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1.
J Cancer Res Clin Oncol ; 147(1): 153-165, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32968877

RESUMO

PURPOSE: Ewing sarcoma (ES) is one of the most common malignant bone tumors in children and adolescents. The immune microenvironment plays an important role in the development of ES. Here, we developed an optimal signature for determining ES patient prognosis based on immune-related genes (IRGs). METHODS: We analyzed the ES gene expression profile dataset, GSE17679, from the GEO database and extracted differential expressed IRGs (DEIRGs). Then, we conducted functional correlation and protein-protein interaction (PPI) analyses of the DEIRGs and used the machine learning algorithm-iterative Lasso Cox regression analysis to build an optimal DEIRG signature. In addition, we applied ES samples from the ICGC database to test the optimal gene signature. We performed univariate and multivariate Cox regressions on clinicopathological characteristics and optimal gene signature to evaluate whether signature is an important prognostic factor. Finally, we calculated the infiltration of 24 immune cells in ES using the ssGSEA algorithm, and analyzed the correlation between the DEIRGs in the optimal gene signature and immune cells. RESULTS: A total of 249 DEIRGs were screened and an 11-gene signature with the strongest correlation with patient prognoses was analyzed using a machine learning algorithm. The 11-gene signature also had a high prognostic value in the ES external verification set. Univariate and multivariate Cox regression analyses showed that 11-gene signature is an independent prognostic factor. We found that macrophages and cytotoxic, CD8 T, NK, mast, B, NK CD56bright, TEM, TCM, and Th2 cells were significantly related to patient prognoses; the infiltration of cytotoxic and CD8 T cells in ES was significantly different. By correlating prognostic biomarkers with immune cell infiltration, we found that FABP4 and macrophages, and NDRG1 and Th2 cells had the strongest correlation. CONCLUSION: Overall, the IRG-related 11-gene signature can be used as a reliable ES prognostic biomarker and can provide guidance for personalized ES therapy.

2.
Biomed Pharmacother ; 133: 111042, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378950

RESUMO

The application of photodynamic therapy (PDT) for the treatment of skin diseases has been receiving much attention. Here, we examined the anti-tumor effect of a novel porphyrin-based photosensitizer TBPoS-2OH in the malignant melanoma A375 and B16 cells. TBPoS-2OH has obvious cell photo-cytotoxicity, but it has low cell dark-cytotoxicity. Further research showed that TBPoS-2OH is enriched in lysosomes after being taken up by cells. Subsequently, the apoptotic rates were significantly increased in TBPoS-2OH-treated A375 and B16 cells. The specific mechanism may be that after receiving light stimulation, TBPoS-2OH could effectively increase the level of intracellular reactive oxygen species (ROS), thereby activating mitochondrial apoptosis pathway-related proteins in A375 and B16 cells. We found an increase in the content of cytochrome C in the cytoplasm, and the levels of related proteins, such as cleaved caspase-3, cleaved caspase-9, and cleaved PARP1, were significantly increased in TBPoS-2OH-treated cells. These results indicated that the new compound TBPoS-2OH could be developed and become an alternative drug for the treatment of melanoma. Some reference ideas for the development of new photosensitizers are also provided.

3.
Proc Natl Acad Sci U S A ; 117(52): 33295-33304, 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33318171

RESUMO

Adipocytes have been implicated in breast tumor growth and stemness maintenance through secreted factors. However, the mechanisms by which these cytokines are regulated during diet-induced obesity and contribute to breast tumorigenesis remain largely unknown. Here we show that transcription cofactor TAZ in adipocytes is directly up-regulated by the free fatty acid/PPARγ axis upon dietary fat stimulation. TAZ knockdown alters the expression profile of a series of secreted proteins and attenuates the tumor-supporting function of adipocytes. Moreover, we identify Resistin, an adipose-derived hormone, as a functional downstream target of TAZ, which facilitates tumorigenesis, and its expression correlated with adipocyitc TAZ in triple-negative breast cancer samples. Further, Adiponectin-cre-mediated TAZ knockout in adipocytes mitigates breast tumor growth. Taken together, our findings highlight how diet-induced TAZ expression in adipocytes promotes tumorigenesis, suggesting promising cancer therapeutic targets.

