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Ovarian cancer is one of the most common gynecological tumors worldwide. Despite the availability of multiple treatments for ovarian cancer, its resistance to chemotherapy remains a significant challenge. miRNAs play crucial roles in the initiation and progression of cancer by affecting processes such as differentiation, proliferation, and chemoresistance. According to microarray and qPCR analyses, miR-7704 is significantly downregulated in cisplatin-resistant cells compared to parental cells. In this study, we found that miR-7704 inhibited the proliferation and promoted cisplatin sensitivity of ovarian cancer cells in vitro and in vivo. Moreover, ectopic expression of miR-7704 had the same effect as IL2RB knockdown. Further mechanistic studies revealed that miR-7704 played an inhibitory role by regulating IL2RB expression to inactivate the AKT signaling pathway. Furthermore, IL2RB reversed the miR-7704 mediated resistance to cisplatin in ovarian cancer. Based on these findings, miR-7704 and IL2RB show the potential as novel therapeutic targets for ovarian cancer.
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MicroRNAs , Neoplasias Ovarianas , Feminino , Humanos , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Retroalimentação , Regulação Neoplásica da Expressão Gênica , Subunidade beta de Receptor de Interleucina-2/metabolismo , Subunidade beta de Receptor de Interleucina-2/farmacologia , Subunidade beta de Receptor de Interleucina-2/uso terapêutico , MicroRNAs/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
BACKGROUND: Colon cancer is a common and highly malignant tumor. Its incidence is increasing rapidly with poor prognosis. At present, immunotherapy is a rapidly developing treatment for colon cancer. The aim of this study was to construct a prognostic risk model based on immune genes for early diagnosis and accurate prognostic prediction of colon cancer. METHODS: Transcriptome data and clinical data were downloaded from the cancer Genome Atlas database. Immunity genes were obtained from ImmPort database. The differentially expressed transcription factors (TFs) were obtained from Cistrome database. Differentially expressed (DE) immune genes were identified in 473 cases of colon cancer and 41 cases of normal adjacent tissues. An immune-related prognostic model of colon cancer was established and its clinical applicability was verified. Among 318 tumor-related transcription factors, differentially expressed transcription factors were finally obtained, and a regulatory network was constructed according to the up-down regulatory relationship. RESULTS: A total of 477 DE immune genes (180 up-regulated and 297 down-regulated) were detected. We developed and validated twelve immune gene models for colon cancer, including SLC10A2, FABP4, FGF2, CCL28, IGKV1-6, IGLV6-57, ESM1, UCN, UTS2, VIP, IL1RL2, NGFR. The model was proved to be an independent prognostic variable with good prognostic ability. A total of 68 DE TFs (40 up-regulated and 23 down-regulated) were obtained. The regulation network between TF and immune genes was plotted by using TF as source node and immune genes as target node. In addition, Macrophage, Myeloid Dendritic cell and CD4+ T cell increased with the increase of risk score. CONCLUSION: We developed and validated twelve immune gene models for colon cancer, including SLC10A2, FABP4, FGF2, CCL28, IGKV1-6, IGLV6-57, ESM1, UCN, UTS2, VIP, IL1RL2, NGFR. This model can be used as a tool variable to predict the prognosis of colon cancer.
