CAV2 vector gene transfer into central nervious System

Estudi realitzat a partir d’una estada al Institut de Génétique Moléculaire de Montpellier, França, entre 2010 i 2012. En aquest projecte s’ha avaluat les avantatges dels vectors adenovirals canins tipus 2 (CAV2) com a vectors de transferència gènica al sistema nerviós central (SNC) en un model primat no-humà i en un model caní del síndrome de Sly (mucopolisacaridosis tipus 7, MPS VII), malaltia monogènica que cursa amb neurodegeneració. En una primera part del projecte s’ha avaluat la biodistribució, l’eficàcia i la durada de l’expressió del transgen en un model primat no humà, (Microcebus murinus). Com ha vector s’ha utilitzat un CAV2 de primera generació que expressa la proteïna verda fluorescent (CAVGFP). Els resultats aportats en aquesta memòria demostren que en primats no humans, com en d’altres espècies testades anteriorment per l’equip de l’EJ Kremer, la injecció intracerebral de CAV2 resulta en una extensa transducció del SNC, siguent les neurones i els precursors neuronals les cèl•lules preferencialment transduïdes. Els vectors canins, servint-se de vesícules intracel•lulars són transportats, majoritàriament, des de les sinapsis cap al soma neuronal, aquest transport intracel•lular permet una extensa transducció del SNC a partir d’una única injecció intracerebral dels vectors virals. En una segona part d’aquest projecte s’ha avaluat l’ús terapèutic dels CAV2. S’ha injectat un vector helper-dependent que expressa el gen la b-glucuronidasa i el gen de la proteïna verda fluorescent (HD-RIGIE), en el SNC del model caní del síndrome de Sly (MPS VII). La biodistribució i la eficàcia terapèutica han estat avaluades. Els nivells d’activitat enzimàtica en animals malalts injectats amb el vector terapèutic va arribar a valors similars als dels animals no afectes. A més a més s’ha observat una reducció en la quantitat dels GAGs acumulats en les cèl•lules dels animals malalts tractats amb el vector terapèutic, demostrant la potencialitat terapèutica dels CAV2 per a malalties que afecten al SNC. Els resultats aportats en aquest treball ens permeten dir que els CAV2 són unes bones eines terapèutiques per al tractament de malalties que afecten al SNC.

Signatures of selection in the human olfactory receptor OR5I1 gene

The human olfactory receptor repertoire is reduced in comparison to other mammalsand to other non-human primates. Nonetheless, this olfactory decline opens an opportunity forevolutionary innovation and improvement. In the present study, we focus on an olfactoryreceptor gene, OR5I1, which had previously been shown to present an excess of amino acidreplacement substitutions between humans and chimpanzees. We analyze the geneticvariation in OR5I1 in a large worldwide human panel and find an excess of derived allelessegregating at relatively high frequencies in all populations. Additional evidence for selectionincludes departures from neutrality in allele frequency spectra tests but no unusually extendedhaplotype structure. Moreover, molecular structural inference suggests that one of thenonsynonymous polymorphisms defining the presumably adaptive protein form of OR5I1may alter the functional binding properties of the olfactory receptor. These results arecompatible with positive selection having modeled the pattern of variation found in the OR5I1gene and with a relatively ancient, mild selective sweep predating the “Out of Africa”expansion of modern humans.

Comparative analysis of cancer genes in the human and chimpanzee genomes

Background: Cancer is a major medical problem in modern societies. However, the incidence of this disease in non-human primates is very low. To study whether genetic differences between human and chimpanzee could contribute to their distinct cancer susceptibility, we have examined in the chimpanzee genome the orthologous genes of a set of 333 human cancer genes. Results: This analysis has revealed that all examined human cancer genes are present in chimpanzee, contain intact open reading frames and show a high degree of conservation between both species. However, detailed analysis of this set of genes has shown some differences in genes of special relevance for human cancer. Thus, the chimpanzee gene encoding p53 contains a Pro residue at codon 72, while this codon is polymorphic in humans and can code for Arg or Pro, generating isoforms with different ability to induce apoptosis or interact with p73. Moreover, sequencing of the BRCA1 gene has shown an 8 Kb deletion in the chimpanzee sequence that prematurely truncates the co-regulated NBR2 gene. Conclusion: These data suggest that small differences in cancer genes, as those found in tumor suppressor genes, might influence the differences in cancer susceptibility between human and chimpanzee. Nevertheless, further analysis will be required to determine the exact contribution of the genetic changes identified in this study to the different cancer incidence in non-human primates.