4.
Cancer Discov ; 2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33328215

RESUMO

Glioblastoma (GBM) contains self-renewing GBM stem cells (GSCs) potentially amenable to immunologic targeting, but chimeric antigen receptor (CAR) T cell therapy has demonstrated limited clinical responses in GBM. Here, we interrogated molecular determinants of CAR-mediated GBM killing through whole-genome CRISPR screens in both CAR T cells and patient-derived GSCs. Screening of CAR T cells identified dependencies for effector functions, including TLE4 and IKZF2. Targeted knockout of these genes enhanced CAR antitumor efficacy. Bulk and single cell-RNA sequencing of edited CAR T cells revealed transcriptional profiles of superior effector function and inhibited exhaustion responses. Reciprocal screening of GSCs identified genes essential for susceptibility to CAR-mediated killing, including RELA and NPLOC4, the knockout of which altered tumor-immune signaling and increased responsiveness of CAR therapy. Overall, CRISPR screening of CAR T cells and GSCs discovered avenues for enhancing CAR therapeutic efficacy against GBM, with the potential to be extended to other solid tumors.

5.
Eur J Dent ; 2020 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-33368065

RESUMO

OBJECTIVES: The aim was to evaluate the characteristics of the mandibular third molars, especially in relation to the inferior alveolar nerve. Further aims were to investigate incidental findings in panoramic radiographs in an adult population, and to investigate image quality related to patient positioning. MATERIALS AND METHODS: From a previous study with 451 randomly selected adult participants who lived in Sweden, 442 panoramic radiographs from four dental public health clinics were used. The third molars' characteristics and relation to inferior alveolar nerve were evaluated. Incidental findings and patient positioning were recorded. STATISTICAL ANALYSIS: Frequency analysis was used to investigate the occurrence of all findings and their possible interconnections. Whether the patients' age or gender had an impact or not was also analyzed. RESULTS: The third molars were erupted in vertical position among 73% regardless of age. When retained or semi-retained, they were most commonly in mesioangular positions. The inferior alveolar nerve was located inferior to the roots in 52%, whereas an overlapped position was most common if the third molar was retained (90%), semi-retained (83%) or the age was less than 30 years (66%). Common incidental findings were apical radiolucencies, idiopathic osteosclerosis, and tooth fragments. Suboptimal patient positioning was found in one-third of the radiographs. CONCLUSIONS: Panoramic radiography is a useful method to evaluate third molar prior to surgical removal and may be the only image required. Most incidental findings on panoramic radiographs does not seem to require any further odontological management.

6.
Cancer Discov ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023892

RESUMO

Glioblastoma is a universally lethal cancer driven by glioblastoma stem cells (GSCs). Here, we interrogated N6-methyladenosine (m6A) mRNA modifications in GSCs by methyl RNA-immunoprecipitation followed by sequencing (meRIP-seq) and transcriptome analysis, finding transcripts marked by m6A often upregulated compared to normal neural stem cells (NSCs). Interrogating m6A regulators, GSCs displayed preferential expression, as well as in vitro and in vivo dependency, of the m6A reader, YTHDF2, in contrast to NSCs. While YTHDF2 has been reported to destabilize mRNAs, YTHDF2 stabilized MYC and VEGFA transcripts in GSCs in an m6A-dependent manner. We identified IGFBP3 as a downstream effector of the YTHDF2-MYC axis in GSCs. The IGF1/IGF1R inhibitor, linsitinib, preferentially targeted YTHDF2-expressing cells, inhibiting GSC viability without affecting NSCs and impairing in vivo glioblastoma growth. Thus, YTHDF2 links RNA epitranscriptomic modifications and GSC growth, laying the foundation for the YTHDF2-MYC-IGFBP3 axis as a specific and novel therapeutic target in glioblastoma.

