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1.
Nat Commun ; 11(1): 5079, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033234

RESUMO

Tumor heterogeneity and lack of knowledge about resistant cell states remain a barrier to targeted cancer therapies. Basal cell carcinomas (BCCs) depend on Hedgehog (Hh)/Gli signaling, but can develop mechanisms of Smoothened (SMO) inhibitor resistance. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies noncanonical Gli1 activity, but characteristics and drivers of the nMRTF cell state remain unknown. Here, we use single cell RNA-sequencing of patient tumors to identify three prognostic surface markers (LYPD3, TACSTD2, and LY6D) which correlate with nMRTF and resistance to SMO inhibitors. The nMRTF cell state resembles transit-amplifying cells of the hair follicle matrix, with AP-1 and TGFß cooperativity driving nMRTF activation. JNK/AP-1 signaling commissions chromatin accessibility and Smad3 DNA binding leading to a transcriptional program of RhoGEFs that facilitate nMRTF activity. Importantly, small molecule AP-1 inhibitors selectively target LYPD3+/TACSTD2+/LY6D+ nMRTF human BCCs ex vivo, opening an avenue for improving combinatorial therapies.


Assuntos
Carcinoma Basocelular/metabolismo , Proteínas Hedgehog/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Fator de Transcrição AP-1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Cromatina/metabolismo , DNA de Neoplasias/metabolismo , Resistencia a Medicamentos Antineoplásicos , Matriz Extracelular/metabolismo , Ontologia Genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Folículo Piloso/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Proteínas de Neoplasias/metabolismo , Ligação Proteica , Proteína Smad3/metabolismo , Transativadores/metabolismo , Regulação para Cima
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1585-1591, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067958

RESUMO

OBJECTIVE: To identify the molecular pathogenesis of diffuse large B cell lymphoma (DLBCL) and to screen potential biomarkers or therapeutic targets for diagnosis, treatment and prognosis evaluation of patients with DLBCL. METHODS: Gene expression profiles of GSE56315 were downloaded from GEO database. Analysis of differentially expressed genes (DEGs) in the microarray was performed using"R"software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of up-regulated DEGs were performed using DAVID database. The survival analysis of up-regulated DEGs was performed using GEPIA database. RESULTS: There were 55 DLBCL biopsy tissue specimes and 33 normal tonsil tissue specimes in the datasets. A total of 2001 differentially expressed genes were identified, including 1 079 up-regulated DEGs and 922 down-regulated DEGs. Function enrichment analysis indicated that the up-regulated DEGs were involved in 425 GO terms, including 31 genes of FDR<0.05 (P<0.05) and 17 pathways. In the GEPIA database, the expression levels of 12 up-regulated DEGs (AK8、AP2M1、ATOX1、 CSF2RA、CYP27A1、HEBP1、HTRA1、HTRA4、IGFBP3、PTGDS、SIGLEC15、UQCRC1) were found to be significantly correlated with shorter overall survival of DLBCL patients. CONCLUSION: The internal biological information in DLBCL revealed by integrative bioinformatical analysis may provide an important theoretical basis for further research on molecular mechanism of DLBCL, screening of potential therapeutic targets and evaluation of prognosis.


Assuntos
Biologia Computacional , Linfoma Difuso de Grandes Células B , Perfilação da Expressão Gênica , Ontologia Genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Linfoma Difuso de Grandes Células B/genética , Transcriptoma
3.
Medicine (Baltimore) ; 99(37): e22142, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925767

RESUMO

Osteoarthritis (OA) is a high prevalent musculoskeletal problem, which can cause severe pain, constitute a huge social and economic burden, and seriously damage the quality of life. This study was intended to identify genetic characteristics of subchondral bone in patients with OA and to elucidate the potential molecular mechanisms involved. Data of gene expression profiles (GSE51588), which contained 40 OA samples and 10 normal samples, was obtained from the Gene Expression Omnibus (GEO). The raw data were integrated to obtain differentially expressed genes (DEGs) and were further analyzed with bioinformatic analysis. The protein-protein interaction (PPI) networks were built and analyzed via Search Tool for the Retrieval of Interacting Genes (STRING). The significant modules and hub genes were identified via Cytoscape. Moreover, Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analysis were performed. Totally 235 DEGs were differentially expressed in the subchondral bone from OA patients compared with those of normal individuals, of which 78 were upregulated and 157 were downregulated. Eight hub genes were identified, including DEFA4, ARG1, LTF, RETN, PGLYRP1, OLFM4, ORM1, and BPI. The enrichment analyses of the DEGs and significant modules indicated that DEGs were mainly involved in inflammatory response, extracellular space, RAGE receptor binding, and amoebiasis pathway. The present study provides a novel and in-depth understanding of pathogenesis of the OA subchondral bone at molecular level. DEFA4, ARG1, LTF, RETN, PGLYRP1, OLFM4, ORM1, and BPI may be the new candidate targets for diagnosis and therapies on patients with OA in the future.


