Genetic basis of cognitive disability

The importance of genetic influences on cognitive disability has been recognized for a long time, but molecular analysis has only recently begun to yield insights into the pathogenesis of this common and disabling condition. The availability of genome sequences has enabled the characterization of the chromosomal deletions and trisomies that result in cognitive disability, and mutations in rare single-gene conditions are being discovered. The molecular pathology of cognitive disability is turning out to be as heterogeneous as the condition itself, with unexpected complexities even in apparently simple gene-deletion syndromes. One remarkable finding from studies on X-linked mental retardation is that mutations in different small guanosine triphosphate (GTP)-binding proteins result in cognitive disability without other somatic features. Advances are also being made in cognitive disability with polygenic origins, such as dyslexia and autism. However, the genetic basis of mild intellectual disability has yet to be satisfactorily explained

Strategic restraint : modelling the role of moral weight in modern conflicts

Strategic Restraint: Modelling the Role of Moral Weight in Modern Conflicts is a PhD thesis that seeks to make the argument that restraint has a strategic purpose. It begins with a discussion of an understanding of ethics as the negotiation of hierarchies of ‘goods’ and develops an idea of Primary and Contingent goods, how those goods are decided and the role of morality, ethics and the law in human affairs. Following that is a consideration of strategy, and the nature of war. These discussions begin to form the basis of the following chapters. It develops a model for understanding the nature of war, and using this model makes suggestions about the controlled application of force and the effects of overapplication of force. The construction of the model is supported by examination of military history, concentrating on conflicts in the latter part of the of the 20th century to more recent conflicts.In considering the difficulties the model indicates in this overapplication, the work argues that there is need for the ‘artificial’ application of perceived mass, and suggests that it is here that the utility of ethical behaviour in warfare can be found for strategy. In using restraint, guided by higher ethical choices which necessarily reduce efficacy, it is argued that there is strategic advantage to be found. This is supported by analyses from modern Counter Insurgency campaigns, where such activity has been undertaken by commanders independently, while attempting to provide a theoretical explanation for the seeming success of these decisions. The work also considers outcomes from applying such strategic choices, from operational and policy concerns to the consequences in interstate relations before, during and after armed conflict

The Poetry In-Between: Presence and Absence in Whitman, Rimbaud, and Hopkins.

The Poetry In-Between: Presence and Absence in Whitman, Rimbaud, and Hopkins analyzes three major nineteenth-century poets and their development of a poetics which has as its chief focus of concern the issue of presencing an eternal and universal Other by which to assess self identity. After the Kantian critique and the seeming reduction of human knowledge to phenomenal perceptions, early nineteenth-century poets and theorists feared the entrapment and isolation of the self in subjective awareness. The romantics, such as Friedrich Schlegel, sought ways to overcome such alienating subjectivity and ultimately conceived of the poet as a privileged spokesman and arbiter for a harmonious and divine origin of life; it is through the poet\u27s imagination, argue Schlegel and his followers, that the noumenal or total, eternal Other is presenced. Through such presencing, which essentially involves the collapsing of boundaries between the phenomenal body and the transcendent soul, the individual self gains identity as part of an integrated, universal, and eternal cosmos. However, each poet faced crises of separation which challenged their presencing of this Other ; in general, the death of the body in war or sickness threatened to cut the poet off from his vision and participation in an eternal, harmonious Other. Ultimately, towards the end of their poetic careers, Whitman, Rimbaud, and Hopkins negotiated a poetic stance which views the self as in-between a full presence and a complete absence of cosmic totality; the desire of the self for the Other banishes its complete absence, but the self must also recognize the transiency of humanity and our inability to grasp individually the complete presence of an eternity

So You Want Your Child to Be a Genius?

Geneticist Jonathan Flint reviews David Plotz's book The Genius Factory: The Curious History of the Nobel Prize Sperm Bank

Association studies in outbred mice in a new era of full-genome sequencing

Thousands of loci that contribute to quantitative traits in outbred crosses of mice have been reported over the last two decades. In this review we discuss how outbred mouse populations can be used to map and identify the genes and sequence variants that give rise to quantitative variation. We discuss heterogeneous stocks, the diversity outbred, and commercially available outbred populations of mice. All of these populations are descended from a small number of progenitor strains. The availability of the complete sequence of laboratory strains means that in many cases it will be possible to reconstruct the genomes of the outbred animals so that in a genetic association study we can detect the effect of all variants, a situation that has so far eluded studies in completely outbred populations. These resources constitute a major advance and make it possible to progress from a quantitative trait locus to a gene at an unprecedented spee

