Loss of the nutrient sensor TAS1R3 leads to reduced bone resorption

The taste receptor type 1 (TAS1R) family of heterotrimeric G protein-coupled receptors participates in monitoring energy and nutrient status. TAS1R member 3 (TAS1R3) is a bi-functional protein that recognizes amino acids such as L-glycine and L-glutamate or sweet molecules such as sucrose and fructose when dimerized with TAS1R member 1 (TAS1R1) or TAS1R member 2 (TAS1R2), respectively. It was recently reported that deletion of TAS1R3 expression in Tas1R3 mutant mice leads to increased cortical bone mass but the underlying cellular mechanism leading to this phenotype remains unclear. Here, we independently corroborate the increased thickness of cortical bone in femurs of 20-week-old male Tas1R3 mutant mice and confirm that Tas1R3 is expressed in the bone environment. Tas1R3 is expressed in undifferentiated bone marrow stromal cells (BMSCs) in vitro and its expression is maintained during BMP2-induced osteogenic differentiation. However, levels of the bone formation marker procollagen type I N-terminal propeptide (PINP) are unchanged in the serum of 20-week-old Tas1R3 mutant mice as compared to controls. In contrast, levels of the bone resorption marker collagen type I C-telopeptide are reduced greater than 60% in Tas1R3 mutant mice. Consistent with this, Tas1R3 and its putative signaling partner Tas1R2 are expressed in primary osteoclasts and their expression levels positively correlate with differentiation status. Collectively, these findings suggest that high bone mass in Tas1R3 mutant mice is due to uncoupled bone remodeling with reduced osteoclast function and provide rationale for future experiments examining the cell-type-dependent role for TAS1R family members in nutrient sensing in postnatal bone remodeling

La modificación genética dirigida en ratones es premiada con el Nobel de Fisiología o Medicina de 2007 / Gene targeting in mice awarded with the 2007 Nobel Prize in Physiology or Medicine

El Premio Nobel de Fisiología o Medicina 2007 ha sido otorgado, merecidamente,a los investigadores norteamericanos Mario Capecchi y Oliver Smithies, yal científico británico Sir Martin Evans, por sus contribuciones pioneras y diseñoexperimental conducentes a la obtención de los primeros ratones mutantes conuna modificación genética dirigida, con la inactivación específica de un gen, dejandointacto el resto del genoma. Martin Evans describió, en 1981, la extraordinariaplasticidad de las células troncales embrionales pluripotentes de la masa internacelular del blastocisto, lo que permitía mantenerlas en cultivo indefinidamente,modificarlas genéticamente y reintroducirlas en un nuevo blastocisto, sin que perdieranla posibilidad de convertirse en cualquiera de los tipos celulares que pueblanun organismo adulto, incluyendo la línea germinal. Mario Capecchi exploró,en los años ochenta, las estrategias que permitieron modificar, de forma selectiva,una determinada secuencia genética mediante el procedimiento de recombinaciónhomóloga y estableció en 1988 el método general de selección doble positiva-negativa.Finalmente, Oliver Smithies, en 1989, fue el primer investigador que integrólas evidencias experimentales de sus dos colegas, modificó un gen (lo inactivó) encélulas troncales embrionales pluripotentes en cultivo, obtuvo después un ratónquimérico y, finalmente, mediante cruces, un animal que, en todas sus células, eraportador de la mutación inicial del gen seleccionado

The Nobel Prize in Physiology or Medicine for 2007 has been awarded jointly,well deserved, to the American scientists Mario Capecchi and Oliver Smithies,and to the British scientist Sir Martin Evans, for their pioneer contributions andexperimental design resulting in the obtention of the first knockout mice with agene targeted event, with the specific inactivation of a gene, leaving the rest of thegenome intact. Martin Evans described, in 1981, the extraordinary plasticity ofpluripotent embryonic stem cells, from the inner cell mass of the blastocyst, thusallowing their maintenance in culture indefinitely, their genetic manipulation and,eventually, their reintroduction in a new blastocyst, without loosing their capacityto differentiate to any of the cellular types found in an adult organism, includingthe germ line. Mario Capecchi explored, in the 80s, the strategies that allowed himto selectively alter a given genetic sequence, using the homologous recombinationprocedure, and established, in 1988, the general method of positive-negative doubleselection. Finally, Oliver Smithies, in 1989, modified a first gene (inactivated) inembryonic stem cells in culture, later obtained a chimera and eventually, througha number of crosses, an animal that, in all of its cells, was carrying the initialmutation of the selected gene

Cilios y cistogénesis / Cilia and cystogenesis

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Factor de necrosis tumoral / Tumor necrosis factor

El asma bronquial actualmente se considera un trastorno fundamentalmente inflamatorio. En el niño existe una clara asociación entre alergia a neumoalergenos y el desarrollo de asma. A través de una compleja interacción entre factores ambientales y genéticos, se desencadenarían los mecanismos celulares responsables de su fisiopatología. Los linfocitos con un fenotipo similar a los descritos en el ratón TH-2, se consideran los responsables de regular este proceso inflamatorio. A través de la producción de IL-4 inducirían la hiperproducción de IgE, principal alteración del sistema inmunológico en los sujetos alérgicos y responsable en último término del desencadenamiento de la reacción alérgica. Las principales células efectoras implicadas son los eosinófilos y mastocitos, por su capacidad de segregar mediadores de la inflamación preformados y sintetizados de novo. En los últimos años se han multiplicado los trabajos de investigación en búsqueda de marcadores inflamatorios de la enfermedad, intentando correlacionarlos con su gravedad. En teoría, a mayor nivel de marcadores inflamatorios debería corresponderse mayor gravedad de la inflamación, así la utilidad de estos marcadores se dirigiría a la monitorización del tratamiento, su respuesta y cumplimiento, la identificación de pacientes de riesgo, y su aplicación en el diagnóstico diferencial del asma. El TNF-* es una citocina muy versátil y ubicua, que se ha implicado en la fisiopatología del asma bronquial, tanto en el proceso inflamatorio como en la hiperreactividad bronquial. Nuestro objetivo es revisar el papel de este mediador inflamatorio en el asma bronquial en general y los problemas particulares del asma del niño (AU)

Bronchial asthma is currently considered as basically an inflammatory disorder. In children there is a clear association between the allergy to aeroallergens and the development of asthma. By means of a complex interaction between environmental and genetic factors, the cellular mechanisms responsible for their pathophysiology are set off. The lymphocytes with a phenotype similar to those describe in the TH-2 mouse, are considered to be responsible for controlling this inflammatory process. By means of the production of Il-4 they would induce the hyper-production of IgE, the main alteration of the immunologic system in people who are allergic and it is eventually responsible for setting off the allergic reaction. The main effector cells involved are the eosinophils and the mastocytes, due to their capacity to segregate preformed and synthesised mediators of the inflammation again. Over the last few years the research work has been multiplied in search of the inflammatory markers of the illness, trying to co-relate them to the seriousness. In theory, the higher the level of inflammatory markers should correspond to a more serious inflammation, in this way the use of these markers would be aimed at monitoring the treatment, the response and the performance, the identification of risk patients and their application to the differential diagnosis of asthma. The TNF-* is a very versatile and ubiquitous cytokine that has been involved in the pathophysiology of bronchial asthma, both in the inflammatory process as well as in the bronchial hyper-reactivity. Our aim is to review the role of this inflammatory mediator in bronchial asthma in general and the specific problems of asthma in children (AU)