Quaternary fossil horses within the Prados-Guatén Depression (Pantoja de La Sagra, Toledo)

Durante la primera reunión de campo del Grupo Madrileño de Cuaternario (GQM-AEQUA) se localizaron restos fragmentarios de dentición de caballos fósiles en los antiguos areneros de Pantoja de La Sagra (Toledo), actualmente en proceso de desmantelamiento y relleno. Ante la posibilidad de deterioro y pérdida los restos fueron recolectados y trasladados al Museo Nacional de Ciencias Naturales (CSIC, Madrid) donde se ha procedido a su análisis. Las piezas fósiles analizadas responden a un maxilar izquierdo con tres piezas dentales in situ (molares y premolares), y otras siete más aisladas. Todos los dientes aislados, junto con el fragmento de maxilar existente, corresponden a un adulto joven. Los restos fósiles se encontraban asociados a un nivel de arenas fluviales situado unos cuatro metros por debajo de la superficie de la Terraza de +15 m de la Depresión Prados-Guatén definida como un nivel perteneciente al tránsito Pleistoceno inferior-medio, del antiguo Sistema fluvial Manzanares-Guatén por Silva (1988). En concreto los niveles superiores de esta terraza han sido interpretados como resultado de la superposición de los últimos depósitos del antiguo sistema fluvial y los primeros asociados al relleno de la Depresión por tributarios de área fuente más local tras su abandono como consecuencia del proceso de captura del valle inferior del Manzanares por parte del Río Jarama al SW de la Ciudad de Madrid (Silva et al., 1988). Los caracteres morfológicos y morfométricos de las piezas dentarias permiten identificarlos como Equus ferus cf. mosbachensis cuya distribución bioestratigráfica abarca la parte final del Pleistoceno Medio (c.a. 500-200 ka B.P.). Junto a los restos fósiles aparecieron también escasos fragmentos líticos correspondientes a productos de lascado en sílex de difícil atribución tecnológica. Los restos fósiles analizados, indican que el depósito extensivo de arenas fluviales en el eje de la Depresión, culminó durante el final del Pleistoceno medio, y que la dinámica fluvial de la Depresión tras su proceso de abandono fue de hecho más activa de lo que se pensaba con la instalación de sistemas de arroyos relevantes alimentados por cabeceras locales antes del encajamiento definitivo actual de los arroyos Prados y Guatén.During the first field-meeting of the Madrid Quaternary Research Group (GQM-AEQUA) several fossil teeth remnants of horses were localised at the ancient sand-quarries of Pantoja de La Sagra (Toledo), which presently are abandoned and refilling in progress. The possibility of deterioration and loss of the localised fossils remnants induced by the quarry works, they were collected and taken away to the Museo Nacional de Ciencias Naturales (CSIC, Madrid) for their preservation and analysis. Fossil remains correspond to a left maxilla with two in situ molars, another one inset on its alveolar cavity, fragments of premolar cavities, as well as other seven more isolated teeth. These fossils were outcropping in a sandy level at four meters below the +15 m fluvial terrace surface of the axial sector of de Prados-Guatén Depression, which is considered the last fluvial level belonging to the ancient Manzanares-Guatén fluvial system during the Lower-Middle Pleistocene transit (Silva, 1988). In detail, the upper fluvial sediments of this particular terrace level were interpreted as the result of the overlapping between the last materials deposited by the ancient Manzanares-Guatén fluvial system and the first ones resulting from the readjustment of former tributaries after the abandonment of the Depression caused by fluvial capture of the Lower Manzanares Valley SW Madrid City. The morphological features of the oclusal surface of the horse teeth and morphometric comparative analyses indicate that they belong to the specie Equus ferus, and probably to the subspecie mosbachensis. However due to the bad definition of this group in Europe and the few individuals analysed the better classification is Equus ferus cf. mosbachensis. The bioestratigraphic distribution of this fossil horse group in Europe extends on the upper part of the Middle Pleistocene (c.a. 500-200 ka B.P.). Few lithic artefacts outcropped also associated to the fossil remains, constituted by laminar flakes of hard technological classification. Fossil remains analysed in this work joint to the unique previous quaternary fossil mammal described for the Prados-Guatén Depression constituted by Mammuthus meridionalis NESTI of the former quarry of Esquivias adjacent to the AVE railway line (Silva et al., 1988b; 1999). The chronostratigraphic attribution of the fossil horses (Upper Middle Pleistocene) described here indicate that fluvial sedimentary activity within the Depression was relevant after its abandonment. Ancient tributaries of the former Manzanares-Guatén fluvial system, feed by local-intrabasinal headwaters, reworked the previous sandy sediments triggering multiepisodic deposition during the upper part of the Middle Pleistocene, before the more recent eventual incision of present streams dissecting the Depression

