Spectral learning of transducers over continuous sequences

In this paper we present a spectral algorithm for learning weighted nite state transducers (WFSTs) over paired input-output sequences, where the input is continuous and the output discrete. WFSTs are an important tool for modeling paired input-output sequences and have numerous applications in real-world problems. Recently, Balle et al (2011) proposed a spectral method for learning WFSTs that overcomes some of the well known limitations of gradient-based or EM optimizations which can be computationally expensive and su er from local optima issues. Their algorithm can model distributions where both inputs and outputs are sequences from a discrete alphabet. However, many real world problems require modeling paired sequences where the inputs are not discrete but continuos sequences. Modelling continuous sequences with spectral methods has been studied in the context of HMMs (Song et al 2010), where a spectral algorithm for this case was derived. In this paper we follow that line of work and propose a spectral learning algorithm for modelling paired input-output sequences where the inputs are continuous and the outputs are discrete. Our approach is based on generalizing the class of weighted nite state transducers over discrete input-output sequences to a class where transitions are linear combinations of elementary transitions and the weights of this linear combinations are determined by dynamic features of the continuous input sequence. At its core, the algorithm is simple and scalable to large data sets. We present experiments on a real task that validate the eff ectiveness of the proposed approach.Postprint (published version

Differential Roles of TREM2+ Microglia in Anterograde and Retrograde Axonal Injury Models

Microglia are the main immune cells of the central nervous system (CNS), and they are devoted to the active surveillance of the CNS during homeostasis and disease. In the last years, the microglial receptor Triggering Receptor Expressed on Myeloid cells-2 (TREM2) has been defined to mediate several microglial functions, including phagocytosis, survival, proliferation, and migration, and to be a key regulator of a new common microglial signature induced under neurodegenerative conditions and aging, also known as disease-associated microglia (DAM). Although microglial TREM2 has been mainly studied in chronic neurodegenerative diseases, few studies address its regulation and functions in acute inflammatory injuries. In this context, the present work aims to study the regulation of TREM2 and its functions after reparative axonal injuries, using two-well established animal models of anterograde and retrograde neuronal degeneration: the perforant pathway transection (PPT) and the facial nerve axotomy (FNA). Our results indicate the appearance of a subpopulation of microglia expressing TREM2 after both anterograde and retrograde axonal injury. TREM2+ microglia were not directly related to proliferation, instead, they were associated with specific recognition and/or phagocytosis of myelin and degenerating neurons, as assessed by immunohistochemistry and flow cytometry. Characterization of TREM2+ microglia showed expression of CD16/32, CD68, and occasional Galectin-3. However, specific singularities within each model were observed in P2RY12 expression, which was only downregulated after PPT, and in ApoE, where de novo expression was detected only in TREM2+ microglia after FNA. Finally, we report that the pro-inflammatory or anti-inflammatory cytokine microenvironment, which may affect phagocytosis, did not directly modify the induction of TREM2+ subpopulation in any injury model, although it changed TREM2 levels due to modification of the microglial activation pattern. In conclusion, we describe a unique TREM2+ microglial subpopulation induced after axonal injury, which is directly associated with phagocytosis of specific cell remnants and show different phenotypes, depending on the microglial activation status and the degree of tissue injury

Fine tune control of dopamine neurotransmission by alpha-synuclein: down- and over-expression models

