Reversal of a full-length mutant huntingtin neuronal cell phenotypeby chemical inhibitors of polyglutamine-mediated aggregation

Background: Huntington's disease (HD) is an inherited neurodegenerative disorder triggered by an expanded polyglutamine tract in huntingtin that is thought to confer a new conformational property on this large protein. The propensity of small amino-terminal fragments with mutant, but not wild-type, glutamine tracts to self-aggregate is consistent with an altered conformation but such fragments occur relatively late in the disease process in human patients and mouse models expressing full-length mutant protein. This suggests that the altered conformational property may act within the full-length mutant huntingtin to initially trigger pathogenesis. Indeed, genotypephenotype studies in HD have defined genetic criteria for the disease initiating mechanism, and these are all fulfilled by phenotypes associated with expression of full-length mutant huntingtin, but not amino-terminal fragment, in mouse models. As the in vitro aggregation of amino-terminal mutant huntingtin fragment offers a ready assay to identify small compounds that interfere with the conformation of the polyglutamine tract, we have identified a number of aggregation inhibitors, and tested whether these are also capable of reversing a phenotype caused by endogenous expressionof mutant huntingtin in a striatal cell line from the HdhQ111/Q111 knock-in mouse. Results: We screened the NINDS Custom Collection of 1,040 FDA approved drugs and bioactive compounds for their ability to prevent in vitro aggregation of Q58-htn 1¿171 amino terminal fragment. Ten compounds were identified that inhibited aggregation with IC50 < 15 ¿M, including gossypol, gambogic acid, juglone, celastrol, sanguinarine and anthralin. Of these, both juglone and celastrol were effective in reversing the abnormal cellular localization of full-length mutant huntingtin observed in mutant HdhQ111/Q111 striatal cells. Conclusions: At least some compounds identified as aggregation inhibitors also prevent a neuronal cellular phenotype caused by full-length mutant huntingtin, suggesting that in vitro fragment aggregation can act as a proxy for monitoring the disease-producing conformational property in HD. Thus, identification and testing of compounds that alter in vitro aggregation is a viable approach for defining potential therapeutic compounds that may act on the deleterious conformational property of full-length mutant huntingtin.

The spatial inequality of wage income in Barcelona Metropolitan Area

ABSTRACT The measure and estimation of income levels in Barcelona Metropolitan Area (BMA) goes back a long way. Using different approaches and focusing on different municipalities, there is a lot of work in the field. The majority of the literature has focused on the estimation of income levels using variables related to consumption. The empirical evidence on wage differentials has shown an important growth during 80’s and 90’s especially in United Kingdom and USA. Less is known on spatial distribution of inequality. This paper presents a new data set for analyzing spatial distribution of wage income. This data is obtained by matching Wage Structure Survey (WSS) with data from Census disaggregated by census tracts. In this way we have a unique data set with wage incomes for every census track for 36 municipalities belonging to BMA. We develop a descriptive analysis of spatial distribution, testing for spatial autocorrelation and use the family of Generalised Entropy Indices to measure inequality. Properties of the index allow us to decompose inequality into inter and intra-municipality measures. Since we have two cross-sectional data for WSS (1995-2002) we can also analyze the evolution of the inequality in this period of economic growth. Key words: spatial distribution of wages, spatial autocorrelation, inequality indices.

Agapornis: relació entre fertilitat i neixements en els Agapornis lilianae i negrigenis

Treball de recerca realitzat per un alumne d'ensenyament secundari i guardonat amb un Premi CIRIT per fomentar l'esperit científic del Jovent l'any 2009. A partir d’ous exemplars de dues espècies d’agapornis -nigrigenis i lilianae-, es pretén realitzar un estudi comparatiu d’ambdues, tant pel que fa a l’etologia com a la reproducció, als hàbits alimentaris, etc. La idea inicial parteix de la possibilitat d’intercanviar alguns ous de cada espècie per mirar d’esbrinar si els ocells reproductors s’adonen de tal canvi. La hipòtesi inicial del treball considera que els ocells els criaran de la mateixa forma que si es tractés dels seus propis pollets. Les conclusions, però, han anat més enllà de la formulació de la hipòtesi inicial, de tal manera que, al final, i en forma de diagrama, s’ha pogut parlar de l’eclosió o manca d’eclosió dels ous d’aquesta espècie, tot relacionant temes diversos que van des de la fertilitat a les diferents mides dels ous. A més, l’autor també ha pogut concloure que els Agapornis lilianae són capaços de criar ocells d’una altra espècie (en aquest cas d Agapornis roseicollis) amb tota normalitat.

