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1.
Transl Psychiatry ; 11(1): 160, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33723208

RESUMEN

Psychiatric symptoms are seen in some COVID-19 patients, as direct or indirect sequelae, but it is unclear whether SARS-CoV-2 infection interacts with underlying neuronal or psychiatric susceptibilities. Such interactions might arise from COVID-19 immune responses, from infection of neurons themselves or may reflect social-psychological causes. To clarify this we sought the key gene expression pathways altered in COVID-19 also affected in bipolar disorder, post-traumatic stress disorder (PTSD) and schizophrenia, since this may identify pathways of interaction that could be treatment targets. We performed large scale comparisons of whole transcriptome data and immune factor transcript data in peripheral blood mononuclear cells (PBMC) from COVID-19 patients and patients with psychiatric disorders. We also analysed genome-wide association study (GWAS) data for symptomatic COVID-19 patients, comparing GWAS and whole-genome sequence data from patients with bipolar disorder, PTSD and schizophrenia patients. These studies revealed altered signalling and ontology pathways shared by COVID-19 patients and the three psychiatric disorders. Finally, co-expression and network analyses identified gene clusters common to the conditions. COVID-19 patients had peripheral blood immune system profiles that overlapped with those of patients with psychiatric conditions. From the pathways identified, PTSD profiles were the most highly correlated with COVID-19, perhaps consistent with stress-immune system interactions seen in PTSD. We also revealed common inflammatory pathways that may exacerbate psychiatric disorders, which may support the usage of anti-inflammatory medications in these patients. It also highlights the potential clinical application of multi-level dataset studies in difficult-to-treat psychiatric disorders in this COVID-19 pandemic.


Asunto(s)
Trastorno Bipolar/genética , Esquizofrenia/genética , Trastornos por Estrés Postraumático/genética , Trastorno Bipolar/inmunología , Comorbilidad , Perfilación de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Estudio de Asociación del Genoma Completo , Genómica , Humanos , Inmunidad/genética , Inflamación/genética , Trastornos Mentales/genética , Trastornos Mentales/inmunología , Esquizofrenia/inmunología , Transducción de Señal/genética , Trastornos por Estrés Postraumático/inmunología , Secuenciación Completa del Genoma
2.
Nat Commun ; 12(1): 1894, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33767165

RESUMEN

Neural crest stem cells arising from caudal hindbrain (often called cardiac and posterior vagal neural crest) migrate long distances to form cell types as diverse as heart muscle and enteric ganglia, abnormalities of which lead to common congenital birth defects. Here, we explore whether individual caudal hindbrain neural crest precursors are multipotent or predetermined toward these particular fates and destinations. To this end, we perform lineage tracing of chick neural crest cells at single-cell resolution using two complementary approaches: retrovirally mediated multiplex clonal analysis and single-cell photoconversion. Both methods show that the majority of these neural crest precursors are multipotent with many clones producing mesenchymal as well as neuronal derivatives. Time-lapse imaging demonstrates that sister cells can migrate in distinct directions, suggesting stochasticity in choice of migration path. Perturbation experiments further identify guidance cues acting on cells in the pharyngeal junction that can influence this choice; loss of CXCR4 signaling results in failure to migrate to the heart but no influence on migration toward the foregut, whereas loss of RET signaling does the opposite. Taken together, the results suggest that environmental influences rather than intrinsic information govern cell fate choice of multipotent caudal hindbrain neural crest cells.


Asunto(s)
Sistema Nervioso Entérico/embriología , Corazón/embriología , Células Madre Multipotentes/citología , Cresta Neural/citología , Células-Madre Neurales/citología , Animales , Diferenciación Celular/fisiología , Movimiento Celular/fisiología , Pollos , Proteínas Proto-Oncogénicas c-ret/genética , Receptores CXCR4/genética , Rombencéfalo/citología , Transducción de Señal/genética
3.
Nat Commun ; 12(1): 1788, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741909

RESUMEN

Biological regulatory systems, such as cell signaling networks, nervous systems and ecological webs, consist of complex dynamical interactions among many components. Network motif models focus on small sub-networks to provide quantitative insight into overall behavior. However, such models often overlook time delays either inherent to biological processes or associated with multi-step interactions. Here we systematically examine explicit-delay versions of the most common network motifs via delay differential equation (DDE) models, both analytically and numerically. We find many broadly applicable results, including parameter reduction versus canonical ordinary differential equation (ODE) models, analytical relations for converting between ODE and DDE models, criteria for when delays may be ignored, a complete phase space for autoregulation, universal behaviors of feedforward loops, a unified Hill-function logic framework, and conditions for oscillations and chaos. We conclude that explicit-delay modeling simplifies the phenomenology of many biological networks and may aid in discovering new functional motifs.


