Barreras naturales para las horquillas de replicación DNA en Schizosaccharomyces pombe

106 p.-35 fig.En la naturaleza, el crecimiento vegetativo de S. pombe es normalmente haploide. Sólo bajo condiciones ambientales adversas, como en condiciones de ayuno de fuentes nitrógeno, dos células de tipos de apareamiento contrarios, P (plus) y M (minus), conjugan y forman un cigoto diploide (Egel, 1989; Dalgaard y Klar, 2001). Para cada tipo de apareamiento, existen células denominadas switchable (s) y células unswitchable (u). Cada célula de S. pombe que acaba de adquirir un tipo de apareamiento concreto, da lugar a otra del tipo de apareamiento contrario tras dos divisiones mitóticas. Cuando una célula u se divide da lugar a dos células del mismo tipo de apareamiento que la célula parental, una de ellas s y la otra u. Cuando se divida, la célula s dará lugar a una célula u de tipo de apareamiento contrario a la parental y a otra célula s del mismo tipo de apareamiento que la parental (Miyata y Miyata, 1981; Egel y Eie, 1987; Klar, 1987, 1990). Aunque el mecanismo molecular responsable del cambio del tipo de apareamiento en S. pombe no se conoce aún en detalle, algunas de las claves han sido ya descifradas (ver Dalgaard y Klar, 2001 y apartado 1.4.2.). Una vez que producida la conjugación, los núcleos se fusionan y el cigoto diploide resultante sufre meiosis inmediatamente. El cigoto se convierte en una estructura de resistencia denominada asca, que contiene cuatro esporas haploides. Este proceso representa un ejemplo de diferenciación celular. Cuando las condiciones ambientales vuelven a ser favorables, las esporas son liberadas y pueden germinar, cerrándose de este modo el ciclo. Las poblaciones naturales de S. pombe, son homotálicas, es decir, están compuestas por células de los dos tipos de apareamiento y entran en diferenciación sexual bajo condiciones de estrés ambiental. En el laboratorio, a menudo se emplean estirpes heterotálicas, las cuales necesitan otra estirpe del tipo de apareamiento contrario para aparear. En el laboratorio se puede promover la entrada de los cigotos a la división mitótica y seleccionarlos usando mutaciones auxotróficas complementarias en el proceso de conjugación, obteniendo así estirpes diploides que, eventualmente, pueden inducirse a entrar en ciclo mitótico colocándolas en unas condiciones de cultivo adecuadas.Financiación del Proyecto SAF2001-1740; de la Beca del CSIC de Postgrado para la Formación y Especialización en Líneas de Investigación para el Sector Industrial con REF.: I3P-BPG2004 y del Proyecto BFU2004-00125/BMC.Peer reviewe

Structural insight into GRIP1-PDZ6 in Alzheimer’s disease: study from protein expression data to molecular dynamics simulations

<p>Protein–protein interaction domain, PDZ, plays a critical role in efficient synaptic transmission in brain. Dysfunction of synaptic transmission is thought to be the underlying basis of many neuropsychiatric and neurodegenerative disorders including Alzheimer’s disease (AD). In this study, Glutamate Receptor Interacting Protein1 (GRIP1) was identified as one of the most important differentially expressed, topologically significant proteins in the protein–protein interaction network. To date, very few studies have analyzed the detailed structural basis of PDZ-mediated protein interaction of GRIP1. In order to gain better understanding of structural and dynamic basis of these interactions, we employed molecular dynamics (MD) simulations of GRIP1-PDZ6 dimer bound with Liprin-alpha and GRIP1-PDZ6 dimer alone each with 100 ns simulations. The analyses of MD simulations of Liprin-alpha bound GRIP1-PDZ6 dimer show considerable conformational differences than that of peptide-free dimer in terms of SASA, hydrogen bonding patterns, and along principal component 1 (PC1). Our study also furnishes insight into the structural attunement of the PDZ6 domains of Liprin-alpha bound GRIP1 that is attributed by significant shift of the Liprin-alpha recognition helix in the simulated peptide-bound dimer compared to the crystal structure and simulated peptide-free dimer. It is evident that PDZ6 domains of peptide-bound dimer show differential movements along PC1 than that of peptide-free dimers. Thus, Liprin-alpha also serves an important role in conferring conformational changes along the dimeric interface of the peptide-bound dimer. Results reported here provide information that may lead to novel therapeutic approaches in AD.</p

IR hub miRs identified on the basis of intermediate regulation measure from the regulatory network of Group2 miRs which are not previously reported to be associated with PD.

