2,258 research outputs found
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β7 Integrin Inhibition Can Increase Intestinal Inflammation by Impairing Homing of CD25hiFoxP3+ Regulatory T Cells.
Background & aimsIntegrin α4β7 mediates lymphocyte trafficking to the gut and gut-associated lymphoid tissues, a process critical for recruitment of effector lymphocytes from the circulation to the gut mucosa in inflammatory bowel disease (IBD) and murine models of intestinal inflammation. Antibody blockade of β7 integrins generally is efficacious in IBD; however, some patients fail to respond, and a few patients can experience exacerbations. This study examined the effects of loss of β7 integrin function in murine models of IBD.MethodsIn a mouse IBD model caused by lack of interleukin 10, a cytokine important in CD25hiFoxP3+ regulatory T cell (Treg) function, genetic deletion of β7 integrin or antibody blockade of α4β7-mucosal addressin cell adhesion molecule-1 interaction paradoxically exacerbated colitis.ResultsLoss of β7 impaired the capacity of Tregs homing to the gut and therefore suppress intestinal inflammation in an adoptive T-cell transfer model; however, the intrinsic suppressive function of β7-deficient Tregs remained intact, indicating that the β7 deficiency selectively impacts gut homing. Deletion of β7 integrin did not worsen colitis in an acute dextran sodium sulfate model in which Treg number and function were normal.ConclusionsIn Integrin subunit beta (Itgb)7-/-Il10-/- mice, loss of β7-dependent Treg homing to gut-associated lymphoid tissues combined with loss of intrinsic Treg function exacerbated intestinal inflammation. These results suggest that IBD patients with reduced CD25hiFoxP3+ Treg numbers or function or lack of interleukin 10 could be at risk for failure of α4β7 blocking therapy
Regulation of brain endothelial barrier function by microRNAs in health and neuroinflammation
Brain endothelial cells constitute the major cellular element of the highly specialized blood–brain barrier (BBB) and thereby contribute to CNS homeostasis by restricting entry of circulating leukocytes and blood-borne molecules into the CNS. Therefore, compromised function of brain endothelial cells has serious consequences for BBB integrity. This has been associated with early events in the pathogenesis of several disorders that affect the CNS, such as multiple sclerosis, HIV-associated neurologic disorder, and stroke. Recent studies demonstrate that brain endothelial microRNAs play critical roles in the regulation of BBB function under normal and neuroinflammatory conditions. This review will focus on emerging evidence that indicates that brain endothelial microRNAs regulate barrier function and orchestrate various phases of the neuroinflammatory response, including endothelial activation in response to cytokines as well as restoration of inflamed endothelium into a quiescent state. In particular, we discuss novel microRNA regulatory mechanisms and their contribution to cellular interactions at the neurovascular unit that influence the overall function of the BBB in health and during neuroinflammatio
Cytokine-induced changes in the gene expression profile of a human cerebral microvascular endothelial cell-line, hCMEC/D3.
Background: The human cerebral microvascular endothelial cell line, hCMEC/D3, has been used extensively to
model the blood–brain barrier (BBB) in vitro. Recently, we reported that cytokine-treatment induced loss of brain
endothelial barrier properties. In this study, we further determined the gene expression pattern of hCMEC/D3 cells
in response to activation with TNFα and IFNγ.
Findings: Using a microarray approach, we observed that expression of genes involved in the control of barrier
permeability, including inter-brain endothelial junctions (e.g. claudin-5, MARVELD-2), integrin-focal adhesions
complexes (e.g. integrin β1, ELMO-1) and transporter systems (e.g. ABCB1, SLC2A1), are altered by pro-inflammatory
cytokines.
