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1.
Proc Natl Acad Sci U S A ; 120(12): e2220032120, 2023 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-36917662

RESUMO

Finely controlled flow forces in extrusion-based additive manufacturing can be exploited to program the self-assembly of malleable nanostructures in soft materials by integrating bottom-up design into a top-down processing approach. Here, we leverage the processing parameters offered by direct ink-writing (DIW) to reconfigure the photonic chiral nematic liquid crystalline phase in hydroxypropyl cellulose (HPC) solutions prior to deposition on the writing substrate to direct structural evolution from a particular initial condition. Moreover, we incorporate polyethylene glycol (PEG) into iridescent HPC inks to form a physically cross-linked network capable of inducing kinetic arrest of the cholesteric/chiral pitch at length scales that selectively reflect light throughout the visible spectrum. Based on thorough rheological measurements, we have found that printing the chiral inks at a shear rate where HPC molecules adopt pseudonematic state results in uniform chiral recovery following flow cessation and enhanced optical properties in the solid state. Printing chiral inks at high shear rates, on the other hand, shifts the monochromatic appearance of the extruded filaments to a highly angle-dependent state, suggesting a preferred orientation of the chiral domains. The optical response of these filaments when exposed to mechanical deformation can be used in the development of optical sensors.

2.
PLoS Pathog ; 19(2): e1011119, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36724179

RESUMO

As new mutations continue to emerge, the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus to evade the human immune system and neutralizing antibodies remains a huge challenge for vaccine development and antibody research. The majority of neutralizing antibodies have reduced or lost activity against SARS-CoV-2 variants. In this study, we reported a novel protein surface display system on a mammalian cell for obtaining a higher-affinity antibody in high-throughput manner. Using a saturation mutagenesis strategy through integrating microarray-based oligonucleotide synthesis and single-cell screening assay, we generated a group of new antibodies against diverse prevalent SARS-CoV-2 variants through high-throughput screening the human antibody REGN10987 within 2 weeks. The affinity of those optimized antibodies to seven prevalent mutants was greatly improved, and the EC50 values were no higher than 5 ng/mL. These results demonstrate the robustness of our screening system in the rapid generation of an antibody with higher affinity against a new SARS-CoV-2 variant, and provides a potential application to other protein molecular interactions.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Humanos , SARS-CoV-2/genética , Mutagênese , Proteínas de Membrana , Anticorpos Neutralizantes , Glicoproteína da Espícula de Coronavírus/genética , Anticorpos Antivirais , Mamíferos
3.
Immunology ; 173(1): 185-195, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38859694

RESUMO

SET domain-containing 2 (SETD2) is a histone methyltransferase. It regulates the activity of H3K36me3 to enhance gene transcription. Macrophages (Mϕs) are one of the cell types involved in immune response. The purpose of this study is to clarify the role of SETD2 in regulating the immune property of Mϕ. The Mφs were isolated from the bronchoalveolar lavage fluid (BALF) and analysed through flow cytometry and RNA sequencing. A mouse strain carrying Mφs deficient in SETD2 was used. A mouse model of airway allergy was established with the ovalbumin/alum protocol. Less expression of SETD2 was observed in airway Mϕs in patients with allergic asthma. SETD2 of M2 cells was associated with the asthmatic clinical response. Sensitization reduced the expression of SETD2 in mouse respiratory tract M2 cells, which is associated with the allergic reaction. Depletion of SETD2 in Mφs resulted in Th2 pattern inflammation in the lungs. SETD2 maintained the immune regulatory ability in airway M2 cells. SETD2 plays an important role in the maintenance of immune regulatory property of airway Mφs.


