RESUMEN
OBJECTIVE: Assess strengths and limitations of mixed bipolar depression definitions made more inclusive than that of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) by requiring fewer than three 'non-overlapping' mood elevation symptoms (NOMES). METHOD: Among bipolar disorder (BD) out-patients assessed with Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, we assessed prevalence, demographics, and clinical correlates of mixed vs. pure depression, using less inclusive (≥3 NOMES, DSM-5), more inclusive (≥2 NOMES), and most inclusive (≥1 NOMES) definitions. RESULTS: Among 153 depressed BD, compared to less inclusive DSM-5 threshold, our more and most inclusive thresholds, yielded approximately two- and five-fold higher mixed depression rates (7.2%, 15.0%, and 34.6% respectively), and important statistically significant clinical correlates for mixed compared to pure depression (e.g. more lifetime anxiety disorder comorbidity, more current irritability), which were not significant using the DSM-5 threshold. CONCLUSION: Further studies assessing strengths and limitations of more inclusive mixed depression definitions are warranted, including assessing the extent to which enhanced statistical power vs. other factors contributes to more vs. less inclusive mixed bipolar depression thresholds having more statistically significant clinical correlates, and whether 'overlapping' mood elevation symptoms should be counted.
Asunto(s)
Trastorno Bipolar/diagnóstico , Trastorno Depresivo/diagnóstico , Adulto , Trastorno Bipolar/psicología , Comorbilidad , Trastorno Depresivo/psicología , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Masculino , Agitación Psicomotora/psicología , Adulto JovenRESUMEN
OBJECTIVE: The objective of this study was to assess the strengths and limitations of a mixed bipolar depression definition made more inclusive than that of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) by counting not only 'non-overlapping' mood elevation symptoms (NOMES) as in DSM-5, but also 'overlapping' mood elevation symptoms (OMES, psychomotor agitation, distractibility, and irritability). METHODS: Among bipolar disorder (BD) out-patients assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, we assessed prevalence, demographics, and clinical correlates of mixed vs. pure depression, using more inclusive (≥3 NOMES/OMES) and less inclusive DSM-5 (≥3 NOMES) definitions. RESULTS: Among 153 depressed BD, counting not only NOMES but also OMES yielded a three-fold higher mixed depression rate (22.9% vs. 7.2%) and important statistically significant clinical correlates for mixed compared to pure depression (more lifetime anxiety disorder comorbidity, more current irritability, and less current antidepressant use), which were not significant using the DSM-5 threshold. CONCLUSION: To conclude, further studies with larger numbers of patients with DSM-5 bipolar mixed depression assessing strengths and limitations of more inclusive mixed depression definitions are warranted, including efforts to ascertain whether or not OMES should count toward mixed depression.
Asunto(s)
Trastorno Bipolar/diagnóstico , Trastornos del Humor/diagnóstico , Pacientes Ambulatorios/psicología , Adulto , Afecto , Trastorno Bipolar/psicología , Diagnóstico Diferencial , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Entrevista Psicológica , Masculino , Persona de Mediana Edad , Trastornos del Humor/psicología , Escalas de Valoración Psiquiátrica , Agitación Psicomotora , Adulto JovenRESUMEN
Corticotropin-releasing hormone (Crh), a 41-residue polypeptide, activates two G-protein-coupled receptors, Crhr1 and Crhr2, causing (among other transductional events) phosphorylation of the transcription factor Creb. The physiologic role of these receptors is only partially understood. Here we report that male, but not female, Crhr2-deficient mice exhibit enhanced anxious behaviour in several tests of anxiety in contrast to mice lacking Crhr1. The enhanced anxiety of Crhr2-deficient mice is not due to changes in hypothalamic-pituitary-adrenal (HPA) axis activity, but rather reflects impaired responses in specific brain regions involved in emotional and autonomic function, as monitored by a reduction of Creb phosphorylation in male, but not female, Crhr2-/- mice. We propose that Crhr2 predominantly mediates a central anxiolytic response, opposing the general anxiogenic effect of Crh mediated by Crhr1. Neither male nor female Crhr2-deficient mice show alterations of baseline feeding behaviour. Both respond with increased edema formation in response to thermal exposure, however, indicating that in contrast to its central role in anxiety, the peripheral role of Crhr2 in vascular permeability is independent of gender.
