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Histone lysine demethylases (KDMs) have been reported in various malignances, which affect transcriptional regulation of tumor suppressor or oncogenes. However, the relationship between KDMs and formation of tumor microenvironment (TME) in gastric cancer (GC) remain unclear and need to be comprehensively analyzed.In the present study, 24 KDMs were obtained and consensus molecular subtyping was performed using the "NMF" method to stratify TCGA-STAD into three clusters. The ssGSEA and CIBERSORT algorithms were employed to assess the relative infiltration levels of various cell types in the TME. The KDM_score was devised to predict patient survival outcomes and responses to both immunotherapy and chemotherapy.Three KDM genes-related molecular subtypes were Figured out in GC with distinctive clinicopathological and prognostic features. Based on the robust KDM genes-related risk_score and nomogram, established in our work, GC patients' clinical outcome can be well predicted. Furthermore, low KDM genes-related risk_score exhibited the more effective response to immunotherapy and chemotherapy.This study characterized three KDM genes-related TME pattern with unique immune infiltration and prognosis by comprehensively analyses of transcriptomic profiling. Risk_score was also built to help clinicians decide personalized anticancer treatment for GC patients, including in prediction of immunotherapy and chemotherapy response for patients.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Transcriptoma , Microambiente Tumoral/genética , Oncogenes , Imunoterapia , PrognósticoRESUMO
Traffic sign detection is an important part of environment-aware technology and has great potential in the field of intelligent transportation. In recent years, deep learning has been widely used in the field of traffic sign detection, achieving excellent performance. Due to the complex traffic environment, recognizing and detecting traffic signs is still a challenging project. In this paper, a model with global feature extraction capabilities and a multi-branch lightweight detection head is proposed to increase the detection accuracy of small traffic signs. First, a global feature extraction module is proposed to enhance the ability of extracting features and capturing the correlation within the features through self-attention mechanism. Second, a new, lightweight parallel decoupled detection head is proposed to suppress redundant features and separate the output of the regression task from the classification task. Finally, we employ a series of data enhancements to enrich the context of the dataset and improve the robustness of the network. We conducted a large number of experiments to verify the effectiveness of the proposed algorithm. The accuracy of the proposed algorithm is 86.3%, the recall is 82.1%, the mAP@0.5 is 86.5% and the mAP@0.5:0.95 is 65.6% in TT100K dataset, while the number of frames transmitted per second is stable at 73, which meets the requirement of real-time detection.
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Chronical hyperuricemia, a severe metabolic disease characterized by increased serum uric acid, urea nitrogen, and creatinine, has a positive correlation with the risks of gouty arthritis, diabetes, hypertension, and kidney damage. Abnormal purine metabolism and reduced uric acid excretion are the major causes of hyperuricemia, which, thus, points to a potential strategy of preventing from or delaying the progress of hyperuricemia-related diseases and its complications by effectively controlling the serum uric acid level. Increasing evidence has revealed that Chinese medicines alleviate hyperuricemia through regulating intestinal flora, which plays a pivotal role in regulating metabolites, including uric acid level. The disease treatment with traditional Chinese medicine is based on syndrome differentiation, and Chinese medicines often have multiple effects and a wide range of targets. In this review, we summarized the anti-hyperuricemia effects and mechanisms of active compounds in Chinese medicines, single Chinese medicinal herbs, and Chinese medicinal prescriptions in regulating the uric acid level via intestinal flora and metabolites, which will be helpful for further study and application of Chinese medicines in hyperuricemia treatment.