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Neoplasias do Colo , Microambiente Tumoral , Humanos , Prognóstico , Microambiente Tumoral/genética , Fator 2 de Crescimento de Fibroblastos , Neoplasias do Colo/genética , Bases de Dados FactuaisRESUMO
BACKGROUND: The advantages of parenchymal-sparing resection (PSR) over anatomic resection (AR) of colorectal liver metastases (CRLM) remain controversial. Here, we aim to evaluate their safety and efficacy. METHODS: A systematic review and meta-analysis of short-term perioperative outcomes and long-term oncological outcomes for PSR and AR were performed by searching Pubmed, Embase, the Cochrane Library and Web of Science databases. RESULTS: Twenty-two studies were considered eligible (totally 7228 patients: AR, n = 3154 (43.6%) vs. PSR, n = 4074 (56.4%)). Overall survival (OS, HR = 1.08, 95% CI: 0.95-1.22, P = 0.245) and disease-free survival (DFS, HR = 1.09, 95% CI: 0.94-1.28, P = 0.259) were comparable between the two groups. There were no significant differences in 3-year OS, 5-year OS, 3-year DFS, 5-year DFS, 3-year liver recurrence-free survival (liver-RFS) and 5-year liver-RFS. In terms of perioperative outcome, patients undergoing AR surgery were associated with prolonged operation time (WMD = 51.48 min, 95% CI: 29.03-73.93, P < 0.001), higher amount of blood loss (WMD = 189.92 ml, 95% CI: 21.39-358.45, P = 0.027), increased intraoperative blood transfusion rate (RR = 2.24, 95% CI: 1.54-3.26, P < 0.001), prolonged hospital stay (WMD = 1.00 day, 95% CI: 0.34-1.67, P = 0.003), postoperative complications (RR = 2.28, 95% CI: 1.88-2.77, P < 0.001), and 90-day mortality (RR = 3.08, 95% CI: 1.88-5.03, P < 0.001). While PSR surgery was associated with positive resection margins (RR = 0.77, 95% CI: 0.61-0.97, P = 0.024), intrahepatic recurrence (RR = 0.90, 95% CI: 0.82-0.98, P = 0.021) and repeat hepatectomy (RR = 0.64, 95% CI: 0.55-0.76, P < 0.001). CONCLUSION: Considering relatively acceptable heterogeneity, PSR had better perioperative outcomes without compromising oncological long-term outcomes. However, these findings must be carefully interpreted, requiring more supporting evidence. TRIAL REGISTRATION: PROSPERO registration number: CRD42023445332.
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Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/patologia , Hepatectomia/efeitos adversos , Intervalo Livre de Doença , Neoplasias Colorretais/patologia , Resultado do TratamentoRESUMO
Covalent organic frameworks (COFs) have emerged as promising electrocatalysts due to their controllable architectures, highly exposed molecular active sites, and ordered structures. In this study, a series of porphyrin-based COFs (TAPP-x-COF) with various transition metals (Co, Ni, Fe) were synthesized via a facile post-metallization strategy under solvothermal synthesis. The resulting porphyrin-based COFs showed oxygen reduction reaction (ORR) activity with a trend in Co > Fe > Ni. Among them, TAPP-Co-COF exhibited the best ORR activity (E1/2 = 0.66 V and jL = 4.82 mA cm-2) in alkaline media, which is comparable to those of Pt/C under the same conditions. Furthermore, TAPP-Co-COF was employed as a cathode in a Zn-air battery, demonstrating a high power density of 103.73 mW cm-2 and robust cycling stability. This work presents a simple method for using COFs as a smart platform to fabricate efficient electrocatalysts.
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BACKGROUND: We aimed to develop and validate a nomogram model, which could predict metachronous liver metastasis in colorectal cancer within two years after diagnosis. METHODS: A retrospective study was performed on colorectal cancer patients who were admitted to Beijing Shijitan Hospital from January 1, 2016 to June 30, 2019. The least absolute shrinkage and selection operator (LASSO) regression model was used to optimize feature selection for susceptibility to metachronous liver metastasis in colorectal cancer. Multivariable logistic regression analysis was applied to establish a predictive model through incorporating features selected in the LASSO regression model. C-index, receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis (DCA) were employed to assess discrimination, distinctiveness, consistency with actual occurrence risk, and clinical utility of candidate predictive model. Internal validation was assessed with bootstrapping method. RESULTS: Predictors contained in candidate prediction nomogram included age, CEA, vascular invasion, T stage, N stage, family history of cancer, and KRAS mutation. This model displayed good discrimination with a C-index of 0.787 (95% confidence interval: 0.728-0.846) and good calibration, whereas area under the ROC curve (AUC) of 0.786. Internal validation obtained C-index of 0.786, and AUC of validation cohort is 0.784. Based on DCA, with threshold probability range from 1 to 60%; this predictive model might identify colorectal cancer metachronous liver metastasis to achieve a net clinical benefit. CONCLUSION: We have developed and validated a prognostic nomogram with good discriminative and high accuracy to predict metachronous liver metastasis in CRC patients.
