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Nanoscale structures can produce extreme strain that enables unprecedented material properties, such as tailored electronic bandgap1-5, elevated superconducting temperature6,7 and enhanced electrocatalytic activity8,9. While uniform strains are known to elicit limited effects on heat flow10-15, the impact of inhomogeneous strains has remained elusive owing to the coexistence of interfaces16-20 and defects21-23. Here we address this gap by introducing inhomogeneous strain through bending individual silicon nanoribbons on a custom-fabricated microdevice and measuring its effect on thermal transport while characterizing the strain-dependent vibrational spectra with sub-nanometre resolution. Our results show that a strain gradient of 0.112% per nanometre could lead to a drastic thermal conductivity reduction of 34 ± 5%, in clear contrast to the nearly constant values measured under uniform strains10,12,14,15. We further map the local lattice vibrational spectra using electron energy-loss spectroscopy, which reveals phonon peak shifts of several millielectron-volts along the strain gradient. This unique phonon spectra broadening effect intensifies phonon scattering and substantially impedes thermal transport, as evidenced by first-principles calculations. Our work uncovers a crucial piece of the long-standing puzzle of lattice dynamics under inhomogeneous strain, which is absent under uniform strain and eludes conventional understanding.
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Immune-mediated necrotizing myopathy (IMNM) is an autoimmune disorder associated with the presence of autoantibodies, characterized by severe clinical presentation with rapidly progressive muscular weakness and elevated levels of creatine kinase, while traditional pharmacological approaches possess varying and often limited effects. Considering the pathogenic role of autoantibodies, chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA) have emerged as a promising therapeutic strategy. We reported here a patient with anti-signal recognition particle IMNM refractory to multiple available therapies, who was treated with BCMA-targeting CAR-T cells, exhibited favorable safety profiles, sustained reduction in pathogenic autoantibodies, and persistent clinical improvements over 18 mo. Longitudinal single-cell RNA, B cell receptor, T cell receptor sequencing analysis presented the normalization of immune microenvironment after CAR-T cell infusion, including reconstitution of B cell lineages, replacement of T cell subclusters, and suppression of overactivated immune cells. Analysis on characteristics of CAR-T cells in IMNM demonstrated a more active expansion of CD8+ CAR-T cells, with a dynamic phenotype shifting pattern similar in CD4+ and CD8+ CAR-T cells. A comparison of CD8+ CAR-T cells in patients with IMNM and those with malignancies collected at different timepoints revealed a more NK-like phenotype with enhanced tendency of cell death and neuroinflammation and inhibited proliferating ability of CD8+ CAR-T cells in IMNM while neuroinflammation might be the distinct characteristics. Further studies are warranted to define the molecular features of CAR-T cells in autoimmunity and to seek higher efficiency and longer persistence of CAR-T cells in treating autoimmune disorders.
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Doenças Autoimunes , Mieloma Múltiplo , Doenças Musculares , Receptores de Antígenos Quiméricos , Humanos , Mieloma Múltiplo/tratamento farmacológico , Antígeno de Maturação de Linfócitos B , Doenças Neuroinflamatórias , Imunoterapia Adotiva , Doenças Autoimunes/terapia , Autoanticorpos , Doenças Musculares/terapia , Análise de Célula Única , Terapia Baseada em Transplante de Células e Tecidos , Microambiente TumoralRESUMO
Myogenic regeneration relies on the proliferation and differentiation of satellite cells. TECRL (trans-2,3-enoyl-CoA reductase like) is an endoplasmic reticulum protein only expressed in cardiac and skeletal muscle. However, its role in myogenesis remains unknown. We show that TECRL expression is increased in response to injury. Satellite cell-specific deletion of TECRL enhances muscle repair by increasing the expression of EGR2 through the activation of the ERK1/2 signaling pathway, which in turn promotes the expression of PAX7. We further show that TECRL deletion led to the upregulation of the histone acetyltransferase general control nonderepressible 5, which enhances the transcription of EGR2 through acetylation. Importantly, we showed that AAV9-mediated TECRL silencing improved muscle repair in mice. These findings shed light on myogenic regeneration and muscle repair.