Póster presentado en el IX Simposi de Neurobiologia Experimental, celebrado los días 22 y 23 de octubre de 2014 en Barcelona y organizado por la Societat Catalana de Biologia del Institut d'Estudis CatalansAlpha-synuclein protein (α-syn) accumulates in the brain of patients with Parkinson´s disease (PD) and leaves a degeneration of midbrain dopamine (DA) neurons. However, the normal function of α-syn on DA neurotransmission in vivo remains poorly understood. Here, we used two mouse models with a) reduced α-syn expression in the substantia nigra compacta (SNc) and ventral tegmental area (VTA) induced by antisense oligonucleotide molecule (ASO) and, b) modest α-syn over-expression in tyrosine hydroxylase (TH)-positive neurons in the absence of overt toxicity. ASO sequence against α-syn was conjugated to a cell-specific ligand, indatraline (monoamine transporter inhibitor), to promote its selective delivery into monoamine neurons after intranasal administration. Indatraline-α-syn-ASO conjugate (1233ASO) entered into midbrain DA cells followed by trafficking to deep endomembrane vesicles associated with Rab7 resulting in an efficient α-syn knockdown. Indeed, 4-day 1233ASO treatment (30µg/day) decreased α-syn mRNA and protein levels in SNc/VTA (84.1±1.7% and 57.7±7.8% of PBS-treated animals, respectively). Alpha-synuclein suppression displayed an enhancement striatal DA tone using intracerebral microdialysis. Local veratridine (50 µM) perfusion increased extracellular DA levels more efficient in 1233ASO-treated than PBS-treated mice. Similarly, nomifensine (1-10-50 µM) or amphetamine (1-10-100 µM) showed a marked doseeffect which phenotypic differences. Tetrabenazine (VMAT2 inhibitor, 100 µM) reduced striatal DA levels in 1233ASO-treated mice. This effect was lower than in control mice. Conversely, we found that over-expressed α-syn inhibits striatal DA release. Together, this evidence indicates a physiological role for a-syn as a >fine tune> modulator of nigroestriatal DA release and the effects depend on the a-syn expression levelsSpanish Ministery of Economy and Competitiveness, INNPACTO Subprogram IPT-2012-1208-300000; Instituto de Salud Carlos III (ISCIII) Grant PI13/01390. Some of these grants are co-financed by the European Regional Development Fund “A way to build Europe”Peer Reviewe

Selective suppression of α-Synuclein in monoaminergic neurons of mice by intranasal delivery of targeted small interfering RNA or antisense oligonucleotides: Potential therapy for Parkinson's disease

Póster presentado en: ACNP (American College of Neuropsychopharmacology) 52nd Annual Conference, celebrada del 8 al 12 de diciembre de 2013 en Hollywood, Florida (Estados Unidos)Abstract publicado en: Neuropsychopharmacology 38:S419-S420 (2013). ISSN: 0893-133X. eISSN: 1740-634X. DOI:10.1038/npp.2013.280α-Synuclein (α-Syn) appears to play a crucial role in the pathogenesis of several neurodegenerative disorders including Parkinson's disease (PD). The brains of Parkinson patients typically contain insoluble intracellular protein inclusions called Lewy bodies. Increased neuronal α-Syn levels represent a major component of Lewy bodies and therefore, the suppression of α-Syn expression provides a valid therapeutic target for PD. The goal of this study was to assess the ability of various small interfering RNA (siRNA) and antisense oligonucleotide (ASO) sequences directed against α-Syn to downregulate endogenous or overexpressed α-Syn mRNA levels in BE-M17 neuroblastoma cells. Moreover, we evaluated the feasibility of reducing α-Syn expression selectively in PD-vulnerable brain areas including substantia nigra pars compacta (SNc), ventral tegmental area (VTA), locus coeruleus (LC) and dorsal raphe nucleus (DR) of mice after the internalization of conjugated siRNA/ASO molecules into monoamine neurons following intranasal administration. Conclusions: These results set the stage for the testing of these molecules as potential disease-modifying agents in neurotoxin-based and genetic models of PD linked to pathogenic increases in α-Syn. In this study we have characterized conjugated siRNA and ASO molecules that actively reduce endogenous α-Syn expression in vivo using the intranasal route to deliver directly siRNA/ASO into the brainPeer Reviewe

Initiation, progression and extension of parkinson’s disease: role of α-synuclein