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Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Colorretais/patologia , Humanos , Nomogramas , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Although Trapa is a well-defined genus of distinctive freshwater plants with accumulations of extensive morphological and embryological autapomorphies, its phylogenetic relationships have long been unclear. Formerly placed in the monotypic family Trapaceae, Trapa is now recognized as sister to Sonneratia within Lythraceae s.l., although both genera lack morphological synapomorphies. Thus, a split between the two taxa must have occurred in deep evolutionary time, which raises the possibility of finding transitional forms in the fossil record. RESULTS: Here we describe a new genus and species, Primotrapa weichangensis Y. Li et C.-S. Li (Lythraceae s.l.: Trapoideae), based on three-dimensionally preserved floral cups, fruits, and seeds from the early Miocene of Weichang County, Hebei Province, China. Primotrapa is characterized by a shallow, saucer-shaped floral cup, four distally barbellate sepals, four intersepal appendages alternating with the sepals at the rim of cup, a superior to basally inferior ovary, a fusiform or ovoid, one-seeded fruit with a ribbed surface, and a long persistent peduncle. Two fossil species of Hemitrapa are proposed as new combinations of Primotrapa, namely P. alpina (T. Su et Z.-K. Zhou) Y. Li et C.-S. Li comb. nov. and P. pomelii (Boulay) Y. Li et C.-S. Li comb. nov. Our phylogenetic analysis based on fifteen flower and fruit characters supports the placement of Primotrapa, Hemitrapa and Trapa in a monophyletic clade, which comprise subfamily Trapoideae. The phylogenetic analysis places Primotrapa at the base of Trapoideae. CONCLUSIONS: In view of its superior ovary, which is a plesiomorphic character of Lythraceae s.l., the newly recognized genus Primotrapa and its three species likely represent transitional forms that bridge the evolutionary gap between the basal taxa of Lythraceae s.l., i.e. Lythrum, and the highly derived taxon Trapa.
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Especiação Genética , Lythraceae/classificação , Filogenia , China , Extinção BiológicaRESUMO
PURPOSE: To evaluate the feasibility of histogram analysis of T2* value for the detection and grading of degenerative lumbar intervertebral discs (IVDs) and for the characterization of microstructural heterogeneity of discs. METHODS: Two hundred fourteen lumbar IVDs of 44 subjects with chronic low back pain were examined using sagittal T2WI and axial T2* mapping. All IVDs were classified according to the Pfirrmann grade on T2WI. The correlations between histogram-derived parameters based on T2* values (T2*-HPs) of IVDs and Pfirrmann grade as well as between "red zone ratio" (area of "red zone" on T2* color maps over cross-sectional area of corresponding IVDs) and Pfirrmann grade were calculated. RESULTS: The agreement for Pfirrmann grade of IVDs was excellent (κ = 0.808, P < 0.001). The consistency of the measured T2*-HPs was excellent, with ICCs ranging from 0.828-0.960. Each histogram-derived parameter had a statistically significant relationship with Pfirrmann grade (P < 0.001). The bright "red zone" on T2* color maps of IVDs displayed as a separated peak relative to the rest of voxels in histograms. The mean area ratio of "red zone" over the corresponding IVD was 9.234% ± 6.680 and ranged from 0.517% to 30.598%. The "red zone ratio" was highly related to Pfirrmann grade (r = - 0.732, P < 0.001). CONCLUSION: Histogram analysis of T2* value is an effective tool for the detection and grading of degenerative IVDs. Identification of the "red zone" may provide new breakthroughs in the study of disc degeneration initiation and generate new hypotheses in anatomical and histological studies of IVDs.
