Conserved chromosomal clustering of genes governed by chromatin regulators in Drosophila

BACKGROUND: The trithorax group (trxG) and Polycomb group (PcG) proteins are responsible for the maintenance of stable transcriptional patterns of many developmental regulators. They bind to specific regions of DNA and direct the post-translational modifications of histones, playing a role in the dynamics of chromatin structure. RESULTS: We have performed genome-wide expression studies of trx and ash2 mutants in Drosophila melanogaster. Using computational analysis of our microarray data, we have identified 25 clusters of genes potentially regulated by TRX. Most of these clusters consist of genes that encode structural proteins involved in cuticle formation. This organization appears to be a distinctive feature of the regulatory networks of TRX and other chromatin regulators, since we have observed the same arrangement in clusters after experiments performed with ASH2, as well as in experiments performed by others with NURF, dMyc, and ASH1. We have also found many of these clusters to be significantly conserved in D. simulans, D. yakuba, D. pseudoobscura and partially in Anopheles gambiae. CONCLUSION: The analysis of genes governed by chromatin regulators has led to the identification of clusters of functionally related genes conserved in other insect species, suggesting this chromosomal organization is biologically important. Moreover, our results indicate that TRX and other chromatin regulators may act globally on chromatin domains that contain transcriptionally co-regulated genes.

A T42A Ran Mutation: Differential Interactions with Effectors and Regulators, and Defect in Nuclear Protein Import

Ran, the small, predominantly nuclear GTPase, has been implicated in the regulation of a variety of cellular processes including cell cycle progression, nuclear-cytoplasmic trafficking of RNA and protein, nuclear structure, and DNA synthesis. It is not known whether Ran functions directly in each process or whether many of its roles may be secondary to a direct role in only one, for example, nuclear protein import. To identify biochemical links between Ran and its functional target(s), we have generated and examined the properties of a putative Ran effector mutation, T42A-Ran. T42A-Ran binds guanine nucleotides as well as wild-type Ran and responds as well as wild-type Ran to GTP or GDP exchange stimulated by the Ran-specific guanine nucleotide exchange factor, RCC1. T42A-Ran·GDP also retains the ability to bind p10/NTF2, a component of the nuclear import pathway. In contrast to wild-type Ran, T42A-Ran·GTP binds very weakly or not detectably to three proposed Ran effectors, Ran-binding protein 1 (RanBP1), Ran-binding protein 2 (RanBP2, a nucleoporin), and karyopherin ß (a component of the nuclear protein import pathway), and is not stimulated to hydrolyze bound GTP by Ran GTPase-activating protein, RanGAP1. Also in contrast to wild-type Ran, T42A-Ran does not stimulate nuclear protein import in a digitonin permeabilized cell assay and also inhibits wild-type Ran function in this system. However, the T42A mutation does not block the docking of karyophilic substrates at the nuclear pore. These properties of T42A-Ran are consistent with its classification as an effector mutant and define the exposed region of Ran containing the mutation as a probable effector loop.

Conserved chromosomal clustering of genes governed by chromatin regulators in Drosophila

Background: The trithorax group (trxG) and Polycomb group (PcG) proteins are responsible for the maintenance of stable transcriptional patterns of many developmental regulators. They bind to specific regions of DNA and direct the post-translational modifications of histones, playing a role in the dynamics of chromatin structure.Results: We have performed genome-wide expression studies of trx and ash2 mutants in Drosophila melanogaster. Using computational analysis of our microarray data, we have identified 25 clusters of genes potentially regulated by TRX. Most of these clusters consist of genes that encode structural proteins involved in cuticle formation. This organization appears to be a distinctive feature of the regulatory networks of TRX and other chromatin regulators, since we have observed the same arrangement in clusters after experiments performed with ASH2, as well as in experiments performed by others with NURF, dMyc, and ASH1. We have also found many of these clusters to be significantly conserved in D. simulans, D. yakuba, D. pseudoobscura and partially in Anopheles gambiae.Conclusion: The analysis of genes governed by chromatin regulators has led to the identification of clusters of functionally related genes conserved in other insect species, suggesting this chromosomal organization is biologically important. Moreover, our results indicate that TRX and other chromatin regulators may act globally on chromatin domains that contain transcriptionally co-regulated genes.