Programari de codi lliure per gestionar dipòsits digitals: el procés de tria dut a terme al CBUC

Es descriu el procés de selecció dut a terme en el Consorci de Biblioteques Universitàries de Catalunya (CBUC) durant el 2004 per tal de seleccionar el programa per gestionar els dipòsits digitals del CBUC. Dues de les condicions per a la selecció eren que es tractés de programari lliure i, a més, que es pogués implementar de manera immediata. Els programes analitzats van ser ARNO, CDSware, DSpace, EPrints, Fedora, i-Tor i MyCoRe. En el text es descriuen les principals característiques de cada un d'aquests programes i es justifica l'elecció de DSpace.

Nogo, myelin and axonal regeneration

Adult mammalian central nervous system (CNS) axons have very limited capacity of regrowth after injury. In recent years, advances in the field of axonal regeneration have proved that neurons do not regenerate, mainly because of the presence of inhibitory molecules. Myelin-associated proteins limit axonal outgrowth and their blockage improves the regeneration of damaged fiber tracts. Three of these proteins, Nogo, MAG and OMgp, share a common neuronal receptor (NgR), and together represent one of the main hindrances to neuronal regeneration. The recent molecular cloning of Nogo and its receptors opened a new door to the study of axon regeneration. However, many of the elements involved in the myelin inhibitory pathway are still unknown, and the preliminary experiments with knockout mice are rather contradictory. Because of this complexity, Nogo and NgR need to be characterized before precise strategies to promote axon regeneration in the CNS can be designed.

Vascular endothelial growth factor and angiopoietin-2 play a major role in the pathogenesis of vascular leakage in cirrhotic rats.

Background and aims: The extent and molecular mechanisms governing plasma extravasation and formation of ascites in cirrhosis are unknown. Vascular endothelial growth factor-A (VEGF-A) and angiopoietin-2 (Ang-2) are endogenous substances with powerful vascular permeability effects. We assessed regional blood flow, vascular leakage, mRNA and tissular expression of VEGF-A and Ang-2 and vascular permeability following VEGF receptor 2 blockade in control and cirrhotic rats to define the vascular territories showing altered vascular permeability in cirrhosis and to determine whether VEGF-A and Ang-2 are involved in this phenomenon. Methods: Arterial blood flow was analysed with the coloured microsphere method. Vascular leakage was measured and visualised with the dye Evan¿s Blue and colloidal carbon techniques, respectively. VEGF-A and Ang-2 expression were determined by real-time polymerase chain reaction (RT-PCR), immunohistochemistry and western blot. The effect on vascular permeability induced by VEGFR2 blockade was assessed by administration of the receptor inhibitor SU11248. Results: Arterial blood flow was increased in the mesentery, pancreas and small intestine but not in the kidney and spleen of cirrhotic rats as compared to controls. Increased vascular leakage was observed in the mesentery and liver, where colloidal carbon spread from microvessels to the adjacent fibrotic tracts. Increased hepatic and mesenteric expression of VEGF-A and Ang-2 was found in cirrhotic rats as compared to controls. Blockade of VEGFR2 markedly reduced hepatic and mesenteric vascular leakage in cirrhotic rats. Conclusions: Enhanced endothelial permeability is restricted to the hepatic and mesenteric vascular beds in cirrhotic rats with ascites and VEGF-A and Ang-2 are key factors in the signalling pathways regulating this dysfunction.

Emerging functions of myelin associated proteins during development neuronal plasticity and and neurpdegeneration.

