Positional bias of general and tissue-specific regulatory motifs in mouse gene promoters

Background: The arrangement of regulatory motifs in gene promoters, or promoterarchitecture, is the result of mutation and selection processes that have operated over manymillions of years. In mammals, tissue-specific transcriptional regulation is related to the presence ofspecific protein-interacting DNA motifs in gene promoters. However, little is known about therelative location and spacing of these motifs. To fill this gap, we have performed a systematic searchfor motifs that show significant bias at specific promoter locations in a large collection ofhousekeeping and tissue-specific genes.Results: We observe that promoters driving housekeeping gene expression are enriched inparticular motifs with strong positional bias, such as YY1, which are of little relevance in promotersdriving tissue-specific expression. We also identify a large number of motifs that show positionalbias in genes expressed in a highly tissue-specific manner. They include well-known tissue-specificmotifs, such as HNF1 and HNF4 motifs in liver, kidney and small intestine, or RFX motifs in testis,as well as many potentially novel regulatory motifs. Based on this analysis, we provide predictionsfor 559 tissue-specific motifs in mouse gene promoters.Conclusion: The study shows that motif positional bias is an important feature of mammalianproximal promoters and that it affects both general and tissue-specific motifs. Motif positionalconstraints define very distinct promoter architectures depending on breadth of expression andtype of tissue.

Atmospheric deposition and migration of artificial radionuclides in Alpine soils (Val Piora, Switzerland) compared to the distribution of selected major and trace elements.

Artificial radionuclides ((137)Cs, (90)Sr, Pu, and (241)Am) are present in soils because of Nuclear Weapon Tests and accidents in nuclear facilities. Their distribution in soil depth varies according to soil characteristics, their own chemical properties, and their deposition history. For this project, we studied the atmospheric deposition of (137)Cs, (90)Sr, Pu, (241)Am, (210)Pb, and stable Pb. We compared the distribution of these elements in soil profiles from different soil types from an alpine Valley (Val Piora, Switzerland) with the distribution of selected major and trace elements in the same soils. Our goals were to explain the distribution of the radioisotopes as a function of soil parameters and to identify stable elements with analogous behaviors. We found that Pu and (241)Am are relatively immobile and accumulate in the topsoil. In all soils, (90)Sr is more mobile and shows some accumulations at depth into Fe-Al rich horizons. This behavior is also observed for Cu and Zn, indicating that these elements may be used as chemical analogues for the migration of (90)Sr into the soil.

Influence of CD4+/CD25+ regulatory T cells on atherogenesis in patients with end-stage kidney disease.

Atherosclerosis, which is influenced by both traditional and nontraditional cardiovascular risk factors and has been characterized as an inflammatory process, is considered to be the main cause of the elevated cardiovascular risk associated with chronic kidney disease. The inflammatory component of atherosclerosis can be separated into an innate immune response involving monocytes and macrophages that respond to the excessive uptake of lipoproteins and an adaptive immune response that involves antigen-specific T cells. Concurrent with the influx of immune cells to the site of atherosclerotic lesion, the role of the adaptive immune response gradually increases. One of those cells are represented by the CD4+/CD25+ Tregs, which play indispensable roles in the maintenance of natural self-tolerance and negative control of pathological, as well as physiological, immune responses. Altered self-antigens such as oxidized LDLs may induce the development of CD4+/CD25+ Tregs with atheroprotective properties. However, atherosclerosis may be promoted by an imbalance between regulatory and pathogenic immunity that may be represented by the low expression of the forkhead box transcription factor (Foxp3) in CD4+/CD25+ Tregs. Such a defect may break immunologic tolerance and alter both specific and bystander immune suppression, leading to exacerbation of plaque development. Patients with end-stage kidney disease (ESKD) display a cellular immune dysfunction and accelerated atherosclerosis. Uremic solutes that accumulate during ESKD may be involved in these processes. In patients with ESKD and especially in those that are chronically hemodialyzed, oxidative stress induced by oxidized LDLs may increase CD4+/CD25+ Treg sensitivity to Fas-mediated apoptosis as a consequence of specific dysregulation of IL-2 expression. This review will focus on the current state of knowledge regarding the influence of CD4+/CD25+ Tregs on atherogenesis in patients with ESKD, and the potential effect of statins on the circulating number and the functional properties of these cells.

Exploring the effect of aminoglycoside guanidinylation on ligands for Tau exon 10 splicing regulatory element RNA

We describe the effect of guanidinylation of the aminoglycoside moiety on acridine-neamine-containing ligands for the stem-loop structure located at the exon 10-5′-intron junction of Tau pre-mRNA, an important regulatory element of tau gene alternative splicing. On the basis of dynamic combinatorial chemistry experiments, ligands that combine guanidinoneamine and two different acridines were synthesized and their RNA-binding properties were compared with those of their amino precursors. Fluorescence titration experiments and UV-monitored melting curves revealed that guanidinylation has a positive effect both on the binding affinity and specificity of the ligands for the stemloop RNA, as well as on the stabilization of all RNA sequences evaluated, particularly some mutated sequences associated with the development of FTDP-17 tauopathy. However, this correlation between binding affinity and stabilization due to guanidinylation was only found in ligands containing a longer spacer between the acridine and guanidinoneamine moieties, since a shorter spacer produced the opposite effect (e.g. lower binding affinity and lower stabilization). Furthermore, spectroscopic studies suggest that ligand binding does not significantly change the overall RNA structure upon binding (circular dichroism) and that the acridine moiety might intercalate near the bulged region of the stem->loop structure (UV-Vis and NMR spectroscopy).

