T Cell Priming by Activated Nlrc5-Deficient Dendritic Cells Is Unaffected despite Partially Reduced MHC Class I Levels.

NLRC5, a member of the NOD-like receptor (NLR) protein family, has recently been characterized as the master transcriptional regulator of MHCI molecules in lymphocytes, in which it is highly expressed. However, its role in activated dendritic cells (DCs), which are instrumental to initiate T cell responses, remained elusive. We show in this study that, following stimulation of DCs with inflammatory stimuli, not only did NLRC5 level increase, but also its importance in directing MHCI transcription. Despite markedly reduced mRNA and intracellular H2-K levels, we unexpectedly observed nearly normal H2-K surface display in Nlrc5(-/-) DCs. Importantly, this discrepancy between a strong intracellular and a mild surface defect in H2-K levels was observed also in DCs with H2-K transcription defects independent of Nlrc5. Hence, alongside with demonstrating the importance of NLRC5 in MHCI transcription in activated DCs, we uncover a general mechanism counteracting low MHCI surface expression. In agreement with the decreased amount of neosynthesized MHCI, Nlrc5(-/-) DCs exhibited a defective capacity to display endogenous Ags. However, neither T cell priming by endogenous Ags nor cross-priming ability was substantially affected in activated Nlrc5(-/-) DCs. Altogether, these data show that Nlrc5 deficiency, despite significantly affecting MHCI transcription and Ag display, is not sufficient to hinder T cell activation, underlining the robustness of the T cell priming process by activated DCs.

Direct Interrogation of Viral Peptides Presented by the Class I HLA of HIV-Infected T Cells

Identification of CD8+ cytotoxic T lymphocyte (CTL) epitopes has traditionally relied upon testing of overlapping peptide libraries for their reactivity with T cells in vitro. Here, we pursued deep ligand sequencing (DLS) as an alternative method of directly identifying those ligands that are epitopes presented to CTLs by the class I human leukocyte antigens (HLA) of infected cells. Soluble class I HLA-A*11:01 (sHLA) was gathered from HIV-1 NL4-3-infected human CD4+ SUP-T1 cells. HLA-A*11:01 harvested from infected cells was immunoaffinity purified and acid boiled to release heavy and light chains from peptide ligands that were then recovered by size-exclusion filtration. The ligands were first fractionated by high-pH high-pressure liquid chromatography and then subjected to separation by nano-liquid chromatography (nano-LC)–mass spectrometry (MS) at low pH. Approximately 10 million ions were selected for sequencing by tandem mass spectrometry (MS/MS). HLA-A*11:01 ligand sequences were determined with PEAKS software and confirmed by comparison to spectra generated from synthetic peptides. DLS identified 42 viral ligands presented by HLA-A*11:01, and 37 of these were previously undetected. These data demonstrate that (i) HIV-1 Gag and Nef are extensively sampled, (ii) ligand length variants are prevalent, particularly within Gag and Nef hot spots where ligand sequences overlap, (iii) noncanonical ligands are T cell reactive, and (iv) HIV-1 ligands are derived from de novo synthesis rather than endocytic sampling. Next-generation immunotherapies must factor these nascent HIV-1 ligand length variants and the finding that CTL-reactive epitopes may be absent during infection of CD4+ T cells into strategies designed to enhance T cell immunity.

Aprenentatge sobre les emocions: la seva influència en l'aprenentage sobre habilitats socials. Desenvolupament i anàlisi d'una intervenció en una aula de P3

Amb aquest treball es pretén comprovar, si l’aplicació d’un conjunt d’activitats dirigides a treballar les emocions, millora les habilitats socials dels alumnes d’Educació Infantil. En primer lloc, es presenta un marc teòric basat en les aportacions i els descobriments de diferents autors sobre diversos aspectes relacionats amb les emocions i, sobre la importància de crear un bon clima dins d’una aula. Posteriorment es presenta el desenvolupament de les activitats que s’han posat en pràctica a l’aula. Per últim, es fa un anàlisi de les dades recollides en aquest estudi i se’n mostren els resultats i les conclusions que s’han extret.

