnGen study (n = 196,592). Effect estimates were assessed using inverse variance weighting (IVW) as the primary method. Sensitivity analyses were performed using weighted median, MR-Egger, and MR-PRESSO to evaluate heterogeneity and pleiotropy. Results: In the random-effects IVW approach, there was a significant causal relationship between genetic susceptibility to CRP levels and ISSHL (OR = 1.23, 95% CI = 1.02-1.49, P = 0.03). In contrast, genetic TNF-α and fibrinogen were not risked factors for ISSHL (OR = 1.14, 95% CI = 0.88-1.49, P = 0.30; OR = 0.74, 95% CI = 0.07-7.96, P = 0.30; OR = 1.05, 95% CI = 0.88-1.25, P = 0.59). All the above results were consistent after validation by different Mendelian randomization methods and sensitivity analyses. Conclusion: This Mendelian randomization study provides causal evidence that CRP is a risk factor for ISSHL, while TNF-α and fibrinogen do not increase the risk for ISSHL Introduction.
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Scanning tunneling microscopy (STM) can image material surfaces with atomic resolution, making it a useful tool in the areas of physics and materials. Many materials are synthesized at micron size, especially few-layer materials. Limited by their complex structure, very few STMs are capable of directly positioning and imaging a micron-sized sample with atomic resolution. Traditional STMs are designed to study the material behavior induced by temperature variation, while the physical properties induced by magnetic fields are rarely studied. In this paper, we present the design and construction of an atomic-resolution STM that can operate in a 9 T high magnetic field. More importantly, the homebuilt STM is capable of imaging micron-sized samples. The performance of the STM is demonstrated by high-quality atomic images obtained on a graphite surface, with low drift rates in the X-Y plane and Z direction. The atomic-resolution image obtained on a 32-µm graphite flake illustrates the new STM's ability of positioning and imaging micron-sized samples. Finally, we present atomic resolution images at a magnetic field range from 0 T to 9 T. The above advantages make our STM a promising tool for investigating the quantum hall effect of micron-sized layered materials.
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We present the design and construction of a nonmetallic tip-sample mechanical loop featured Scanning Tunneling Microscope (STM) that operates in a 22 T water-cooled magnet at a low temperature of l.8 K. The STM head mainly consists of a spider-drive motor, stand-alone scanner, moveable sapphire sample holder, and sapphire frame. All parts exist in the tip-sample mechanical loop are made of sapphire to reduce the interference from high magnetic fields. Except for the necessary movement of the tip and scanner, all STM parts are stationary. More importantly, the tip-sample mechanical loop is separate from the motor after detecting the tunneling current, which helps prevent the high voltage signal interference from entering the tip-sample junction, leading to a high stable imaging. A Janis liquid helium cryostat is used to obtain a variable temperature range from 1.8 K to 300 K, and the STM head is cooled down via helium exchange gas. The STM head hangs at the bottom of a probe with a two-stage spring suspension to prevent the huge vibration generated by the water-cooled magnet from entering the tip-sample junction. The performance is demonstrated by atomically resolved STM images of graphite surface at 0 T and 22.8 T under room temperature. Furthermore, the obtained atomic-resolution images of NbSe2 at 1.8 K and 22 T, as well as high-resolution dI/dV spectrums at temperatures from 1.8 K to 8.5 K and magnetic fields from 0 T to 22 T are displayed. This is the first STM capable of atomic-resolution imaging and dI/dV measurement at 1.8 K in a 22 T water-cooled magnet. The high immunity to the magnetic field makes the nonmetallic tip-sample mechanical loop widely useable for atomic-resolution STM imaging in ultra-high magnetic field conditions.
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Incidence rates of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) are lower but more aggressive in children than in adults due to different biological and host factors. After the clinical application of tyrosine kinase inhibitor (TKI) blocking BCR/ABL kinase activity, the prognosis of children with CML and Ph+ ALL has improved dramatically. Yet, off-target effects and drug tolerance will occur during the TKI treatments, contributing to treatment failure. In addition, compared to adults, children may need a longer course of TKIs therapy, causing detrimental effects on growth and development. In recent years, accumulating evidence indicates that drug resistance and side effects during TKI treatment may result from the cellular metabolism alterations. In this review, we provide a detailed summary of the current knowledge on alterations in metabolic pathways including glucose metabolism, lipid metabolism, amino acid metabolism, and other metabolic processes. In order to obtain better TKI treatment outcomes and avoid side effects, it is essential to understand how the TKIs affect cellular metabolism. Hence, we also discuss the relevance of cellular metabolism in TKIs therapy to provide ideas for better use of TKIs in clinical practice.