A nuclear factor I-like activity and a liver-specific repressor govern estrogen-regulated in vitro transcription from the Xenopus laevis vitellogenin B1 promoter.

A hormone-controlled in vitro transcription system derived from Xenopus liver nuclear extracts was exploited to identify novel cis-acting elements within the vitellogenin gene B1 promoter region. In addition to the already well-documented estrogen-responsive element (ERE), two elements were found within the 140 base pairs upstream of the transcription initiation site. One of them, a negative regulatory element, is responsible for the lack of promoter activity in the absence of the hormone and, as demonstrated by DNA-binding assays, interacts with a liver-specific transcription factor. The second is required in association with the estrogen-responsive element to mediate hormonal induction and is recognized by the Xenopus liver homolog of nuclear factor I.

Study of the Regulatory Issues Affecting Truck Freight Movement in the Midwest, RB29-013, 2014

This project investigated regulatory issues that may affect or limit freight movement in Iowa and other Midwest states: Illinois, Kansas, Minnesota, Missouri, Nebraska, South Dakota, and Wisconsin. Current state regulations for the following are reviewed and summarized: - Vehicle dimensions - Vehicle weights - Speed limits - Weight compliance enforcement - Fees and taxes - Driver qualifications - Medical certification - Hours of service - Oversize-overweight permits

Elements ressaltats per infants i mestres en la creació d'un conte integrant les TIC i intercanvi d'aquest entre dues escoles a través d'una videoconferència

Les noves tecnologies de la Informació i la Comunicació esdevenen el tema principal d’aquesta investigació. L’objectiu primordial del treball és donar resposta al següent interrogant: què destaquen els infants i mestres d’una experiència d’aula en la qual s’integren les TIC? Aquesta recerca s’aproxima a la Grounded Theory, que es centra en crear la teoria a partir de l’anàlisi de les dades. En aquest treball és a partir de les dades analitzades que es defineixen les dimensions i indicadors per tal de donar resposta a la pregunta formulada inicialment. La intervenció que s’ha realitzat ha estat portada a terme amb les classes de P-4 i P-5 de dues escoles. Consisteix en explicar el mateix conte, sense final, a les dues aules i que aquestes s’inventin un final per tal d’explicar-se’l a través d’una videoconferència. Els resultats obtinguts amb els instruments de recollida de dades utilitzats en la investigació (dibuix infantil, grups de discussió i entrevistes) mostren que infants i mestres no destaquen el mateix d’una intervenció d’aula utilitzant les TIC. Els infants es centren més en el contingut, mentre que les mestres destaquen la metodologia i la tecnologia emprada.

Integrative analysis of the Regulatory Region of the FGFR3 Oncogene

The study of transcriptional regulation often needs the integration of diverse yet independent data. In the present work, sequence conservation, predic-tion of transcription factor binding sites (TFBS) and gene expression analysis have been applied to the detection of putative transcription factor (TF) modules in the regulatory region of the FGFR3 oncogene. Several TFs with conserved binding sites in the FGFR3 regulatory region have shown high positive or negative corre-lation with FGFR3 expression both in urothelial carcinoma and in benign nevi. By means of conserved TF cluster analysis, two different TF modules have been iden-tified in the promoter and first intron of FGFR3 gene. These modules contain acti-vating AP2, E2F, E47 and SP1 binding sites plus motifs for EGR with possible repressor function.

A regulatory role for the cohesin loader NIPBL in nonhomologous end joining during immunoglobulin class switch recombination.

DNA double strand breaks (DSBs) are mainly repaired via homologous recombination (HR) or nonhomologous end joining (NHEJ). These breaks pose severe threats to genome integrity but can also be necessary intermediates of normal cellular processes such as immunoglobulin class switch recombination (CSR). During CSR, DSBs are produced in the G1 phase of the cell cycle and are repaired by the classical NHEJ machinery. By studying B lymphocytes derived from patients with Cornelia de Lange Syndrome, we observed a strong correlation between heterozygous loss-of-function mutations in the gene encoding the cohesin loading protein NIPBL and a shift toward the use of an alternative, microhomology-based end joining during CSR. Furthermore, the early recruitment of 53BP1 to DSBs was reduced in the NIPBL-deficient patient cells. Association of NIPBL deficiency and impaired NHEJ was also observed in a plasmid-based end-joining assay and a yeast model system. Our results suggest that NIPBL plays an important and evolutionarily conserved role in NHEJ, in addition to its canonical function in sister chromatid cohesion and its recently suggested function in HR.

