Perspectives in the study of thyroid hormone action on brain development and function

The purpose of this review is to provide an up-to-date report on the molecular and physiologic processes involved in the role of thyroid hormone as an epigenetic factor in brain maturation. We summarize the available data on the control of brain gene expression by thyroid hormone, the correlation between gene expression and physiologic effects, and the likely mechanisms of action of thyroid hormone on brain gene expression. In addition we propose a role for unliganded thyroid hormone receptors in the pathogenesis of hypothyroidism. Finally, we review recent data indicating that thyroid hormone receptors have an impact on behavior.Supported by grants BF12002-00489 of Ministerio de Ciencia y Tecnología, and 08.5/0044.1/2000 from Comunidad de Madrid.Peer Reviewe

Monocyte-mediated regulation of genes by the amyloid and prion peptides in SH-SY5Y neuroblastoma cells

El pdf del artículo es la versión manuscrita de autor.Alzheimer's disease as well as prion-related encephalopathies are neurodegenerative disorders of the central nervous system, which cause mental deterioration and progressive dementia. Both pathologies appear to be primarily associated with the pathological accumulation and deposit of β-amyloid or prion peptides in the brain, and it has been even suggested that neurotoxicity induced by these peptides would be associated to essentially similar pathogenic mechanisms, in particular to those that follow the activation of microglial cells. To probe whether the neurotoxic effects induced by the β-amyloid and prion peptides are actually mediated by similar glial-associated mechanisms, we have examined the differential expression of genes in SH-SY5Y neuroblastoma cells incubated with conditioned media from β-amyloid or prion-stimulated THP-1 monocytic cells. According to microarray analysis, not many coincidences are observed and only four genes (Hint3, Psph, Daam1 and c-Jun) appear to be commonly upregulated by both peptides. Furthermore, c-Jun appears to be involved in the cell death mediated by both peptides. © 2011 Elsevier Ltd. All rights reserved.Peer Reviewe

The human RC3 gene homolog, NRGN contains a thyroid hormone-responsive element located in the first intron

9 pages, 5 figures.NRGN is the human homolog of the neuron-specific rat RC3/neurogranin gene. This gene encodes a postsynaptic 78-amino acid protein kinase substrate that binds calmodulin in the absence of calcium, and that has been implicated in dendritic spine formation and synaptic plasticity. In the rat brain RC3 is under thyroid hormone control in specific neuronal subsets in both developing and adult animals. To evaluate whether the human gene is also a target of thyroid hormone we have searched for T3-responsive elements in NRGN cloned genomic fragments spanning the whole gene. Labeled DNA fragments were incubated with T3 receptors (T3R) and 9-cis-retinoic acid receptors and immunoprecipitated using an anti T3R antibody. A receptor-binding site was localized in the first intron, 3000 bp downstream from the origin of transcription. Footprinting analysis revealed the sequence GGATTAAATGAGGTAA, closely related to the consensus T3-responsive element of the direct repeat (DR4) type. This sequence binds the T3R-9-cis-retinoic acid receptors heterodimers, but not T3R monomers or homodimers, and is able to confer regulation by T3R and T3 when fused upstream of the NRGN or thymidine kinase promoters. The data reported in this work suggest that NRGN is a direct target of thyroid hormone in human brain, and that control of expression of this gene could underlay many of the consequences ofhypothyroidism on mental states during development as well as in adult subjects.This work was supported by grants from Fundación Ramon Areces and DGICYT (PM95–0019).Peer reviewe

CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative

CIBER (Center for Biomedical Network Research; Centro de Investigacion Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mis sion is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low prevalence diseases, in line with the International Rare Diseases Research Consor tium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this arti cle, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Lack of action of exogenously administered T3 on the fetal rat brain despite expression of the monocarboxylate transporter 8