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BACKGROUND: Congenital pyriform sinus fistula (CPSF) is a rare congenital disease derived from the remnants of the third or fourth branchial cleft. OBJECTIVES: To investigate the imaging characteristics, clinical manifestations, surgical methods, complications, and personalized treatment of CPSF. MATERIAL AND METHODS: The clinical data of 12 CPSF patients admitted to the Department of Otorhinolaryngology Head and Neck Surgery of the First Affiliated Hospital of Wenzhou Medical University from March 2016 to May 2021 were retrospectively analyzed. Cryogenic plasma radiofrequency ablation, carbon dioxide laser resection, and external cervical excision were selected based on the individual condition, and postoperative complications and efficacy were evaluated. RESULTS: There were 6 men and 6 women. Neck abscess or thyroiditis was considered at the initial diagnosis. In 11 of the cases, the CPSF was on the left side, whereas in the rest one case, it was on the right. A pyriform fossa fistula was observed during hypopharyngeal iodine angiography. Eight patients were treated with endoscopic piriform fossa fistula laser resection, two with cryogenic plasma radiofrequency ablation, and the rest with external cervical fistula resection. There was no evidence of postoperative hoarseness, pharyngeal fistula, dysphagia, and other complications. CONCLUSION AND SIGNIFICANCE: CPSF is less common in adults than in children. For patients with recurrent neck abscesses, CPSF should be highly suspected, timely angiography should be performed as soon as possible, and care should be taken to avoid missed diagnoses. The primary method for piriform fossa fistula removal is surgical treatment. Finally, tailoring treatment regimens to the patient's condition can significantly improve curative efficacy.
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PURPOSE: To explore the diagnostic approach and therapeutic method of migratory pharyngeal foreign bodies and related complications, to improve the understanding of such disease and to reduce misdiagnosis and missed diagnosis. MATERIAL AND METHODS: A retrospective study was performed by collecting patients who were treated because of the related complications caused by migratory pharyngeal foreign bodies from 2012 to 2020. RESULTS: A total of 20 patients were admitted to hospital due to the related complications. 14 cases showed cervical mass; 3 cases showed abscess of the mouth floor; 1 cases showed retropharyngeal abscess; 1 cases showed laryngeal granuloma; 1 cases showed mass of tongue. All patients received imaging examination of B-ultrasonography or computed tomography (CT). 19 patients were treated by surgery, and 1 patient was taken conservative treatment. All foreign bodies was successfully removed. As for the type of foreign bodies, there have 15 cases of fishbone, 2 cases of crabshell, 2 cases of shrimp shell, 1 cases of duck bone. CONCLUSIONS: Migrating foreign bodies and related complications are rare in clinic, much attention should be paid to avoid missed diagnosis or misdiagnosis.
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Cuerpos Extraños , Absceso Retrofaríngeo , Cuerpos Extraños/complicaciones , Cuerpos Extraños/diagnóstico por imagen , Cuerpos Extraños/cirugía , Humanos , Faringe , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
Self-powered fabric electronic devices are critical for next-generation wearable technologies, biomedical applications, and human-machine interfaces. The flexible magnetoelectric strategy is an emerging self-powered approach that can adapt to diverse environments and yield efficient electric outputs. However, there is an urgent need to develop a continuous manufacturing method for fabricating self-powered sensing magnetoelectric yarns with a high magnetic powder ratio and resistance to severe surroundings. In this study, we report particle flow spinning mass-manufactured magnetoelectric yarns for self-powered mechanical sensing. It has been shown that mechanical stretching/bending forces can be sensed and recognized by magnetoelectric yarns without an additional power supply. Through a combination of parameter optimization experiments and Maxwell modeling, we reveal the mechanism behind this mechanical-to-electric conversion capability. We further show that these self-powered sensing magnetoelectric yarns can monitor human motions after being attached to texture clothing. We expect that our results will stimulate further research on fabric electronics in a self-powered manner and will substantially advance the field.