7.
Proc Natl Acad Sci U S A ; 117(44): 27694-27702, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33077597

RESUMO

Abscisic acid (ABA) is the key phytohormone in plant drought tolerance and stress adaptation. The clade A protein phosphatase 2Cs (PP2Cs) like ABI1 (ABA-INSENSITIVE 1) work as coreceptors of ABA and regulate multiple ABA responses. Ubiquitination of ABI1 has been proven to play important regulatory roles in ABA signaling. However, the specific ubiquitin conjugating enzyme (E2) involved is unknown. Here, we report that UBC27 is an active E2 that positively regulates ABA signaling and drought tolerance. UBC27 forms the E2-E3 pair with the drought regulator RING E3 ligase AIRP3. Both UBC27 and AIRP3 interact with ABI1 and affect the ubiquitination and degradation of ABI1. ABA activates the expression of UBC27, inhibits the proteasome degradation of UBC27, and enhances the interaction between UBC27 and ABI1 to increase its activity. These findings uncover a regulatory mechanism in ABA signaling and drought response and provide a further understanding of the plant ubiquitination system and ABA signaling pathway.


Assuntos
Ácido Abscísico/metabolismo , Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiologia , Fosfoproteínas Fosfatases/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Aclimatação/genética , Proteínas de Arabidopsis/genética , Secas , Retroalimentação Fisiológica , Regulação da Expressão Gênica de Plantas , Técnicas de Silenciamento de Genes , Mutação , Fosfoproteínas Fosfatases/genética , Plantas Geneticamente Modificadas , Proteólise , Transdução de Sinais/genética , Enzimas de Conjugação de Ubiquitina/genética , Ubiquitinação
8.
Medicine (Baltimore) ; 99(40): e22399, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019414

RESUMO

BACKGROUND: Essential hypertension remains an enormous public health concern, imposing a major burden of morbidity and mortality worldwide. Relevant studies showed that acupuncture therapy might be effective in treating essential hypertension. However, there is no consistent conclusion so far. The aim of this study was to assess the efficacy and safety of acupuncture therapy for patients with essential hypertension. METHODS: We searched the PubMed, Embase, the Cochrane Library, Web of Science, the Chinese National Knowledge Infrastructure (CNKI), and the Wan-fang databases from inception through November 29, 2019. Randomized controlled trials investigating acupuncture therapy for hypertension were included. We will use Endnote software X8 for studies selection, Review Manager software 5.3 for the data analysis. RESULTS: We will synthesize current studies to evaluate the safeties and effectiveness of acupuncture for essential hypertension. CONCLUSIONS: Our study will provide the evidence of acupuncture therapy for essential hypertension.


Assuntos
Terapia por Acupuntura/métodos , Hipertensão Essencial/terapia , Pontos de Acupuntura , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
9.
Medicine (Baltimore) ; 99(43): e22939, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120853

RESUMO

RATIONALE: Some diseases contribute to hypopituitarism without clinical manifestations and the glucocorticoid therapy may unveil central diabetes insipidus. The condition is rare and usually causes problems for clinical physicians. PATIENT CONCERNS: A 59-year-old woman presented to our hospital due to facial numbness and persistent eyelid heaviness. DIAGNOSIS: Physical examination and cerebrospinal fluid examination supported a diagnosis of Guillain-Barre[Combining Acute Accent] syndrome. Magnetic resonance imaging showed an empty sella. Hormone test indicated hypopituitarism. INTERVENTIONS: The patient received intravenous immunoglobulin and glucocorticoid. Central diabetes insipidus appeared after 20 days. Subsequently, the patient was prescribed 1-desamino-8-D-arginine vasopressin and prednisone. OUTCOMES: During 6 months' follow-up, the patient's urine output was gradually reduced to normal level. LESSONS: This case indicated that hypopituitarism may be caused by an empty sella and be masked by adrenal insufficiency. Central diabetes insipidus may present after glucocorticoid therapy.


