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Additional file 1: mRNA levels following overexpression and siRNA transfection.

We study whether incumbents facing uncontested elections channel public spending towards co-partisan officials more than is the case of incumbents that are worried about their chances of re-election. To do so, we draw on data detailing capital transfers allocated by Spanish regions to local governments during the period 1995-2007. Using a regression discontinuity design, we document strong and robust effects. We find that, on average, a mayor belonging to the same party as that of the regional president obtains nearly twice the amount in grants as is received by a mayor belonging to an opposition party. This effect is much greater for regional incumbents that won the previous election by a large margin, but it disappears in the case of highly competitive elections. The effects estimated by difference-in-differences are not so great but they point in the same direction. Overall, the results are consistent with predictions that regional incumbents focus on obtaining the most votes possible when elections are strongly contested, while they seek to increase the number of aligned mayors when their position at the ballot box is not vulnerable.

Ante nosotros se nos presenta una obra que elabora un profundo estudio acerca de una práctica nociva llevada a cabo en numerosos países del mundo y que supone una grave violación de derechos humanos. En este contexto, la aportación de la autora resulta especialmente grata, asimismo, el desarrollo de la obra nos aporta un conocimiento completo del marco legislativo y jurisprudencial que prohíbe esta práctica e, igualmente, nos incita a reflexionar sobre las lagunas normativas y sobre la necesidad de crear nuevas y mejores medidas que protejan, verdaderamente, los derechos de aquellas personas que ven el desarrollo de sus vidas determinadas por el matrimonio infantil. La obra se compone de cinco capítulos. En primer lugar, la autora comienza con una introducción donde ofrece un análisis del concepto de matrimonio infantil, precoz y forzado y, para ello, acude a diversos informes y resoluciones de organizaciones internacionales. Tras el desglose de cada uno de estos conceptos, llega a la conclusión de que todos ellos se encuentran relacionados entre sí y que, por consiguiente, siempre que sea un matrimonio infantil, es también un matrimonio forzado, ya que, un menor de dieciocho años carece de capacidad suficiente para dar consentimiento de contraer matrimonio.

BACKGROUND: Cognitive impairment affects approximately 50% of people with amyotrophic lateral sclerosis (ALS). Research has indicated that impairment may worsen with disease progression. The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was designed to measure neuropsychological functioning in ALS, with its alternate forms (ECAS-A, B, and C) allowing for serial assessment over time.OBJECTIVE: The aim of the present study was to establish reliable change scores for the alternate forms of the ECAS, and to explore practice effects and test-retest reliability of the ECAS's alternate forms.METHOD: Eighty healthy participants were recruited, with 57 completing two and 51 completing three assessments. Participants were administered alternate versions of the ECAS serially (A-B-C) at four-month intervals. Intra-class correlation analysis was employed to explore test-retest reliability, while analysis of variance was used to examine the presence of practice effects. Reliable change indices (RCI) and regression-based methods were utilized to establish change scores for the ECAS alternate forms.RESULTS: Test-retest reliability was excellent for ALS Specific, ALS Non-Specific, and ECAS Total scores of the combined ECAS A, B, and C (all > .90). No significant practice effects were observed over the three testing sessions. RCI and regression-based methods produced similar change scores.CONCLUSION: The alternate forms of the ECAS possess excellent test-retest reliability in a healthy control sample, with no significant practice effects. The use of conservative RCI scores is recommended. Therefore, a change of ≥8, ≥4, and ≥9 for ALS Specific, ALS Non-Specific, and ECAS Total score is required for reliable change.

Ante nosotros se nos presenta una obra que elabora un profundo estudio acerca de una práctica nociva llevada a cabo en numerosos países del mundo y que supone una grave violación de derechos humanos. En este contexto, la aportación de la autora resulta especialmente grata, asimismo, el desarrollo de la obra nos aporta un conocimiento completo del marco legislativo y jurisprudencial que prohíbe esta práctica e, igualmente, nos incita a reflexionar sobre las lagunas normativas y sobre la necesidad de crear nuevas y mejores medidas que protejan, verdaderamente, los derechos de aquellas personas que ven el desarrollo de sus vidas determinadas por el matrimonio infantil. La obra se compone de cinco capítulos. En primer lugar, la autora comienza con una introducción donde ofrece un análisis del concepto de matrimonio infantil, precoz y forzado y, para ello, acude a diversos informes y resoluciones de organizaciones internacionales. Tras el desglose de cada uno de estos conceptos, llega a la conclusión de que todos ellos se encuentran relacionados entre sí y que, por consiguiente, siempre que sea un matrimonio infantil, es también un matrimonio forzado, ya que, un menor de dieciocho años carece de capacidad suficiente para dar consentimiento de contraer matrimonio.