Assuntos
Biologia Computacional , Osteoartrite/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Ontologia Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mapas de Interação de Proteínas , Transcriptoma , beta-Defensinas
4.
PLoS One ; 15(9): e0238420, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32931492

RESUMO

BACKGROUND: Patients diagnosed with Oral Floor Squamous Cell Carcinoma (OFSCC) face considerable challenges in physiology and psychology. This study explored prognostic signatures to predict prognosis in OFSCC through a detailed transcriptomic analysis. METHOD: We built an interactive competing endogenous RNA (ceRNA) network that included lncRNAs, miRNAs and mRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to predict the gene functions and regulatory pathways of mRNAs. Least absolute shrinkage and selection operator algorithm (LASSO) analysis and Cox regression analysis were used to screen prognosis factors. The Kaplan-Meier method was used to analyze the survival rate of prognosis factors. Risk score was used to assess the reliability of the prediction model. RESULTS: A specific ceRNA network consisting of 56 mRNAs, 16 miRNAs and 31 lncRNAs was established. Three key genes (HOXC13, TGFBR3, KLHL40) and 4 clinical factors (age, gender, TNM, and clinical stage) were identified and effectively predicted the for survival time. The expression of a gene signature was validated in two external validation cohorts. The signature (areas under the curve of 3 and 5 years were 0.977 and 0.982, respectively) showed high prognostic accuracy in the complete TCGA cohort. CONCLUSIONS: Our study successfully developed an extensive ceRNA network for OFSCC and further identified a 3-mRNA and 4-clinical-factor signature, which may serve as a biomarker.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Neoplasias Bucais/genética , RNA Neoplásico/genética , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Bases de Dados de Ácidos Nucleicos , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Proteínas de Homeodomínio/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Soalho Bucal , Neoplasias Bucais/mortalidade , Proteínas Musculares/genética , Prognóstico , Proteoglicanas/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Fatores de Risco
5.
PLoS One ; 15(9): e0237618, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32877413

RESUMO

Hepatitis E virus (HEV) genotype 1 (gt1) and gt3 infections have distinct epidemiologic characteristics and genotype-specific molecular mechanisms of pathogenesis are not well characterized. Previously, we showed differences in immune response-related gene expression profiles of HEV gt1 and gt3 infections using qPCR. We hypothesize that HEV gt1 and gt3 infections induce transcriptome modifications contributing to disease pathogenesis. RNAseq analysis was performed using liver biopsy samples of naïve (baseline), HEV gt1, or gt3-infected rhesus macaques, and nine anti-HEV positive rhesus macaques re-inoculated with HEV gt1. All 10 primary HEV gt1/gt3 infected animals exhibited the typical course of acute viral hepatitis and cleared the infection between 27 to 67 days after inoculation. Viremic stages of HEV infection were defined as early, peak, and decline based on HEV RNA titers in daily stool specimens. During early, peak, and decline phases of infection, HEV gt1 induced 415, 417, and 1769 differentially expressed genes, respectively, and 310, 678, and 388 genes were differentially expressed by HEV gt3, respectively (fold change ≥ 2.0, p-value ≤ 0.05). In the HEV gt1 infection, genes related to metabolic pathways were differentially expressed during the three phases of infection. In contrast, oxidative reduction (early phase), immune responses (peak phase), and T cell cytokine production (decline phase) were found to be regulated during HEV gt3 infection. In addition, FoxO and MAPK signaling pathways were differentially regulated in re-infected and protected animals against HEV gt1 reinfection, respectively. Significant differences of hepatic gene regulation exist between HEV gt1 and gt3 infections. These findings reveal a new link between molecular pathogenesis and epidemiological characteristics seen in HEV gt1 and gt3 infections.