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Artrite Gotosa , Microbioma Gastrointestinal , Hiperuricemia , China , Humanos , Hiperuricemia/tratamento farmacológico , Ácido ÚricoRESUMO
Objective: Inflammation-mediated thyroid cell dysfunction and apoptosis increases the like-hood of hypothyroidism.Aim: Our aim in the present study is to explore the role of mitochondrial elongation factor 1 (Mief1) in thyroid cell dysfunction induced by TNFα.Materials and methods: Different doses of TNFα were used to incubate with thyroid cells in vitro. The survival rate, apoptotic index and proliferation capacity of thyroid cells were measured. Cellular energy metabolism and endoplasmic reticulum function related to protein synthesis were detected.Results: In response to TNFα treatment, the levels of Mief1 were increased, coinciding with a drop in the viability of thyroid cells in vitro. Loss of Mief1 attenuates TNFα-induced cell death through reducing the ratio of cell apoptosis. Further, we found that Mief1 deletion reversed cell energy metabolism and this effect was attributable to mitochondrial protection. Mief1 knockdown sustained mitochondrial membrane potential and reduced mitochondrial ROS overproduction. In addition, Mief1 knockdown also reduced endoplasmic reticulum stress, as evidenced by decreased levels of Chop and Caspase-12. Finally, our data verified that TNFα treatment inhibited the activity of AMPK-PTEN pathway whereas Mief1 deletion reversed the activity of AMPK and thus promoted the upregulation of PTEN. However, inhibition of AMPK-PTEN pathways could abolish the beneficial effects exerted by Mief1 deletion on thyroid cells damage and dysfunction.Conclusions: Altogether, our data indicate that immune abnormality-mediated thyroid cell dysfunction and death are alleviated by Mief1 deletion possible driven through reversing the activity of AMPK-PTEN pathways.
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Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose , PTEN Fosfo-Hidrolase/metabolismo , Fatores de Alongamento de Peptídeos/metabolismo , Transdução de Sinais , Glândula Tireoide/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Deleção de Genes , Substâncias Protetoras/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
This work presents a magnetic-driven deterministic lateral displacement (m-DLD) microfluidic device. A permanent magnet located at the outlet of the microchannel was used to generate the driving force. Two stages of mirrored round micropillar array were designed for the separation of magnetic beads with three different sizes in turn. The effects of the forcing angle and the inlet width of the micropillar array on the separating efficiency were studied. The m-DLD device with optimal structure parameters shows that the separating efficiencies for the 10 µm, 20 µm and 40 µm magnetic beads are 87%, 89% and 94%, respectively. Furthermore, this m-DLD device was used for antibody recognition and separation among a mixture solution of antibodies. The trajectories of different kinds of magnetic beads coupled with different antigens showed that the m-DLD device could realize a simple and low-cost diagnostic test.
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Anticorpos , Dispositivos Lab-On-A-Chip , Técnicas Analíticas Microfluídicas , Anticorpos/análise , Fenômenos Magnéticos , Magnetismo , ImãsRESUMO
BACKGROUND: Imbalances in circulating T lymphocytes play critical roles in the pathogenesis of hypertension-mediated inflammation. Connexins (Cxs) in immune cells are involved in the maintenance of homeostasis of T lymphocytes. However, the association between Cxs in peripheral blood T lymphocytes and hypertension-mediated inflammation remains unknown. This study was designed to investigate the role of Cxs in T lymphocytes in hypertension-mediated inflammation in spontaneously hypertensive rats (SHRs). METHODS: The systolic blood pressure (SBP) in Wistar-Kyoto (WKY) rats and SHRs was monitored using the tail-cuff method. The serum cytokine level was determined using ELISA. The proportions of different T-lymphocyte subtypes in the peripheral blood, the expressions of Cx40/Cx43 in the T-cell subtypes, and the gap junctional intracellular communication (GJIC) of peripheral blood lymphocytes were measured using flow cytometry (FC). The accumulations of Cx40/Cx43 at the plasma membrane and/or in the cytoplasm were determined using immunofluorescence staining. The in vitro mRNA levels of cytokines and GJIC in the peripheral blood lymphocytes were respectively examined using real-time PCR and FC after treatment with Gap27 and/or concanavalin A (Con A). RESULTS: The percentage of CD4+ T cells and the CD4+/CD8+ ratio were high, and the accumulation or expressions of Cx40/Cx43 in the peripheral blood lymphocytes in SHRs were higher than in those of WKY rats. The percentage of CD8+ and CD4+CD25+ T cells was lower in SHRs. The serum levels of IL-2, IL-4 and IL-6 from SHRs were higher than those from WKY rats, and the serum levels of IL-2 and IL-6 positively correlated with the expression of Cx40/Cx43 in the peripheral blood T lymphocytes from SHRs. The peripheral blood lymphocytes of SHRs exhibited enhanced GJIC. Cx43-based channel inhibition, which was mediated by Gap27, remarkably reduced GJIC in lymphocytes, and suppressed IL-2 and IL-6 mRNA expressions in Con A stimulated peripheral blood lymphocytes. CONCLUSIONS: Our data suggest that Cxs may be involved in the regulation of T-lymphocyte homeostasis and the production of cytokines. A clear association was found between alterations in Cxs expression or in Cx43-based GJIC and hypertension-mediated inflammation.