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Degeneração do Disco Intervertebral , Disco Intervertebral , Estudos de Viabilidade , Humanos , Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Imageamento por Ressonância MagnéticaRESUMO
Magnetic dimers with very large magnetic anisotropy have great potential in information storage applications. By using density functional theory calculations (DFT), we systematically investigated the magnetic anisotropy energy (MAE) of bi-iridium (Ir2) dimers on four types of graphene-like two-dimensional (2D) material substrates. We considered four possible adsorption sites for Ir2 on each substrate. The Ir2 dimer prefers to remain at the single vacancy site with the largest binding energy for all the 2D materials considered. The spin moment and MAE of Ir2 can be largely affected by the substrate. On the substrate of germanene, the MAE of Ir2 can be enlarged to approximately 100 meV, even with the higher Ir2 areal density of 1.804 nm-2. Moreover, the direction of the easy magnetization axis is determined by the d states in the vicinity of the Fermi level. The present DFT results can be understood with the help of perturbation theory analysis.
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An unbiased global search was employed to explore the low-energy structures of SnN, SnN -, and SnNCl- clusters with N = 4-20 atoms based on the genetic algorithm combined with density functional theory calculations. Some unprecedented low-energy isomers are reported for SnN and SnNCl- clusters. The theoretical electronic properties such as binding energy per atom, ionization potential, adiabatic detachment energy, and vertical detachment energy compare well with the experimental data. Based on the equilibrium structures, the simulated photoelectron spectra are in good agreement with the experimental data in the range of N = 4-20. With addition of a Cl atom on the SnN - cluster, which causes almost no rearrangement on the structural framework, the first peaks in all original photoelectron spectra of SnN - clusters disappear and other peaks nearly retain the original feature at most sizes.
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Face detection is the basic step in video face analysis and has been studied for many years. However, achieving real-time performance on computation-resource-limited embedded devices still remains an open challenge. To address this problem, in this paper we propose a face detector, EagleEye, which shows a good trade-off between high accuracy and fast speed on the popular embedded device with low computation power (e.g., the Raspberry Pi 3b+). The EagleEye is designed to have low floating-point operations per second (FLOPS) as well as enough capacity, and its accuracy is further improved without adding too much FLOPS. Specifically, we design five strategies for building efficient face detectors with a good balance of accuracy and running speed. The first two strategies help to build a detector with low computation complexity and enough capacity. We use convolution factorization to change traditional convolutions into more sparse depth-wise convolutions to save computation costs and we use successive downsampling convolutions at the beginning of the face detection network. The latter three strategies significantly improve the accuracy of the light-weight detector without adding too much computation costs. We design an efficient context module to utilize context information to benefit the face detection. We also adopt information preserving activation function to increase the network capacity. Finally, we use focal loss to further improve the accuracy by handling the class imbalance problem better. Experiments show that the EagleEye outperforms the other face detectors with the same order of computation costs, on both runtime efficiency and accuracy.
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Face/fisiologia , Algoritmos , Humanos , Processamento de Imagem Assistida por Computador , Reconhecimento Automatizado de Padrão/métodosRESUMO
INTRODUCTION: Despite major progress in the imaging diagnosis of spondyloarthritis (SpA), the relative advantages of various available imaging techniques remain unclear. The aim of this study is to assess the current use of imaging in the diagnosis of SpA and to provide suitable recommendations for the use of imaging as an outcome measure as defined in the Assessment in SpondyloArthritis international Society (ASAS) criteria. EVIDENCE ACQUISITION: A systematic literature search regarding imaging in SpA was performed. Articles were assessed by two reviewers to identify and summarized key information pertaining to imaging in SpA. EVIDENCE SYNTHESIS: The search identified 180 relevant articles. Conventional radiography (CR) (17 articles), ultrasound (US) (26 articles), conventional computed tomography (CT) (13 articles), spectral computed tomography (spectral CT) (2 articles), bone scintigraphy (24 articles), and magnetic resonance imaging (MRI) were assessed (98 articles). Sacroiliitis and enthesitis were the major imaging findings in SpA. Multiple studies assessed the feasibility, validity, or differences among imaging modalities for the diagnosis of SpA; however, comprehensive assessments were not available due to a paucity of prospective imaging studies. CR is a widely available, inexpensive initial approach to evaluate patients with suspected SpA. CT enables assessment of structural changes from chronic sacroiliitis including bony erosions, subchondral sclerosis, joint space narrowing, and ankyloses; however, both CR and CT modalities are insensitive for demonstrating early enthesitis and sacroiliitis in SpA. US mainly identifies appendicular enthesitis but is more limited with respect to the sacroiliac joints. Bone scintigraphy can identify sacroiliac joint lesions and semi-quantitatively assess active sacroiliitis. MRI optimally evaluates not only early enthesitis and sacroiliitis of SpA but also chronic structural changes to the sacroiliac joints. CONCLUSIONS: More than one modality may be required for diagnostic and assessment of SpA depending upon disease characteristics and evolution. CR is a suitable initial examination while MRI is able to detect both early and late changes of SpA. A combination of CR and MRI is recommended for the diagnosis and assessment of SpA.
