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1.
Molecules ; 26(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205019

RESUMO

Clinically, different approaches are adopted worldwide for the treatment of cancer, which still ranks second among all causes of death. Immunotherapy for cancer treatment has been the focus of attention in recent years, aiming for an eventual antitumoral effect through the immune system response to cancer cells both prophylactically and therapeutically. The application of nanoparticulate delivery systems for cancer immunotherapy, which is defined as the use of immune system features in cancer treatment, is currently the focus of research. Nanomedicines and nanoparticulate macromolecule delivery for cancer therapy is believed to facilitate selective cytotoxicity based on passive or active targeting to tumors resulting in improved therapeutic efficacy and reduced side effects. Today, with more than 55 different nanomedicines in the market, it is possible to provide more effective cancer diagnosis and treatment by using nanotechnology. Cancer immunotherapy uses the body's immune system to respond to cancer cells; however, this may lead to increased immune response and immunogenicity. Selectivity and targeting to cancer cells and tumors may lead the way to safer immunotherapy and nanotechnology-based delivery approaches that can help achieve the desired success in cancer treatment.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Sistema Imunitário/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Imunoterapia , Nanopartículas , Neoplasias/imunologia
2.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208365

RESUMO

The development of DNA microarray and RNA-sequencing technology has led to an explosion in the generation of transcriptomic differential expression data under a wide range of biologic systems including those recapitulating the monogenic muscular dystrophies. Data generation has increased exponentially due in large part to new platforms, improved cost-effectiveness, and processing speed. However, reproducibility and thus reliability of data remain a central issue, particularly when resource constraints limit experiments to single replicates. This was observed firsthand in a recent rare disease drug repurposing project involving RNA-seq-based transcriptomic profiling of primary cerebrocortical cultures incubated with clinic-ready blood-brain penetrant drugs. Given the low validation rates obtained for single differential expression genes, alternative approaches to identify with greater confidence genes that were truly differentially expressed in our dataset were explored. Here we outline a method for differential expression data analysis in the context of drug repurposing for rare diseases that incorporates the statistical rigour of the multigene analysis to bring greater predictive power in assessing individual gene modulation. Ingenuity Pathway Analysis upstream regulator analysis was applied to the differentially expressed genes from the Care4Rare Neuron Drug Screen transcriptomic database to identify three distinct signaling networks each perturbed by a different drug and involving a central upstream modulating protein: levothyroxine (DIO3), hydroxyurea (FOXM1), dexamethasone (PPARD). Differential expression of upstream regulator network related genes was next assessed in in vitro and in vivo systems by qPCR, revealing 5× and 10× increases in validation rates, respectively, when compared with our previous experience with individual genes in the dataset not associated with a network. The Ingenuity Pathway Analysis based gene prioritization may increase the predictive value of drug-gene interactions, especially in the context of assessing single-gene modulation in single-replicate experiments.


Assuntos
Bases de Dados Genéticas , Sequências Reguladoras de Ácido Nucleico/genética , Transcriptoma/genética , Animais , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Redes Reguladoras de Genes/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Reprodutibilidade dos Testes , Tiroxina/farmacologia , Transcriptoma/efeitos dos fármacos
3.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208383