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Junções Comunicantes/patologia , Hipertensão/complicações , Hipertensão/patologia , Inflamação/etiologia , Inflamação/patologia , Linfócitos/patologia , Animais , Relação CD4-CD8 , Conexina 43/análise , Conexina 43/imunologia , Conexinas/análise , Conexinas/imunologia , Junções Comunicantes/imunologia , Hipertensão/sangue , Hipertensão/imunologia , Inflamação/sangue , Inflamação/imunologia , Interleucinas/sangue , Interleucinas/imunologia , Linfócitos/imunologia , Masculino , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Proteína alfa-5 de Junções ComunicantesRESUMO
BACKGROUND: Defects in programmed cell death, or apoptosis, are a hallmark of cancer. The anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins, including BCL-2, BCL-X(L), and MCL-1 have been characterized as key survival factors in multiple cancer types. Because cancer types with BCL2 and MCL1 amplification are more prone to inhibition of their respectively encoded proteins, we hypothesized that cancers with a significant frequency of BCL2L1 amplification would have greater dependency on BCL-X(L) for survival. METHODS: To identify tumor subtypes that have significant frequency of BCL2L1 amplification, we performed data mining using The Cancer Genome Atlas (TCGA) database. We then assessed the dependency on BCL-X(L) in a panel of cell lines using a selective and potent BCL-X(L) inhibitor, A-1155463, and BCL2L1 siRNA. Mechanistic studies on the role of BCL-X(L) were further undertaken via a variety of genetic manipulations. RESULTS: We identified colorectal cancer as having the highest frequency of BCL2L1 amplification across all tumor types examined. Colorectal cancer cell lines with BCL2L1 copy number >3 were more sensitive to A-1155463. Consistently, cell lines with high expression of BCL-XL and NOXA, a pro-apoptotic protein that antagonizes MCL-1 activity were sensitive to A-1155463. Silencing the expression of BCL-X(L) via siRNA killed the cell lines that were sensitive to A-1155463 while having little effect on lines that were resistant. Furthermore, silencing the expression of MCL-1 in resistant cell lines conferred sensitivity to A-1155463, whereas silencing NOXA abrogated sensitivity. CONCLUSIONS: This work demonstrates the utility of characterizing frequent genomic alterations to identify cancer survival genes. In addition, these studies demonstrate the utility of the highly potent and selective compound A-1155463 for investigating the role of BCL-X(L) in mediating the survival of specific tumor types, and indicate that BCL-X(L) inhibition could be an effective treatment for colorectal tumors with high BCL-X(L) and NOXA expression.
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Neoplasias Colorretais/genética , Genômica , Proteína bcl-X/genética , Benzotiazóis/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Análise por Conglomerados , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Isoquinolinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/metabolismoRESUMO
BACKGROUND: Evasion of apoptosis is a hallmark of cancer cells. One mechanism to deregulate the apoptotic pathway is by upregulation of the anti-apoptotic Bcl-2 family members. Navitoclax (ABT-263) is a Bcl-2/Bcl-xL inhibitor that restores the ability of cancer cells to undergo apoptosis. METHODS: In this study we performed a high-throughput screen with 640 FDA-approved drugs to identify potential therapeutic combinations with navitoclax in a non-small cell lung cancer (NSCLC) cell line. RESULTS: Other than a panel of cancer compounds such as doxorubicin, camptothecin, and docetaxel, four antihelminthic compounds (benzimidazoles) potentiated navitoclax activity. Treatment with benzimidazoles led to induction of the pro-apoptotic protein Noxa at the mRNA and protein level. Noxa binds and antagonizes antiapoptotic protein Mcl-1. siRNA-mediated knock-down of Noxa completely rescued benzimidazole-potentiated navitoclax activity. In addition, inhibiting caspase 3 and 9 partially rescued benzimidazole-potentiated navitoclax activity. CONCLUSIONS: We have identified compounds and mechanisms which potentiate navitoclax activity in lung cancer cell lines. Further validation of the benzimidazole-potentiated navitoclax effect in vivo is required to evaluate the potential for translating this observation into clinical benefit.
