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1.
Proc Natl Acad Sci U S A ; 120(13): e2221432120, 2023 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-36943889

RESUMO

It is known that external mechanical forces can regulate structures and functions of living cells and tissues in physiology and diseases. However, after cessation of the force, how structures are altered in response to the dynamics of the chromatin and molecules in the nucleoplasm remains elusive. Here, using single-molecule imaging approaches, we show that exogenous local forces via integrins applied for 2 to 10 min decondensed the chromatin and increased chromatin and nucleoplasm protein mobility inside the nucleus, leading to elevated diffusivity of single protein molecules in the nucleoplasm, tens of minutes after the cessation of force. Diffusion experiments with fluorescence correlation spectroscopy in live single cells show that the mechanomemory in chromatin and nucleoplasm protein diffusivity was regulated by nuclear pore complexes. Protein molecular dynamics simulation recapitulated the experimental findings in live cells and showed that nucleoplasm protein diffusivity was regulated by the number of nuclear pore complexes. The mechanomemory in elevated protein diffusivity of the nucleoplasm after force cessation represents a physical process that reverses protein-protein condensation in phase separation via unjamming of the chromatin. Our findings of mechanomemory in chromatin and nucleoplasm protein diffusivity suggest that the effect of force on the nucleus remains tens of minutes after force cessation and thus is more far-reaching than previously anticipated.


Assuntos
Núcleo Celular , Cromatina , Cromatina/metabolismo , Núcleo Celular/metabolismo , Poro Nuclear/metabolismo
2.
Proc Natl Acad Sci U S A ; 120(39): e2302878120, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37722058

RESUMO

Although tumor-intrinsic fatty acid ß-oxidation (FAO) is implicated in multiple aspects of tumorigenesis and progression, the impact of this metabolic pathway on cancer cell susceptibility to immunotherapy remains unknown. Here, we report that cytotoxicity of killer T cells induces activation of FAO and upregulation of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO in cancer cells. The repression of CPT1A activity or expression renders cancer cells more susceptible to destruction by cytotoxic T lymphocytes. Our mechanistic studies reveal that FAO deficiency abrogates the prosurvival signaling in cancer cells under immune cytolytic stress. Furthermore, we identify T cell-derived IFN-γ as a major factor responsible for induction of CPT1A and FAO in an AMPK-dependent manner, indicating a dynamic interplay between immune effector cells and tumor targets. While cancer growth in the absence of CPT1A remains largely unaffected, established tumors upon FAO inhibition become significantly more responsive to cellular immunotherapies including chimeric antigen receptor-engineered human T cells. Together, these findings uncover a mode of cancer resistance and immune editing that can facilitate immune escape and limit the benefits of immunotherapies.


Assuntos
Carnitina O-Palmitoiltransferase , Neoplasias , Humanos , Carnitina O-Palmitoiltransferase/genética , Citotoxicidade Imunológica , Ácidos Graxos , Metabolismo dos Lipídeos , Neoplasias/terapia , Linfócitos T Citotóxicos
3.
Gut ; 73(7): 1169-1182, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38395437

RESUMO

OBJECTIVE: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further. DESIGN: Here, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice. RESULTS: These HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p (TERT), 6q, 8p, 16q, 9p (CDKN2A/B), 17p (TP53) and 13q (RB1), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and TP53 mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the TONSL and TMEM65 amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials. CONCLUSION: HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient's life.


Assuntos
Carcinoma Hepatocelular , Vírus da Hepatite B , Neoplasias Hepáticas , Integração Viral , Carcinoma Hepatocelular/virologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/patologia , Vírus da Hepatite B/genética , Humanos , Integração Viral/genética , Animais , Camundongos , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Sequenciamento Completo do Genoma , Variações do Número de Cópias de DNA , Idoso
4.
J Biol Chem ; 299(6): 104823, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37187293