RESUMO

Hereditary retinal degenerations like retinitis pigmentosa (RP) are among the leading causes of blindness in younger patients. To enable in vivo investigation of cellular and molecular mechanisms responsible for photoreceptor cell death and to allow testing of therapeutic strategies that could prevent retinal degeneration, animal models have been created. In this study, we deeply characterized the transcriptional profile of mice carrying the transgene rhodopsin V20G/P23H/P27L (VPP), which is a model for autosomal dominant RP. We examined the degree of photoreceptor degeneration and studied the impact of the VPP transgene-induced retinal degeneration on the transcriptome level of the retina using next generation RNA sequencing (RNASeq) analyses followed by weighted correlation network analysis (WGCNA). We furthermore identified cellular subpopulations responsible for some of the observed dysregulations using in situ hybridizations, immunofluorescence staining, and 3D reconstruction. Using RNASeq analysis, we identified 9256 dysregulated genes and six significantly associated gene modules in the subsequently performed WGCNA. Gene ontology enrichment showed, among others, dysregulation of genes involved in TGF-ß regulated extracellular matrix organization, the (ocular) immune system/response, and cellular homeostasis. Moreover, heatmaps confirmed clustering of significantly dysregulated genes coding for components of the TGF-ß, G-protein activated, and VEGF signaling pathway. 3D reconstructions of immunostained/in situ hybridized sections revealed retinal neurons and Müller cells as the major cellular population expressing representative components of these signaling pathways. The predominant effect of VPP-induced photoreceptor degeneration pointed towards induction of neuroinflammation and the upregulation of neuroprotective pathways like TGF-ß, G-protein activated, and VEGF signaling. Thus, modulation of these processes and signaling pathways might represent new therapeutic options to delay the degeneration of photoreceptors in diseases like RP.


Assuntos
Perfilação da Expressão Gênica , Neuroproteção/genética , Retinite Pigmentosa/genética , Transcrição Genética , Regulação para Cima/genética , Animais , Quimiocina CCL2/metabolismo , Feminino , Proteínas de Ligação ao GTP/metabolismo , Redes Reguladoras de Genes , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neuroglia/metabolismo , Degeneração Retiniana/complicações , Degeneração Retiniana/patologia , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/patologia , Rodopsina/genética , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
BMC Plant Biol ; 21(1): 321, 2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34217211

RESUMO

BACKGROUND: Browning spot (BS) disorders seriously affect the appearance quality of 'Huangguan' pear and cause economic losses. Many studies on BS have mainly focused on physiological and biochemical aspects, and the molecular mechanism remains unclear. RESULTS: In the present study, the structural characteristics of 'Huangguan' pear with BS were observed via scanning electron microscopy (SEM), the water loss and brown spots were evaluated, and transcriptomic and metabolomics analyses were conducted to reveal the molecular mechanism underlying 'Huangguan' pear skin browning disorder. The results showed that the occurrence of BS was accompanied by a decrease in the wax layer and an increase in lignified cells. Genes related to wax biosynthesis were downregulated in BS, resulting in a decrease in the wax layer in BS. Genes related to lignin were upregulated at the transcriptional level, resulting in upregulation of metabolites related to phenylpropanoid biosynthesis. Expression of calcium-related genes were upregulated in BS. Cold-induced genes may represent the key genes that induce the formation of BS. In addition, the results demonstrated that exogenous NaH2PO4·2H2O and ABA treatment could inhibit the incidence of BS during harvest and storage time by increasing wax-related genes and calcium-related genes expression and increasing plant resistance, whereas the transcriptomics results indicated that GA3 may accelerate the incidence and index of BS. CONCLUSIONS: The results of this study indicate a molecular mechanism that could explain BS formation and elucidate the effects of different treatments on the incidence and molecular regulation of BS.


Assuntos
Metabolômica , Doenças das Plantas/genética , Pyrus/genética , Pyrus/metabolismo , Transcriptoma/genética , Ácido Abscísico/farmacologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Giberelinas/farmacologia , Metaboloma/genética , Modelos Biológicos , Fenótipo , Pyrus/efeitos dos fármacos , Pyrus/ultraestrutura , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/metabolismo , Transcriptoma/efeitos dos fármacos
5.
BMC Plant Biol ; 21(1): 304, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193039

RESUMO

BACKGROUND: The production of cereal crops is frequently affected by diseases caused by Fusarium graminearum and Magnaporthe oryzae, two devastating fungal pathogens. To improve crop resistance, many studies have focused on understanding the mechanisms of host defense against these two fungi individually. However, our knowledge of the common and different host defenses against these pathogens is very limited. RESULTS: In this study, we employed Brachypodium distachyon as a model for cereal crops and performed comparative transcriptomics to study the dynamics of host gene expression at different infection stages. We found that infection with either F. graminearum or M. oryzae triggered massive transcriptomic reprogramming in the diseased tissues. Numerous defense-related genes were induced with dynamic changes during the time course of infection, including genes that function in pattern detection, MAPK cascade, phytohormone signaling, transcription, protein degradation, and secondary metabolism. In particular, the expression of jasmonic acid signaling genes and proteasome component genes were likely specifically inhibited or manipulated upon infection by F. graminearum. CONCLUSIONS: Our analysis showed that, although the affected host pathways are similar, their expression programs and regulations are distinct during infection by F. graminearum and M. oryzae. The results provide valuable insight into the interactions between B. distachyon and two important cereal pathogens.


