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Prostacyclin infusion for pulmonary arterial hypertension (PAH) is an effective therapy with varied dosing requirements and clinical response. The major aim of this study was to determine new biologically-based predictors of prostacyclin treatment response heterogeneity.Ninety-eight patients with hemodynamically defined PAH at two academic medical centers volunteered for registry studies. A stable dose of treprostinil was the quantitative phenotype for the genome-wide association study (GWAS). Candidate genes with the largest effect sizes and strongest statistical associations were further characterized with in silico and in-vitro assays to confirm mechanistic hypotheses. The clinical significance of these candidate predictors was assessed for mechanistically consistent physiologic effects in an independent cohort of patients.GWAS identified three loci for association with P 10-6. All three loci had clinically significant effect sizes. Specific single-nucleotide polymorphisms (SNPs) at two of the loci: rs11078738 in phosphoribosylformylglycinamidine synthase and rs10023113 in CAMK2D encoded sequence changes with clear predicted consequences. Production of the primary mediator of prostacyclin-induced vasodilation, cyclic AMP, was reduced in human cell lines by the missense variant rs11078738 (p.L621P). Located in the promoter of CAMK2D, the allele of rs10023113 associated with a higher treprostinil dose has higher ventricular transcription of CAMK2δ. At initial diagnostic catheterization in a separate cohort of patients, the same allele of rs10023113 was associated with elevated right mean atrial and ventricular diastolic pressures.The quantitative phenotype of stable treprostinil dose identified two gene loci associated with pharmacodynamic response and right ventricular function in PAH worth further investigation.

Exfoliation syndrome (XFS) is an age-related systemic disorder characterized by excessive production and progressive accumulation of abnormal extracellular material, with pathognomonic ocular manifestations. It is the most common cause of secondary glaucoma, resulting in widespread global blindness. We performed Transcriptomic Wide Association Studies (TWAS) using PrediXcan models trained in 48 GTEx tissues to identify genetically- determined gene expression changes associated with XFS risk, leveraging on results from a global GWAS that included 123,457 individuals from 24 countries. We observed twenty-eight genes in a three-Megabase chr15q22-25 region that showed statistically significant associations, which were further whittled down to ten genes after additional statistical validations. In experimental analysist of these ten genes, mRNA transcript levels for ARID3B, CD276, LOXL1, NEO1, SCAMP2, and UBL7 were significantly decreased in iris tissues from XFS patients compared to control samples. Genes with genetically determined expression changes in XFS were significantly enriched for genes associated with inflammatory conditions. We further explored the health consequences of high susceptibility to XFS using a large electronic health record and observed a higher incidence of XFS comorbidity with inflammatory and connective tissue diseases. Our results implicate a role for connective tissues and inflammation in the etiology of XFS. Targeting the inflammatory pathway may be a potential therapeutic option to reduce progression in XFS.

Exfoliation syndrome (XFS) is an age-related systemic disorder characterized by excessive production and progressive accumulation of abnormal extracellular material, with pathognomonic ocular manifestations. It is the most common cause of secondary glaucoma, resulting in widespread global blindness. We performed Transcriptomic Wide Association Studies using PrediXcan models trained in 48 GTEx tissues to identify genetically-determined gene expression changes associated with XFS risk, leveraging on results from a global GWAS that included 123,457 individuals from 24 countries. Twenty-eight genes in the chr15q22-25 region showed statistically significant associations in both single-tissue and multi-tissue analysis. Reduced models for these genes that excluded variants in LD with the known LOXL1 signal showed genome-wide significant association signals in nine genes, independently of LOXL1. Out of these ten genes, mRNA transcript levels for ARID3B, CD276, LOXL1, NEO1, SCAMP2, and UBL7 were significantly decreased in iris tissues from XFS patients compared to control samples. Genes with genetically determined expression changes in XFS were significantly enriched for genes associated with inflammatory conditions. We further explored the health consequences of high susceptibility to XFS using a large electronic health record and observed a higher incidence of XFS comorbidity with inflammatory and connective tissue diseases. Our results implicate a role for connective tissues and inflammation in the etiology of XFS. Targeting the inflammatory pathway may be a potential therapeutic option to reduce progression in XFS.

© 2017 The Author(s). Variation in the expression level and activity of genes involved in drug disposition and action ('pharmacogenes') can affect drug response and toxicity, especially when in tissues of pharmacological importance. Previous studies have relied primarily on microarrays to understand gene expression differences, or have focused on a single tissue or small number of samples. The goal of this study was to use RNA-sequencing (RNA-seq) to determine the expression levels and alternative splicing of 389 Pharmacogenomics Research Network pharmacogenes across four tissues (liver, kidney, heart and adipose) and lymphoblastoid cell lines, which are used widely in pharmacogenomics studies. Analysis of RNA-seq data from 139 different individuals across the 5 tissues (20-45 individuals per tissue type) revealed substantial variation in both expression levels and splicing across samples and tissue types. Comparison with GTEx data yielded a consistent picture. This in-depth exploration also revealed 183 splicing events in pharmacogenes that were previously not annotated. Overall, this study serves as a rich resource for the research community to inform biomarker and drug discovery and use.