Assuntos
Diabetes Insípido Neurogênico/etiologia , Síndrome da Sela Vazia/complicações , Glucocorticoides/efeitos adversos , Hipopituitarismo/etiologia , Adolescente , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Desamino Arginina Vasopressina/uso terapêutico , Diabetes Insípido Neurogênico/tratamento farmacológico , Quimioterapia Combinada , Síndrome da Sela Vazia/diagnóstico por imagem , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Síndrome de Guillain-Barré/líquido cefalorraquidiano , Síndrome de Guillain-Barré/etiologia , Humanos , Hipopituitarismo/sangue , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/uso terapêutico , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Resultado do Tratamento
10.
Differentiation ; 116: 9-15, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33080410

RESUMO

BACKGROUND: Congenital hypospadias is a common congenital malformation of the urinary system in male children. However, the role of circRNA in congenital hypospadias remains unknown. METHODS: Differentially expressed circRNAs and mRNAs were identified by RNA sequencing. GO and KEEG analysis were performed to uncover the key function and pathways. The interaction networks were constructed and analyzed by competing endogenous (ce)RNA analysis. Immunohistochemistry (IHC) and qRT-PCR were used to detect the expressions of androgen receptor (AR) and hsa_circ_0000417 in normal and hypospadias tissues. Further, the correlation between hsa_circ_0000417 and other clinical indicators were calculated. RESULTS: Compared with normal foreskin tissues, 1329 circRNAs and 978 mRNAs were significantly upregulated, 3176 circRNAs and 614 mRNAs were significantly downregulated in hypospadias tissues, respectively. MAPK and PI3K-Akt signaling pathways play important roles in congenital hypospadias. The expression of AR and hsa_circ_0000417 in 68 hypospadias tissues was significantly lower than that in 68 normal foreskin tissues (P < 0.05). The expression of the AR, as analyzed using IHC, was consistent with the qPCR results. A significant correlation was noted between the expression of AR and hsa_circ_0000417 in 68 clinical samples (P < 0.05). Furthermore, the expression level of hsa_circ_0000417 was associated with the incidence of other diseases and the location of the hypospadias site (P < 0.05). Expression of hsa_circ_0000417 was significantly downregulated in hypospadias patients without other diseases (P < 0.05). CONCLUSION: Hsa_circ_0000417 may regulate the expression of AR, and the expression of hsa_circ_0000417 in normal foreskin tissues is associated with the occurrence of hypospadias.

11.
Sci Rep ; 10(1): 18402, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110201

RESUMO

Immune-related genes (IRGs) are responsible for osteosarcoma (OS) initiation and development. We aimed to develop an optimal IRGs-based signature to assess of OS prognosis. Sample gene expression profiles and clinical information were downloaded from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Genotype-Tissue Expression (GTEx) databases. IRGs were obtained from the ImmPort database. R software was used to screen differentially expressed IRGs (DEIRGs) and functional correlation analysis. DEIRGs were analyzed by univariate Cox regression and iterative LASSO Cox regression analysis to develop an optimal prognostic signature, and the signature was further verified by independent cohort (GSE39055) and clinical correlation analysis. The analyses yielded 604 DEIRGs and 10 hub IRGs. A prognostic signature consisting of 13 IRGs was constructed, which strikingly correlated with OS overall survival and distant metastasis (p < 0.05, p < 0.01), and clinical subgroup showed that the signature's prognostic ability was independent of clinicopathological factors. Univariate and multivariate Cox regression analyses also supported its prognostic value. In conclusion, we developed an IRGs signature that is a prognostic indicator in OS patients, and the signature might serve as potential prognostic indicator to identify outcome of OS and facilitate personalized management of the high-risk patients.

12.
New Phytol ; 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32990949

RESUMO

CERBERUS (also known as LIN) and VAPYRIN (VPY) are essential for infection of legumes by rhizobia and arbuscular mycorrhizal fungi (AMF). Medicago truncatula LIN (MtLIN) was reported to interact with MtVPY, but the significance of this interaction is unclear and the function of VPY in Lotus japonicus has not been studied. We demonstrate that CERBERUS has auto-ubiquitination activity in vitro and is localized within distinct motile puncta in L. japonicus root hairs and in Nicotiana benthamiana leaves. CERBERUS colocalized with the trans-Golgi network/early endosome markers. In L. japonicus, two VPY orthologs (LjVPY1 and LjVPY2) were identified. CERBERUS interacted with and colocalized with both LjVPY1 and LjVPY2. Co-expression of CERBERUS with LjVPY1 or LjVPY2 in N. benthamiana led to increased protein levels of LjVPY1 and LjVPY2, which accumulated as mobile punctate bodies in the cytoplasm. Conversely, LjVPY2 protein levels decreased in cerberus roots after rhizobial inoculation. Mutant analysis indicates that LjVPY1 and LjVPY2 are required for rhizobial infection and colonization by AMF. Our data suggest that CERBERUS stabilizes LjVPY1 and LjVPY2 within the trans-Golgi network/early endosome, where they might function to regulate endocytic trafficking and/or the formation or recycling of signaling complexes during rhizobial and AMF symbiosis.

