Molecular genetics of schizophrenia

1. Schizophrenia is a chronic, disabling brain disease that affects approxmately 1% of the world's population. It is characterized by delusions, hallucinations and formal thought disorder, together with a decline in socio-occupational functioning. While the causes for schizophrenia remain unknown, evidence from family, twin and adoption studies clearly demonstrates that it aggregates in families, with this clustering largely attributable to genetic rather than cultural or environmental factors. Identifying the genes involved, however, has proven to be a difficult task because schizophrenia is a complex trait characterized by an imprecise phenotype, the existence of phenocopies and the presence of low disease penetrance, 2. The current working hypothesis for schizophrenia causation is that multiple genes of small to moderate effect confer compounding risk through interactions with each other and with non-genetic risk factors, The same genes may be commonly involved in conferring risk across populations or they may vary in number and strength between different populations. To search for evidence of such genetic loci, both candidate gene and genome-wide linkage studies have been used in clinical cohorts collected from a variety of populations. Collectively, these works provide some evidence for the involvement of a number of specific genes (e.g. the 5-hydroxytryptamine (5-HT) type 2a receptor (5-HT2a) gene and the dopamine D-3 receptor gene) and as yet unidentified factors localized to specific chromosomal regions, including 6p, 6q, 8p, 13q and 22q, These data provide suggestive, but no conclusive, evidence for causative genes. 3. To enable further progress there is a need to: (i) collect fine-grained clinical datasets while searching the schizophrenia phenotype for subgroups or dimensions that may provide a more direct route to causative genes; and (ii) integrate recent refinements in molecular genetic technology, including modern composite marker maps, DNA expression assays and relevant animal models, while using the latest analytical techniques to extract maximum information in order to help distinguish a true result from a false-positive finding.

Mouse Sox8 is located between, not within, the t-complex deletions t(w18) and t(h20) on chromosome 17

The SOX family of developmental transcription factors is known to play critical roles in cell lineage specification, fate determination and differentiation during development in diverse phyla. Their importance is underscored by their involvement in a number of human diseases and mouse mutants, and by targeted mutation in mice. SOX8 is broadly expressed during development and is located on human chromosome 16p and within the t-complex on mouse chromosome 17, in the vicinity of two mutations t(w18) and t(h20). Here we analyse mutant genomic DNA to show that the Sox8 gene locus lies outside the deletion regions of both t(w18) and t(h20) and between these deletions. These data exclude Sox8 from contributing to the t(w18) and t(h20) phenotypes, and provide an additional marker for structural characterization of this complex genomic region. Copyright (C) 2001 S. Karger AG, Basel.

Set-valued Markov chains and negative semitrajectories of discretized dynamical systems

Computer simulation of dynamical systems involves a phase space which is the finite set of machine arithmetic. Rounding state values of the continuous system to this grid yields a spatially discrete dynamical system, often with different dynamical behaviour. Discretization of an invertible smooth system gives a system with set-valued negative semitrajectories. As the grid is refined, asymptotic behaviour of the semitrajectories follows probabilistic laws which correspond to a set-valued Markov chain, whose transition probabilities can be explicitly calculated. The results are illustrated for two-dimensional dynamical systems obtained by discretization of fractional linear transformations of the unit disc in the complex plane.

Resources for security and stability? The politics of regional cooperation on the Mekong, 1957-2001

This article tells about the relationship between resource politics and security in international relations. Using the Mekong River Basin as its case study, the article examines the place of resource and development issues in attempts to develop regional institutions. The question of whether a resource development regime with apparently low productivity in terms of technical output, but high levels of resilience and longevity, should be considered a failure or not, is considered. This question is examined within the broader context of Southeast Asian politics during the First, Second, and Third Indochina conflicts as well as the post-cold war era. The article argues that survival and a capacity to change to meet the challenges of extreme broader events are clear evidence of regime success. From this standpoint, the article explores ways in which the Mekong resource regime is linked to more general concerns for political security and stability and may in fact reflect political concerns for subregional neighborhood maintenance.

