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People’s differences in cognitive functions are partly heritable and are associated with important life outcomes. Previous genome-wide association (GWA) studies of cognitive functions have found evidence for polygenic effects yet, to date, there are few replicated genetic associations. Here we use data from the UK Biobank sample to investigate the genetic contributions to variation in tests of three cognitive functions and in educational attainment. GWA analyses were performed for verbal–numerical reasoning (N=36 035), memory (N=112 067), reaction time (N=111 483) and for the attainment of a college or a university degree (N=111 114). We report genome-wide significant single-nucleotide polymorphism (SNP)-based associations in 20 genomic regions, and significant gene-based findings in 46 regions. These include findings in the ATXN2, CYP2DG, APBA1 and CADM2 genes. We report replication of these hits in published GWA studies of cognitive function, educational attainment and childhood intelligence. There is also replication, in UK Biobank, of SNP hits reported previously in GWA studies of educational attainment and cognitive function. GCTA-GREML analyses, using common SNPs (minor allele frequency>0.01), indicated significant SNP-based heritabilities of 31% (s.e.m.=1.8%) for verbal–numerical reasoning, 5% (s.e.m.=0.6%) for memory, 11% (s.e.m.=0.6%) for reaction time and 21% (s.e.m.=0.6%) for educational attainment. Polygenic score analyses indicate that up to 5% of the variance in cognitive test scores can be predicted in an independent cohort. The genomic regions identified include several novel loci, some of which have been associated with intracranial volume, neurodegeneration, Alzheimer’s disease and schizophrenia.

Throughout history the values and meanings attached to habitats and species in particular places have seen considerable change. Such shifts in perspective are of particular relevance to the biology of invasions, with human attention and values often determining both the initial movement of species around the world, and the decision that subsequent independent spread should be considered damaging to the environment. This chapter examines such a case for the Akrotiri peninsula, Cyprus, where a particular colonial story about the degraded state of the environment, and the need to combat malaria, led to the introduction of various Australian trees for sanitation and other purposes. Today, some of these non-native species are considered invasive, and are having impacts on valued wetland habitats on the peninsula. We use archival research to investigate the changes in policy towards these habitats and the non-native species that affect them, and field research to describe the ecological context. Our study illustrates the complex interactions between ideas, practical aims, and values that lie behind the planned and invaded habitats at Akrotiri.

The Trail Making Test (TMT) is a widely used test of executive function and has been thought to be strongly associated with general cognitive function. We examined the genetic architecture of the TMT and its shared genetic aetiology with other tests of cognitive function in 23 821 participants from UK Biobank. The single-nucleotide polymorphism-based heritability estimates for trail-making measures were 7.9% (part A), 22.4% (part B) and 17.6% (part B-part A). Significant genetic correlations were identified between trail-making measures and verbal-numerical reasoning (r

International audience; NASA’s Solar Probe Plus (SPP) mission will make the first in situ measurements of the solar corona and the birthplace of the solar wind. The FIELDS instrument suite on SPP will make direct measurements of electric and magnetic fields, the properties of in situ plasma waves, electron density and temperature profiles, and interplanetary radio emissions, amongst other things. Here, we describe the scientific objectives targeted by the SPP/FIELDS instrument, the instrument design itself, and the instrument concept of operations and planned data products.