Assuntos
Perfilação da Expressão Gênica , Vírus da Hepatite E/genética , Hepatite E/veterinária , Macaca mulatta/virologia , Animais , Biópsia , Ontologia Genética , Genótipo , Fígado/patologia , Análise de Sequência de RNA
6.
PLoS One ; 15(8): e0233818, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857777

RESUMO

Macrophages serve as a first line of defense against infection with the facultative intracellular pathogen, Cryptococcus neoformans (Cn). However, the ability of these innate phagocytic cells to destroy ingested Cn is strongly influenced by polarization state with classically (M1) activated macrophages better able to control cryptococcal infections than alternatively (M2) activated cells. While earlier studies have demonstrated that intracellular Cn minimally affects the expression of M1 and M2 markers, the impact on the broader transcriptome associated with these states remains unclear. To investigate this, an in vitro cell culture model of intracellular infection together with RNA sequencing-based transcriptome profiling was used to measure the impact of Cn infection on gene expression in both polarization states. The gene expression profile of both M1 and M2 cells was extensively altered to become more like naive (M0) macrophages. Gene ontology analysis suggested that this involved changes in the activity of the Janus kinase-signal transducers and activators of transcription (JAK-STAT), p53, and nuclear factor-κB (NF-κB) pathways. Analyses of the principle polarization markers at the protein-level also revealed discrepancies between the RNA- and protein-level responses. In contrast to earlier studies, intracellular Cn was found to increase protein levels of the M1 marker iNos. In addition, common gene expression changes were identified that occurred post-Cn infection, independent of polarization state. This included upregulation of the transcriptional co-regulator Cited1, which was also apparent at the protein level in M1-polarized macrophages. These changes constitute a transcriptional signature of macrophage Cn infection and provide new insights into how Cn impacts gene expression and the phenotype of host phagocytes.


Assuntos
Cryptococcus neoformans/patogenicidade , Macrófagos/metabolismo , Macrófagos/microbiologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Cryptococcus neoformans/imunologia , Ontologia Genética , Redes Reguladoras de Genes , Imunidade Inata/genética , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Transativadores/genética , Transativadores/metabolismo , Transcriptoma
7.
BMC Bioinformatics ; 21(1): 355, 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32787776

RESUMO

BACKGROUND: The accurate annotation of protein functions is of great significance in elucidating the phenomena of life, treating disease and developing new medicines. Various methods have been developed to facilitate the prediction of these functions by combining protein interaction networks (PINs) with multi-omics data. However, it is still challenging to make full use of multiple biological to improve the performance of functions annotation. RESULTS: We presented NPF (Network Propagation for Functions prediction), an integrative protein function predicting framework assisted by network propagation and functional module detection, for discovering interacting partners with similar functions to target proteins. NPF leverages knowledge of the protein interaction network architecture and multi-omics data, such as domain annotation and protein complex information, to augment protein-protein functional similarity in a propagation manner. We have verified the great potential of NPF for accurately inferring protein functions. According to the comprehensive evaluation of NPF, it delivered a better performance than other competing methods in terms of leave-one-out cross-validation and ten-fold cross validation. CONCLUSIONS: We demonstrated that network propagation, together with multi-omics data, can both discover more partners with similar function, and is unconstricted by the "small-world" feature of protein interaction networks. We conclude that the performance of function prediction depends greatly on whether we can extract and exploit proper functional information of similarity from protein correlations.


Assuntos
Algoritmos , Biologia Computacional/métodos , Mapas de Interação de Proteínas , Análise por Conglomerados , Ontologia Genética , Ligação Proteica , Reprodutibilidade dos Testes , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
8.
Plant Mol Biol ; 104(3): 263-281, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32740898