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Proteína 2 de Resposta de Crescimento Precoce , Desenvolvimento Muscular , Músculo Esquelético , Regeneração , Animais , Camundongos , Músculo Esquelético/metabolismo , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Proteína 2 de Resposta de Crescimento Precoce/genética , Desenvolvimento Muscular/genética , Regeneração/genética , Regulação para Cima , Células Satélites de Músculo Esquelético/metabolismo , Fator de Transcrição PAX7/metabolismo , Fator de Transcrição PAX7/genética , Sistema de Sinalização das MAP Quinases , Camundongos Knockout , Diferenciação CelularRESUMO
A 44.610.8 topology hybrid ultramicroporous material (HUM), {[Cu1.5F(SiF6)(L)2.5]·G}n, (L = 4,4'-bisimidazolylbiphenyl, G = guest molecules), 1, formed by cross-linking interpenetrated 3D four-connected CdSO4-type nets with hexafluorosilicate anions is synthesized and evaluated in the context of gas sorption and separation herein. 1 is the first HUM functionalized with two different types of fluorinated sites (SiF6 2- and F- anions) lining along the pore surface. The optimal pore size (≈5 Å) combining mixed and high-density electronegative fluorinated sites enable 1 to preferentially adsorb C2H2 over CO2 and C2H4 by hydrogen bonding interactions with a high C2H2 isosteric heat of adsorption (Qst) of ≈42.3 kJ mol-1 at zero loading. The pronounced discriminatory sorption behaviors lead to excellent separation performance for C2H2/CO2 and C2H2/C2H4 that surpasses many well-known sorbents. Dynamic breakthrough experiments are conducted to confirm the practical separation capability of 1, which reveal an impressive separation factor of 6.1 for equimolar C2H2/CO2 mixture. Furthermore, molecular simulation and density functional theory (DFT) calculations validate the strong binding of C2H2 stems from the chelating fix of C2H2 between SiF6 2- anion and coordinated F- anion.
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Uranyl cation, as an emerging photocatalyst, has been successfully applied to synthetic chemistry in recent years and displayed remarkable catalytic ability under visible light. However, the molecular-level reaction mechanisms of uranyl photocatalysis are unclear. Here, we explore the mechanism of the stepwise benzylic C-H oxygenation of typical alkyl-substituted aromatics (i.e., toluene, ethylbenzene, and cumene) via uranyl photocatalysis using theoretical and experimental methods. Theoretical calculation results show that the most favorable reaction path for uranyl photocatalytic oxidation is as follows: first, hydrogen atom transfer (HAT) from the benzyl position to form a carbon radical ([Râ¢]), then oxygen addition ([Râ¢] + O2 â [ROOâ¢]), then radical-radical combination ([ROOâ¢] + [Râ¢] â [ROOR] â 2[ROâ¢]), and eventually [ROâ¢] reduction to produce alcohols, of which 2° alcohol would further be oxidized to ketones and 1° would be stepwise-oxygenated to acids. The results of the designed verification experiments and the capture of reactive intermediates were consistent with those of theoretical calculations and the previously reported research that the active benzylic C-H would be stepwise-oxygenated in the presence of uranyl. This work deepens our understanding of the HAT mechanism of uranyl photocatalysis and provides important theoretical support for the relevant application of uranyl photocatalysts in organic transformation.