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Diagnóstico por Imagem/métodos , Espondilartrite/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por ComputadorRESUMO
The structural, electronic, and magnetic properties of FeGen-/0 (n = 3-12) clusters were investigated by using anion photoelectron spectroscopy in combination with density functional theory calculations. For both anionic and neutral FeGen (n = 3-12) clusters with n ≤ 7, the dominant structures are exohedral. The FeGe8-/0 clusters have half-encapsulated boat-shaped structures, and the opening of the boat-shaped structure is gradually covered by the additional Ge atoms to form Gen cage from n = 9 to 11. The structures of FeGe10-/0 can be viewed as two Ge atoms symmetrically capping the opening of the boat-shaped structure of FeGe8, and those of FeGe12-/0 are distorted hexagonal prisms with the Fe atom at the center. Natural population analysis shows that there is an electron transfer from the Ge atoms to the Fe atom at n = 8-12. The total magnetic moment of FeGen-/0 and local magnetic moment of the Fe atom have not been quenched.
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The anionic silicon clusters doped with three boron atoms, B3Sin- (n = 4-10), have been generated by laser vaporization and investigated by anion photoelectron spectroscopy. The vertical detachment energies (VDEs) and adiabatic detachment energies (ADEs) of these anionic clusters are determined. The lowest energy structures of B3Sin- (n = 4-10) clusters are globally searched using genetic algorithm incorporated with density functional theory (DFT) calculations. The photoelectron spectra, VDEs, ADEs of these B3Sin- clusters (n = 4-10) are simulated using B3LYP/6-311+G(d) calculations. Satisfactory agreement is found between theory and experiment. Most of the lowest-energy structures of B3Sin- (n = 4-10) clusters can be derived by using the squashed pentagonal bipyramid structure of B3Si4- as the major building unit. Analyses of natural charge populations show that the boron atoms always possess negative charges, and that the electrons transfer from the 3s orbital of silicon and the 2s orbital of boron to the 2p orbital of boron. The calculated average binding energies, second-order differences of energies, and the HOMO-LUMO gaps show that B3Si6- and B3Si9- clusters have relatively high stability and enhanced chemical inertness. In particular, the B3Si9- cluster with high symmetry (C3v) stands out as an interesting superatom cluster with a magic number of 40 skeletal electrons and a closed-shell electronic configuration of 1S21P61D102S22P61F14 for superatom orbitals.
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Because of the complex and fine structure, visualization of the heart still remains a challenging task, which makes it an active research topic. In this paper, we present a visualization system for medical data, which takes advantage of the recent graphics processing unit (GPU) and can provide real-time cardiac visualization. This work focuses on investigating the anatomical structure visualization of the human heart, which is fundamental to the cardiac visualization, medical training and diagnosis assistance. Several state-of-the-art cardiac visualization methods are integrated into the proposed system and a task specified visualization method is proposed. In addition, auxiliary tools are provided to generate user specified visualization results. The contributions of our work lie in two-fold: for doctors and medical staff, the system can provide task specified visualization with interactive visualization tools; for researchers, the proposed platform can serve as a baseline for comparing different rendering methods and can easily incorporate new rendering methods. Experimental results show that the proposed system can provide favorable cardiac visualization results in terms of both effectiveness and efficiency.