RESUMO

KEY MESSAGE: Plant-specific Dof transcription factors VDOF1 and VDOF2 are novel regulators of vascular cell differentiation through the course of a lifetime in Arabidopsis, with shifting their transcriptional target genes. Vascular system is one of critical tissues for vascular plants to transport low-molecular compounds, such as water, minerals, and the photosynthetic product, sucrose. Here, we report the involvement of two Dof transcription factors, named VASCULAR-RELATED DOF1 (VDOF1)/VDOF4.6 and VDOF2/VDOF1.8, in vascular cell differentiation and lignin biosynthesis in Arabidopsis. VDOF genes were expressed in vascular tissues, but the detailed expression sites were partly different between VDOF1 and VDOF2. Vein patterning and lignin analysis of VDOF overexpressors and double mutant vdof1 vdof2 suggested that VDOF1 and VDOF2 would function as negative regulators of vein formation in seedlings, and lignin deposition in inflorescence stems. Interestingly, effects of VDOF overexpression in lignin deposition were different by developmental stages of inflorescence stems, and total lignin contents were increased and decreased in VDOF1 and VDOF2 overexpressors, respectively. RNA-seq analysis of inducible VDOF overexpressors demonstrated that the genes for cell wall biosynthesis, including lignin biosynthetic genes, and the transcription factor genes related to stress response and brassinosteroid signaling were commonly affected by VDOF1 and VDOF2 overexpression. Taken together, we concluded that VDOF1 and VDOF2 are novel regulators of vascular cell differentiation through the course of a lifetime, with shifting their transcriptional target genes: in seedlings, the VDOF genes negatively regulate vein formation, while at reproductive stages, the VDOF proteins target lignin biosynthesis.


Assuntos
Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Diferenciação Celular/fisiologia , Lignina/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Ligação a DNA , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Ontologia Genética , Inflorescência , Mutação , Caules de Planta/citologia , Caules de Planta/metabolismo , Plantas Geneticamente Modificadas/genética , Sementes , Análise de Sequência
9.
Nat Commun ; 11(1): 3822, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732898

RESUMO

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. However, the regulation of AM development and maintenance remains poorly understood. Here, we show that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. Single-cell RNA sequencing analyses reveal four distinct AM sub-clusters and a dysregulated cluster-specific pathway in the HDAC3-deficient AMs. Moreover, HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Mechanistically, HDAC3 directly binds to Pparg enhancers, and HDAC3 deficiency impairs Pparg expression and its signaling pathway. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.


Assuntos
Histona Desacetilases/genética , Homeostase/genética , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Animais , Apoptose/genética , Diferenciação Celular/genética , Linhagem Celular , Células Cultivadas , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento , Ontologia Genética , Histona Desacetilases/deficiência , Histona Desacetilases/metabolismo , Pulmão/embriologia , Pulmão/crescimento & desenvolvimento , Macrófagos Alveolares/citologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
10.
Medicine (Baltimore) ; 99(34): e21863, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846838

RESUMO

Dermatomyositis is a common connective tissue disease. The occurrence and development of dermatomyositis is a result of multiple factors, but its exact pathogenesis has not been fully elucidated. Here, we used biological information method to explore and predict the major disease related genes of dermatomyositis and to find the underlying pathogenic molecular mechanism.The gene expression data of GDS1956, GDS2153, GDS2855, and GDS3417 including 94 specimens, 66 cases of dermatomyositis specimens and 28 cases of normal specimens, were obtained from the Gene Expression Omnibus database. The 4 microarray gene data groups were combined to get differentially expressed genes (DEGs). The gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments of DEGs were operated by the database for annotation, visualization and integrated discovery and KEGG orthology based annotation system databases, separately. The protein-protein interaction networks of the DEGs were built from the STRING website. A total of 4097 DEGs were extracted from the 4 Gene Expression Omnibus datasets, of which 2213 genes were upregulated, and 1884 genes were downregulated. Gene ontology analysis indicated that the biological functions of DEGs focused primarily on response to virus, type I interferon signaling pathway and negative regulation of viral genome replication. The main cellular components include extracellular space, cytoplasm, and blood microparticle. The molecular functions include protein binding, double-stranded RNA binding and MHC class I protein binding. KEGG pathway analysis showed that these DEGs were mainly involved in the toll-like receptor signaling pathway, cytosolic DNA-sensing pathway, RIG-I-like receptor signaling pathway, complement and coagulation cascades, arginine and proline metabolism, phagosome signaling pathway. The following 13 closely related genes, XAF1, NT5E, UGCG, GBP2, TLR3, DDX58, STAT1, GBP1, PLSCR1, OAS3, SP100, IGK, and RSAD2, were key nodes from the protein-protein interaction network.This research suggests that exploring for DEGs and pathways in dermatomyositis using integrated bioinformatics methods could help us realize the molecular mechanism underlying the development of dermatomyositis, be of actual implication for the early detection and prophylaxis of dermatomyositis and afford reliable goals for the curing of dermatomyositis.


