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Quantitative susceptibility mapping (QSM) is a rising MRI-based technology and quite a few QSM-related algorithms have been proposed to reconstruct maps of tissue susceptibility distribution from phase images. In this paper, we develop a comprehensive susceptibility imaging process and analysis studio (SIPAS) that can accomplish reliable QSM processing and offer a standardized evaluation system. Specifically, SIPAS integrates multiple methods for each step, enabling users to select algorithm combinations according to data conditions, and QSM maps could be evaluated by two aspects, including image quality indicators within all voxels and region-of-interest (ROI) analysis. Through a sophisticated design of user-friendly interfaces, the results of each procedure are able to be exhibited in axial, coronal, and sagittal views in real-time, meanwhile ROIs can be displayed in 3D rendering visualization. The accuracy and compatibility of SIPAS are demonstrated by experiments on multiple in vivo human brain datasets acquired from 3T, 5T, and 7T MRI scanners of different manufacturers. We also validate the QSM maps obtained by various algorithm combinations in SIPAS, among which the combination of iRSHARP and SFCR achieves the best results on its evaluation system. SIPAS is a comprehensive, sophisticated, and reliable toolkit that may prompt the QSM application in scientific research and clinical practice.
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Algoritmos , Encéfalo , Imageamento por Ressonância Magnética , Humanos , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Processamento de Imagem Assistida por Computador/normas , Mapeamento Encefálico/métodos , SoftwareRESUMO
The multireference coupled-cluster Monte Carlo (MR-CCMC) algorithm is a determinant-based quantum Monte Carlo (QMC) algorithm that is conceptually similar to Full Configuration Interaction QMC (FCIQMC). It has been shown to offer a balanced treatment of both static and dynamic correlation while retaining polynomial scaling, although application to large systems with significant strong correlation remained impractical. In this paper, we document recent algorithmic advances that enable rapid convergence and a more black-box approach to the multireference problem. These include a logarithmically scaling metric-tree-based excitation acceptance algorithm to search for determinants connected to the reference space at the desired excitation level and a symmetry-screening procedure for the reference space. We show that, for moderately sized reference spaces, the new search algorithm brings about an approximately 8-fold acceleration of one MR-CCMC iteration, while the symmetry screening procedure reduces the number of active reference space determinants with essentially no loss of accuracy. We also introduce a stochastic implementation of an approximate wall projector, which is the infinite imaginary time limit of the exponential projector, using a truncated expansion of the wall function in Chebyshev polynomials. Notably, this wall-Chebyshev projector can be used to accelerate any projector-based QMC algorithm. We show that it requires significantly fewer applications of the Hamiltonian to achieve the same statistical convergence. We benchmark these acceleration methods on the beryllium and carbon dimers, using initiator FCIQMC and MR-CCMC with basis sets up to cc-pVQZ quality.
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Mitochondrial dysfunction contributes to cerebral ischemia-reperfusion (CI/R) injury, which can be ameliorated by Sirtuin-3 (SIRT3). Under stress conditions, the SIRT3-promoted mitochondrial functional recovery depends on both its activity and expression. However, the approach to enhance SIRT3 activity after CI/R injury remains unelucidated. In this study, Sprague-Dawley (SD) rats were intracranially injected with either adeno-associated viral Sirtuin-1 (AAV-SIRT1) or AAV-sh_SIRT1 before undergoing transient middle cerebral artery occlusion (tMCAO). Primary cortical neurons were cultured and transfected with lentiviral SIRT1 (LV-SIRT1) and LV-sh_SIRT1 respectively before oxygen-glucose deprivation/reoxygenation (OGD/R). Afterwards, rats and neurons were respectively treated with a selective SIRT3 inhibitor, 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP). The expression, function, and related mechanism of SIRT1 were investigated by Western Blot, flow cytometry, immunofluorescence staining, etc. After CI/R injury, SIRT1 expression decreased in vivo and in vitro. The simulation and immune-analyses reported strong interaction between SIRT1 and SIRT3 in the cerebral mitochondria before and after CI/R. SIRT1 overexpression enhanced SIRT3 activity by increasing the deacetylation of SIRT3, which ameliorated CI/R-induced cerebral infarction, neuronal apoptosis, oxidative stress, neurological and motor dysfunction, and mitochondrial respiratory chain dysfunction, promoted mitochondrial biogenesis, and retained mitochondrial integrity and mitochondrial morphology. Meanwhile, SIRT1 overexpression alleviated OGD/R-induced neuronal death and mitochondrial bioenergetic deficits. These effects were reversed by AAV-sh_SIRT1 and the neuroprotective effects of SIRT1 were partially offset by 3-TYP. These results suggest that SIRT1 restores the structure and function of mitochondria by activating SIRT3, offering neuroprotection against CI/R injury, which signifies a potential approach for the clinical management of cerebral ischemia.