Adult mammalian central nervous system (CNS) axons have a limited regrowth capacity following injury. Myelin-associated inhibitors (MAIs) limit axonal outgrowth and their blockage improves the regeneration of damaged fiber tracts. Three of these proteins, Nogo-A, MAG and OMgp, share two common neuronal receptors: NgR1, together with its co-receptors (p75(NTR), TROY and Lingo-1), and the recently described paired immunoglobulin-like receptor B (PirB). These proteins impair neuronal regeneration by limiting axonal sprouting. Some of the elements involved in the myelin inhibitory pathways may still be unknown, but the discovery that blocking both PirB and NgR1 activities leads to near-complete release from myelin inhibition, sheds light on one of the most competitive and intense fields of neuroregeneration study during in recent decades. In parallel with the identification and characterization of the roles and functions of these inhibitory molecules in axonal regeneration, data gathered in the field strongly suggest that most of these proteins have roles other than axonal growth inhibition. The discovery of a new group of interacting partners for myelin-associated receptors and ligands, as well as functional studies within or outside the CNS environment, highlights the potential new physiological roles for these proteins in processes such as development, neuronal homeostasis, plasticity and neurodegeneration.

Comparative analysis of amino acid repeats in rodents and humans

Amino acid tandem repeats, also called homopolymeric tracts, are extremely abundant in eukaryotic proteins. To gain insight into the genome-wide evolution of these regions in mammals, we analyzed the repeat content in a large data set of rat-mouse-human orthologs. Our results show that human proteins contain more amino acid repeats than rodent proteins and that trinucleotide repeats are also more abundant in human coding sequences. Using the human species as an outgroup, we were able to address differences in repeat loss and repeat gain in the rat and mouse lineages. In this data set, mouse proteins contain substantially more repeats than rat proteins, which can be at least partly attributed to a higher repeat loss in the rat lineage. The data are consistent with a role for trinucleotide slippage in the generation of novel amino acid repeats. We confirm the previously observed functional bias of proteins with repeats, with overrepresentation of transcription factors and DNA-binding proteins. We show that genes encoding amino acid repeats tend to have an unusually high GC content, and that differences in coding GC content among orthologs are directly related to the presence/absence of repeats. We propose that the different GC content isochore structure in rodents and humans may result in an increased amino acid repeat prevalence in the human lineage.

Dissecting the role of low-complexity regions in the evolution of vertebrate proteins

Low-complexity regions (LCRs) in proteins are tracts that are highly enriched in one or a few aminoacids. Given their high abundance, and their capacity to expand in relatively short periods of time through replication slippage, they can greatly contribute to increase protein sequence space and generate novel protein functions. However, little is known about the global impact of LCRs on protein evolution. We have traced back the evolutionary history of 2,802 LCRs from a large set of homologous protein families from H.sapiens, M.musculus, G.gallus, D.rerio and C.intestinalis. Transcriptional factors and other regulatory functions are overrepresented in proteins containing LCRs. We have found that the gain of novel LCRs is frequently associated with repeat expansion whereas the loss of LCRs is more often due to accumulation of amino acid substitutions as opposed to deletions. This dichotomy results in net protein sequence gain over time. We have detected a significant increase in the rate of accumulation of novel LCRs in the ancestral Amniota and mammalian branches, and a reduction in the chicken branch. Alanine and/or glycine-rich LCRs are overrepresented in recently emerged LCR sets from all branches, suggesting that their expansion is better tolerated than for other LCR types. LCRs enriched in positively charged amino acids show the contrary pattern, indicating an important effect of purifying selection in their maintenance. We have performed the first large-scale study on the evolutionary dynamics of LCRs in protein families. The study has shown that the composition of an LCR is an important determinant of its evolutionary pattern.

A pathogenic mechanism in Huntington"s disease involves small CAG-repeated RNAs with neurotoxic activity

Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches

Distribución espacial y desigualdad de la renta salarial en el área metropolitana de Barcelona

Las diferencias geográficas en los niveles de ingresos son importantes para elaborar e implementar políticas en las ciudades. Con el objetivo de estimar el nivel de ingresos y analizar su distribución espacial se presenta un método alternativo e innovador que enlaza estimaciones de salarios provenientes de la Encuesta de Estructura Salarial (EES) con datos del padrón de habitantes (1996) y del Censo (2001) desagregados por secciones censales. Los resultados tienen un nivel de detalle espacial significativamente mejor que los disponibles. Se obtiene el valor de la Renta Salarial Media para cada una de las 2500 secciones censales de los 36 municipios pertenecientes a la AMB y para dos periodos. La Renta Salarial presenta una elevada autocorrelación espacial positiva; zonas con niveles similares se concentran espacialmente. La desigualdad en el AMB ha aumentado en el periodo analizado. Este aumento se debe principalmente al componente intra-municipal, es decir, las diferencias en el interior de cada municipio.