We study whether incumbents facing uncontested elections channel public spending towards co‐partisan officials more than is the case of incumbents that are worried about their chances of re‐election. To do so, we draw on data detailing capital transfers allocated by Spanish regions to local governments during the period 1995‐2007. Using a regression discontinuity design, we document strong and robust effects. We find that, on average, a mayor belonging to the same party as that of the regional president obtains nearly twice the amount in grants as is received by a mayor belonging to an opposition party. This effect is much greater for regional incumbents that won the previous election by a large margin, but it disappears in the case of highly competitive elections. The effects estimated by difference‐in‐differences are not so great but they point in the same direction. Overall, the results are consistent with predictions that regional incumbents focus on obtaining the most votes possible when elections are strongly contested, while they seek to increase the number of aligned mayors when their position at the ballot box is not vulnerable.

Niemann-Pick disease type C (NPC) is a rare neurovisceral disease caused mainly by mutations in the NPC1 gene. This autosomal recessive lysosomal disorder is characterised by the defective lysosomal secretion of cholesterol and sphingolipids. No effective therapy exists for the disease. We previously described a deep intronic point mutation (c.1554-1009 G > A) in NPC1 that generated a pseudoexon, which could be corrected at the cellular level using antisense oligonucleotides. Here, we describe the generation of two mouse models bearing this mutation, one in homozygosity and the other in compound heterozygosity with the c.1920delG mutation. Both the homozygotes for the c.1554-1009 G > A mutation and the compound heterozygotes recapitulated the hallmarks of NPC. Lipid analysis revealed accumulation of cholesterol in the liver and sphingolipids in the brain, with both types of transgenic mice displaying tremor and ataxia at 7-8 weeks of age. Behavioural tests showed motor impairment, hyperactivity, reduced anxiety-like behaviour and impaired learning and memory performances, features consistent with those reported previously in NPC animal models and human patients. These mutant mice, the first NPC models bearing a pseudoexon-generating mutation, could be suitable for assessing the efficacy of specific splicing-targeted therapeutic strategies against NPC. © The Author(s) 2017., The authors declare no competing financial interests. This study was partly funded by grants from the Spanish Ministry of Science and Innovation (SAF2011-25431, SAF2013-49129-C2-1-R and SAF2014-56562-R) and from the Catalan Government (2014SGR/932 and SGR2014/1125), as well as the Addi and Cassi Fund. We are particularly grateful for the support from the Addi and Cassi Fund, who also provided the heterozygous mice. The Centre for Genomic Regulation has received support as a Severo Ochoa Centre of Excellence SEV- 2012–0208. We thank Alexandre Garcia for technical assistance. The authors are also grateful for the support from the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), which is an initiative of the ISCIII. MGG was supported by a grant from the University of Barcelona (APIF).

We study whether incumbents facing uncontested elections channel public spending towards co‐partisan officials more than is the case of incumbents that are worried about their chances of re‐election. To do so, we draw on data detailing capital transfers allocated by Spanish regions to local governments during the period 1995‐2007. Using a regression discontinuity design, we document strong and robust effects. We find that, on average, a mayor belonging to the same party as that of the regional president obtains nearly twice the amount in grants as is received by a mayor belonging to an opposition party. This effect is much greater for regional incumbents that won the previous election by a large margin, but it disappears in the case of highly competitive elections. The effects estimated by difference‐in‐differences are not so great but they point in the same direction. Overall, the results are consistent with predictions that regional incumbents focus on obtaining the most votes possible when elections are strongly contested, while they seek to increase the number of aligned mayors when their position at the ballot box is not vulnerable.

