Genetic Heterogeneity in Autism Spectrum Disorders in a Population Isolate

Positional cloning has enabled hypothesis-free, genome-wide scans for genetic factors contributing to disorders or traits. Traditionally linkage analysis has been used to identify regions of interest, followed by meticulous fine mapping and candidate gene screening using association methods and finally sequencing of regions of interest. More recently, genome-wide association analysis has enabled a more direct approach to identify specific genetic variants explaining a part of the variance of the phenotype of interest. Autism spectrum disorders (ASDs) are a group of childhood onset neuropsychiatric disorders with shared core symptoms but varying severity. Although a strong genetic component has been established in ASDs, genetic susceptibility factors have largely eluded characterization. Here, we have utilized modern molecular genetic methods combined with the advantages provided by the special population structure in Finland to identify genetic risk factors for ASDs. The results of this study show that numerous genetic risk factors exist for ASDs even within a population isolate. Stratification based on clinical phenotype resulted in encouraging results, as previously identified linkage to 3p14-p24 was replicated in an independent family set of families with Asperger syndrome, but no other ASDs. Fine-mapping of the previously identified linkage peak for ASDs at 3q25-q27 revealed association between autism and a subunit of the 5-hydroxytryptamine receptor 3C (HTR3C). We also used dense, genome-wide single nucleotide polymorphism (SNP) data to characterize the population structure of Finns. We observed significant population substructure which correlates with the known history of multiple consecutive bottle-necks experienced by the Finnish population. We used this information to ascertain a genetically homogenous subset of autism families to identify possible rare, enriched risk variants using genome-wide SNP data. No rare enriched genetic risk factors were identified in this dataset, although a subset of families could be genealogically linked to form two extended pedigrees. The lack of founder mutations in this isolated population suggests that the majority of genetic risk factors are rare, de novo mutations unique to individual nuclear families. The results of this study are consistent with others in the field. The underlying genetic architecture for this group of disorders appears highly heterogeneous, with common variants accounting for only a subset of genetic risk. The majority of identified risk factors have turned out to be exceedingly rare, and only explain a subset of the genetic risk in the general population in spite of their high penetrance within individual families. The results of this study, together with other results obtained in this field, indicate that family specific linkage, homozygosity mapping and resequencing efforts are needed to identify these rare genetic risk factors.

Board of Delegates of American Israelites records 1859-1881, 1887, 1932

Contains printed copies of the 1860 constitution and by-laws, copies of proceedings and annual reports, 1859-1877, of the Board of Delegates; report on Jews in Roumania, an 1874 annual report of the Hebrew Benevolent and Orphan Asylum Society, manuscript minute books and minutes of meetings, 1859-1876, resolutions, executive, financial, ritual slaughtering and other special committee reports, newspaper clippings and correspondence with synagogues and organizations in the U.S. who constitute the membership of the Board of Delegates, with the Union of American Hebrew Congregations with whom they later merged, the Union's Board of Delegates of Civil and Religious Rights, and with individuals and organizations in foreign countries including the Alliance Israelite Universelle, the Anglo-Jewish Association, the Board of Deputies of British Jews, the Committee for the Roumanian Jews (Berlin), the Koenigsberg Committee, and the London Roumanian Committee.

Louis Marshall papers undated, 1905-1933

Chiefly material relating to activities against restrictive immigration legislation; also some items referring to decisions of the United States Supreme Court and naturalization of immigrants. Correspondence with members of the American Jewish Committee, primarily Herbert Friedenwald, Fulton Brylawski, and Max James Kohler. Contains also printed extracts of Congressional hearings and Congressional record.

Max James Kohler papers, 1888-1934.

Contains scrapbooks, correspondence and reports relating to Kohler's extensive activities on behalf of liberal immigration and naturalization laws in the United States, his opposition to the registration of aliens, the problems of Chinese immigration to the United States, his opposition to the use of the term "Hebrew Race" in the classification of immigrants, the drafting of minority clauses at the Paris Peace Conference in 1919, Jewish and Christian relations in the U.S., and the condition of Jews in Russia, Roumania, Poland and Nazi-Germany with the following institutions: the American Civil Liberties Union, 1926-1934, the American Jewish Committee, 1909-1934, B'nai Brith, 1930-1933, the Union of American Hebrew Congregations - Board of Delegates on Civil Rights, the Committee on Ellis Island, the Foreign Language Information Service, the Hebrew Benevolent Society of Baltimore, the Hebrew Sheltering and Immigrant Aid Society, the Jewish Immigrants' Information Bureau in Galveston, Texas, the Industrial Removal Office, the National Conference of Jews and Christians, the National Council of Jewish Women, the National Council on Naturalization and Citizenship, the Bureau of Immigration to the United States Department of Laborm the United States Department of Commerce and Labor, the Department of State and individual United States Congressmen.