Conclusions: Our study shows that previously-described cytokine-induced changes in the pattern of gene expression of endothelium are reproduced in hCMEC/D3 cells, suggesting that this model is suitable to study inflammation at the BBB, while at the same time it has provided insights into novel key molecular processes that are altered in brain endothelium during neuroinflammation, such as modulation of cell-to-matrix contacts
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Neuroinflammation Plays a Critical Role in Cerebral Cavernous Malformation Disease
BackgroundCerebral cavernous malformations (CCMs) are neurovascular lesions caused by loss of function mutations in 1 of 3 genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3). CCMs affect ≈1 out of 200 children and adults, and no pharmacologic therapy is available. CCM lesion count, size, and aggressiveness vary widely among patients of similar ages with the same mutation or even within members of the same family. However, what determines the transition from quiescent lesions into mature and active (aggressive) CCM lesions is unknown.MethodsWe use genetic, RNA-sequencing, histology, flow cytometry, and imaging techniques to report the interaction between CCM endothelium, astrocytes, leukocytes, microglia/macrophages, neutrophils (CCM endothelium, astrocytes, leukocytes, microglia/macrophages, neutrophils interaction) during the pathogenesis of CCMs in the brain tissue.ResultsExpression profile of astrocytes in adult mouse brains using translated mRNAs obtained from the purification of EGFP (enhanced green fluorescent protein)-tagged ribosomes (Aldh1l1-EGFP/Rpl10a) in the presence or absence of CCM lesions (Slco1c1-iCreERT2;Pdcd10fl/fl; Pdcd10BECKO) identifies a novel gene signature for neuroinflammatory astrocytes. CCM-induced reactive astrocytes have a neuroinflammatory capacity by expressing genes involved in angiogenesis, chemotaxis, hypoxia signaling, and inflammation. RNA-sequencing analysis on RNA isolated from brain endothelial cells in chronic Pdcd10BECKO mice (CCM endothelium), identified crucial genes involved in recruiting inflammatory cells and thrombus formation through chemotaxis and coagulation pathways. In addition, CCM endothelium was associated with increased expression of Nlrp3 and Il1b. Pharmacological inhibition of NLRP3 (NOD [nucleotide-binding oligomerization domain]-' LRR [leucine-rich repeat]- and pyrin domain-containing protein 3) significantly decreased inflammasome activity as assessed by quantification of a fluorescent indicator of caspase-1 activity (FAM-FLICA [carboxyfluorescein-fluorochrome-labeled inhibitors of caspases] caspase-1) in brain endothelial cells from Pdcd10BECKO in chronic stage. Importantly, our results support the hypothesis of the crosstalk between astrocytes and CCM endothelium that can trigger recruitment of inflammatory cells arising from brain parenchyma (microglia) and the peripheral immune system (leukocytes) into mature active CCM lesions that propagate lesion growth, immunothrombosis, and bleedings. Unexpectedly, partial or total loss of brain endothelial NF-κB (nuclear factor κB) activity (using Ikkbfl/fl mice) in chronic Pdcd10BECKO mice does not prevent lesion genesis or neuroinflammation. Instead, this resulted in a trend increase in the number of lesions and immunothrombosis, suggesting that therapeutic approaches designed to target inflammation through endothelial NF-κB inhibition may contribute to detrimental side effects.ConclusionsOur study reveals previously unknown links between neuroinflammatory astrocytes and inflamed CCM endothelium as contributors that trigger leukocyte recruitment and precipitate immunothrombosis in CCM lesions. However, therapeutic approaches targeting brain endothelial NF-κB activity may contribute to detrimental side effects
Rap1 binding and a lipid-dependent helix in talin F1 domain promote integrin activation in tandem.