Branching processes and computational collapse of discretized unimodal mappings

In computer simulations of smooth dynamical systems, the original phase space is replaced by machine arithmetic, which is a finite set. The resulting spatially discretized dynamical systems do not inherit all functional properties of the original systems, such as surjectivity and existence of absolutely continuous invariant measures. This can lead to computational collapse to fixed points or short cycles. The paper studies loss of such properties in spatial discretizations of dynamical systems induced by unimodal mappings of the unit interval. The problem reduces to studying set-valued negative semitrajectories of the discretized system. As the grid is refined, the asymptotic behavior of the cardinality structure of the semitrajectories follows probabilistic laws corresponding to a branching process. The transition probabilities of this process are explicitly calculated. These results are illustrated by the example of the discretized logistic mapping.

Inhibition of tubulin assembly and covalent binding to microtubular protein by valproic acid glucuronide in vitro

Acyl glucuronides are reactive metabolites of carboxylate drugs, able to undergo a number of reactions in vitro and in vivo, including isomerization via intramolecular rearrangement and covalent adduct formation with proteins. The intrinsic reactivity of a particular acyl glucuronide depends upon the chemical makeup of the drug moiety. The least reactive acyl glucuronide yet reported is valproic acid acyl glucuronide (VPA-G), which is the major metabolite of the antiepileptic agent valproic acid (VPA). In this study, we showed that both VPA-G and its rearrangement isomers (iso-VPA-G) interacted with bovine brain microtubular protein (MTP, comprised of 85% tubulin and 15% microtubule associated proteins {MAPs}). MTP was incubated with VPA, VPA-G and iso-VPA-G for 2 h at room temperature and pH 7.5 at various concentrations up to 4 mM. VPA-G and iso-VPA-G caused dose-dependent inhibition of assembly of MTP into microtubules, with 50% inhibition (IC50) values of 1.0 and 0.2 mM respectively, suggesting that iso-VPA-G has five times more inhibitory potential than VPA-G. VPA itself did not inhibit microtubule formation except at very high concentrations (greater than or equal to2 mM). Dialysis to remove unbound VPA-G and iso-VPA-G (prior to the assembly assay) diminished inhibition while not removing it. Comparison of covalent binding of VPA-G and iso-VPA-G (using [C-14]-labelled species) showed that adduct formation was much greater for iso-vTA-G. When [C-14]-iso-VPA-G was reacted with MTP in the presence of sodium cyanide (to stabilize glycation adducts), subsequent separation into tubulin and MAPs fractions by ion exchange chromatography revealed that 78 and 22% of the covalent binding occurred with the MAPs and tubulin fractions respectively. These experiments support the notion of both covalent and reversible binding playing parts in the inhibition of microtubule formation from MTP (though the acyl glucuronide of VPA is less important than its rearrangement isomers in this regard), and that both tubulin and (perhaps more importantly) MAPs form adducts with acyl glucuronides. (C) 2002 Elsevier Science Inc. All rights reserved.

Localization of a novel melanoma susceptibility locus to 1p22

Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82; recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta = 0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores 13 in this subset, with the highest parametric LOD score, 4.95 (theta = 0) ( nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.

Deviance and marginal occupations: the case of taxi drivers

The taxi industry provides a strategic site to explore workplace deviance in low supervision, low status, occupational settings. Despite this theoretical opportunity and the objective importance of the taxi industry worldwide, very little is known about deviance among taxi drivers. Making use of interview data, this exploratory study maps out forms of workplace deviance and the explanations given for them by a sample of male taxi drivers. Major illegal activities reported included speeding, driving unsafe vehicles, taking drugs, and fraud. Theories pertaining to worker alienation, stress management, victim precipitation, and social control were relevant to the rationalizations some of the drivers provided to account for their illegal behaviors. We conclude that the occupational culture of taxi drivers and the structure of the taxi industry facilitate the forms of deviance reported here.

Linking physiological and architectural models of cotton

Despite the strong influence of plant architecture on crop yield, most crop models either ignore it or deal with it in a very rudimentary way. This paper demonstrates the feasibility of linking a model that simulates the morphogenesis and resultant architecture of individual cotton plants with a crop model that simulates the effects of environmental factors on critical physiological processes and resulting yield in cotton. First the varietal parameters of the models were made concordant. Then routines were developed to allocate the flower buds produced each day by the crop model amongst the potential positions generated by the architectural model. This allocation is done according to a set of heuristic rules. The final weight of individual bolls and the shedding of buds and fruit caused by water, N, and C stresses are processed in a similar manner. Observations of the positions of harvestable fruits, both within and between plants, made under a variety of agronomic conditions that had resulted in a broad range of plant architectures were compared to those predicted by the model with the same environmental inputs. As illustrated by comparisons of plant maps, the linked models performed reasonably well, though performance of the fruiting point allocation and shedding algorithms could probably be improved by further analysis of the spatial relationships of retained fruit. (C) 2002 Elsevier Science Ltd. All rights reserved.