CD4+CD25+Foxp3+ regulatory T cells: from basic research to potential therapeutic use.

Regulatory T cells control immune responses to self- and foreign-antigens and play a major role in maintaining the balance between immunity and tolerance. This article reviews recent key developments in the field of CD4+CD25+Foxp3+ regulatory T (TREG) cells. It presents their characteristics and describes their range of activity and mechanisms of action. Some models of diseases triggered by the imbalance between TREG cells and effector pathogenic T cells are described and their potential therapeutic applications in humans are outlined.

Cognate microRNA-Gene Regulatory Networks Mediating Glioblastoma Oncogenic Properties

Malignant gliomas, including the most common and fatal form glioblastoma (GBM, WHO grade IV astrocytoma), remain a challenge to treat. In the United States and Europe, more than 30,000 patients per year are newly diagnosed with GBM. Despite ongoing trials, the best currently available multimodal treatment approaches include surgical resection followed by concomitant and adjuvant radiation (RT) and temozolomide (TMZ) therapy, resulting in a low median overall survival (OS) rate ranging from 12.2 - 15.9 months. The important role of genetic and epigenetic changes in DNA, RNA, and protein alteration as well as epigenetic changes secondary to the tumor microenvironment and outside selection pressure (therapeutic interventions), are increasingly being recognized. In GBM treatment, the focus is shifting toward a more patient-centered (personalized) therapy. In this regard, in particular, microRNAs are being increasingly studied. MicroRNAs are non¬protein coding small RNAs that serve as negative gene regulators by binding to a specific sequence in the promoter region of a target gene, thus regulating gene expression. A single microRNA potentially targets hundreds of genes; thus, microRNAs and their cognate target genes have important roles as tumor suppressors and oncogenes as well as regulators of various cancer- specific cellular features, such as proliferation, apoptosis, invasion, and metastasis. The identification of distinct microRNA-gene regulatory networks in GBM patients can be expected to provide novel therapeutic insights by identifying candidate patients for targeted therapies. To this end, in this work we identified and validated clinically relevant and meaningful novel gene- microRNA regulatory networks that correlated with MR tumor phenotypes, histopathology, and patient survival and response rates to therapy. - Le traitement des gliomes malins, y compris sous leur forme la plus commune et meurtrière, le glioblastome (GBM, ou astrocytome de grade IV selon l'OMS), demeure à ce jour un défi. Aux États-Unis et en Europe, un nouveau diagnostic de GBM est prononcé dans plus de 30Ό00 cas par an. En dépit de tests en cours, les meilleures approches thérapeutiques combinées actuellement disponibles comprennent la résection chirurgicale de la tumeur, suivie d'une radiothérapie adjuvante ainsi que d'un traitement au temozolomide (RT/TMZ), thérapies dont résulte une médiane de survie globale basse (overall survival, OS), comprise entre 12.2 et 15.9 mois. On reconnaît de plus en plus le rôle majeur de l'ADN, de l'ARN et de l'altération des protéines ainsi que des modifications épigénétiques, secondaires par rapport au microenvironnement de la tumeur et à la pression de sélection extérieure (les interventions thérapeutiques). Dans le traitement du GBM, le centre d'intérêt se déplace vers une thérapie centrée sur le cas individuel du patient. Dans ce but, en particulier les microARN sont de plus en plus analysés. Les microARN sont de petits ARN non-codants (les protéines) qui servent de régulateurs négatifs de gènes en s'attachant à une séquence spécifique dans la région promotrice d'un gène-cible, régulant ainsi l'expression du gène. Un seul microARN cible potentiellement des centaines de gènes; on a ainsi découvert que les microARN et leurs gènes-cibles apparentés ont une fonction importante en tant que suppresseurs de tumeurs et d'oncogènes, ainsi que comme régulateurs de diverses caractéristiques cellulaires spécifiques du cancer, comme la prolifération, l'apoptose, l'invasion et la métastase. On peut s'attendre à ce que l'identification de réseaux microARN régulateurs de gènes, distincts selon les patients de GBM, fournisse une approche thérapeutique inédite par la détermination des patients susceptibles de réagir favorablement à des thérapies ciblées.

Primers resultats dels estudis dels elements marmoris del jaciment de l'antiguitat tardana del Pla de Ses Figueres de l'illa de Cabrera

El Pla de ses Figueres és un jaciment que es troba a la riba del port de Cabrera, una petita illa de 1.836 ha. situada en el sud de les illes Balears. Diversos treballs de prospecció i d’excavació han donat a conèixer una important ocupació humana del lloc centrada en els segles V a VII dC. A les zones intervingudes s’han identificat una factoria de salaons, un possible taller de producció de porpra i una necròpoli. En el present treball s’exposaran set peces de marbre localitzades en dit jaciment dintre del projecte “Recuperació, consolidació i museïtzació del monestir bizantí de l’illa de Cabrera”, el qual ja fa dotze anys que finança ininterrompudament l’Ajuntament de Palma.