Assuntos
Ascomicetos/fisiologia , Brachypodium/genética , Brachypodium/microbiologia , Fusarium/fisiologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Ontologia Genética , Redes Reguladoras de Genes , Interações Hospedeiro-Patógeno/genética , Doenças das Plantas/microbiologia , Mapas de Interação de Proteínas/genética
6.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198485

RESUMO

Brain microvascular endothelial cells (BMECs) constitute the structural and functional basis for the blood-brain barrier (BBB) and play essential roles in bacterial meningitis. Although the BBB integrity regulation has been under extensive investigation, there is little knowledge regarding the roles of long non-coding RNAs (lncRNAs) in this event. The present study aimed to investigate the roles of one potential lncRNA, lncRSPH9-4, in meningitic E. coli infection of BMECs. LncRSPH9-4 was cytoplasm located and significantly up-regulated in meningitic E. coli-infected hBMECs. Electrical cell-substrate impedance sensing (ECIS) measurement and Western blot assay demonstrated lncRSPH9-4 overexpression in hBMECs mediated the BBB integrity disruption. By RNA-sequencing analysis, 639 mRNAs and 299 miRNAs were significantly differentiated in response to lncRSPH9-4 overexpression. We further found lncRSPH9-4 regulated the permeability in hBMECs by competitively sponging miR-17-5p, thereby increasing MMP3 expression, which targeted the intercellular tight junctions. Here we reported the infection-induced lncRSPH9-4 aggravated disruption of the tight junctions in hBMECs, probably through the miR-17-5p/MMP3 axis. This finding provides new insights into the function of lncRNAs in BBB integrity during meningitic E. coli infection and provides the novel nucleic acid targets for future treatment of bacterial meningitis.


Assuntos
Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Escherichia coli/fisiologia , Metaloproteinase 3 da Matriz/metabolismo , Meningites Bacterianas/genética , Meningites Bacterianas/microbiologia , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Sequência de Bases , Citoplasma/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/microbiologia , Redes Reguladoras de Genes , Humanos , MicroRNAs/genética , Microvasos/patologia , Modelos Biológicos , Permeabilidade , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Junções Íntimas/metabolismo , Transcrição Genética , Regulação para Cima/genética
7.
Science ; 373(6551): 192-197, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244409

RESUMO

Throughout development, plant meristems regularly produce organs in defined spiral, opposite, or whorl patterns. Cauliflowers present an unusual organ arrangement with a multitude of spirals nested over a wide range of scales. How such a fractal, self-similar organization emerges from developmental mechanisms has remained elusive. Combining experimental analyses in an Arabidopsis thaliana cauliflower-like mutant with modeling, we found that curd self-similarity arises because the meristems fail to form flowers but keep the "memory" of their transient passage in a floral state. Additional mutations affecting meristem growth can induce the production of conical structures reminiscent of the conspicuous fractal Romanesco shape. This study reveals how fractal-like forms may emerge from the combination of key, defined perturbations of floral developmental programs and growth dynamics.