SMRT-mediated co-shuttling enables export of class IIa HDACs independent of their CaM kinase phosphorylation sites

The Class IIa histone deacetylases (HDAC)4 and HDAC5 play a role in neuronal survival and behavioral adaptation in the CNS. Phosphorylation at 2/3 N-terminal sites promote their nuclear export. We investigated whether non-canonical signaling routes to Class IIa HDAC export exist because of their association with the co-repressor Silencing Mediator Of Retinoic And Thyroid Hormone Receptors (SMRT). We found that, while HDAC5 and HDAC4 mutants lacking their N-terminal phosphorylation sites (HDAC4(MUT), HDAC5(MUT)) are constitutively nuclear, co-expression with SMRT renders them exportable by signals that trigger SMRT export, such as synaptic activity, HDAC inhibition, and Brain Derived Neurotrophic Factor (BDNF) signaling. We found that SMRT's repression domain 3 (RD3) is critical for co-shuttling of HDAC5(MUT), consistent with the role for this domain in Class IIa HDAC association. In the context of BDNF signaling, we found that HDAC5(WT), which was more cytoplasmic than HDAC5(MUT), accumulated in the nucleus after BDNF treatment. However, co-expression of SMRT blocked BDNF-induced HDAC5(WT) import in a RD3-dependent manner. In effect, SMRT-mediated HDAC5(WT) export was opposing the BDNF-induced HDAC5 nuclear accumulation observed in SMRT's absence. Thus, SMRT's presence may render Class IIa HDACs exportable by a wider range of signals than those which simply

Semantic domain and grammatical class effects in the picture-word interference paradigm

The role of grammatical class in lexical access and representation is still not well understood. Grammatical effects obtained in picture-word interference experiments have been argued to show the operation of grammatical constraints during lexicalization when syntactic integration is required by the task. Alternative views hold that the ostensibly grammatical effects actually derive from the coincidence of semantic and grammatical differences between lexical candidates. We present three picture-word interference experiments conducted in Spanish. In the first two, the semantic relatedness (related or unrelated) and the grammatical class (nouns or verbs) of the target and the distracter were manipulated in an infinitive form action naming task in order to disentangle their contributions to verb lexical access. In the third experiment, a possible confound between grammatical class and semantic domain (objects or actions) was eliminated by using action-nouns as distracters. A condition in which participants were asked to name the action pictures using an inflected form of the verb was also included to explore whether the need of syntactic integration modulated the appearance of grammatical effects. Whereas action-words (nouns or verbs), but not object-nouns, produced longer reaction times irrespective of their grammatical class in the infinitive condition, only verbs slowed latencies in the inflected form condition. Our results suggest that speech production relies on the exclusion of candidate responses that do not fulfil task-pertinent criteria like membership in the appropriate semantic domain or grammatical class. Taken together, these findings are explained by a response-exclusion account of speech output. This and alternative hypotheses are discussed.

Synthesis of angiotensin-converting enzyme (ACE) inhibitors: an important class of antihypertensive drugs

This report outlines the discovery, the design and development of new compounds, and, structure-activity relationships for this drug category. Updated approaches to planned syntheses of new worthy ACE-inhibitors are also exploited.

Identification of molecular subtypes and gene expression patterns of breast cancer analysing RNA-seq data

Breast cancer is the most common diagnosed cancer and the leading cause of cancer death among females worldwide. It is considered a highly heterogeneous disease and it must be classified into more homogeneous groups. Hence, the purpose of this study was to classify breast tumors based on variations in gene expression patterns derived from RNA sequencing by using different class discovery methods. 42 breast tumors paired-samples were sequenced by Illumine Genome Analyzer and the data was analyzed and prepared by TopHat2 and htseq-count. As reported previously, breast cancer could be grouped into five main groups known as basal epithelial-like group, HER2 group, normal breast-like group and two Luminal groups with a distinctive expression profile. Classifying breast tumor samples by using PAM50 method, the most common subtype was Luminal B and was significantly associated with ESR1 and ERBB2 high expression. Luminal A subtype had ESR1 and SLC39A6 significant high expression, whereas HER2 subtype had a high expression of ERBB2 and CNNE1 genes and low luminal epithelial gene expression. Basal-like and normal-like subtypes were associated with low expression of ESR1, PgR and HER2, and had significant high expression of cytokeratins 5 and 17. Our results were similar compared with TGCA breast cancer data results and with known studies related with breast cancer classification. Classifying breast tumors could add significant prognostic and predictive information to standard parameters, and moreover, identify marker genes for each subtype to find a better therapy for patients with breast cancer.