RESUMO

An imbalance of human mesenchymal stem cells (MSCs) adipogenic and osteogenic differentiation plays an important role in the pathogenesis of osteoporosis. Our previous study verified that Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1)/myoferlin deficiency promotes adipogenic differentiation of MSCs by blocking autophagic flux in osteoporosis. However, the function of APPL1 in the osteogenic differentiation of MSCs remains unclear. This study aimed to investigate the role of APPL1 in the osteogenic differentiation of MSCs in osteoporosis and the underlying regulatory mechanism. In this study, we demonstrated the downregulation of APPL1 expression in patients with osteoporosis and osteoporosis mice. The severity of clinical osteoporosis was negatively correlated with the expression of APPL1 in bone marrow MSCs. We found that APPL1 positively regulates the osteogenic differentiation of MSCs in vitro and in vivo. Moreover, RNA sequencing showed that the expression of MGP, an osteocalcin/matrix Gla family member, was significantly upregulated after APPL1 knockdown. Mechanistically, our study showed that reduced APPL1 impaired the osteogenic differentiation of mesenchymal stem cells by facilitating Matrix Gla protein expression to disrupt the BMP2 pathway in osteoporosis. We also evaluated the significance of APPL1 in promoting osteogenesis in a mouse model of osteoporosis. These results suggest that APPL1 may be an important target for the diagnosis and treatment of osteoporosis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Ligação ao Cálcio , Células-Tronco Mesenquimais , Osteoporose , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Diferenciação Celular , Células Cultivadas , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/metabolismo , Proteínas Musculares/metabolismo , Osteogênese , Osteoporose/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteína de Matriz Gla
5.
Anal Chem ; 96(6): 2360-2368, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38289229

RESUMO

Ion mobility spectrometry (IMS) is a reliable and sensitive technique for the detection and analysis of compounds at the trace level. Depending on the chemical composition of the sample, compounds may be positively or negatively charged to form different polarity ions and detected in positive or negative polarity of the electric field. In order to detect multiple threats simultaneously with miniaturized devices, using a single detection unit to achieve high resolving power and high sensitivity is important. In this work, a miniaturized drift tube with fast polarity switching capabilities integrated with Fourier deconvolution multiplexing techniques is proposed for the first time as a means to improve the performance of ion mobility spectrometry. The sensitivity and resolving power are improved compared to traditional polarity switching signal averaging data acquisition methods. The displayed device had a high resolving power up to 52 at a drift length of 41 mm and a drift tube voltage of 2 kV. Trinitrotoluene (TNT), methamphetamine (MA), benzene, toluene, methyl tert-butyl ether (MTBE), acetic acid, and methylene chloride were evaluated using the proposed fast polarity switching multiplexing spectrometer and exhibited satisfied performance.

6.
Small ; : e2400115, 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38678491

RESUMO

High-power-density electronic devices under vibrations call for soft and damping thermal interface materials (TIMs) for efficient heat dissipation. However, integrating low hardness, high damping, and superior heat transfer capability into one TIM is highly challenging. Herein, soft, damping, and thermally conductive TIMs are designed and prepared by constructing a honeycomb-board-mimetic boron nitride nanosheet (BNNS) network in a dynamic polyimine via one-step horizontal centrifugal casting. The unique filler network makes the TIMs perform a high through-plane thermal conductivity (> 7.69 W m-1 K-1) and a uniform heat transfer process. Meanwhile, the hierarchical dynamic bonding of the polyimine endows the TIMs with low compressive strength (2.16 MPa at 20% strain) and excellent damping performance (tan δ > ≈0.3 at 10-2-102 Hz). The resulting TIMs also exhibit electrical insulation and remarkable recycling ability. Compared with the commercial ones, the TIMs provide better heat dissipation (4.1 °C) for a high-power 5G base station and less temperature fluctuation (1.8 °C) for an automotive insulated gate bipolar transistor (IGBT) under vibrations. This rational design offers a viable approach to prepare soft and damping TIMs for effective heat dissipation of high-power-density electronic devices under vibrations.

