Epigenetic heredity in mice: involvement of RNA and miRNas.

By contrast with a wide definition of the 'epigenetic variation', including all changes in gene expression that do not result from alteration of the gene structure, a more restricted class had been defined, initially in plants, under the name 'paramutation'. It corresponds to epigenetic modifications distinct from the regulatory interactions of the cell differentiation pathways, mitotically stable and sexually transmitted with non-Mendelian patterns. This class of epigenetic changes appeared for some time restricted to the plant world, but examples progressively accumulated of epigenetic inheritance in organisms ranging from mice to humans. Occurrence of paramutation in the mouse and possible mechanisms were then established in the paradigmatic case of a mutant phenotype maintained and hereditarily transmitted by wild type homozygotes. Together with recent findings in plants indicative of a necessary step of RNA amplification in the reference maize paramutation, the mouse studies point to a new role of RNA, as an inducer and hereditary determinant of epigenetic variation. Given the known presence of a wide range of RNAs in human spermatozoa, as well as a number of unexplained cases of familial disease predisposition and transgenerational maintenance, speculations can be extended to possible roles of RNA-mediated inheritance in human biology and pathology.La paramutation est une modification épigénétique héréditaire, découverte chez des plantes et récemment, chez la souris. C'est un changement héréditaire du phénotype associé avec un allèle sauvage à la suite de son passage dans une structure hétérozygote avec un allèle mutant (phénomène quelquefois appelé "conversation interchromosomique"). Souvent il est considéré comme une exception à la base de lois de Mendel, "les allèles sont retrouvés inchangés lors des ségrégations au cours des croisements". Au contraire la paramutation observée chez la souris résulte d'une modification de l'allèle sauvage du gène Kit après transmission à partir d'un hétérozygote avec un allèle mutant "insertion". Le phénotype des taches blanches visibles aisément par la couleur du pelage est transmis en absence de l'allèle inducteur sur plusieurs générations. Il est corrélé avec une diminution du niveau d'ARNm de Kit et une accumulation d'ARN de taille variable de Kit dans les spermatozo?des des souris paramutantes. La micro-injection de l'ARN de l'hétérozygote, ou de l'ARN et des microARN spécifiques de Kit dans l'oeuf fécondé induit le phénotype "taches blanches". Le r?le de l'ARN dans l'établissement et le maintien d'un état épigénétique héréditaire est proposé et discuté.     

Minimizing the overlap problem in protein NMR: a computational framework for precision amino acid labeling

MOTIVATION: Recent advances in cell-free protein expression systems allow specific labeling of proteins with amino acids containing stable isotopes ((15)N, (13) C and (2)H), an important feature for protein structure determination by nuclear magnetic resonance (NMR) spectroscopy. Given this labeling ability, we present a mathematical optimization framework for designing a set of protein isotopomers, or labeling schedules, to reduce the congestion in the NMR spectra. The labeling schedules, which are derived by the optimization of a cost function, are tailored to a specific protein and NMR experiment. RESULTS: For 2D (15)N-(1)H HSQC experiments, we can produce an exact solution using a dynamic programming algorithm in under 2 h on a standard desktop machine. Applying the method to a standard benchmark protein, calmodulin, we are able to reduce the number of overlaps in the 500 MHz HSQC spectrum from 10 to 1 using four samples with a true cost function, and 10 to 4 if the cost function is derived from statistical estimates. On a set of 448 curated proteins from the BMRB database, we are able to reduce the relative percent congestion by 84.9% in their HSQC spectra using only four samples. Our method can be applied in a high-throughput manner on a proteomic scale using the server we developed. On a 100-node cluster, optimal schedules can be computed for every protein coded for in the human genome in less than a month. AVAILABILITY: A server for creating labeling schedules for (15)N-(1)H HSQC experiments as well as results for each of the individual 448 proteins used in the test set is available at http://nmr.proteomics.ics.uci.edu.     

Differentiating megakaryocytes in myelodysplastic syndromes succumb to mitochondrial derangement without caspase activation

Myelodysplastic syndromes (MDS) constitute a preneoplastic condition in which potentially malignant cancer stem cells continuously die during differentiation. This MDS-associated cell death often involves caspase-3 activation, yet can also occur without caspase activation, for instance in differentiating megakaryocytes (MK). We investigated, the mechanisms through which MK from MDS patients undergo premature cell death. While polyploid, mature MK from healthy subjects or MDS patients manifested caspase-3 activation during terminal differentiation, freshly isolated, immature MK from MDS died without caspase-3 activation. Similarly, purified bone marrow CD34⁺ cells from MDS patients that were driven into MK differentiation in vitro died without caspase-3 activation at an immature stage, before polyploidization. The premature death of MDS MK was accompanied by the mitochondrial release of cytochrome c, Smac/DIABLO and endonuclease G, a caspase-independent death effector, as well loss of the mitochondrial membrane potential and plasma membrane phosphatidylserine exposure before definitive loss of viability. Thus, a stereotyped pattern of mitochondrial alterations accompanies differentiation-associated MK death in MDS. T. Braun and G. Carvalho contributed equally to this paper.     

Genome ecosystem and transposable elements species

Transposable elements are known to be “selfish DNA” sequences able to spread and be maintained in all genomes analyzed so far. Their evolution depends on the interaction they have with the other components of the genome, including genes and other transposable elements. These relationships are complex and have often been compared to those of species living and competing in an ecosystem. The aim of this current work is a proposition to fill the conceptual gap existing between genome biology and ecology, assuming that genomic components, such as transposable elements families, can be compared to species interacting in an ecosystem. Using this framework, some of the main models defined in the population genetics of transposable elements can then been reformulated, and some new kinds of realistic relationships, such as symbiosis between different genomic components, can then be modelled and explored.     

