Genetic Mechanisms Underlying Autism Spectrum Disorders

Autism is a childhood-onset developmental disorder characterized by deficits in reciprocal social interaction, verbal and non-verbal communication, and dependence on routines and rituals. It belongs to a spectrum of disorders (autism spectrum disorders, ASDs) which share core symptoms but show considerable variation in severity. The whole spectrum affects 0.6-0.7% of children worldwide, inducing a substantial public health burden and causing suffering to the affected families. Despite having a very high heritability, ASDs have shown exceptional genetic heterogeneity, which has complicated the identification of risk variants and left the etiology largely unknown. However, recent studies suggest that rare, family-specific factors contribute significantly to the genetic basis of ASDs. In this study, we investigated the role of DISC1 (Disrupted-in-schizophrenia-1) in ASDs, and identified association with markers and haplotypes previously associated with psychiatric phenotypes. We identified four polymorphic micro-RNA target sites in the 3 UTR of DISC1, and showed that hsa-miR-559 regulates DISC1 expression in vitro in an allele-specific manner. We also analyzed an extended autism pedigree with genealogical roots in Central Finland reaching back to the 17th century. To take advantage of the beneficial characteristics of population isolates to gene mapping and reduced genetic heterogeneity observed in distantly related individuals, we performed a microsatellite-based genome-wide screen for linkage and linkage disequilibrium in this pedigree. We identified a putative autism susceptibility locus on chromosome 19p13.3 and obtained further support for previously reported loci at 1q23 and 15q11-q13. To follow-up these findings, we extended our study sample from the same sub-isolate and initiated a genome-wide analysis of homozygosity and allelic sharing using high-density SNP markers. We identified a small number of haplotypes shared by different subsets of the genealogically connected cases, along with convergent biological pathways from SNP and gene expression data, which highlighted axon guidance molecules in the pathogenesis of ASDs. In conclusion, the results obtained in this thesis show that multiple distinct genetic variants are responsible for the ASD phenotype even within single pedigrees from an isolated population. We suggest that targeted resequencing of the shared haplotypes, linkage regions, and other susceptibility loci is essential to identify the causal variants. We also report a possible micro-RNA mediated regulatory mechanism, which might partially explain the wide-range neurobiological effects of the DISC1 gene.

World parliament – fact or fiction? On the feasibility of world parliamentary models

Cosmopolitan ideals have been on the philosophical agenda for several millennia but the end of the Cold War started a new discussion on state sovereignty, global democracy, the role of international law and global institutions. The Westphalian state system in practice since the 17th century is transforming and the democracy deficit needs new solutions. An impetus has been the fact that in the present world, an international body representing global citizens does not exist. In this Master’s thesis, the possibility of establishing a world parliament is examined. In a case analysis, 17 models on world parliament from two journals, a volume of essays and two other publications are discussed. Based on general observations, the models are divided into four thematic groups. The models are analyzed with an emphasis on feasible and probable elements. Further, a new scenario with a time frame of thirty years is proposed based on the methodology of normative futures studies, taking special interest in causal relationships and actions leading to change. The scenario presents three gradual steps that each need to be realized before a sustainable world parliament is established. The theoretical framework is based on social constructivism, and changes in international and multi-level governance are examined with the concepts of globalization, democracy and sovereignty. A feasible, desirable and credible world parliament is constituted gradually by implying electoral, democratic and legal measures for members initially from exclusively democratic states, parliamentarians, non-governmental organizations and other groups. The parliament should be located outside the United Nations context, since a new body avoids the problem of inefficiency currently prevailing in the UN. The main objectives of the world parliament are to safeguard peace and international law and to offer legal advice in cases when international law has been violated. A feasible world parliament is advisory in the beginning but it is granted legislative powers in the future. The number of members in the world parliament could also be extended following the example of the EU enlargement process.