7.
Hepatology ; 78(1): 45-57, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36632993

RESUMO

BACKGROUND AND AIM: Drug-induced liver injury occurs frequently and can be life threatening. Although drug-induced liver injury is mainly caused by the direct drug cytotoxicity, increasing evidence suggests that the interplay between hepatocytes and immune cells can define this pathogenic process. Here, we interrogate the role of the pattern recognition scavenger receptor A (SRA) for regulating hepatic inflammation and drug-induced liver injury. APPROACH AND RESULTS: Using acetaminophen (APAP) or halothane-induced liver injury models, we showed that SRA loss renders mice highly susceptible to drug hepatotoxicity, indicated by the increased mortality and liver pathology. Mechanistic studies revealed that APAP-induced liver injury exaggerated in the absence of SRA was associated with the decreased anti-inflammatory and prosurvival cytokine IL-10 concomitant with excessive hepatic inflammation. The similar correlation between SRA and IL-10 expression was also seen in human following APAP uptake. Bone marrow reconstitution and liposomal clodronate depletion studies established that the hepatoprotective activity of SRA mostly resized in the immune sentinel KCs. Furthermore, SRA-facilitated IL-10 production by KCs in response to injured hepatocytes mitigated activation of the Jun N-terminal kinase-mediated signaling pathway in hepatocytes. In addition, supplemental use of IL-10 with N -acetylcysteine, only approved treatment of APAP overdose, conferred mice improved protection from APAP-induced liver injury. CONCLUSION: We identify a novel hepatocyte-extrinsic pathway governed by the immune receptor SRA that maintains liver homeostasis upon drug insult. Giving that drug (ie, APAP) overdose is the leading cause of acute liver failure, targeting this hepatoprotective SRA-IL-10 axis may provide new opportunities to optimize the current management of drug-induced liver injury.


Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Halotano , Hepatócitos , Receptores Depuradores , Receptores Depuradores/metabolismo , Animais , Camundongos , Acetaminofen/toxicidade , Halotano/toxicidade , Fígado/efeitos dos fármacos , Inflamação , Hepatócitos/metabolismo , Homeostase
8.
Opt Express ; 32(3): 3316-3328, 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38297556

RESUMO

Structured illumination microscopy (SIM) is a powerful technique for super-resolution (SR) image reconstruction. However, conventional SIM methods require high-contrast illumination patterns, which necessitate precision optics and highly stable light sources. To overcome these challenges, we propose a new method called contrast-robust structured illumination microscopy (CR-SIM). CR-SIM employs a deep residual neural network to enhance the quality of SIM imaging, particularly in scenarios involving low-contrast illumination stripes. The key contribution of this study is the achievement of reliable SR image reconstruction even in suboptimal illumination contrast conditions. The results of our study will benefit various scientific disciplines.

9.
Opt Express ; 32(2): 1635-1649, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38297711

RESUMO

High throughput has become an important research direction in the field of super-resolution (SR) microscopy, especially in improving the capability of dynamic observations. In this study, we present a hexagonal lattice structured illumination microscopy (hexSIM) system characterized by a large field of view (FOV), rapid imaging speed, and high power efficiency. Our approach employs spatial light interference to generate a two-dimensional hexagonal SIM pattern, and utilizes electro-optical modulators for high-speed phase shifting. This design enables the achievement of a 210-µm diameter SIM illumination FOV when using a 100×/1.49 objective lens, capturing 2048 × 2048 pixel images at an impressive 98 frames per second (fps) single frame rate. Notably, this method attains a near 100% full field-of-view and power efficiency, with the speed limited only by the camera's capabilities. Our hexSIM demonstrates a substantial 1.73-fold improvement in spatial resolution and necessitates only seven phase-shift images, thus enhancing the imaging speed compared to conventional 2D-SIM.