13.
Mol Plant ; 13(11): 1556-1569, 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-32919085

RESUMO

A myriad of abiotic stress responses in plants are controlled by abscisic acid (ABA) signaling. ABA receptors can be degraded by both the 26S proteasome pathway and vacuolar degradation pathway after processing via the endosomal sorting complex required for transport (ESCRT) proteins. Despite being essential for ABA signaling, the upstream regulators of ESCRTs remain unknown. Here, we report that the ESCRT-I component VPS23A is an unstable protein that is degraded via the ubiquitin-proteasome system (UPS). The UEV domain of VPS23A physically interacts with the two PSAP motifs of XBAT35, an E3 ubiquitin ligase, and this interaction results in the deposition of K48 polyubiquitin chains on VPS23A, marking it for degradation by 26S proteasomes. We showed that XBAT35 in plants is a positive regulator of ABA responses that acts via the VPS23A/PYL4 complex, specifically by accelerating VPS23A turnover and thereby increasing accumulation of the ABA receptor PYL4. This work deciphers how an ESCRT component is regulated in plants and deepens our understanding of plant stress responses by illustrating a mechanism whereby crosstalk between the UPS and endosome-vacuole-mediated degradation pathways controls ABA signaling.

14.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(5): 714-719, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-32975090

RESUMO

Objective: To summarize the clinicopathological characteristics, diagnosis and treatment of IgG4-related disease (IgG4-RD). Methods: The clinical data of 43 cases with IgG4-RD diagnosed from January 2013 to December 2017 were retrospectively analyzed. The clinical data of the patients including clinical characteristics, accessory examinations, diagnosis, and treatment were collected. Results: Among the 43 patients with IgG4-RD, the ratio of male to female was 3∶1, the mean age was (51.3±15.9) years. Eleven patients had gastrointestinal symptoms, including 5 cases of IgG4-related cholangitis with the feature of dilation of the biliary system and narrowing of the lumen in the abdominal enhanced CT scans, and 6 cases of IgG4-related autoimmune pancreatitis with the feature of pancreatic enlargement or soft tissue density shadow in the abdominal enhanced CT scans. There were 10 cases (23.3%) with periorbital involvement, with the feature of intraorbital soft tissue nodule in the CT scan. Besides, 9 cases (20.9%) had lymphadenopathy, 6 cases (14.0%) had fever. The results of autoimmune antibody tests showed that 14 of 42 patients had increased antinuclear antibody (ANA). Among 40 patients who underwent immunoglobulin tests, 25 cases had elevated IgG, 12 cases had increased IgA, and 29 cases had increased IgE. Coombs test were performed for 6 cases and 4 patients were positive. Serum immunoglobulin G4 subtypes showed that the IgG4 levels of 35 patients were higher than 1 350 mg/L. The immunohistochemistry showed that IgG4 (+) cells (3->500/HPF) were infiltrated, with the CD20 (+), CD3ε (+) or CD138 (+). Among the 43 patients, 5 patients underwent operations due to misdiagnosis. All patients were treated with steroid and immunosuppressive agents after diagnosis, and their clinical symptoms were improved. Conclusion: The clinical symptoms of IgG4-RD are various, involving multiple organs. Therefore, the standardized diagnosis and treatment of IgG4-RD should be strengthened.