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Coração/anatomia & histologia , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Gráficos por Computador , HumanosRESUMO
UNLABELLED: ⢠PREMISE OF THE STUDY: The paleogeographical origin of the relict North American Sequoia sempervirens is controversial. Fossil records indicate a Neogene origin for its foliage characteristics. Although several fossils from the Miocene sediments in eastern Asia have been considered to have close affinities with the modern S. sempervirens, they lack the typical features of a leafy twig bearing linear as well as scale leaves, and the fertile shoots terminating by a cone. The taxonomic status of these fossils has remained unclear.⢠METHODS: New better-preserved fossils from the upper Miocene of China indicate a new species of Sequoia. This finding not only confirms the former presence of this genus in eastern Asia, but it also confirms the affinity of this Asian form to the modern relict S. sempervirens.⢠KEY RESULTS: The principal foliage characteristics of S. sempervirens had already originated by the late Miocene. The eastern Asian records probably imply a Beringian biogeographic track of the ancestor of S. sempervirens in the early Neogene, at a time when the land bridge was not too cool for this thermophilic conifer to spread between Asia and North America.⢠CONCLUSIONS: The climatic context of the new fossil Sequoia in Southeast Yunnan, based on other floristic elements of the fossil assemblage in which it is found, is presumed to be warm and humid. Following the uplift of the Qinghai-Tibet Plateau, this warm, humid climate was replaced by the present monsoonal climate with dry winter and spring. This change may have led to the disappearance of this hygrophilous conifer from eastern Asia.
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Evolução Biológica , Fósseis , Dispersão Vegetal , Sequoia/classificação , China , Mudança Climática , Fósseis/anatomia & histologia , Filogenia , Folhas de Planta/anatomia & histologia , Sequoia/anatomia & histologia , Sequoia/fisiologiaRESUMO
The roles of a tomato (Lycopersicon esculentum) chloroplast-targeted DnaJ protein (LeCDJ1) were investigated using wild-type (WT) and sense transgenic tomatoes. The LeCDJ1 expression was upregulated by 38 °C, 42 °C, 45 °C, NaCl, PEG, methyl viologen (MV) and hydrogen peroxide (H2O2), but not by 30 °C and 35 °C. Meanwhile, LeCDJ1 was involved in the response of plants to abscisic acid (ABA). Under heat stress, the sense plants showed better growth, higher chlorophyll content, lower malondialdehyde (MDA) accumulation and relative electrical conductivity (REC), and also less PSII photoinhibition than WT. Interestingly, the sense plants treated with streptomycin (SM), an inhibitor of organellar translation, still showed higher maximum photochemistry efficiency of PSII (Fv/Fm) and D1 protein levels than the SM-untreated WT, suggesting that the protective effect of LeCDJ1 on PSII was, at least partially, independent of D1 protein synthesis. Furthermore, the relatively lower superoxide radical (O2(â¢-)) and H2O2 levels in the sense plants were considered to be due to the higher ascorbate peroxidase (APX) and superoxide dismutase (SOD) activity, which seemed unlikely dependent on their transcription level. These results indicated that LeCDJ1 overexpression facilitated heat tolerance in transgenic tomatoes.