10.
Ann Hematol ; 103(3): 771-780, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38294533

RESUMO

The objective of this study was to analyze the correlation between skeletal muscle mass and the distribution of peripheral blood lymphocytes and natural killer (NK) cells, as well as their impact on prognosis in patients with acute myeloid leukemia (AML). A retrospective analysis was conducted on 211 newly diagnosed AML patients, evaluating skeletal muscle index (SMI), NK cell proportion, and absolute value, along with relevant clinical data. Linear regression and Spearman's correlation coefficient were used to assess the relationship between various indicators and SMI, followed by multiple linear regression for further modeling. Univariate and multivariate Cox proportional hazards regression models were used to identify independent predictors for overall survival (OS). Among the 211 AML patients, 38 cases (18.0%) were diagnosed with sarcopenia. Multiple linear regression analysis included weight, fat mass, ECOG score, body mass index, and peripheral blood NK cell proportion, constructing a correlation model for SMI (R2 = 0.745). Univariate analysis identified higher NK cell count (> 9.53 × 106/L) as a poor predictor for OS. Multivariate Cox proportional hazards regression model indicated that age ≥ 60 years, PLT < 100 × 109/L, ELN high risk, sarcopenia, and B cell count > 94.6 × 106/L were independent adverse prognostic factors for AML patients. Low skeletal muscle mass may negatively impact the count and function of NK cells, thereby affecting the prognosis of AML. However, further basic and clinical research is needed to explore the specific mechanisms underlying the relationship between NK cells and SMI in AML.


Assuntos
Leucemia Mieloide Aguda , Sarcopenia , Humanos , Pessoa de Meia-Idade , Sarcopenia/patologia , Estudos Retrospectivos , Prognóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patologia , Músculo Esquelético , Células Matadoras Naturais
11.
Catheter Cardiovasc Interv ; 103(3): 391-403, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38204355

RESUMO

BACKGROUND: The SYNTAX score Ⅱ 2020 (SSⅡ-2020) was created as a customized decision-making tool for individuals diagnosed with complex coronary artery disease (CAD). Nevertheless, there has been a scarcity of research investigating the long-term predictive significance of SSⅡ-2020 for patients with both CAD and chronic renal insufficiency (CRI) who undergo percutaneous coronary intervention (PCI). AIMS: We sought to showcase the prognostic capacity of SSII-2020 in evaluating long-term all-cause mortality (ACM) within this high-risk patient cohort. METHODS: A retrospective cohort comprising 1156 individuals diagnosed with CRI and exhibiting left main CAD, three-vessel CAD or both was included in this investigation. We categorized participants into three groups based on the optimal SSII-2020 threshold for predicting long-term ACM, determined using the X-tile software. RESULTS: At the median follow-up duration of 6.3 years, the ACM rates were determined to be 10% in the low, 17% in the moderate, and 28% in the high SSII-2020 groups (p < 0.001). Employing multivariate Cox regression analysis, it was observed that the high SSII-2020 group exhibited a 3.289-fold increased risk of ACM (95% confidence interval [CI]: 2.229-4.856, p < 0.001) compared with the low SSII-2020 group, whereas the high SSII-2020 group displayed a 1.757-fold (95% CI: 1.190-2.597, p = 0.005) in comparison to the median SSII-2020 groups. Compared with SSII, the SSII-2020 had an incremental value for predicting 7-year ACM (C-index: 0.662 vs. 0.534, p = 0.007; IDI: 0.016, p < 0.001). CONCLUSIONS: SSII-2020 enhances long-term ACM prediction, facilitates improved risk stratification, and improves clinical utility for PCI patients with complex CAD and CRI.


Assuntos
Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Insuficiência Renal Crônica , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/terapia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Fatores de Risco , Medição de Risco
12.
Langmuir ; 40(6): 3024-3034, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38295287

RESUMO

A monolithic catalyst was fabricated through an emulsion-templating method, postpolymerization modification, and in situ loading of active constituents. To achieve a high specific surface area, divinylbenzene (DVB) was solely employed as the monomer, while the porous structure was adjusted with the porogen content and the types of initiators. Then, anchor points were introduced on the pore wall through nitration and amination of the polymeric scaffold. Using a controlled "silver mirror reaction", monolithic catalysts were obtained after loading of silver nanoparticles (Ag NPs), which was verified from morphological and crystallinity characteristics. The catalytic performance of the resultant monolithic catalyst was determined with the model reduction of 4-nitrophenol (4-NP). In static catalysis, the monolithic catalyst was proved to have a reactively high apparent rate constant and a good reusability. Furthermore, a flow reactor was fabricated with the monolithic catalyst, showing a high efficiency and long-term durability for the continuous reduction of 4-NP. This work broadened the adjustment of porous structures and the subsequent application for emulsion-templated monoliths.