Pietismin kuva - ikkuna yksityiseen hengellisyyteen : Johann Arndtin opetukset pietistisen embleemin perustana

The image of Pietism a window to personal spirituality. The teachings of Johann Arndt as the basis of Pietist emblems The Pietist effect on spiritual images has to be scrutinised as a continuum initiating from the teachings of Johann Arndt who created a protestant iconography that defended the status of pictures and images as the foundation of divine revelation. Pietist artworks reveal Arndtian part of secret, eternal world, and God. Even though modern scholars do not regarded him as a founding father of Pietism anymore, his works have been essential for the development of iconography, and the themes of the Pietist images are linked with his works. For Arndt, the starting point is in the affecting love for Christ who suffered for the humankind. The reading experience is personal and the words point directly at the reader and thus appear as evidence of the guilt of the reader as well as of the love of God. Arndt uses bounteous and descriptive language which has partially affected promoting and picturing of many themes. Like Arndt, Philipp Jakob Spener also emphasised the heart that believes. The Pietist movement was born to oppose detached faith and the lack of the Holy Ghost. Christians touched by the teachings of Arndt and Spener began to create images out of metaphors presented by Arndt. As those people were part of the intelligentsia, it was natural that the fashionable emblematics of the 17th century was moulded for the personal needs. For Arndt, the human heart is manifested as a symbol of soul, personal faith or unbelief as well as an allegory of the burning love for Jesus. Due to this fact, heart emblems were gradually widely used and linked with the love of Christ. In the Nordic countries, the introduction of emblems emanated from the gentry s connections to the Central Europe where emblems were exploited in order to decorate books, artefacts, interiors, and buildings as well as visual/literal trademarks of the intelligentsia. Emblematic paintings in the churches of the castles of Venngarn (1665) and Läckö (1668), owned by Magnus Gabriel De la Gardie, are one of the most central interior paintings preserved in the Nordic countries, and they emphasise personal righteous life. Nonetheless, it was the books by Arndt and the Poet s Society in Nurnberg that bound the Swedish gentry and the scholars of the Pietist movement together. The Finnish gentry had no castles or castle churches so they supported county churches, both in building and in maintenance. As the churches were not private, their iconography could not be private either. Instead, people used Pietist symbols such as Agnus Dei, Cor ardens, an open book, beams, king David, frankincense, wood themes and Virtues. In the Pietist images made for public spaces, the attention is focused on pedagogical, metaphorical, and meaningful presentation as well as concealed statements.

Comparing type counts

This work is a case study of applying nonparametric statistical methods to corpus data. We show how to use ideas from permutation testing to answer linguistic questions related to morphological productivity and type richness. In particular, we study the use of the suffixes -ity and -ness in the 17th-century part of the Corpus of Early English Correspondence within the framework of historical sociolinguistics. Our hypothesis is that the productivity of -ity, as measured by type counts, is significantly low in letters written by women. To test such hypotheses, and to facilitate exploratory data analysis, we take the approach of computing accumulation curves for types and hapax legomena. We have developed an open source computer program which uses Monte Carlo sampling to compute the upper and lower bounds of these curves for one or more levels of statistical significance. By comparing the type accumulation from women’s letters with the bounds, we are able to confirm our hypothesis.

Sea-level changes and its impact on coastal archaeological monuments: seven pagodas of Mahabalipuram, a case study

The name `Seven Pagodas' has served as a nickname for the south Indian port of Mahabalipuram since the early European explorers used it as landmark for navigation as they could see summits of seven temples from the sea. There are many theories concerning the name Seven Pagodas. The present study has compared coastline and adjacent seven monuments illustrated in a 17th century Portolan Chart (maritime map) with recent remote sensing data. This analysis throws new light on the name ``Seven Pagodas'' for the city. This study has used DEM of the site to simulate the coastline which is similar to the one depicted in the old portolan chart. Through this, the then sea level and corresponding flooding extent according to topography of the area and their effect on monuments could be analyzed. Most importantly this work has in the process identified possibly the seven monuments that constituted the name Seven Pagodas and this provides an alternative explanation to one of the mysteries of history. This work has demonstrated unique method of studying coastal archaeological sites. As large numbers of heritage sites around the world are on coastlines, this methodology has potential to be very useful for coastal heritage preservation and management.