La malaltia de Parkinson és un trastorn neurodegeneratiu freqüent d’origen desconegut que es caracteritza principalment per la pèrdua de neurones dopaminèrgiques de la substància nigra pars compacta (SNpc) i la presencia d’inclusions proteiques intacitoplasmàtiques anomenades cossos de Lewy (CL), en diverses regions cerebrals afectades. Tot i que els CL es van descriure per primera vegada fa una dècada, encara es desconeix la seva rellevància en el procés patològic de la MP. Recentment s’ha suggerit que l’ α-synucleina, el principal component dels CL, pot iniciar i extendre el procés patològic de la MP. Reforçant aquesta idea, la injecció intracerebral de fibrilles sintètiques d’α-synucleina recombinant poden iniciar una patologia de l’ α-synucleina en ratolins. Tot i així, encara es desconeix si aquest efecte patogènic de l’ α-synucleina recombinant sintètica es pot aplicar també a l’α-synuclein humana associada a la MP i ocórrer en especies més properes als humans. En aquesta tesis em tractat aquesta qüestió avaluant el possible efecte patogènic d’inocular extractes de CL nigrals que contenen α-synucleina i que han sigut obtinguts de pacients amb MP, en el cervell de ratolins i macacs. Aquests CL nigrals van ser purificats de cervells postmortem de pacients amb MP mitjançant un fraccionament de gradient de sucrosa i posteriorment es van inocular en la SNpc o estriat de ratolins i macacs. En ambdues espècies, les inoculacions intranigrals o intraestriatals dels extractes de CL derivats de pacients amb MP van provocar una neurodegeneració nigrostriatal progressiva que va començar als terminals dopaminèrgics de l’estriat. En animals injectats amb CL, l’α-synucleina humana exògena va ser ràpidament internalitzada per les neurones de l’hoste i va iniciar la conversió patològica de l’α-synucleina endògena. Al principi del procés neurodegenetiu induït pels CL, l’α-synucleina patològica del hoste es va acumular de manera difusa en les neurones de la SNpc i de regions cerebrals interconectades anatòmicament. Els efectes patogènics induïts pels CL van requerir tant l’α-synucleina present als CL com l’expressió d’α-synucleina endògena del hoste. Aquests resultats indiquen que les espècies humanes d’ α-synucleina presents en els CL derivats de pacients amb MP són patogènics i tenen la capacitat d’iniciar un procés patològic semblant a la MP. Reforçant el rol patogènic de l’α-synucleina en la MP, s’ha descrit que els pacients amb MP contenen nivells incrementats d’aquesta proteina. En aquest sentit, la utilització d’eines molecular capaces de revertir l’expressió anormal d’α-synucleina a nivells fisiològics podria ser beneficiosa per la MP. Basant-nos en aquesta hipòtesis, el segon objectiu d’aquesta tesis era determinar la viabilitat i seguretat de disminuir l’expressió d’α-synucleina in vivo específicament en poblacions neuronals vulnerables en la MP mitjançant l’administració intranasal de small interferring RNA (siRNA. Per aconseguir-ho, primer de tot vam fer un screening in vitro de diferents siRNA per seleccionar aquells siRNA capaços de disminuir els nivells basals o sobreexpressats d’α-synuclein sense disminuir els nivells de β- ni γ-synucleina. A continuació, vam confirmar que la molècula seleccionada (SNCA499-siRNA) era capaç de disminuir els nivells de mRNA de la SN in vivo després de la infusió local en la SN de ratolins. Aquesta molècula es va modificar químicament per incrementar la seva bioestabilitat i es va conjugar al lligand indaltralina (IND) per promoure la seva entrada en neurones aminèrgiques, sent aquest últim validat en cultius primaris de mesencèfal de rata. Finalment, l’administració intranasal de IND-SNCA499-siRNA en ratolins va disminuir específicament l’expressió α-synucleina en la SNpc, tant a nivell de mRNA com de proteïna, sense afectar la integritat de la via nigrostriatal dopaminèrgica. Aquests resultats estableixen l’escenari per estudis futurs dirigits a determinar l’efecte beneficiós d’administrar intranasalment el IND-SNCA499-siRNA en models experimentals de la MP associats amb nivells incrementats d’α-synucleina.Parkinson’s disease (PD) is a common neurodegenerative disorder of unknown origin mainly characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of intraneuronal proteinaceous cytoplasmic inclusions, called Lewy bodies (LB), in several affected brain areas. Although LB were identified a century ago, their significance to the pathogenic process in PD remains unknown. Mounting evidence suggest that α-synuclein, a major protein component of LB, may be responsible for initiating and spreading the pathological process in PD. Supporting this concept, intracerebral inoculation of synthetic recombinant α-synuclein fibrils can trigger α-synuclein pathology in mice. However, it remains uncertain whether the observed pathogenic effects of recombinant synthetic α-synuclein can actually apply to PD-linked human α-synuclein and occur in species closer to humans. In this thesis, we addressed this question by assessing the potential pathogenic effects of inoculating α-synuclein-containing nigral LB extracts from PD patients into the brains of wild-type mice and macaque monkeys. Nigral LB containing pathological α-synuclein were purified from post-mortem PD brains by sucrose gradient fractionation and subsequently inoculated into the SNpc or striatum of wild-type mice and macaque monkeys. In both mice and monkeys, intranigral or intrastriatal inoculations of PD-derived LB extracts resulted in progressive nigrostriatal neurodegeneration starting at striatal dopaminergic terminals. In LB-injected animals, exogenous human α-synuclein was quickly internalized within host neurons and triggered the pathological conversion of endogenous α-synuclein. At the onset of LB-induced neurodegeneration, host pathological α-synuclein diffusely accumulated within nigral neurons and anatomically interconnected brain regions. LB-induced pathogenic effects required both human α-synuclein present in LB extracts and host expression of α-synuclein. These results indicate that human α-synuclein species contained in PD-derived LB are pathogenic and have the capacity to initiate a PD-like pathological process. Further supporting a pathogenic role of α-synuclein in PD, increased levels of this protein have been described in PD patients. Therefore, molecular tools able to reverse abnormal α-synuclein expression back to physiological levels might provide therapeutic benefit in PD. Based on this hypothesis, in the second aim of this thesis we assessed the feasibility and safety of downregulating α-synuclein expression in vivo specifically in PD-vulnerable neuronal populations by intransal administration of cell-targeted small interfering RNA (siRNA) directed against α-synuclein. To achieve this goal, we performed first an in vitro screening of various siRNA sequences to select those able to downregulate basal or overexpressed α-synuclein without decreasing β- or γ-synuclein levels. Once identified, the selected molecule (SNCA499-siRNA) was then confirmed to be able to downregulate nigral α-synuclein mRNA in vivo by its local infusion in the SN of mice. This molecule was then chemically modified to enhance its biostability and conjugated to the cell-specific ligand indatraline (IND) to promote its selective delivery into aminergic neurons, the latter being validated in rat ventral midbrain primary cultures. Finally, intranasal administration of IND-SNCA499-siRNA to mice was able to selectively downregulate α-synuclein SNpc expression, both at mRNA and protein levels, without affecting the integrity of the dopaminergic nigrostriatal pathway. These results set the stage for future studies aimed at assessing the disease-modifying potential of intranasally delivered IND-SNCA499-siRNA in experimental PD models associated with increased α-synuclein levels