Caminho das letras: educação, formação e perspectivas

ial que se apresenta com o tema “Caminho das letras: Educação, Formação e Perspectivas”, partindo da vida escolar como aluno, chegando a atuação como professora, caracteriza-se também por uma reflexão teórica acerca do papel que as escolas cumprem na sociedade - será que servem como redutoras, ou apenas como indutoras da desigualdade social? A igualdade já deve começar em relação aos conhecimentos, conteúdos, de forma que contemplem suas aspirações, capacidades e possibilidades dos educandos, uma vez que o poder do capital refletiu também no sistema educacional, pois esta ficou com a tarefa de preparar mão-de-obra para a indústria, se preocupando apenas em atender ao mercado de trabalho, educando-se para seguir modelos, regras, se disciplinar e especializar. Deste modo, com base em textos trabalhados durante as aulas, vou teorizar minhas memórias, muitas não tão distantes. Neste trabalho, procuro relatar como compreendi o sentido da escola, se o seu papel é de formar ou apenas informar. Fiz-me esta questão, uma vez que Educação e instrução caminham juntas, completando o intelectual e o social, e assim a Gestão Escolar, há de ter representatividade, não ser meramente funcional. Dessa forma, uma Gestão Escolar com representatividade é democrática e autônoma, que envolve os diferentes atores da Educação (alunos, pais, professores, coordenação e direção). Deve garantir um ensino não fragmentado, proporcionar um intercâmbio entre as matérias, para que o aluno tenha uma visão unificada dos conhecimentos. Por fim, cheguei à conclusão entendendo que, o aluno não aprende por discursos, e sim pela vivência, muitos aprendizados são adquiridos com base nos relacionamentos, ou seja, nas interações e conflitos com o outro

Thyroid Hormone Economy in the Perinatal Mouse Brain: Implications for Cerebral Cortex Development.

Thyroid hormones (THs, T4 and the transcriptionally active hormone T3) play an essential role in neurodevelopment; however, the mechanisms underlying T3 brain delivery during mice fetal development are not well known. This work has explored the sources of brain T3 during mice fetal development using biochemical, anatomical, and molecular approaches. The findings revealed that during late gestation, a large amount of fetal brain T4 is of maternal origin. Also, in the developing mouse brain, fetal T3 content is regulated through the conversion of T4 into T3 by type-2 deiodinase (D2) activity, which is present from earlier prenatal stages. Additionally, D2 activity was found to be essential to mediate expression of T3-dependent genes in the cerebral cortex, and also necessary to generate the transient cerebral cortex hyperthyroidism present in mice lacking the TH transporter Monocarboxylate transporter 8. Notably, the gene encoding for D2 (Dio2) was mainly expressed at the blood-cerebrospinal fluid barrier (BCSFB). Overall, these data signify that T4 deiodinated by D2 may be the only source of T3 during neocortical development. We therefore propose that D2 activity at the BCSFB converts the T4 transported across the choroid plexus into T3, thus supplying the brain with active hormone to maintain TH homeostasis.This work was supported by the Spanish Ministry of Economy and Competitiveness (grant numbers SAF2011-25608, SAF2012-32491, and SAF2014-54919-R), the Center for Biomedical Research on Rare Diseases (CIBERER) of Instituto de Salud Carlos III under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases (project acronym THYRONERVE) and by Comunidad de Madrid (CAM; grant number S2010/BMD-2423). S.B.-L. is a recipient of a predoctoral fellowship and contract from the FPI program of the Plan Nacional de I+D+i. The cost of this publication has been paid in part by FEDER funds.Peer reviewe

