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1.
EBioMedicine ; 53: 102672, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32114387

RESUMO

BACKGROUND: Abnormal expression of the orphan nuclear receptor Nurr1 is a critical factor in the etiology of multiple cancers. However, its potential role in gastric cancer (GC) remains elusive. In this study, we have demonstrated that the expression of Nurr1 was elevated and had an oncogenic function in GC. METHODS: Nurr1 expression was analyzed in clinical specimens and the GEO database. Functions of Nurr1 in GC cells were analyzed using Nurr1 knockdown and overexpression. Various cell and molecular biological methods were used to explore the potential mechanisms of Nurr1 upregulation and its role in promoting GC. FINDINGS: Overexpression of Nurr1 was directly related to the poor prognosis of GC patients. What's more, Nurr1 was induced by Helicobacter pylori (H. pylori) via the PI3K/AKT-Sp1 pathway. Sp1 enhanced Nurr1 expression by binding to its promoter to activate the transcription. Upregulated Nurr1 then directly targeted CDK4 by binding to its promoter region to increase its expression, thereby facilitated GC cells proliferation both in vitro and in vivo. INTERPRETATION: We identified Nurr1 as a driving oncogenic factor in GC. In addition, Nurr1 could be used as a potential therapeutic target for the diagnosis and treatment of H. pylori-associated GC. FUNDING: This work was supported by the National Natural Science Foundation of China (Nos 81801983, 81871620, 81971901, 81772151 and 81571960), and the Department of Science and Technology of Shandong Province (2018CXGC1208).

2.
Environ Pollut ; 262: 114288, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32155550

RESUMO

As an essential micronutrient for animals with a narrow range between essentiality and toxicity, selenium (Se) usually coexists with chromium (Cr) in contaminated aquatic environments. This study investigated effects of three diets (Microcystis aeruginosa, Chlorella vulgaris and biofilms) exposed to Se or/and Cr on Aedes albopictus as a vector for the aquatic-terrestrial transfer of Se and Cr. Se(IV)-exposed mosquitoes concentrated Se up to 66-fold faster than Se(VI)-exposed ones, corresponding to the greater Se enrichment in Se(IV)-treated diets. Analysis using synchrotron-based X-ray absorption spectroscopy (XAS) showed that Se(0) (61.9-74.6%) dominated Se(VI)-exposed mosquitoes except for the C. vulgaris-fed larvae (organo-Se, 94.0%), while organo-Se accounted for 93.3-100.0% in Se(IV)-exposed mosquitoes. Cr accumulation in larvae (56.40-87.24 µg Cr/g DW) or adults (19.41-50.77 µg Cr/g DW) was not significantly different among all Cr(VI) treatments, despite varying diet Cr levels. With Cr(0) being dominant (57.7-94.0%), Cr(VI)-exposed mosquitoes posed little threat to predators. Although mosquitoes exposed to Se or Cr had shorter wings, adults supplied with C. vulgaris or biofilms co-exposed to Se(VI) and Cr(VI) had wings significantly (1.1-1.2 fold) longer than Se(VI) only exposed ones. Overall, our study reveals the role of Ae. albopictus in transferring waterborne Se and Cr from the contaminated aquatic ecosystem to the terrestrial ecosystem with the resulting eco-risks to wildlife in both ecosystems.

3.
Int J Biol Macromol ; 151: 344-354, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32084473

RESUMO

Marine algae contain unique polysaccharides which differ from terrestrial plant polysaccharides, having a different composition, substitution, and linkage types. These are non-digestible by digestive enzymes in humans. Remarkably, marine algae polysaccharides (MAPs) may selectively enhance the activities of some populations of beneficial bacteria and stimulate the production of functional metabolites by gut microbiota. The MAPs also stimulate a range of biological activities, such as anti-cancer, anti-oxidant, immune-modulatory, and anti-diabetic. There is great potential to explore prebiotic MAP compounds. However, the exact digestion and fermentation behaviors in the human gastrointestinal tract, as well as their beneficial physiological effects, are to a large extent unexplored. An in-depth investigation of MAPs will provide us novel insights into the specific fermentation behavior for the observed human gut benefits. This paper is envisioned to offer a new perspective on the sustainability-promoting applications of MAPs as prebiotics in the functional food and pharmaceutical industries.