Asunto(s)
Algoritmos , Biología Computacional/métodos , Redes Reguladoras de Genes , Modelos Genéticos , Dinámicas no Lineales , Animales , Retroalimentación Fisiológica , Regulación de la Expresión Génica , Humanos , Transducción de Señal/genética
4.
Nat Commun ; 12(1): 1749, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741928

RESUMEN

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.


Asunto(s)
Neoplasias Cerebelosas/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Hedgehog/genética , Meduloblastoma/genética , Transcriptoma , Adolescente , Adulto , Niño , Preescolar , Femenino , Redes Reguladoras de Genes , Variación Genética , Humanos , Lactante , Masculino , Persona de Mediana Edad , Transducción de Señal/genética , Adulto Joven
5.
Nat Commun ; 12(1): 1789, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741976

RESUMEN

Sensory perception and metabolic homeostasis are known to deteriorate with ageing, impairing the health of aged animals, while mechanisms underlying their deterioration remain poorly understood. The potential interplay between the declining sensory perception and the impaired metabolism during ageing is also barely explored. Here, we report that the intraflagellar transport (IFT) in the cilia of sensory neurons is impaired in the aged nematode Caenorhabditis elegans due to a daf-19/RFX-modulated decrease of IFT components. We find that the reduced IFT in sensory cilia thus impairs sensory perception with ageing. Moreover, we demonstrate that whereas the IFT-dependent decrease of sensory perception in aged worms has a mild impact on the insulin/IGF-1 signalling, it remarkably suppresses AMP-activated protein kinase (AMPK) signalling across tissues. We show that upregulating daf-19/RFX effectively enhances IFT, sensory perception, AMPK activity and autophagy, promoting metabolic homeostasis and longevity. Our study determines an ageing pathway causing IFT decay and sensory perception deterioration, which in turn disrupts metabolism and healthy ageing.


Asunto(s)
Envejecimiento , Caenorhabditis elegans/metabolismo , Cilios/metabolismo , Flagelos/metabolismo , Células Receptoras Sensoriales/fisiología , Transducción de Señal/fisiología , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Animales Modificados Genéticamente , Transporte Biológico , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Longevidad/genética , Percepción/fisiología , Interferencia de ARN , Factor Regulador X1/genética , Factor Regulador X1/metabolismo , Células Receptoras Sensoriales/metabolismo , Transducción de Señal/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
6.
Nat Commun ; 12(1): 1518, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750796

RESUMEN

Growing evidences suggest that cancer stem cells exhibit many molecular characteristics and phenotypes similar to their ancestral progenitor cells. In the present study, human embryonic stem cells are induced to differentiate into hepatocytes along hepatic lineages to mimic liver development in vitro. A liver progenitor specific gene, RALY RNA binding protein like (RALYL), is identified. RALYL expression is associated with poor prognosis, poor differentiation, and metastasis in clinical HCC patients. Functional studies reveal that RALYL could promote HCC tumorigenicity, self-renewal, chemoresistance, and metastasis. Moreover, molecular mechanism studies show that RALYL could upregulate TGF-ß2 mRNA stability by decreasing N6-methyladenosine (m6A) modification. TGF-ß signaling and the subsequent PI3K/AKT and STAT3 pathways, upregulated by RALYL, contribute to the enhancement of HCC stemness. Collectively, RALYL is a liver progenitor specific gene and regulates HCC stemness by sustaining TGF-ß2 mRNA stability. These findings may inspire precise therapeutic strategies for HCC.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo C/metabolismo , Neoplasias Hepáticas/metabolismo , Estabilidad del ARN/fisiología , Factor de Crecimiento Transformador beta2/metabolismo , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Diferenciación Celular , Línea Celular Tumoral , Movimiento Celular , Células Madre Embrionarias , Femenino , Regulación Neoplásica de la Expresión Génica , Ribonucleoproteína Heterogénea-Nuclear Grupo C/genética , Humanos , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Ratones , Persona de Mediana Edad , Células Madre Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/genética , Regulación hacia Arriba
7.
Front Immunol ; 12: 618807, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33679760