Assuntos
Biologia Computacional/instrumentação , Dermatomiosite/genética , Ontologia Genética/tendências , Interferon Tipo I/genética , Mapas de Interação de Proteínas/genética , Dermatomiosite/epidemiologia , Motivo de Ligação ao RNA de Cadeia Dupla/genética , Regulação para Baixo , Humanos , Incidência , Análise em Microsséries/métodos , Anotação de Sequência Molecular/métodos , Ligação Proteica , Transdução de Sinais , Regulação para Cima
11.
PLoS One ; 15(8): e0237930, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841274

RESUMO

Chinese hamster ovary cells have been the workhorse for the production of recombinant proteins in mammalian cells. Since biochemical, cellular and omics studies are usually affected by the lack of suitable fractionation procedures to isolate compartments from these cells, differential and isopycnic centrifugation based techniques were characterized and developed specially for them. Enriched fractions in intact nuclei, mitochondria, peroxisomes, cis-Golgi, trans-Golgi and endoplasmic reticulum (ER) were obtained in differential centrifugation steps and subsequently separated in discontinuous sucrose gradients. Nuclei, mitochondria, cis-Golgi, peroxisomes and smooth ER fractions were obtained as defined bands in 30-60% gradients. Despite the low percentage represented by the microsomes of the total cell homogenate (1.7%), their separation in a novel sucrose gradient (10-60%) showed enough resolution and efficiency to quantitatively separate their components into enriched fractions in trans-Golgi, cis-Golgi and ER. The identity of these organelles belonging to the classical secretion pathway that came from 10-60% gradients was confirmed by proteomics. Data are available via ProteomeXchange with identifier PXD019778. Components from ER and plasma membrane were the most frequent contaminants in almost all obtained fractions. The improved sucrose gradient for microsomal samples proved being successful in obtaining enriched fractions of low abundance organelles, such as Golgi apparatus and ER components, for biochemical and molecular studies, and suitable for proteomic research, which makes it a useful tool for future studies of this and other mammalian cell lines.


Assuntos
Microssomos/metabolismo , Proteômica , Animais , Células CHO , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Centrifugação , Cricetinae , Cricetulus , Citosol/metabolismo , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Ontologia Genética , Complexo de Golgi/metabolismo , Complexo de Golgi/ultraestrutura , Microssomos/ultraestrutura , Mitocôndrias/ultraestrutura , Proteoma/metabolismo , Software , Frações Subcelulares/metabolismo
12.
PLoS One ; 15(8): e0237715, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822374

RESUMO

Transcriptomic responses of plants to weed presence gives insight on the physiological and molecular mechanisms involved in the stress response. This study evaluated transcriptomic and morphological responses of two teosinte (Zea mays ssp parviglumis) (an ancestor of domesticated maize) lines (Ames 21812 and Ames 21789) to weed presence and absence during two growing seasons. Responses were compared after 6 weeks of growth in Aurora, South Dakota, USA. Plant heights between treatments were similar in Ames 21812, whereas branch number decreased when weeds were present. Ames 21789 was 45% shorter in weedy vs weed-free plots, but branch numbers were similar between treatments. Season-long biomass was reduced in response to weed stress in both lines. Common down-regulated subnetworks in weed-stressed plants were related to light, photosynthesis, and carbon cycles. Several unique response networks (e.g. aging, response to chitin) and gene sets were present in each line. Comparing transcriptomic responses of maize (determined in an adjacent study) and teosinte lines indicated three common gene ontologies up-regulated when weed-stressed: jasmonic acid response/signaling, UDP-glucosyl and glucuronyltransferases, and quercetin glucosyltransferase (3-O and 7-O). Overall, morphologic and transcriptomic differences suggest a greater varietal (rather than a conserved) response to weed stress, and implies multiple responses are possible. These findings offer insights into opportunities to define and manipulate gene expression of several different pathways of modern maize varieties to improve performance under weedy conditions.