4.
J Clin Invest ; 130(1): 507-522, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31714901

RESUMO

X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαß+ T cells (αßDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.

5.
Nature ; 577(7788): 103-108, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31827281

RESUMO

RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1-/- mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.

6.
Comput Methods Programs Biomed ; : 105059, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31582263

RESUMO

BACKGROUND AND OBJECTIVE: With the rapid development of medical imaging and intelligent diagnosis, artificial intelligence methods have become a research hotspot of radiography processing technology in recent years. The low definition of knee magnetic resonance image texture seriously affects the diagnosis of knee osteoarthritis. This paper presents a super-resolution reconstruction method to address this problem. METHODS: In this paper, we propose an efficient medical image super-resolution (EMISR) method, in which we mainly adopted three hidden layers of super-resolution convolution neural network (SRCNN) and a sub-pixel convolution layer of efficient sub-pixel convolution neural network (ESPCN). The addition of the efficient sub-pixel convolutional layer in the hidden layer and the small network replacement consisting of concatenated convolutions to address low-resolution images but not high-resolution images are important. The EMISR method also uses cascaded small convolution kernels to improve reconstruction speed and deepen the convolution neural network to improve reconstruction quality. RESULTS: The proposed method is tested in the public dataset IDI, and the reconstruction quality of the algorithm is higher than that of the sparse coding-based network (SCN) method, the SRCNN method, and the ESPCN method (+ 2.306 dB, + 2.540 dB, + 1.089 dB improved); moreover, the reconstruction speed is faster than its counterparts (+ 4.272 s, + 1.967 s, and + 0.073 s improved). CONCLUSION: The experimental results show that our EMISR framework has improved performance and greatly reduces the number of parameters and training time. Furthermore, the reconstructed image presents more details, and the edges are more complete. Therefore, the EMISR technique provides a more powerful medical analysis in knee osteoarthritis examinations.

7.
EBioMedicine ; 47: 44-57, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31409573

RESUMO

BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors worldwide. Patients with poorly differentiated OSCC often exhibit a poor prognosis. AUNIP (Aurora Kinase A and Ninein Interacting Protein), also known as AIBp, plays a key role in cell cycle and DNA damage repair. However, the function of AUNIP in OSCC remains elusive. METHODS: The differentially expressed genes (DEGs) were obtained using R language. Receiver operating characteristic curve analysis was performed to identify diagnostic markers for OSCC. The effectiveness of AUNIP in diagnosing OSCC was evaluated by machine learning. AUNIP expression was analyzed in publicly available databases and clinical specimens. Bioinformatics analysis and in vitro experiments were conducted to explore biological functions and prognostic value of AUNIP in OSCC. FINDINGS: The gene integration analysis revealed 90 upregulated DEGs. One candidate biomarker, AUNIP, for the diagnosis of OSCC was detected, and its expression gradually increased along with malignant differentiation of OSCC. Bioinformatics analysis demonstrated that AUNIP could be associated with tumor microenvironment, human papillomavirus infection, and cell cycle in OSCC. The suppression of AUNIP inhibited OSCC cell proliferation and resulted in G0/G1 phase arrest in OSCC cells. The survival analysis showed that AUNIP overexpression predicted poor prognosis of OSCC patients. INTERPRETATION: AUNIP could serve as a candidate diagnostic and prognostic biomarker for OSCC and suppression of AUNIP may be a potential approach to preventing and treating OSCC. FUND: Taishan Scholars Project in Shandong Province (ts201511106) and the National Natural Science Foundation of China (Nos. 61603218).


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Proteínas de Ligação a DNA/genética , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/genética , Adulto , Idoso , Carcinoma de Células Escamosas/mortalidade , Ciclo Celular/genética , Linhagem Celular Tumoral , Biologia Computacional , Bases de Dados Genéticas , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/mortalidade , Prognóstico , Curva ROC , Análise de Sobrevida , Transcriptoma
8.
Comput Methods Programs Biomed ; : 104964, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31262537