Private Governance of Financial Markets: the US Regulatory Regime on Hedge Funds

The article investigates the private governance of financial markets by looking at the evolution of the regulatory debate on hedge funds in the US market. It starts from the premise that the privatization of regulation is always the result of a political decision and analyzes how this decision came about and was implemented in the case of hedge funds. The starting point is the failure of two initiatives on hedge funds that US regulators launched between 1999 an 2004, which the analysis explains by elaborating the concept of self-capture. Facing a trade off between the need to tackle publicly demonized issues and the difficulty of monitoring increasingly sophisticated and powerful private markets, regulators purposefully designed initiatives that were not meant to succeed, that is, they “self-captured” their own activity. By formulating initiatives that were inherently flawed, regulators saved their public role and at the same time paved the way for the privatization of hedge fund regulation. This explanation identifies a link between the failure of public initiatives and the success of private ones. It illustrates a specific case of formation of private authority in financial markets that points to a more general practice emerging in the regulation of finance.

Introducció experimental a la biotecnologia amb clavellina: cultiu in vitro

Treball de recerca realitzat per una alumna d'ensenyament secundari i guardonat amb un Premi CIRIT per fomentar l'esperit científic del Jovent l'any 2009. Es tracta d’una recerca experimental en la que s’han assajat vuit tècniques de cultiu in vitro amb clavellina. El material vegetal s’ha esterilitzat per immersió en una solució diluïda de lleixiu i s’ha manipulat de manera estèril. En tots els casos el medi de cultiu utilitzat ha estat el MS amb una concentració de sacarosa i reguladors de creixement variable segons l’experiment. La incubació dels cultius s’han dut a terme en una cambra amb control de fotoperíode durant 4 setmanes. Els diferents reguladors de creixement han mostrat un clar efecte sobre les seccions de tija. Els explants cultivats en medi lliure d’hormones han crescut menys que els exposats a diverses concentracions de NAA i BA. Aquests tractaments hormonals han originat símptomes de creixement anòmals (engruiximents a la base i vitrificació). La presencia de 2,4-D ha afavorit la formació de cal•lus i d’arrels per organogènesi adventícia indirecta. L’obtenció de plàntules per germinació in vitro de llavors ha permès reduir notablement les pèrdues per contaminació, mentre que el subcultiu d’aquestes ha donat unes tases de micropropagació de 7.2 seccions/plàntula. Ha estat possible aclimatar aquestes vitroplantes per tal d’adaptar-les a les condicions de camp. No hem pogut obtenir organogènesis adventícia ni embriogènesi somàtica a partir d anteres ni hem pogut iniciar un cultiu de cèl•lules a partir dels cal•lus. Tot i la complexitat d’aquestes tècniques, és possible dur-les a terme en un laboratori escolar.

Mobile termination, network externalities, and consumer expectations

We re-examine the literature on mobile termination in the presence of network externalities. Externalities arise when firms discriminate between on- and off-net calls or when subscription demand is elastic. This literature predicts that profit decreases and consumer surplus increases in termination charge in a neighborhood of termination cost. This creates a puzzle since in reality we see regulators worldwide pushing termination rates down while being opposed by network operators. We show that this puzzle is resolved when consumers' expectations are assumed passive but required to be fulfilled in equilibrium (as defined by Katz and Shapiro, AER 1985), instead of being rationally responsive to non-equilibrium prices, as assumed until now.

Obtenció de nous anàlegs amb activitat brassinoesteroide mitjançant modelització molecular i síntesi