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Adaptação Fisiológica/genética , Cloroplastos/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Temperatura Alta , Proteínas de Plantas/metabolismo , Solanum lycopersicum/genética , Solanum lycopersicum/fisiologia , Adaptação Fisiológica/efeitos dos fármacos , Ascorbato Peroxidases/metabolismo , Clorofila/metabolismo , Cloroplastos/efeitos dos fármacos , Condutividade Elétrica , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Proteínas de Choque Térmico HSP40/genética , Resposta ao Choque Térmico/efeitos dos fármacos , Resposta ao Choque Térmico/genética , Solanum lycopersicum/enzimologia , Solanum lycopersicum/crescimento & desenvolvimento , Malondialdeído/metabolismo , Complexo de Proteína do Fotossistema II/metabolismo , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Plântula/genética , Plântula/fisiologia , Estreptomicina/farmacologia , Estresse Fisiológico/genética , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND AND AIM: Tight junctions maintain gut homeostasis by forming a physical barrier that protects the gut from invasion by microbiota. Cldn-7 is an important component involved in this protection, but the relationship between Cldn-7, intestinal inflammation, and gut microbiota has not been clarified. Here, we hypothesize that Cldn-7 depletion affects intestinal inflammation by altering the gut microbiota. METHODS: Based on the induced intestinal condition of Cldn-7 knockout mice (Cldn7fl/fl;villin-CreaERT2), we established the intestinal flora depletion model and colitis model by antibiotic drinking and feeding with dextran sodium sulfate (DSS). The environment of Cldn-7 gene deletion mice was changed by co-housing experiment. AB-PAS staining and Muc2 were used to detect the effect of co-housing and Cldn-7 deficiency on the mucus layer after flora depletion. qRT-PCR was used to detect the expression of intestinal inflammatory factors and AMPs in mice. Feces were collected and proportions of microbiota were analyzed by 16â¯S rRNA amplicon sequencing. RESULTS: Mice in the co-housing experiment had altered intestinal microbiota, including diversity, composition, and functional prediction, compared to controls. Intestinal inflammation was restored to some extent following altered intestinal microbiota. The intestinal inflammation caused by Cldn-7 deficiency and susceptibility to DSS could be reduced after antibiotic administration compared to controls, in terms of phenotype, pathological changes, inflammatory factors, mucus barrier, and expression of AMPs. CONCLUSIONS: In analyses of intestinal tissues, colitis induction, and gut microbiota in mice with intestinal disruption of Cldn-7, we found this protein to prevent intestinal inflammation by regulating the gut microbiota. Cldn-7might therefore be an important mediator of host-microbiome interactions. Our research has revealed that Cldn-7 plays an indispensable role in maintaining intestinal homeostasis by regulating the gut microbiota and impacting intestinal inflammation. These findings provide new insights into the pathogenesis of ulcerative colitis.
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Claudinas , Colite , Microbioma Gastrointestinal , Mucosa Intestinal , Camundongos Knockout , Animais , Microbioma Gastrointestinal/fisiologia , Claudinas/metabolismo , Claudinas/genética , Camundongos , Colite/patologia , Colite/microbiologia , Colite/metabolismo , Colite/induzido quimicamente , Mucosa Intestinal/patologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
Intestinal stem cells (ISCs) play a crucial role in the continuous self-renewal and recovery of the intestinal epithelium. In previous studies, we have revealed that the specific absence of Claudin-7 (Cldn-7) in intestinal epithelial cells (IECs) can lead to the development of spontaneous colitis. However, the mechanisms by which Cldn-7 maintains homeostasis in the colonic epithelium remain unclear. Therefore, in the present study, we used IEC- and ISC-specific Cldn-7 knockout mice to investigate the regulatory effects of Cldn-7 on colonic Lgr5+ stem cells in the mediation of colonic epithelial injury and repair under physiological and inflammatory conditions. Notably, our findings reveal that Cldn-7 deletion disrupts the self-renewal and differentiation of colonic stem cells alongside the formation of colonic organoids in vitro. Additionally, these Cldn-7 knockout models exhibited heightened susceptibility to experimental colitis, limited epithelial repair and regeneration, and increased differentiation toward the secretory lineage. Mechanistically, we also established that Cldn-7 facilitates the proliferation, differentiation, and organoid formation of Lgr5+ stem cells through the maintenance of Wnt and Notch signalling pathways in the colonic epithelium. Overall, our study provides new insights into the maintenance of ISC function and colonic epithelial homoeostasis.