RESUMO

BACKGROUND AND OBJECTIVE: Computer aided diagnosis systems based on deep learning and medical imaging is increasingly becoming research hotspots. At the moment, the classical convolutional neural network generates classification results by hierarchically abstracting the original image. These abstract features are less sensitive to the position and orientation of the object, and this lack of spatial information limits the further improvement of image classification accuracy. Therefore, how to develop a suitable neural network framework and training strategy in practical clinical applications to avoid this problem is a topic that researchers need to continue to explore. METHODS: We propose a deep learning framework that combines residual thought and dilated convolution to diagnose and detect childhood pneumonia. Specifically, based on an understanding of the nature of the child pneumonia image classification task, the proposed method uses the residual structure to overcome the over-fitting and the degradation problems of the depth model, and utilizes dilated convolution to overcome the problem of loss of feature space information caused by the increment in depth of the model. Furthermore, in order to overcome the problem of difficulty in training model due to insufficient data and the negative impact of the introduction of structured noise on the performance of the model, we use the model parameters learned on large-scale datasets in the same field to initialize our model through transfer learning. RESULTS: Our proposed method has been evaluated for extracting texture features associated with pneumonia and for accurately identifying the performance of areas of the image that best indicate pneumonia. The experimental results of the test dataset show that the recall rate of the method on children pneumonia classification task is 96.7%, and the f1-score is 92.7%. Compared with the prior art methods, this approach can effectively solve the problem of low image resolution and partial occlusion of the inflammatory area in children chest X-ray images. CONCLUSIONS: The novel framework focuses on the application of advanced classification that directly performs lesion characterization, and has high reliability in the classification task of children pneumonia.

9.
J Biol Chem ; 294(37): 13638-13656, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31337704

RESUMO

Magnesium transporter 1 (MAGT1) critically mediates magnesium homeostasis in eukaryotes and is highly-conserved across different evolutionary branches. In humans, loss-of-function mutations in the MAGT1 gene cause X-linked magnesium deficiency with Epstein-Barr virus (EBV) infection and neoplasia (XMEN), a disease that has a broad range of clinical and immunological consequences. We have previously shown that EBV susceptibility in XMEN is associated with defective expression of the antiviral natural-killer group 2 member D (NKG2D) protein and abnormal Mg2+ transport. New evidence suggests that MAGT1 is the human homolog of the yeast OST3/OST6 proteins that form an integral part of the N-linked glycosylation complex, although the exact contributions of these perturbations in the glycosylation pathway to disease pathogenesis are still unknown. Using MS-based glycoproteomics, along with CRISPR/Cas9-KO cell lines, natural killer cell-killing assays, and RNA-Seq experiments, we now demonstrate that humans lacking functional MAGT1 have a selective deficiency in both immune and nonimmune glycoproteins, and we identified several critical glycosylation defects in important immune-response proteins and in the expression of genes involved in immunity, particularly CD28. We show that MAGT1 function is partly interchangeable with that of the paralog protein tumor-suppressor candidate 3 (TUSC3) but that each protein has a different tissue distribution in humans. We observed that MAGT1-dependent glycosylation is sensitive to Mg2+ levels and that reduced Mg2+ impairs immune-cell function via the loss of specific glycoproteins. Our findings reveal that defects in protein glycosylation and gene expression underlie immune defects in an inherited disease due to MAGT1 deficiency.

10.
J Exp Med ; 216(8): 1828-1842, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31196981

RESUMO

Mg2+ is required at micromolar concentrations as a cofactor for ATP, enzymatic reactions, and other biological processes. We show that decreased extracellular Mg2+ reduced intracellular Mg2+ levels and impaired the Ca2+ flux, activation marker up-regulation, and proliferation after T cell receptor (TCR) stimulation. Reduced Mg2+ specifically impairs TCR signal transduction by IL-2-inducible T cell kinase (ITK) due to a requirement for a regulatory Mg2+ in the catalytic pocket of ITK. We also show that altered catalytic efficiency by millimolar changes in free basal Mg2+ is an unrecognized but conserved feature of other serine/threonine and tyrosine kinases, suggesting a Mg2+ regulatory paradigm of kinase function. Finally, a reduced serum Mg2+ concentration in mice causes an impaired CD8+ T cell response to influenza A virus infection, reduces T cell activation, and exacerbates morbidity. Thus, Mg2+ directly regulates the active site of specific kinases during T cell responses, and maintaining a high serum Mg2+ concentration is important for antiviral immunity in otherwise healthy animals.