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Isquemia Encefálica , Mitocôndrias , Neurônios , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Sirtuína 1 , Sirtuína 3 , Animais , Sirtuína 1/metabolismo , Sirtuína 1/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Mitocôndrias/metabolismo , Masculino , Sirtuína 3/metabolismo , Sirtuína 3/genética , Neurônios/metabolismo , Neurônios/patologia , Ratos , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Apoptose , SirtuínasRESUMO
OPINION STATEMENT: Non-melanoma skin cancers (NMSCs) are the most common malignancy and surgical excision is considered treatment of choice for the majority of cases. However, surgery can be very extensive in cases of large, multiple, or cosmetic-sensitive tumors located on areas such as scalp and face or genital region, leading to significant functional and cosmetic deficit. Aminolaevulinic acid photodynamic therapy (ALA-PDT) has emerged as a widely used approach in a variety of skin diseases, demonstrating remarkable efficacy in treatment of actinic keratosis, Bowen disease and basal cell carcinoma. Besides, when employed as a preoperative intervention, ALA-PDT effectively reduces tumor size and minimizes subsequent local surgical morbidity. With its minimally invasive nature and proven effectiveness, ALA-PDT holds significant promise as a neoadjuvant treatment option for NMSCs. In cases where the tumor is large, invasive, multiple, or located in cosmetically and functionally sensitive areas, or when considering patient factors such as age, comorbidity, willingness to undergo surgery, and post-operative quality-of-life, surgical intervention or radiotherapy alone may be impracticable or unacceptable. In such scenarios, neoadjuvant ALA-PDT can offer remarkable outcomes. In order to further ensure the maximum benefit of patients from neoadjuvant PDT, collaboration with multidisciplinary teams and whole-process management may be in need.
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Terapia Neoadjuvante , Fotoquimioterapia , Neoplasias Cutâneas , Humanos , Fotoquimioterapia/métodos , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/tratamento farmacológico , Terapia Neoadjuvante/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Resultado do Tratamento , Ácido Aminolevulínico/uso terapêutico , Carcinoma Basocelular/terapia , Carcinoma Basocelular/tratamento farmacológico , Gerenciamento Clínico , Terapia Combinada/métodosRESUMO
Forte is an open-source library specialized in multireference electronic structure theories for molecular systems and the rapid prototyping of new methods. This paper gives an overview of the capabilities of Forte, its software architecture, and examples of applications enabled by the methods it implements.