RESUMEN

Type 2 inflammation is found in most forms of asthma, which may co-exist with recurrent viral infections, bacterial colonization, and host cell death. These processes drive the accumulation of intracellular cyclic-di-nucleotides such as cyclic-di-GMP (CDG). Group 2 innate lymphoid cells (ILC2s) are critical drivers of type 2 lung inflammation during fungal allergen exposure in mice; however, it is unclear how CDG regulates lung ILC responses during lung inflammation. Here, we show that intranasal CDG induced early airway type 1 interferon (IFN) production and dramatically suppressed CD127+ST2+ ILC2s and type 2 lung inflammation during Alternaria and IL-33 exposure. Further, CD127-ST2-Thy1.2+ lung ILCs, which showed a transcriptomic signature consistent with ILC1s, were expanded and activated by CDG combined with either Alternaria or IL-33. CDG-mediated suppression of type 2 inflammation occurred independent of IL-18R, IL-12, and STAT6 but required the stimulator of interferon genes (STING) and type 1 IFN signaling. Thus, CDG potently suppresses ILC2-driven lung inflammation and promotes ILC1 responses. These results suggest potential therapeutic modulation of STING to suppress type 2 inflammation and/or increase anti-viral responses during respiratory infections.


Asunto(s)
Alternaria/inmunología , Alternariosis/inmunología , GMP Cíclico/análogos & derivados , Inmunidad Innata , Pulmón/inmunología , Proteínas de la Membrana/inmunología , Neumonía/inmunología , Alternariosis/genética , Alternariosis/patología , Animales , GMP Cíclico/genética , GMP Cíclico/inmunología , Citocinas/genética , Citocinas/inmunología , Inflamación/genética , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Pulmón/microbiología , Pulmón/patología , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Neumonía/genética , Neumonía/microbiología , Neumonía/patología , Transducción de Señal/genética , Transducción de Señal/inmunología
8.
Molecules ; 26(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670164

RESUMEN

Neurodegenerative diseases are chronic, progressive disorders that occur in the central nervous system (CNS). They are characterized by the loss of neuronal structure and function and are associated with inflammation. Inflammation of the CNS is called neuroinflammation, which has been implicated in most neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Much evidence indicates that these different conditions share a common inflammatory mechanism: the activation of the inflammasome complex in peripheral monocytes and in microglia, with the consequent production of high quantities of the pro-inflammatory cytokines IL-1ß and IL-18. Inflammasomes are a group of multimeric signaling complexes that include a sensor Nod-like receptor (NLR) molecule, the adaptor protein ASC, and caspase-1. The NLRP3 inflammasome is currently the best-characterized inflammasome. Multiple signals, which are potentially provided in combination and include endogenous danger signals and pathogens, trigger the formation of an active inflammasome, which, in turn, will stimulate the cleavage and the release of bioactive cytokines including IL-1ß and IL-18. In this review, we will summarize results implicating the inflammasome as a pivotal player in the pathogenesis of neurodegenerative diseases and discuss how compounds that hamper the activation of the NLRP3 inflammasome could offer novel therapeutic avenues for these diseases.