11.
Cancer Med ; 8(8): 3965-3980, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31145543

RESUMO

Gastric cancer (GC) is one of the most common and malignant pathologies, and a significant portion of GC incidences develops from Helicobacter pylori (Hp)-induced chronic gastritis. Although the exact mechanisms of GC are complex and poorly understood, gastric carcinogenesis is a good model to investigate how inflammation and infection collaboratively promote tumorigenesis. Yes-associated protein 1 (YAP1) is the key effector of the Hippo pathway, which is silenced in most human cancers. Herein, we verified the tumor-promoting effect of YAP1 in vitro, in vivo, and in human specimens. We revealed that YAP1 displays nuclear translocation and works with TEAD to activate transcription of the crucial inflammatory cytokine IL-1ß in gastric cells infected with Hp. As IL-1ß accounts for inflammation-associated tumorigenesis, this process can lead to gastric carcinogenesis. Thus, in addition to activating proliferation genes, YAP1 also plays a major role in inflammation amplification by activating inflammatory cytokine genes. Excitingly, our research demonstrates that transfection of mutant plasmid YAP-5SA/S94A or addition of the drug verteporfin, both of which are thought to disrupt the YAP1-TEAD interaction, can arrest the carcinogenesis process. These findings can provide new approaches to GC treatment.

13.
Sci Adv ; 5(1): eaau7426, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30662948

RESUMO

Hyperactivation of the NLRP3 inflammasome contributes to the pathogenesis of multiple diseases, but the mechanisms underlying transcriptional regulation of Nlrp3 remain elusive. We demonstrate here that macrophages lacking V-set and immunoglobulin domain-containing 4 (Vsig4) exhibit significant increases in Nlrp3 and Il-1ß transcription, caspase-1 activation, pyroptosis, and interleukin-1ß (IL-1ß) secretion in response to NLRP3 inflammasome stimuli. VSIG4 interacts with MS4A6D in the formation of a surface signaling complex. VSIG4 occupancy triggers Ser232 and Ser235 phosphorylation in MS4A6D, leading to activation of JAK2-STAT3-A20 cascades that further results in nuclear factor κB suppression and Nlrp3 and Il-1ß repression. Exaggerated NLRP3 and IL-1ß expression in Vsig4-/- mice is accountable for deleterious disease severity in experimental autoimmune encephalomyelitis (EAE) and resistance to dextran sulfate sodium (DSS)-induced colitis. The agonistic VSIG4 antibodies (VG11), acting through NLRP3 and IL-1ß suppression, show significant therapeutic efficacy in mouse EAE. These findings highlight VSIG4 as a prospective target for treating NLRP3-associated inflammatory disorders.

14.
FASEB J ; 33(2): 2199-2211, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30226811

RESUMO

Corneal immune privilege is integral in maintaining the clear avascular window to the foreign world. The presence of distinct populations of corneal leukocytes (CLs) in the normal cornea has been firmly established. However, their precise function and kinetics remain, as of yet, unclear. Through intravital multiphoton microscopy (IV-MPM), allowing the means to accumulate critical spatial and temporal cellular information, we provide details for long-term investigation of CL morphology and kinetics under steady state and following inflammation. Significant alterations in size and morphology of corneal CD11c+ dendritic cells (DCs) were noted following acute sterile inflammation, including cell volume (4364.4 ± 489.6 vs. 1787.6 ± 111.0 µm3, P < 0.001) and sphericity (0.82 ± 0.01 vs. 0.42 ± 0.02, P < 0.001) compared with steady state. Furthermore, IV-MPM analyses revealed alterations in both the CD11c+ DC and major histocompatibility complex class II (MHC)-II+ mature antigen-presenting cell population kinetics during inflammation, including track displacement length (CD11c: 16.57 ± 1.41 vs. 4.64 ± 0.56 µm, P < 0.001; MHC-II: 9.03 ± 0.37 vs. 4.09 ± 0.39, P < 0.001) and velocity (CD11c: 1.91 ± 0.07 µm/min vs. 1.73 ± 0.1302 µm/min; MHC-II: 2.97 ± 0.07 vs. 1.62 ± 0.08, P < 0.001) compared with steady state. Our results reveal in vivo evidence of sessile CL populations exhibiting dendritic morphology under steady state and increased velocity of spherical leukocytes following inflammation. IV-MPM represents a powerful tool to study leukocytes in corneal diseases in context.-Seyed-Razavi, Y., Lopez, M. J., Mantopoulos, D., Zheng, L., Massberg, S., Sendra, V. G., Harris, D. L., Hamrah, P. Kinetics of corneal leukocytes by intravital multiphoton microscopy.