Assuntos
Asma , Histona-Lisina N-Metiltransferase , Macrófagos , Animais , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Camundongos , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Asma/imunologia , Asma/genética , Feminino , Modelos Animais de Doenças , Células Th2/imunologia , Camundongos Endogâmicos C57BL , Masculino , Camundongos Knockout , Hipersensibilidade Respiratória/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Ovalbumina/imunologia , Pulmão/imunologia , Pulmão/patologia , Hipersensibilidade/imunologia
4.
Apoptosis ; 2024 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-38853201

RESUMO

This study delivers a thorough analysis of long non-coding RNAs (lncRNAs) in regulating programmed cell death (PCD), vital for neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD). We propose a new framework PCDLnc, and identified 20 significant lncRNAs, including HEIH, SNHG15, and SNHG5, associated with PCD gene sets, which were known for roles in proliferation and apoptosis in neurodegenerative diseases. By using GREAT software, we identified regulatory functions of top lncRNAs in different neurodegenerative diseases. Moreover, lncRNAs cis-regulated mRNAs linked to neurodegeneration, including JAK2, AKT1, EGFR, CDC42, SNCA, and ADIPOQ, highlighting their therapeutic potential in neurodegenerative diseases. A further exploration into the differential expression of mRNA identified by PCDLnc revealed a role in apoptosis, ferroptosis and autophagy. Additionally, protein-protein interaction (PPI) network analysis exposed abnormal interactions among key genes, despite their consistent expression levels between disease and normal samples. The randomforest model effectively distinguished between disease samples, indicating a high level of accuracy. Shared gene subsets in AD and PD might serve as potential biomarkers, along with disease-specific gene sets. Besides, we also found the strong relationship between AD and immune infiltration. This research highlights the role of lncRNAs and their associated genes in PCD in neurodegenerative diseases, offering potential therapeutic targets and diagnostic markers for future study and clinical application.

5.
Plant Biotechnol J ; 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39058556

RESUMO

Branch length is an important plant architecture trait in cotton (Gossypium) breeding. Development of cultivars with short branch has been proposed as a main object to enhance cotton yield potential, because they are suitable for high planting density. Here, we report the molecular cloning and characterization of a semi-dominant quantitative trait locus, Short Branch Internode 1(GhSBI1), which encodes a NAC transcription factor homologous to CUP-SHAPED COTYLEDON 2 (CUC2) and is regulated by microRNA ghr-miR164. We demonstrate that a point mutation found in sbi1 mutants perturbs ghr-miR164-directed regulation of GhSBI1, resulting in an increased expression level of GhSBI1. The sbi1 mutant was sensitive to exogenous gibberellic acid (GA) treatments. Overexpression of GhSBI1 inhibited branch internode elongation and led to the decreased levels of bioactive GAs. In addition, gene knockout analysis showed that GhSBI1 is required for the maintenance of the boundaries of multiple tissues in cotton. Transcriptome analysis revealed that overexpression of GhSBI1 affects the expression of plant hormone signalling-, axillary meristems initiation-, and abiotic stress response-related genes. GhSBI1 interacted with GAIs, the DELLA repressors of GA signalling. GhSBI1 represses expression of GA signalling- and cell elongation-related genes by directly targeting their promoters. Our work thus provides new insights into the molecular mechanisms for branch length and paves the way for the development of elite cultivars with suitable plant architecture in cotton.

6.
Cell Immunol ; 401-402: 104829, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38754338

RESUMO

Eosinophils account for a significant portion of immune cells in the body. It is well known that eosinophils play a role in the pathogenesis of many diseases. In which the interaction between eosinophils and other immune cells is incompletely understood. The aim of this study is to characterize the immune suppressive functions of eosinophils. In this study, an irway allergy mouse model was established. Eosinophils were isolated from the airway tissues using flow cytometry cell sorting. The RAW264.7 cell line was used to test the immune suppressive functions of eosinophils. We observed that eosinophils had immune suppressive functions manifesting inhibiting immune cell proliferation and cytokine release from other immune cells. The eosinophil's immune suppressive functions were mediated by eosinophil-derived molecules, such as eosinophil peroxidase (EPX) and major basic protein (MBP). The expression of Ras-like protein in the brain 27a (Rab27a) was detected in eosinophils, which controlled the release of MBP and EPX by eosinophils. Eosinophil mediators had two contrast effects on inducing inflammatory responses or rendering immune suppressive effects, depending on the released amounts. Administration of an inhibitor of Rab27a at proper dosage could alleviate experimental airway allergy. To sum up, eosinophils have immune suppressive functions and are also inflammation inducers. Rab27a governs the release of EPX and MBP from eosinophils, which leads to immune suppression or inflammation. Modulation of Rab27a can alleviate airway allergy responses by modulating eosinophil's immune suppressive functions, which has the translational potential for the management of eosinophil-related diseases.