Purpose Prostacyclin infusion is an effective therapy for pulmonary arterial hypertension (PAH) but has variable clinical response and dosing requirements. We performed a genome-wide association study (GWAS) to identify biologically-based predictors of prostacyclin response heterogeneity and gene variants associated with PAH pathogenesis . Methods Ninety-eight patients with hemodynamically-defined PAH treated at two academic centers were included. Stably dosed treprostinil therapy was the quantitative phenotype for the GWAS. Candidate genes with the largest effect sizes and strongest statistical associations were further characterized in silico and in vitro to confirm mechanistic hypotheses, and at cardiac catheterization to assess for mechanistically consistent physiological effects. Results Three loci associated with treprostinil dose with P encoded sequence changes with predictable consequences. Production of the prostacyclin-induced pulmonary vasodilator cyclic adenosine monophosphate was reduced in human cell lines by the missense variant rs11078738. The allele of rs10023113 in the promoter of CAMK2D associated with higher treprostinil dose, conferred a reduced affinity for the FOXP1 transcriptional repressor , was associated with increased expression of CAMKIIδ in ventricular tissue, and was associated with elevated right mean atrial and ventricular diastolic pressures in a separate cohort of patients at cardiac catheterization. Conclusion The conduct of effective GWAS is challenging with small numbers of patients. However, by employing the quantitative phenotype of stable treprostinil dose we identified 2 novel loci for treatment response in PAH, gene variants associated with more severe right ventricular dysfunction and higher ultimate dose of treprostinil. Work is ongoing to further characterize these variants.

Ethnic variation of TET2 SNP rs2454206 and association with clinical outcome in childhood AML: a report from the Children’s Oncology Group

Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.Method: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders Polygenic score analyses identified a significant polygenic component for OCD (p=2x10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).Conclusions: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring burette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P

False-positive or false-negative results attributable to undetected genotyping errors and confounding factors present a constant challenge for genome-wide association studies (GWAS) given the low signals associated with complex phenotypes and the noise associated with high-throughput genotyping. In the context of the genetics of kidneys in diabetes (GoKinD) study, we identify a source of error in genotype calling and demonstrate that a standard battery of quality-control (QC) measures is not sufficient to detect and/or correct it. We show that, if genotyping and calling are done by plate (batch), even a few DNA samples of marginally acceptable quality can profoundly alter the allele calls for other samples on the plate. In turn, this leads to significant differential bias in estimates of allele frequency between plates and, potentially, to false-positive associations, particularly when case and control samples are not sufficiently randomized to plates. This problem may become widespread as investigators tap into existing public databases for GWAS control samples. We describe how to detect and correct this bias by utilizing additional sources of information, including raw signal-intensity data.

Motivation: Genome-wide association studies (GWAS) generate relationships between hundreds of thousands of single nucleotide polymorphisms (SNPs) and complex phenotypes. The contribution of the traditionally overlooked copy number variations (CNVs) to complex traits is also being actively studied. To facilitate the interpretation of the data and the designing of follow-up experimental validations, we have developed a database that enables the sensible prioritization of these variants by combining several approaches, involving not only publicly available physical and functional annotations but also multilocus linkage disequilibrium (LD) annotations as well as annotations of expression quantitative trait loci (eQTLs). Results: For each SNP, the SCAN database provides: (i) summary information from eQTL mapping of HapMap SNPs to gene expression (evaluated by the Affymetrix exon array) in the full set of HapMap CEU (Caucasians from UT, USA) and YRI (Yoruba people from Ibadan, Nigeria) samples; (ii) LD information, in the case of a HapMap SNP, including what genes have variation in strong LD (pairwise or multilocus LD) with the variant and how well the SNP is covered by different high-throughput platforms; (iii) summary information available from public databases (e.g. physical and functional annotations); and (iv) summary information from other GWAS. For each gene, SCAN provides annotations on: (i) eQTLs for the gene (both local and distant SNPs) and (ii) the coverage of all variants in the HapMap at that gene on each high-throughput platform. For each genomic region, SCAN provides annotations on: (i) physical and functional annotations of all SNPs, genes and known CNVs within the region and (ii) all genes regulated by the eQTLs within the region. Availability: http://www.scandb.org Contact: ncox@medicine.bsd.uchicago.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Edge-localized modes (ELMs) and disruptions remain a major concern to divertor plasma-facing components (PFCs) during normal and abnormal operation of future tokamaks. Of particular concern are the pulses of energy and particles that are transported during ELMs to the divertor surface. ELMs, therefore, can result in excessive divertor erosion and plasma contamination. A two-fluid model is enhanced to include detail atomic physics data for tungsten, lithium, and neon in multidimensional geometry to integrate core, SOL parameters, and divertor surface evolution (melting, vaporization, vapor cloud dynamics, etc.) using the HEIGHTS numerical simulation package. ELM mitigation using liquid Li surface and neon gas puffing are also simulated. Initial results indicate that a thin layer of Li ( 10 17 cm −2 ) is needed to prevent tungsten surface from melting during giant ELMs. Vapor impurity diffusion through the private flux region can be major source of plasma contamination during ELMs and could terminate the plasma in a disruption.