Asunto(s)
Inflamasomas/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Enfermedades Neurodegenerativas/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Humanos , Interleucina-18/genética , Interleucina-1beta/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Enfermedades Neurodegenerativas/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Transducción de Señal/genética
9.
Molecules ; 26(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673080

RESUMEN

This study investigated the effect of type 1 gonadotropin releasing hormone receptor (GnRH-R) localization within lipid rafts on the properties of plasma membrane (PM) nanodomain structure. Confocal microscopy revealed colocalization of PM-localized GnRH-R with GM1-enriched raft-like PM subdomains. Electron paramagnetic resonance spectroscopy (EPR) of a membrane-partitioned spin probe was then used to study PM fluidity of immortalized pituitary gonadotrope cell line αT3-1 and HEK-293 cells stably expressing GnRH-R and compared it with their corresponding controls (αT4 and HEK-293 cells). Computer-assisted interpretation of EPR spectra revealed three modes of spin probe movement reflecting the properties of three types of PM nanodomains. Domains with an intermediate order parameter (domain 2) were the most affected by the presence of the GnRH-Rs, which increased PM ordering (order parameter (S)) and rotational mobility of PM lipids (decreased rotational correlation time (τc)). Depletion of cholesterol by methyl-ß-cyclodextrin (methyl-ß-CD) inhibited agonist-induced GnRH-R internalization and intracellular Ca2+ activity and resulted in an overall reduction in PM order; an observation further supported by molecular dynamics (MD) simulations of model membrane systems. This study provides evidence that GnRH-R PM localization may be related to a subdomain of lipid rafts that has lower PM ordering, suggesting lateral heterogeneity within lipid raft domains.


Asunto(s)
Lípidos de la Membrana/química , Microdominios de Membrana/química , Receptores LHRH/química , Colesterol/química , Colesterol/genética , Espectroscopía de Resonancia por Spin del Electrón , Células HEK293 , Humanos , Lípidos de la Membrana/genética , Microdominios de Membrana/genética , Microdominios de Membrana/ultraestructura , Dominios Proteicos/genética , Receptores LHRH/genética , Receptores LHRH/uso terapéutico , Receptores LHRH/ultraestructura , Transducción de Señal/genética
10.
Molecules ; 26(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673188

RESUMEN

Virtually all types of cardiovascular diseases are associated with pathological activation of the innate immune system. The NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is a protein complex that functions as a platform for rapid induction of the inflammatory response to infection or sterile injury. NLRP3 is an intracellular sensor that is sensitive to danger signals, such as ischemia and extracellular or intracellular alarmins during tissue injury. The NLRP3 inflammasome is regulated by the presence of damage-associated molecular patterns and initiates or amplifies inflammatory response through the production of interleukin-1ß (IL-1ß) and/or IL-18. NLRP3 activation regulates cell survival through the activity of caspase-1 and gasdermin-D. The development of NLRP3 inflammasome inhibitors has opened the possibility to targeting the deleterious effects of NLRP3. Here, we examine the scientific evidence supporting a role for NLRP3 and the effects of inhibitors in cardiovascular diseases.


Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Inmunidad Innata/genética , Inflamasomas/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Enfermedades Cardiovasculares/genética , Caspasa 1/genética , Humanos , Interleucina-18/genética , Interleucina-1beta/genética , Transducción de Señal/genética
11.
Medicine (Baltimore) ; 100(6): e24471, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578541

RESUMEN

BACKGROUND: In osteosarcoma, the lung is the most common metastatic organ. Intensive work has been made to illuminate the pathogeny, but the specific metastatic mechanism remains unclear. Thus, we conducted the study to seek to find the key genes and critical functional pathways associated with progression and treatment in lung metastasis originating from osteosarcoma. METHODS: Two independent datasets (GSE14359 and GSE85537) were screened out from the Gene Expression Omnibus (GEO) database and the overlapping differentially expressed genes (DEGs) were identified using GEO2R online platform. Subsequently, the Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis of DEGs were conducted using DAVID. Meanwhile, the protein-protein interaction (PPI) network constructed by STRING was visualized using Cytoscape. Afterwards, the key module and hub genes were extracted from the PPI network using the MCODE and cytoHubba plugin. Moreover, the raw data obtained from GSE73166 and GSE21257 were applied to verify the expression differences and conduct the survival analyses of hub genes, respectively. Finally, the interaction network of miRNAs and hub genes constructed by ENCORI was visualized using Cytoscape. RESULTS: A total of 364 DEGs were identified, comprising 96 downregulated genes and 268 upregulated genes, which were mainly involved in cancer-associated pathways, adherens junction, ECM-receptor interaction, focal adhesion, MAPK signaling pathway. Subsequently, 10 hub genes were obtained and survival analysis demonstrated SKP2 and ASPM were closely related to poor prognosis of patients with osteosarcoma. Finally, hsa-miR-340-5p, has-miR-495-3p, and hsa-miR-96-5p were found to be most closely associated with these hub genes according to the interaction network of miRNAs and hub genes. CONCLUSION: The key genes and functional pathways identified in the study may contribute to understanding the molecular mechanisms involved in the carcinogenesis and progression of lung metastasis originating from osteosarcoma, and provide potential diagnostic and therapeutic targets.