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BACKGROUND: To investigate the impact of chronic endometritis (CE) on the recurrence of endometrial polyps (EPs) in premenopausal women after transcervical resection of endometrial polyps (TCRP). METHODS: This prospective study enrolled 507 women who underwent TCRP between January 1, 2022 and December 31, 2022. The patients were divided into a CE group (n = 133) and non-CE group (n = 374) based on the expression of CD138 in the endometrium. The EP recurrence rate at 1 year after TCRP was compared between the CE and non-CE groups and between groups with mild CE and severe CE. The impact of CD138 expression by resected EPs on EP recurrence also was investigated. RESULTS: The EP recurrence rate at 1 year post-TCRP was higher in the CE group than in the non-CE group (25.6% vs. 10.4%) and also higher in the severe CE group than in the mild CE group (34.5% vs. 18.7%). Additionally, the EP recurrence rate was higher among patients with CD138-expressing EPs than among those with EPs lacking CD138 expression (30.5% vs. 6.5%). The odds ratio (OR) for EP recurrence in the CE cohort compared with the non-CE cohort was 3.10 (95% confidence interval [CI] 1.84-5.23) after adjustment for EP number and precautions against EP recurrence. The ORs for EP recurrence in patients with mild CE and severe CE were 2.21 (95%CI 1.11-4.40) and 4.32 (95%CI 2.26-8.26), respectively. Similarly, the OR for EP recurrence in cases with CD138-expressing EPs relative to cases with EPs lacking CD138 expression was 6.22 (95%CI 3.59-10.80) after adjustment for EP number and precautions against EP recurrence. CONCLUSIONS: CE multiplied the recurrence rate of EPs in premenopausal women after TCRP, and this effect positively correlated with CE severity. CD138 expression by EPs also was associated with a higher risk for EP recurrence.
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Endometrite , Pólipos , Recidiva , Humanos , Feminino , Estudos Prospectivos , Adulto , Pólipos/cirurgia , Endometrite/epidemiologia , Endometrite/etiologia , Doença Crônica , Sindecana-1/metabolismo , Pessoa de Meia-Idade , Doenças Uterinas/cirurgia , Doenças Uterinas/etiologia , Fatores de RiscoRESUMO
BACKGROUND: Photodynamic therapy (PDT) has been strongly recommended as an excellent alternative treatment for Bowen's disease (BD). However, reported data on 5-aminolevulinic acid-mediated PDT (ALA-PDT) with red light irradiation are limited and the long-term effectiveness remains to be determined, especially in dark-skinned populations. METHODS: Medical records of BD patients who received ALA-PDT with red light irradiation between February 2011 and June 2021 were reviewed and summarized. Univariate and multivariate analyses of clinically relevant variables that may affect treatment outcomes were performed to identify risk predictors. RESULTS: The overall clearance rate of 122 BD lesions was 89.3% with a median follow-up time of 36 months. The correlation between the effectiveness and fluorescence intensity of pre-PDT or PDT sessions was statistically significant after eliminating the interference of confounding factors. All recurrences occurred in the first two years following ALA-PDT. CONCLUSION: ALA-PDT is an effective treatment for BD in the skin of color patients. Well-executed operation and effective pre-treatment are the determinants of effectiveness. Fluorescence intensity of pre-PDT appeared to be a significant predictor of final effectiveness. In addition, two years of follow-up is necessary following ALA-PDT.
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Introduction: Teledermatology adoption continues to increase, in part, spurred by the COVID-19 pandemic. This study analyzes the utility and cost savings of a store-and-forward teledermatology consultative system within the Veterans Health Administration (VA). Methods: Retrospective cohort of 4,493 patients across 14 remote sites in Tennessee and Kentucky from May 2017 through August 2019. The study measured the agreement between the teledermatology diagnoses and follow-up face-to-face clinic evaluations as well as the cost effectiveness of the teledermatology program over the study period. Results: Fifty-four percent of patients were recommended for face-to-face appointment for biopsy or further evaluation. Most patients, 80.5% received their face-to-face care by a VA dermatologist. There was a high level of concordance between teledermatologist and clinic dermatologist for pre-malignant and malignant cutaneous conditions. Veterans were seen faster at a VA clinic compared with a community dermatology site. Image quality improved as photographers incorporated teledermatologist feedback. From a cost perspective, teledermatology saved the VA system $1,076,000 in community care costs. Discussion: Teledermatology is a useful diagnostic tool within the VA system providing Veteran care at a cost savings.