Architectural characterization of a delta-front reservoir analogue combining ground penetrating radar and electrical resistivity tomography: Roda Sandstone (Lower Eocene, Graus-Tremp basin, Spain)

Three-dimensional reconstruction of reservoir analogues can be improved combining data from different geophysical methods. Ground Penetrating Radar (GPR) and Electrical Resistivity Tomography (ERT) data are valuable tools, since they provide subsurface information from internal architecture and facies distribution of sedimentary rock bodies, enabling the upgrading of depositional models and heterogeneity reconstruction. The Lower Eocene Roda Sandstone is a well-known deltaic complex widely studied as a reservoir analogue that displays a series of sandstone wedges with a general NE to SW progradational trend. To provide a better understanding of internal heterogeneity of a 10m-thick progradational delta-front sandstone unit, 3D GPR data were acquired. In addition, common midpoints (CMP) to measure the sandstone subsoil velocity, test profiles with different frequency antennas (25, 50 and 100MHz) and topographic data for subsequent correction in the geophysical data were also obtained. Three ERT profiles were also acquired to further constrain GPR analysis. These geophysical results illustrate the geometry of reservoir analogue heterogeneities both depositional and diagenetic in nature, improving and complementing previous outcrop-derived data. GPR interpretation using radar stratigraphy principles and attributes analysis provided: 1)tridimensional geometry of major stratigraphic surfaces that define four units in the GPR Prism, 2) image the internal architecture of the units and their statistical study of azimuth and dips, useful for a quick determination of paleocurrent directions. These results were used to define the depositional architecture of the progradational sandbody that shows an arrangement in very-high-frequency sequences characterized by clockwise paleocurrent variations and decrease of the sedimentary flow, similar to those observed at a greater scale in the same system. This high-frequency sequential arrangement has been attributed to the autocyclic dynamics of a supply-dominated delta- front where fluvial and tidal currents are in competition. The resistivity models enhanced the viewing of reservoir quality associated with cement distribution caused by depositional and early diagenetic processes related to the development of transgressive and regressive systems tracts in igh-frequency sequences.

Individual Differences in True and False Memory Retrieval Are Related to White Matter Brain Microstructure

We sometimes vividly remember things that did not happen, a phenomenon with general relevance, not only in the courtroom. It is unclear to what extent individual differences in false memories are driven by anatomical differences in memory-relevant brain regions. Here we show in humans that microstructural properties of different white matter tracts as quantified using diffusion tensor imaging are strongly correlated with true and false memory retrieval. To investigate these hypotheses, we tested a large group of participants in a version of the Deese-Roediger-McDermott paradigm (recall and recognition) and subsequently obtained diffusion tensor images. A voxel-based whole-brain level linear regression analysis was performedto relatefractional anisotropyto indices oftrue andfalse memory recall and recognition. True memory was correlated to diffusion anisotropy in the inferior longitudinal fascicle, the major connective pathway of the medial temporal lobe, whereas a greater proneness to retrieve false items was related to the superior longitudinal fascicle connecting frontoparietal structures. Our results show that individual differences in white matter microstructure underlie true and false memory performance.

"Aquí es redacten i s'esculpeixen inscripcions" : aproximació al corpus epigràfic de la ciutat de Girona

La idea primera d'aquest projecte d’investigació, sobre les escripturesexposades del Claustre de la Catedral de Santa Maria de Girona, va sorgir d'unsenzill treball de classe de doctorat. Es tractava de fer un estudi que tractés sobre elmón de la mort: el ritual, la cerimònia, l'enterrament, el dol, etc. Tot el que envolta elsprimers dies de la mort d'un individu i com el seu record pretén ser etern. Si bél'època històrica que tractaven era l'antiguitat, el treball que jo pretenia dur a termeera d'una època diferent la qual cosa ja presentava una sèrie de reptes com el fet detractar-se d'un estudi inèdit degut al plantejament que pretenia portar a la pràctica.Es tractava, doncs, de l'anàlisi de l'actitud socio-cultural de la dona i l'home davant lamort a partir dels testimonis escrits en les seves tombes. Amb la qual cosa es podiaveure l'evolució del pensament humà en vers un dels temes que més va preocupar ipreocupa i interessa al llarg de tots els temps històrics