Dynamics of Gray Matter Loss in Alzheimer's Disease

We detected and mapped a dynamically spreading wave of gray matter loss in the brains of patients with Alzheimer's disease (AD). The loss pattern was visualized in four dimensions as it spread over time from temporal and limbic cortices into frontal and occipital brain regions, sparing sensorimotor cortices. The shifting deficits were asymmetric (left hemisphere >right hemisphere) and correlated with progressively declining cognitive status ( p 15% loss). The maps distinguished different phases of AD and differentiated AD from normal aging. Local gray matter loss rates (5.3 +/- 2.3% per year in AD v 0.9 +/- 0.9% per year in controls) were faster in the left hemisphere ( p < 0.029) than the right. Transient barriers to disease progression appeared at limbic/frontal boundaries. This degenerative sequence, observed in vivo as it developed, provides the first quantitative, dynamic visualization of cortical atrophic rates in normal elderly populations and in those with dementia.

The paternity of the price-quality 'value map'

In the literature on firm strategy and product differentiation, consumer price-quality trade-offs are sometimes represented using consumer 'value maps'. These involve the geometric representation of indifferent price and quality combinations as points along curves that are concave to the 'quality' axis. In this paper, it is shown that the value map for price-quality tradeoffs may be derived from a Hicksian compensated demand curve for product quality. The paper provides the theoretical link between analytical methods employed in the existing literature on firm strategy and competitive advantage with the broader body of economic analysis.

A genetic map of macadamia based on randomly amplified DNA fingerprinting (RAF) markers

The first genetic linkage map of macadamia (Macadamia integrifolia and M. tetraphylla) is presented. The map is based on 56 F-1 progeny of cultivars 'Keauhou' and 'A16'. Eighty-four percent of the 382 markers analysed segregated as Mendelian loci. The two-way pseudo-testcross mapping strategy allowed construction of separate parental cultivar maps. Ninety bridging loci enabled merging of these maps to produce a detailed genetic map of macadamia, 1100 cM in length and spanning 70-80% of the genome. The combined map comprised 24 linkage groups with 265 framework markers: 259 markers from randomly amplified DNA fingerprinting (RAF), five random amplified polymorphic DNA (RAPD), and one sequence-tagged microsatellite site (STMS). The RAF marker system unexpectedly revealed 16 codominant markers, one of them a putative microsatellite locus and exhibiting four distinct alleles in the cross. This molecular study is the most comprehensive examination to date of genetic loci of macadamia, and is a major step towards developing marker-assisted selection for this crop.

Editorial

The year 2003 marks the 30th anniversary of The Australian Journal of Indigenous Education (AJIE) and coincides with the re-launching of the journal as a peer reviewed research journal.Beginning life in 1973 as The Aboriginal Child at School, AJIE has played a vital role in raising awareness of educational issues for Aboriginal and Torres Strait Islander peoples; fostering debate amongst researchers, government representatives and community groups; and sharing stories of success between both Indigenous and non- Indigenous practitioners positioned in the broad area of Aboriginal and Torres Strait Islander education. The dialogue which has taken place in AJIE over the past 30 years maps out the social, political and cultural history of Indigenous education in Australia, and draws attention to the shifting paradigms,problems and practical outcomes.

Ensino primário e matemática dos imigrantes e descendentes germânicos em Santa Leopoldina (1857-1907)