Assuntos
Arabidopsis/anatomia & histologia , Arabidopsis/genética , Brassica/anatomia & histologia , Brassica/genética , Redes Reguladoras de Genes , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Brassica/crescimento & desenvolvimento , Flores/anatomia & histologia , Flores/genética , Flores/crescimento & desenvolvimento , Fractais , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Inflorescência/anatomia & histologia , Inflorescência/genética , Inflorescência/crescimento & desenvolvimento , Meristema/crescimento & desenvolvimento , Modelos Biológicos , Mutação , Fenótipo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Transcriptoma
8.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34200099

RESUMO

Non-coding RNAs (ncRNAs) have been reported to be implicated in cell fate determination and various human diseases. All ncRNA molecules are emerging as key regulators of diverse cellular processes; however, little is known about the regulatory interaction among these various classes of RNAs. It has been proposed that the large-scale regulatory network across the whole transcriptome is mediated by competing endogenous RNA (ceRNA) activity attributed to both protein-coding and ncRNAs. ceRNAs are considered to be natural sponges of miRNAs that can influence the expression and availability of multiple miRNAs and, consequently, the global mRNA and protein levels. In this review, we summarize the current understanding of the role of ncRNAs in two neuromuscular diseases, myotonic dystrophy type 1 and 2 (DM1 and DM2), and the involvement of expanded CUG and CCUG repeat-containing transcripts in miRNA-mediated RNA crosstalk. More specifically, we discuss the possibility that long repeat tracts present in mutant transcripts can be potent miRNA sponges and may affect ceRNA crosstalk in these diseases. Moreover, we highlight practical information related to innovative disease modelling and studying RNA regulatory networks in cells. Extending knowledge of gene regulation by ncRNAs, and of complex regulatory ceRNA networks in DM1 and DM2, will help to address many questions pertinent to pathogenesis and treatment of these disorders; it may also help to better understand general rules of gene expression and to discover new rules of gene control.


Assuntos
Redes Reguladoras de Genes , MicroRNAs/genética , Distrofia Miotônica/patologia , RNA Circular/genética , RNA Mensageiro/genética , Animais , Humanos , Distrofia Miotônica/genética
9.
Molecules ; 26(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34198975

RESUMO

The past decade has seen growing interest in marine natural pigments for biotechnological applications. One of the most abundant classes of biological pigments is the tetrapyrroles, which are prized targets due their photodynamic properties; porphyrins are the best known examples of this group. Many animal porphyrinoids and other tetrapyrroles are produced through heme metabolic pathways, the best known of which are the bile pigments biliverdin and bilirubin. Eulalia is a marine Polychaeta characterized by its bright green coloration resulting from a remarkably wide range of greenish and yellowish tetrapyrroles, some of which have promising photodynamic properties. The present study combined metabolomics based on HPLC-DAD with RNA-seq transcriptomics to investigate the molecular pathways of porphyrinoid metabolism by comparing the worm's proboscis and epidermis, which display distinct pigmentation patterns. The results showed that pigments are endogenous and seemingly heme-derived. The worm possesses homologs in both organs for genes encoding enzymes involved in heme metabolism such as ALAD, FECH, UROS, and PPOX. However, the findings also indicate that variants of the canonical enzymes of the heme biosynthesis pathway can be species- and organ-specific. These differences between molecular networks contribute to explain not only the differential pigmentation patterns between organs, but also the worm's variety of novel endogenous tetrapyrrolic compounds.


Assuntos
Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Metabolômica/métodos , Poliquetos/genética , Tetrapirróis/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Epiderme/metabolismo , Redes e Vias Metabólicas , Especificidade de Órgãos , Fármacos Fotossensibilizantes/metabolismo , Poliquetos/metabolismo , Análise de Sequência de RNA , Especificidade da Espécie , Tetrapirróis/genética
10.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199411

RESUMO

The human testis and epididymis play critical roles in male fertility, including the spermatogenesis process, sperm storage, and maturation. However, the unique functions of the two organs had not been systematically studied. Herein, we provide a systematic and comprehensive multi-omics study between testis and epididymis. RNA-Seq profiling detected and quantified 19,653 in the testis and 18,407 in the epididymis. Proteomic profiling resulted in the identification of a total of 11,024 and 10,386 proteins in the testis and epididymis, respectively, including 110 proteins that previously have been classified as MPs (missing proteins). Furthermore, Five MPs expressed in testis were validated by the MRM method. Subsequently, multi-omcis between testis and epididymis were performed, including biological functions and pathways of DEGs (Differentially Expressed Genes) in each group, revealing that those differences were related to spermatogenesis, male gamete generation, as well as reproduction. In conclusion, this study can help us find the expression regularity of missing protein and help related scientists understand the physiological functions of testis and epididymis more deeply.


Assuntos
Epididimo/química , Perfilação da Expressão Gênica/métodos , Mapas de Interação de Proteínas , Proteômica/métodos , Testículo/química , Cromatografia Líquida , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Especificidade de Órgãos , Análise de Sequência de RNA , Espermatogênese , Espectrometria de Massas em Tandem
11.
BMC Bioinformatics ; 22(1): 363, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238210

RESUMO

BACKGROUND: Gene regulatory networks coordinate the expression of genes across physiological states and ensure a synchronized expression of genes in cellular subsystems, critical for the coherent functioning of cells. Here we address the question whether it is possible to predict gene synchronization from network structure alone. We have recently shown that synchronized gene expression can be predicted from symmetries in the gene regulatory networks described by the concept of symmetry fibrations. We showed that symmetry fibrations partition the genes into groups called fibers based on the symmetries of their 'input trees', the set of paths in the network through which signals can reach a gene. In idealized dynamic gene expression models, all genes in a fiber are perfectly synchronized, while less idealized models-with gene input functions differencing between genes-predict symmetry breaking and desynchronization. RESULTS: To study the functional role of gene fibers and to test whether some of the fiber-induced coexpression remains in reality, we analyze gene fibrations for the gene regulatory networks of E. coli and B. subtilis and confront them with expression data. We find approximate gene coexpression patterns consistent with symmetry fibrations with idealized gene expression dynamics. This shows that network structure alone provides useful information about gene synchronization, and suggest that gene input functions within fibers may be further streamlined by evolutionary pressures to realize a coexpression of genes. CONCLUSIONS: Thus, gene fibrations provide a sound conceptual tool to describe tunable coexpression induced by network topology and shaped by mechanistic details of gene expression.


Assuntos
Escherichia coli , Redes Reguladoras de Genes , Escherichia coli/genética , Expressão Gênica , Fenótipo
12.
BMC Bioinformatics ; 22(1): 364, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238220

RESUMO

BACKGROUND: Analyzing single-cell RNA sequencing (scRNAseq) data plays an important role in understanding the intrinsic and extrinsic cellular processes in biological and biomedical research. One significant effort in this area is the identification of cell types. With the availability of a huge amount of single cell sequencing data and discovering more and more cell types, classifying cells into known cell types has become a priority nowadays. Several methods have been introduced to classify cells utilizing gene expression data. However, incorporating biological gene interaction networks has been proved valuable in cell classification procedures. RESULTS: In this study, we propose a multimodal end-to-end deep learning model, named sigGCN, for cell classification that combines a graph convolutional network (GCN) and a neural network to exploit gene interaction networks. We used standard classification metrics to evaluate the performance of the proposed method on the within-dataset classification and the cross-dataset classification. We compared the performance of the proposed method with those of the existing cell classification tools and traditional machine learning classification methods. CONCLUSIONS: Results indicate that the proposed method outperforms other commonly used methods in terms of classification accuracy and F1 scores. This study shows that the integration of prior knowledge about gene interactions with gene expressions using GCN methodologies can extract effective features improving the performance of cell classification.


Assuntos
Aprendizado de Máquina , Redes Neurais de Computação , Redes Reguladoras de Genes
13.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 43(3): 371-381, 2021 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-34238413