OBJECTIVE—The objective of this study was to identify DNA polymorphisms associated with type 2 diabetes in a Mexican-American population. RESEARCH DESIGN AND METHODS—We genotyped 116,204 single nucleotide polymorphisms (SNPs) in 281 Mexican Americans with type 2 diabetes and 280 random Mexican Americans from Starr County, Texas, using the Affymetrix GeneChip Human Mapping 100K set. Allelic association exact tests were calculated. Our most significant SNPs were compared with results from other type 2 diabetes genome-wide association studies (GWASs). Proportions of African, European, and Asian ancestry were estimated from the HapMap samples using structure for each individual to rule out spurious association due to population substructure. RESULTS—We observed more significant allelic associations than expected genome wide, as empirically assessed by permutation (14 below a P of 1 × 10−4 [8.7 expected]). No significant differences were observed between the proportion of ancestry estimates in the case and random control sets, suggesting that the association results were not likely confounded by substructure. A query of our top ∼1% of SNPs (P < 0.01) revealed SNPs in or near four genes that showed evidence for association (P < 0.05) in multiple other GWAS interrogated: rs979752 and rs10500641 near UBQLNL and OR52H1 on chromosome 11, rs2773080 and rs3922812 in or near RALGPS2 on chromosome 1, and rs1509957 near EGR2 on chromosome 10. CONCLUSIONS—We identified several SNPs with suggestive evidence for replicated association with type 2 diabetes that merit further investigation.

One of the critical technological challenges of future tokamak fusion devices is the ability for plasma-facing components to handle both normal and abnormal plasma/surface interaction events that compromise their lifetime and operation of the machine. Under normal operation plasma/surface interactions that are important include: sputtering, particle implantation and recycling, He pumping and ELM (edge localized modes)-induced erosion. In abnormal or off-normal operation: disruptions and vertical displacement events (VDEs) are important. To extend PFC lifetime under these conditions, liquid-metals have been considered as candidate PFCs (Plasma-Facing Components), including: liquid lithium, tin-lithium, gallium and tin.Liquid lithium has been measured to have nonlinear increase of physical sputtering with rise in temperature. Such increase can be a result of exposure to ELM-level particle fluxes. The significant increase in particle flux to the divertor and nearby PFCs can enhance sputtering erosion by an order of magnitude or more. In addition from the standpoint of hydrogen recycling and helium pumping liquid lithium appears to be a good candidate plasma-facing material (PFM). Advanced designs of first wall and divertor systems propose the application of liquid-metals as an alternate PFC to contend with high-heat flux constraints of large-scale tokamak devices. Additional issues include PFC operation under disruptions andmore » long temporal instabilities such as VDEs. A comprehensive two-fluid model is developed to integrate core and SOL (scrape-off layer) parameters during ELMs with PFC surface evolution using the HEIGHTS package. Special emphasis is made on the application of lithium as a candidate plasma-facing liquid-metal.« less

We outline a model of breakdown in RF cavities. In this model, the breakdown trigger is the injection of ions, atoms and clusters into cavities by either of two mechanisms. One mechanism is some combination of fracture and field evaporation of ions from solid surfaces caused by locally high electric fields. The second mechanism, driven by high local current densities, is localized Ohmic heating at grain boundaries and defects. Field evaporation and fracturing are similar processes, both driven by the high tensile stresses in the electric field that occur at local electric fields of ∼10 10 V/m, which have been measured in a number of experimental environments. We also outline how ions can be injected into cavities in the presence of large RF electric fields. The model can explain most of the behavior seen in a variety of cavities at different frequencies without assuming that melting or gas emission occurs at breakdown sites. This model may also be relevant to DC vacuum breakdown.

The chamber walls in inertial fusion energy (IFE) reactors are exposed to harsh conditions following each target implosion. Key issues of the cyclic IFE operation include intense photon and ion deposition, wall thermal and hydrodynamic evolution, wall erosion and fatigue lifetime, and chamber clearing and evacuation to ensure desirable conditions prior to next target implosion. Several methods for wall protection have been proposed in the past, each having its own advantages and disadvantages. These methods include use of solid bare walls, gas-filled cavities, and liquid walls/jets. Detailed models have been developed for reflected laser light, emitted photons, neutrons, and target debris deposition and interaction with chamber components and have been implemented in the comprehensive heights software package. The hydrodynamic response of gas-filled cavities and photon radiation transport of the deposited energy have been calculated by means of new and advanced numerical techniques for accurate shock treatment and propagation. Photon radiation transport models are developed for either the gas-filled cavity or in the evolving vapor cloud layer above the wall surface. The focus of this work is to examine the overall wall response and lifetime due to various erosion mechanisms.

During the normal operation of the high confinement regime (H-mode) in next generation tokamaks, edge-localized modes (ELMs) are a serious concern for divertor plasma-facing components. The periodic relaxation of edge pressure gradient results in pulses of energy and particles transported across the Separatrix to the scrape-off-layer (SOL) and eventually to the divertor surface. ELMs could, therefore, result in cyclic thermal stresses, excessive target erosion, and consequently shorter divertor lifetime. In this study a comprehensive two-fluid model has been developed to integrate SOL parameters during ELMs with divertor surface evolution (melting, vaporization, vapor cloud dynamics, and macroscopic spallation) for different ELM parameters. Calculations were performed using the HEIGHTS numerical simulation package. Initial results indicate that high-power ELMs in ITER-like machines can cause serious damage to divertor components, may terminate plasma in disruptions, and may affect subsequent plasma operations due to extensive contamination.

ObjectiveObsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.MethodThe authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.ResultsAlthough no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).ConclusionsPrevious work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

The development of solid plasma-facing components (PFCs) that can withstand high heat and particle fluxes during normal and abnormal events has proven to be a difficult task for future power-producing magnetically confined reactors. Solid PFC cannot be reliably used because of the large erosion losses during normal and off-normal events such as disruptions and their consequences. The use of liquid metal surfaces for protection of PFCs seems attractive but is not easily implemented. The ability to use liquids as PFC surfaces depends on their overall integrated interaction with the plasma as well as with the strong magnetic field in the reactor. The temperature of a flowing liquid surface governed by surface velocity should be low enough to avoid core plasma contamination by the metal vapor. A high liquid flow velocity, V, may also be necessary to overcome the force F = [J x B], where J is current and B is magnetic field. In this study, MHD flow patterns of the liquid metal across the magnetic field (B = 5 T) are investigated. The retarding force F= [J x B] results in a rather high pressure drop required to move the liquid metal across the magnetic field. New two-dimensional calculations of MHD effects and resulting pressure drop have been completed with the upgraded HEIGHTS software package.

Erosion losses due to ablation during a plasma disruption can be extremely high. This can severely limit divertor system lifetime to only a few disruptions. Ablation is mass loss in the form of macroscopic particles (MPs), i.e., droplets of liquid metals or large pieces (grains or crystallites) of non-melting materials such as carbon-based materials. Results of self-consistent magnetohydrodynamic (MHD) calculations are obtained that couple the dynamics of both vapor cloud and MP interaction to incoming ions and electrons from the collisionless scrape-off layer during the disruption. The equation of motion of the MPs is solved inside the inhomogeneous vapor-cloud conditions. For a well-confined vapor cloud, the flight time of MPs in the vapor is short, and complete vaporization of the emitted MPs occurs. This will result in further reduction of net radiation power to the surface, i.e., `droplet shielding' effect. However, if the vapor cloud has a high velocity component along the divertor surface, the MPs are quickly removed from the hot vapor region. A shorter flight time of the MPs in the vapor cloud can result in significant mass losses and extremely short erosion lifetime of the divertor surface and nearby components.

The structure of collisionless scrape-off-layer (SOL) plasma in tokamak reactors is being studied to define the electron distribution function and the corresponding sheath potential between the divertor plate and the edge plasma. One feature of the collisionless SOL plasma is that the edge plasma acts as an electrostatic trap for electrons because electrons that originally have parallel energy lower than the wall potential will be trapped between the inner and outer divertor plates. Trapped electrons are very important in collisionless SOL plasma and are mainly responsible for charge neutralization of ions. Therefore, a full solution of the kinetic equation of particle transport to determine various electron fluxes is required. In this study, the dynamics of the SOL plasma during disruption was investigated with a 2-D numerical model that solves the kinetic Fokker–Planck equation for electron distribution. The main component of the electric potential exists within a region where the SOL ions are absorbed, i.e., at the front of the expanding vapor cloud.

Loss of plasma confinement causes surface and structural damage to plasma-facing materials (PFMs) and remains a major obstacle for tokamak reactors. The deposited plasma energy results in surface erosion and structural failure. The surface erosion consists of vaporization, spallation, and liquid splatter of metallic materials, while the structural damage includes large temperature increases in structural materials and at the interfaces between surface coatings and structural members. Comprehensive models (contained in the HEIGHTS computer simulation package) are being used self-consistently to evaluate material damage. Splashing mechanisms occur as a result of volume bubble boiling and liquid hydrodynamic instabilities and brittle destruction mechanisms of nonmelting materials. The effect of macroscopic erosion on total mass losses and lifetime is evaluated. The macroscopic erosion products may further protect PFMs from severe erosion (via the droplet-shielding effect) in a manner similar to that of the vapor-shielding concept.

Surface and structural damage to plasma-facing components (PFCs) due to the frequent loss of plasma confinement remains a serious problem for the tokamak reactor concept. The deposited plasma energy causes significant surface erosion, possible structural failure and frequent plasma contamination. Surface damage consists of vaporization, spallation, and liquid splatter of metallic materials. Structural damage includes large temperature increases in structural materials and at the interfaces between surface coatings and structural members. To evaluate the lifetimes of plasma-facing materials and nearby components and to predict the various forms of damage that they experience, comprehensive models (contained in the HEIGHTS computer simulation package) are developed, integrated self-consistently and enhanced. Splashing mechanisms, such as bubble boiling and various liquid magnetohydrodynamic instabilities and brittle destruction mechanisms of non-melting materials, are being examined. The design requirements and implications of plasma-facing and nearby components are discussed, along with recommendations to mitigate and reduce the effects of plasma instabilities on reactor components.

The structure of a collisionless scrape-off-layer (SOL) plasma in tokamak reactors is studied in order to define the electron distribution function and the corresponding sheath potential between the divertor plate and the edge plasma. The collisionless model is shown to be valid during the thermal phase of plasma disruption, as well as during the newly desired low-recycling normal phase of operation with low-density, high-temperature, edge plasma conditions. An analytical solution is developed by solving the Fokker–Planck equation for electron distribution and balance in the SOL. The solution is in good agreement with numerical studies using Monte Carlo methods. The analytical solutions provide insight into the role of different physical and geometrical processes in a collisionless SOL during disruptions and during the enhanced phase of normal operation over a wide range of parameters.