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COVID-19 , Redução de Custos , Dermatologia , Dermatopatias , Telemedicina , United States Department of Veterans Affairs , Humanos , Dermatologia/economia , Dermatologia/normas , Dermatologia/organização & administração , Estudos Retrospectivos , Dermatopatias/diagnóstico , Dermatopatias/economia , Estados Unidos , Telemedicina/economia , United States Department of Veterans Affairs/organização & administração , Feminino , Kentucky , Masculino , Controle de Qualidade , Pessoa de Meia-Idade , Tennessee , SARS-CoV-2 , Consulta Remota/economia , Idoso , Análise Custo-BenefícioRESUMO
OBJECTIVES: Available literature documents that ischemic stroke can disrupt the morphology and function of mitochondria and that the latter in other disease models can be preserved by neuropilin-1 (NRP-1) via oxidative stress suppression. However, whether NRP-1 can repair mitochondrial structure and promote functional recovery after cerebral ischemia is still unknown. This study tackled this very issue and explored the underlying mechanism. METHODS: Adeno-associated viral (AAV)-NRP-1 was stereotaxically inoculated into the cortex and ipsilateral striatum posterior of adult male Sprague-Dawley (SD) rats before a 90-min transient middle cerebral artery occlusion (tMCAO) and subsequent reperfusion. Lentivirus (LV)-NRP-1 was transfected into rat primary cortical neuronal cultures before a 2-h oxygen-glucose deprivation and reoxygenation (OGD/R) injury to neurons. The expression and function of NRP-1 and its specific protective mechanism were investigated by Western Blot, immunofluorescence staining, flow cytometry, magnetic resonance imaging, transmission electron microscopy, etc. The binding was detected by molecular docking and molecular dynamics simulation. RESULTS: Both in vitro and in vivo models of cerebral ischemia/reperfusion (I/R) injury presented a sharp increase in NRP-1 expression. The expression of AAV-NRP-1 markedly ameliorated the cerebral I/R-induced damage to the motor function and restored the mitochondrial morphology. The expression of LV-NRP-1 alleviated mitochondrial oxidative stress and bioenergetic deficits. AAV-NRP-1 and LV-NRP-1 treatments increased the wingless integration (Wnt)-associated signals and ß-catenin nuclear localization. The protective effects of NRP-1 were reversed by the administration of XAV-939. CONCLUSIONS: NRP-1 can produce neuroprotective effects against I/R injury to the brain by activating the Wnt/ß-catenin signaling pathway and promoting mitochondrial structural repair and functional recovery, which may serve as a promising candidate target in treating ischemic stroke.
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Isquemia Encefálica , AVC Isquêmico , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Ratos , Animais , Masculino , Ratos Sprague-Dawley , Neuropilina-1 , Simulação de Acoplamento Molecular , Traumatismo por Reperfusão/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/metabolismo , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Mitocôndrias/metabolismo , ApoptoseRESUMO
Gliomas are the most common primary malignant brain tumors, with a poor prognosis and high mortality, and there is no effective treatment regimen. A number of studies have shown that replication protein A3 (RPA3) can regulate DNA replication and that the abnormal expression of RPA3 can lead to genomic instability and induce the development of a variety of tumors. However, the relationship between RPA3 and gliomas and the mechanism of action remains unclear. In this study, we investigated the role of RPA3 in the development of gliomas and the possible mechanism. The Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) databases were used to analyze the expression level of RPA3 and its correlation with clinical prognosis. A univariate Cox regression model was established to predict the prognosis of glioma patients and analyze the correlation between RPA3 and immune cell infiltration and activation. Immunohistochemistry, RT-PCR, and Western blot (WB) were used to detect the expression of RPA3 in glioma specimens. After knocking down and overexpressing RPA3 with plasmids, effects on glioma cell proliferation, migration and invasive capacity were investigated in vitro. The possible molecular mechanisms were analyzed using WB. Results showed that the expression of RPA3 in glioma tissue and cells was significantly higher than that in normal glial cells and was positively correlated with the poor prognosis of patients with gliomas. The overexpression of RPA3 expression activated the phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of the rapamycin (mTOR) pathway by promoting the phosphorylation of PI3K, AKT, and mTOR, thereby promoting the proliferation, migration and invasion of glioma cells. In conclusion, RPA3 is highly expressed in gliomas and promotes the proliferation, migration and invasion of gliomas by activating the PI3K-AKT-mTOR pathway. Therefore, RPA3 may be a prognostic biomarker and therapeutic target for gliomas.