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In broiler chickens, heat stress disrupts nutrient digestion and absorption. However, the underlying molecular mechanism is not clearly understood. Hence, to investigate the effects of high ambient temperatures on the expression levels of nutrient transporters in the jejunum of broiler chickens, seventy-two 35-day-old male broiler chickens with similar body weights were randomly allocated into two groups: control (24 ± 1 °C) and heat-stressed (32 ± 1 °C). The chickens in the heat-stressed group were exposed to 10 h of heat daily from 08:00 to 18:00 and then raised at 24 ± 1 °C. The rectal temperature and feed intake of the chickens were recorded daily. After 7 days, nine chickens per group were sacrificed by exsanguination, and the jejunum was collected. The results show that heat exposure significantly decreased the feed intake and increased the rectal temperature of the broiler chickens. The plasma concentrations of uric acid and triglyceride significantly increased and decreased, respectively, in the heat-stressed group. No significant differences in the levels of plasma glucose, total amino acids, and very low-density lipoprotein were observed between the heat-stressed and control groups. However, the plasma concentration of glucose tended to be higher (P = 0.09) in the heat-stressed group than in the control group. Heat exposure did not significantly affect the mRNA levels of Na(+)-dependent glucose transporter 1 and amino acid transporters y + LAT1, CAT1, r-BAT, and PePT-1. However, the expression levels of GLUT-2, FABP1, and CD36 were significantly decreased by heat exposure. The results of this study provide new insights into the mechanisms by which heat stress affects nutrient absorption in broiler chickens. Our findings suggest that periodic heat exposure might alter the jejunal glucose and lipid transport rather than amino acid transport. However, intestinal epithelial damage and cell loss should be considered when interpreting the effects of heat stress on the expression of intestinal transporters.
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Proteínas de Transporte/genética , Galinhas , Transtornos de Estresse por Calor/genética , Jejuno/metabolismo , Aminoácidos/sangue , Animais , Glicemia/análise , Temperatura Corporal , Galinhas/sangue , Galinhas/genética , Galinhas/metabolismo , LDL-Colesterol/sangue , Corticosterona/sangue , Ingestão de Alimentos , Expressão Gênica , Transtornos de Estresse por Calor/sangue , Transtornos de Estresse por Calor/metabolismo , Transtornos de Estresse por Calor/veterinária , Masculino , Triglicerídeos/sangue , Ácido Úrico/sangueRESUMO
Apoptosis is regulated by the BCL-2 family of proteins, which is comprised of both pro-death and pro-survival members. Evasion of apoptosis is a hallmark of malignant cells. One way in which cancer cells achieve this evasion is thru overexpression of the pro-survival members of the BCL-2 family. Overexpression of MCL-1, a pro-survival protein, has been shown to be a resistance factor for Navitoclax, a potent inhibitor of BCL-2 and BCL-XL. Here we describe the use of fragment screening methods and structural biology to drive the discovery of novel MCL-1 inhibitors from two distinct structural classes. Specifically, cores derived from a biphenyl sulfonamide and salicylic acid were uncovered in an NMR-based fragment screen and elaborated using high throughput analog synthesis. This culminated in the discovery of selective and potent inhibitors of MCL-1 that may serve as promising leads for medicinal chemistry optimization efforts.