Elihu Stone collection undated, 1913-1962.

Collection contains materials pertaining to the life and work of Stone.

Cryptographic Software Export Controls in the EU

Certain software products employing digital techniques for encryption of data are subject to export controls in the EU Member States pursuant to Community law and relevant laws in the Member States. These controls are agreed globally in the framework of the so-called Wassenaar Arrangement. Wassenaar is an informal non-proliferation regime aimed at promoting international stability and responsibility in transfers of strategic (dual-use) products and technology. This thesis covers provisions of Wassenaar, Community export control laws and export control laws of Finland, Sweden, Germany, France and United Kingdom. This thesis consists of five chapters. The first chapter discusses the ratio of export control laws and the impact they have on global trade. The ratio is originally defence-related - in general to prevent potential adversaries of participating States from having the same tools, and in particular in the case of cryptographic software to enable signals intelligence efforts. Increasingly as the use of cryptography in a civilian context has mushroomed, export restrictions can have negative effects on civilian trade. Information security solutions may also be took weak because of export restrictions on cryptography. The second chapter covers the OECD's Cryptography Policy, which had a significant effect on its member nations' national cryptography policies and legislation. The OECD is a significant organization,because it acts as a meeting forum for most important industrialized nations. The third chapter covers the Wassenaar Arrangement. The Arrangement is covered from the viewpoint of international law and politics. The Wassenaar control list provisions affecting cryptographic software transfers are also covered in detail. Control lists in the EU and in Member States are usually directly copied from Wassenaar control lists. Controls agreed in its framework set only a minimum level for participating States. However, Wassenaar countries can adopt stricter controls. The fourth chapter covers Community export control law. Export controls are viewed in Community law as falling within the domain of Common Commercial Policy pursuant to Article 133 of the EC Treaty. Therefore the Community has exclusive competence in export matters, save where a national measure is authorized by the Community or falls under foreign or security policy derogations established in Community law. The Member States still have a considerable amount of power in the domain of Common Foreign and Security Policy. They are able to maintain national export controls because export control laws are not fully harmonized. This can also have possible detrimental effects on the functioning of internal market and common export policies. In 1995 the EU adopted Dual-Use Regulation 3381/94/EC, which sets common rules for exports in Member States. Provisions of this regulation receive detailed coverage in this chapter. The fifth chapter covers national legislation and export authorization practices in five different Member States - in Finland, Sweden, Germany, France and in United Kingdom. Export control laws of those Member States are covered when the national laws differ from the uniform approach of the Community's acquis communautaire. Keywords: export control, encryption, software, dual-use, license, foreign trade, e-commerce, Internet

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.

Late Svecofennian leucogranites of southern Finland : Chronicles of an orogenic collapse

Leucogranite magmatism occurred in southern Finland during the later stages of the Paleoproterozoic Svecofennian orogeny. The leucogranites are considered to have formed from pre-existing crustal rocks that have undergone anatexis in the extensional stage of the orogeny, following continental collision and resultant crustal thickening. The leucogranites have been studied in the field using petrographic and mineralogical methods, elemental and isotope geochemistry on whole rocks and minerals, and U-Pb geochronology. On outcrop scale, these granites typically form heterogeneous, layered, sheet-like bodies that migmatize their country rocks. All of the leucogranites are peraluminous and rich in SiO2, but otherwise display significant geochemical variation. Their Nd isotope composition ranges from fairly juvenile to very unradiogenic, and the Hf isotope composition of their zircon shows a varying degree of mixing in the source, the zircon populations becoming more heterogeneous and generally less radiogenic towards the east. The leucogranites have been dated using U-Pb isotopic analyses, utilizing thermal ionization mass spectrometry, secondary ion mass spectrometry, and laser ablation multicollector ICP mass spectrometry on zircon and monazite. The results show that the granites were emplaced between 1.85 Ga and 1.79 Ga, which is a considerably longer period than has traditionally been perceived for these rocks. The rocks tend to become younger towards the east. Single crystal data also display a wide array of inherited zircons, especially in the eastern part of the leucogranite belt. The most common inherited age groups are ~2.8 2.5 Ga, ~2.1 2.1 Ga, and ~1.9 Ga. Magmatic zircon and monazite usually record similar ages for any one sample.Thermobarometric calculations indicate that the leucogranites in the Veikkola area of southcentral Finland were formed from relatively low-temperature melts, and emplaced at 17-25 km depth, i.e. at mid-crustal level. It is likely that these conditions apply to the Svecofennian leucogranites in general. Large differences in the Hf and Nd isotope compositions, emplacement ages, and distributions of inherited zircon ages show that these granites were formed from different types of source rocks, which probably included both sedimentary and igneous rocks.