Asunto(s)
Ansiedad/genética , Eliminación de Gen , Receptores de Hormona Liberadora de Corticotropina/genética , Hormona Adrenocorticotrópica/sangre , Animales , Trastornos de Ansiedad/genética , Encéfalo/metabolismo , Corticosterona/sangre , Hormona Liberadora de Corticotropina/administración & dosificación , Hormona Liberadora de Corticotropina/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Edema/genética , Conducta Alimentaria/fisiología , Femenino , Calor/efectos adversos , Sistema Hipotálamo-Hipofisario/fisiología , Inyecciones Intraventriculares , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Fosforilación , Sistema Hipófiso-Suprarrenal/fisiología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Restricción Física , Factores Sexuales , Estrés Fisiológico/sangre , Estrés Fisiológico/metabolismo , Estrés Fisiológico/fisiopatología , Aumento de PesoRESUMEN
Reciprocal gene activation and restriction during cell type differentiation from a common lineage is a hallmark of mammalian organogenesis. A key question, then, is whether a critical transcriptional activator of cell type-specific gene targets can also restrict expression of the same genes in other cell types. Here, we show that whereas the pituitary-specific POU domain factor Pit-1 activates growth hormone gene expression in one cell type, the somatotrope, it restricts its expression from a second cell type, the lactotrope. This distinction depends on a two-base pair spacing in accommodation of the bipartite POU domains on a conserved growth hormone promoter site. The allosteric effect on Pit-1, in combination with other DNA binding factors, results in the recruitment of a corepressor complex, including nuclear receptor corepressor N-CoR, which, unexpectedly, is required for active long-term repression of the growth hormone gene in lactotropes.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , ADN/metabolismo , Regulación de la Expresión Génica , Hormona del Crecimiento/genética , Hipófisis/metabolismo , Prolactina/genética , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Regulación Alostérica , Animales , Secuencia de Bases , Sitios de Unión , Línea Celular , Secuencia Conservada , Cristalización , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Femenino , Genes Reporteros , Masculino , Ratones , Ratones Transgénicos , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Co-Represor 1 de Receptor Nuclear , Hipófisis/citología , Regiones Promotoras Genéticas , Conformación Proteica , Estructura Terciaria de Proteína , Ratas , Proteínas Represoras/química , Proteínas Represoras/genética , Factor de Transcripción Pit-1 , Factores de Transcripción/química , Factores de Transcripción/genética , Activación TranscripcionalRESUMEN
We have produced transgenic mice that express rearranged T cell Ag receptor gamma and delta transgenes in the alpha beta lineage of thymocytes. Thymi in these mice contain normal numbers of CD4+CD8+ cells that express low levels of the TCR-gamma delta. Analysis of the delta locus in these thymi indicates that these cells are in the alpha beta lineage even though they express the TCR-gamma delta. This shows that expression of the TCR-gamma delta in early thymocytes can lead to all of the consequences that are normally mediated by the beta-chain. These consequences include maturation to the CD4+CD8+ stage, entry into the cell cycle, and cessation of beta rearrangement. Therefore, the data support a model in which formation of a functional CD3 complex on immature CD4-CD8- thymocytes leads to further development in the absence of extracellular ligand recognition. The data also show that the gamma delta vs alpha beta lineage decision is made in a manner that is independent of gamma and beta gene expression.
Asunto(s)
Reordenamiento Génico de Linfocito T/genética , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Timo/citología , Animales , Secuencia de Bases , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Clonación Molecular , Citometría de Flujo , Biblioteca Genómica , Ratones , Ratones Transgénicos , Datos de Secuencia MolecularRESUMEN
9-O-acetylation of sialic acids is tissue specific and developmentally regulated. We have selectively destroyed these O-acetyl groups during murine embryogenesis by expressing the 9-O-acetyl-sialic acid-specific esterase of influenza C. DNA constructs driven by the metallothionein promoter arrested development at the 2-cell stage and gave a markedly decreased yield of live mice. A similar construct driven by the phenylethanolamine-N-methyltransferase promoter did not cause this block, but gave transgenic mice with selective expression of esterase in the retina and the adrenal gland. These organs showed variable abnormalities in organization, while all other tissues examined appeared normal. The ganglioside 9-O-acetyl-GD3 was selectively destroyed in target tissues. Thus, 9-O-acetylated sialic acids may play an role in murine development at the 2-cell stage and in certain differentiated tissues.