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Desenho de Fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Sítios de Ligação , Compostos de Bifenilo/química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Ácido Salicílico/química , Ácido Salicílico/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismoRESUMO
Objective.Transcranial magnetic stimulation is a non-invasive brain stimulation technique that changes the activity of the cerebral cortex. Contralesional continuous theta burst stimulation (cTBS) has been proposed and verified beneficial to stroke motor recovery. However, the underlying mechanism is still unclear.Approach.20 healthy right-handed subjects were recruited in this study, receiving real-cTBS over their left primary motor cortex or sham-cTBS. We designed the finger tapping task (FTT) before and after stimulation and recorded the accuracy and reaction time (RT) of the task. The electroencephalogram and surface electromyogram signals were recorded during the left finger pinching task (FPT) before and after stimulation. We calculated cortico-muscular coherence (CMC) in the contralateral hemisphere and cortico-cortical coherence (CCC) in the bilateral hemisphere. The two-way repeated measures analysis of variance was used to analyze the effect of cTBS.Main results.In the FTT, there was a significant main effect of 'time' on RT (F(1, 38) = 24.739,p< 0.001). In the FPT, the results showed that there was a significant interaction effect on the CMC peak and area in the beta band (peak:F(1, 38) = 8.562,p= 0.006; area:F(1, 38) = 5.273,p= 0.027), on the CCC peak in the alpha band (F(1, 38) = 4.815,p= 0.034) and area in the beta band (F(1, 38) = 4.822,p= 0.034). The post hoc tests showed that the CMC peak (W= 20,p= 0.002), the CMC area (W= 13,p= 0.003) and the CCC peak (t= -2.696,p= 0.014) increased significantly after real-cTBS. However, there was no significant decrease or increase after sham-cTBS.Significance.Our study found that cTBS can improve CMC of contralateral hemisphere and CCC of bilateral hemisphere, indicating that cTBS can strengthen cortico-muscular and cortico-cortical coupling.
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Córtex Motor , Acidente Vascular Cerebral , Humanos , Córtex Motor/fisiologia , Estimulação Magnética Transcraniana/métodos , Eletroencefalografia , Eletromiografia , Potencial Evocado Motor/fisiologiaRESUMO
AIMS: We investigated whether human umbilical cord mesenchymal stem cell (hUC-MSC)-derived exosomes bear therapeutic potential against lipopolysaccharide (LPS)-induced neuroinflammation. METHODS: Exosomes were isolated from hUC-MSC supernatant by ultra-high-speed centrifugation and characterized by transmission electron microscopy and western blotting. Inflammatory responses were induced by LPS in BV-2 cells, primary microglial cultures, and C57BL/6J mice. H2 O2 was also used to induce inflammation and oxidative stress in BV-2 cells. The effects of hUC-MSC-derived exosomes on inflammatory cytokine expression, oxidative stress, and microglia polarization were studied by immunofluorescence and western blotting. RESULTS: Treatment with hUC-MSC-derived exosomes significantly decreased the LPS- or H2 O2 -induced oxidative stress and expression of pro-inflammatory cytokines (IL-6 and TNF-α) in vitro, while promoting an anti-inflammatory (classical M2) phenotype in an LPS-treated mouse model. Mechanistically, the exosomes increased the NRF2 levels and inhibited the LPS-induced NF-κB p65 phosphorylation and NLRP3 inflammasome activation. In contrast, the reactive oxygen species scavenger NAC and NF-κB inhibitor BAY 11-7082 also inhibited the LPS-induced NLRP3 inflammasome activation and switched to the classical M2 phenotype. Treatment with the NRF2 inhibitor ML385 abolished the anti-inflammatory and anti-oxidative effects of the exosomes. CONCLUSION: hUC-MSC-derived exosomes ameliorated LPS/H2 O2 -induced neuroinflammation and oxidative stress by inhibiting the microglial NRF2/NF-κB/NLRP3 signaling pathway.
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Exossomos , Células-Tronco Mesenquimais , Animais , Humanos , Camundongos , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Exossomos/metabolismo , Inflamassomos/metabolismo , Lipopolissacarídeos/toxicidade , Células-Tronco Mesenquimais/metabolismo , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo , Cordão Umbilical/metabolismoRESUMO
Microplastics (MPs) and fouling organisms are prevalent in oceans worldwide. The study aims to investigate the pollution characteristics of MPs in fouling organisms. The study found significant inter-specific differences in the MPs abundance, while the length of MPs is consistent. The average number of MPs in N. exigua is 0.00 ± 0.00. There is a correlation between MPs abundance and weight in sessile group, while gastropods don't. Direct observation has demonstrated that the radulae of N. radula can envelop MPs. Fiber and blue are the predominant forms and colors of MPs found in fouling organisms. It is noteworthy that all film and fragment MPs observed were of a blue hue and had a size limitation of 500 µm. The characteristics of MPs between sessile organisms are more similar than those between gastropods. This study has improved our understanding of the pollution characteristics of MPs in fouling organisms, specifically gastropods.