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Glioma , Fosfatidilinositol 3-Quinase , Humanos , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Glioma/patologia , Proliferação de Células/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proteínas de Ligação a DNARESUMO
The immune microenvironment in hepatocellular carcinoma (HCC), especially T-cell infiltration, plays a key role in the prognosis and drug sensitivity of HCC. Our study aimed to analyze genes related to non-regulatory CD4+ and CD8+ T cell in HCC. Data of HCC samples were downloaded from The Cancer Genome Atlas (TCGA) database. According to stromal and immune score retrieved by Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithm, differentiated expressed genes (DEGs) between high and low stromal/immune scoring groups were collected. Using Cibersort algorithm, abundance of immune cells was calculated and genes related with CD4+ and CD8+ T cells were selected. Protein-protein interaction (PPI) networks and networks of microRNA (miRNA)-target gene interactions were illustrated, in which CD4+ and CD8+ T cell-related core genes were selected. Finally, Cox regression test and Kaplan-Meier (K-M) survival analysis were conducted. Totally, 1579 DEGs were identified, where 103 genes and 407 genes related with CD4+ and CD8+ T cell were selected, respectively. Each of 30 core genes related to CD4+ T cells and CD8+ T cells were selected by PPI network. Four genes each related with the two types of T cells had a significant impact on prognosis of HCC patients. Amongst, KLRB1 and IL18RAP were final two genes related to both two kinds of T cells and associated with overall survival of the HCC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores Tumorais/genética , Linfócitos T CD8-Positivos/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Occult breast cancer (OBC) is a special type of breast cancer. Because of its rarity, clinicopathological information is still insufficient, causing a controversial condition about its treatment recommendation. Thus, we aimed to clarify major clinicopathological information, treatment strategies and prognosis of OBC based on a large population. METHODS: We retrospectively collected adult female OBC population from Surveillance, Epidemiology, and End Results database. We divided the whole cohort into two groups based on surgical treatment in-breast. Descriptive analysis of 18 clinicopathological variables was conducted. Survival analysis was performed based on different clinicopathological factors. Univariate and multivariate Cox regression analysis was performed to identify potential independent predictor for prognosis of OBC. RESULTS: 1189 OBC patients were in final analysis and most of them were diagnosed as an early-stage carcinoma. Patients received breast-conserving treatment (BCT) was nearly two times of ones received mastectomy. Patients receiving radiotherapy in BCT group were significantly more than patients receiving radiotherapy in mastectomy group (61.76 vs. 50.9%, P < 0.001). After a median follow-up period of 62 months, 5-year and 10-year overall survival (OS) of all subjects was 81.6% and 68.8%, respectively. No significant difference in OS and breast-cancer specific survival (BCSS) was found between mastectomy and local breast-conserving surgery. Older age and larger number of positive lymph nodes causes a worse prognosis whereas radiotherapy brought a better clinical outcome for OBC patients. CONCLUSIONS: OBC has a generally good prognosis. Less-intensive surgery does not negatively impact clinical outcomes of OBC while additional radiotherapy is totally beneficial to prolong OS and BCSS.