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Soft robotics have substantial benefits of safety, adaptability, and cost efficiency compared to conventional rigid robotics. Textiles have applications in soft robotics either as an auxiliary material to reinforce the conventional soft material or as an active soft material. Textiles of various types and configurations have been fabricated into key components of soft robotics in adaptable formats. Despite significant advancements, the efficiency and characteristics of textile actuators in practical applications remain unsatisfactory. To address these issues, novel structural and material designs as well as new textile technologies have been introduced. Herein, we aim at giving an insight into the current state of the art in textile technology for soft robotic manufacturing. We firstly discuss the fundamental actuation mechanisms for soft robotics. We then provide a critical review on the recently developed functional textiles as reinforcements, sensors, and actuators in soft robotics. Finally, the future trends and current strategies that can be employed in textile-based actuator manufacturing process have been explored to address the critical challenges in soft robotics.
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Técnicas Biosensibles , Robótica , TextilesRESUMEN
Incorporating passive radiative cooling structures into personal thermal management technologies could effectively defend humans against intensifying global climate change. We show that large-scale woven metafabrics can provide high emissivity (94.5%) in the atmospheric window and high reflectivity (92.4%) in the solar spectrum because of the hierarchical-morphology design of the randomly dispersed scatterers throughout the metafabric. Through scalable industrial textile manufacturing routes, our metafabrics exhibit desirable mechanical strength, waterproofness, and breathability for commercial clothing while maintaining efficient radiative cooling ability. Practical application tests demonstrated that a human body covered by our metafabric could be cooled ~4.8°C lower than one covered by commercial cotton fabric. The cost-effectiveness and high performance of our metafabrics present substantial advantages for intelligent garments, smart textiles, and passive radiative cooling applications.
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OBJECTIVE: The aim of the study was to check on the reliability and validity of the translated version of Nociception Coma Scale-Revised. DESIGN: Prospective psychometric study. SETTING: Rehabilitation and neurology unit in hospital. SUBJECTS: Patients with prolonged disorders of consciousness. INTERVENTIONS: None. MAIN MEASURES: The original English version of the Nociception Coma Scale-Revised was translated into Chinese. The reliability and validity were undertaken by trained raters. Intraclass correlation coefficients were used to assess inter-rater reliability and test-retest reliability. Cronbach's alpha test was used to investigate internal consistency. Spearman's correlation was used to calculate concurrent validity. The Coma Recovery Scale-revised was used to assess the consciousness of patients. RESULTS: Eighty-four patients were enrolled in the study. Inter-rater reliability of the Chinese version of Nociception Coma Scale-Revised was high for total scores and motor and verbal subscores and good for facial subscores. Test-retest reliability was high for total score and for all subscores. Analysis revealed a moderate internal consistency for subscores. For the concurrent validity, a strong correlation was found between the Nociception Coma Scale-Revised and the Face, Legs, Activity, Cry, and Consolability behavioral scale for all patients. A moderate correlation was found between the Nociception Coma Scale-Revised and the Coma Recovery Scale-revised scores for all patients. CONCLUSION: The Chinese version of Nociception Coma Scale-Revised has good reliability and validity data for assessing responses to pain in patients with prolonged disorders of consciousness.
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Coma/diagnóstico , Coma/fisiopatología , Nocicepción/fisiología , Adulto , Anciano , Anciano de 80 o más Años , China , Coma/etiología , Femenino , Escala de Coma de Glasgow , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Psicometría , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
In this paper, we develop a novel N-doped 3D interconnected carbon bubbles (NCBs) by a facile method of nitric acid extraction precursor at room temperature for the lithium-ion batteries (LIBs) and sodium-ion batteries (SIBs). The NCBs with hollow carbon bubbles having a size of ~100 nm interconnected to each other exhibits high specific surface area and abundant active sites, which ensures continuous diffusion paths for ions and electrons and keeps the electrode structure more stable, thus significantly enhancing the lithium-ion and sodium-ion storage capability. In lithium-ion batteries, the NCBs electrode shows a high reversible capacity of 1180 mA h g-1 after 380 cycles at a current density of 1 C. As the current density increased from 1 to 10 C, the capacity still retains 407.1 mA h g-1. While in sodium-ion batteries, the NCBs electrode provides a capacity of 222.5 mA h g-1 after 200 cycles at a current density of 50 mA g-1. And the capacity maintains at 107.5 mA h g-1 even the current density increased from 0.05 to 5 A g-1. The excellent cycling performance and high-rate capability should be attributed to the synergistic effect of the 3D interconnected hollow structure and the incorporation of nitrogen atoms.