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Microplásticos , Poluentes Químicos da Água , Plásticos , Baías , Poluentes Químicos da Água/análise , Monitoramento Ambiental , Aquicultura , ChinaRESUMO
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is one of the fundamental mechanisms of the body's defense, which responds to the abnormal presence of double-stranded DNA in the cytoplasm to establish an effective natural immune response. In addition to detecting microbial infections, the cGAS pathway may be triggered by any cytoplasmic DNA, which is absent from the normal cytoplasm, and only conditions such as senescence and mitochondrial stress can lead to its leakage and cause sterile inflammation. A growing body of research has shown that the cGAS-STING pathway is strongly associated with sterile inflammation. In this study, we reviewed the regulatory mechanisms and biological functions of the cGAS-STING pathway through its involvement in aseptic inflammation in liver disease, kidney disease, and cellular senescence.
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Senescência Celular , Nefropatias , Hepatopatias , Proteínas de Membrana , Nucleotidiltransferases , Transdução de Sinais , Humanos , Nucleotidiltransferases/metabolismo , Senescência Celular/imunologia , Proteínas de Membrana/metabolismo , Nefropatias/imunologia , Nefropatias/metabolismo , Nefropatias/patologia , Animais , Hepatopatias/imunologia , Hepatopatias/metabolismoRESUMO
Although breakthroughs have been achieved with immune checkpoint inhibitors (ICI) therapy, some tumors do not respond to those therapies due to primary or acquired resistance. GARP, a type I transmembrane cell surface docking receptor mediating latent transforming growth factor-ß (TGF-ß) and abundantly expressed on regulatory T lymphocytes and platelets, is a potential target to render these tumors responsive to ICI therapy, and enhancing anti-tumor response especially combined with ICI. To facilitate these research efforts, we developed humanized mouse models expressing humanized GARP (hGARP) instead of their mouse counterparts, enabling in vivo assessment of GARP-targeting agents. We created GARP-humanized mice by replacing the mouse Garp gene with its human homolog. Then, comprehensive experiments, including expression analysis, immunophenotyping, functional assessments, and pharmacologic assays, were performed to characterize the mouse model accurately. The Tregs and platelets in the B-hGARP mice (The letter B is the first letter of the company's English name, Biocytogen.) expressed human GARP, without expression of mouse GARP. Similar T, B, NK, DCs, monocytes and macrophages frequencies were identified in the spleen and blood of B-hGARP and WT mice, indicating that the humanization of GARP did not change the distribution of immune cell in these compartments. When combined with anti-PD-1, monoclonal antibodies (mAbs) against GARP/TGF-ß1 complexes demonstrated enhanced in vivo anti-tumor activity compared to monotherapy with either agent. The novel hGARP model serves as a valuable tool for evaluating human GARP-targeting antibodies in immuno-oncology, which may enable preclinical studies to assess and validate new therapeutics targeting GARP. Furthermore, intercrosses of this model with ICI humanized models could facilitate the evaluation of combination therapies.
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Anticorpos Monoclonais , Proteínas de Membrana , Neoplasias , Fator de Crescimento Transformador beta , Animais , Humanos , Camundongos , Anticorpos Monoclonais/uso terapêutico , Plaquetas/metabolismo , Modelos Animais de Doenças , Neoplasias/terapia , Linfócitos T Reguladores , Fator de Crescimento Transformador beta/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos Endogâmicos C57BL , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
Motor impairment after stroke is generally caused by damage to the neural networks that control movement. Corticomuscular coherence (CMC) is a valid method to analyze the functional connectivity of the corticospinal pathway between the cerebral cortex and muscles. However, current studies on CMC in stroke patients only focused on the upper limbs. The functional connectivity between the brain and lower limbs in stroke patients has not been well studied. Therefore, twelve stroke patients and fifteen healthy controls were recruited and their electroencephalogram (EEG) and electromyogram (EMG) of Tibialis Anterior (TA), Lateral Gastrocnemius (LG) and Medial Gastrocnemius (MG) during unilateral static ankle dorsiflexion were recorded. We found the mean beta and gamma CMC values of Cz electrode of stroke patients were significantly lower than those of healthy controls (p < 0.05). The brain topography showed significant coherence in the center of the cerebral cortex in healthy controls, while there was no significant coherence in stroke patients. For clinical assessment, there was a significant positive correlation between CMC and lower limb Fugl-Meyer Assessment (FMA) for Cz-TA in beta band (r = 0.6296, p = 0.0282), Cz-LG in beta band (r = 0.6816, p = 0.0147), and Cz-MG in gamma band (r = 0.6194, p = 0.0317). A multiple linear regression model was established between CMC and lower limb FMA ( R2 = 0.6600 , p = 0.0280). Therefore, CMC between the cerebral cortex and lower limb muscles may be used as a new rehabilitation assessment biomarker in stroke.