Assuntos
Peroxidase de Eosinófilo , Eosinófilos , Animais , Eosinófilos/imunologia , Eosinófilos/metabolismo , Camundongos , Células RAW 264.7 , Peroxidase de Eosinófilo/metabolismo , Camundongos Endogâmicos BALB C , Citocinas/metabolismo , Citocinas/imunologia , Modelos Animais de Doenças , Proteína Básica Maior de Eosinófilos/metabolismo , Proteína Básica Maior de Eosinófilos/imunologia , Feminino , Hipersensibilidade/imunologia , Proliferação de Células , Inflamação/imunologia
7.
Am J Pathol ; 193(11): 1845-1862, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37517685

RESUMO

The transcription factor forkhead box protein (FOX)-O3 is a core regulator of cellular homeostasis, stress response, and longevity. The cellular localization of FOXO3 is closely related to its function. Herein, the role of FOXO3 in cataract formation was explored. FOXO3 showed nuclear translocation in lens epithelial cells (LECs) arranged in a single layer on lens capsule tissues from both human cataract and N-methyl-N-nitrosourea (MNU)-induced rat cataract, also in MNU-injured human (H)-LEC lines. FOXO3 knockdown inhibited the MNU-induced increase in expression of genes related to cell cycle arrest (GADD45A and CCNG2) and apoptosis (BAK and TP53). H2 is highly effective in reducing oxidative impairments in nuclear DNA and mitochondria. When H2 was applied to MNU-injured HLECs, FOXO3 underwent cleavage by MAPK1 and translocated into mitochondria, thereby increasing the transcription of oxidative phosphorylation-related genes (MTCO1, MTCO2, MTND1, and MTND6) in HLECs. Furthermore, H2 mediated the translocation of FOXO3 from the nucleus to the mitochondria within the LECs of cataract capsule tissues of rats exposed to MNU. This intervention ameliorated MNU-induced cataracts in the rat model. In conclusion, there was a correlation between the localization of FOXO3 and its function in cataract formation. It was also determined that H2 protects HLECs from injury by leading FOXO3 mitochondrial translocation via MAPK1 activation. Mitochondrial FOXO3 can increase mtDNA transcription and stabilize mitochondrial function in HLECs.

8.
Stem Cells ; 41(6): 592-602, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37061809

RESUMO

Corneal alkali burns cause extensive damage not only to the cornea but also to the intraocular tissues. As an anti-inflammatory therapy, subconjunctival administration of mesenchymal stem cells (MSCs) for corneal protection after corneal alkali burn has been explored. Little evidence demonstrates the potential of subconjunctival MSCs delivery in protecting the post-burn intraocular tissues. This study aimed to evaluate the therapeutic efficacy of subconjunctival injection of human placental (hP)-MSCs in protecting against ocular destruction after the burn. hP-MSCs were subconjunctivally administered to C57/BL mice after corneal alkali burn. Western blot of iNOS and CD206 was performed to determine the M1 and M2 macrophage infiltration in the cornea. Infiltration of inflammatory cells in the anterior uvea and retina was analyzed by flow cytometry. The TUNEL assay or Western blot of Bax and Bcl2 was used to evaluate the anti-apoptotic effects of MSCs. MSCs could effectively facilitate cornea repair by suppressing inflammatory cytokines IL-1ß, MCP-1, and MMP9, and polarizing CD206 positive M2 macrophages. Anterior uveal and retinal inflammatory cytokines expression and inflammatory cell infiltration were inhibited in the MSC-treated group. Reduced TUNEL positive staining and Bax/Bcl2 ratio indicated the anti-apoptosis of MSCs. MSC-conditioned medium promoted human corneal epithelial cell proliferation and regulated LPS-stimulated inflammation in RAW 264.7 macrophages, confirming the trophic and immunoregulatory effects of MSCs. Our findings demonstrate that subconjunctival administration of MSCs exerted anti-inflammatory and anti-apoptotic effects in the cornea, anterior uvea, and retina after corneal alkali burn. This strategy may provide a new direction for preventing post-event complications after corneal alkali burn.