The NASA Time History of Events and Macroscale Interactions during Substorms (THEMIS) project is intended to investigate magnetospheric substorm phenomena, which are the manifestations of a basic instability of the magnetosphere and a dominant mechanism of plasma transport and explosive energy release. The major controversy in substorm science is the uncertainty as to whether the instability is initiated near the Earth, or in the more distant >20 Re magnetic tail. THEMIS will discriminate between the two possibilities by using five in-situ satellites and ground-based all-sky imagers and magnetometers, and inferring the propagation direction by timing the observation of the substorm initiation at multiple locations in the magnetosphere. An array of stations, consisting of 20 all-sky imagers (ASIs) and 30-plus magnetometers, has been developed and deployed in the North American continent, from Alaska to Labrador, for the broad coverage of the nightside magnetosphere. Each ground-based observatory (GBO) contains a white light imager that takes auroral images at a 3-second repetition rate (“cadence”) and a magnetometer that records the 3 axis variation of the magnetic field at 2 Hz frequency. The stations return compressed images, “thumbnails,” to two central databases: one located at UC Berkeley and the other at the University of Calgary, Canada. The full images are recorded at each station on hard drives, and these devices are physically returned to the two data centers for data copying. All data are made available for public use by scientists in “browse products,” accessible by using internet browsers or in the form of downloadable CDF data files (the “browse products” are described in detail in a later section). Twenty all-sky imager stations are installed and running at the time of this publication. An example of a substorm was observed on the 23rd of December 2006, and from the THEMIS GBO data, we found that the substorm onset brightening of the equatorward arc was a gradual process (>27 seconds), with minimal morphology changes until the arc breaks up. The breakup was timed to the nearest frame (

The comprehensive THEMIS approach to solving the substorm problem calls for monitoring the nightside auroral oval with low-cost, robust white-light imagers and magnetometers that can deliver high time resolution data (0.33 and 2 Hz, respectively). A network of 20 Ground-Based Observatories (GBOs) are deployed across Canada and Alaska to support the collection of data from these instruments. Here we describe the system design of the observatory, with emphasis on how the design meets the environmental and data-collection requirements. We also review the design of the All Sky Imager (ASI), discuss how it was built to survive Arctic deployments, and summarize the optical characterizations performed to qualify the design to meet THEMIS mission requirements.

Genetic polymorphisms in the APOE ɛ and TOMM40 '523' poly-T repeat gene loci have been associated with significantly increased risk of Alzheimer's disease. This study investigated the independent effects of these polymorphisms on human cognitive ageing, and the extent to which nominally significant associations with cognitive ageing were mediated by previously reported genetic associations with brain white matter tract integrity in this sample. Most participants in the Lothian Birth Cohort 1936 completed a reasoning-type intelligence test at age 11 years, and detailed cognitive/physical assessments and structural diffusion tensor brain magnetic resonance imaging at a mean age of 72.70 years (s.d.=0.74). Participants were genotyped for APOE ɛ2/ɛ3/ɛ4 status and TOMM40 523 poly-T repeat length. Data were available from 758-814 subjects for cognitive analysis, and 522-543 for mediation analysis with brain imaging data. APOE genotype was significantly associated with performance on several different tests of cognitive ability, including general factors of intelligence, information processing speed and memory (raw P-values all0.05), independently of childhood IQ and vascular disease history. Formal tests of mediation showed that several significant APOE-cognitive ageing associations--particularly those related to tests of information processing speed--were partially mediated by white matter tract integrity. TOMM40 523 genotype was not associated with cognitive ageing. A range of brain phenotypes are likely to form the anatomical basis for significant associations between APOE genotype and cognitive ageing, including white matter tract microstructural integrity.

Myotonic dystrophy (DM; OMIM 160900, also known as dystrophia myotonica, myotonia atrophica and Steinert disease) is an autosomal dominant myotonic myopathy associated with abnormalities of other organs, including eyes, heart, endocrine system, central and peripheral nervous systems, gastrointestinal organs, bone, and skin.1 The mutation underlying DM is an expansion of an unstable cytosine-thymine-guanine (CTG) trinucleotide repeat in the 3' untranslated region of the myotonic dystrophy protein kinase (DMPK) gene in chromosome 19q13.3.2-4 In 1994, Thornton et al.5 described an autosomal dominant disorder similar to DM without CTG repeat expansion at the DM locus. Ricker et al.6 named this disease "proximal myotonic myopathy" (PROMM; OMIM 600109) because of predominantly proximal muscle weakness without atrophy as opposed to the distal muscle involvement seen in DM. Subsequently, Meola et al.7 described a variant of PROMM with unusual myotonic and myopathic features, which they named "proximal myotonic myopathy syndrome," and Udd et al.8 described a PROMM-like family with dystrophic features, which they named "proximal myotonic dystrophy" (PDM). Researchers at the University of Minnesota9,10 found another multisystemic myotonic disorder that closely resembles DM with distal muscle weakness but no CTG repeat expansion. Because of the close phenotypic resemblance to DM, they called this disease "myotonic dystrophy type 2" (DM2; OMIM 602668). In 1998, Ranum et al.9 assigned the DM2 locus to chromosome 3q in a large kindred. Shortly after that, Ricker et al.11 found that the majority of German PROMM families show linkage to the DM2 locus. PDM was also mapped to this region (Krahe and Udd, personal communication, 1999). Whether PROMM, PDM, and DM2 represent different phenotypic expressions of a disease caused by the same mutation or if they are allelic disorders remains to be determined. It is also possible that these disorders are caused by mutations in different genes that are closely linked in the chromosome 3q region.12 Furthermore, the disease loci in some typical PROMM families11 and other families with multisystemic myotonic disorders have been excluded from both DM and DM2 loci. Because of the genetic and phenotypic heterogeneity in this group of disorders, it became necessary to establish a new nomenclature foreseeing the future discovery of new disease loci and phenotypic variability.