First approach to intranasal-delivered thyroid hormone replacement therapy in the Allan-Herndon-Dudley Syndrome

Trabajo presentado en el 3rd Symposium on Biomedical Research "Advances and Perspectives in Neuroscience, celebrado en Madrid (España) el 22 de abril de 2016

Maternal Administration of the CNS-Selective Sobetirome Prodrug Sob-AM2 Exerts Thyromimetic Effects in Murine MCT8-Deficient Fetuses

[Background]: Monocarboxylate transporter 8 (MCT8) deficiency is a rare X-linked disease where patients exhibit peripheral hyperthyroidism and cerebral hypothyroidism, which results in severe neurological impairments. These brain defects arise from a lack of thyroid hormones (TH) during critical stages of human brain development. Treatment options for MCT8-deficient patients are limited and none have been able to prevent or ameliorate effectively the neurological impairments. This study explored the effects of the TH agonist sobetirome and its CNS-selective amide prodrug, Sob-AM2, in the treatment of pregnant dams carrying fetuses lacking Mct8 and deiodinase type 2 (Mct8/Dio2 KO), as a murine model for MCT8 deficiency. [Methods]: Pregnant dams carrying Mct8/Dio2 KO fetuses were treated with 1 mg of sobetirome/kg body weight/day, or 0.3 mg of Sob-AM2/kg body weight/day for 7 days, starting at embryonic day 12.5 (E12.5). As controls, pregnant dams carrying wild-type and pregnant dams carrying Mct8/Dio2 KO fetuses were treated with daily subcutaneous injections of vehicle. Dams TH levels were measured by enzyme-linked immunosorbent assay (ELISA). Samples were extracted at E18.5 and the effect of treatments on the expression of triiodothyronine (T3)-dependent genes was measured in the placenta, fetal liver, and fetal cerebral cortex by real-time polymerase chain reaction. [Results]: Maternal sobetirome treatment led to spontaneous abortions. Sob-AM2 treatment, however, was able to cross the placental as well as the brain barriers and exert thyromimetic effects in Mct8/Dio2 KO fetal tissues. Sob-AM2 treatment did not affect the expression of the T3-target genes analyzed in the placenta, but it mediated thyromimetic effects in the fetal liver by increasing the expression of Dio1 and Dio3 genes. Interestingly, Sob-AM2 treatment increased the expression of several T3-dependent genes in the brain such as Hr, Shh, Dio3, Kcnj10, Klf9, and Faah in Mct8/Dio2 KO fetuses. [Conclusions]: Maternal administration of Sob-AM2 can cross the placental barrier and access the fetal tissues, including the brain, in the absence of MCT8, to exert thyromimetic actions by modulating the expression of T3-dependent genes. Therefore, Sob-AM2 has the potential to address the cerebral hypothyroidism characteristic of MCT8 deficiency from fetal stages and to prevent neurodevelopmental alterations in the MCT8-deficient fetal brain.This study was supported by the Spanish Ministry of Science and Innovation (MCIN)/AEI/10.13039/501100011033 (grant no. SAF2017-86342-R to A.G.-F.); MCIN/AEI/10.13039/501100011033/FEDER ‘‘Una manera de hacer Europa’’ (grant no. PID2020-113139RB-I00 to A.G.-F.); Consejo Superior de Investigaciones Cientı´ficas (grant no. 2020AEP044 to A.G.-F.); the Sherman Foundation (grant no. OTR02211 to S.B.-L. and A.G.-F.); Asociacio´n Corriendo con el Corazo´n por Hugo (grant no. OTR06190 to A.G.-F.), and MCIN/EU (grant no. IJC2020-043543-I) to S.B.-L. V.V.-H. is recipient of a contract from MCIN ‘‘El FSE invierte en tu futuro’’ (grant no. PRE2018-086185) and M.G.-Y. from the MCIN, Programa de Formacio´n de Profesorado Universitario (FPU, FPU19/02006).Peer reviewe