Assuntos
Queimaduras Químicas , Lesões da Córnea , Células-Tronco Mesenquimais , Gravidez , Camundongos , Feminino , Humanos , Animais , Queimaduras Químicas/tratamento farmacológico , Modelos Animais de Doenças , Álcalis/farmacologia , Álcalis/uso terapêutico , Proteína X Associada a bcl-2 , Placenta , Lesões da Córnea/induzido quimicamente , Lesões da Córnea/terapia , Córnea , Inflamação , Anti-Inflamatórios , Citocinas/farmacologia
9.
Stem Cells ; 41(12): 1171-1184, 2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-37659098

RESUMO

Acute-on-chronic liver failure (ACLF) is a severe disease with a high mortality. Macrophage-related inflammation plays a crucial role in ACLF development. Mesenchymal stem cells (MSCs) treatment was demonstrated to be beneficial in ACLF in our previous study; however, the underlying mechanisms remain unknown. Therefore, mouse bone marrow-derived MSCs were used to treat an ACLF mouse model or cocultured with RAW264.7/J774A.1 macrophages that were stimulated with LPS. Histological and serological parameters and survival were analyzed to evaluate efficacy. We detected changes of Mer tyrosine kinase (Mertk), JAK1/STAT6, inflammatory cytokines, and markers of macrophage polarization in vitro and in vivo. In ACLF mice, MSCs improved liver function and 48-h survival of ACLF mice and alleviated inflammatory injury by promoting M2 macrophage polarization and elevated Mertk expression levels in macrophages. This is significant, as Mertk regulates M2 macrophage polarization via the JAK1/STAT6 signaling pathway.


Assuntos
Insuficiência Hepática Crônica Agudizada , Células-Tronco Mesenquimais , Camundongos , Animais , Insuficiência Hepática Crônica Agudizada/metabolismo , Proteínas Tirosina Quinases/metabolismo , Macrófagos/metabolismo , Transdução de Sinais , Células-Tronco Mesenquimais/metabolismo , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/metabolismo
10.
Respir Res ; 25(1): 90, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355515

RESUMO

BACKGROUND: Exposure to PM2.5 has been implicated in a range of detrimental health effects, particularly affecting the respiratory system. However, the precise underlying mechanisms remain elusive. METHODS: To address this objective, we collected ambient PM2.5 and administered intranasal challenges to mice, followed by single-cell RNA sequencing (scRNA-seq) to unravel the heterogeneity of neutrophils and unveil their gene expression profiles. Flow cytometry and immunofluorescence staining were subsequently conducted to validate the obtained results. Furthermore, we assessed the phagocytic potential of neutrophils upon PM2.5 exposure using gene analysis of phagocytosis signatures and bacterial uptake assays. Additionally, we utilized a mouse pneumonia model to evaluate the susceptibility of PM2.5-exposed mice to Pseudomonas aeruginosa infection. RESULTS: Our study revealed a significant increase in neutrophil recruitment within the lungs of PM2.5-exposed mice, with subclustering of neutrophils uncovering subsets with distinct gene expression profiles. Notably, exposure to PM2.5 was associated with an expansion of PD-L1high neutrophils, which exhibited impaired phagocytic function dependent upon PD-L1 expression. Furthermore, PM2.5 exposure was found to increase the susceptibility of mice to Pseudomonas aeruginosa, due in part to increased PD-L1 expression on neutrophils. Importantly, monoclonal antibody targeting of PD-L1 significantly reduced bacterial burden, dissemination, and lung inflammation in PM2.5-exposed mice upon Pseudomonas aeruginosa infection. CONCLUSIONS: Our study suggests that PM2.5 exposure promotes expansion of PD-L1high neutrophils with impaired phagocytic function in mouse lungs, contributing to increased vulnerability to bacterial infection, and therefore targeting PD-L1 may be a therapeutic strategy for reducing the harmful effects of PM2.5 exposure on the immune system.