Els brassinoesteroides són productes naturals que actuen com a potents reguladors del creixement vegetal. Presenten aplicacions prometedores en l’agricultura degut a que, aplicats exògenament, augmenten la qualitat i la quantitat de les collites. Ara bé, el seu ús s’ha vist restringit degut a la seva costosa obtenció. Aquest fet ha motivat la recerca de nous compostos actius més assequibles. En aquest projecte es planteja el disseny i obtenció de nous anàlegs seguint diferents estratègies que impliquen tant l’ús de mètodes de modelització molecular com de síntesi orgànica. La primera d’aquestes estratègies consisteix en buscar compostos actius en bases de dades de compostos comercials a través de processos de Virtual Screening desenvolupats amb mètodes computacionals basats en Camps d’Interacció Molecular. Així, es van establir i interpretar models de Relacions Quantitatives Estructura-Activitat (QSAR) emprant descriptors independents de l’alineament (GRIND) i, amb col•laboració amb la Universitat de Perugia, aquest criteri de cerca es va ampliar amb l’aplicació de descriptors FLAP de nova generació. Una altra estratègia es va basar en intentar substituir l’esquelet esteroide dels brassinoesteroides per una estructura equivalent, fixant com a cadena lateral el grup (R)-hexahidromandelil. S’han aplicat dos criteris: mètodes computacionals basats en models QSAR establerts amb descriptors GRIND i també en la metodologia SHOP (scaffold hopping), i, per altra banda, anàlegs proposats racionalment a partir d’un estudi efectuat sobre disruptors endocrins no esteroïdals. Sobre les estructures trobades s’hi va unir la cadena lateral comercial esmentada per via sintètica, en la qual s’ha hagut de fer un èmfasi especial en grups protectors. En total, 49 estructures es proposen per a ser obtingudes sintèticament. També s’ha treballat en l’obtenció un agonista derivat de l’hipotètic antagonista KM-01. Totes les molècules candidates, ja siguin comercials o obtingudes sintèticament, estant sent avaluades en el test d’inclinació de la làmina d’arròs (RLIT).

Regulatory federalism in network industries

Report for the scientific sojourn at the UC Berkeley, USA, from march until july 2008. This document starts by surveying the literature on economic federalism and relating it to network industries. The insights and some new developments (which focus on the role of interjurisdictional externalities, multiple objectives and investment incentives) are used to analyze regulatory arrangements in telecommunications and energy in the EU and the US. In the long history of vertically integrated monopolies in telecommunications and energy, there was a historical trend to move regulation up in the vertical structure of government, at least form the local level to the state or nation-state level. This move alleviated the pressure on regulators to renege on the commitment not to expropriate sunk investments, although it did not eliminate the practice of taxation by regulation that was the result of multiple interest group action. Although central or federal policy making is more focused and especialized and makes it difficult for more interest groups to organize, it is not clear that under all conditions central powers will not be associated with underinvestment. When technology makes the introduction of competition in some segments possible, the possibilities for organizing the institutional architechture of regulation expand. The central level may focus on structural regulation and the location of behavioral regulation of the remaining monopolists may be resolved in a cooperative way or concentrated at the level where the relevant spillovers are internalized.

La millor comprensió del desenvolupament cardíac i el dany cel•lular en els miòcits ajudarà a definir dianes terapèutiques

En el cor embrional, la senyalització de mort cel•lular apoptòtica iniciada per receptors de mort i les caspases executores 3 i 7 exerceixen un paper important durant el desenvolupament cardíac no relacionat amb la mort cel•lular, i posteriorment són silenciats en l’adult, on les vies independents de caspases estan implicades en la mort cel•lular patològica. Resultats previs del nostre grup han contribuït a entendre com es regula i silencia en el cor l’expressió dels gens de la via apoptòtica depenent de caspases durant el desenvolupament; a més, resultats no publicats demostren que les caspases regulen el procés d’expressió de gens en el cor i, contràriament a la maquinària depenent de caspases, TatD, una nucleasa, ’expressa abundantment al cor postnatal. Es desconeixen les funcions de la senyalització apoptòtica durant el desenvolupament cardíac, tot i que són essencials per al desenvolupament, a més, la senyalització independent de caspases implicada al dany cel•lular en els miòcits només es coneix parcialment, el nostre objectiu és contribuir al coneixement d’ambdós fenòmens. Creiem que les caspases podrien processar proteïnes reguladores de l’expressió de gens musculars alterant la seva activitat, mentre que TatD té un paper rellevant en el dany cel•lular però també en la funció cardíaca normal. Volem caracteritzar la contribució de les caspases 3 i 7 en el desenvolupament cardíac, utilitzant models in vivo (estem finalitzant els creuaments necessaris per a disposar dels animals amb el genotip desitjat) i in vitro (pràcticament hem preparat tot el material i hem optimitzat els protocols per a tirar-ho endavant). També volem caracteritzar la funció de TatD durant el desenvolupament i fisiologia del cor i conèixer-ne la seva funció utilitzant models in vitro i in vivo.