Yhden uhka, toisen toive? : Somalien ja venäläisten asumistoiveet etnisen segregaatiokehityksen valossa

Ethnic minorities residential patterns and integration are widely discussed issues in many European countries. They have also become topical in Finland due to an increase in foreign migration, especially in recent decades. This dissertation contributes to debates associated with attempts to explain ethnic minorities residential patterns by examining the role of cultural factors and ethnic preferences of the residential choices of Somali and Russian immigrants in Finland. The research is based on in-depth interviews with Somali (n=24) and Russian (n=26) immigrants living in the Helsinki metropolitan area. Housing officials and social workers (n=18) working in cities of Helsinki and Vantaa were also interviewed. The results of this study show that propinquity to one s own ethnic group is important to Somalis living in Finland. This is important for maintaining their traditional, communal life styles, but also as a safe haven against the racism which they experience on a regular basis. They have a preference for mixed neighbourhoods that contain both native Finnish residents and some ethnic minorities. For Russians the spatial propinquity to their country people is less significant at the neighbourhood level. However, this is not to indicate the insignificance of intra-ethnic networks or one s cultural background. Rather, the differences in ethnic preferences between Somalis and Russians predominantly reflect their varying levels of exposure to racial harassment and diverse meanings that they give to social relations with their neighbours. According to this study, the time spent in a host-country and interactions with other ethnic groups affect ethnic preferences. The importance of one s own ethnic community also varies in accordance with life situations. Therefore, ethnic minorities residential preferences and choices should not be viewed as static or something deriving from cultural background alone. Residential preferences and aspirations are constantly being reshaped vis-à-vis to immigrants experiences. Past and present experiences and the way that immigrants observe the host society and its functions are important for the interpretation of residential preferences and patterns.

Neoarchean sanukitoid series in the Karelian Province, Finland

Sanukitoid series intrusions can be found throughout the Archean Karelian Province of the Fennoscandian shield. All sanukitoids share the same controversial elemental characteristics: they have high content of incompatible elements such as K, Ba, and Sr as well as high content of the compatible elements Mg, Cr, and Ni, and high Mg#. This composition is explained by an enriched mantle wedge origin in a Neoarchean subduction setting. This study concentrates on sanukitoid intrusions and tonalite-trondhjemite-granodiorite series (TTGs) from Finnish part of the Karelian Province. The collected rock samples have been studied in the field and under microscope as well as for their whole-rock (including isotopes) and mineral compositions. The new data together with previously published analyses help us to better understand the petrogenesis, tectonic setting and reworking of the Archean rock units. TTGs from the Karelian Province form a voluminous series of granitoids and reworked migmatites. This study divides TTG series into two subgroups based on their elemental composition: low-HREE (heavy rare earth element) TTGs and high-HREE TTGs indicating pressure differences in their source. Sanukitoid series is a minor, divergent group of intrusions. These intrusions are variable sized, and the texture varies from even-grained to K-feldspar porphyritic. The elemental composition differentiates sanukitoids from more voluminous TTG groups, the SiO2 in sanukitoids varies to include series of gabbro, diorite, and granodiorite. U Pb age determinations from sanukitoid series show temporally limited emplacement between ~ 2745 2715 Ma after the main crust forming period in the area. Hafnium, neodymium, common lead, and oxygene isotopes indicate well homogenized characteristics. Recycled crust has made a variable, yet minor, contribution to sanukitoids, as evidenced by oxygene isotopes and inherited zircon cores. A proposed tectonic setting for the formation of the sanukitoid series is slab breakoff of oceanic lithosphere in subduction setting, with sanukitoids deriving from an enriched mantle wedge. The proposed setting explains some of the peculiar features of sanukitoids, such as their temporally limited occurrence and controversial elemental composition. Sanukitoids would occur after cessation of the regional growth of Archean crust, and they could be derived from mantle wedge previously enriched by melts and fluids from oceanic crust and sediments. A subsequent event during the Paleoproterozoic Svecofennian orogeny at ~1.9 Ga affected the appearance and microstructures of the rocks as well as caused redistribution of lead between minerals and whole rock. However, the deformation was not able to obliterate the original geochemical characteristics of these sanukitoids.