Modeling the Emergence of Social Structure from a Phylogenetic Point of View

Based on provious (Hemelrijk 1998; Puga-González, Hildenbrant & Hemelrijk 2009), we have developed an agent-based model and software, called A-KinGDom, which allows us to simulate the emergence of the social structure in a group of non-human primates. The model includes dominance and affiliative interactions and incorporate s two main innovations (preliminary dominance interactions and a kinship factor), which allow us to define four different attack and affiliative strategies. In accordance with these strategies, we compared the data obtained under four simulation conditions with the results obtained in a provious study (Dolado & Beltran 2012) involving empirical observations of a captive group of mangabeys (Cercocebus torquatus)

African signatures of recent positive selection in human FOXI1

Background: The human FOXI1 gene codes for a transcription factor involved in the physiology of the inner ear, testis, and kidney. Using three interspecies comparisons, it has been suggested that this may be a gene underhuman-specific selection. We sought to confirm this finding by using an extended set of orthologous sequences.Additionally, we explored for signals of natural selection within humans by sequencing the gene in 20 Europeans,20 East Asians and 20 Yorubas and by analysing SNP variation in a 2 Mb region centered on FOXI1 in 39worldwide human populations from the HGDP-CEPH diversity panel.Results: The genome sequences recently available from other primate and non-primate species showed that FOXI1divergence patterns are compatible with neutral evolution. Sequence-based neutrality tests were not significant inEuropeans, East Asians or Yorubas. However, the Long Range Haplotype (LRH) test, as well as the iHS and XP-Rsbstatistics revealed significantly extended tracks of homozygosity around FOXI1 in Africa, suggesting a recentepisode of positive selection acting on this gene. A functionally relevant SNP, as well as several SNPs either on theputatively selected core haplotypes or with significant iHS or XP-Rsb values, displayed allele frequencies stronglycorrelated with the absolute geographical latitude of the populations sampled.Conclusions: We present evidence for recent positive selection in the FOXI1 gene region in Africa. Climate mightbe related to this recent adaptive event in humans. Of the multiple functions of FOXI1, its role in kidney-mediatedwater-electrolyte homeostasis is the most obvious candidate for explaining a climate-related adaptation.

Access as a motivational device: implications for human resource management

This paper analyzes the employment relationship on the basis of the notion of access. We argue that the degree of access provided by a job is an incentive to activate the employee’s self-actualization needs. We investigate the effect of access on the workers’ performance through an agency model and provide a number of propositions with practical implications for personnel policies. Our results are consistent with the intuition emerged from the real business practice as well as with many of the arguments on the substitutive role between monetary and non-monetary incentives frequently reported in the literature.

Are Dictators Immune to Human Rights Shaming?

This paper examines whether human rights naming and shaming destabilizes the rule of authoritarian leaders. We argue that human rights shaming can destabilize autocratic leaders by signaling international disapproval to elites in the targeted country, increasing their capacity to replace the incumbent. In personalist regimes, shaming increases the risk of irregular exit because regime elite do not have a means to peacefully replace the incumbent. Shaming campaigns also decrease foreign aid and international trade in personalist regimes, denying the leader access to resources to pay his coalition – further destabilizing his rule. In non-personalist regimes where parties or the military allow elites to peacefully replace incumbents, human rights shaming increases the risk of regular turnover of power, but has little effect on the risk of irregular exit or international flows of aid and trade. These findings have implications for understanding when and where shaming campaigns are likely to reduce or deter repression.