Assuntos
Pneumonia , Infecções por Pseudomonas , Animais , Camundongos , Neutrófilos/metabolismo , Material Particulado/toxicidade , Infecções por Pseudomonas/microbiologia , Antígeno B7-H1/metabolismo , Pulmão , Pneumonia/metabolismo , Pseudomonas aeruginosa
11.
Chemistry ; 30(11): e202303695, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38085103

RESUMO

Strained compounds constitute a highly topical area of research in chemistry. Borirene and borirane both feature a BC2 three-membered ring. They can be viewed as the structural analogues of cyclopropane and cyclopropene, where a CH2 unit of the carbonaceous counterparts is replaced with BH, respectively. Indeed, this structural variation introduces numerous intriguing aspects. For instance, borirane and borirene are both Lewis acidic due to the presence of a tricoordinate borane center. In addition, borirene is 2π aromatic according to Hückel's rule. In addition to their ability to form adducts with Lewis bases and the capacity of borirenes to act as ligands in coordination with metals, both borirenes and boriranes exhibit ring-opening reactivity due to the considerable ring strain. Under specific conditions, coordinated boriranes can even cleave two BC bonds to serve as formal borylene sources (although the reaction mechanisms are quite complex). On the other hand, recent successful syntheses of benzoborienes and their carborane-based three-dimensional analogues (also referred to as carborane-fused boriranes) have introduced novel perspectives to this field. For instance, they display excellent ring-expanding reactivity, possibly attributed to the boosted ring strain arising from the fusion of borirenes with benzene and boriranes with o-carborane. Importantly, their applications as valuable "BC2 " synthons have become increasingly evident along with the newly disclosed reactivity. Additionally, the boosted Lewis acidity of carborane-fused boriranes, thanks to the potent electron-withdrawing effect of o-carborane, combined with their readiness for ring enlargement, makes them promising candidates as electron-accepting building blocks in the construction of chemically responsive luminescent materials. This review provides a summary of the synthesis and reactivity of borirene and borirane derivatives, with the aim of encouraging the design of new borierene- and borirane-based molecules and inspiring further exploration of their potential applications.

12.
Biotechnol Bioeng ; 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39138638

RESUMO

Engineered bacteria-based cancer therapy has increasingly been considered to be a promising therapeutic strategy due to the development of synthetic biology. Wherein, engineering bacteria-mediated photodynamic therapy (PDT)-immunotherapy shows greater advantages and potential in treatment efficiency than monotherapy. However, the unsustainable regeneration of photosensitizers (PSs) and weak immune responses limit the therapeutic efficiency. Herein, we developed an engineered bacteria-based delivery system for sequential delivery of PSs and checkpoint inhibitors in cancer PDT-immunotherapy. The biosynthetic pathway of 5-aminolevulinic acid (5-ALA) was introduced into Escherichia coli, yielding a supernatant concentration of 172.19 mg/L after 10 h of growth. And another strain was endowed with the light-controllable releasement of anti-programmed cell death-ligand 1 nanobodies (anti-PD-L1). This system exhibited a collaborative effect, where PDT initiated tumor cell death and the released tumor cell fragments stimulated immunity, followed by the elimination of residual tumor cells. The tumor inhibition rate reached 74.97%, and the portion of activated T cells and inflammatory cytokines were reinforced. The results demonstrated that the engineered bacteria-based collaborative system could sequentially deliver therapeutic substance and checkpoint inhibitors, and achieve good therapeutic therapy. This paper will provide a new perspective for the cancer PDT-immunotherapy.