Assuntos
Doença Relacionada a Imunoglobulina G4 , Adulto , Idoso , Feminino , Humanos , Imunoglobulina G , Doença Relacionada a Imunoglobulina G4/diagnóstico , Doença Relacionada a Imunoglobulina G4/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
15.
Front Immunol ; 11: 1956, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983126

RESUMO

Advances in cancer immunity have promoted a major breakthrough in the field of cancer therapy. This is mainly associated with the successful development of immune checkpoint inhibitors (ICIs) for multiple types of human tumors. Blockade with different ICIs, including programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, may activate the immune system of the host against malignant cells. However, only a subgroup of patients with cancer would benefit from immune checkpoint blockade. Some patients experience primary resistance to initial immunotherapy, and a majority eventually develop acquired resistance to ICIs. However, the mechanisms involved in the development of drug resistance to immune checkpoint blockade remain unclear. Recent studies supported that combination of ICIs and anti-angiogenic agents could be a promising therapeutic strategy for overcoming the low efficacy of ICIs. Moreover, through their direct anti-cancer effect by inhibiting tumor growth and metastasis, anti-angiogenic drugs reprogram the tumor milieu from an immunosuppressive to an immune permissive microenvironment. Activated immunity by immune checkpoint blockade also facilitates anti-angiogenesis by downregulating the expression of vascular endothelial growth factor and alleviating hypoxia condition. Many clinical trials showed an improved anti-cancer efficacy and prolonged survival following the addition of anti-angiogenic agents to ICIs. This review summarizes the current understanding and clinical development of combination therapy with immune checkpoint blockade and anti-angiogenic strategy.

16.
Artigo em Inglês | MEDLINE | ID: mdl-32780695

RESUMO

Multispectral and hyperspectral image fusion (MS/HS fusion) has become one of the most commonly addressed problems for hyperspectral image processing. In this paper, we specifically design a network architecture for the MS/HS fusion task, called MHF-net, which not only contains clear interpretability, but also well embeds the intrinsic generalization mechanism of low-resolution images. In particular, we first construct an MS/HS fusion model which merges the generalization models of low-resolution images and the low-rankness prior knowledge of hyperspectral image into a concise formulation, and then we build the proposed network by unfolding the proximal gradient algorithm for solving the proposed model. As a result of the careful design of the model and algorithm, all of the fundamental modules in MHF-net have clear physical meanings and are thus easily interpretable. Based on the architecture of MHF-net, we further design two deep learning regimes: consistent MHF-net and blind MHF-net, which are suitable in the presences that spectral and spatial responses of train and test data are consistent and inconsistent, respectively. Experimental results on simulated and real data substantiate the superiority of our method both visually and quantitatively as compared with state-of-the-art methods along this line of research.

17.
Proc Natl Acad Sci U S A ; 117(36): 22193-22203, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32839317

RESUMO

The establishment of axon/dendrite polarity is fundamental for neurons to integrate into functional circuits, and this process is critically dependent on microtubules (MTs). In the early stages of the establishment process, MTs in axons change dramatically with the morphological building of neurons; however, how the MT network changes are triggered is unclear. Here we show that CAMSAP1 plays a decisive role in the neuronal axon identification process by regulating the number of MTs. Neurons lacking CAMSAP1 form a multiple axon phenotype in vitro, while the multipolar-bipolar transition and radial migration are blocked in vivo. We demonstrate that the polarity regulator MARK2 kinase phosphorylates CAMSAP1 and affects its ability to bind to MTs, which in turn changes the protection of MT minus-ends and also triggers asymmetric distribution of MTs. Our results indicate that the polarized MT network in neurons is a decisive factor in establishing axon/dendritic polarity and is initially triggered by polarized signals.


Assuntos
Polaridade Celular/fisiologia , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/fisiologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Imunoprecipitação , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Neurônios , Paclitaxel , Ligação Proteica
18.
Int Immunopharmacol ; 88: 106873, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32795897