Monitoring switch-type sensors and powering autonomous sensors via inductive coupling: application to removable seats in vehicles

Aquesta tesi explora la possibilitat de fer servir enllaços inductius per a una aplicació de l’automòbil on el cablejat entre la centraleta (ECU) i els sensors o detectors és difícil o impossible. S’han proposat dos mètodes: 1) el monitoratge de sensors commutats (dos possibles estats) via acoblament inductiu i 2) la transmissió mitjançant el mateix principi físic de la potència necessària per alimentar els sensors autònoms remots. La detecció d'ocupació i del cinturó de seguretat per a seients desmuntables pot ser implementada amb sistemes sense fils passius basats en circuits ressonants de tipus LC on l'estat dels sensors determina el valor del condensador i, per tant, la freqüència de ressonància. Els canvis en la freqüència són detectats per una bobina situada en el terra del vehicle. S’ha conseguit provar el sistema en un marge entre 0.5 cm i 3 cm. Els experiments s’han dut a terme fent servir un analitzador d’impedàncies connectat a una bobina primària i sensors comercials connectats a un circuit remot. La segona proposta consisteix en transmetre remotament la potència des d’una bobina situada en el terra del vehicle cap a un dispositiu autònom situat en el seient. Aquest dispositiu monitorarà l'estat dels detectors (d'ocupació i de cinturó) i transmetrà les dades mitjançant un transceptor comercial de radiofreqüència o pel mateix enllaç inductiu. S’han avaluat les bobines necessàries per a una freqüència de treball inferior a 150 kHz i s’ha estudiat quin és el regulador de tensió més apropiat per tal d’aconseguir una eficiència global màxima. Quatre tipus de reguladors de tensió s’han analitzat i comparat des del punt de vista de l’eficiència de potència. Els reguladors de tensió de tipus lineal shunt proporcionen una eficiència de potència millor que les altres alternatives, els lineals sèrie i els commutats buck o boost. Les eficiències aconseguides han estat al voltant del 40%, 25% i 10% per les bobines a distàncies 1cm, 1.5cm, i 2cm. Les proves experimentals han mostrat que els sensors autònoms han estat correctament alimentats fins a distàncies de 2.5cm.

Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders

Eating disorders (EDs) are complex psychiatric diseases that include anorexia nervosa and bulimia nervosa, and have higher than 50% heritability. Previous studies have found association of BDNF and NTRK2 to ED, while animal models suggest that other neurotrophin genes might also be involved in eating behavior. We have performed a family-based association study with 151 TagSNPs covering 10 neurotrophin signaling genes: NGFB, BDNF, NTRK1, NGFR/p75, NTF4/5, NTRK2, NTF3, NTRK3, CNTF and CNTFR in 371 ED trios of Spanish, French and German origin. Besides several nominal associations, we found a strong significant association after correcting for multiple testing (P = 1.04 × 10−4) between ED and rs7180942, located in the NTRK3 gene, which followed an overdominant model of inheritance. Interestingly, HapMap unrelated individuals carrying the rs7180942 risk genotypes for ED showed higher levels of expression of NTRK3 in lymphoblastoid cell lines. Furthermore, higher expression of the orthologous murine Ntrk3 gene was also detected in the hypothalamus of the anx/anx mouse model of anorexia. Finally, variants in NGFB gene appear to modify the risk conferred by the NTRK3 rs7180942 risk genotypes (P = 4.0 × 10−5) showing a synergistic epistatic interaction. The reported data, in addition to the previous reported findings for BDNF and NTRK2, point neurotrophin signaling genes as key regulators of eating behavior and their altered cross-regulation as susceptibility factors for EDs.

Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders

Genetic and functional data indicate that variation in the expression of the neurotrophin-3 receptor gene (NTRK3) may have an impact on neuronal plasticity, suggesting a role for NTRK3 in the pathophysiology of anxiety disorders. MicroRNA (miRNA) posttranscriptional gene regulators act by base-pairing to specific sequence sites, usually at the 3'UTR of the target mRNA. Variants at these sites might result in gene expression changes contributing to disease susceptibility. We investigated genetic variation in two different isoforms of NTRK3 as candidate susceptibility factors for anxiety by resequencing their 3'UTRs in patients with panic disorder (PD), obsessive-compulsive disorder (OCD), and in controls. We have found the C allele of rs28521337, located in a functional target site for miR-485-3p in the truncated isoform of NTRK3, to be significantly associated with the hoarding phenotype of OCD. We have also identified two new rare variants in the 3'UTR of NTRK3, ss102661458 and ss102661460, each present only in one chromosome of a patient with PD. The ss102661458 variant is located in a functional target site for miR-765, and the ss102661460 in functional target sites for two miRNAs, miR-509 and miR-128, the latter being a brain-enriched miRNA involved in neuronal differentiation and synaptic processing. Interestingly, these two variants significantly alter the miRNA-mediated regulation of NTRK3, resulting in recovery of gene expression. These data implicate miRNAs as key posttranscriptional regulators of NTRK3 and provide a framework for allele-specific miRNA regulation of NTRK3 in anxiety disorders.

Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility

Background: Germline genetic variation is associated with the differential expression of many human genes. The phenotypic effects of this type of variation may be important when considering susceptibility to common genetic diseases. Three regions at 8q24 have recently been identified to independently confer risk of prostate cancer. Variation at 8q24 has also recently been associated with risk of breast and colorectal cancer. However, none of the risk variants map at or relatively close to known genes, with c-MYC mapping a few hundred kilobases distally. Results: This study identifies cis-regulators of germline c-MYC expression in immortalized lymphocytes of HapMap individuals. Quantitative analysis of c-MYC expression in normal prostate tissues suggests an association between overexpression and variants in Region 1 of prostate cancer risk. Somatic c-MYC overexpression correlates with prostate cancer progression and more aggressive tumor forms, which was also a pathological variable associated with Region 1. Expression profiling analysis and modeling of transcriptional regulatory networks predicts a functional association between MYC and the prostate tumor suppressor KLF6. Analysis of MYC/Myc-driven cell transformation and tumorigenesis substantiates a model in which MYC overexpression promotes transformation by down-regulating KLF6. In this model, a feedback loop through E-cadherin down-regulation causes further transactivation of c-MYC.Conclusion: This study proposes that variation at putative 8q24 cis-regulator(s) of transcription can significantly alter germline c-MYC expression levels and, thus, contribute to prostate cancer susceptibility by down-regulating the prostate tumor suppressor KLF6 gene.

Designing institutions for financial stability: Regulation and supervision by objective for the Euro area

In this paper, we discuss pros and cons ofdifferent models for financial market regulationand supervision and we present a proposal forthe re-organisation of regulatory and supervisoryagencies in the Euro Area. Our arguments areconsistent with both new theories and effectivebehaviour of financial intermediaries inindustrialized countries. Our proposed architecturefor financial market regulation is based on theassignment of different objectives or "finalities"to different authorities, both at the domesticand the European level. According to thisperspective, the three objectives of supervision- microeconomic stability, investor protectionand proper behaviour, efficiency and competition- should be assigned to three distinct Europeanauthorities, each one at the centre of a Europeansystem of financial regulators and supervisorsspecialized in overseeing the entire financialmarket with respect to a single regulatoryobjective and regardless of the subjective natureof the intermediaries. Each system should bestructured and organized similarly to the EuropeanSystem of Central Banks and work in connectionwith the central bank which would remain theinstitution responsible for price and macroeconomicstability. We suggest a plausible path to buildour 4-peak regulatory architecture in the Euro area.

Creative accounting: Some ethical issues of macro- and micro-manipulation

This paper examines two principal categories of manipulative behaviour. The term'macro-manipulation' is used to describe the lobbying of regulators to persuadethem to produce regulation that is more favourable to the interests of preparers.'Micro-manipulation' describes the management of accounting figures to produce abiased view at the entity level. Both categories of manipulation can be viewed asattempts at creativity by financial statement preparers. The paper analyses twocases of manipulation which are considered in an ethical context. The paperconcludes that the manipulations described in it can be regarded as morallyreprehensible. They are not fair to users, they involve an unjust exercise ofpower, and they tend to weaken the authority of accounting regulators.