13.
Pharmacol Res ; 200: 107070, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38218353

RESUMO

Fibrotic hypersensitivity pneumonitis (FHP) is a fatal interstitial pulmonary disease with limited treatment options. Lung macrophages are a heterogeneous cell population that exhibit distinct subsets with divergent functions, playing pivotal roles in the progression of pulmonary fibrosis. However, the specific macrophage subpopulations and underlying mechanisms involved in the disease remain largely unexplored. In this study, a decision tree model showed that matrix metalloproteinase-14 (MMP14) had higher scores for important features in the up-regulated genes in macrophages from mice exposed to the Saccharopolyspora rectivirgula antigen (SR-Ag). Using single-cell RNA sequencing (scRNA-seq) analysis of hypersensitivity pneumonitis (HP) mice profiles, we identified MMP14high macrophage subcluster with a predominant M2 phenotype that exhibited higher activity in promoting fibroblast-to myofibroblast transition (FMT). We demonstrated that suppressing toll-like receptor 2 (TLR2) and nuclear factor kappa-B (NF-κB) could attenuate MMP14 expression and exosome secretion in macrophages stimulation with SR-Ag. The exosomes derived from MMP14-overexpressing macrophages were found to be more effective in regulating the transition of fibroblasts through exosomal MMP14. Importantly, it was observed that the transfer of MMP14-overexpressing macrophages into mice promoted lung inflammation and fibrosis induced by SR-Ag. NSC-405020 binding to the hemopexin domain (PEX) of MMP-14 ameliorated lung inflammation and fibrosis induced by SR-Ag in mice. Thus, MMP14-overexpressing macrophages may be an important mechanism contributing to the exacerbation of allergic reactions. Our results indicated that MMP14 in macrophages has the potential to be a therapeutic target for HP.


Assuntos
Alveolite Alérgica Extrínseca , Pneumonia , Fibrose Pulmonar , Camundongos , Animais , Fibrose Pulmonar/metabolismo , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 14 da Matriz/metabolismo , Alveolite Alérgica Extrínseca/metabolismo , Alveolite Alérgica Extrínseca/patologia , Macrófagos/metabolismo , Pneumonia/metabolismo , Camundongos Endogâmicos C57BL
14.
J Org Chem ; 89(5): 3010-3019, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38329891

RESUMO

A facile and novel N-heteroarenium iodide-catalyzed hydroalkoxylation of enamides has been described. The protocol provides easy access to N,O-acetals, which proved to be a versatile synthetic synthon. The hydrosulfonylation, hydroamination, and hydrophosphorylation products of enamide could be indirectly provided from N,O-acetals. The reaction mechanism was further investigated, which indicated that the hydroalkoxylation of enamides was driven by weak coordination between enamide and the contact ion pair of N-heteroarenium iodide.

15.
Pediatr Blood Cancer ; 71(9): e31158, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38970222

RESUMO

Eligible pediatric hospitals can purchase clinician-administered drugs at discounted rates through the 340B Drug Pricing Program and charge payers prices exceeding drug acquisition costs, but the magnitude of these markups is not known. In a study of newly approved oncology drugs at pediatric 340B hospitals, median negotiated prices ranged from 102% (interquartile range [IQR]: 91%-156%) of average sales price (ASP) at Phoenix Children's Hospital to 630% (IQR: 526%-630%) at Driscoll Children's Hospital. Pediatric hospitals participating in the federal 340B Drug Pricing Program can extract steep payments on new drugs from commercial insurers, though with wide variation between and within hospitals.