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Claudinas , Homeostase , Receptores Notch , Células-Tronco , Via de Sinalização Wnt , Animais , Camundongos , Diferenciação Celular , Proliferação de Células , Claudinas/metabolismo , Claudinas/genética , Colite/metabolismo , Colite/patologia , Colite/induzido quimicamente , Colo/metabolismo , Mucosa Intestinal/metabolismo , Camundongos Knockout , Organoides/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Notch/metabolismo , Células-Tronco/metabolismo , Células-Tronco/citologiaRESUMO
Gene therapy aims to add, replace or turn off genes to help treat disease. To date, the US Food and Drug Administration (FDA) has approved 14 gene therapy products. With the increasing interest in gene therapy, feasible gene delivery vectors are necessary for inserting new genes into cells. There are different kinds of gene delivery vectors including viral vectors like lentivirus, adenovirus, retrovirus, adeno-associated virus et al, and non-viral vectors like naked DNA, lipid vectors, polymer nanoparticles, exosomes et al, with viruses being the most commonly used. Among them, the most concerned vector is adeno-associated virus (AAV) because of its safety, natural ability to efficiently deliver gene into cells and sustained transgene expression in multiple tissues. In addition, the AAV genome can be engineered to generate recombinant AAV (rAAV) containing transgene sequences of interest and has been proven to be a safe gene vector. Recently, rAAV vectors have been approved for the treatment of various rare diseases. Despite these approvals, some major limitations of rAAV remain, namely nonspecific tissue targeting and host immune response. Additional problems include neutralizing antibodies that block transgene delivery, a finite transgene packaging capacity, high viral titer used for per dose and high cost. To deal with these challenges, several techniques have been developed. Based on differences in engineering methods, this review proposes three strategies: gene engineering-based capsid modification (capsid modification), capsid surface tethering through chemical conjugation (surface tethering), and other formulations loaded with AAV (virus load). In addition, the major advantages and limitations encountered in rAAV engineering strategies are summarized.
Assuntos
Dependovirus , Terapia Genética , Vetores Genéticos , Transgenes , Dependovirus/genética , Humanos , Vetores Genéticos/genética , Vetores Genéticos/administração & dosagem , Terapia Genética/métodos , Evasão da Resposta Imune , Animais , Engenharia Genética/métodos , Técnicas de Transferência de Genes , Tropismo ViralRESUMO
Basic research shows that flavonoids have anti-inflammatory effects that influence rheumatoid arthritis (RA) in rats. Investigating potential dietary interventions for RA helps prevent the onset and progression of the disease. Clinical evidence on the association of flavonoid and subclass intake with RA is lacking. Using three survey cycles of 2007-2008, 2009-2010, and 2017-2018 from the National Health and Nutrition Survey and the United States Department of Agriculture's Food and Nutrient Database for Dietary Studies (FNDDS), we analyzed 7,419 American adults (≥20 years old). The values of flavonoid and subclass intake were calculated using FNDDS. The status questions for self-reported RA were from the NHANES codebook. Weighted analyses, revealed that among the 7,419 participants included in this study (mean age of 44.69 years [standard error, 0.40] and 3,584 [48.31%] were female), 408 met the classification criteria for RA. According to the multivariable logistic regression model, compared with the risk of RA in the first quartile (Q1), the risks of RA in the second quartile (Q2), the third quartile (Q3) and the fourth quartile (Q4) were lower (Q2: OR=0.55, 95% CI: 0.38-0.80; Q3: OR=0.66, 95% CI: 0.44-0.97; Q4: OR=0.64, 95% CI: 0.46-0.89; trend: P=.03). The association between total flavonoids and RA remained significant after full consideration of confounding factors. With regard to the subclasses of flavonoids, high flavanones intake was associated with low RA prevalence in Model 3 (Q3: OR= 0.60, 95% CI:0.39-0.92; Q4: OR = 0.56, 95% CI: 0.32-0.99, trend: P=.02), but no such association was found in the other subclasses. Total flavonoids intake protected against RA, and the risk of developing RA decreased significantly with increasing intake of total flavonoids. Total flavonoids and flavanones were significantly associated with reduced RA risk for the American adult population. We highlighted the importance of employing diverse methodologies to assess the health effects of flavonoids.