Espectáculos cortesanos en la América española del siglo XVII : las fiestas como caso para el análisis de la relación entre la Corte y la Corte virreinal

La Corte madrileña de los Austrias, al igual que el resto de las monarquías europeas del siglo XVII, generó una variada gama de fiestas públicas y privadas, como por ejemplo teatro musical, mascaradas y procesiones callejeras en las que desfilaban carros alegóricos con danzantes y músicos. Estos espectáculos no eran un mero entretenimiento sino que estaban destinados a resaltar las virtudes del monarca y a hacer conscientes a los espectadores del lugar que les cabía ocupar en esa sociedad recurriendo para ello a un complejo discurso simbólico. Las Cortes virreinales de América trasladaron a sus territorios estas prácticas que valían, fundamentalmente, para hacer presente la figura del rey y mantener viva la lealtad a la corona. Analizamos dos ejemplos de fiesta, una mascarada celebrada en Pausa (Perú) y un intermedio dramáticomusical en Sucre, que nos revelan la forma de pensamiento, las conductas y la organización de la sociedad cortesana virreinal.

Justicia caballeresca en América

Integran este número de la revista ponencias presentadas en Studia Hispanica Medievalia VIII: Actas de las IX Jornadas Internacionales de Literatura Española Medieval, 2008, y de Homenaje al Quinto Centenario de Amadis de Gaula.

La actividad siderometalúrgica guipuzcoana durante el siglo XVII: transformaciones y productividad

[ES]Este artículo pretende analizar la situación de la actividad siderometalúrgica guipuzcoana durante el siglo XVII y testar la verdadera repercusión de la crisis del siglo XVII en dicho sector. Para ello se ha utilizado un amplio elenco documental procedente tanto de archivos locales como regionales y nacionales, que responde a una amplia variedad tipológica.

Relaciones comerciales entre puertos franceses y guipuzcoanos en las décadas finales del siglo XVI y la primera mitad del siglo XVII: síntoma de vitalidad económica

[ES]El presente trabajo presenta una fuente documental infrautilizada, la de los libros de manifestaciones, que representa un interesantísimo instrumento de estudio para el conocimiento de la realidad comercial e industrial de la Guipúzcoa de los siglos XVI y XVII. Esta documentación permite matizar algunas de las afirmaciones que durante décadas han venido marcando la historiografía vasca sobre la tan manida “crisis del siglo XVII”, más en consonancia con los criterios que en los últimos años se vienen imponiendo en los ámbitos español y europeo. Las relaciones comerciales con puertos, principalmente franceses, que se pueden seguir a través de las mencionadas fuentes permiten seguir los fluidos intercambios y las llegadas de cereales y bastimentos, así como la salida de hierro y moneda desde algunos de los principales puertos guipuzcoanos. Una de las principales conclusiones es que la exportación de hierro a los puertos franceses tuvo continuidad a fines del siglo XVI y principios del siglo XVII

Una longeva técnica forestal: los trasmochos o desmochos guiados en Guipúzcoa durante la Edad Moderna

[ES] A fin de garantizar el aprovechamiento deun recurso renovable como la madera, en un momento de retroceso forestal y escasez de materiales, los habitantes de la provincia de Guipúzcoa, ante lo exiguo de su territorio, arbitraron un sistema que permitió combinar las necesidades y demandas de actividades tan dispares como la ganadería, el consumo doméstico, la siderurgia o la construcción naval. El presente artículo pretende analizar el origen, desarrollo y desaparición de los trasmochos guiados y describir su técnica en el territorio guipuzcoano. A falta de mayores evidencias, parece que la técnica del trasmochado o desmochado guiado inició su andadura en la Baja Edad Media, aunque hasta las primeras décadas del siglo XVI no existen datos documentales de su utilización en territorio guipuzcoano. Su generalización en todo el territorio guipuzcoano no parece producirse definitivamente hasta finales del siglo XVII, aunque para entonces se venía aplicando en la costa y el sector oriental de la reclamaciones de las autoridades reales y territoriales, la obligación de dejar horca y pendón se encontró con la oposición de carboneros y ferrones, quienes trasmochaban los árboles pero sin guiarlos, perjudicando de ese modo a las autoridades e intereses de la Marina Real. Precisamente el incumplimiento de las ordenanzas fue lo que provocó la aparición de dos modelos, con usos diferenciados: trasmochos sin guiar y trasmochos guiados. A lo largo del siglo XIX dicha técnica se fue perdiendo, coincidiendo con la paulatina desaparición de la construcción naval en madera.

Euskal gramatikagintza zaharraren historia laburra: XVII-XVIII. mendeak

Julio Urkixo Euskal Filologi Mintegiaren Urtekariaren Gehigarriak, LI.