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Hyperosmolality has been commonly investigated due to its effects on the production and quality characteristics of monoclonal antibodies (mAbs) produced in CHO cell fed-batch cultures. However, the application of hyperosmolality at different times and its effect on biopotency have seldom been researched, especially in perfusion culture. In our study, different degrees of hyperosmolality induced by sodium chloride were investigated in anti-IgE rCHO cell fed-batch cultures and anti-CD52 rCHO cell perfusion cultures during the initial and stable phases. The results showed that the initial hyperosmolality group (IHG) in fed-batch and early phase of perfusion cultures exhibited significant suppression of the viable cell density yet an enhancement in specific productivity, whereas the stable hyperosmolality group (SHG) achieved higher mAb production in both fed-batch and perfusion cultures. Additionally, the SHG produced less aggregates and acidic charge variants than IHG in fed-batch culture, which differed from perfusion cultures. However, the contents of non-glycosylation heavy chain (NGHC) and man5 were higher in SHG than in IHG in fed-batch cultures at plus 60 and 120 mOsm/kg, which was similar to perfusion cultures. Furthermore, the biopotency in the IHG was higher than in the SHG at plus 60 and 120 mOsm/kg in fed-batch cultures, which is similar to complement-dependent cytotoxicity (CDC) efficacy in perfusion cultures. The biopotency of all group was acceptable, except FI3. Thus, the study shows that hyperosmolality at a certain level could be beneficial for both mAb production, quality and biopotency, which could play an important role in process development for commercial production.
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Anticuerpos Monoclonales/biosíntesis , Técnicas de Cultivo Celular por Lotes/métodos , Antígeno CD52/inmunología , Inmunoglobulina E/biosíntesis , Concentración Osmolar , Cloruro de Sodio/análisis , Animales , Reactores Biológicos/microbiología , Células CHO , Línea Celular , Proliferación Celular/efectos de los fármacos , Cricetinae , CricetulusRESUMEN
Incorporation of carbon nanotubes (CNTs) into textiles without sacrificing their intrinsic properties provides a promising platform in exploring wearable technology. However, manufacture of flexible, durable, and stretchable CNT/textile composites on an industrial scale is still a great challenge. We hereby report a facile way of incorporating CNTs into the traditional yarn manufacturing process by dipping and drying CNTs into cotton rovings followed by fabricating CNT/cotton/spandex composite yarn (CCSCY) in sirofil spinning. The existence of CNTs in CCSCY brings electrical conductivity to CCSCY while the mechanical properties and stretchability are preserved. We demonstrate that the CCSCY can be used as wearable strain sensors, exhibiting ultrahigh strain sensing range, excellent stability, and good washing durability. Furthermore, CCSCY can be used to accurately monitor the real-time human motions, such as leg bending, walking, finger bending, wrist activity, clenching fist, bending down, and pronouncing words. We also demonstrate that the CCSCY can be assembled into knitted fabrics as the conductors with electric heating performance. The reported manufacturing technology of CCSCY could lead to an industrial-scale development of e-textiles for wearable applications.
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A graphene encapsulated Co2SnO4 nanoparticles (Co2SnO4 NPs@rGO) was synthesized via the analogous mechanism of electrostatic interactions followed by thermal treatment. The Co2SnO4 NPs were uniformly encapsulated in the graphene sheets. As an anode material for rechargeable lithium batteries Co2SnO4 NPs@rGO exhibits enhanced cyclability and rate performance compared with free Co2SnO4 NPs. Even after 200 cycles, it still delivered large reversible capacity of 1037.9 mA h g-1 at 200 mA g-1. The excellent electrochemical performance should be associated with the uniform encapsulation of Co2SnO4 NPs by graphene sheets, which could not only effectively buffer the volume expansion and prevent the aggregation of the Co2SnO4 NPs but maintain good electrical conductivity of the whole electrode during the discharge/charge process.