Rap1 GTPases bind effectors, such as RIAM, to enable talin1 to induce integrin activation. In addition, Rap1 binds directly to the talin1 F0 domain (F0); however, this interaction makes a limited contribution to integrin activation in CHO cells or platelets. Here, we show that talin1 F1 domain (F1) contains a previously undetected Rap1-binding site of similar affinity to that in F0. A structure-guided point mutant (R118E) in F1, which blocks Rap1 binding, abolishes the capacity of Rap1 to potentiate talin1-induced integrin activation. The capacity of F1 to mediate Rap1-dependent integrin activation depends on a unique loop in F1 that has a propensity to form a helix upon binding to membrane lipids. Basic membrane-facing residues of this helix are critical, as charge-reversal mutations led to dramatic suppression of talin1-dependent activation. Thus, a novel Rap1-binding site and a transient lipid-dependent helix in F1 work in tandem to enable a direct Rap1-talin1 interaction to cause integrin activation
Vulnerabilidad territorial ante la expansión urbana
En México según el INEGI para el 2010 la población urbana fue del 77.8%, lo que significa que un porcentaje importante de la población vive en localidades mayores a los 2500 habitantes. Las cuales tienen sus propios ritmos de crecimiento, funciones, especialización, cambios de usos del suelo y problemáticas específicas. Las ciudades principales se han expandido, en las últimas décadas, con escasa acción planificadora y bajos resultados en el ordenamiento territorial. Ello ha configurado crecimientos físicos dispersos y fragmentados con importantes efectos ambientales. En México, la dispersión urbana genera ocupación del territorio en riesgos, situaciones de vulnerabilidad con inexistencia de acciones públicas, porque se encuentra en pendientes abruptas, lugares que se inundan, en áreas naturales protegidas, entre otras formas, genera tejido construido en áreas no óptimas para el desarrollo urbano, todo ello impacta negativamente al medio ambiente y la calidad de vida de la población. El crecimiento urbano continuará porque en las ciudades se genera la riqueza del país, en ellas se encuentran las oportunidades y soluciones. La urbanización es el modelo para conseguir el desarrollo de la sociedad. En dicho desarrollo se aspira el crecimiento sustentable y armonioso con el ambiente. Se espera cambios regulatorios para revertir los efectos negativos generados durante décadas con la expansión urbana consumidora de recursos naturales, energía y recursos financieros. En este marco problemático se integra el libro “Vulnerabilidad territorial ante la expansión urbana”, es producto de las actividades científicas –foro y congreso realizados en 2015- de la Red internacional de territorios, sustentabilidad y gobernanza en México y Polonia (RETESYG) de la Facultad de Geografía, Facultad de Planeación Urbana y Regional de la Universidad Autónoma del Estado de México (UAEM), así como de la Facultad de Geografía y Estudios Regionales de la Universidad de Varsovia (UV) y la Facultad de Geografía y Biología de la Universidad Pedagógica “Comisión de Educación Nacional” de Cracovia. El libro tiene una visión integral de la vulnerabilidad territorial ante la expansión urbana, considera los enfoques de la geografía, de la planeación y del ordenamiento territorial para abordar las problemáticas ambiental y social. Presenta una visión amplia y de síntesis sobre vulnerabilidad del territorio y de las ciudades, en él se integran los saberes de la Geografía y de la Planeación Territorial. Destaca la necesidad de controlar el crecimiento anárquico y desordenado, las desigualdades sociales, los riesgos, los problemas ambientales, la falta de bases de datos geoespaciales dinámicas, entre otros. Los resultados de las investigaciones apuntan hacia el desarrollo territorial sustentable. El libro se conforma de dos partes, la primera presenta aspectos teóricos conceptuales y metodológicos de la vulnerabilidad territorial, estructural, física, ambiental y socioeconómica, los riesgos geomorfológicos, la sustentabilidad y manejo de recursos naturales, áreas naturales protegidas, metodologías para la evaluación de los impactos de la expansión metropolitana y gobernanza territorial. La segunda parte, desarrolla estudios de caso, a distintas escalas: desde huertos familiares, subcuentas, ciudad, municipio, zonas metropolitanas, megalópolis, regiones y país. En cada capítulo del libro se presenta bibliografía extensa, diversificada y actualizada que aportan al lector sobre el estado del arte de la vulnerabilidad territorial
MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation.
Blood-brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuroinflammation at the BBB. miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis (EAE). In mice, loss of miR-155 reduced CNS extravasation of systemic tracers, both in EAE and in an acute systemic inflammation model induced by lipopolysaccharide. In cultured human brain endothelium, miR-155 was strongly and rapidly upregulated by inflammatory cytokines. miR-155 up-regulation mimicked cytokine-induced alterations in junctional organization and permeability, whereas inhibition of endogenous miR-155 partially prevented a cytokine-induced increase in permeability. Furthermore, miR-155 modulated brain endothelial barrier function by targeting not only cell-cell complex molecules such as annexin-2 and claudin-1, but also focal adhesion components such as DOCK-1 and syntenin-1. We propose that brain endothelial miR-155 is a negative regulator of BBB function that may constitute a novel therapeutic target for CNS neuroinflammatory disorders
¡El pueblo no se rinde en la pandemia!