13.
J Org Chem ; 89(6): 4098-4112, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38421813

RESUMO

A method for the selective construction of S-N/C(sp2)-S bonds using N-substituted O-thiocarbamates and indoles as substrates is reported. This protocol features good atom utilization, mild conditions, short reaction time, and wide substrate scope, which can provide a convenient path for the functionalization of indoles. In addition, the reaction could be scaled up on gram scale, showing potential application value in industry synthesis.

14.
Fish Shellfish Immunol ; 144: 109259, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38040132

RESUMO

Deoxynivalenol (DON) is one of the most common sources of fungal toxins in fish feed, posing a significant risk to the immune and reproductive systems of fish. Microalgal astaxanthin (MIA), a potent antioxidant derived from microalgae, confers multifarious advantages upon piscine organisms, notably encompassing its anti-inflammatory and antioxidant prowess. Herein, we investigated the potential of MIA in ameliorating the immunotoxicity of DON on carp (Cyprinus carpio L.) based on spleen lymphocytes treated with DON (1.5 ng/ml) and/or MIA (96 µM). Firstly, CCK8 results showed that DON resulted in excessive death of spleen lymphocytes. Secondly, spleen lymphocytes treated with DON had a higher proportion of pyroptosis, and the mRNA and protein levels of pyroptosis (NLRP3, IL-1ß and ASC) in spleen lymphocytes were increased. Thirdly, the relative red fluorescence intensity of JC-1 and DCFH-DA showed decreased mitochondrial membrane potential and increased ROS in spleen lymphocytes treated with DON. Mitochondrial ATP, DNA and NADPH/NADP+ analysis revealed decreased mitochondrial ATP, DNA and NADPH/NADP+ levels in DON-treated lymphocytes, corroborating the association between DON exposure and elevated intracellular ATP, DNA and NADPH/NADP+ in lymphocytes. DON exposure resulted in the downregulation of mitophagy-related genes and proteins (PINK1, Parkin and LC3) in lymphocytes. Notably, these effects were counteracted by treatment with MIA. Furthermore, DON led to the elevated secretion of inflammatory factors (TNF-α, IL-4 and IFN-γ), thereby inducing immune dysfunction in spleen lymphocytes. Encouragingly, MIA treatment effectively mitigated the immunotoxic effects induced by DON, demonstrating its potential in ameliorating pyroptosis, mitochondrial dysfunction and mitophagy impairment via regulating the mtROS-NF-κB axis in lymphocytes. This study sheds light on safeguarding farmed fish against agrobiological threats posed by DON, highlighting the valuable applications of MIA in aquaculture.


Assuntos
Carpas , Inflamassomos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , NF-kappa B/metabolismo , Piroptose , Baço/metabolismo , Carpas/metabolismo , NADP/farmacologia , Antioxidantes/metabolismo , Mitofagia , Linfócitos , DNA , Trifosfato de Adenosina/metabolismo , Espécies Reativas de Oxigênio/metabolismo
15.
J Sep Sci ; 47(1): e2300597, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38095454

RESUMO

Using high-performance liquid chromatography coupled with electrospray ionization-ion mobility spectrometry and mass spectrometry, we proposed a dual-detection method for the identification and profiling of alkaloids in various lotus parts including leaf, plumule, stem, seed epicarp, and receptacle. The eluent from high-performance liquid chromatography was split and conducted to electrospray ionization-ion mobility spectrometry and time-of-flight mass spectrometry separately to facilitate the compound identification. In total, 23 kinds of alkaloids were identified based on m/z, drift time, and retention time, including alkaloid isomers such as lirinidine, N-nornuciferine, and O-nornuciferine with identical m/z that are difficult to differentiate using mass spectrometry alone. Using this method, we investigated the changing dynamics of alkaloid accumulation in lotus leaves and lotus stems at different harvesting periods. The total alkaloid content showed an increasing trend with the growth and development of leave and stem. Overall, the developed dual detection method has the advantages of high peak capacity and high sensitivity compared with the conventional detection method and facilitates the identification of detected compounds.