Eel community structure,fluvial recruitment of <Emphasis Type="Italic">Anguilla marmorata</Emphasis> and indication for a weak local production of spawners from rivers of Réunion and Mauritius islands

Anguillid eels were sampled from permanent rivers in the Réunion and Mauritius islands, western Indian Ocean, with a standardized electrofishing method. A. marmorata was very dominant, corresponding to 91.7 and 90.7% of all the eels collected in Réunion and Mauritius, respectively. Three other species (A. mossambica, A. bicolor bicolor and A. nebulosa labiata) were also present in both islands. A. marmorata showed a strong altitudinal gradient of densities from the lower to upper zones, especially in the younger stages (TL <250 mm), while A. mossambica was only found in the upper zones and A. bicolor bicolor occurred only in the lower zones (A. nebulosa labiata was rare). The eel species composition in freshwaters of both islands is very similar because these two adjoining islands are located in the same trail of drifting marine larvae. Mean estimated eel biomasses were noticeably low (11.1 and 22.2 kg ha⁻¹ in Réunion and Mauritius islands, respectively), especially when compared to those of other tropical insular systems without any eel fishery (Comoros or Polynesia, more than 100 kg ha⁻¹). Nevertheless, the fluvial recruitment of A. marmorata seemed to be regular during the surveyed period, staggering from October to April. The obvious lack of large eels in Mauritius but more significantly in Réunion suggests a high pressure from traditional fishery, and the local reproductive turnover is uncertain. Because sexual maturation seems to occur at a large body size for A. marmorata, as for temperate species, the Réunion and Mauritius rivers may only have a weak contribution to the regional production of spawners. However, the giant mottled eel population in the western Indian Ocean is believed to be panmictic at the regional scale, and may not rely exclusively on these islands’ contribution. A comparison is made with those of freshwater systems in other tropical islands.     

Genetic transformation of Arabidopsis lyrata: specific expression of the green fluorescent protein (GFP) in pistil tissues

Arabidopsis thaliana has become widely used as a model system for plant biology. Recent phylogenetic studies led to a severe revision of the systematic relationships across species of the Brassicaceae family. This provided an opportunity to examine close relatives of A. thaliana and to study the function and molecular evolution of genes that play roles in ecology and speciation. In this context, developing tools to genetically transform “non-model plants” appears as a major issue to ascertain gene function. Here, we report a method to transform A. lyrata, one of the closest relatives of A. thaliana.     

The green tea compound, (-)-epigallocatechin-3-gallate downregulates N-cadherin and suppresses migration of bladder carcinoma cells

Green tea has been reported as potential dietary protection against numerous cancers and has been shown to have activity in bladder tumor inhibition in different animal models. The goal of this study was to examine the effects of (-)-epigallocatechin gallate (EGCG-the major phytochemical in green tea) on growth inhibition and behavior of human bladder carcinoma cells and to identify the altered signaling pathway(s) underlying the response to EGCG exposure. EGCG inhibited the in vitro growth of invasive bladder carcinoma cells with an IC(50) range of 70-87 microM. At a concentration of 20 microM, EGCG decreased the migratory potential of bladder carcinoma cells with concomitant activation of p42/44 MAPK and STAT3 and inactivation of Akt. Using biochemical inhibitors of MAPK/ERK, and siRNA to knockdown STAT3 and Akt, inhibition of migration was recorded associated with Akt but not MAPK/ERK or STAT3 signaling in bladder cells. In addition, EGCG downregulated N-cadherin in a dose-dependent manner where reduction in N-cadherin expression paralleled declining migratory potential. Continuous feeding of EGCG to mice prior to and during the establishment of bladder carcinoma xenografts in vivo revealed >50% reduction in mean final tumor volume (P 相似文献   

Tridimensional evaluation and optimization of the orthotic treatment of adolescent idiopathic scoliosis

Adolescent idiopathic scoliosis involves complex tridimensional deformities of the spine, rib cage and pelvis. Moderate curves generally are treated using an orthosis. This paper presents different studies performed over the last fifteen years related to the biomechanical evaluation and optimization of the orthopedic treatment of scoliotic deformities. Patient specific 3D models of the spine, pelvis and rib cage are computed from calibrated radiographs, and are used to calculate 2D and 3D clinical indices. The torso shape is acquired using surface topography. With such internal and external 3D models, the efficacy of the most frequently used orthoses can be analyzed and new treatments can be developed. Pressures generated by a brace on the patient's trunk were measured using a flexible matrix of pressure sensors and displayed over the patient's internal geometry in order to analyze the brace efficacy. Patient specific finite element models have been developed, including the osseo-ligamentous structures as well as the muscles, the neuro-control, trunk growth and its adaptation to the stress. These models were used to analyze the effects of the Boston brace. The electro-myographic activity also was measured to analyze the < active > correction mechanisms. Adjustment techniques and software are used to help the orthotists with real time feedback when the brace is being fabricated and adjusted to the patient. Residual growth potential is also being added to the computer model to simulate the long term effect of a brace. The improvement of the orthotic treatments of scoliotic deformities is very encouraging. The exploitation of such tools is expected to allow reaching optimal treatment personalized to each patient. double dagger.