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1.
Ann Am Thorac Soc ; 21(2): 218-227, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37696027

RESUMEN

Rationale: Radiologic pattern has been shown to predict survival in patients with fibrosing interstitial lung disease. The additional prognostic value of fibrosis extent by quantitative computed tomography (CT) is unknown. Objectives: We hypothesized that fibrosis extent provides information beyond visually assessed CT pattern that is useful for outcome prediction. Methods: We performed a retrospective analysis of chest CT, demographics, longitudinal pulmonary function, and transplantation-free survival among participants in the Pulmonary Fibrosis Foundation Patient Registry. CT pattern was classified visually according to the 2018 usual interstitial pneumonia criteria. Extent of fibrosis was objectively quantified using data-driven textural analysis. We used Kaplan-Meier plots and Cox proportional hazards and linear mixed-effects models to evaluate the relationships between CT-derived metrics and outcomes. Results: Visual assessment and quantitative analysis were performed on 979 enrollment CT scans. Linear mixed-effect modeling showed that greater baseline fibrosis extent was significantly associated with the annual rate of decline in forced vital capacity. In multivariable models that included CT pattern and fibrosis extent, quantitative fibrosis extent was strongly associated with transplantation-free survival independent of CT pattern (hazard ratio, 1.04; 95% confidence interval, 1.04-1.05; P < 0.001; C statistic = 0.73). Conclusions: The extent of lung fibrosis by quantitative CT is a strong predictor of physiologic progression and survival, independent of visually assessed CT pattern.


Asunto(s)
Aprendizaje Profundo , Fibrosis Pulmonar Idiopática , Enfermedades Pulmonares Intersticiales , Humanos , Estudios Retrospectivos , Pulmón/diagnóstico por imagen , Pronóstico , Tomografía Computarizada por Rayos X/métodos
2.
Genetics ; 227(3)2024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38717968

RESUMEN

The final step in Notch signaling activation is the transmembrane cleavage of Notch receptor by γ secretase. Thus far, genetic and biochemical evidence indicates that four subunits are essential for γ secretase activity in vivo: presenilin (the catalytic core), APH-1, PEN-2, and APH-2/nicastrin. Although some γ secretase activity has been detected in APH-2/nicastrin-deficient mammalian cell lines, the lack of biological relevance for this activity has left the quaternary γ secretase model unchallenged. Here, we provide the first example of in vivo Notch signal transduction without APH-2/nicastrin. The surprising dispensability of APH-2/nicastrin is observed in Caenorhabditis elegans germline stem cells (GSCs) and contrasts with its essential role in previously described C. elegans Notch signaling events. Depletion of GLP-1/Notch, presenilin, APH-1, or PEN-2 causes a striking loss of GSCs. In contrast, aph-2/nicastrin mutants maintain GSCs and exhibit robust and localized expression of the downstream Notch target sygl-1. Interestingly, APH-2/nicastrin is normally expressed in GSCs and becomes essential under conditions of compromised Notch function. Further insight is provided by reconstituting the C. elegans γ secretase complex in yeast, where we find that APH-2/nicastrin increases but is not essential for γ secretase activity. Together, our results are most consistent with a revised model of γ secretase in which the APH-2/nicastrin subunit has a modulatory, rather than obligatory role. We propose that a trimeric presenilin-APH-1-PEN-2 γ secretase complex can provide a low level of γ secretase activity, and that cellular context determines whether or not APH-2/nicastrin is essential for effective Notch signal transduction.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide , Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Células Germinativas , Receptores Notch , Transducción de Señal , Animales , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Receptores Notch/metabolismo , Receptores Notch/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Células Germinativas/metabolismo , Células Madre/metabolismo , Células Madre/citología , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética
3.
Nucleic Acids Res ; 37(Database issue): D680-5, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18948278