El joc com a eina inclusiva

El tema central d'aquest Treball Final de Grau és el joc i les seves potencialitats com a eina inclusiva. El objectiu de la recerca és conèixer la importància que té el joc en l'educació infantil i indagar sobre las possibilitats que aporta a la inclusió de nens i nenes amb necessitats educatives especials. El treball es divideix en diferents apartats. Inicialment, es fa una recerca teòrica sobre com el joc col·labora en l’educació dels infants a nivell acadèmic i transversal i sobre els beneficis de l’activitat lúdica en els alumnes amb necessitats educatives especials. A continuació, es realitza un estudi de cas d’un infant amb certes necessitats dins d’un context escolar i s’analitza la funció el joc com el mecanisme d’ajuda per incloure’l dins d’un grup. L’estudi es porta a terme mitjançant l’observació de l’infant a l’escola i de entrevistes realitzades amb diferents persones del seu entorn. Per últim, es presenta una anàlisi de les dades recollides amb l’objectiu d’extreure conclusions sobre com el joc pot ser una eina per incloure els infants amb necessitats educatives especials dins d’un grup-classe.

Creative thinking

Portal web d'intercanvi d'idees creatives, confeccionat en tecnología JEE i Liferay com a gestor de continguts i gestor de portlets.

Celebrating Creative Consciousness: Insights Into Oscar Wilde’s Aesthetics

Tutkielmani valottaa irlantilaisen kirjailijan Oscar Wilden (1854-1900) vähemmän tunnettua työtä ja ajattelua taidekriitikkona fin de sièclen ja modernismin välisen siirtymävaiheen estetiikassa. Wilden voidaan sanoa olleen edellä aikaansa estetiikkakäsityksensä suhteen: Hän käsittelee taidekritiikissään teemoja, jotka tulivat keskeisiksi modernismin ja postmodernismin myötä – esimerkiksi kielen pettävyyttä, sellaisten käsitteiden kuin ’todellisuus’, ’luonto’ tai ’yhteiskunta’ sattumanvaraisuutta sekä yhteisön ja yksilön identiteettien fragmentoitumista. Wilde myös kyseenalaistaa – paradoksien, kielellisten nokkeluuksien ja ironian avulla – monia länsimaisessa filosofiassa ’normatiivisina’ pidettyjä arvoja, kuten totuuteen pyrkimisen. Lisäksi hän haastaa taiteenkritiikin akateemisen tradition hylkäämällä sellaiset sen hyveinä pitämät piirteet kuin johdonmukaisuus ja ristiriidattomuus. Tarkastelen Wilden estetiikkakäsitystä pääasiassa esseekokoelman Intentions (1891), etenkin esseen Valehtelun rappio, sekä De Profundis –teoksen (1905) kautta. Tekstejä analysoimalla ja vertaamalla osoitan miten 1890-luvun alkupuolen ja vankilatuomiotaan istuvan Wilden estetiikkakäsitys muuttui ja kehittyi. Wilden kohdalla on syytä puhua taidefilosofiasta taiteenteorian sijaan. Hänen kriittiset esseensä eivät tähtää ’harmonisen’ kokonaisuuden luomiseen tai pragmaattis-loogisen mallin rakentamiseen taiteen ymmärtämiseksi vaan tulvivat ironiaa ja ristiriitaisuuksia. Wildella taideteoksen tarkasteluun liittyy aina eettisiä, ontologisia ja metafyysisiä kysymyksiä, jotka syventävät mutta myös monimutkaistavat esteettistä kokemusta. Keskeinen teema Wildelle onkin taiteen ja elämän vastakkainasettelu sekä niiden välisen yhteyden tunnistaminen ja tunnustaminen: taide on sekä autonomista että subjektiivista. Tämä paradoksi kulminoituu esteettisessä kokemuksessa. Wildelle luomistyö ja vastaanottajan elämys ovat tiedostamattomia prosesseja – tietoista luovuutta ei ole. Esteettinen kuitenkin voidaan yhdistää tietoisuuteen, mutta se edellyttää että myös tietoisuuden on oltava luovaa. Siksipä lähestyäkseen taidetta kritiikin on tultava enemmän taiteen kaltaiseksi – epänormatiiviseksi ja epäloogiseksi. Tässä prosessissa paradokseilla on merkittävä tehtävä: ne muistuttavat siitä, että puhuttaessa taiteesta ei ole oikeita vastauksia, on vain hyviä kysymyksiä.