In this paper, we analyse the development of initially small, periodic, voidage disturbances in gas-fluidized beds. The one-dimensional model was proposed by Needham & Merkin (1983), and Crighton (1991) showed that weakly nonlinear waves satisfied a perturbed Korteweg–de Vries or KdV equation. Here, we take periodic cnoidal wave solutions of the KdV equation and follow their evolution when the perturbation terms are amplifying. Initially, all such waves grow, but at a later stage a rescaling shows that shorter wavelengths are stabilized in a weakly nonlinear state. Longer wavelengths continue to develop and eventually strongly nonlinear solutions are required. Necessary conditions for periodic waves are found and matching back onto the growing cnoidal waves is possible. It is shown further that these fully nonlinear waves also reach an equilibrium state. A comparison with numerical results from Needham & Merkin (1986) and Anderson, Sundaresan & Jackson (1995) is then carried out.

In this paper, we investigate the evolution of N-waves in a medium governed by the modified Burgers' equation. It is shown that the general behaviour when the nonlinearity is of arbitrary odd integer order is the same as for the cubic case. For an N-wave of zero mean displacement, a shock is formed immediately to prevent a multi-valued solution and a second shock is formed at later times. At a finite time, the second shock satisfies a sonic condition and this state persists. The Taylor-type shock structure ceases to be the appropriate description, and instead we have a shock which matches only algebraically to the outer wave on one side. At a larger time still, the other shock is affected but the two shocks remain distinct until the wave dies under linear mechanisms. The behaviour of N-waves of non-zero mean is also examined and it is shown that in some cases, a purely one-signed profile remains.

This paper is concerned with a nonlinear wave equation which has been proposed as a model for conduit flow and migration of magma, namely A systematic search for conservation laws is performed, allowing all possible values of the two parameters n and m. In most cases, it is demonstrated that there exist precisely two independent laws and these are exhibited. However, two special cases m = 1, and m = n + 1, are discovered for which the proof is inconclusive and the second of these leads to a third law for a single parameter family.

The non-bonded N...H interactions between N atoms of R 1 (X =)C-N(R 2 R 3 ) (R 2 ,R 3 = Csp 3 or H) substructures and the H atoms of N-H and O-H donors have been analysed using crystallographic data and ab initio molecular orbital calculations. A total of 946 contacts having N...H (d NH ) ≤ 2.75 A were retrieved from the Cambridge Structural Database. For the preferred all-planar (Nsp 2 ) conformation, d NH ranges upwards from ca 2.5 A and H approaches N approximately perpendicular to the plane. However, it is shown that close intramolecular steric interactions lead to major geometrical distortions [pyramidalization at N and rotation about the C-N bond : Ferretti, Bertolasi, Gilli & Gilli (1993). J. Phys. Chem. 49, 13568-13574]. The N atom undergoes a transition from sp 2 to sp 3 with gradual lone-pair formation on N. If N-pyramidality is measured by X N (the angle between the C-N vector and the NR 2 R 3 plane), then as X N increases beyond ca 35° towards the sp 3 value of ca 60° the N...H contacts tend to become significantly shorter (stronger), the N...H donor angle approaches linearity and H approaches N within a 20° cone that has the assumed N lone-pair vector as an axis. A plot of X N versus d NH is interpreted as the reaction pathway for protonation of N and data points from R 1 (X=)C-N + (R 2 R 3 )H systems (the reaction product) occur at the end of this pathway. Crystallographic evidence shows that all 153 contacts 35° and a N...H donor angle above 130° are true hydrogen bonds. The evidence also suggests that the incoming H atoms track the developing N lone-pair density as X N increases from ca 35 to 60°. Ab initio molecular orbital calculations for aniline (6-31G * basis set) give electrostatic potential maps at incremental values of X N (in the range 0-48.5°) that clearly show the developing N lone-pair density.