This paper studies the relationship between party discipline and discretionary spending with theory and data. We propose a theoretical model in which a politician faces a conflict between her constituents' interests and the party line. Party loyalty is electorally costly for the politician and is therefore rewarded by the party leader with greater amounts of discretionary spending allocated to the politician's constituency. The more intense the conflict between the voters' and the party's interests, the more grants the district receives. Using panel data on party discipline in the U.S. House of Representatives and federal grants to congressional districts between 1984 and 2010, we provide evidence that districts represented by loyal legislators receive greater amounts of discretionary spending. This effect holds only for legislators in the majority party, who may enjoy a legislative advantage. Districts represented by loyal legislators who face a greater conflict of interest between following the party and serving their constituents (e.g., Republican legislators representing liberal-leaning districts) are rewarded to a larger extent.

A inicios del siglo XXI, se puede observar como se ha creado una codependencia entre el cine independiente americano y la industria de Hollywood, por lo que el objetivo de esta tesis ha sido investigar si siguen persistiendo algunos elementos esenciales de la narrativa clásica que han permitido a ciertas películas independientes ser fácilmente absorbidas y distribuidas por Hollywood. A través de una perspectiva neurocientífica particularmente centrada en la psicología cognitiva y partiendo de una base intrínsecamente vinculada a la narratología, hemos buscado aquellos elementos claves en el procesamiento emocional y cognitivo del cerebro, para comprender cuáles son esos componentes fundamentales de la narrativa clásica que han pervivido escondidos bajo las complejas mecánicas narrativas de películas de algunos de los autores independientes americanos contemporáneos (Tarantino, Jonze, Lynch, Linklater, González Iñárritu, Nolan...)., A inicis del segle XXI, es pot observar que s'ha creat una codependència entre el cinema independent americà i la indústria de Hollywood, de tal manera que l'objectiu d'aquesta tesi ha estat investigar si segueixen persistint alguns elements essencials de la narrativa clàssica que han permès a certes pel•lícules independents ser fàcilment absorbides i distribuïdes per Hollywood. A través d'una perspectiva neurocientífica particularment centrada en la psicologia cognitiva i partint d'una base intrínsecament vinculada a la narratologia, hem buscat aquells elements claus en el processament emocional i cognitiu del cervell, per comprendre quins són aquests components fonamentals de la narrativa clàssica que han perviscut amagats sota les complexes mecàniques narratives de pel•lícules d'alguns dels autors independents americans contemporanis (Tarantino, Jonze, Lynch, Linklater, González Iñárritu, Nolan...)., At the beginning of the 21st century we can see how a co-dependency between independent American cinema and the Hollywood film industry has been created. Thus, the aim of this thesis is to investigate if some essential elements of classical narrative persist which have allowed certain independent films to be easily absorbed and distributed by Hollywood. From a neuroscientific perspective, particularly focused on cognitive psychology, and from a starting point intrinsically tied to narratology, key elements in the emotional and cognitive processing of the brain have been researched in order to understand what are the essentials of classical narrative which have survived hidden under the complex narrative mechanics of some contemporary American independent authors' films (Tarantino, Jonze, Lynch, Linklater, González Iñárritu, Nolan...).