Assuntos
Antineoplásicos , Custos de Medicamentos , Hospitais Pediátricos , Humanos , Hospitais Pediátricos/economia , Antineoplásicos/economia , Criança , Estados Unidos , Neoplasias/tratamento farmacológico , Neoplasias/economia
16.
Arch Virol ; 169(2): 20, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38191819

RESUMO

The global impact of the COVID-19 pandemic has been substantial. Emerging evidence underscores a strong clinical connection between COVID-19 and sepsis. Numerous studies have identified the unfolded protein response (UPR) pathway as a crucial pathogenic pathway for both COVID-19 and sepsis, but it remains to be investigated whether this signaling pathway operates as a common pathogenic mechanism for both COVID-19 and sepsis. In this study, single-cell RNA-seq data and transcriptome data for COVID-19 and sepsis cases were downloaded from GEO (Gene Expression Omnibus). By analyzing the single-cell transcriptome data, we identified B cells as the critical cell subset and the UPR pathway as the critical signaling pathway. Based on the transcriptome data, a machine learning diagnostic model was then constructed using the interleaved genes of B-cell-related and UPR-pathway-related genes. We validated the diagnostic model using both internal and external datasets and found the accuracy and stability of this model to be extremely strong. Even after integrating our algorithmic model with the patient's clinical status, it continued to yield identical results, further emphasizing the reliability of this model. This study provides a novel molecular perspective on the pathogenesis of sepsis and COVID-19 at the single-cell level and suggests that these two diseases may share a common mechanism.


Assuntos
COVID-19 , Sepse , Humanos , Pandemias , Reprodutibilidade dos Testes , Sepse/genética , Resposta a Proteínas não Dobradas
17.
Exp Cell Res ; 425(1): 113537, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36858343

RESUMO

Aberrant regulation of ubiquitination is an essential fundamental process in tumors, especially intrahepatic cholangiocarcinoma (iCCA). We reported that OTUB2, an OTU deubiquitinase, is upregulated in iCCA and stabilizes the CTNNB1-ZEB1 axis, resulting in epithelial-mesenchymal transition (EMT) and iCCA metastasis. Mechanistically, OTUB2 promotes CTNNB1 expression by interacting with the E3 ligase TRAF6. OTUB2 inhibits the lysosomal degradation of CTNNB1 by interacting with TRAF6 and thus regulates the progression of iCCA through ZEB1. Clinically, high OTUB2 expression is related to increased ZEB1 expression and activity and reduced overall survival in iCCA patients. Therefore, advanced iCCA patients may benefit from drugs targeting OTUB2 and its pathway.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Fator 6 Associado a Receptor de TNF/metabolismo , Colangiocarcinoma/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/metabolismo , Enzimas Desubiquitinantes/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Tioléster Hidrolases/metabolismo
18.
J Chem Phys ; 161(10)2024 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-39248384

RESUMO

Water adsorption energy, Eads, is a key physical quantity in sustainable chemical technologies such as (photo)electrocatalytic water splitting, water desalination, and water harvesting. In many of these applications, the electrode surface is operated outside the point (potential) of zero charge, which attracts counter-ions to form the electric double layer and controls the surface properties. Here, by applying density functional theory-based finite-field molecular dynamics simulations, we have studied the effect of water adsorption energy Eads on surface acidity and the Helmholtz capacitance of BiVO4 as an example of metal oxide electrodes with weakly chemisorbed water. This allows us to establish the effect of Eads on the coordination number, the H-bond network, and the orientation of chemisorbed water by comparing an oxide series composed of BiVO4, TiO2, and SnO2. In particular, it is found that a positive correlation exists between the degree of asymmetry ΔCH in the Helmholtz capacitance and the strength of Eads. This correlation is verified and extended further to graphene-like systems with physisorbed water, where the electric double layers (EDLs) are controlled by electronic charge rather than proton charge as in the oxide series. Therefore, this work reveals a general relationship between water adsorption energy Eads and EDLs, which is relevant to both electrochemical reactivity and the electrowetting of aqueous interfaces.