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Hidrolasas de Éster Carboxílico/biosíntesis , Desarrollo Embrionario y Fetal/fisiología , Ácidos Siálicos/fisiología , Acetilación , Acetilesterasa , Glándulas Suprarrenales/anomalías , Glándulas Suprarrenales/enzimología , Animales , Hidrolasas de Éster Carboxílico/genética , Hidrolasas de Éster Carboxílico/metabolismo , Células Cultivadas , Clonación Molecular , Metalotioneína/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microinyecciones , Especificidad de Órganos , Feniletanolamina N-Metiltransferasa/genética , Plásmidos , Regiones Promotoras Genéticas , Retina/anomalías , Retina/enzimología , Ácidos Siálicos/metabolismo , Organismos Libres de Patógenos EspecíficosRESUMEN
The antigen receptor on T cells (TCR) has been predicted to have a structure similar to a membrane-anchored form of an immunoglobulin F(ab) fragment. Virtually all of the conserved amino acids that are important for inter- and intramolecular interactions in the VH-VL pair are also conserved in the TCR V alpha and V beta chains. A molecular model of the TCR has been constructed by homology and we have used the information from this, as well as the earlier structural predictions of others, to study the basis for specificity. Specifically, regions of a TCR cloned from an antigen-specific T cell were stitched into the corresponding framework of a second TCR. Results indicate that the substitution of amino acid sequences corresponding to the complementarity determining regions (CDRs) of immunoglobulin can convey the specificity for antigen and major histocompatibility complex molecules. These data are consistent with a role, but not an exclusive role, for CDR3 in antigen peptide recognition.
Asunto(s)
Epítopos/inmunología , Modelos Moleculares , Conformación Proteica , Receptores de Antígenos de Linfocitos T alfa-beta/química , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Columbidae , Secuencia Conservada/genética , Grupo Citocromo c/inmunología , Antígenos H-2/inmunología , Inmunoglobulinas/química , Células L , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Datos de Secuencia Molecular , Mutación/fisiología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Linfocitos T/inmunologíaRESUMEN
The genes encoding a gamma delta T-cell receptor specific for a major histocompatibility complex class I molecule encoded by the TIa locus have been inserted into the mouse germ line. In mice that do not express the TIa-encoded determinant, transgenic gamma delta T cells are a functional component of the CD4-CD8- 'double-negative' T cells in the thymus and peripheral lymphoid organs. In mice that express the TIa-encoded determinant, there are no transgenic gamma delta T cells in peripheral lymphoid organs, and there are no thymocytes expressing normal levels of the transgenic gamma delta T-cell receptor.
Asunto(s)
Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Timo/citología , Animales , Secuencia de Bases , Linfocitos T CD4-Positivos/inmunología , Clonación Molecular , Expresión Génica , Antígenos H-2/inmunología , Antígeno de Histocompatibilidad H-2D , Antígenos de Histocompatibilidad Clase I/inmunología , Tolerancia Inmunológica , Recuento de Leucocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Datos de Secuencia Molecular , Receptores de Antígenos de Linfocitos T/genética , Bazo/citología , Linfocitos T Reguladores/inmunología , Timo/inmunologíaRESUMEN
Members of the POU-homeodomain gene family encode transcriptional regulatory molecules that play important roles in terminal differentiation of many organ systems. Sperm-1 (Sprm-1) is a POU domain factor that is exclusively expressed in the differentiating male germ cell. We show here that the Sprm-1 protein is expressed in the haploid spermatid and that 129/Sv Sprm-1(-/-) mice are subfertile when compared with wild-type or heterozygous littermates yet exhibit normal testicular morphology and produce normal numbers of mobile spermatozoa. Our data suggest that the Sprm-1 protein plays a discrete regulatory function in the haploid spermatid, which is required for the optimal function, but not the terminal differentiation, of the male germ cell.