Les relacions família-escola en una comunitat d'aprenentatge

Curs 2014-2015En aquest treball es realitza un estudi de cas qualitatiu sobre les relacions que hi ha entre les famílies i l’escola la qual es basa en una comunitat d’aprenentatge, les diferents formes de participació existents, així com una compilació de les principals habilitats o estratègies comunicatives que s’han de tenir en compte per aconseguir una comunicació fluïda, eficaç i beneficiosa. S’ha portat a terme en un centre d’educació primària situat en una zona urbana on hi ha força diversitat cultural. Per obtenir tota la informació sobre aquest estudi les tècniques utilitzades van ser la observació, el diari de camp i les entrevistes per poder arribar a les idees principals, com ara la col·laboració i la participació de les famílies a l’escola, la relació d’ambdòs, l’aprenentatge i els valors. És necessari crear diferents camins perquè famílies i docents treballin conjuntament i en una mateixa línea per aconseguir la formació adequada del alumnat, ja que tots dos contextos són essencials en la vida dels infants i tenen un objectiu en comú que és el ple desenvolupament dels nens i nenes partint dels valors de respecte, implicació i confiança.In this work, a qualitative case study on the relationship between families and the school which is based on a learning community, different forms of participation exist, as well as a sumary of the main skills and communication strategies that taken into account to ensure smooth communication, effective and beneficial. Was conducted in a primary center located in an urban area where there is considerable cultural diversity. For complete information about this study, the techniques used were observation, field diary and interviews to get the main ideas, such as cooperation and participation of families in school, the relationship of both, learning and values. It is necessary to create different ways for families and teachers work together and on the same line to get the proper training of students, as both are essential contexts on children's lives and have a common goal is the full development of children and girls based on the values of respect, involvement and trust