Assuntos
Alcaloides , Extratos Vegetais , Cromatografia Líquida de Alta Pressão/métodos , Extratos Vegetais/química , Espectrometria de Mobilidade Iônica , Alcaloides/análise , Espectrometria de Massas/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos
16.
J Acoust Soc Am ; 155(5): 3436-3446, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38780196

RESUMO

Fueled by the concepts of topological insulators, analogous topological acoustics offer an alternative approach to manipulate sound. Theoretical proposals for subwavelength acoustic topological insulators are considered to be ideal effective parameters or utilizeing artificial coiling-space metamaterials. However, the corresponding realization using realistic soft metamaterials remains challenging. In this study, we present the design of an acoustic subwavelength second-order topological insulator using nanoscale porous solid material, silica aerogel, which supports pseudospin-dependent topological edge and corner states simultaneously. Through simulations and experiments, we demonstrate that silica aerogel can function as a soft acoustic metamaterial at the subwavelength scale. By embedding silica aerogel in an air matrix to construct a honeycomb lattice, a double Dirac cone is obtained. A topological phase transition is induced by expanding or contracting the supercell, resulting in band inversion. Additionally, we propose topologically robust acoustic transmission along the one-dimensional edge. Furthermore, we discover that the proposed sonic crystal sustains zero-dimensional corner states, which can efficiently confine energy at subwavelength corners. These findings offer potential for the realization of subwavelength topological acoustic devices using realistic soft metamaterials.

17.
Arch Pharm (Weinheim) ; 357(2): e2300404, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38010470

RESUMO

Multitarget-directed ligands (MTDLs) have recently attracted significant interest due to their superior effectiveness in multifactorial Alzheimer's disease (AD). Combined inhibition of two important AD targets, glycogen synthase kinase-3ß (GSK-3ß) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), may be a breakthrough in the treatment of AD. Based on our previous work, we have designed and synthesized a series of novel harmine derivatives, investigated their inhibition of GSK-3ß and DYRK1A, and evaluated a variety of biological activities. The results of the experiments showed that most of these compounds exhibited good activity against GSK-3ß and DYRK1A in vitro. ZLQH-5 was selected as the best compound due to the most potent inhibitory effect against GSK-3ß and DYRK1A. Molecular docking studies demonstrated that ZLQH-5 could form stable interactions with the ATP binding pocket of GSK-3ß and DYRK1A. In addition, ZLQH-5 showed low cytotoxicity against SH-SY5Y and HL-7702, good blood-brain barrier permeability, and favorable pharmacokinetic properties. More importantly, ZLQH-5 also attenuated the tau hyperphosphorylation in the okadaic acid SH-SY5Y cell model. These results indicated that ZLQH-5 could be a promising dual-target drug candidate for the treatment of AD.


Assuntos
Doença de Alzheimer , Neuroblastoma , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Glicogênio Sintase Quinase 3 beta , Harmina/farmacologia , Harmina/uso terapêutico , Proteínas tau/metabolismo , Proteínas tau/uso terapêutico , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Fosforilação
18.
Int J Mol Sci ; 25(2)2024 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-38256077

RESUMO

Members of the C-X-C motif chemokine receptor (CXCR) superfamily play central roles in initiating the innate immune response in mammalian cells by orchestrating selective cell migration and immune cell activation. With its multilayered structure, the skin, which is the largest organ in the body, performs a crucial defense function, protecting the human body from harmful environmental threats and pathogens. CXCRs contribute to primary immunological defense; these receptors are differentially expressed by different types of skin cells and act as key players in initiating downstream innate immune responses. While the initiation of inflammatory responses by CXCRs is essential for pathogen elimination and tissue healing, overactivation of these receptors can enhance T-cell-mediated autoimmune responses, resulting in excessive inflammation and the development of several skin disorders, including psoriasis, atopic dermatitis, allergic contact dermatitis, vitiligo, autoimmune diseases, and skin cancers. In summary, CXCRs serve as critical links that connect innate immunity and adaptive immunity. In this article, we present the current knowledge about the functions of CXCRs in the homeostasis function of the skin and their contributions to the pathogenesis of allergic contact dermatitis and psoriasis. Furthermore, we will examine the research progress and efficacy of therapeutic approaches that target CXCRs.