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The exploration of deep space significantly increases the probability of spacecraft failures due to surface electrostatic discharge, which imposes higher vacuum insulation protection requirements on polyimide, the external insulation material of spacecrafts. To address this challenge, this study proposes using silane coupling agent KH550 for organic grafting treatment of Cr2O3 nanoparticles, which are then used to dope and modify polyimide to enhance the vacuum surface insulation of polyimide films. The KH550 grafting improves the interface strength between the fillers and the matrix, allowing the fillers to be uniformly dispersed in the matrix. Compared to pure polyimide films, the prepared PI-Cr2O3@KH550 composite films exhibit significantly enhanced vacuum surface flashover voltage, improved surface/volume resistivity, and dielectric properties. The results demonstrate that polyimide composite films with 0.8% by mass of Cr2O3@KH550 show the most notable performance improvement, with the DC flashover voltage and impulse flashover voltage in vacuum increasing by 20.7% and 27.8%, respectively. The doping of chromium oxide nanoparticles introduces more deep traps into the polyimide films and reduce the surface resistivity. The higher deep trap density inhibits charge migration, thereby alleviating secondary electron emission and surface electric field distortion. Simultaneously, the lower surface resistivity facilitates dissipating surface charges and improves the surface insulation. These findings are of significant reference value for promoting the enhancement of aerospace insulation performance.
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Machine learned potentials (MLPs) have been widely employed in molecular dynamics simulations to study thermal transport. However, the literature results indicate that MLPs generally underestimate the lattice thermal conductivity (LTC) of typical solids. Here, we quantitatively analyze this underestimation in the context of the neuroevolution potential (NEP), which is a representative MLP that balances efficiency and accuracy. Taking crystalline silicon, gallium arsenide, graphene, and lead telluride as examples, we reveal that the fitting errors in the machine-learned forces against the reference ones are responsible for the underestimated LTC as they constitute external perturbations to the interatomic forces. Since the force errors of a NEP model and the random forces in the Langevin thermostat both follow a Gaussian distribution, we propose an approach to correcting the LTC by intentionally introducing different levels of force noises via the Langevin thermostat and then extrapolating to the limit of zero force error. Excellent agreement with experiments is obtained by using this correction for all the prototypical materials over a wide range of temperatures. Based on spectral analyses, we find that the LTC underestimation mainly arises from increased phonon scatterings in the low-frequency region caused by the random force errors.
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Stimuli-responsive physisorbents that undergo reversible structural transformations induced by external stimuli (e.g. light, guests, or heat) offer the promise of utility in gas storage and separation. Whereas reports on guest or light-responsive sorbents have increased in recent years, we are unaware of reports on sorbents that exhibit both light and guest-induced structural transformations. Herein, we report that the square lattice, sql, topology coordination network Zn(fba)(bis) â 2DMF (sql-5,6-Zn-α, 5=trans-4,4'-bis(1-imidazolyl)stilbene=bis, 6=2,2-bis(4-carboxyphenyl)hexafluoropropane=H2fba) underwent single-crystal-to-single-crystal transformation (SCSC) upon activation, affording nonporous sql-5,6-Zn-ß. Parallel alignment at 3.23â Å of olefinic moieties on adjacent bis ligands in sql-5,6-Zn-α enabled SCSC [2+2] photocycloaddition upon exposure to UV light (365â nm) or sunlight. sql-5,6-Zn-α thereby transformed to mot-5,6-Zn-α, which was subsequently activated to the narrow pore phase mot-5,6-Zn-ß. sql-5,6-Zn-ß and mot-5,6-Zn-ß both exhibited S-shaped adsorption isotherms characteristic of guest-induced structural changes when exposed to CO2 at 195â K (type-F-IV and typeâ F-I, respectively). Cycling experiments conducted upon sql-5,6-Zn-ß reduced particle size after cycle 1 and induced transformation into a rare example of a shape memory coordination network, sql-5,6-Zn-γ. Insight into this smorgasbord of SCSC phase changes was gained from in situ PXRD, single crystal XRD and 1H NMR spectroscopy experiments.