The Imager of Sprites and Upper Atmospheric Lightning (ISUAL) is a scien- tific payload on Taiwan's FORMOSAT-2 (previously known as ROCSAT-2) that provides new observations of transient luminous events (TLEs) from space. The ISUAL project is an international collaboration between the National Cheng Kung University, Taiwan, Tohoku University, Japan and the instrument devel- opment team from the University of California, Berkeley. The project was sup- ported by the National Space Program Office in Taiwan. The ISUAL payload includes a visible wavelength intensified CCD imager, a boresighted six wave- length spectrophotometer, and a two channel Array Photometer (AP) with 16 vertically spaced horizontally wide sensitive regions. The imager is equipped with 5 selectable filters on a filter wheel and a 6 th open position. The spec- trophotometer contains six filter photometer channels, their bandpasses ranging from the far ultraviolet to the near infrared regions. The two channel AP is fitted with broadband blue and red filters. The orbiting platform with this set of instru- ments will provide the first comprehensive global latitude and longitude survey of TLEs near the midnight local time region. One of the great advantages of spaceborne observations is the lack of the intervening atmosphere between the TLEs and the observer. Ground based observations are often adversely affected by clouds, atmospheric extinction or scattering whereas the space-borne ISUAL instrument measurements provide true emission ratios unobstructed by the vari- able atmospheric extinction. The channels of the spectrophotometer channels cover the far and mid ultraviolet in addition to channels that respond to various excitation levels of the neutral and ionized nitrogen molecule atmosphere and to emissions from oxygen. The preliminary data shows that the ratio of the emis- sions is highly variable during the lightning and the associated TLEs. The data is qualitatively consistent with harder characteristic energy electron production

This report summarizes our work on the use of electromagnetically induced transparency to make new types of optical devices. Key accomplishments during this program period include the generation of the first single-cycle optical pulse and the development of a radiation source with four octaves of bandwidth. In a second area of work we have demonstrated nonlinear optical processes at the lowest photon flux ever used.

Recent evidence indicates that mammalian gametogenesis and preimplantation development may be adversely affected by both assisted reproductive and stem cell technologies. Thus, a better understanding of the developmental regulation of the underlying epigenetic processes that include DNA methylation is required. We have, therefore, monitored the expression, by PCR, of the mRNAs of DNA methyltransferases (DNMTs), methyl-CpG-binding domain proteins (MBDs), and CpG binding protein (CGBP) in a developmental series of amplified cDNA samples derived from staged human ovarian follicles, oocytes, preimplantation embryos, human embryonic stem (hES) cells and in similar murine cDNA samples. Transcripts of these genes were detected in human ovarian follicles (DNMT3A, DNMT3b1, DNMT3b4, DNMT1, MDBs1-4, MeCP2, CGBP), germinal vesicle (GV) oocytes (DNMT3A, DNMT3b1, DNMT1, MDBs1-4, MeCP2, CGBP), mature oocytes (DNMT3A, DNMT3b1, DNMT1, CGBP), and preimplantation embryos (DNMT3A, DNMT3b1, DNMT1, DNMT3L, MBD2, MDB4, CGBP). Differential expression of DNMT3B gene transcripts in undifferentiated (DNMT3b1) and in vitro differentiated human ES cells (DNMT3b3) further demonstrated an association of the DNMT3b1 transcript variant with totipotent and pluripotent human cells. Significantly, whilst the murine Dnmt3L gene is both expressed and essential for imprint establishment during murine oogenesis, transcripts of the human DNMT3L gene were only detected after fertilisation. Therefore, the mechanisms and/or the timing of imprint establishment may differ in humans.