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Neoplasias da Mama , Adulto , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/cirurgia , Feminino , Humanos , Mastectomia/métodos , Mastectomia Segmentar , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Transferring the genome of distant species to crops is an efficient way to create new germplasms. However, the molecular mechanisms involved are unclear. In this study, a new rice restorer line R21 with heat tolerance was created by introgressing the genomic DNA of sorghum into the recipient restorer line Jin Hui 1. Assembly of rice R21 and Jin Hui 1 genomes was performed using PacBio sequencing technology. Comparative genome analysis and coverage statistics showed that the repetitive sequence atr0026 was a candidate introgression fragment of sorghum DNA. Sequence similarity analysis revealed that atr0026 was distributed at different copy numbers on the telomeric position of chromosomes 9 or 10 in R21, Jin Hui 1, and several rice varieties, indicating that the repetitive sequence from sorghum was highly conserved in rice. The repeat annotation in Gramineae indicated that ribosomal DNA loci that existed in atr0026 may be cause a rearrangement of chromosomes 9 and 10 of the R21 genome, resulting in a copy number variation at the 5' end of it. Our study lays the foundation for further elucidation of the molecular mechanisms underlying the heat tolerance of sorghum DNA introgression variant line R21, which is of great significance for guiding crop genetic breeding.
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Oryza , Sorghum , Variações do Número de Cópias de DNA , DNA Ribossômico , Grão Comestível/genética , Genoma de Planta , Genômica , Oryza/genética , Melhoramento Vegetal , Sequências Repetitivas de Ácido Nucleico , Sorghum/genéticaRESUMO
OBJECTIVE: To develop a guideline that reliably identifies cutaneous adherent and rolling leukocytes from mimicking scenarios via in vivo reflectance confocal videomicroscopy. METHODS: We used a clinical reflectance confocal microscope, the VivaScope 1500, to acquire 1522 videos of the upper dermal microcirculation from 12 healthy subjects and 60 patients after allogeneic hematopoietic cell transplantation. Blinded to clinical information, two trained raters independently counted the number of adherent and rolling leukocytes in 88 videos. Based on discrepancies in the initial assessments, we developed a guideline to identify both types of leukocyte-endothelial interactions via a modified Delphi method (without anonymity). To test the guideline's ability to improve the inter-rater reliability, the two raters assessed the remaining 1434 videos by using the guideline. RESULTS: We demonstrate a guideline that consists of definitions, a step-by-step flowchart, and corresponding visuals of adherent and rolling leukocytes and mimicking scenarios. The guideline improved the inter-rater reliability of the manual assessment of both interactions. The intraclass correlation coefficient (ICC) of adherent leukocyte counts increased from 0.056 (95% confidence interval: 0-0.236, n = 88 videos, N = 10 subjects) to 0.791 (0.770-0.809, n = 1434, N = 67). The ICC of rolling leukocyte counts increased from 0.385 (0.191-0.550, n = 88, N = 10) to 0.626 (0.593-0.657, n = 1434, N = 67). Intra-rater ICC post-guideline was 0.953 (0.886-0.981, n = 20, N = 12) and 0.956 (0.894-0.983, n = 20, N = 12) for adherent and rolling, respectively. CONCLUSION: The guideline aids in the manual identification of adherent and rolling leukocytes via in vivo reflectance confocal videomicroscopy.