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8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) base is the predominant form of commonly observed DNA oxidative damage. DNA impairment profoundly impacts gene expression and serves as a pivotal factor in stimulating neurodegenerative disorders, cancer, and aging. Therefore, precise quantification of 8-oxoG has clinical significance in the investigation of DNA damage detection methodologies. However, at present, the existing approaches for 8-oxoG detection pose challenges in terms of convenience, expediency, affordability, and heightened sensitivity. We employed the sandwich enzyme-linked immunosorbent assay (ELISA) technique, a highly efficient and swift colorimetric method, to detect variations in 8-oxo-dG content in MCF-7 cell samples stimulated with different concentrations of hydrogen peroxide (H2O2). We determined the concentration of H2O2 that induced oxidative damage in MCF-7 cells by detecting its IC50 value in MCF-7 cells. Subsequently, we treated MCF-7 cells with 0, 0.25, and 0.75 mM H2O2 for 12 h and extracted 8-oxo-dG from the cells. Finally, the samples were subjected to ELISA. Following a series of steps, including plate spreading, washing, incubation, color development, termination of the reaction, and data collection, we successfully detected changes in the 8-oxo-dG content in MCF-7 cells induced by H2O2. Through such endeavors, we aim to establish a method to evaluate the degree of DNA oxidative damage within cell samples and, in doing so, advance the development of more expedient and convenient approaches for DNA damage detection. This endeavor is poised to make a meaningful contribution to the exploration of associative analyses between DNA oxidative damage and various domains, including clinical research on diseases and the detection of toxic substances.
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8-Hidroxi-2'-Desoxiguanosina , Dano ao DNA , Ensaio de Imunoadsorção Enzimática , Peróxido de Hidrogênio , Estresse Oxidativo , Humanos , Dano ao DNA/efeitos dos fármacos , Células MCF-7 , Ensaio de Imunoadsorção Enzimática/métodos , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Desoxiguanosina/análogos & derivados , Desoxiguanosina/análiseRESUMO
Programmed cell death (PCD) is a basic process of life that is closely related to the growth, development, aging and disease of organisms and is one of the hotspots of life science research today. PCD is a kind of genetic control, autonomous and orderly important cell death that involves the activation, expression, and regulation of a series of genes. In recent years, with the deepening of research in this field, new mechanisms of multiple PCD pathways have been revealed. This article reviews and summarizes the multiple PCD pathways that have been discovered, analyses and compares the morphological characteristics and biomarkers of different types of PCD, and briefly discusses the role of various types of PCD in the diagnosis and treatment of different diseases, especially malignant tumors.
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Apoptose , Humanos , Apoptose/genética , Animais , Neoplasias/patologia , Neoplasias/genética , Neoplasias/metabolismo , Transdução de SinaisRESUMO
Emotional disorders, such as anxiety and depression, represent a major societal problem; however, the underlying neurological mechanism remains unknown. The ventral lateral septum (LSv) is implicated in regulating processes related to mood and motivation. In this study, we found that LSv GABAergic neurons were significantly activated in mice experiencing chronic social defeat stress (CSDS) after exposure to a social stressor. We then controlled LSv GABAergic neuron activity using a chemogenetic approach. The results showed that although manipulation of LSv GABAergic neurons had little effect on anxiety-like behavioral performances, the activation of LSv GABAergic neurons during CSDS worsened social anxiety during a social interaction (SI) test. Moreover, LSv GABAergic neurons showed strong projections to the paraventricular nucleus (PVN) of the hypothalamus, which is a central hub for stress reactions. Remarkably, while activation of GABAergic LSv-PVN projections induced social anxiety under basal conditions, activation of this pathway during CSDS alleviated social anxiety during the SI test. On the other hand, the chemogenetic manipulation of LSv GABAergic neurons or LSvGABA-PVN projections had no significant effect on despair-like behavioral performance in the tail suspension test. Overall, LS GABAergic neurons, particularly the LSv GABAergic-PVN circuit, has a regulatory role in pathological anxiety and is thus a potential therapeutic target for the treatment of emotional disorders.