Assuntos
Plantas Daninhas , Transcriptoma , Zea mays/crescimento & desenvolvimento , Regulação da Expressão Gênica de Plantas , Ontologia Genética , Luz , Fotossíntese , Plantas Daninhas/fisiologia , Estresse Fisiológico , Zea mays/genética , Zea mays/fisiologia
13.
Arch Virol ; 165(10): 2397-2400, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32748177

RESUMO

Enterobacter aerogenes is a member of the ESKAPE group of bacteria, and multi-drug-resistant strains are increasingly being found. In this study, a novel bacteriophage, ATCEA85, which infects E. aerogenes, has been isolated and characterized. ATCEA85 is seen to have a circularly permuted linear double-stranded DNA genome of 47,484 base pairs in length. The closest related phage found in the databases is the Klebsiella phage Kp3, which exhibits 77% identity over a 34% query coverage. The G+C content of ATCEA85 is 56.2%, and 15 putative open reading frames are functionally annotated.


Assuntos
DNA Viral/genética , Enterobacter aerogenes/virologia , Genoma Viral , Fases de Leitura Aberta , Filogenia , Siphoviridae/genética , Composição de Bases , DNA/genética , Ontologia Genética , Anotação de Sequência Molecular , Siphoviridae/classificação , Siphoviridae/isolamento & purificação , Sequenciamento Completo do Genoma
14.
Aging (Albany NY) ; 12(15): 15784-15796, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32805728

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an epidemic disease characterized by rapid infection and a high death toll. The clinical diagnosis of patients with COVID-19 has risen sharply, especially in Western countries. Globally, an effective treatment for COVID-19 is still limited. Vitamin A (VA) exhibits pharmacological activity in the management of pneumonia. Thus, we reason that VA may potentially serve as an anti-SARS-CoV-2 regimen. In this study, bioinformatics analysis and computation assays using a network pharmacology method were conducted to explore and uncover the therapeutic targets and mechanisms of VA for treating COVID-19. We identified candidate targets, pharmacological functions, and therapeutic pathways of VA against SARS-CoV-2. Bioinformatics findings indicate that the mechanisms of action of VA against SARS-CoV-2 include enrichment of immunoreaction, inhibition of inflammatory reaction, and biological processes related to reactive oxygen species. Furthermore, seven core targets of VA against COVID-19, including MAPK1, IL10, EGFR, ICAM1, MAPK14, CAT, and PRKCB were identified. With this bioinformatics-based report, we reveal, for the first time, the anti-SARS-CoV-2 functions and mechanisms of VA and suggest that VA may act as a potent treatment option for COVID-19, a deadly global epidemic.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Imunidade/efeitos dos fármacos , Inflamação , Pandemias , Pneumonia Viral , Vitamina A , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/genética , Betacoronavirus/fisiologia , Disponibilidade Biológica , Biologia Computacional/métodos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Ontologia Genética , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Transdução de Sinais/efeitos dos fármacos , Vitamina A/farmacocinética , Vitamina A/uso terapêutico , Vitaminas/farmacocinética , Vitaminas/uso terapêutico
15.
PLoS One ; 15(7): e0233814, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726313

RESUMO

The clinical efficacy for treating of celastrol rheumatoid arthritis (RA) has been well-documented, but its mechanism of action remains unclear. Here we explored through what proteins and processes celastrol may act in activated fibroblast-like synoviocytes (FLS) from RA patients. Differential expression of genes and proteins after celastrol treatment of FLS was examined using RNA sequencing, label-free relatively quantitative proteomics and molecular docking. In this paper, expression of 26,565 genes and 3,372 proteins was analyzed. Celastrol was associated with significant changes in genes that respond to oxidative stress and oxygen levels, as well as genes that stabilize or synthesize components of the extracellular matrix. These results identify several potential mechanisms through which celastrol may inhibit inflammation in RA.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Reumatoide/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Proteômica/métodos , Transcriptoma/efeitos dos fármacos , Triterpenos/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Células Cultivadas , Cromatografia Líquida , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Espectrometria de Massas por Ionização por Electrospray , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Espectrometria de Massas em Tandem , Triterpenos/uso terapêutico
16.
Nat Commun ; 11(1): 3695, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32728065