O objetivo da pesquisa é descrever o cenário da imigração germânica no século XIX, tratando também, de trilhar o caminho da educação por meio de educadores e das comunidades na Colônia de Santa Leopoldina, criada em 1857, na Província do Espírito Santo, considerando 50 anos a partir do início da imigração (1857-1907). A pesquisa histórica ancorou-se em consultas a documentos oficiais do Império, documentos e relatórios oficiais dos Presidentes da Província do Espírito Santo, jornais de circulação da época, fotografias, mapas geográficos, mapas estatísticos, livros didáticos antigos e livros de autores que abordaram o processo imigratório do Espírito Santo. O diálogo com Marc Bloch ajudou a entender essa multiplicidade de documentos, na complexa relação entre o passado e o presente da educação do Espírito Santo. O trabalho apresenta uma trajetória do imigrante germânico vindo da Europa até a ex-colônia e como a administração da província tratou a imigração e a educação. O ensino primário iniciou-se a partir de iniciativas públicas e particulares. Foram identificados as primeiras escolas e os nomes de muitos professores que atuaram no período estudado. Os livros utilizados nas escolas das comunidades teuto-brasileiras eram oriundos da Alemanha e posteriormente foram produzidos no sul do Brasil. Entre os livros escritos em alemão encontrados destacam-se o livro texto de alfabetização „Lese – Schule I für Deutsche Kinder in Brasilien‟, editado na Alemanha no final do século XIX, de autoria do diretor de uma escola particular em Santa Leopoldina, Albert Richard Dietze, e o primeiro volume do livro de matemática „Rechenbuch für Deutsch-Brasilianische Volksschulen‟, de Ferdinand Hackbart, Konrad Glaus e Hermann Lange. Foi feita uma análise sob os aspectos físicos e formais, o processo de ensino e os conteúdos do livro de matemática. A análise evidenciou que a proposta de ensino apoia-se no “cálculo mental” e o escrito, com a repetição dos conteúdos, envolvendo o treino intensivo. Os conceitos de matemática são apresentados partindo de problemas com situações concretas do aluno para a aquisição de competências necessárias para inserir o aluno em sua comunidade. Levando-se em conta que o livro foi editado em 1906, conclui-se que se trata de uma obra relevante com uma proposta de ensino que se manteve presente nos livros didáticos de matemática até os dias atuais.

O papel da cidade de Viçosa-MG na rede urbana : a especialização funcional de uma cidade média mineira

Rede é o nome dado para se referenciar qualquer forma que seja composta por linhas interligadas por pontos, sendo assim essa denominação é utilizada para participar de nomes e conceitos em diversas área do conhecimento. Na geografia isso não ocorre de forma diferente. As redes geográficas são a denominação dada as ligações feitas no espaço articuladas por pontos, notadamente são usadas para se fazer referência a redes materiais, mas podem ser mais imateriais ou abstratas a depender do objeto de pesquisa e do adjetivo adotado. A noção de redes urbanas nasceu vinculada aos objetos materiais, entretanto com a evolução da técnica passou a abranger objetos cada vez mais virtuais. As redes urbanas são compostas pelo conjunto de cidades, cada qual com sua centralidade representadas por pontos ou nós na rede, e pelas ligações entre elas, rodovias, hidrovias, infovias etc. As cidades que compõem a rede, por mais semelhanças que possam ter entre si, tem diferentes tipos e graus de centralidade, de poder de atração de pessoas, de recursos; sendo uma região de influência singular, que muda de tempos em tempos, face a evolução do território onde se insere. Tanto as centralidades quanto as redes de urbanas estão em constante mudança, necessitando sempre de atualização tornando o estudo das redes e das centralidades uma questão sempre nova; em especial quando considerado um território tão vasto e complexo como o brasileiro. Neste trabalho relatamos os resultados do estudo das especificidades da centralidade da cidade de Viçosa, que está localizada no interior do estado de Minas Gerais, Brasil. Este estudo fez uso de dados numéricos, fotográficos e cartográficos coletados em diversos momentos da evolução do município e da região onde este se insere, que revelaram as mudanças de qualidade e de intensidade na centralidade dessa cidade, hoje tipificada como média ou intermediária, inserida na rede urbana mineira. No período compreendido entre os anos de 1850 e 1930, Viçosa passou de uma inexpressiva localidade rural, a importante centro de produção de café, galgando ganhos políticos nesse período. Seguiu-se um período de menor pujança, por cerca de setenta anos, para depois, na virada do século XX para XXI, ressurgi como uma localidade especializada em oferecer serviços, notadamente vinculados ao ensino superior e à produção de ciência e tecnologia. Essa nova centralidade, ao contrário do que muitas vezes ocorre, não foi fruto nem de um recurso natural inerente ao território e nem, tão pouco, pela atuação de grandes grupos capitalistas. Foi galgado principalmente pela atuação do Estado que construiu ali as bases de uma especialização funcional, através da implantação de uma universidade pública.