Mutations of the monocarboxylate transporter 8 gene (MCT8, SLC16A2) cause the Allan-Herndon-Dudley syndrome, an X-linked syndrome of severe intellectual deficit and neurological impairment. Mct8 transports thyroid hormones (T4 and T3), and the Allan-Herndon-Dudley syndrome is likely caused by lack of T3 transport to neurons during critical periods of fetal brain development. To evaluate the role of Mct8 in thyroid hormone action in the fetal brain we administered T4 or T3 to thyroidectomized pregnant dams treated with methyl-mercapto-imidazol to produce maternal and fetal hypothyroidism. Gene expression was then measured in the fetal cerebral cortex. T4 increased Camk4, Sema3c, and Slc7a3 expression, but T3 was without effect. To investigate the cause for the lack of T3 action we analyzed the expression of organic anion transport polypeptide (Oatp14, Slco1c1), a T4 transporter, and Mct8 (Slc16a2), a T4 and T3 transporter, by confocal microscopy. Both proteins were present in the brain capillaries forming the blood-brain barrier and in the epithelial cells of the choroid plexus forming the blood-cerebrospinal fluid barrier. It is concluded that T4 from the maternal compartment influences gene expression in the fetal cerebral cortex, possibly after transport via organic anion transporter polypeptide and/or Mct8, and conversion to T3 in the astrocytes. On the other hand, T3 does not reach the target neurons despite the presence of Mct8. The data indicate that T4, through local deiodination, provides most T3 in the fetal rat brain. The role of Mct8 as a T3 transporter in the fetal rat brain is therefore uncertain. Copyright © 2011 by The Endocrine Society.This work was supported by Grants SAF2008-01168 and SAF2008-00429E from the Ministry of Science and Innovation, Spain, the European Union Integrated Project CRESCENDO (LSHM-CT-2005-018652), and by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III. D.D. was supported by the I3P program of the Consejo Superior de Investigaciones Científicas, Spain and by a postdoctoral fellowship from The Japanese Society for the Promotion of Science.Peer Reviewe

María de Urrea, priora y mecenas de las artes en el Real Monasterio de Sijena (1510-1521)

María de Urrea, priora del Real Monasterio de Santa María de Sijena (1510-1521), vendió en 1514 el vizcondado de Biota, su herencia familiar, para hacer frente a las obras de su monasterio; entre ellas, el monumental Retablo Mayor de pintura. La renovación del patrimonio artístico del monasterio implicaba trabajo para los artistas, lo que justifica la presencia de pintores y otros artífices en Sijena en 1514, tal como aparece en el documento que damos a conocer aquí. La priora dictó testamento, a su vez inventario de sus bienes muebles, el 28 de marzo de 1521, documento que transcribimos por primera vez. Aquí remarca la priora la relación de su linaje con el cenobio aragonés desde su fundación en el siglo XII, razón por la que expresa el deseo de que sus restos descansen en la iglesia junto a los de su antepasada y antecesora en el gobierno del monasterio, Teresa de Urrea (1297-1321)

Biological-based and remote sensing techniques to link vegetative and reproductive development and assess pollen emission in Mediterranean grasses

Connecting the signals of the vegetative and reproductive cycles of plants using large-scale phenological techniques is not always an easy task, and this complexity increases considerably when analysing the plant life cycle in grasses, due to the ubiquity and diversity of this taxonomic family. This work integrates remote sensing techniques (NDVI from satellite remote sensing data and greenness from near-surface imagery) and biologicalbased techniques (airborne pollen monitoring and field observations and sampling) to analyse phenological patterns and productivity in grass-dominated vegetation types. We aim to answer two main applied and unanswered questions; i) how are the specific phases of vegetative and reproductive cycles in grasses linked at the species and plant community level? and ii) which grass-dominant habitats are the major contributors of grass pollen emission to the atmosphere at the plant community level? The multi-scale integration and validation of large-scale methods such as satellite remote sensing data and aerobiological monitoring using high-resolution or field phenological techniques is recommended. The results clearly support the hypothesis that the highest rates of grass pollen emission are successively produced when the major grass-dominated vegetation types go through the final phases of vegetative development during their biological senescence or equivalent phases. At the plant community level, natural and semi-natural grass-dominated vegetation types, rather than grass cropland habitats, constitute the major sources of pollen emission. The major contributors to the grass pollen emission at the species level are also identified. Finally, a positive relationship between year-to-year primary productivity (measured as annual sum or maximum NDVI) and pollen production (measured as airborne pollen intensity) was observed at the community level. This is a very timely study, as the availability of remote sensing data is increasing interest in generating enhanced forecasting model of allergenic airborne pollen

Cerebral cortex hyperthyroidism of newborn Mct8-deficient mice transiently suppressed by Lat2 inactivation