Damage to plasma-facing components (PFCs) from plasma instabilities remains a major obstacle to a successful tokamak concept. The extent of the damage depends on the detailed physics of the disrupting plasma, as well as on the physics of plasma-material interactions. A comprehensive computer package called High Energy Interaction with General Heterogeneous Target Systems (HEIGHTS) has been developed and consists of several integrated computer models that follow the beginning of a plasma disruption at the scrape-off layer (SOL) through the transport of the eroded debris and splashed target materials to nearby locations as a result of the deposited energy. The package can study, for the first time, plasma-turbulent behavior in the SOL and predict the plasma parameters and conditions at the divertor plate. Full two-dimensional (2-D) comprehensive radiation magnetohydrodynamic (MHD) models are coupled with target thermodynamics and liquid hydrodynamics to evaluate the integrated response of plasma-facing materials. Factors that influence the lifetime of plasma-facing and nearby components, such as loss of vapor cloud confinement and vapor removal due to MHD effects, damage to nearby components due to intense vapor radiation, melt splashing, and brittle destruction of target materials, are also modeled and discussed.

Estimations and experimental studies on the possibility of capillary-pore systems with lithium as the first wall and divertor target plate plasma-facing material have been conducted in support of the lithium liquid metal fusion reactor concept. The possibility of the lithium-filled capillary-pore systems to withstand a high energy plasma flux has been demonstrated.

Tritium behavior in plasma-facing components (PFCs) of future tokamak reactors such as ITER is an essential factor in evaluating and choosing the ideal plasma-facing materials (PFMs). One important parameter that influences tritium buildup and release in candidate materials is the effect of material porosity on tritium diffusion and retention. Diffusion in porous materials, for example, consists of three different processes: along grain boundaries, along microcrystallite boundaries, and in pure crystallite structures. Such diffusion processes have strong nonlinear behavior due to temperature, solubility, and existing trap sites. Therefore, a realistic model for tritium diffusion in porous and neutron-irradiated materials must account for both nonlinear and multidimensional effects. A tritium transport computer model Tritium Accumulation in Porous Structure (TRAPS) has been developed to evaluate and predict the kinetics of tritium transport in porous media. This two-dimensional model incorporates tritium diffusion and trapping processes that also account for hydrogen-isotope solubility limits in PFMs. This model is being coupled with the computer model Tritium In Compound System (TRICS) which has been developed to study the effects of surface erosion to tritium behavior in PFCs.

Surface and structural damage to plasma-facing components due to the frequent loss of plasma confinement is a serious problem for the tokamak reactor concept. The plasma energy deposited on these components during loss of confinement causes significant surface erosion, possible structural failure, and frequent plasma contamination. Surface damage consists of vaporization, spallation, and liquid splatter of metallic materials. Comprehensive multidimensional models that include thermodynamics and thermal hydraulics of plasma-facing materials, eroded-debris/vapor atomic physics and magnetohydrodynamics, resulting photon radiation and photon transport, as well as liquid splashing and brittle destruction of materials, are used self-consistently to evaluate and assess our current understanding of the lifetime of plasma-facing materials and the various forms of damage they experience. Models are developed to study the stability of the vapor shielding layer, erosion of the melt-layer, brittle destruction/explosive erosion, and the issues involved therein.

Damage to plasma-facing components (PFCs) and structural materials during abnormal plasma behavior such as hard disruptions, edge-localized modes (ELMs), and vertical displacement events (VDEs) is considered a serious life-limiting concern for these components. The PFCs in the International Thermonuclear Experimental Reactor (ITER), such as the divertor, limiter and parts of the first wall, will be subjected to high energy deposition during these plasma instabilities. High erosion losses on material surfaces, high temperature rise in structural materials (particularly at the bonding interface), and high heat flux levels and possible burnout of the coolant tubes are critical constraints that severely limit component lifetime and therefore degrade reactor performance, safety and economics. Recently developed computer models and simulation experiments are being used to evaluate various damage to PFCs during the abnormal events. The design implications of plasma-facing and nearby components are discussed, and recommendations are made to mitigate the effects of these events.

Damage to plasma-facing and nearby components due to plasma instabilities remains a major obstacle to a successful tokamak concept. The high energy deposited on facing materials during plasma instabilities can cause severe erosion, plasma contamination, and structural failure of these components. Erosion damage can take various forms such as surface vaporization, spallation, and liquid ejection of metallic materials. Comprehensive thermodynamic and radiation hydrodynamic codes have been developed, integrated, and used to evaluate the extent of various damage to plasma-facing and nearby components. The eroded and splashed materials will be transported and then redeposited elsewhere on other plasma-facing components. Detailed physics of plasma/solid-liquid/vapor interaction in a strong magnetic field have been developed, optimized, and implemented in a self-consistent model. The plasma energy deposited in the evolving divertor debris is quickly and intensely reradiated, which may cause severe erosi...

Metallic plasma-facing components (PFCs) e.g. beryllium and tungsten, will be subjected to severe melting during plasma instabilities such as disruptions, edge-localized modes and high power excursions. Because of the greater thickness of the resulting melt layers relative to that of the surface vaporization, the potential loss of the developing melt-layer can significantly shorten PFC lifetime, severely contaminate the plasma and potentially prevent successful operation of the tokamak reactor. Mechanisms responsible for melt-layer loss during plasma instabilities are being modeled and evaluated. Of particular importance are hydrodynamic instabilities developed in the liquid layer due to various forces such as those from magnetic fields, plasma impact momentum, vapor recoil and surface tension. Another mechanism found to contribute to melt-layer splashing loss is volume bubble boiling, which can result from overheating of the liquid layer. To benchmark these models, several new experiments were designed and performed in different laboratory devices for this work; the results are examined and compared. Theoretical predictions (A ∗ THERMAL-S and SPLASH codes) are generally in good agreement with the experimental results. The effect of in-reactor disruption conditions, which do not exist in simulation experiments, on melt-layer erosion is discussed.