19.
Cell Mol Life Sci ; 80(9): 242, 2023 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-37552373

RESUMO

Radiotherapy resistance is a major obstacle to nasopharyngeal carcinoma (NPC) therapy and contributes to tumour recurrence and metastasis. Lipid metabolism is a key regulatory mechanism in cancer biology; however, its role in NPC radiotherapy resistance remains unclear. In this study, we identified hypoxia-inducible lipid droplet-associated protein (HILPDA) as a newly discovered regulator of radioresistance that induces not only lipid droplet (LD) formation but also intracellular lipid remodelling, notably changing mitochondrial cardiolipin (CL) levels. Additionally, we found that the upregulation of CL promotes mitophagy in response to irradiation exposure. Mechanistically, HILPDA inhibits PINK1-mediated CLS1 ubiquitination and degradation. The combination of a mitophagy inhibitor and irradiation significantly increases the radiosensitivity of NPC cells. Human cancer-derived data confirmed that the HILPDA-CLS1 pathway promotes NPC radioresistance. Collectively, these findings suggest that HILPDA plays a critical role in promoting NPC radioresistance and might be targeted to overcome radiotherapeutic resistance in NPC patients in the clinic.


Assuntos
Neoplasias Nasofaríngeas , Proteínas de Neoplasias , Humanos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Lipidômica , Mitofagia , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/patologia , Proteínas de Neoplasias/genética
20.
BMC Geriatr ; 24(1): 118, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38297201

RESUMO

BACKGROUND: Fine motor skills are closely related to cognitive function. However, there is currently no comprehensive assessment of fine motor movement and how it corresponds with cognitive function. To conduct a complete assessment of fine motor and clarify the relationship between various dimensions of fine motor and cognitive function. METHODS: We conducted a cross-sectional study with 267 community-based participants aged ≥ 60 years in Beijing, China. We assessed four tests performance and gathered detailed fine motor indicators using Micro-Electro-Mechanical System (MEMS) motion capture technology. The wearable MEMS device provided us with precise fine motion metrics, while Chinese version of the Montreal Cognitive Assessment (MoCA) was used to assess cognitive function. We adopted logistic regression to analyze the relationship between fine motor movement and cognitive function. RESULTS: 129 (48.3%) of the participants had cognitive impairment. The vast majority of fine motor movements have independent linear correlations with MoCA-BJ scores. According to logistic regression analysis, completion time in the Same-pattern tapping test (OR = 1.033, 95%CI = 1.003-1.063), Completion time of non-dominant hand in the Pieces flipping test (OR = 1.006, 95%CI = 1.000-1.011), and trajectory distance of dominant hand in the Pegboard test (OR = 1.044, 95%CI = 1.010-1.068), which represents dexterity, are related to cognitive impairment. Coordination, represented by lag time between hands in the Same-pattern tapping (OR = 1.663, 95%CI = 1.131-2.444), is correlated with cognitive impairment. Coverage in the Dual-hand drawing test as an important indicator of stability is negatively correlated with cognitive function (OR = 0.709, 95%CI = 0.6501-0.959). Based on the above 5-feature model showed consistently high accuracy and sensitivity at the MoCA-BJ score (ACU = 0.80-0.87). CONCLUSIONS: The results of a comprehensive fine-motor assessment that integrates dexterity, coordination, and stability are closely related to cognitive functioning. Fine motor movement has the potential to be a reliable predictor of cognitive impairment.


Assuntos
Cognição , Disfunção Cognitiva , Humanos , Idoso , Estudos Transversais , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , China/epidemiologia , Testes de Estado Mental e Demência
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