Euskal testu ahantzi bat frantses komedia batean

[EN] In this paper a short basque text included in a french comedy from XVIIth century is published and analyzed. That text appears in the second scene ofthe Raymond Poisson's comedy, "Le Poète Basque". It seems difficult to specify which variety of Basque is used by Poisson; anyway, I try to demonstrate that text shows characteristics of the dialects of Labourd and Low Navarre.

Descripción y defensa de la lengua vasca durante los siglos XVI y XVII

Ed. por Antonio Manuel González Carrillo

Characterization of diverse megathrust fault behavior related to seismic supercycles, Mentawai Islands, Sumatra

Long paleoseismic histories are necessary for understanding the full range of behavior of faults, as the most destructive events often have recurrence intervals longer than local recorded history. The Sunda megathrust, the interface along which the Australian plate subducts beneath Southeast Asia, provides an ideal natural laboratory for determining a detailed paleoseismic history over many seismic cycles. The outer-arc islands above the seismogenic portion of the megathrust cyclically rise and subside in response to processes on the underlying megathrust, providing uncommonly good illumination of megathrust behavior. Furthermore, the growth histories of coral microatolls, which record tectonic uplift and subsidence via relative sea level, can be used to investigate the detailed coseismic and interseismic deformation patterns. One particularly interesting area is the Mentawai segment of the megathrust, which has been shown to characteristically fail in a series of ruptures over decades, rather than a single end-to-end rupture. This behavior has been termed a seismic “supercycle.” Prior to the current rupture sequence, which began in 2007, the segment previously ruptured during the 14th century, the late 16th to late 17th century, and most recently during historical earthquakes in 1797 and 1833. In this study, we examine each of these previous supercycles in turn.

First, we expand upon previous analysis of the 1797–1833 rupture sequence with a comprehensive review of previously published coral microatoll data and the addition of a significant amount of new data. We present detailed maps of coseismic uplift during the two great earthquakes and of interseismic deformation during the periods 1755–1833 and 1950–1997 and models of the corresponding slip and coupling on the underlying megathrust. We derive magnitudes of Mw 8.7–9.0 for the two historical earthquakes, and determine that the 1797 earthquake fundamentally changed the state of coupling on the fault for decades afterward. We conclude that while major earthquakes generally do not involve rupture of the entire Mentawai segment, they undoubtedly influence the progression of subsequent ruptures, even beyond their own rupture area. This concept is of vital importance for monitoring and forecasting the progression of the modern rupture sequence.

Turning our attention to the 14th century, we present evidence of a shallow slip event in approximately A.D. 1314, which preceded the “conventional” megathrust rupture sequence. We calculate a suite of slip models, slightly deeper and/or larger than the 2010 Pagai Islands earthquake, that are consistent with the large amount of subsidence recorded at our study site. Sea-level records from older coral microatolls suggest that these events occur at least once every millennium, but likely far less frequently than their great downdip neighbors. The revelation that shallow slip events are important contributors to the seismic cycle of the Mentawai segment further complicates our understanding of this subduction megathrust and our assessment of the region’s exposure to seismic and tsunami hazards.

Finally, we present an outline of the complex intervening rupture sequence that took place in the 16th and 17th centuries, which involved at least five distinct uplift events. We conclude that each of the supercycles had unique features, and all of the types of fault behavior we observe are consistent with highly heterogeneous frictional properties of the megathrust beneath the south-central Mentawai Islands. We conclude that the heterogeneous distribution of asperities produces terminations and overlap zones between fault ruptures, resulting in the seismic “supercycle” phenomenon.

Arctic charr (Salvelinus alpinus) in Windermere (Cumbria)

The Arctic charr of the British Isles are all non-migratory and are near their most southernmost range. Windermere is one of the few lowland lakes at southerly latitudes to contain a substantial proportion of Arctic charr. The first recorded mention of charr in Windermere was made around 1540 but it was not till the 17th century that different "sons" of charr were recognized, based on differences in their breeding behaviour. In the 1960's, the presence of two distinct populations, autumn spawners and spring spawners were discovered. In the 1980's it was shown that there were at least four races of charr in Windermere, based on genetic characteristics. Recently, the lake has changed due to inputs of phosphorus from treated sewage released into the lake resulting in eutrophication particularly in the south basin. Since the mid-1980's the numbers of charr caught in the south basin have declined.