Generalized three-sided assignment markets: consistency and the core

A class of three-sided markets (and games) is considered, where value is generated by pairs or triplets of agents belonging to different sectors, as well as by individuals. For these markets we analyze the situation that arises when some agents leave the market with some payoff To this end, we introduce the derived market (and game) and relate it to the Davis and Maschler (1965) reduced game. Consistency with respect to the derived market, together with singleness best and individual anti-monotonicity axiomatically characterize the core for these generalized three-sided assignment markets. These markets may have an empty core, but we define a balanced subclass, where the worth of each triplet is defined as the addition of the worths of the pairs it contains. Keywords: Multi-sided assignment market, Consistency, Core, Nucleolus. JEL Classification: C71, C78

Investigating the impact of small versus large firms on economic performance of countries and industries

Following earlier work by Audretsch et al. (2002), we assume that an optimal size-class structure exists, in terms of achieving maximal economic growth rates. Such an optimal structure is likely to exist as economies need a balance between the core competences of large firms (such as exploitation of economies of scale) and those of smaller firms (such as flexibility and exploration of new ideas). Accordingly, changes in size-class structure (i.e., changes in the relative shares in economic activity accounted for by micro, small, medium-sized and large firms) may affect macro-economic growth. Using a unique data base of the EU-27 countries for the period 2002-2008 for five broad sectors of economic activity and four size-classes, we find empirical support which suggests that, on average for these countries over this period, the share of micro and large firms may have been ‘above optimum’ (particularly in lower income EU countries) whereas the share of medium-sized firms may have been ‘below optimum’ (particularly in higher income EU countries). This evidence suggests that the transition from a ‘managed’ to an ‘entrepreneurial’ economy (Audretsch and Thurik, 2001) has not been completed yet in all countries of the EU-27. Keywords: small firms, large firms, size-classes, macro-economic performance

Singing Desire : erotismo y deseo en las canciones para laúd en Inglaterra, 1597-1615

Las canciones para laúd o ayres en la Inglaterra de finales del siglo XVI y principios del XVII además de ser un género muy importante dentro de la música inglesa, son una manifestación cultural de varios ámbitos, tales como patronaje, comercio, género, clase social, filosofía y religión. Con sus letras eróticas en combinación con la voz solista, la música del laúd y la viola da gamba, fueron un medio de expresión muy intenso que permitía la entrada a un universo de sentimiento, pero que también representaba un pensamiento filosófico y una conciencia retórica. Basado en estudios previos, este ensayo explora las ayres desde diferentes ámbitos: el social, el de género, el humanista y el literario para entender el género de las ayres a fondo de manera que le sea útil al intérprete al momento de abordar este repertorio.

A human immune data-informed vaccine concept elicits strong and broad T-cell specificities associated with HIV-1 control in mice and macaques

Background: None of the HIV T-cell vaccine candidates that have reached advanced clinical testing have been able to induce protective T cell immunity. A major reason for these failures may have been suboptimal T cell immunogen designs. Methods: To overcome this problem, we used a novel immunogen design approach that is based on functional T cell response data from more than 1,000 HIV-1 clade B and C infected individuals and which aims to direct the T cell response to the most vulnerable sites of HIV-1. Results: Our approach identified 16 regions in Gag, Pol, Vif and Nef that were relatively conserved and predominantly targeted by individuals with reduced viral loads. These regions formed the basis of the HIVACAT T-cell Immunogen (HTI) sequence which is 529 amino acids in length, includes more than 50 optimally defined CD4+ and CD8+ T-cell epitopes restricted by a wide range of HLA class I and II molecules and covers viral sites where mutations led to a dramatic reduction in viral replicative fitness. In both, C57BL/6 mice and Indian rhesus macaques immunized with an HTI-expressing DNA plasmid (DNA.HTI) induced broad and balanced T-cell responses to several segments within Gag, Pol, and Vif. DNA.HTI induced robust CD4+ and CD8+ T cell responses that were increased by a booster vaccination using modified virus Ankara (MVA.HTI), expanding the DNA.HTI induced response to up to 3.2% IFN-γ T-cells in macaques. HTI-specific T cells showed a central and effector memory phenotype with a significant fraction of the IFN-γ+ CD8+ T cells being Granzyme B+ and able to degranulate (CD107a+). Conclusions: These data demonstrate the immunogenicity of a novel HIV-1 T cell vaccine concept that induced broadly balanced responses to vulnerable sites of HIV-1 while avoiding the induction of responses to potential decoy targets that may divert effective T-cell responses towards variable and less protective viral determinants.

Creative Industries: a Preliminary Insight to their Location Determinants

This paper is about location decisions of Creative Industries and the role played by existent spatial distribution and agglomeration economies of these kinds of activities in order to analyse their location determinants. Our main statistical source is the REIC (Catalan Manufacturing Establishments Register), which has plant-level microdata on location of new plants. Using Count Data Models, our main results show that location determinants are quite similar between both industries and also both non-creative and creative firms are positively influenced by the specialisation level in Creative Industries of municipalities. Moreover, our results provide evidence that the unobserved ‘creative milieu’ has a limited impact on attracting firms. Keywords: creative industries, creative milieu, count data models, industrial location, agglomeration economies