Asunto(s)
Neoplasias Óseas/patología , Neoplasias Pulmonares/secundario , Osteosarcoma/patología , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/genética , Biología Computacional , Regulación Neoplásica de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Genes Relacionados con las Neoplasias/genética , Marcadores Genéticos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , MicroARNs/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteosarcoma/diagnóstico , Osteosarcoma/genética , Transducción de Señal/genética
12.
J Biol Regul Homeost Agents ; 35(1): 35-44, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33601878

RESUMEN

There are many risk factors for gastric cancer (GC), including chronic atrophic gastritis, which involves multiple genes and signaling pathways. Weighted gene co-expression network analysis (WGCNA) was performed on GSE111762 to construct free-scale gene co-expression networks and identified four significant modules that consisted of blue, dark orange, dark red and dark violet. In each module, genes with the most connectivity were selected as hub genes, including G antigen 12J (GAGE12J) in blue, proline, histidine and glycine rich 1 (PHGR1) in dark orange, DNA polymerase gamma 2, accessory subunit (POLG2) in dark red and collagen type XXI alpha 1 chain (COL21A1) in dark violet. The transcription level of COL21A1 and GAGE12J was up-regulated in atrophic gastritis vs normal gastric mucosa, but down-regulated in GC vs atrophic gastritis. PHGR1 was consistently down-regulated from normal gastric mucosa to GC, while POLG2 was up-regulated. Gene set enrichment analysis (GSEA) was then conducted to study the biological functions of hub genes in the development of GC. It showed that multiple tumorigenesis-related pathways were enriched, including peroxisome, DNA repair and KRAS signaling pathway in COL21A1, IL6-JAK-STAT3, epithelial mesenchymal transition (EMT) and TNFα-NF-κB signaling pathway in PHGR1, MYC targets, E2F targets and angiogenesis in POLG2 and peroxisome, Notch signaling pathway and androgen response in GAGE12J. The identified four genes, especially for COL21A1, PHGR1 and POLG2, were important in GC tumorigenesis and affected many cancer-related pathways.


Asunto(s)
Neoplasias Gástricas , Transición Epitelial-Mesenquimal , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Transducción de Señal/genética , Neoplasias Gástricas/genética
13.
Nat Commun ; 12(1): 1079, 2021 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-33597532

RESUMEN

SARS-CoV-2 infection has been shown to trigger a wide spectrum of immune responses and clinical manifestations in human hosts. Here, we sought to elucidate novel aspects of the host response to SARS-CoV-2 infection through RNA sequencing of peripheral blood samples from 46 subjects with COVID-19 and directly comparing them to subjects with seasonal coronavirus, influenza, bacterial pneumonia, and healthy controls. Early SARS-CoV-2 infection triggers a powerful transcriptomic response in peripheral blood with conserved components that are heavily interferon-driven but also marked by indicators of early B-cell activation and antibody production. Interferon responses during SARS-CoV-2 infection demonstrate unique patterns of dysregulated expression compared to other infectious and healthy states. Heterogeneous activation of coagulation and fibrinolytic pathways are present in early COVID-19, as are IL1 and JAK/STAT signaling pathways, which persist into late disease. Classifiers based on differentially expressed genes accurately distinguished SARS-CoV-2 infection from other acute illnesses (auROC 0.95 [95% CI 0.92-0.98]). The transcriptome in peripheral blood reveals both diverse and conserved components of the immune response in COVID-19 and provides for potential biomarker-based approaches to diagnosis.