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Tornozelo , Acidente Vascular Cerebral , Humanos , Tornozelo/fisiologia , Músculo Esquelético/fisiologia , Eletromiografia/métodos , EletroencefalografiaRESUMO
In recent years, neural architecture search (NAS) methods have been proposed for the automatic generation of task-oriented network architecture in image classification. However, the architectures obtained by existing NAS approaches are optimized only for classification performance and do not adapt to devices with limited computational resources. To address this challenge, we propose a neural network architecture search algorithm aiming to simultaneously improve the network performance and reduce the network complexity. The proposed framework automatically builds the network architecture at two stages: block-level search and network-level search. At the stage of block-level search, a gradient-based relaxation method is proposed, using an enhanced gradient to design high-performance and low-complexity blocks. At the stage of network-level search, an evolutionary multiobjective algorithm is utilized to complete the automatic design from blocks to the target network. The experimental results demonstrate that our method outperforms all evaluated hand-crafted networks in image classification, with an error rate of 3.18% on Canadian Institute for Advanced Research (CIFAR10) and an error rate of 19.16% on CIFAR100, both at network parameter size less than 1 M. Obviously, compared with other NAS methods, our method offers a tremendous reduction in designed network architecture parameters.
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Contralaterally controlled functional electrical stimulation (CCFES) is a rehabilitation method whose efficacy has been proved in several randomized controlled trials. Symmetrical CCFES (S-CCFES) and asymmetrical CCFES (A-CCFES) are two basic strategies of CCFES. The cortical response can reflect the instant efficacy of CCFES. However, it is still unclear of the difference on cortical responses of these different strategies. Therefore, the aim of the study is to determine what cortical response CCFES may engage. Thirteen stroke survivors were recruited to complete three training sessions with S-CCFES, A-CCFES and unilateral functional electrical stimulation (U-FES), in which the affected arm was stimulated. The electroencephalogram (EEG) signals were recorded during the experiment. The event-related desynchronization (ERD) value of stimulation-induced EEG and phase synchronization index (PSI) for resting EEG were calculated and compared in different tasks. We found that S-CCFES induced significantly stronger ERD at affected MAI(motor area of interest) in alpha-rhythm (8-15Hz), which indicated stronger cortical activity. Meanwhile, S-CCFES also increased intensity of cortical synchronization within the affected hemisphere and between hemispheres, and the significantly increased PSI occurred in a wider area after S-CCFES. Our results suggested that S-CCFES could enhance cortical activity during stimulation and cortical synchronization after stimulation in stroke survivors. S-CCFES seems to have better prospects for stroke recovery.