Assuntos
Córnea/citologia , Leucócitos/citologia , Microscopia/métodos , Animais , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fótons
15.
EBioMedicine ; 39: 301-314, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30502053

RESUMO

BACKGROUND: Rhythm abnormalities are crucial for diverse diseases. However, their role in disease progression induced by Helicobacter pylori (H. pylori) remains elusive. METHODS: H. pylori infection was used in in vivo and in vitro experiments to examine its effect on rhythmic genes. The GEO database was used to screen H. pylori affecting rhythm genes, and the effect of rhythm genes on inflammatory factors. Chromatin immunoprecipitation and dual luciferase assays were used to further find out the regulation between molecules. Animal models were used to confirm the relationship between rhythm genes and H. pylori-induced inflammation. FINDINGS: BMAL1 disorders aggravate inflammation induced by H. pylori. Specifically, H. pylori induce BMAL1 expression in vitro and in vivo through transcriptional activation of LIN28A, breaking the circadian rhythm. Mechanistically, LIN28A binds to the promoter region of BMAL1 and directly activates its transcription under H. pylori infection. BMAL1 in turn functions as a transcription factor and enhances the expression of proinflammatory cytokine TNF-α, thereby promoting inflammation. Of note, BMAL1 dysfunction in the rhythm disorder animal model aggravates inflammatory response induced by H. pylori infection in vivo. INTERPRETATION: These findings in this study imply the pathogenic relationship between BMAL1 and H. pylori. BMAL1 may serve as a potential diagnostic marker and therapeutic target for the early diagnosis and treatment of diseases related to H. pylori infection. FUND: National Natural Science Foundation of China.


Assuntos
Fatores de Transcrição ARNTL/genética , Gastrite/microbiologia , Infecções por Helicobacter/genética , Helicobacter pylori/patogenicidade , Proteínas de Ligação a RNA/genética , Fator de Necrose Tumoral alfa/genética , Animais , Linhagem Celular , Ritmo Circadiano , Modelos Animais de Doenças , Feminino , Gastrite/genética , Humanos , Masculino , Camundongos , Regiões Promotoras Genéticas , Ativação Transcricional
16.
EBioMedicine ; 38: 69-78, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30449701

RESUMO

BACKGROUND: Histones chaperones have been found to play critical roles in tumor development and progression. However, the role of histone chaperone CHAF1A in gastric carcinogenesis and its underlying mechanisms remain elusive. METHODS: CHAF1A expression in gastric cancer (GC) was analyzed in GEO datasets and clinical specimens. CHAF1A knockdown and overexpression were used to explore its functions in gastric cancer cells. The regulation and potential molecular mechanism of CHAF1A expression in gastric cancer cells were studied by using cell and molecular biological methods. FINDINGS: CHAF1A was upregulated in GC tissues and its high expression predicted poor prognosis in GC patients. Overexpression of CHAF1A promoted gastric cancer cell proliferation both in vitro and in vivo, whereas CHAF1A suppression exhibited the opposite effects. Mechanistically, CHAF1A acted as a co-activator in the Wnt pathway. CHAF1A directly interacted with TCF4 to enhance the expression of c-MYC and CCND1 through binding to their promoter regions. In addition, the overexpression of CHAF1A was modulated by specificity protein 1 (Sp1) in GC. Sp1 transcriptionally enhanced the expression of CHAF1A in GC. Furthermore, CHAF1A expression induced by Helicobacter pylori was Sp1 dependent. INTERPRETATION: CHAF1A is a potential oncogene in GC, and may serve as a novel therapeutic target for GC treatment.


Assuntos
Ciclina D1/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-myc/genética , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/metabolismo , Fator de Transcrição 4/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Fator 1 de Modelagem da Cromatina/metabolismo , Modelos Animais de Doenças , Xenoenxertos , Humanos , Camundongos , Modelos Biológicos , Ligação Proteica , Fator de Transcrição Sp1/metabolismo , Neoplasias Gástricas/patologia
17.
Phys Rev Lett ; 121(13): 137401, 2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-30312094

RESUMO

Electron-hole excitation theory is used to unveil the role of nuclear quantum effects on the x-ray absorption spectral signatures of water, whose structure is computed via path-integral molecular dynamics with the MB-pol intermolecular potential model. Compared to spectra generated from the classically modeled water, quantum nuclei introduce important effects on the spectra in terms of both the energies and line shapes. Fluctuations due to delocalized protons influence the short-range ordering of the hydrogen bond network via changes in the intramolecular covalence, which broaden the preedge spectra. For intermediate-range and long-range ordering, quantum nuclei approach the neighboring oxygen atoms more closely than classical protons, promoting an "icelike" spectral feature with the intensities shifted from the main edge to the postedge. Computed spectra are in nearly quantitative agreement with the available experimental data.