RESUMEN

The IUPHAR database (IUPHAR-DB) integrates peer-reviewed pharmacological, chemical, genetic, functional and anatomical information on the 354 nonsensory G protein-coupled receptors (GPCRs), 71 ligand-gated ion channel subunits and 141 voltage-gated-like ion channel subunits encoded by the human, rat and mouse genomes. These genes represent the targets of approximately one-third of currently approved drugs and are a major focus of drug discovery and development programs in the pharmaceutical industry. IUPHAR-DB provides a comprehensive description of the genes and their functions, with information on protein structure and interactions, ligands, expression patterns, signaling mechanisms, functional assays and biologically important receptor variants (e.g. single nucleotide polymorphisms and splice variants). In addition, the phenotypes resulting from altered gene expression (e.g. in genetically altered animals or in human genetic disorders) are described. The content of the database is peer reviewed by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR); the data are provided through manual curation of the primary literature by a network of over 60 subcommittees of NC-IUPHAR. Links to other bioinformatics resources, such as NCBI, Uniprot, HGNC and the rat and mouse genome databases are provided. IUPHAR-DB is freely available at http://www.iuphar-db.org.


Asunto(s)
Bases de Datos de Proteínas , Canales Iónicos/genética , Canales Iónicos/fisiología , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiología , Animales , Descubrimiento de Drogas , Humanos , Canales Iónicos/química , Ligandos , Ratones , Subunidades de Proteína/química , Subunidades de Proteína/genética , Subunidades de Proteína/fisiología , Ratas , Receptores Acoplados a Proteínas G/química
4.
Genetics ; 208(2): 745-762, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29242286

RESUMEN

Functionally redundant genes present a puzzle as to their evolutionary preservation, and offer an interesting opportunity for molecular specialization. In Caenorhabditis elegans, either one of two presenilin genes (sel-12 or hop-1) facilitate Notch activation, providing the catalytic subunit for the γ secretase proteolytic enzyme complex. For all known Notch signaling events, sel-12 can mediate Notch activation, so the conservation of hop-1 remains a mystery. Here, we uncover a novel "late-onset" germline Notch phenotype in which HOP-1-deficient worms fail to maintain proliferating germline stem cells during adulthood. Either SEL-12 or HOP-1 presenilin can impart sufficient Notch signaling for the establishment and expansion of the germline, but maintenance of an adult stem cell pool relies exclusively on HOP-1-mediated Notch signaling. We also show that HOP-1 is necessary for maximum fecundity and reproductive span. The low-fecundity phenotype of hop-1 mutants can be phenocopied by switching off glp-1/Notch function during the last stage of larval development. We propose that at the end of larval development, dual presenilin usage switches exclusively to HOP-1, perhaps offering opportunities for differential regulation of the germline during adulthood. Additional defects in oocyte size and production rate in hop-1 and glp-1 mutants indicate that the process of oogenesis is compromised when germline Notch signaling is switched off. We calculate that in wild-type adults, as much as 86% of cells derived from the stem cell pool function to support oogenesis. This work suggests that an important role for Notch signaling in the adult germline is to furnish a large and continuous supply of nurse cells to support the efficiency of oogenesis.


Asunto(s)
Caenorhabditis elegans/genética , Células Germinativas/metabolismo , Proteínas de la Membrana/deficiencia , Receptores Notch/metabolismo , Transducción de Señal , Alelos , Animales , Proteínas de Caenorhabditis elegans , Proliferación Celular , Mutación con Ganancia de Función , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Gónadas/metabolismo , Masculino , Mutación , Oocitos/metabolismo , Oogénesis , Fenotipo , Reproducción/genética
5.
Genetics ; 190(3): 1043-57, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22209900