Human biology: cibernética y biología humana en el nuevo discurso expositivo de la década de 1970

En este trabajo se explica cuáles fueron las estrategias utilizadas y los resultados obtenidos en la primera exposición del nuevo esquema museográfico del Museo de Historia Natural de Londres, concebido por Roger Miles, Jefe del Departamento de Servicios Públicos de esa prestigiada institución. Esta iniciativa pretendía atraer a un mayor número de visitantes a partir de exposiciones basadas en modelos y módulos interactivos que relegaban a los objetos de las colecciones a un segundo plano. La exposición se tituló Human Biology y fue inaugurada el 24 de mayo de 1977. El tema de la exposición fue la biología humana, pero como se argumenta en este trabajo, Human Biology sirvió también como medio para legitimar el discurso modernizador de la biología humana, en tanto disciplina más rigurosa por las herramientas y técnicas más precisas que las utilizadas por la antropología física tradicional. Se buscaba también generar una audiencia para reforzar el campo interdisciplinario de la ciencia cognitiva y en particular la inteligencia artificial. El equipo de asesores científicos de la exposición contó entre sus miembros con personalidades que jugaron un papel protagónico en el desarrollo de esas disciplinas, y necesitaban demostrar su validez y utilidad ante los no especialistas y el público en general.

Association between HIV status and HIV knowledge in the population attending Non-Governmental Organizations to perform the rapid HIV test in Catalonia

Human Immunodeficiency Virus continues to be a pandemic. Spain is one of the European countries with the highest incidence of HIV. Within Catalonia, Spain many projects have been implemented with the intention of improving HIV knowledge and lowering the incidence. HIV knowledge is also known to have a positive effect on lowering stigma and discrimination of the people living with HIV. However, few studies study the distribution of HIV knowledge and its association to HIV status, age, sex, geographical zone of origin and level of education within the same study. Objectives: To identify if HIV knowledge is associated with HIV status, age, sex, geographical zone of origin and level of education. Method: Quantitative, cross-sectional, centre-based study comprising of people receiving an HIV test in Catalonia, Spain. Data will be collected from the 11 HIV Non-Governmental Organisations in Catalonia, Spain. The Brief HIV Knowledge Scale will be used to assess HIV knowledge; information from the HIV test session will be used to assess HIV status, age, sex, geographic zone of origin and level of education. The association between HIV knowledge and the afore mentioned variables will then be calculated.

Noninvasive functional and structural exploration of human subcortical structures with high resolution

Projecte de recerca elaborat a partir d’una estada al Max Planck Institute for Human Cognitive and Brain Sciences, Alemanya, entre 2010 i 2012. El principal objectiu d’aquest projecte era estudiar en detall les estructures subcorticals, en concret, el rol dels ganglis basals en control cognitiu durant processament lingüístic i no-lingüístic. Per tal d’assolir una diferenciació minuciosa en els diferents nuclis dels ganglis basals s’utilitzà ressonància magnètica d’ultra-alt camp i alta resolució (7T-MRI). El còrtex prefrontal lateral i els ganglis basals treballant conjuntament per a mitjançar memòria de treball i la regulació “top-down” de la cognició. Aquest circuit regula l’equilibri entre respostes automàtiques i d’alt-ordre cognitiu. Es crearen tres condicions experimentals principals: frases/seqüències noambigües, no-gramatical i ambigües. Les frases/seqüències no-ambigües haurien de provocar una resposta automàtica, mentre les frases/seqüències ambigües i no-gramaticals produïren un conflicte amb la resposta automàtica, i per tant, requeririen una resposta de d’alt-ordre cognitiu. Dins del domini de la resposta de control, la ambigüitat i no-gramaticalitat representen dues dimensions diferents de la resolució de conflicte, mentre per una frase/seqüència temporalment ambigua existeix una interpretació correcte, aquest no és el cas per a les frases/seqüències no-gramaticals. A més, el disseny experimental incloïa una manipulació lingüística i nolingüística, la qual posà a prova la hipòtesi que els efectes són de domini-general; així com una manipulació semàntica i sintàctica que avaluà les diferències entre el processament d’ambigüitat/error “intrínseca” vs. “estructural”. Els resultats del primer experiment (sintax-lingüístic) mostraren un gradient rostroventralcaudodorsal de control cognitiu dins del nucli caudat, això és, les regions més rostrals sostenint els nivells més alts de processament cognitiu