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Leucócitos , Microvasos , Adesão Celular , Humanos , Microcirculação , Microscopia de Vídeo , Microvasos/diagnóstico por imagem , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Interleukin 9 (IL-9), produced mainly by T helper 9 (Th9) cells, has been recognized as an important regulator in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Astrocytes respond to IL-9 and reactive astrocytes always associate with blood-brain barrier damage, immune cell infiltration, and spinal injury in MS and EAE. Several long non-coding RNAs (lncRNAs) with aberrant expression have been identified in the pathogenesis of MS. Here, we examined the effects of lncRNA Gm13568 (a co-upregulated lncRNA both in EAE mice and in mouse primary astrocytes activated by IL-9) on the activation of astrocytes and the process of EAE. METHODS: In vitro, shRNA-recombinant lentivirus with glial fibrillary acidic protein (GFAP) promoter were performed to determine the relative gene expression and proinflammatory cytokines production in IL-9 treated-astrocytes using Western blot, real-time PCR, and Cytometric Bead Array, respectively. RIP and ChIP assays were analyzed for the mechanism of lncRNA Gm13568 regulating gene expression. Immunofluorescence assays was performed to measure the protein expression in astrocytes. In vivo, H&E staining and LFB staining were applied to detect the inflammatory cells infiltrations and the medullary sheath damage in spinal cords of EAE mice infected by the recombinant lentivirus. Results were analyzed by one-way ANOVA or Student's t test, as appropriate. RESULTS: Knockdown of the endogenous lncRNA Gm13568 remarkably inhibits the Notch1 expression, astrocytosis, and the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) as well as the production of inflammatory cytokines and chemokines (IL-6, TNF-α, IP-10) in IL-9-activated astrocytes, in which Gm13568 associates with the transcriptional co-activators CBP/P300 which are enriched in the promoter of Notch1 genes. More importantly, inhibiting Gm13568 with lentiviral vector in astrocytes ameliorates significantly inflammation and demyelination in EAE mice, therefore delaying the EAE process. CONCLUSIONS: These findings uncover that Gm13568 regulates the production of inflammatory cytokines in active astrocytes and affects the pathogenesis of EAE through the Notch1/STAT3 pathway. LncRNA Gm13568 may be a promising target for treating MS and demyelinating diseases.
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Astrócitos/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Interleucina-9/metabolismo , RNA Longo não Codificante/imunologia , Receptor Notch1/biossíntese , Fatores de Transcrição de p300-CBP/metabolismo , Animais , Astrócitos/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Regulação da Expressão Gênica/imunologia , Interleucina-9/imunologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Longo não Codificante/metabolismo , Receptor Notch1/imunologia , Fatores de Transcrição de p300-CBP/imunologiaRESUMO
For decades, problems of parasitic emissions have been ubiquitously encountered in nearly all deep ultraviolet light-emitting diodes (DUV-LEDs). In this work, 450 nm parasitic peaks in 275 nm AlGaN DUV-LEDs have been studied in details. Upon careful comparisons and analyses on the electroluminescence and photoluminescence spectra at various injection levels and different temperatures, we have discovered a mechanism of exciton-assisted radiative recombination, namely, the reinforcement on radiative recombination via other impurity-trap levels (ITLs) by excitons that are generated in the midst of the band gap. For DUV-LED samples under investigation herein, a system of radiative ITLs within the band gap cannot be neglected. It includes two types of impurities located at two different energy levels, 3.80 eV and 2.75 eV, respectively. The former, establishing a sub-band edge, which behaves like an energy entrance to this system, contains a series of hydrogen-like excitons at a temperature lower than 100 K, which behaves like an energy entrance to this system. On the one hand, these excitons absorb carriers from band-edge and reduce the band-edge recombination. On the other hand they transfer the energy to lower impurity levels, enhancing the radiative recombination and giving rise to the 450 nm parasitic peak.
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OBJECTIVE: To describe upper dermal microvasculature of healthy human skin in terms of density and size of cutaneous blood vessels, leukocyte velocity, and leukocyte interactions with the endothelium. METHODS: We used a reflectance confocal microscope, the VivaScope 1500, to acquire videos of individual cell motion. RESULTS: We found no rolling leukocytes in the upper microvasculature of ten healthy subjects. We observed "paused" leukocytes, that is, leukocytes that temporarily stop, coinciding with the simultaneous stopping of the rest of the blood flow. We imaged more paused (median: 1.0 per subject) and adherent (1.5) leukocytes in the forearm than in the chest (median 0 paused and 0 adherent per subject) per 5 minutes of videos per body site. Leukocytes were paused for a median of 7 seconds in the forearm and 3 seconds in the chest, and we found no correlation between this parameter and the blood vessel or leukocyte size. We visualized blood flow change direction. Flowing leukocyte velocities followed a lognormal distribution and were on average higher in the chest (117 µm/s) than in the forearm (66 µm/s). CONCLUSION: The proposed method and reported values in healthy skin provide new insights into intact human skin microcirculation.