RESUMO

Pseudogenes are ideal markers of genome remodelling. In turn, the mouse is an ideal platform for studying them, particularly with the recent availability of strain-sequencing and transcriptional data. Here, combining both manual curation and automatic pipelines, we present a genome-wide annotation of the pseudogenes in the mouse reference genome and 18 inbred mouse strains (available via the mouse.pseudogene.org resource). We also annotate 165 unitary pseudogenes in mouse, and 303, in human. The overall pseudogene repertoire in mouse is similar to that in human in terms of size, biotype distribution, and family composition (e.g. with GAPDH and ribosomal proteins being the largest families). Notable differences arise in the pseudogene age distribution, with multiple retro-transpositional bursts in mouse evolutionary history and only one in human. Furthermore, in each strain about a fifth of all pseudogenes are unique, reflecting strain-specific evolution. Finally, we find that ~15% of the mouse pseudogenes are transcribed, and that highly transcribed parent genes tend to give rise to many processed pseudogenes.


Assuntos
Pseudogenes/genética , Transcrição Genética , Animais , Sequência Conservada/genética , Evolução Molecular , Ontologia Genética , Genoma , Humanos , Camundongos Endogâmicos C57BL , Anotação de Sequência Molecular , Especificidade da Espécie
17.
Artigo em Inglês | MEDLINE | ID: mdl-32696819

RESUMO

Myocardial ischemia/reperfusion (MI/R) injury is a complex phenomenon that causes severe damage to the myocardium. However, the potential molecular mechanisms of MI/R injury have not been fully clarified. We identified potential molecular mechanisms and therapeutic targets in MI/R injury through analysis of Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were found between MI/R injury and normal samples, and overlapping DEGs were found between GSE61592 and GSE67308. Gene Ontology (GO) and pathway analysis were performed for overlapping DEGs by Database for Annotation, Visualization and Integration Discovery (DAVID). Then, a network of protein-protein interaction (PPI) was constructed through the Search Tool for the Retrieval of Interacting Genes (STRING) database. Potential microRNAs (miRNAs) and therapeutic small molecules were screened out using microRNA.org database and the Comparative Toxicogenomics database (CTD), respectively. Finally, we identified 21 overlapping DEGs related to MI/R injury. These DEGs were significantly enriched in IL-17 signaling pathway, cytosolic DNA-sensing pathway, chemokine signaling, and cytokine-cytokine receptor interaction pathway. According to the degree in the PPI network, CCL2, LCN2, HP, CCL7, HMOX1, CCL4, and S100A8 were found to be hub genes. Furthermore, we identified potential miRNAs (miR-24-3p, miR-26b-5p, miR-2861, miR-217, miR-4251, and miR-124-3p) and therapeutic small molecules like ozone, troglitazone, rosiglitazone, and n-3 polyunsaturated fatty acids for MI/R injury. These results identified hub genes and potential small molecule drugs, which could contribute to the understanding of molecular mechanisms and treatment for MI/R injury.


Assuntos
MicroRNAs , Traumatismo por Reperfusão Miocárdica , Biologia Computacional , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Mapas de Interação de Proteínas
18.
Mol Cell ; 79(3): 504-520.e9, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32707033

RESUMO

Protein kinases are essential for signal transduction and control of most cellular processes, including metabolism, membrane transport, motility, and cell cycle. Despite the critical role of kinases in cells and their strong association with diseases, good coverage of their interactions is available for only a fraction of the 535 human kinases. Here, we present a comprehensive mass-spectrometry-based analysis of a human kinase interaction network covering more than 300 kinases. The interaction dataset is a high-quality resource with more than 5,000 previously unreported interactions. We extensively characterized the obtained network and were able to identify previously described, as well as predict new, kinase functional associations, including those of the less well-studied kinases PIM3 and protein O-mannose kinase (POMK). Importantly, the presented interaction map is a valuable resource for assisting biomedical studies. We uncover dozens of kinase-disease associations spanning from genetic disorders to complex diseases, including cancer.