The development of technologies to grow and mature oocytes from the most abundant primordial follicles holds many attractions for clinical practice, animal production technology and research. However, despite much research attention, it has proved difficult to grow follicles from early stages to maturity in vitro, as relatively little is known about the biology of oogenesis. It is clear that throughout oocyte development in vivo, follicle cell support is fundamental to provide the germ cell with nutrients and growth regulators to ensure progression through the protracted growth phase. Conversely, the oocyte actively promotes growth and differentiation of the follicular cells. Both of these characteristics must be mimicked in vitro. Replication of the normal follicular growth span from the primordial to Graafian follicle stages and the changes in the trophic requirements of the cells, cellular interactions, morphogenesis and the sheer increase in bulk as the antrum forms present major challenges for follicle culture technology. These observations could explain why methods that have proved successful for the culture of isolated rodent follicles are unable to support the growth of larger human and ruminant follicles in vitro and are incompatible with the requirements for primordial follicle growth activation. At present, the best option available for the complete growth and maturation of oocytes in vitro is to develop an extended multistage culture strategy which will provide a complex support system that closely resembles the ovary in vivo. In an attempt to achieve this goal primordial follicle growth is first initiated and maintained to the preantral stages through the culture of thin slices of ovarian cortex. The isolation and continued culture of these preantral follicles will support antral cavity formation and the induction of differentiated function in the somatic cell compartment. Finally, after exposure to an appropriate steroid milieu in vitro it should be possible to induce nuclear and cytoplasmic maturation in the fully grown oocytes. The prospects of succeeding at each stage, and of finally producing a fertile gamete, are likely to be increased by preserving cellular interactions and the phenotype of follicle cells as these provide the physiological environment in which oocytes develop. Although the technology for the in vitro maturation (IVM) of fully grown oocytes has been exploited successfully in ruminants, in human assisted reproduction IVM is still experimental as the efficiency of IVM is low and only a small number of pregnancies and live births have been reported. Thus, although complete in vitro growth and maturation may be achieved eventually, immediate goals must include the optimization of methods for isolating and culturing oocytes at both ends of the size spectrum and the full evaluation of the normality of the oocytes grown for extended periods in vitro.

Summary form only given, as follows. A small amplitude electromagnetic wave can propagate in a plasma below cutoff in the presence of a high frequency large amplitude wave. This is referred to electromagnetically induced transparency (EIT). We extend the analysis of EIT to include relativistic and collisional effects as well as density gradients. We show that the small amplitude wave is unstable in certain parameter regimes. Well above cutoff the instability goes over to the usual backward Raman instability. In addition, the propagation of a large amplitude wave in an inhomogeneous plasma and its penetration beyond the critical surface is analyzed.

This review focuses on using microarray data on a clonal osteoblast cell model to demonstrate how various current and future bioinformatic tools can be used to understand, at a more global or comprehensible level, how cells grow and differentiate. In this example, BMP2 was used to stimulate growth and differentiation of osteoblast to a mineralized matrix. A discussion is included on various methods for clustering gene expression data, statistical evaluation of data, and various new tools that can be used to derive deeper insight into a particular biological problem. How these tools can be obtained is also discussed. New tools for the biologists to compare their datasets with others, as well as examples of future bioinformatic tools that can be used for developing gene networks and pathways for a given set of data are included and discussed.

A mathematical model for gas-fluidized beds is examined which treats both the particles and gas as continua by volume averaging. The system is then considered as two interlocking one-phase fluids. For small perturbations to the uniform state, these equations have been shown by Crighton (1991) to reduce to the Burgers-KdV equation and under certain criteria, we have instability. We consider the unstable situation when the amplification effects are a perturbation to the KdV equation and take an initial condition of a single KdV soliton. The growth of this soliton is followed through several regions in which the unstable Burgers-KdV equation is no longer appropriate, but KdV remains the leading order equation. Eventually, there is a fundamental change in the solution and the new governing equations are fully nonlinear and O(1). These admit a solitary wave solution which matches back onto the KdV soliton. Thus, we can follow the formation of a bubble from a small amplitude perturbation to the uniform state.