RESUMO

Objective To explore the function and mechanism of related genes in the occurrence and development of liver cancer, and the possibility of key genes as potential biomarkers and prognostic indicators for the treatment of liver cancer.Methods We selected 4 datasets(GSE57957, GSE121248, GSE36376 and GSE14520)from the GEO database.With P<0.05 and |log2FC|>1 as the thresholds, we used GEO2R and Venn Diagram Software to filter out the common significant differentially expressed genes(DEGs).Cytoscape 3.6.1 plug-ins CytoHubba and molecular complex detection(MCODE)were used to screen out the hub genes and modules of DEGs.In addition, survival analysis of DEGs was performed by gene expression profiling(GEPIA), and Human Protein Atlas(HPA)were used to examine the protein expression levels of key genes in normal liver tissue and liver cancer tissue.Results There were 45 obviously up-regulated genes and 132 down-regulated genes, and MCODE identified 13 clusters.The cluster 1 and cluster 2 with higher scores included 16 genes and 13 genes, respectively.Among the 32 significant DEGs, IGFALS, HGFAC, CYP3A4, SLC22A1, TAT and CYP2E1 demonstrated significantly higher expression levels in liver tissue than in other organs.The HPA immunohistochemistry(IHC)data showed that the expression levels of IGFALS, CYP3A4, SLC22A1 and CYP2E1 in liver cancer tissue were significantly down-regulated and related to the low overall survival rate of patients.Conclusion The liver tissue-specific genes IGFALS, CYP3A4, SLC22A1 and CYP2E1 are under-expressed in liver cancer and associated with poor prognosis, which may be potential biomarkers and prognostic indicators for liver cancer.


Assuntos
Citocromo P-450 CYP2E1 , Neoplasias Hepáticas , Biomarcadores Tumorais/genética , Biologia Computacional , Citocromo P-450 CYP3A , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasias Hepáticas/genética , Prognóstico , Mapas de Interação de Proteínas
14.
BMC Bioinformatics ; 22(1): 365, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238207

RESUMO

BACKGROUND: The topology of metabolic networks is both well-studied and remarkably well-conserved across many species. The regulation of these networks, however, is much more poorly characterized, though it is known to be divergent across organisms-two characteristics that make it difficult to model metabolic networks accurately. While many computational methods have been built to unravel transcriptional regulation, there have been few approaches developed for systems-scale analysis and study of metabolic regulation. Here, we present a stepwise machine learning framework that applies established algorithms to identify regulatory interactions in metabolic systems based on metabolic data: stepwise classification of unknown regulation, or SCOUR. RESULTS: We evaluated our framework on both noiseless and noisy data, using several models of varying sizes and topologies to show that our approach is generalizable. We found that, when testing on data under the most realistic conditions (low sampling frequency and high noise), SCOUR could identify reaction fluxes controlled only by the concentration of a single metabolite (its primary substrate) with high accuracy. The positive predictive value (PPV) for identifying reactions controlled by the concentration of two metabolites ranged from 32 to 88% for noiseless data, 9.2 to 49% for either low sampling frequency/low noise or high sampling frequency/high noise data, and 6.6-27% for low sampling frequency/high noise data, with results typically sufficiently high for lab validation to be a practical endeavor. While the PPVs for reactions controlled by three metabolites were lower, they were still in most cases significantly better than random classification. CONCLUSIONS: SCOUR uses a novel approach to synthetically generate the training data needed to identify regulators of reaction fluxes in a given metabolic system, enabling metabolomics and fluxomics data to be leveraged for regulatory structure inference. By identifying and triaging the most likely candidate regulatory interactions, SCOUR can drastically reduce the amount of time needed to identify and experimentally validate metabolic regulatory interactions. As high-throughput experimental methods for testing these interactions are further developed, SCOUR will provide critical impact in the development of predictive metabolic models in new organisms and pathways.


Assuntos
Aprendizado de Máquina , Redes e Vias Metabólicas , Algoritmos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Metabolômica
15.
Nat Commun ; 12(1): 4237, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244483

RESUMO

Brain network hubs are both highly connected and highly inter-connected, forming a critical communication backbone for coherent neural dynamics. The mechanisms driving this organization are poorly understood. Using diffusion-weighted magnetic resonance imaging in twins, we identify a major role for genes, showing that they preferentially influence connectivity strength between network hubs of the human connectome. Using transcriptomic atlas data, we show that connected hubs demonstrate tight coupling of transcriptional activity related to metabolic and cytoarchitectonic similarity. Finally, comparing over thirteen generative models of network growth, we show that purely stochastic processes cannot explain the precise wiring patterns of hubs, and that model performance can be improved by incorporating genetic constraints. Our findings indicate that genes play a strong and preferential role in shaping the functionally valuable, metabolically costly connections between connectome hubs.