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Chronic stress is a major risk factor for psychiatric disorders. However, certain individuals may be at higher risk due to greater stress susceptibility. Elucidating the neurobiology of stress resilience and susceptibility may facilitate the development of novel strategies to prevent and treat stress-related disorders such as depression. Mounting evidence suggests that the serotonin (5-HT) system is a major regulator of stress sensitivity. In this study, we assessed the functions of 5-HT1A and 5-HT2A receptors within the lateral septum (LS) in regulating stress vulnerability. Among a group of male mice exposed to chronic social defeat stress (CSDS), 47.2% were classified as stress-susceptible, and these mice employed more passive coping strategies during the defeat and exhibited more severe anxiety- and depression-like behaviors during the following behavioral tests. These stress-susceptible mice also exhibited elevated neuronal activity in the LS as evidenced by greater c-Fos expression, greater activity of 5-HT neurons in both the dorsal and median raphe nucleus, and downregulated expression of the 5-HT1A receptor in the intermediate LS (LSi). Finally, we found the stress-induced social withdrawal symptoms could be rapidly relieved by LSi administration of 8-OH-DPAT, a 5-HT1A receptor agonist. These results indicate that 5-HT1A receptors within the LSi play an important role in stress vulnerability in mice. Therefore, modulation of stress vulnerable via 5-HT1A receptor activation in the LSi is a potential strategy to treat stress-related psychiatric disorders.
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Receptor 5-HT1A de Serotonina , Serotonina , Animais , Masculino , Camundongos , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Neurônios/metabolismo , Núcleos da Rafe/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologiaRESUMO
Propane (C3H8) is a widely used fuel gas. Metal-organic framework (MOF) physisorbents that are C3H8 selective offer the potential to significantly reduce the energy footprint for capturing C3H8 from natural gas, where C3H8 is typically present as a minor component. Here we report the C3H8 recovery performance of a previously unreported lonsdaleite, lon, topology MOF, a chiral metal-organic material, [Ni(S-IEDC)(bipy)(SCN)]n, CMOM-7. CMOM-7 was prepared from three low-cost precursors: Ni(SCN)2, S-indoline-2-carboxylic acid (S-IDECH), and 4,4'-bipyridine (bipy), and its structure was determined by single crystal X-ray crystallography. Pure gas adsorption isotherms revealed that CMOM-7 exhibited high C3H8 uptake (2.71 mmol g-1) at 0.05 bar, an indication of a higher affinity for C3H8 than both C2H6 and CH4. Dynamic column breakthrough experiments afforded high purity C3H8 capture from a gas mixture comprising C3H8/C2H6/CH4 (v/v/v = 5/10/85). Despite the dilute C3H8 stream, CMOM-7 registered a high dynamic uptake of C3H8 and a breakthrough time difference between C3H8 and C2H6 of 79.5 min g-1, superior to those of previous MOF physisorbents studied under the same flow rate. Analysis of crystallographic data and Grand Canonical Monte Carlo simulations provides insight into the two C3H8 binding sites in CMOM-7, both of which are driven by C-H···π and hydrogen bonding interactions.
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Layered sodium transition-metal (TM) oxides generally suffer from severe capacity decay and poor rate performance during cycling, especially at a high state of charge (SoC). Herein, an insight into failure mechanisms within high-voltage layered cathodes is unveiled, while a two-in-one tactic of charge localization and coherent structures is devised to improve structural integrity and Na+ transport kinetics, elucidated by density functional theory calculations. Elevated Jahn-Teller [Mn3+O6] concentration on the particle surface during sodiation, coupled with intense interlayer repulsion and adverse oxygen instability, leads to irreversible damage to the near-surface structure, as demonstrated by X-ray absorption spectroscopy and in situ characterization techniques. It is further validated that the structural skeleton is substantially strengthened through the electronic structure modulation surrounding oxygen. Furthermore, optimized Na+ diffusion is effectively attainable via regulating intergrown structures, successfully achieved by the Zn2+ inducer. Greatly, good redox reversibility with an initial Coulombic efficiency of 92.6%, impressive rate capability (86.5 mAh g-1 with 70.4% retention at 10C), and enhanced cycling stability (71.6% retention after 300 cycles at 5C) are exhibited in the P2/O3 biphasic cathode. It is believed that a profound comprehension of layered oxides will herald fresh perspectives to develop high-voltage cathode materials for sodium-ion batteries.