The use of transgenic animals in biomedical research is increasing rapidly and may be the best means of determining gene function. Generating transgenic animals typically requires time-consuming screening processes, and gene function is assessed by an array of difficult phenotypic and biochemical assays performed ex vivo. To address the unmet need in transgenic research for functional assays performed with ease in living animals, we demonstrate here that in vivo detection of luciferase enzyme as a transcriptional reporter facilitates rapid screening for both the presence and function of transgenes in intact living mice. Using this approach we identified three bioluminescent transgenic founders where the transgene consisted of the heme oxygenase promoter fused to the modified coding sequence of the luciferase gene. These founders were identified from 183 pups and confirmed by PCR analysis. Identification of HO-1-luc homozygotes from back- crossed F2 littermates was then accelerated by in vivo imaging. In another transgenic mouse line, where the transgene was comprised of the bone morphogenic-4 (BMP4) promoter fused to the modified luciferase gene, we were able to identify transgenic animals and in each line we were able to visualize patterns of expression in living animals over time. The light production from these transgenic mice indicated that the desired DNA fragment was functional and different expression profiles apparent at different ages and after gene induction.

Multiterawatt, 30‐fs optical pulses are used to create an eight times ionized plasma in a few torr of Xe gas. Energetic electrons which are also created by the circularly polarized laser pulse are used to produce a population inversion on a 41.8‐nm transition in Xe IX. Observation of gain >exp(10) is presented.

Nonlinear optical mixing of existing laser frequencies to access portions of the spectrum where lasing action is not easily obtainable is common practice today. Although nonlinear solid-state media are available [1] for frequency conversion from just under 200 nm in the ultraviolet to about a few microns in the infrared, the generation of widely-tunable laser radiation in the mid-to-far infrared and VUV regions typically requires four-frequency mixing in atomic vapors. In the past, frequency conversion in atomic vapors suffered from poor conversion efficiencies due to the small magnitude of the third-order nonlinear susceptibility and the difficulty in phasematching. We demonstrate a method [2] for performing four-frequency mixing which overcomes both of these shortcomings, allowing efficient frequency conversion with moderate pump intensities.

Electromagnetically induced transparency (EIT) is a technique for making an otherwise optically-thick medium transparent to laser radiation.’ The basic idea is to use two lasers or electromagnetic fields whose frequency difference is equal to a Raman (or two-photon) transition of the atom or molecule. We term these fields as the coupling field and the probe field. Figure 1 shows some of the possibilities. Transparency may be created in a (a) three-state system, or (b) in the continuum. Instead, (c) a medium which is already transparent, but is refractively thick (sL » 1), may be made refractively thin (sL « 1).

Bone morphogenetic protein-4 (BMP-4) is one of a member of related polypeptides that are important in bone formation and other developmental processes. We isolated the BMP-4 gene from a mouse genomic library and characterized the exon-intron structure and one of the candidate promoters. Two alternative 5'-noncoding exons, 1A and 1B, were identified by reverse transcription polymerase chain reaction assays. Quantitative competitive polymerase chain reaction using Exon 1A, Exon 1B, and Exon 3 primers indicate the 1A-containing transcript is the primary BMP-4 mRNA expressed in bone cell cultures. Primer extension analysis supports that 1A is the major promoter utilized in bone cell cultures as well as in 9.5-day mouse embryos. 1A promoter activity indicate selective DNA regions functional in bone cells. We found potential regulatory response regions in the 1A 5'-flanking region of the BMP-4 gene for the chicken ovalbumin upstream-transcription factor I (COUP-TFI). Specific binding to the COUP-TFI response regions in the BMP-4 1A promoter was demonstrated. By co-transfection of a COUP-TFI expression plasmid with the BMP-4 1A promoter in fetal rat calvarial osteoblasts, we demonstrated that COUP-TFI inhibits the BMP-4 promoter activity. This suggests that COUP-TFI could act as a silencer for BMP-4 transcription in vivo.