Multiple non-collinear TF-map alignments of promoter regions

Background: The analysis of the promoter sequence of genes with similar expression patterns isa basic tool to annotate common regulatory elements. Multiple sequence alignments are on thebasis of most comparative approaches. The characterization of regulatory regions from coexpressedgenes at the sequence level, however, does not yield satisfactory results in manyoccasions as promoter regions of genes sharing similar expression programs often do not shownucleotide sequence conservation.Results: In a recent approach to circumvent this limitation, we proposed to align the maps ofpredicted transcription factors (referred as TF-maps) instead of the nucleotide sequence of tworelated promoters, taking into account the label of the corresponding factor and the position in theprimary sequence. We have now extended the basic algorithm to permit multiple promotercomparisons using the progressive alignment paradigm. In addition, non-collinear conservationblocks might now be identified in the resulting alignments. We have optimized the parameters ofthe algorithm in a small, but well-characterized collection of human-mouse-chicken-zebrafishorthologous gene promoters.Conclusion: Results in this dataset indicate that TF-map alignments are able to detect high-levelregulatory conservation at the promoter and the 3'UTR gene regions, which cannot be detectedby the typical sequence alignments. Three particular examples are introduced here to illustrate thepower of the multiple TF-map alignments to characterize conserved regulatory elements inabsence of sequence similarity. We consider this kind of approach can be extremely useful in thefuture to annotate potential transcription factor binding sites on sets of co-regulated genes fromhigh-throughput expression experiments.

Comparative gene finding in chicken indicates that we are closing in on the set of multi-exonic widely-expressed human genes

The recent availability of the chicken genome sequence poses the question of whether there are human protein-coding genes conserved in chicken that are currently not included in the human gene catalog. Here, we show, using comparative gene finding followed by experimental verification of exon pairs by RT–PCR, that the addition to the multi-exonic subset of this catalog could be as little as 0.2%, suggesting that we may be closing in on the human gene set. Our protocol, however, has two shortcomings: (i) the bioinformatic screening of the predicted genes, applied to filter out false positives, cannot handle intronless genes; and (ii) the experimental verification could fail to identify expression at a specific developmental time. This highlights the importance of developing methods that could provide a reliable estimate of the number of these two types of genes.

Decay of linkage disequilibrium within genes across HGDP-CEPH human samples: most population isolates do not show increased LD

Background: It is well known that the pattern of linkage disequilibrium varies between human populations, with remarkable geographical stratification. Indirect association studies routinely exploit linkage disequilibrium around genes, particularly in isolated populations where it is assumed to be higher. Here, we explore both the amount and the decay of linkage disequilibrium with physical distance along 211 gene regions, most of them related to complex diseases, across 39 HGDP-CEPH population samples, focusing particularly on the populations defined as isolates. Within each gene region and population we use r2 between all possible single nucleotide polymorphism (SNP) pairs as a measure of linkage disequilibrium and focus on the proportion of SNP pairs with r2 greater than 0.8.Results: Although the average r2 was found to be significantly different both between and within continental regions, a much higher proportion of r2 variance could be attributed to differences between continental regions (2.8% vs. 0.5%, respectively). Similarly, while the proportion of SNP pairs with r2 > 0.8 was significantly different across continents for all distance classes, it was generally much more homogenous within continents, except in the case of Africa and the Americas. The only isolated populations with consistently higher LD in all distance classes with respect to their continent are the Kalash (Central South Asia) and the Surui (America). Moreover, isolated populations showed only slightly higher proportions of SNP pairs with r2 > 0.8 per gene region than non-isolated populations in the same continent. Thus, the number of SNPs in isolated populations that need to be genotyped may be only slightly less than in non-isolates. Conclusion: The "isolated population" label by itself does not guarantee a greater genotyping efficiency in association studies, and properties other than increased linkage disequilibrium may make these populations interesting in genetic epidemiology.

Automatic Detection of Non-deverbal Event Nouns for Quick Lexicon Production

In this work we present the results of experimental work on the development of lexical class-based lexica by automatic means. Our purpose is to assess the use of linguistic lexical-class based information as a feature selection methodology for the use of classifiers in quick lexical development. The results show that the approach can help reduce the human effort required in the development of language resources significantly.

Human capital and externalities in cities

We combine growth theory with US Census data on individual schooling and wages to estimate the aggregate return to human capital and human capital externalities in cities. Our estimates imply that a one-year increase in average schooling in cities increases their aggregate labor productivity by 8 to 11 percent. We find no evidence for aggregate human capital externalities in cities however althoughwe use three different approaches. Our main theoretical contribution is to show how human capital externalities can be identified (non-parametically) even if workers with different levels of human capital are imperfect substitutes in production.