18.
ACS Nano ; 12(11): 11579-11590, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30265798

RESUMO

While there has been extensive development of soluble epitope-specific peptides to induce immune tolerance for the treatment of autoimmune diseases, the clinical efficacy of soluble-peptides-based immunotherapy was still uncertain. Recent strategies to develop antigen carriers coupled with peptides have shown promising results in preclinical animal models. Here we developed functional amphiphilic hyperbranched (HB) polymers with different grafting degrees of hydrophobic chains as antigen myelin antigen oligodendrocyte glycoprotein (MOG) peptide carriers and evaluated their ability to induce immune tolerance. We show that these polymers could efficiently deliver antigen peptide, and the uptake amount by bone marrow dendritic cells (BMDCs) was correlated with the hydrophobicity of polymers. We observe that these polymers have a higher ability to activate BMDCs and a higher efficacy to induce antigen-specific T cell apoptosis than soluble peptides, irrespective of hydrophobicity. We show that intravenous injection of polymer-conjugated MOG peptide, but not soluble peptide, markedly treats the clinical symptoms of experimental autoimmune encephalomyelitis in mice. Together, these results demonstrate the potential for using amphiphilic HB polymers as antigen carriers to deliver peptides for pathogenic autoreactive T cell deletion/tolerance strategies to treat autoimmune disorders.


Assuntos
Membrana Celular/química , Sistemas de Liberação de Medicamentos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/uso terapêutico , Polímeros/química , Animais , Apoptose/efeitos dos fármacos , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Glicoproteína Mielina-Oligodendrócito/química , Glicoproteína Mielina-Oligodendrócito/imunologia , Linfócitos T/efeitos dos fármacos
19.
J Chem Phys ; 148(16): 164505, 2018 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-29716217

RESUMO

We perform ab initio molecular dynamics (AIMD) simulation of liquid water in the canonical ensemble at ambient conditions using the strongly constrained and appropriately normed (SCAN) meta-generalized-gradient approximation (GGA) functional approximation and carry out systematic comparisons with the results obtained from the GGA-level Perdew-Burke-Ernzerhof (PBE) functional and Tkatchenko-Scheffler van der Waals (vdW) dispersion correction inclusive PBE functional. We analyze various properties of liquid water including radial distribution functions, oxygen-oxygen-oxygen triplet angular distribution, tetrahedrality, hydrogen bonds, diffusion coefficients, ring statistics, density of states, band gaps, and dipole moments. We find that the SCAN functional is generally more accurate than the other two functionals for liquid water by not only capturing the intermediate-range vdW interactions but also mitigating the overly strong hydrogen bonds prescribed in PBE simulations. We also compare the results of SCAN-based AIMD simulations in the canonical and isothermal-isobaric ensembles. Our results suggest that SCAN provides a reliable description for most structural, electronic, and dynamical properties in liquid water.

20.
Nat Chem ; 10(4): 413-419, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29531374

RESUMO

Proton transfer via hydronium and hydroxide ions in water is ubiquitous. It underlies acid-base chemistry, certain enzyme reactions, and even infection by the flu. Despite two centuries of investigation, the mechanism underlying why hydroxide diffuses slower than hydronium in water is still not well understood. Herein, we employ state-of-the-art density-functional-theory-based molecular dynamics-with corrections for non-local van der Waals interactions, and self-interaction in the electronic ground state-to model water and hydrated water ions. At this level of theory, we show that structural diffusion of hydronium preserves the previously recognized concerted behaviour. However, by contrast, proton transfer via hydroxide is less temporally correlated, due to a stabilized hypercoordination solvation structure that discourages proton transfer. Specifically, the latter exhibits non-planar geometry, which agrees with neutron-scattering results. Asymmetry in the temporal correlation of proton transfer leads to hydroxide diffusing slower than hydronium.

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