The Realfooding movement as an alternative to Nutri-Score labelling

El movimiento Realfooding es un estilo de vida que lucha contra las grandes empresas que ofrecen comida ultraprocesada. Bajo el hashtag #StopNutriScore, ha liderado un llamamiento en las redes sociales pidiendo una alternativa al etiquetado Nutri-Score, un sistema cuyo algoritmo ayuda a clasificar productos alimentarios en función de su valor nutricional. Este enfrentamiento conduce a la búsqueda de un nexo común entre el etiquetado Nutri-Score y la alternativa que se propone desde el Realfooding, con el fin de alcanzar un nuevo sistema de clasificación más aceptado. El trabajo ha sido dividido en dos grandes bloques: en el primero se desarrolla un marco teórico general centrado en el papel de los movimientos sociales, y un marco teórico específico centrado en el Realfooding y Nutri-Score, así como sus discrepancias. En el segundo bloque se profundiza en su discurso a través de dos entrevistas llevadas a cabo a expertos del sector. Sus argumentos demuestran que el etiquetado Nutri-Score cumple con los objetivos de comprensión, sencillez e intuición, a partir de una base científica muy sólida e indiscutible. Sin embargo, su algoritmo centrado en la clasificación de alimentos de un mismo grupo, en el valor nutricional en lugar del ultraprocesamiento y en su alta flexibilidad en cuanto a azúcares, crea confusión a las personas consumidoras. Esto lleva al movimiento Realfooding a oponerse a Nutri-Score y a proponer la implementación de un etiquetado que tenga en cuenta el procesamiento de los alimentos. Una opción válida, pero difícil de llegar por la lucha constante que se generaría con las grandes empresas del sector. No obstante, países como Chile ya están llevando a cabo este modelo, un sistema que demuestra una vez más los grandes logros que se consiguen gracias a los expertos y expertas que trabajan día a día para mejorar nuestra salud.The Realfooding movement is a lifestyle that fights against large companies that offer ultra-processed food. Under the hashtag #StopNutriScore, it has led a call on social networks asking for an alternative to Nutri-Score labeling, a system whose algorithm helps to classify food products according to their nutritional value. This confrontation leads to the search for a common link between Nutri-Score labeling and the alternative proposed by Realfooding, in order to reach a new and more accepted classification system. The work has been divided into two main blocks: in the first one, a general theoretical framework is developed, focused on the role of social movements, and a specific theoretical framework focused on Realfooding and Nutri-Score, as well as their discrepancies. In the second section, the discourse is deepened through two interviews conducted with industry experts. Their arguments show that Nutri-Score labeling meets the objectives of comprehension, simplicity and intuition, based on a very solid and indisputable scientific basis. However, its algorithm focused on the classification of foods in the same group, on nutritional value rather than ultra-processing and on its high flexibility in terms of sugars, creates confusion for consumers. This leads the Realfooding movement to oppose Nutri-Score and to propose the implementation of labeling that takes into account food processing. A valid option, but difficult to achieve because of the constant struggle that would be generated with large companies in the sector. However, countries like Chile are already implementing this model, a system that demonstrates once again the great achievements that are achieved thanks to the experts who work every day to improve our health.Unidad Deptal. de Sociología: Metodología y TeoríaFac. de Ciencias de la InformaciónTRUEunpu

Role of microRNAs in the Regulation of alpha-Synuclein Expression: a Systematic Review

Growing evidence suggests that increased levels of α-synuclein might contribute to the pathogenesis of Parkinson’s disease (PD) and therefore, it is crucial to understand the mechanisms underlying α-synuclein expression. Recently, microRNAs (miRNAs) have emerged as key regulators of gene expression involved in several diseases such as PD and other neurodegenerative disorders. A systematic literature search was performed here to identify microRNAs that directly or indirectly impact in α-synuclein expression/accumulation and describe its mechanism of action. A total of 27 studies were incorporated in the review showing evidences that 6 microRNAs directly bind and regulate α-synuclein expression while several miRNAs impact on α-synuclein expression indirectly by targeting other genes. In turn, α-synuclein overexpression also impacts miRNAs expression, indicating the complex network between miRNAs and α-synuclein. From the current knowledge on the central role of α-synuclein in PD pathogenesis/progression, miRNAs are likely to play a crucial role at different stages of PD and might potentially be considered as new PD therapeutic approaches

Alpha-synuclein spreading in Parkinson's disease

International audienceFormation and accumulation of misfolded protein aggregates are a central hallmark of several neurodegenerative diseases. In Parkinson's disease (PD), the aggregation-prone protein alpha-synuclein (α-syn) is the culprit. In the past few years, another piece of the puzzle has been added with data suggesting that α-syn may self-propagate, thereby contributing to the progression and extension of PD. Of particular importance, it was the seminal observation of Lewy bodies (LB), a histopathological signature of PD, in grafted fetal dopaminergic neurons in the striatum of PD patients. Consequently, these findings were a conceptual breakthrough, generating the "host to graft transmission" hypothesis, also called the "prion-like hypothesis." Several in vitro and in vivo studies suggest that α-syn can undergo a toxic templated conformational change, spread from cell to cell and from region to region, and initiate the formation of "LB-like aggregates," contributing to the PD pathogenesis. Here, we will review and discuss the current knowledge for such a putative mechanism on the prion-like nature of α-syn, and discuss about the proper use of the term prion-like