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Microcirculação/fisiologia , Pele/irrigação sanguínea , Adolescente , Adulto , Idoso , Velocidade do Fluxo Sanguíneo , Feminino , Humanos , Masculino , Microscopia Confocal , Microscopia de Vídeo , Pessoa de Meia-IdadeRESUMO
Post-translational modifications of the histone H2A represent an important mechanism by which cells modulate the structure and function of chromatin. Ubiquitination at K119 of histone H2A is associated transcriptional repression, which is shown to be regulated by deubiquitinases (DUBs). Here, we performed a screen to identify novel DUBs for histone H2A. Although RNAi-mediated knockdown of USP28, USP32 and USP36 showed that their depletion resulted in the increase of ub-K119-H2A, only USP28-depleted cells showed increased cell proliferation. Notably, USP28 knockdown cells had decreased expression of p53, p21 and p16INK4a, suggesting that the effect of USP28 on cell proliferation was mediated by regulating the expression of p53, p21 and p16INK4a. In summary, we have shown that USP28 is a deubiquitinase for histone H2A and is involved in regulation of cell proliferation. Thus, USP28 represents a potentially novel therapeutic target for cancer.
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Proliferação de Células/genética , Histonas/genética , Ubiquitina Tiolesterase/genética , Ubiquitinação/genética , Linhagem Celular , Cromatina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Células HEK293 , Humanos , Processamento de Proteína Pós-Traducional/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND Autophagy has a principal role in mediating tumor cell metabolism. However, the role of autophagy-pathway-related genes (APRGs) as prognostic markers remains obscure in lung adenocarcinoma (LUAD). More potential prognostic biomarkers are needed to deepen our understanding to explore the prognostic role of APRGs in LUAD. MATERIAL AND METHODS We used The Cancer Genome Atlas (TCGA) database to identify differentially expressed APRGs. Cox proportional hazard regression was used to identify prognostic APRGs, and then a risk model was constructed. The efficacy of the risk model was confirmed using a testing group. Lastly, we explored mutational signatures of prognostic of APRGs. T-tests were used to analyze all the expression patterns of genes by SPSS 19.0. RESULTS Using TCGA database, 5 differently expressed APRGs were identified in LUAD patients, and functional enrichment analyze of the genes that were closely associated with the survival status in LUAD patients. Cox proportional hazard regression was facilitated to identify 9 APRGs (CCR2, LAMP1, RELA, ATG12, ATG9A, NCKAP1, ATG10, DNAJB9, and MBTPS2). Multivariate Cox proportional hazards regression analyses further identified 5 key prognostic APRGs (CCR2, LAMP1, RELA, ATG12, and MBTPS2) that were closely related to the survival status in LUAD. Then the prognostic scores based on the 5 genes as independent prognostic indicators were constructed for overall survival (OS) of LUAD patients; area under the curve (AUC) values >0.70 (all P<0.05). The efficacy of prognostic scores was confirmed by data from the testing group and showed significant differences between the low-risk and the high-risk groups for OS (P<0.05). CONCLUSIONS The risk model based on the construction of 5 APRGs can predict the prognosis of patients with LUAD, which may potentially predict prognostic signatures for LUAD.
Assuntos
Adenocarcinoma/patologia , Proteínas Relacionadas à Autofagia/genética , Autofagia/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , Adenocarcinoma/genética , Bases de Dados Genéticas , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Análise de SobrevidaRESUMO
Parvovirus B19 is the most common causative agent of papular-purpuric gloves and socks syndrome (PPGSS), an often-underreported condition in the pediatric population. Classically, PPGSS presents with a papular-purpuric and at times petechial eruption of the hands and feet. (Dermatology. 1994;188:85; Int J Dermatol. 1996;35:626) We report a unique variant of juvenile PPGSS with prominent involvement of the flexural and extensor elbows, wrists, and knees.