Asunto(s)
/genética , Perfilación de la Expresión Génica/métodos , Leucocitos Mononucleares/metabolismo , Análisis de Secuencia de ARN/métodos , Transcriptoma/genética , /sangre , Citocinas/genética , Interacciones Huésped-Patógeno , Humanos , Gripe Humana/genética , Neumonía Bacteriana/genética , Transducción de Señal/genética
14.
Nat Commun ; 12(1): 1111, 2021 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-33597542

RESUMEN

Follicular B (FoB) and marginal zone B (MZB) cells are functionally and spatially distinct mature B cell populations in the spleen, originating from a Notch2-dependent fate decision after splenic influx of immature transitional B cells. In the B cell follicle, a Notch2-signal is provided by DLL-1-expressing fibroblasts. However, it is unclear whether FoB cells, which are in close contact with these DLL-1 expressing fibroblasts, can also differentiate to MZB cells if they receive a Notch2-signal. Here, we show induced Notch2IC-expression in FoB cells re-programs mature FoB cells into bona fide MZB cells as is evident from the surface phenotype, localization, immunological function and transcriptome of these cells. Furthermore, the lineage conversion from FoB to MZB cells occurs in immunocompetent wildtype mice. These findings demonstrate plasticity between mature FoB and MZB cells that can be driven by a singular signaling event, the activation of Notch2.


Asunto(s)
Linfocitos B/metabolismo , Diferenciación Celular/genética , Perfilación de la Expresión Génica/métodos , Receptor Notch2/genética , Transducción de Señal/genética , Bazo/metabolismo , Animales , Linfocitos B/citología , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Células Cultivadas , Femenino , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Células Precursoras de Linfocitos B/citología , Células Precursoras de Linfocitos B/metabolismo , Receptor Notch2/metabolismo , Bazo/citología
15.
Nat Commun ; 12(1): 1272, 2021 02 24.
Artículo en Inglés | MEDLINE | ID: mdl-33627672

RESUMEN

Cellular responses to environmental changes are encoded in the complex temporal patterns of signaling proteins. However, quantifying the accumulation of information over time to direct cellular decision-making remains an unsolved challenge. This is, in part, due to the combinatorial explosion of possible configurations that need to be evaluated for information in time-course measurements. Here, we develop a quantitative framework, based on inferred trajectory probabilities, to calculate the mutual information encoded in signaling dynamics while accounting for cell-cell variability. We use it to understand NFκB transcriptional dynamics in response to different immune threats, and reveal that some threats are distinguished faster than others. Our analyses also suggest specific temporal phases during which information distinguishing threats becomes available to immune response genes; one specific phase could be mapped to the functionality of the IκBα negative feedback circuit. The framework is generally applicable to single-cell time series measurements, and enables understanding how temporal regulatory codes transmit information over time.


Asunto(s)
Simulación de Dinámica Molecular , Humanos , FN-kappa B/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiología
16.
Yonsei Med J ; 62(3): 215-223, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33635011

RESUMEN

PURPOSE: This study aimed to elucidate whether lncRNA ZFAS1 is involved in neuronal apoptosis and inflammation in temporal lobe epilepsy (TLE). MATERIALS AND METHODS: Ninety-six TLE patients were recruited, and their peripheral venous blood was gathered to determine Zfas1 expression with polymerase chain reaction. Neurons were separated from hippocampal tissue of newborn SD rats, and si-Zfas1 or pcDNA3.1-Zfas1 was transfected into the neurons. Inflammatory cytokines released by neurons were determined, and neuronal activities were evaluated through MTT assay, colony formation assay, and flow cytometry. RESULTS: Serum levels of Zfas1 were higher in TLE patients than in healthy controls (p<0.05). Furthermore, Zfas1 expression in neurons was raised by pcDNA3.1-Zfas1 and declined after silencing of Zfas1 (p<0.05). Transfection of pcDNA-Zfas1 weakened the viability and proliferation of neurons and increased neuronal apoptosis (p<0.05). Meanwhile, pcDNA3.1-Zfas1 transfection promoted lipopolysaccharide-induced release of cytokines, including tumor necrosis factor-α, interleukin (IL)-1, IL-6, and intercellular adhesion molecule-1 (p<0.05), and boosted NF-κB activation by elevating the expression of NF-κB p65, pIκBα, and IKKß in neurons (p<0.05). CONCLUSION: Our results indicated that lncRNA ZFAS1 exacerbates epilepsy development by promoting neuronal apoptosis and inflammation, implying ZFAS1 as a promising treatment target for epilepsy.