Assuntos
Encéfalo/fisiologia , Conectoma , Redes Reguladoras de Genes , Rede Nervosa/fisiologia , Adulto , Encéfalo/diagnóstico por imagem , Conjuntos de Dados como Assunto , Imagem de Difusão por Ressonância Magnética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Modelos Genéticos , Gêmeos
16.
Planta ; 254(2): 35, 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34292405

RESUMO

MAIN CONCLUSION: Accumulation patterns and gene regulatory networks of sugars and cucurbitacins and related primary and secondary metabolites during cultivated watermelon 'Cheng Lan' and wild watermelon 'PI 632,751' fruit development were identified. Metabolites are the end products of cellular regulatory processes and play important roles in fruit taste formation. However, comprehensive studies on the accumulation patterns of watermelon fruit metabolites and transcriptional regulatory networks are still scarce. In this study, 451 annotated metabolites were identified at four key fruit developmental stages in wild watermelon 'PI 632,751' and modern cultivated watermelon 'Cheng Lan'. Interestingly, 11 sugars and 25 major primary metabolites were mainly accumulated in 'Cheng Lan' during fruit development, which are considered to be the potential metabolites beneficial to the formation of watermelon taste. Cucurbitacins and the main flavonoids were mainly specifically accumulated in 'PI 632,751', not being considered to be responsible for the taste. Moreover, forty-seven genes involved in carbohydrate metabolism, glycolysis, and TCA cycle were highly expressed in 'Cheng Lan', which was positively correlated with the accumulation of major primary metabolites. Alternatively, seven UDP-glycosyltransferase genes are closely related to the glycosylation of cucurbitacins through co-expression analysis. Our findings established a global map of metabolite accumulation and gene regulation during fruit development in wild and cultivated watermelons and provided valuable information on taste formation in watermelon fruit.


Assuntos
Citrullus , Citrullus/genética , Frutas/genética , Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes , Metaboloma , Paladar , Transcriptoma/genética
17.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(6): 659-664, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34296682

RESUMO

OBJECTIVE: To identify the Key genes in the development of sepsis through Weighted Gene Co-Expression Network Analysis (WGCNA). METHODS: The gene expression dataset GSE154918 was downloaded from the public database Gene Expression Omnibus (GEO) database, which containes data from 105 microarrays of 40 control cases, 12 cases of asymptomatic infection, 39 cases of sepsis, and 14 cases of follow-up sepsis. The R software was used to screen out differentially expressed genes (DEG) in sepsis, and the Distributed Access View Integrated Database (DAVID), SEARCH TOOL FOR RETRIEVAL OF INTERACTING NEIGHBOURING GENES (STRING) and visualization software Cytoscape were used to perform gene function and pathway enrichment analysis, Protein-protein interaction (PPI) network analysis and key gene analysis to screen out the key genes in the development of sepsis. RESULTS: Forty-six candidate genes were obtained by WGCNA and combined with DEG expression analysis, and these 46 genes were analyzed by gene ontology (GO) and Kyoto City Encyclopedia of Genes and Genomes (KEGG) pathway enrichment to obtain gene functions and involved signaling pathways. The PPI network was further constructed using the STRING database, and 5 key genes were selected by the PPI network visualization software Cytoscape, including the mast cell expressed membrane protein 1 gene (MCEMP1), the S100 calcium-binding protein A12 gene (S100A12), the adipokine resistance factor gene (RETN), the c-type lectin structural domain family 4 member gene (CLEC4D), and peroxisome proliferator-activated receptor gene (PPARG), and differential expression analysis of each of these 5 genes showed that the expression levels of the above 5 genes were significantly upregulated in sepsis patients compared with healthy controls. CONCLUSIONS: In this study, 5 key genes related to sepsis were screened by constructing WGCNA method, which may be potential candidate targets related to sepsis diagnosis and treatment.