Summary BackgroundVKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. MethodsWe did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 −1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P

Erosion losses of plasma-facing materials in a tokamak reactor during major disruptions, giant ELMS, and large power excursions are serious concerns that influence component survivability and overall lifetime. Two different mechanisms lead to material erosion during these events: surface vaporization and loss of the melt layer. Hydrodynamics and radiation transport in the rapidly developed vapor-cloud region above the exposed area are found to control and determine the net erosion thickness from surface vaporization. A comprehensive self-consistent kinetic model has been developed in which the time-dependent optical properties and the radiation field of the vapor cloud are calculated in order to correctly estimate the radiation flux at the divertor surface. The developed melt layer of metallic divertor materials will, however, be free to move and can be eroded away due to various forces. , Physical mechanisms that affect surface vaporization and cause melt layer erosion are integrated in a comprehensive model. It is found that for metallic components such as beryllium and tungsten, lifetime due to these abnormal events will be controlled and dominated by the evolution and hydrodynamics of the melt layer during the disruption. The dependence of divertor plate lifetime on various aspects of plasma/material interaction physics is discussed.

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.

The high divertor heat load during a tokamak plasma disruption results in sudden evaporation of a thin layer of divertor plate material, which acts as vapor shield and protects the target from further excessive evaporation. Formation and effectiveness of the vapor shield are theoretically modeled and are experimentally analyzed at the 2MK-200 facility under conditions simulating the thermal quench phase of ITER tokamak plasma disruptions.

A comprehensive disruption erosion model which takes into account the interplay of major physical processes during plasma-material interaction has been developed. The model integrates with sufficient detail and in a self-consistent way, material thermal evolution response, plasma-vapor interaction physics, vapor hydrodynamics and radiation transport in order to realistically simulate the effects of a plasma disruption on plasma-facing components. Candidate materials such as beryllium and carbon have been analyzed. The dependence of the net erosion rate on disruption physics and various parameters was analyzed and is discussed.

The behavior of divertor materials during a major disruption in ITER is very important to successful and reliable operation of the reactor. Erosion of material surfaces due to a thermal energy dump can severely limit the lifetimes of plasma-facing components and thus diminish the reactor's economic feasibility. A comprehensive numerical model has been developed and used in this analysis, which includes all major physical processes taking place during plasma/material interactions. Models to account for material thermal evolution, plasma/vapor interaction physics, and models for hydrodynamic radiation transport in the developed vapor cloud are implemented in a self-consistent manner to realistically assess disruption damage. The extent of self-protection from the developed vapor cloud in front of the incoming plasma particles is critically important in determining the overall disruption lifetime. Models to study detailed effects of the strong magnetic field on the behavior of the vapor cloud and on the net erosion rate have been developed and analyzed. Candidate materials such as beryllium and carbon are both considered in this analysis. The dependence of divertor disruption lifetime on disruption physics and reactor conditions was analyzed and discussed.

Neuroblastoma is the most common extracranial solid malignancy in children and is notable for its clinical heterogeneity. Clinical features, including age at diagnosis and stage of disease, and genetic tumor markers are strongly predictive of outcome and used to define risk groups for treatment stratification (1). High-risk neuroblastoma is defined largely by older patients (aged >18 months) with metastatic disease, although all patients with amplification of the MYCN oncogene, regardless of stage, are considered high risk. Ethnic disparities in outcome are well described for many cancers (2–5). However, until recently, little was known about associations between race/ethnicity and survival in neuroblastoma. In 2011, Henderson and colleagues analyzed a cohort of 3539 neuroblastoma patients with known self-reported race and outcome and demonstrated for the first time that black children have an increased prevalence of high-risk disease and inferior survival compared with white children (6). Multiple factors are known to contribute to racial health disparities, including differences in access to healthcare and other environmental and socioeconomic factors. However, because low-risk neuroblastomas only rarely progress to high-risk disease over time, we hypothesized that genetic variation is largely responsible for the ethnic disparities in tumor phenotype and outcome observed in neuroblastoma. Indeed, germline DNA variants associated with susceptibility to high- or low-risk neuroblastoma have been identified in genome-wide studies conducted primarily in children of European descent (7–12). To investigate the role African genomic ancestry plays in determining neuroblastoma phenotype and to identify genetic variants that statistically account for the ethnic disparities in outcome, we analyzed the genotypes of an ethnically admixed population of neuroblastoma patients (N = 2709) accrued through Children’s Oncology Group neuroblastoma biology protocol ANBL00B1 between 2001 and 2009.

The high divertor heat load during a tokamak plasma disruption results in sudden evaporation of a thin layer of divertor plate material, which acts as vapor shield and protects the target from further excessive evaporation. Formation and effectiveness of the vapor shield are theoretically modeled and experimentally investigated at the 2MK-200 facility under conditions simulating the thermal quench phase of ITER tokamak plasma disruptions. In the optical wavelength range C II, C III, C IV emission lines for graphite, Cu I, Cu II lines for copper and continuum radiation for tungsten samples are observed in the target plasma. The plasma expands along the magnetic field lines with velocities of (4 ± 1) × 106 cm/s for graphite and 105 cm/s for copper. Modeling was done with a radiation hydrodynamics code in one-dimensional planar geometry. The multifrequency radiation transport is treated in flux limited diffusion and in forward reverse transport approximation. In these first modeling studies the overall shielding efficiency for carbon and tungsten defined as ratio of the incident energy and the vaporization energy for power densities of 10 MW/cm2 exceeds a factor of 30. The vapor shield is established within 2 μs, the power fraction to the target after 10 μs is below 3% and reaches in the stationary state after about 20 μs a value of around 1.5%.