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Sodium-ion batteries (SIBs) have significant potential for applications in portable electric vehicles and intermittent renewable energy storage due to their relatively low cost. Currently, hard carbon (HC) materials are considered commercially viable anode materials for SIBs due to their advantages, including larger capacity, low cost, low operating voltage, and inimitable microstructure. Among these materials, renewable biomass-derived hard carbon anodes are commonly used in SIBs. However, the reports about biomass hard carbon from basic research to industrial applications are very rare. In this paper, we focus on the research progress of biomass-derived hard carbon materials from the following perspectives: (1) sodium storage mechanisms in hard carbon; (2) optimization strategies for hard carbon materials encompassing design, synthesis, heteroatom doping, material compounding, electrolyte modulation, and presodiation; (3) classification of different biomass-derived hard carbon materials based on precursor source, a comparison of their properties, and a discussion on the effects of different biomass sources on hard carbon material properties; (4) challenges and strategies for practical of biomass-derived hard carbon anode in SIBs; and (5) an overview of the current industrialization of biomass-derived hard carbon anodes. Finally, we present the challenges, strategies, and prospects for the future development of biomass-derived hard carbon materials.
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Layered sodium transition-metal oxides generally encounter severe capacity decay and inferior rate performance during cycling, especially at a high state of charge. Herein, defect concentration is rationally modulated to explore the impact on electrochemical behavior in NaNi1/3Fe1/3Mn1/3O2 layered oxides. Bulk vacancies are increased through annealing in an oxygen-rich atmosphere, demonstrated by electron paramagnetic resonance measurement. It is found that the cathode with enriched oxygen vacancies exhibits significantly enhanced reversibility of redox reactions with a higher initial Coulombic efficiency of 90.0%. Furthermore, the reduced volume variations during the initial charge/discharge process are also confirmed by in situ X-ray diffraction. As a result, the oxygen-vacancy-rich cathode shows great cycling stability and superior rate performances. Also, full cells deliver a specific capacity of approximately 145.2 mAh g-1 at 0.5 C, with a high capacity retention of 78.3% after 100 cycles. This work presents a viable strategy for designing Na+ intercalated cathodes with a high-energy density.
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Metallic zinc has been regarded as an ideal anode material for aqueous batteries due to its high capacity, abundance, and low toxicity. Numerous strategies have been proposed for anode protection to address its intrinsic deficiencies. However, existing methods can only suppress dendrite growth at limited current densities, and achieving stable cycling at high rates remains a great challenge. Herein, density functional theory (DFT) reveals that Mn-MOF, with a distinctive π-π stacking structure (π-MOF), can induce accelerated ion transfer dynamics, providing high-speed pathways for Zn2+ flux, which can enable stable deposition even at high rates. As anticipated, the π-MOF@Zn anode exhibits remarkable stability for over 1900 h with the lowest voltage hysteresis (71 mV) at a current density of 10 mA cm-2. This study presents a viable approach to enhance the interface stability of high-rate metal anodes by modulating charge or ion behavior at the interface.