<p>IR hub miRs identified on the basis of intermediate regulation measure from the regulatory network of Group2 miRs which are not previously reported to be associated with PD.</p

Regulatory relationship between TF, miR and mRNA.

<p>TFs and miRs often function in a coupled way. TFs can regulate the transcription of both the miR and its target mRNA by binding to their respective promoter region, while miRs regulate gene's post-transcription by binding to the 3′ untranslated region (UTR) of target mRNA.</p

Node Statistics obtained from the tYNA (http://tyna.gersteinlab.org/) web interface for the overall co-expression network built with the 195 highly correlated miRs [27].

<p>Node Statistics obtained from the tYNA (<a href="http://tyna.gersteinlab.org/" target="_blank">http://tyna.gersteinlab.org/</a>) web interface for the overall co-expression network built with the 195 highly correlated miRs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093751#pone.0093751-Yip1" target="_blank">[27]</a>.</p

Collection of data from two different sources - miR microarray and text mining.

<p>We obtained 204 DE miRs from microarray expression data. Text mining incorporated information of 73 miRs which were reported to be linked with PD. This 73 miRs included 26 miRs from HMDD and 47 miRs from PubMed. Comparison of these transcriptomic and text mining data revealed a significant overlap of 47 PD related miRs, which were termed as Group1 and the remaining 157 miRs (out of the 204 miRs) were termed as Group 2 which were not previously reported to be associated with PD.</p

Tripartite regulatory network for Group 2 miRs.

<p>59 Group 2 miRs associated with the top 20 most significant GO Biological Processes were used to build this network. This network represents the molecular cross talk between TFs, miRs and mRNAs in PD. Square nodes in the middle layer represent miRs, diamond nodes in the upper layer representing validated TFs of respective miRs and circular nodes in the lower most layer represent mRNA targets of the miRs. Here regulation goes down from TFs to miRs and then miRs to mRNAs. TFs regulate the transcription of miRs whereas miRs regulate the translation process of target mRNAs. miRs with highest intermediate regulatory measure were denoted as IR hubs. The 9 IR hub miRs in the middle layer have been enlarged for proper visualization. These IR hubs represent the novel hub miRs which are not reported previously to be linked in PD. This network was constructed in Cytoscape interface <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093751#pone.0093751-Shannon1" target="_blank">[26]</a>.</p

Conservational view of miR 92a in different species.

<p>According to miRbase information, miR 92a is presently denoted as miR 92a-2. This figure indicates high conservation pattern of this miR which was found to be a common hub between regulatory and co-expression network. The information regarding the conservation analysis was obtained from miRNAviewer which presents a global view of homologous miR genes in many species <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093751#pone.0093751-Kiezun1" target="_blank">[34]</a>. The colored legend indicates the conservation level of each grouped miR. Grey box indicates that the miR was not identified in this genome, under stringent parameters. Symbols • indicate miRs registered in miRbase <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093751#pone.0093751-GriffithsJones1" target="_blank">[35]</a>.</p

Additional file 2: Table S2. of Biological networks in Parkinson’s disease: an insight into the epigenetic mechanisms associated with this disease

Topological properties of the hub genes obtained from the turquoise module. (DOCX 11 kb

Summary statistics for the conservation analysis obtained from the PhastCons dataset of UCSC Genome Browser (http://genome.ucsc.edu/) for the 9 novel IR hub miRs (which are not previously linked with PD) [32].

<p>* hsa-miR -92a appeared as a common hub in both regulatory and co-expression network.</p