Effect of Triiodothyroacetic Acid Treatment in Mct8 Deficiency: A Word of Caution

[Background]: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific cell membrane transporter. Mutations in the MCT8 gene lead to profound psychomotor retardation and abnormal thyroid hormone serum levels with low thyroxine (T4) and high triiodothyronine (T3). Currently, therapeutic options for patients are limited. Triiodothyroacetic acid (TRIAC) has potential therapeutic value. The aim of this study was to evaluate the effects and efficacy of therapeutic doses of TRIAC on Mct8-deficient mice (Mct8KO).[Methods]: Wild-type (Wt) and Mct8KO mice were treated with 30 ng TRIAC/g BW/day, given in drinking water, from postnatal day 21 to 30. TRIAC, T4 and T3 levels in plasma, as well as T3 and TRIAC content in the cerebral cortex and striatum were measured by specific radioimmunoassays. The activities of deiodinases 1 and 2 were measured in liver and cortex. The effect of TRIAC treatment in the expression of T3-dependent genes was measured in the heart, cerebral cortex and striatum.[Results]: Plasma TRIAC concentration were the same in Wt and Mct8KO animals after treatment. TRIAC treatment greatly decreased plasma T4 in Wt and Mct8KO mice, and reduced T3 to normal levels in the Mct8KO. Deiodinase 1 activity and gene expression in the liver increased while it did not have any effect on the expression of Serca2a in the heart. TRIAC treatment did not induce the expression of T3-dependent genes in the cerebral cortex or striatum but further decreased expression of Flywch2 in the cortex and Aldh1a1 and Flywch2 in the striatum. Direct measurements of TRIAC and T3 content in the cortex and striatum revealed a decrease in T3 after treatment with no significant increase in the level of endogenous TRIAC.[Conclusions]: Therapeutic doses of TRIAC in Mct8KO mice restored plasma T3 levels but severely decreased T4 levels. TRIAC has a direct effect on deiodinase 1 in the liver and does not have an effect on gene expression in the heart. The increase in the plasma TRIAC levels after treatment is not sufficient to increase TRIAC levels in the brain and to promote the expression of T3-dependent genes in brain cells. Instead, it leads to a state of brain hypothyroidism with reduced T3 content.This work was supported by Grants from the Mehuer Foundation and the Seville's College of Pharmacists, Ramón Areces Foundation (CIVP16A1805), Spanish Ministry of Economy and Competitiveness (SAF2011-25608, SAF2014-54919-R, SAF 2012-32491) and S2010/BMD-2423 from CAM and under the frame of E‑Rare‑2 and the “Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III” under the frame of the ERA-Net for Research on Rare Diseases. S.B.-L. is recipient of a predoctoral fellowship and contract from the FPI program of the Plan Nacional de I+D+i. The cost of this publication has been paid in part by FEDER funds.Peer reviewe

Análogos de hormonas tiroideas con acciones tiromiméticas en el sistema nervioso central en condiciones de deficiencia del transportador de monocarboxilatos Mct8

Resumen del póster presentado a la XI Reunión Anual CIBERER, celebrada en Castelldefels, Barcelona del 12 al 14 de marzo de 2018.El síndrome de Allan-Herndon-Dudley (SAHD, ORPHA:59) se asocia a mutaciones en el transportador de monocarboxilatos 8 (MCT8), una proteína de membrana que transporta específicamente hormonas tiroideas (HTs). La deficiencia de MCT8 conduce a un retraso psicomotor profundo con niveles anormales de HTs en plasma, con baja tiroxina (T4) y elevada triyodotironina (T3). Numerosas evidencias indican que las graves alteraciones neurológicas se deben a un transporte deficiente de HTs a través de las barreras cerebrales, produciendo un hipotiroidismo cerebral. Existen tratamientos para normalizar el hipertiroidismo periférico, pero ninguno ha sido efectivo para el síndrome neurológico. Nuestro objetivo ha sido explorar posibles terapias farmacológicas efectivas para el SAHD. Para ello hemos realizado estudios preclínicos con modelos animales en los que se ha evaluado la capacidad que tienen distintos análogos de HTs, administrados sistémicamente, de acceder al cerebro y de ejercer acciones tiromiméticas en las células neurales en ausencia del transportador Mct8. También se ha evaluado el efecto de estos análogos en tejidos periféricos. Los resultados en ratones muestran que en ausencia de Mct8 los análogos administrados pueden acceder al cerebro y allí ejercer acciones a nivel genómico modulando la expresión de genes dependientes de T3. A nivel periférico estos análogos no tienen efecto en corazón y corrigen el hipertiroidismo, aunque disminuyendo considerablemente los niveles de T3 y T4 en suero. Nuestros estudios indican que éstos análogos pueden ser beneficiosos para paliar las alteraciones neurológicas de pacientes con SAHD, y que se deberían hacer más estudios para comprender sus mecanismos de acción.Peer Reviewe