The endophenotype concept in psychiatric genetics

The idea that some phenotypes bear a closer relationship to the biological processes that give rise to psychiatric illness than diagnostic categories has attracted considerable interest. Much effort has been devoted to finding such endophenotypes, partly because it is believed that the genetic basis of endophenotypes will be easier to analyse than that of psychiatric disease. This belief depends in part on the assumption that the effect sizes of genetic loci contributing to endophenotypes are larger than those contributing to disease susceptibility, hence increasing the chance that genetic linkage and association tests will detect them. We examine this assumption by applying meta-analytical techniques to genetic association studies of endophenotypes. We find that the genetic effect sizes of the loci examined to date are no larger than those reported for other phenotypes. A review of the genetic architecture of traits in model organisms also provides no support for the view that the effect sizes of loci contributing to phenotypes closer to the biological basis of disease is any larger than those contributing to disease itself. While endophenotype measures may afford greater reliability, it should not be assumed that they will also demonstrate simpler genetic architecture

Genomes and phenomes of a population of outbred rats and its progenitors

Finding genetic variants that contribute to phenotypic variation is one of the main challenges of modern genetics. We used an outbred population of rats (Heterogeneous Stock, HS) in a combined sequence-based and genetic mapping analysis to identify sequence variants and genes contributing to complex traits of biomedical relevance. Here we describe the sequences of the eight inbred progenitors of the HS and the variants that segregate between them. We report the genotyping of 1,407 HS rats, and the collection from 2,006 rats of 195 phenotypic measures that are relevant to models of anxiety, type 2 diabetes, hypertension and osteoporosis. We make available haplotype dosages for the 1,407 genotyped rats, since genetic mapping in the HS is best carried out by reconstructing each HS chromosome as a mosaic of the progenitor genomes. Finally, we have deposited an R object that makes it easy to incorporate our sequence data into any genetic study of HS rats. Our genetic data are available for both Rnor3.4 and Rnor5.0 rat assemblies

G = E:What GWAS Can Tell Us about the Environment

As our understanding of genetics has improved, genome-wide association studies (GWAS) have identified numerous variants associated with lifestyle behaviours and health outcomes. However, what is sometimes overlooked is the possibility that genetic variants identified in GWAS of disease might reflect the effect of modifiable risk factors as well as direct genetic effects. We discuss this possibility with illustrative examples from tobacco and alcohol research, in which genetic variants that predict behavioural phenotypes have been seen in GWAS of diseases known to be causally related to these behaviours. This consideration has implications for the interpretation of GWAS findings

Influence of deterministic geologic trends on spatial variability of hydrologic properties in volcanic tuff

Hydrologic properties have been measured on outcrop samples taken from a detailed, two-dimension grid covering a 1.4 km outcrop exposure of the 10-m thick non-welded-to-welded, shardy base microstratigraphic unit of the Tiva Canyon Member of the Miocene Paintbrush Tuff at Yucca Mountain, Nevada. These data allow quantification of spatial trends in rock matrix properties that exist in this important hydrologic unit. Geologic investigation, combined with statistical and geostatistical analyses of the numerical data, indicates that spatial variability of matrix properties is related to deterministic geologic processes that operated throughout the region. Linear vertical trends in hydrologic properties are strongly developed in the shardy base microstratigraphic unit, and they are more accurately modeled using the concept of a thickness-normalized stratigraphic elevation within the unit, rather than absolute elevation. Hydrologic properties appear to be correlated over distances of 0.25 to 0.3 of the unit thickness after removing the deterministic vertical trend. The use of stratigraphic elevation allows scaling of identified trends by unit thickness which may be of particular importance in a basal, topography-blanketing unit such as this one. Horizontal changes in hydrologic properties do not appear to form obvious trends within the limited lateral geographic extent of the ash-flow environment that was examined. Matrix properties appear to be correlated horizontally over distances between 100 and 400 m. The existence and quantitative description of these trends and patterns of vertical spatial continuity should increase confidence in models of hydrologic properties and groundwater flow in this area that may be constructed to support the design of a potential high-level nuclear waste repository at Yucca Mountain

3D surface-imaging for volumetric measurement in people with obesity

BACKGROUND: Current methods for tracking the progress of people with obesity towards a weight loss goal appear simple and potentially misleading. A technique to quantify change in body shape whilst visualising areas of the body where weight loss occurs would be advantageous, and has the potential to be used as a motivational tool. Three-dimensional (3D) surface-imaging would serve as a good basis for such a technique, however current systems are prohibitively expensive. OBJECTIVE: Highlight the use of a cheaper alternative 3D surface-imaging system for volumetric measurement in people with obesity. METHODS: A recently developed low-cost 3D surface-imaging system was used, having previously being validated in a healthy population. A total of 61 people with obesity, enrolled on a weight-loss programme, were surface-imaged using the system. RESULTS: The findings suggest the low-cost system can obtain 3D surface-images of an obese human body, from which numerical parameters could be calculated and further analysis conducted. CONCLUSIONS: Further studies will focus on the validity and reliability of such analyses and the potential of the system to be considered as a long-term instalment in primary healthcare settings as a weight loss aid