This chapter presents a summary of plasma-surface interactions in electrode and condenser-optic materials in plasma pinch sources for EUV light generation, with special emphasis on DPPs. In DPP EUV devices, electrodes at the source are exposed to short (10–20-ns) high-intensity plasmas, leading to a variety of erosion mechanisms. Erosion of the electrodes is dictated by the dynamics of the plasma pinch for configurations such as the dense plasma focus (DPF), Z pinch, and capillary. The transient discharge deposits 1–2 J∕cm2 per pulse on electrode surfaces. Large heat flux is deposited at corners and edges, leading to enhanced erosion. Understanding of how particular materials respond to these conditions is part of the rigorous design of DPP electrode systems. Erosion mechanisms can include physical sputtering, current-induced macroscopic erosion, melt formation, and droplet and particulate ejection. Erosion at the surface is also governed by the dynamics of how a plasma can generate a vapor cloud, leading to a self-shielding effect, which results in ultimate protection of the surface bombarded. Determining which will dominate—either microscopic erosion mechanisms such as physical sputtering, or macroscopic mechanisms such as melt formation and droplet ejection—remains an open question in DPP electrode design. This is because such mechanisms are inherently dependent on the pinch dynamics and operation of the source. In addition to plasma-surface interactions in electrodes, for condenser optics, especially collector optics, erosion is due to fast ions and neutrals born in the plasma pinch, leading mainly to physical sputtering and other bombardment-induced mechanisms. If the surface is composed of more than one species, which is mostly the case, then radiation-induced and thermally activated effects govern the behavior of the surface and govern lifetime levels of the exposed material. Exposure includes debris from electrodes, high-energy ions and neutrals, highly charged ions (HCIs), background impurities, photon radiation [13.5-nm and out-of-band (OOB)], and redeposited eroded mirror material. Figure 35.1 presents an overview of DPP plasma-surface interaction modeling that can be complemented by materials testing. It shows the transient plasma region (region 1) to the left and the quiescent expanding plasma region (region 3) to the right where the collector optics is located. Region 2 comprises a number of debris mitigation schemes that can also be modeled and experimentally tested. A number of modeling simulators can couple regions 1–3 in a self-consistent manner. This can be useful in designing mirrors that are compatible with the debris mitigation schemes selected as well as the EUV fuel used at the source. This is especially important if alternative EUV radiator fuels are selected, such as Sn or Li. Designs at the source with alternative radiator fuels can be studied and their effect on mirrors assessed.

The molecular basis of the HNA-3a/b (5b/a) leukocyte antigen system has not yet been defined despite evidence that HNA-3a–specific antibodies are particularly prone to cause severe, often fatal, transfusion-related lung injury. We used genome-wide single nucleotide polymorphism scanning and sequencing of DNA from persons of different HNA-3a/b phenotypes to identify a single single nucleotide polymorphism in exon 7 of the CLT2 gene (SLC44A2) that predicts an amino acid substitution in the first extracellular loop of choline transporter-like protein 2, a member of the choline transporter-like protein family of membrane glycoproteins, and correlates perfectly with HNA-3a/b phenotypes (R154 encodes HNA-3a; Q154 encodes HNA-3b). Mass spectrometric analysis of proteins immunoprecipitated from leukocytes by anti–HNA-3a provided direct evidence that anti–HNA-3a recognizes choline transporter-like protein 2. These findings will enable large-scale genotyping for HNA-3a/b to identify blood donors at risk to have HNA-3a–specific antibodies and should facilitate development of practical methods to detect such antibodies and prevent transfusion-related lung injury.

In the past few years the possibility of the space travel to Mars in the beginning of XXI century has been discussed. The main problem is the choice of an engine. Now, the primary engine is a chemi...

This paper describes issues in using single-array algorithms for calling genotypes for Affymetrix arrays, and introduces a computationally efficient procedure that is designed to be used as a complement to the multi-arrays algorithms. The new tool is based on ideas from a previously introduced algorithm [9] with modifications that improve accuracy. These modifications are also necessary for handling the data from the new arrays which have a modified design with no perfect-matches. The main gain in accuracy is obtained from the partitioning of the probes in homogeneous clusters based on measures of efficiency of probe hybridization that are calculated from the probe sequence composition, and based on measures of probe performance that are calculated using a small training dataset.

The need is increasing for development of high-power targets and beam dump areas for the production of intense beams of secondary particles. The severe constraints arising from a megawatt beam deposited on targets and absorbers call for nontrivial procedures to dilute the beam. This study describes the development of targets and absorbers and the advantages of using flowing liquid metal in concave channels first proposed by IFMIF to raise the liquid metal boiling point by increasing the pressure in liquid supported by a centrifugal force. Such flow with a back-wall is subject to Taylor-Couette instability. The instability can play a positive role of increasing the heat transfer from the hottest region in the target/absorber to the back-wall cooled by water. Results of theoretical analysis and numerical modeling of both targets and dump areas for the IFMIF, ILC, and RIA facilities are presented.