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Electrical stimulation (ES) is proposed as a therapeutic solution for managing chronic wounds. However, its widespread clinical adoption is limited by the requirement of additional extracorporeal devices to power ES-based wound dressings. In this study, a novel sandwich-structured photovoltaic microcurrent hydrogel dressing (PMH dressing) is designed for treating diabetic wounds. This innovative dressing comprises flexible organic photovoltaic (OPV) cells, a flexible micro-electro-mechanical systems (MEMS) electrode, and a multifunctional hydrogel serving as an electrode-tissue interface. The PMH dressing is engineered to administer ES, mimicking the physiological injury current occurring naturally in wounds when exposed to light; thus, facilitating wound healing. In vitro experiments are performed to validate the PMH dressing's exceptional biocompatibility and robust antibacterial properties. In vivo experiments and proteomic analysis reveal that the proposed PMH dressing significantly accelerates the healing of infected diabetic wounds by enhancing extracellular matrix regeneration, eliminating bacteria, regulating inflammatory responses, and modulating vascular functions. Therefore, the PMH dressing is a potent, versatile, and effective solution for diabetic wound care, paving the way for advancements in wireless ES wound dressings.
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Diabetes Mellitus , Hidrogéis , Humanos , Biomimética , Proteômica , Cicatrização , BandagensRESUMO
RUNX1 is one of the recurrent mutated genes in newly diagnosed acute myeloid leukemia (AML). Although historically recognized as a provisional distinct entity, the AML subtype with RUNX1 mutations (AML-RUNX1mut) was eliminated from the 2022 WHO classification system. To gain more insight into the characteristics of AML-RUNX1mut, we retrospectively analyzed 1065 newly diagnosed adult AML patients from the First Affiliated Hospital of Soochow University between January 2017 and December 2021. RUNX1 mutations were identified in 112 patients (10.5%). The presence of RUNX1 mutation (RUNX1mut) conferred a lower composite complete remission (CRc) rate (40.2% vs. 58.4%, Pï¼0.001), but no significant difference was observed in the 5-year overall survival (OS) rate (50.2% vs. 53.9%; HR=1.293; P=0.115) and event-free survival (EFS) rate (51.5% vs. 49.4%; HR=1.487, P=0.089), even within the same risk stratification. Multivariate analysis showed that RUNX1mut was not an independent prognostic factor for OS (HR=1.352, P=0.068) or EFS (HR=1.129, P=0.513). When patients were stratified according to induction regimen, RUNX1mut was an unfavorable factor for CRc both on univariate and multivariate analysis in patients receiving conventional chemotherapy, and higher risk stratification predicted worse OS. In those who received venetoclax plus hypomethylating agents, RUNX1mut was not predictive of CRc and comparable OS and EFS were seen between intermediate-risk and adverse-risk groups. The results of this study revealed that the impact of RUNX1mut is limited. Its prognostic value depended more on treatment and co-occurrent abnormalities. VEN-HMA may abrogate the prognostic impact of RUNX1, which merits a larger prospective cohort to illustrate.
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Subunidade alfa 2 de Fator de Ligação ao Core , Leucemia Mieloide Aguda , Adulto , Humanos , Prognóstico , Estudos Retrospectivos , Estudos Prospectivos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Mutação , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genéticaRESUMO
B-cell maturation antigen (BCMA), expressed in plasmablasts and plasma cells, could serve as a promising therapeutic target for autoimmune diseases. We reported here chimeric antigen receptor (CAR) T cells targeting BCMA in two patients with highly relapsed and refractory myasthenia gravis (one with AChR-IgG, and one with MuSk-IgG). Both patients exhibited favorable safety profiles and persistent clinical improvements over 18 months. Reconstitution of B-cell lineages with sustained reduced pathogenic autoantibodies might underlie the therapeutic efficacy. To identify the possible mechanisms underlying the therapeutic efficacy of CAR-T cells in these patients, longitudinal single-cell RNA and TCR sequencing was conducted on serial blood samples post infusion as well as their matching infusion products. By tracking the temporal evolution of CAR-T phenotypes, we demonstrated that proliferating cytotoxic-like CD8 clones were the main effectors in autoimmunity, whereas compromised cytotoxic and proliferation signature and profound mitochondrial dysfunction in CD8+ Te cells before infusion and subsequently defect CAR-T cells after manufacture might explain their characteristics in these patients. Our findings may guide future studies to improve CAR T-cell immunotherapy in autoimmune diseases.