Assuntos
Terapia por Estimulação Elétrica , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Humanos , Reabilitação do Acidente Vascular Cerebral/métodos , Terapia por Estimulação Elétrica/métodos , Estimulação Elétrica/métodos , Eletroencefalografia , Sincronização CorticalRESUMO
We investigated the effect of eldecalcitol on disuse muscle atrophy. C57BL/6J male mice aged 6 weeks were randomly assigned to control, tail suspension (TS), and TS-eldecalcitol-treated groups and were injected intraperitoneally twice a week with either vehicle (control and TS) or eldecalcitol at 3.5 or 5 ng for 3 weeks. Grip strength and muscle weights of the gastrocnemius (GAS), tibialis anterior (TA), and soleus (SOL) were determined. Oxidative stress was evaluated by malondialdehyde, superoxide dismutase, glutathione peroxidase, and catalase. Bone microarchitecture was analyzed using microcomputed tomography. The effect of eldecalcitol on C2C12 myoblasts was analyzed by measuring myofibrillar protein MHC and the atrophy markers Atrogin-1 and MuRF-1 using immunofluorescence. The influence of eldecalcitol on NF-κB signaling pathway and vitamin D receptor (VDR) was assessed through immunofluorescence, (co)-immunoprecipitation, and VDR knockdown studies. Eldecalcitol increased grip strength (P < 0.01) and restored muscle loss in GAS, TA, and SOL (P < 0.05 to P < 0.001) induced by TS. An improvement was noted in bone mineral density and bone architecture in the eldecalcitol group. The impaired oxidative defense system was restored by eldecalcitol (P < 0.05 to P < 0.01 vs. TS). Eldecalcitol (10 nM) significantly inhibited the expression of MuRF-1 (P < 0.001) and Atrogin-1 (P < 0.01), increased the diameter of myotubes (P < 0.05), inhibited the expression of P65 and P52 components of NF-κB and P65 nuclear location, thereby inhibiting NF-κB signaling. Eldecalcitol promoted VDR binding to P65 and P52. VDR signaling is required for eldecalcitol-mediated anti-atrophy effects. In conclusion, eldecalcitol exerted its beneficial effects on disuse-induced muscle atrophy via NF-κB inhibition.
Assuntos
NF-kappa B , Osteoporose , Camundongos , Masculino , Animais , NF-kappa B/metabolismo , Microtomografia por Raio-X , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Transdução de Sinais , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/etiologia , Atrofia Muscular/prevenção & controle , Osteoporose/metabolismo , Osteoporose/patologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Panax quinquefolius Linn. is one of the most valuable herbal medicine in the world for its broad health benefits, including anti-diabetes. Ginsenoside Rb1, the principal active constituent of Panax quinquefolius Linn., could attenuate insulin resistance and metabolic disorders. The dysfunction of gut microbiota and fecal metabolites plays an important role in the pathogenesis of Type 2 Diabetes mellitus (T2DM). However, whether ginsenoside Rb1's hypoglycemic effect is related to gut microbiota remains elusive. AIM OF THE STUDY: Our study aimed to explore the insulin-sensitizing and anti-diabetic effects of ginsenoside Rb1 as well as the underlying mechanisms. MATERIALS AND METHODS: The T2DM model were established by high fat diet (HFD)-induced Kkay mice. The anti-diabetic effect of ginsenoside Rb1 (200 mg/kg/day) was evaluated by random blood glucose (RBG), fasting blood glucose (FBG), glucose tolerance test (OGTT), serum insulin level, insulin resistance index (HOMA-IR), pancreatic histology analysis, liver indexes, total triglyceride (TG) and total cholesterol (TC). Subsequently, 16S rRNA sequencing and LC-MS-based untargeted metabolomics were applied to characterize the microbiome and metabolites profile in HFD-induced Kkay mice, respectively. Finally, antibiotic treatment was used to validate the potential mechanism of ginsenoside Rb1 by modulating gut microbiota. RESULTS: Our results showed that ginsenoside Rb1 reduced blood glucose, OGTT, serum insulin level, HOMA-IR, liver indexes as well as pancreatic injury. In addition, the ginsenoside Rb1 reversed the gut microbiota dysbiosis in diabetic Kkay mice, as indicated by the elevated abundance of Parasutterella, decreased population of Alistipes, f_Prevotellaceae_unclassified, Odoribacter, Anaeroplasma. Moreover, ginsenoside Rb1 altered free fatty acid (FFA) levels in fecal metabolites, such as decreased the level of α-linolenic acid, 13-OxoODE, oleic acid, 13-HODE, arachidonic acid, palmitic acid, stearic acid, while increased the level of PC (14:0/22:1(13Z)) and PC (16:0/16:0). Notably, ginsenoside Rb1 failed to improve HFD-induced diabetes in Kkay mice with antibiotics intervention. CONCLUSION: These findings suggested that ginsenoside Rb1 may serve as a potential prebiotic agent to modulate specific gut microbes and related metabolites, which play essential roles in diabetes-associated metabolic disorders and insulin resistance.