Assuntos
Perfilação da Expressão Gênica , Sepse , Biologia Computacional , Expressão Gênica , Redes Reguladoras de Genes , Humanos , Sepse/genética
18.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209949

RESUMO

Fibrinolysis is a complex enzymatic process aimed at dissolving blood clots to prevent vascular occlusions. The fibrinolytic system is composed of a number of cofactors that, by regulating fibrin degradation, maintain the hemostatic balance. A dysregulation of fibrinolysis is associated with various pathological processes that result, depending on the type of abnormality, in prothrombotic or hemorrhagic states. This narrative review is focused on the congenital and acquired disorders of primary fibrinolysis in both adults and children characterized by a hyperfibrinolytic state with a bleeding phenotype.


Assuntos
Transtornos da Coagulação Sanguínea/metabolismo , Fibrinólise , Hemorragia/metabolismo , Adulto , Transtornos da Coagulação Sanguínea/etiologia , Criança , Redes Reguladoras de Genes , Hemorragia/etiologia , Humanos
19.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209973

RESUMO

In maize, the ear shank is a short branch that connects the ear to the stalk. The length of the ear shank mainly affects the transportation of photosynthetic products to the ear, and also influences the dehydration of the grain by adjusting the tightness of the husks. However, the molecular mechanisms of maize shank elongation have rarely been described. It has been reported that the maize ear shank length is a quantitative trait, but its genetic basis is still unclear. In this study, RNA-seq was performed to explore the transcriptional dynamics and determine the key genes involved in maize shank elongation at four different developmental stages. A total of 8145 differentially expressed genes (DEGs) were identified, including 729 transcription factors (TFs). Some important genes which participate in shank elongation were detected via function annotation and temporal expression pattern analyses, including genes related to signal transduction hormones (auxin, brassinosteroids, gibberellin, etc.), xyloglucan and xyloglucan xyloglucosyl transferase, and transcription factor families. The results provide insights into the genetic architecture of maize ear shanks and developing new varieties with ideal ear shank lengths, enabling adjustments for mechanized harvesting in the future.


Assuntos
Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Zea mays/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Regulação da Expressão Gênica de Plantas , Ontologia Genética , Fenótipo , Proteínas de Plantas/genética , Locos de Características Quantitativas , Fatores de Transcrição , Zea mays/genética
20.
Genome Med ; 13(1): 118, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34281603

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has been associated with neurological and neuropsychiatric illness in many individuals. We sought to further our understanding of the relationship between brain tropism, neuro-inflammation, and host immune response in acute COVID-19 cases. METHODS: Three brain regions (dorsolateral prefrontal cortex, medulla oblongata, and choroid plexus) from 5 patients with severe COVID-19 and 4 controls were examined. The presence of the virus was assessed by western blot against viral spike protein, as well as viral transcriptome analysis covering > 99% of SARS-CoV-2 genome and all potential serotypes. Droplet-based single-nucleus RNA sequencing (snRNA-seq) was performed in the same samples to examine the impact of COVID-19 on transcription in individual cells of the brain. RESULTS: Quantification of viral spike S1 protein and viral transcripts did not detect SARS-CoV-2 in the postmortem brain tissue. However, analysis of 68,557 single-nucleus transcriptomes from three distinct regions of the brain identified an increased proportion of stromal cells, monocytes, and macrophages in the choroid plexus of COVID-19 patients. Furthermore, differential gene expression, pseudo-temporal trajectory, and gene regulatory network analyses revealed transcriptional changes in the cortical microglia associated with a range of biological processes, including cellular activation, mobility, and phagocytosis. CONCLUSIONS: Despite the absence of detectable SARS-CoV-2 in the brain at the time of death, the findings suggest significant and persistent neuroinflammation in patients with acute COVID-19.


Assuntos
Encéfalo/metabolismo , COVID-19/imunologia , Perfilação da Expressão Gênica/métodos , Imunidade/genética , Imunidade/imunologia , Transcriptoma , Plexo Corióideo/metabolismo , Expressão Gênica , Redes Reguladoras de Genes , Humanos , Inflamação , Microglia , Córtex Pré-Frontal/metabolismo , SARS-CoV-2/genética
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