Searching for strategies to overcome the lack of MCT8 in the brain

Trabajo presentado en el MCT8 2018 Symposium in Memory of Theo Visser, celebrado en Doorn (Países Bajos) del 10 al 11 de septiembre de 2018

Sobetirome and its amide prodrug Sob-AM2 exert thyromimetic actions in Mct8-deficient brain

[Background]: Loss of function mutations in the thyroid hormone (TH)-specific cell membrane transporter, the monocarboxylate transporter 8 (MCT8), lead to profound psychomotor retardation and abnormal TH serum levels, with low thyroxine (T4) and high triiodothyronine (T3). Several studies point to impaired TH transport across brain barriers as a crucial pathophysiological mechanism resulting in cerebral hypothyroidism. Treatment options for MCT8-deficient patients are limited and are focused on overcoming the brain barriers. The aim of this study was to evaluate the ability of the TH analog sobetirome and its prodrug Sob-AM2 to access the brain and exert thyromimetic actions in the absence of Mct8.[Methods]: Juvenile wild-type (Wt) mice and mice lacking Mct8 and deiodinase type 2 (Mct8/Dio2KO) were treated systemically with daily injections of vehicle, 1 mg of sobetirome/kg body weight/day, or 0.3 mg of SobAM2/kg body weight/day for seven days. Sobetirome content was measured using liquid chromatography–tandem mass spectrometry, and T4 and T3 levels by specific radioimmunoassays. The effect of sobetirome treatment in the expression of T3-dependent genes was measured in the heart, liver, and cerebral cortex by realtime polymerase chain reaction.[Results]: Sob-AM2 treatment in Mct8/Dio2KO animals led to 1.8-fold more sobetirome content in the brain and 2.5-fold less in plasma in comparison to the treatment with the parent drug sobetirome. Both sobetirome and Sob-AM2 treatments in Mct8/Dio2KO mice greatly decreased plasma T4 and T3 levels. Dio1 and Ucp2 gene expression was altered in the liver of Mct8/Dio2KO mice and was not affected by the treatments. In the heart, Hcn2 but not Atp2a2 expression was increased after treatment with the analogs. Interestingly, both sobetirome and Sob-AM2 treatments increased the expression of several T3-dependent genes in the brain such as Hr, Abcd2, Mme, and Flywch2 in Mct8/Dio2KO mice.[Conclusions]: Sobetirome and its amide prodrug Sob-AM2 can access the brain in the absence of Mct8 and exert thyromimetic actions modulating the expression of T3-dependent genes. At the peripheral level, the administration of these TH analogs results in the depletion of circulating T4 and T3. Therefore, sobetirome and Sob-AM2 have the potential to address the cerebral hypothyroidism and the peripheral hyperthyroidism characteristic of MCT8 deficiency.This work was supported by the Spanish Ministry of Economy Industry and Competitiveness (SAF2014-54919-R and SAF2017-86342-R to A.G.F.), the Sherman Foundation (OTR02211 to A.G.F.), and the National Institutes of Health (DK52798 to T.S.S. and 2T32DK007680-21 to M.D.H.), and the National Multiple Sclerosis Society (FG 2023A 1/2 to M.D.H.). The cost of this publication has been paid in part by FEDER funds.Peer reviewe