Assuntos
Redes Reguladoras de Genes , Doenças Genéticas Inatas/genética , Neoplasias/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Biologia Computacional/métodos , Conjuntos de Dados como Assunto , Regulação da Expressão Gênica , Ontologia Genética , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/patologia , Humanos , Redes e Vias Metabólicas/genética , Anotação de Sequência Molecular , Distrofias Musculares/enzimologia , Distrofias Musculares/genética , Distrofias Musculares/patologia , Neoplasias/enzimologia , Neoplasias/patologia , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Mapeamento de Interação de Proteínas/métodos , Proteínas Quinases/química , Proteínas Quinases/classificação , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais
19.
PLoS One ; 15(7): e0234150, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614830

RESUMO

To investigate a Florida manatee (Trichechus manatus latirostris) mortality event following a red tide bloom in Southwest Florida, an RNA sequencing experiment was conducted. Gene expression changes in white blood cells were assessed in manatees rescued from a red tide affected area (n = 4) and a control group (n = 7) using RNA sequencing. The genes with the largest fold changes were compared between the two groups to identify molecular pathways related to cellular and disease processes. In total, 591 genes (false discovery rate <0.05) were differentially expressed in the red tide group. Of these, 158 were upregulated and 433 were downregulated. This suggests major changes in white blood cell composition following an exposure to red tide. The most highly upregulated gene, Osteoclast associated 2C immunoglobulin-like receptor (OSCAR), was upregulated 12-fold. This gene is involved in initiating the immune response and maintaining a role in adaptive and innate immunity. The most highly downregulated gene, Piccolo presynaptic cytomatrix protein (PCLO), was downregulated by a factor of 977-fold. This gene is associated with cognitive functioning and neurotransmitter release. Downregulation of this gene in other studies was associated with neuronal loss and neuron synapse dysfunction. Among the cellular pathways that were most affected, immune response, including inflammation, wounds and injuries, cell proliferation, and apoptosis were the most predominant. The pathway with the most differentially expressed genes was the immune response pathway with 98 genes involved, many of them downregulated. Assessing the changes in gene expression associated with red tide exposure enhances our understanding of manatee immune response to the red tide toxins and will aid in the development of red tide biomarkers.


Assuntos
Perfilação da Expressão Gênica , Proliferação Nociva de Algas , Trichechus manatus/fisiologia , Animais , Buffy Coat/citologia , Florida , Ontologia Genética , Sistema Imunitário , Leucócitos/metabolismo , Toxinas Marinhas/envenenamento , Redes e Vias Metabólicas/genética , Neurotoxinas/envenenamento , Oxocinas/envenenamento , Envenenamento/sangue , Envenenamento/reabilitação , Envenenamento/veterinária , RNA Mensageiro/biossíntese , RNA Mensageiro/sangue , Transcriptoma , Trichechus manatus/sangue , Trichechus manatus/genética , Trichechus manatus/imunologia
20.
Drug Dev Ind Pharm ; 46(8): 1345-1353, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32643448

RESUMO

PURPOSE: Huashi Baidu formula (HSBDF) was developed to treat the patients with severe COVID-19 in China. The purpose of this study was to explore its active compounds and demonstrate its mechanisms against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through network pharmacology and molecular docking. METHODS: All the components of HSBDF were retrieved from the pharmacology database of TCM system. The genes corresponding to the targets were retrieved using UniProt and GeneCards database. The herb-compound-target network was constructed by Cytoscape. The target protein-protein interaction network was built using STRING database. The core targets of HSBDF were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The main active compounds of HSBDF were docked with SARS-CoV-2 and angiotensin converting enzyme II (ACE2). RESULTS: Compound-target network mainly contained 178 compounds and 272 corresponding targets. Key targets contained MAPK3, MAPK8, TP53, CASP3, IL6, TNF, MAPK1, CCL2, PTGS2, etc. There were 522 GO items in GO enrichment analysis (p < .05) and 168 signaling pathways (p < .05) in KEGG, mainly including TNF signaling pathway, PI3K-Akt signaling pathway, NOD-like receptor signaling pathway, MAPK signaling pathway, and HIF-1 signaling pathway. The results of molecular docking showed that baicalein and quercetin were the top two compounds of HSBDF, which had high affinity with ACE2. CONCLUSION: Baicalein and quercetin in HSBDF may regulate multiple signaling pathways through ACE2, which might play a therapeutic role on COVID-19.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Simulação de Acoplamento Molecular/métodos , Farmacologia Clínica/métodos , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/química , Betacoronavirus/genética , China , Bases de Dados Factuais , Ontologia Genética , Marcação de Genes , Genes Virais/efeitos dos fármacos , Genes Virais/genética , Humanos , Medicina Tradicional Chinesa , Pandemias , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
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