Lysosomal storage disorders (LSDs) are a group of more than 50 different genetic disorders due to the lack of degradation of substrates within lysosomes. Most of them are caused by mutations in genes coding for lysosomal hydrolases. LSDs are mainly inherited in an autosomal recessive manner. Although in the last 25 years there has been much effort and progress to develop therapies aiming the correction of metabolic defects for these diseases, yet there is no effective therapy for many of them, and patients are exclusively treated with supportive care. For several non-neurological LSDs, enzyme replacement therapy may be an option. However, this approach is not efficient, at the moment, for neurological patients. Thus, new therapeutic approaches need to be developed. One of these approaches is the use of drugs that are able to produce a read-through of premature stop codons. One advantage of this strategy is that, if successful, it can be applied to any disease, provided that the molecular cause is a nonsense mutation. The most extensively studied approach involves read-through by drugs affecting the ribosome-decoding site. Niemann-Pick A/B (NPA/B) and Niemann-Pick C (NPC) are two rare inherited monogenic diseases. Although initially were defined as types of the same disease, subsequently they have been considered independent diseases due to the fact that they have different biochemical and molecular features. NPA/B disease is caused by mutations in the SMPD1 gene, localized in chromosome 11, which codes for the enzyme acid sphingomyelinase, a soluble lysosome hydrolase. NPC disease is caused by mutations in the NPC1 gene, localized in chromosome 18, which codes for a lysosomal membrane protein, involved in cholesterol transport. NPC disease also may be caused by mutations in the NPC2 gene, localized in chromosome 14, which codes for a lysosomal soluble protein, involved in cholesterol transport too. The abnormal action of these proteins in patients promotes the accumulation of lipids, which differ in each disease, inside the lysosomes, causing their dysfunction. This thesis makes contributions to the field of LSDs study. Various aspects have been addressed: therapeutic approaches have been tested as a first step in the achievement of a successful therapy for those LSDs bearing nonsense mutations. Important steps in the generation of a new cellular model for NPA/B have been achieved. This model would be helpful to understand the molecular processes that contribute to the development of this pathology and would be a valuable tool for the search of successful treatments. Finally, two new mouse models for NPC have been generated and characterized while one dies few days after birth, the other mimics the main characteristics of the disease and will be useful to probe specific treatments., Las enfermedades de acúmulo lisosómico (LSDs) son un grupo de más de 50 trastornos genéticos diferentes, debido a la falta de degradación de sustratos dentro de los lisosomas. La mayoría de ellas están causadas por mutaciones en los genes que codifican para las hidrolasas lisosomales. Las LSDs se heredan principalmente de forma autosómica recesiva. Aunque en los últimos 25 años ha habido un gran esfuerzo y progreso para desarrollar terapias dirigidas a la corrección de los defectos metabólicos de estas enfermedades, sin embargo, no hay un tratamiento eficaz para muchas de ellas, y los pacientes son tratados exclusivamente con terapias de soporte. Para muchas LSDs sin afectación neurológica, la terapia de reemplazo enzimático puede ser una opción. Sin embargo, este enfoque no es eficiente por el momento para los pacientes con afectación neurológica. Por lo tanto, nuevos aproximaciones terapéuticas han de ser desarrolladas. Una de estas aproximaciones es el uso de fármacos que son capaces de proseguir la lectura a través de los codones de parada prematuros. La ventaja de esta estrategia es que, si tiene éxito, se puede aplicar a cualquier enfermedad cuya causa molecular sea una mutación sin sentido. Niemann-Pick A/B (NPA/B) y Niemann-Pick C (NPC) son dos enfermedades raras, monogénicas y hereditarias. Aunque inicialmente se definieron como tipos de la misma enfermedad, posteriormente se han considerado enfermedades independientes debido al hecho de que tienen diferentes características bioquímicas y moleculares. La enfermedad de NPA/B está causada por mutaciones en el gen SMPD1, localizado en el cromosoma 11, que codifica para la enzima esfingomielinasa ácida, una hidrolasa soluble lisosomal. La enfermedad de NPC está causada por mutaciones en el gen NPC1, localizado en el cromosoma 18, que codifica para una proteína de membrana lisosomal, dicha proteína participa en el transporte del colesterol. La enfermedad de NPC también puede estar causada por mutaciones en el gen NPC2, localizado en el cromosoma 14, que codifica para una proteína soluble lisosomal, que también participa en el transporte del colesterol. La acción anormal de estas proteínas en los pacientes promueve la acumulación de lípidos, diferentes en cada enfermedad, el interior de los lisosomas, provocando su disfunción. Esta tesis realiza contribuciones en el campo de estudio de las LSDs. Se han abordado diversos aspectos. Varias aproximaciones terapéuticas han sido probadas como un primer paso en el logro de una terapia satisfactoria para aquellas LSDs causadas por mutaciones sin sentido. Se han alcanzado importantes avances en la generación de un nuevo modelo celular para NPA/B. Este modelo podría ser útil para entender los procesos moleculares que contribuyen al desarrollo de dicha patología y podría ser una valiosa herramienta para la búsqueda de tratamientos. Por último, se han generado dos nuevos modelos de ratón de NPC y se han caracterizado. Uno de ellos muere pocos días después de su nacimiento, el otro imita las principales características de la enfermedad y podría ser útil para la investigación de tratamientos específicos.