RESUMEN

Notch signaling pathways can be regulated through a variety of cellular mechanisms, and genetically compromised systems provide useful platforms from which to search for the responsible modulators. The Caenorhabditis elegans gene aph-1 encodes a component of γ-secretase, which is essential for Notch signaling events throughout development. By looking for suppressors of the incompletely penetrant aph-1(zu147) mutation, we identify a new gene, sao-1 (suppressor of aph-one), that negatively regulates aph-1(zu147) activity in the early embryo. The sao-1 gene encodes a novel protein that contains a GYF protein-protein interaction domain and interacts specifically with SEL-10, an Fbw7 component of SCF E3 ubiquitin ligases. We demonstrate that the embryonic lethality of aph-1(zu147) mutants can be suppressed by removing sao-1 activity or by mutations that disrupt the SAO-1-SEL-10 protein interaction. Decreased sao-1 activity also influences Notch signaling events when they are compromised at different molecular steps of the pathway, such as at the level of the Notch receptor GLP-1 or the downstream transcription factor LAG-1. Combined analysis of the SAO-1-SEL-10 protein interaction and comparisons of sao-1 and sel-10 genetic interactions suggest a possible role for SAO-1 as an accessory protein that participates with SEL-10 in downregulation of Notch signaling. This work provides the first mutant analysis of a GYF-domain protein in either C. elegans or Drosophila and introduces a new type of Fbw7-interacting protein that acts in a subset of Fbw7 functions.


Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular/metabolismo , Receptores Notch/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Secuencia de Aminoácidos , Animales , Caenorhabditis elegans/embriología , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/química , Proteínas Portadoras/química , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Desarrollo Embrionario/genética , Orden Génico , Genes Letales , Receptor del Péptido 1 Similar al Glucagón , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Datos de Secuencia Molecular , Mutación , Unión Proteica , Estructura Terciaria de Proteína , Receptores de Glucagón/genética , Receptores de Glucagón/metabolismo , Receptores Notch/antagonistas & inhibidores , Alineación de Secuencia , Transducción de Señal
7.
Development ; 132(7): 1713-26, 2005 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15743881

RESUMEN

The proper growth and elaboration of neural processes is essential for the establishment of a functional nervous system during development and is an integral feature of neural plasticity throughout life. Nuclear factor-kappa B (NF-kappaB) is classically known for its ubiquitous roles in inflammation, immune and stress-related responses and regulation of cell survival in all tissues, including the nervous system. NF-kappaB participation in other cellular processes remains poorly understood. Here we report a mechanism for controlling the growth of neural processes in developing peripheral and central neurons involving the transcription factor NF-kappaB. Inhibiting NF-kappaB activation with super-repressor IkappaB-alpha, BAY 11 7082 (IkappaB-alpha phosphorylation inhibitor) or N-acetyl-Leu-Leu-norleucinal (proteosomal degradation inhibitor), or inhibiting NF-kappaB transcriptional activity with kappaB decoy DNA substantially reduced the size and complexity of the neurite arbors of sensory neurons cultured with brain-derived neurotrophic factor while having no effect on their survival. NF-kappaB exerted this effect during a restricted period of development following the phase of naturally occurring neuronal death when the processes and connections of the remaining neurons are extensively modified and refined. Inhibiting NF-kappaB activation or NF-kappaB transcriptional activity in layer 2 pyramidal neurons in postnatal somatosensory cortical slices reduced dendritic arbor size and complexity. This function of NF-kappaB has important implications for neural development and may provide an explanation for reported involvement of NF-kappaB in learning and memory.


Asunto(s)
Sistema Nervioso Central/embriología , FN-kappa B/metabolismo , Sistema Nervioso Periférico/embriología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Sistema Nervioso Central/metabolismo , Proteínas I-kappa B/metabolismo , Ratones , Inhibidor NF-kappaB alfa , Neuritas/metabolismo , Neuronas/metabolismo , Ganglio Nudoso/citología , Ganglio Nudoso/metabolismo , Sistema Nervioso Periférico/metabolismo
8.
Proc Natl Acad Sci U S A ; 99(2): 775-9, 2002 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-11792846

RESUMEN

Early embryonic cells in Caenorhabditis elegans embryos interact through a signaling pathway closely related to the Notch signaling pathway in Drosophila and vertebrates. Components of this pathway include a ligand, receptor, the presenilin proteins, and a novel protein, APH-2, that is related to the Nicastrin protein in humans. Here we identify the aph-1 gene as a new component of the Notch pathway in Caenorhabditis elegans. aph-1 is predicted to encode a novel, highly conserved multipass membrane protein. We show that aph-1 and the presenilin genes share a similar function in that they are both required for proper cell-surface localization of APH-2/Nicastrin.


Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/fisiología , Caenorhabditis elegans/embriología , Caenorhabditis elegans/genética , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/fisiología , Proteínas de la Membrana/genética , Proteínas de la Membrana/fisiología , Secuencia de Aminoácidos , Secretasas de la Proteína Precursora del Amiloide , Animales , Membrana Celular/fisiología , Genes de Helminto , Proteínas del Helminto/genética , Proteínas del Helminto/fisiología , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiología , Datos de Secuencia Molecular , Mutación , Fenotipo , Receptores Notch , Homología de Secuencia de Aminoácido , Transducción de Señal
9.
J Comput Assist Tomogr ; 26(1): 13-20, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-11801899

RESUMEN

PURPOSE: The purpose of this work was to describe the radiographic and CT findings in patients with respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and to correlate them with clinical, physiologic, and pathologic features. METHOD: RB-ILD was proved pathologically in all 21 patients. Sixteen (76%) patients were current smokers, and five (24%) patients were ex-smokers. The mean cigarette consumption was 38.7 pack-years. Chest radiographs and CT scans were semiquantitatively analyzed and correlated with clinical findings, physiologic measures, and a pathologic score of disease extent. RESULTS: The major radiographic findings were bronchial wall thickening in 16 patients (76%) and ground-glass opacity in 12 patients (57%). The predominant initial CT findings were central bronchial wall thickening (proximal to subsegmental bronchi) in 19 patients (90%), peripheral bronchial wall thickening (distal to subsegmental bronchi) in 18 patients (86%), centrilobular nodules in 15 patients (71%), and ground-glass opacity in 14 patients (67%), None of these CT findings had a significant zonal predominance. Other findings were upper lung predominant centrilobular emphysema (57%) and patchy areas of hypoattenuation (38%) with a lower lung predominance. Radiologic findings were similar in both current and ex-smokers. The amount of ground-glass opacity correlated inversely with arterial oxygen saturation ( r = -0.67, p = 0.04), and the areas of hypoattenuation correlated with alveolar-arterial oxygen gradient ( r = 0.56, p = 0.04). The extent of centrilobular nodules correlated with the extent of macrophages in respiratory bronchioles ( r = 0.53, p = 0.03) and with chronic inflammation of respiratory bronchioles ( r = 0.57, p = 0.02). The extent of ground-glass opacity correlated with the amount of macrophage accumulation in the alveoli and alveolar ducts ( r = 0.56, p < 0.01 and r = 0.54, p = 0.04, respectively). At follow-up CT after steroid treatment and smoking cessation, in nine patients, the extent of bronchial wall thickening, centrilobular nodules, and ground-glass opacity had decreased, but the areas of hypoattenuation had increased (p < 0.05). CONCLUSION: The CT findings of RB-ILD are centrilobular nodules, ground-glass opacity, and air trapping. These radiologic features, in patients with a history of heavy cigarette smoking, may differentiate RB-ILD from other interstitial lung diseases.


Asunto(s)
Bronquiolitis/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Pulmón/patología , Tomografía Computarizada por Rayos X , Adulto , Bronquiolitis/patología , Femenino , Estudios de Seguimiento , Humanos , Pulmón/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/patología , Masculino , Fumar/efectos adversos , Factores de Tiempo , Tomografía Computarizada por Rayos X/métodos
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