Asunto(s)
Apoptosis/genética , Epilepsia del Lóbulo Temporal/genética , Inflamación/patología , Neuronas/patología , ARN Largo no Codificante/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Animales Recién Nacidos , Biomarcadores/metabolismo , Estudios de Casos y Controles , Supervivencia Celular/genética , Niño , Citocinas/metabolismo , Femenino , Regulación de la Expresión Génica , Hipocampo/patología , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , FN-kappa B/metabolismo , ARN Largo no Codificante/genética , Ratas Sprague-Dawley , Transducción de Señal/genética , Adulto Joven
17.
Hum Cell ; 34(2): 698-699, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33527306

RESUMEN

The current COVID-19 is one of the deadliest pandemics in recent decades. In the lack of a specific treatment for this novel infection, knowing the role of cell signaling pathways in the pathogenesis of this infection could be useful in finding effective drugs against this disease. The mammalian or mechanistic target of rapamycin (mTOR) is an important cell signaling pathway that has important role in the regulation of cell growth, protein synthesis, and metabolism in reactance to upstream signals in both pathological and normal physiological conditions. Recently, some researchers have suggested the therapeutic potential of mTOR inhibitors such as rapamycin against COVID-19. However, it is important to consider the role of activation of this pathway in controlling immune system response against viral activity in drug repositioning of rapamycin and other mTOR inhibitors in SARS-CoV-2 infection.


Asunto(s)
/tratamiento farmacológico , Reposicionamiento de Medicamentos , Sistema Inmunológico/inmunología , Transducción de Señal/genética , Sirolimus/farmacología , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/fisiología , /inmunología , Humanos , Transducción de Señal/fisiología
18.
Mikrobiyol Bul ; 55(1): 67-80, 2021 Jan.
Artículo en Turco | MEDLINE | ID: mdl-33590982

RESUMEN

Leishmaniasis is a disease caused by the genus Leishmania spp., which are intracellular parasites. Depending on parasite species and host immune response, there are three basic clinical forms of the disease: cutaneous, mucocutaneous, and visceral leishmaniasis. Cutaneous leishmaniasis is a chronic disease and characterized by the presence of ulcerated skin lesions. The type of skin pathology seen during disease is determined in part by the infecting Leishmania spp., but also by a combination of inflammatory and antiinflammatory host immune response factors resulting in diverse clinical outcomes. In this study, it was aimed to determine the genes, molecular signaling mechanisms and biological functions of the molecules that play a role in the pathogenesis of the disease and immune response and determine host-parasite interactions in mice that are naturally resistant and susceptible to Leishmania major and Leishmania braziliensis. For this, transcriptomic series GSE56029 was downloaded from "Gene Expression Omnibus"(GEO) data base, including expression profiling of twenty-four tissue samples that were recovered from both naive mice and mice (BALB/c, C57BL/6) infected with L.major and L.braziliensis. Then, "Differentially Expressed Genes" (DEGs) were identified by limma package in R script. FDR q<0.05 and absolute log2FC> 2 as threshold values were accepted in the analysis. Subsequently, functional and pathway enrichment analyses were performed for the DEGs by "Ingenuity Pathway Analysis" (IPA). For each of DEGs, p<0.01, FDR q<0.01, and absolute log2FC> 1 were used and analyzed with the software program IPA 8.0. Ingenuity Pathway Analysis revealed the most enrichment pathways to be the inflammation, dendritic cell maturation and "Triggering Receptor Expressed on Myeloid Cells 1" (TREM-1) signal mechanisms and that the DEGs related to the regulation of immune system process were closely associated with the progress of cutaneous leishmaniasis. The upstream regulator analysis predicted that TNF-α, IFNy, IL-1 ß, IL-10RA and "Signal Transducer and Activator of Transcription-1" (STAT-1) are the regulators that explained gene expression changes causing biological activities in the tissues. Chemical compounds that may have anti-leishmanial effects were also identified in the study. In this study, the mechanisms belonging to the parasite species and host that determine the resistance/susceptibility phenotype were attempted to elucidate. Assessment of gene expression patterns, cytokine/chemokines, and signaling pathways in BALB/c and C57BL/6 mice infected with L.major and L.braziliensis will provide a better understanding of the potential mechanisms underlying infection from a genetic perspective. These results may guide for the future studies in terms of developing potential biomarkers for the diagnosis and prognosis prediction of cutaneous leishmaniasis and providing information about new treatment targets.