Elämää keskustassa ja kaupunkiseudun reunoilla. Urbaani ja jälkiesikaupungillinen elämäntyyli asumisen valinnoissa ja arkiliikkumisessa Helsingin seudulla.

The lifestyles of people living in single-family housing areas on the outskirts of the Greater Helsinki Region (GHR) are different from those living in inner city area. The urban structure of the GHR is concentrated in the capital on the one hand, and spread out across the outskirts on the other. Socioeconomic spatial divisions are evident as well-paid and educated residents move to the inner city or the single-family house dominated suburban neighbourhoods depending on their housing preferences and life situations. The following thesis explores how these lifestyles have emerged through the housing choices and daily mobility of the residents living in the new single-family housing areas on the outskirts of the GHR and the inner city. The study shows that, when it comes to lifestyles, residents on the outskirts of the region have different housing preferences and daily mobility patterns when compared with their inner city counterparts. Based on five different case study areas my results show that these differences are related to residents values, preferences and attitudes towards the neighbourhood, on the one hand, and limited by urban structure on the other. This also confirms earlier theoretical analyses and findings from the GHR. Residents who moved to the outskirts of Greater Helsinki Region and the apartment buildings of the inner city were similar in the basic elements of their housing preferences: they sought a safe and peaceful neighbourhood close to the natural environment. However, where housing choices, daily mobility and activities vary different lifestyles develop in both the outskirts and the inner city. More specifically, lifestyles in the city apartment blocks were inherently urban. Liveliness and highest order facilities were appreciated and daily mobility patterns were supported by diverse modes of transportation for the purposes of work, shopping and leisure time. On the outskirts, by contrast, lifestyles were largely post-suburban and child-friendliness appreciated. Due to the heterachical urban structure, daily mobility was more car-dependent since work, shopping and free time activities of the residents are more spread around the region. The urban structure frames the daily mobility on the outskirts of the region, but this is not to say that short local trips replace longer regional ones. This comparative case study was carried out in the single-family housing areas of Sundsberg in Kirkkonummi, Landbo in Helsinki and Ylästö in Vantaa, as well as in the inner city apartment building areas of Punavuori and Katajanokka in Helsinki. The data is comprised of residential surveys, interviews, and statistics and GIS data sets that illustrate regional daily mobility, socio-economic structure and vis-à-vis housing stock.

Las mujeres mozárabes : identidades híbridas y campo de acción del colectivo femenino entre Al- Andalus y la cristianidad

Resumen: La historia de los mozárabes de la Península Ibérica ha sido abordada desde múltiples perspectivas. Sin embargo, la situación de las mujeres de este colectivo no ha sido objeto de mayores estudios. El propósito del presente trabajo será realizar un primer acercamiento a la situación de las mujeres mozárabes, sus características y sus posibilidades de actuación tanto bajo las leyes islámicas, como bajo las normas cristianas. El análisis de esta cuestión se realizará teniendo en cuenta la naturaleza plástica de la identidad mozárabe, como así también el conjunto de normas internas y externas al grupo que modelaron sus posibilidades de acción.

Analysis of spallation based upon statistical microdamage mechanics

A relationship between the cumulative length of microcracks and the amplitude and duration of tensile impulse in spallation was established based on the application of statistical microdamage mechanics, which included a statistical formulation and dynamic laws of microdamage under loading. Since the degrees of spallation, called incipient, intermediate and complete spallation, can be characterized by the cumulative length of microcracks, a physical interpretation of an empirical criterion to spallation was presented.