RESUMO

BACKGROUND: COVID-19 characterized by refractory hypoxemia increases patient mortality because of immunosuppression effects. This study aimed to evaluate the efficacy of immunomodulatory with thymosin α1 for critical COVID-19 patients. METHODS: This multicenter retrospective cohort study was performed in 8 government-designated treatment centers for COVID-19 patients in China from Dec. 2019 to Mar. 2020. Thymosin α1 was administrated with 1.6 mg qd or q12 h for >5 days. The primary outcomes were the 28-day and 60-day mortality, the secondary outcomes were hospital length of stay and the total duration of the disease. Subgroup analysis was carried out according to clinical classification. RESULTS: Of the 334 enrolled COVID-19 patients, 42 (12.6%) died within 28 days, and 55 (16.5%) died within 60 days of hospitalization. There was a significant difference in the 28-day mortality between the thymosin α1 and non-thymosin α1-treated groups in adjusted model (P = 0.016), without obvious differences in the 60-day mortality and survival time in the overall cohort (P > 0.05). In the subgroup analysis, it was found that thymosin α1 therapy significantly reduced 28-day mortality (Hazards Ratios HR, 0.11, 95% confidence interval CI 0.02-0.63, P=0.013) via improvement of Pa02/FiO2 (P = 0.036) and prolonged the hospital length of stay (P = 0.024) as well as the total duration of the disease (P=0.001) in the critical type patients, especially those aged over 64 years, with white blood cell >6.8×109/L, neutrophil >5.3×109/L, lymphocyte < 0.73 × 109/L, PaO2/FiO2 < 196, SOFA > 3, and acute physiology and chronic health evaluation (APACHE) II > 7. CONCLUSION: These results suggest that treatment with thymosin α1 can markedly decrease 28-day mortality and attenuate acute lung injury in critical type COVID-19 patients.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Cuidados Críticos/métodos , Pneumonia Viral/tratamento farmacológico , Timalfasina/uso terapêutico , APACHE , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Idoso , Betacoronavirus , China/epidemiologia , Estudos de Coortes , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Timalfasina/administração & dosagem , Timalfasina/efeitos adversos
19.
Plant Cell ; 32(10): 3256-3272, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32769133

RESUMO

Flowering plants and mammals contain imprinted genes that are primarily expressed in the endosperm and placenta in a parent-of-origin manner. In this study, we show that early activation of the geminivirus genes C2 and C3 in Arabidopsis (Arabidopsis thaliana) plants, encoding a viral suppressor of RNA interference and a replication enhancer protein, respectively, is correlated with the transient vegetative expression of VARIANT IN METHYLATION5 (VIM5), an endosperm imprinted gene that is conserved in diverse plant species. VIM5 is a ubiquitin E3 ligase that directly targets the DNA methyltransferases MET1 and CMT3 for degradation by the ubiquitin-26S proteasome proteolytic pathway. Infection with Beet severe curly top virus induced VIM5 expression in rosette leaf tissues, possibly via the expression of the viral replication initiator protein, leading to the early activation of C2 and C3 coupled with reduced symmetric methylation in the C2-3 promoter and the onset of disease symptoms. These findings demonstrate how this small DNA virus recruits a host imprinted gene for the epigenetic activation of viral gene transcription. Our findings reveal a distinct strategy used by plant pathogens to exploit the host machinery in order to inhibit methylation-mediated defense responses when establishing infection.

20.
J Oral Rehabil ; 47(11): 1330-1336, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32757414

RESUMO

OBJECTIVES: To develop and evaluate an educational web-based programme for temporomandibular joint (TMJ) assessment using cone-beam computed tomography (CBCT). METHODS: A web-based educational programme was designed for TMJ assessment using CBCT images. Fifteen CBCT cases of the TMJ (three-dimensional reconstructed volumes) and an assessment module based on image analysis criteria in the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) were added to the programme. Thirty-six undergraduate dental students were invited to test the programme by assessing all cases twice: before and after 2 months of training. Participants submitted written subjective evaluations of the programme. RESULTS: The web-based programme can be accessed on Malmö University webpage (www.cbct-tmj.mau.se). Despite limited CBCT learning in their undergraduate training and not using the programme in the 2-month interval, the students were able to correctly diagnose 80% of the cases at the second assessment. Their diagnoses, however, did not differ significantly from the first assessment. Overall, the students were satisfied with the programme and considered it user-friendly. CONCLUSION: The web-based educational programme that was developed in the present study and tested by dental students could be a useful educational tool for TMJ assessment using CBCT.


Assuntos
Transtornos da Articulação Temporomandibular , Articulação Temporomandibular , Tomografia Computadorizada de Feixe Cônico , Humanos , Processamento de Imagem Assistida por Computador , Internet , Articulação Temporomandibular/diagnóstico por imagem , Transtornos da Articulação Temporomandibular/diagnóstico por imagem
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