Asunto(s)
Leishmaniasis Cutánea , Transducción de Señal , Transcriptoma , Animales , Leishmaniasis Cutánea/genética , Leishmaniasis Cutánea/fisiopatología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Transducción de Señal/genética
19.
PLoS One ; 16(2): e0246150, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33534852

RESUMEN

A coronavirus pandemic caused by a novel coronavirus (SARS-CoV-2) has spread rapidly worldwide since December 2019. Improved understanding and new strategies to cope with novel coronaviruses are urgently needed. Viruses (especially RNA viruses) encode a limited number and size (length of polypeptide chain) of viral proteins and must interact with the host cell components to control (hijack) the host cell machinery. To achieve this goal, the extensive mimicry of SLiMs in host proteins provides an effective strategy. However, little is known regarding SLiMs in coronavirus proteins and their potential targets in host cells. The objective of this study is to uncover SLiMs in coronavirus proteins that are present within host cells. These SLiMs have a high possibility of interacting with host intracellular proteins and hijacking the host cell machinery for virus replication and dissemination. In total, 1,479 SLiM hits were identified in the 16 proteins of 590 coronaviruses infecting humans. Overall, 106 host proteins were identified that may interact with SLiMs in 16 coronavirus proteins. These SLiM-interacting proteins are composed of many intracellular key regulators, such as receptors, transcription factors and kinases, and may have important contributions to virus replication, immune evasion and viral pathogenesis. A total of 209 pathways containing proteins that may interact with SLiMs in coronavirus proteins were identified. This study uncovers potential mechanisms by which coronaviruses hijack the host cell machinery. These results provide potential therapeutic targets for viral infections.


Asunto(s)
Infecciones por Coronavirus/patología , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , Virus del SRAS/metabolismo , Proteínas Virales/metabolismo , Secuencias de Aminoácidos , Infecciones por Coronavirus/virología , Bases de Datos de Proteínas , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/aislamiento & purificación , Filogenia , Dominios y Motivos de Interacción de Proteínas , Proteínas/química , Proteínas/clasificación , Virus del SRAS/aislamiento & purificación , Transducción de Señal/genética , Interfaz Usuario-Computador , Proteínas Virales/química , Proteínas Virales/clasificación
20.
Nat Commun ; 12(1): 751, 2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33531495

RESUMEN

Optogenetic approaches for studying neuronal functions have proven their utility in the neurosciences. However, optogenetic tools capable of inducing synaptic plasticity at the level of single synapses have been lacking. Here, we engineered a photoactivatable (pa)CaMKII by fusing a light-sensitive domain, LOV2, to CaMKIIα. Blue light or two-photon excitation reversibly activated paCaMKII. Activation in single spines was sufficient to induce structural long-term potentiation (sLTP) in vitro and in vivo. paCaMKII activation was also sufficient for the recruitment of AMPA receptors and functional LTP in single spines. By combining paCaMKII with protein activity imaging by 2-photon FLIM-FRET, we demonstrate that paCaMKII activation in clustered spines induces robust sLTP via a mechanism that involves the actin-regulatory small GTPase, Cdc42. This optogenetic tool for dissecting the function of CaMKII activation (i.e., the sufficiency of CaMKII rather than necessity) and for manipulating synaptic plasticity will find many applications in neuroscience and other fields.


Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Potenciación a Largo Plazo/fisiología , Optogenética/métodos , Sinapsis/metabolismo , Animales , Electrofisiología , Femenino , Células HeLa , Hipocampo/metabolismo , Hipocampo/fisiología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/fisiología , Receptores AMPA/genética , Receptores AMPA/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiología , Sinapsis/fisiología
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