Prevalência da Câmara dos Deputados no processo legislativo bicameral : a Lei de improbidade administrativa

Analisa a Constituição Federal e as Leis Ordinárias editadas em 2011 para saber se existe a prevalência de uma das Casas do Congresso Nacional na elaboração das leis. O estudo pretende, a partir da abordagem teórica e da análise das legislações publicadas, observando o processo legislativo bicameral para deliberação dos projetos, verificar as consequências para a definição do texto final das leis publicadas. Para tanto, propõe-se realizar estudo sobre o Poder Legislativo no Brasil e o modelo de sistema bicameral adotado. Também são analisadas todas as Constituições editadas no Brasil para saber os aspectos históricos e políticos em sua elaboração e os efeitos na definição das atribuições das Casas do Congresso Nacional, com repercussões no processo legislativo. É realizada a análise da tramitação legislativa da Lei de Improbidade Administrativa, expondo os textos adotados pelas Casas, com a definição do texto encaminhado para transformação em norma jurídica.

Awakening a sleeping giant: The riddle of Latino political participation

For some time now, the Latino voice has been gradually gaining strength in American politics, particularly in such states as California, Florida, Illinois, New York, and Texas, where large numbers of Latino immigrants have settled and large numbers of electoral votes are at stake. Yet the issues public officials in these states espouse and the laws they enact often do not coincide with the interests and preferences of Latinos. The fact that Latinos in California and elsewhere have not been able to influence the political agenda in a way that is commensurate with their numbers may reflect their failure to participate fully in the political process by first registering to vote and then consistently turning out on election day to cast their ballots.

To understand Latino voting behavior, I first examine Latino political participation in California during the ten general elections of the 1980s and 1990s, seeking to understand what percentage of the eligible Latino population registers to vote, with what political party they register, how many registered Latinos to go the polls on election day, and what factors might increase their participation in politics. To ensure that my findings are not unique to California, I also consider Latino voter registration and turnout in Texas for the five general elections of the 1990s and compare these results with my California findings.

I offer a new approach to studying Latino political participation in which I rely on county-level aggregate data, rather than on individual survey data, and employ the ecological inference method of generalized bounds. I calculate and compare Latino and white voting-age populations, registration rates, turnout rates, and party affiliation rates for California's fifty-eight counties. Then, in a secondary grouped logit analysis, I consider the factors that influence these Latino and white registration, turnout, and party affiliation rates.

I find that California Latinos register and turn out at substantially lower rates than do whites and that these rates are more volatile than those of whites. I find that Latino registration is motivated predominantly by age and education, with older and more educated Latinos being more likely to register. Motor voter legislation, which was passed to ease and simplify the registration process, has not encouraged Latino registration . I find that turnout among California's Latino voters is influenced primarily by issues, income, educational attainment, and the size of the Spanish-speaking communities in which they reside. Although language skills may be an obstacle to political participation for an individual, the number of Spanish-speaking households in a community does not encourage or discourage registration but may encourage turnout, suggesting that cultural and linguistic assimilation may not be the entire answer.

With regard to party identification, I find that Democrats can expect a steady Latino political identification rate between 50 and 60 percent, while Republicans attract 20 to 30 percent of Latino registrants. I find that education and income are the dominant factors in determining Latino political party identification, which appears to be no more volatile than that of the larger electorate.

Next, when I consider registration and turnout in Texas, I find that Latino registration rates are nearly equal to those of whites but that Texas Latino turnout rates are volatile and substantially lower than those of whites.

Low turnout rates among Latinos and the volatility of these rates may explain why Latinos in California and Texas have had little influence on the political agenda even though their numbers are large and increasing. Simply put, the voices of Latinos are little heard in the halls of government because they do not turn out consistently to cast their votes on election day.

While these findings suggest that there may not be any short-term or quick fixes to Latino participation, they also suggest that Latinos should be encouraged to participate more fully in the political process and that additional education may be one means of achieving this goal. Candidates should speak more directly to the issues that concern Latinos. Political parties should view Latinos as crossover voters rather than as potential converts. In other words, if Latinos were "a sleeping giant," they may now be a still-drowsy leviathan waiting to be wooed by either party's persuasive political messages and relevant issues.