El 2020 estuvo marcado por el número de medidas restrictivas emitidas para enfrentar la pandemia del Covid-19[1], fortalecer y preparar el sistema de salud nacional y proteger la salud de los colombianos. Además de la evidente crisis en el sistema de salud, dada su incapacidad para atender un número significativo de ciudadanos, las medidas de confinamiento adoptadas por las autoridades nacionales, regionales y municipales produjeron una crisis social y económica nunca antes vista. Amplios sectores de la sociedad colombiana se quedaron sin empleo o fuente de ingresos. En este sentido, la privación de recursos para el sostenimiento de las familias fue extendida a varios estratos del país. Las carencias económicas para cubrir las necesidades básicas de los hogares colombianos se sintieron tanto en los sectores populares, como en las clases medias y profesionales del país
Ciencias de la Biología y Agronomía
Este volumen I contiene 17 capítulos arbitrados que se ocupan de estos asuntos en Tópicos Selectos de Ciencias de la Biología y Agronomía, elegidos de entre las contribuciones, reunimos algunos investigadores y estudiantes. Se presenta un Estudio Comparativo de los Recursos Hidrológico-Forestales de la Microcuenca de la Laguna de Epatlan, Pue. (1993 a 2014); la Situación Actual de la Mancha de Asfalto en Maíz (Zea mays L.) en los Municipios de Jiquipilas y Ocozocoautla, Chiapas, México; las poblaciones sobresalientes de maíz de la raza Zapalote Chico, en la Región Istmeña de Oaxaca; Se indica el índice de área foliar de cultivo de Chile Poblano mediante dos métodos en condiciones protegidas; Esquivel, Urzúa y Ramírez exploran el efecto de la biofertilización con Azospirillum en el crecimiento y producción de Jitomate; esbozan su artículo sobre la determinación del nivel de Heterosis en híbridos de Maíz para la Comarca Lagunera; una investigación sobre la estabilización de semilla de Solanum lycopersicum durante el almacenamiento y estimulación de la germinación; acotan sobre el CTAB como una nueva opción para la detección de Huanglongbing en cítricos, plantean su evaluación sobre el aluminio y cómo afecta la vida de florero de Heliconia psittacorum; indican sobre el impacto del H-564C, como un híbrido de maíz con alta calidad de proteina para el trópico húmedo de México; presetan su investigación sobre la producción de Piña Cayena Lisa y MD2 (Ananas comosus L.) en condiciones de Loma Bonita, en Oaxaca; acotan sobre el efecto de coberteras como control biológico por conservación contra áfidos en Nogal Pecanero; esbozan sobre la caracterización de cuatro genotipos de Frijol Negro en Martínez de la Torre, Veracruz, México; presentan una caracterización hidroecológica de la microcuenca de Arroyo Prieto, Yuriría, Gto., y alternativas para su restauración ambiental; presentan su investigación sobre el efecto del hongo Beauveria bassiana sobre solubilización de fosfatos y la disponibilidad de fósforo en el suelo; plantean su investigación sobre la Germinación y regeneración in vitro de Epidendrum falcatum LINDL; esbozan su artículo sobre genotipos de frijol negro y su tolerancia a sequía terminal en Veracruz, México
Evolutionary Heritage Influences Amazon Tree Ecology
Lineages tend to retain ecological characteristics of their ancestors through time. However, for some traits, selection during evolutionary history may have also played a role in determining trait values. To address the relative importance of these processes requires large-scale quantification of traits and evolutionary relationships among species. The Amazonian tree flora comprises a high diversity of angiosperm lineages and species with widely differing life-history characteristics, providing an excellent system to investigate the combined influences of evolutionary heritage and selection in determining trait variation. We used trait data related to the major axes of life-history variation among tropical trees (e.g. growth and mortality rates) from 577 inventory plots in closed-canopy forest, mapped onto a phylogenetic hypothesis spanning more than 300 genera including all major angiosperm clades to test for evolutionary constraints on traits. We found significant phylogenetic signal (PS) for all traits, consistent with evolutionarily related genera having more similar characteristics than expected by chance. Although there is also evidence for repeated evolution of pioneer and shade tolerant life-history strategies within independent lineages, the existence of significant PS allows clearer predictions of the links between evolutionary diversity, ecosystem function and the response of tropical forests to global change
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