Asunto(s)
Proteínas de Unión al ADN/genética , Fertilidad/genética , Animales , Northern Blotting , Femenino , Regulación de la Expresión Génica , Masculino , Ratones , Mutación , Factores del Dominio POU , Espermatogénesis/genéticaRESUMEN
Here we report on investigation of the role of the POU domain genes Skin-1a/i (Skn-1a/i/Epoc/Oct-11) and Testes-1 (Tst-1/Oct-6/SCIP) in epidermis where proliferating basal keratinocytes withdraw from the cell cycle, migrate suprabasally, and terminally differentiate to form a multilayered, stratified epithelium. The expression of the Skn-1a/i and Tst-1 genes is linked to keratinocyte differentiation in vivo and in vitro, whereas the ubiquitous POU domain factor Oct-1 is expressed highly in both proliferating and post-mitotic keratinocytes. Analysis of Skn-1a/i gene-deleted mice reveals that the Skn-1a/i gene modulates the pattern of expression of the terminal differentiation marker loricrin and inhibits expression of genes encoding markers of the epidermal keratinocyte wounding response. Although epidermis from Tst-1 gene-deleted mice develops normally, epidermis from mice deleted for both Skn-1a/i and Tst-1 is hyperplastic and fails to suppress expression of K14 and Spr-1 in suprabasal cells when transplanted onto athymic mice. This suggests that Skn-1a/i and Tst-1 serve redundant functions in epidermis. Therefore, at least two POU domain genes, Skn-1a/i and Tst-1, serve both distinct and overlapping functions to regulate differentiation of epidermal keratinocytes during normal development and wound healing.
Asunto(s)
Diferenciación Celular/genética , Proteínas de Unión al ADN/genética , Células Epidérmicas , Proteínas Represoras , Factores de Transcripción/genética , Animales , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Epidermis/crecimiento & desarrollo , Epidermis/metabolismo , Genotipo , Humanos , Queratinocitos/citología , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Factor 6 de Transcripción de Unión a Octámeros , Factores del Dominio POU , Factores de Transcripción/metabolismo , Factores de Transcripción/fisiologíaRESUMEN
The neurally expressed genes Brn-3.1 and Brn-3.2 (refs 1-6) are mammalian orthologues of the Caenorhabditis elegans unc-86 gene that constitute, with Brn-3.0 (refs 1-3,8,9), the class IV POU-domain transcription factors. Brn-3.1 and Brn-3.2 provide a means of exploring the potentially distinct biological functions of expanded gene families in neural development. The highly related members of the Brn-3 family have similar DNA-binding preferences and overlapping expression patterns in the sensory nervous system, midbrain and hindbrain, suggesting functional redundancy. Here we report that Brn-3.1 and Brn-3.2 critically modulate the terminal differentiation of distinct sensorineural cells in which they exhibit selective spatial and temporal expression patterns. Deletion of the Brn-3.2 gene causes the loss of most retinal ganglion cells, defining distinct ganglion cell populations. Mutation of Brn-3.1 results in complete deafness, owing to a failure of hair cells to appear in the inner ear, with subsequent loss of cochlear and vestibular ganglia.
Asunto(s)
Proteínas de Unión al ADN/fisiología , Oído Interno/embriología , Desarrollo Embrionario y Fetal/fisiología , Ojo/embriología , Proteínas de Homeodominio , Factores de Transcripción/fisiología , Animales , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Proteínas de Unión al ADN/genética , Sordera/embriología , Sordera/genética , Desarrollo Embrionario y Fetal/genética , Eliminación de Gen , Células Ciliadas Auditivas/anomalías , Células Ciliadas Auditivas/embriología , Hibridación in Situ , Ratones , Familia de Multigenes , Retina/embriología , Células Ganglionares de la Retina/citología , Factor de Transcripción Brn-3B , Factores de Transcripción/genéticaRESUMEN
The mechanisms by which transient gradients of signaling molecules lead to emergence of specific cell types remain a central question in mammalian organogenesis. Here, we demonstrate that the appearance of four ventral pituitary cell types is mediated via the reciprocal interactions of two transcription factors, Pit1 and GATA2, which are epistatic to the remainder of the cell type-specific transcription programs and serve as the molecular memory of the transient signaling events. Unexpectedly, this program includes a DNA binding-independent function of Pit1, suppressing the ventral GATA2-dependent gonadotrope program by inhibiting GATA2 binding to gonadotrope- but not thyrotrope-specific genes, indicating that both DNA binding-dependent and -independent actions of abundant determining factors contribute to generate distinct cell phenotypes.