Assuntos
Dermatite Alérgica de Contato , Psoríase , Humanos , Animais , Cisteína , Receptores de Quimiocinas , Psoríase/etiologia , Dermatite Alérgica de Contato/etiologia , Homeostase , Mamíferos
19.
J Environ Manage ; 360: 121232, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38801804

RESUMO

Surfactant pollution is escalatitheng in eutrophic waters, but the effect of surfactant charge properties on the physiological and biochemical properties of toxin-producing microalgae remains inadequately explored. To address this gap, this study explores the effects and mechanisms of three common surfactants-cetyltrimethylammonium bromide (CTAB, cationic), sodium dodecyl sulfate (SDS, anionic), and Triton X-100 (nonionic)-found in surface waters, on the agglomeration behavior, physiological indicators, and Microcystin-LR (MC-LR) release of Microcystis aeruginosa (M. aeruginosa) by using UV-visible spectroscope, Malvern Zetasizer, fluorescence spectrometer, etc. Results suggest that charge properties significantly affect cyanobacterial aggregation and cellular metabolism. The CTAB-treated group demonstrates a ∼5.74 and ∼9.74 times higher aggregation effect compared to Triton X-100 and SDS (300 mg/L for 180 min) due to strong electrostatic attraction. Triton X-100 outperforms CTAB and SDS in polysaccharide extraction, attributed to its higher water solubility and lower critical micelle concentration. CTAB stimulates cyanobacteria to secrete proteins, xanthohumic acid, and humic acids to maintain normal physiological cells. Additionally, the results of SEM and ion content showed that CTAB damages the cell membrane, resulting in a ∼90% increase in the release of intracellular MC-LR without cell disintegration. Ionic analyses confirm that all three surfactants alter cell membrane permeability and disrupt ionic metabolic pathways in microalgae. This study highlights the relationship between the surface charge properties of typical surfactants and the dispersion/agglomeration behavior of cyanobacteria. It provides insights into the impact mechanism of exogenous surfactants on toxic algae production in eutrophic water bodies, offering theoretical references for managing surfactant pollution and treating algae blooms.


Assuntos
Microcistinas , Microcystis , Tensoativos , Microcistinas/química , Microcistinas/metabolismo , Microcystis/efeitos dos fármacos , Tensoativos/química , Tensoativos/farmacologia , Octoxinol/química , Octoxinol/farmacologia , Dodecilsulfato de Sódio/química , Dodecilsulfato de Sódio/farmacologia
20.
Int J Environ Health Res ; 34(1): 587-599, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36599011

RESUMO

Studies have showed that LIPA seems to be favorably associated with mortality in the general population and illness individuals, but the association between different cardiovascular health status and mortality is not clear. After adjustment , the HRs of LIPA in individuals with CVRF and CVD from quartiles 2-4 were less than 1, which were 0.78 (95%CI, 0.61 ~ 0.99; P = 0.042), 0.63 (95%CI, 0.47 ~ 0.83; P = 0.001), 0.55(95%CI, 0.40 ~ 0.76; P < 0.001), and 0.52 (95%CI, 0.37 ~ 0.74; P < 0.001),0.39 (95%CI, 0.27 ~ 0.58; P < 0.001), 0.33 (95%CI, 0.22 ~ 0.51; P < 0.001) LIPA is beneficial for reducing mortality, but the shape of the association depends on cardiovascular health status.


Assuntos
Doenças Cardiovasculares , Humanos , Estudos de Coortes , Doenças Cardiovasculares/epidemiologia , Fatores de Risco , Exercício Físico , Nível de Saúde
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