Thyroid hormone entry into cells is facilitated by transmembrane transporters. Mutations of the specific thyroid hormone transporter, MCT8 (Monocarboxylate Transporter 8, SLC16A2) cause an X-linked syndrome of profound neurological impairment and altered thyroid function known as the Allan-Herndon-Dudley syndrome. MCT8 deficiency presumably results in failure of thyroid hormone to reach the neural target cells in adequate amounts to sustain normal brain development. However during the perinatal period the absence of Mct8 in mice induces a state of cerebral cortex hyperthyroidism, indicating increased brain access and/or retention of thyroid hormone. The contribution of other transporters to thyroid hormone metabolism and action, especially in the context of MCT8 deficiency is not clear. We have analyzed the role of the heterodimeric aminoacid transporter Lat2 (Slc7a8), in the presence or absence of Mct8, on thyroid hormone concentrations and on expression of thyroid hormone-dependent cerebral cortex genes. To this end we generated Lat2-/-, and Mct8-/yLat2-/- mice, to compare with wild type and Mct8-/y mice during postnatal development. As described previously the single Mct8 KO neonates had a transient increase of 3,5,3′-triiodothyronine concentration and expression of thyroid hormone target genes in the cerebral cortex. Strikingly the absence of Lat2 in the double Mct8Lat2 KO prevented the effect of Mct8 inactivation in newborns. The Lat2 effect was not observed from postnatal day 5 onwards. On postnatal day 21 the Mct8 KO displayed the typical pattern of thyroid hormone concentrations in plasma, decreased cortex 3,5,3′-triiodothyronine concentration and Hr expression, and concomitant Lat2 inactivation produced little to no modifications. As Lat2 is expressed in neurons and in the choroid plexus, the results support a role for Lat2 in the supply of thyroid hormone to the cerebral cortex during early postnatal development

Schuurs–Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review

Síndrome de Schuurs-Hoeijmakers; Discapacitat intel·lectual; Trastorns rarsSíndrome de Schuurs-Hoeijmakers; Discapacidad intelectual; Trastornos rarosSchuurs–Hoeijmakers syndrome; Intellectual disability; Rare disordersSchuurs–Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopmental disorder is a rare disorder characterized by intellectual disability, abnormal craniofacial features and congenital malformations. SHMS is an autosomal dominant hereditary disease caused by pathogenic variants in the PACS1 gene. PACS1 is a trans-Golgi-membrane traffic regulator that directs protein cargo and several viral envelope proteins. It is upregulated during human embryonic brain development and has low expression after birth. So far, only 54 patients with SHMS have been reported. In this work, we report on seven new identified SHMS individuals with the classical c.607C > T: p.Arg206Trp PACS1 pathogenic variant and review clinical and molecular aspects of all the patients reported in the literature, providing a summary of clinical findings grouped as very frequent (≥75% of patients), frequent (50–74%), infrequent (26–49%) and rare (less than ≤25%).This work was possible thanks to the funding provided by the project “Proyecto Piloto para la mejora del diagnóstico genético en personas y familias afectadas o con sospecha de padecer enfermedades raras de base genética” of the Ministry of Health, under the grant BOCM-20181126-24 provided by the Consejería de Sanidad de la Comunidad de Madrid. Funding to J.P. and F.J.R. was partially provided by the group research grant DGA/FEDER B32_17R/B32_20R

Causes of increased pollen exposure during Saharan-Sahel dust intrusions

Airborne particulate matter such as mineral dust comes mainly from natural sources, and the African regions of Sahara and Sahel originate large amounts of the aerosols dispersed worldwide. There is little knowledge about the influence of dust episodes on airborne pollen concentrations, and although the centre and southeast of the Iberian Peninsula are frequently affected by dust intrusions, until now, no specific works have analysed the effect of these episodes on airborne pollen concentrations in these areas. The aims of this study were to analyse the simultaneous occurrence of airborne pollen peaks and Saharan-Sahel dust intrusions in the central and south-eastern Iberian Peninsula, and to study the weather conditions – air mass pathways and conditions of air temperature, relative humidity and atmospheric pressure – that influence the airborne pollen concentrations during dust episodes. The results showed that the rise in airborne pollen concentrations during dust episodes is apparent in inland Iberian areas, although not in coastal areas in the southeast where pollen concentrations are even observed to decrease, coinciding with prevailing easterly winds from the sea. Total pollen concentrations and specific pollen types such as Olea, Poaceae and Quercus showed an increase in the central Iberian Peninsula during dust episodes when two meteorological phenomena concur: 1) prevailing winds from extensive areas of major wind-pollinated pollen sources over a medium or short distance (mainly from western and southwestern areas); and 2) optimal meteorological conditions that favour pollen release and dispersal into the atmosphere (mainly high temperatures and subsequently low humidity in central areas). Both conditions often occur during the Saharan-Sahel dust intrusions in the centre. Maximum pollen peaks are therefore most likely to occur during dust episodes in the central Iberian Peninsula, thus dramatically increasing the risk of outbreaks of pollinosis and other respiratory diseases in the population