We present a simple model of breakdown in rf cavities. For most events this involves tensile stress and tensile strength, however other effects can also contribute. We discuss the effects of different materials, fatigue, high pressure gas, primary and secondary emission sites, local field enhancements, dark currents, secondary emission, work functions, magnetic fields, macro and microscopic fracture mechanisms high current densities, surface and subsurface defects, and astronomical power densities. While primarily devoted to normal conductors, this work also has consequences for superconducting rf surfaces.

Summary form only given. This study presents the first detail 3-D full modeling of all physical processes in laser-produced plasma (LPP) for various applications. The evolution of the target in 3-D full hydrodynamic response coupled with 3-D photon transport in the LPP with detail atomic physics are simulated for multiple-laser on target systems. For example, several concepts are considered in utilizing a high-power laser to generate plasma that emits photons in the EUV region for lithography to support the throughput requirements of high-volume manufacturing lithography exposure tools. The typical for most LPP devices is providing the initial heating (with possible simultaneous compression) of solid or liquid targets to the temperatures required for generating the radiation in the EUV region. After a short laser pulse with tau=10-50 ns, the energy of the external laser radiation is partly transmitted deeper into the target, partly absorbed by the target plasma, and partly reflected at the plasma-vacuum interface. An integrated model for the description of hydrodynamics and optical processes in a LPP device has been developed and integrated into the HEIGHTS-LPP computer simulation package. Model development consisted of three main tasks: laser absorption induced plasma evolution and magnetohydrodynamic (MHD) processes; detailed photon radiation transport, and physics of plasma expansion. Advanced numerical methods for the description of target compression in various geometries are used in the HEIGHTS package. For opacity calculations several models have been developed and implemented. Radiation transport of both continuum and lines is taken into account with detailed spectral profiles in the EUV region. A multi-group approximation of opacities with detail resolution of several thousand strong spectral lines is used. Radiation transport in LPP devices is solved using two different methods, i.e., by direct integration of the transport equation and by 3-D Monte Carlo techniques. The models and theories developed in this work and implemented in HEIGHTS-LPP will be used to explain recent LPP experiments to understand role of different physical processes causing fast ions generation and the flux of such ions. In addition, parameters such as target design and laser pulse shape should be optimized to find in future devices better target design and a relevant laser pulse shape. The HEIGHTS-LPP package can also study detailed hydrodynamic and radiation processes in various LPP devices as a function of laser energy, wavelength, and dimensions to optimize brightness throughput

Summary form only given. Several new innovative ideas are being considered for tokamak divertors in magnetic fusion devices. One of such concepts is the use of liquid metals as the plasma-facing component. One of main problem for the use of liquid metal divertors is the MHD problem associated with a liquid metal being in the strong tokamak magnetic field. This is particularly important for the conventional tokamaks such as ITER and DEMO that have relatively large aspect ratio. As a result, the magnetic filed lines have small inclination angle to the divertor plate, thus liquid metal flows practically normally to magnetic field and therefore, results in many problems with MHD features (pressure drops, JtimesB splashing effects, etc.). The second problem is related to helium and particle pumping due to high diffusivity of gas in liquid metal. For current existing design concepts of large tokamak aspect ratios, artificially excited fluctuations are needed for sufficient pumping. In this study the possibility of avoiding these problems are considered for spherical tokamaks such as NSTX. Due to small aspect ratio, the inclination of magnetic filed lines nearby the separatrix to the divertor plate is much larger (about 200 or higher). This will permit to use liquid metal flow moving along magnetic filed lines in spaceconcaved trays. Flow parallel to magnetic field lines has no pressure drop except some (small) influence nearby the trays walls. Excitation of the Taylor-Couette vortexes instabilities make possible to sink of He particles deeper in bulk due to liquid metal rotation along velocity direction parallel to magnetic field lines

Material erosion of plasma-facing components during a tokamak disruption is a serious problem that limits reactor operation and economical reactor lifetime. In particular, metallic low-Z components such as Be will be subjected to severe melting during disruptions and edge localized modes (ELMs). Loss of the developed melt layer will critically shorten the lifetime of these components, severely contaminate the plasma, and seriously inhibit successful and reliable operation of the reactor. In this study mechanisms responsible for melt-layer loss during a disruption are modeled and evaluated. Implications of melt-layer loss on the performance of metallic facing components in the reactor environment are discussed.

Summary form only given. Both laser and discharge produced plasma such as Z-pinch devices are being used as a light source for EUV lithography. A key challenge for discharge produced plasma (DPP) devices is achieving sufficient brightness to support the throughput requirements of high-volume manufacturing (HVM) lithography exposure tools. An integrated model for the description of hydrodynamics and optical processes in a DPP device has been developed and integrated into the HEIGHTS-EUV computer simulation package. Model development consisted of three main tasks: plasma evolution and MHD processes; detailed photon radiation transport, and physics of plasma/electrode interactions in DPP devices. Plasma flows have multidimensional character in pinch systems. Advanced numerical methods for the description of magnetic compression and diffusion in a cylindrical geometry are used in the HEIGHTS package. Radiation transport of both continuum and lines is taken into account with detailed spectral profiles in the EUV region. Radiation transport is solved using two different methods. Discharges using xenon and tin gases are simulated and compared. Benchmarking of EUV signals and plasma parameters in both laser and Z-pinch devices is presented