We provide two methods for identifying changes in genotype that are correlated with changes in a phenotype implied by phylogenetic trees. The first method, VENN, works when the number of branches ...over which the change occurred are modest. VENN looks for genetic changes that are completely penetrant with phenotype changes on a tree. The second method, CCTSWEEP, allows for a partial matching between changes in phenotypes and genotypes and provides a score for each change using Maddison's concentrated changes test. The mutations that are highly correlated with phenotypic change can be ranked by score. We use these methods to find SNPs correlated with resistance to Bacillus anthracis in inbred mouse strains. Our findings are consistent with the current biological literature, and also suggest potential novel candidate genes.
Contact:
farhat@pacific.mps.ohio-state.edu for software requests.
Abstract
Costimulation through the TCR and CD28 drives T cell activation and differentiation. TCR engagement without CD28 results in anergy, a dominant state refractory to further stimulation. To ...understand how signals from CD28 and/or TCR imprint anergic and effector cell fates, we analyzed the genome-wide patterns of open chromatin in TCR or TCR/CD28-costimulated CD4+ T cells using ATAC-seq. Remarkably, although anergy represents a loss of T cell function, anergic cells exhibited 40% more open chromatin regions (OCR) than effector cells. Over 85% of the accessible effector genome was shared with anergic cells, and only 6,400 OCR were effector-specific. Conversely, only 60% of the accessible anergic genome overlapped with effectors, while 24,000 OCR were anergy-specific. Nearly one-fifth of effector-specific OCR were located in promoters, and were enriched for ETS, BCL6, and KLF consensus binding motifs. The remaining 5300 OCR, putatively representing the effector-specific enhancer landscape, were enriched for CTCF, ETS, BATF, IRF, and E2F motifs. Conversely, only 5% of anergy-specific OCR were in promoters, and these regions were enriched for motifs for FOS, ETS, IRF, SMAD3, and EGR1. The remaining 23,000 OCR that putatively constitute the anergy-specific enhancer landscape were specifically enriched for NFkB, TBET, NFAT, and Nur77 motifs. These results suggest that while CD28 cooperates with the TCR to activate a minor, effector-specific component of the T cell gene regulatory architecture, the major epigenomic role of costimulation is to actively oppose remodeling of the anergy-associated gene ‘regulome’ imprinted by default by the TCR.
Summary Background Exhaled nitric oxide provides a convenient, non-invasive insight into airway inflammation. However it is suppressed by current smoking, reducing its potential as an endpoint in ...studies of smokers with asthma, a group with increased symptoms and poor clinical responses to corticosteroids. We examined extended nitric oxide analysis as some derived variables are thought to be unaffected. Therefore this approach could reveal hidden inflammation and enable its use as an exploratory endpoint in this group. Methods Smokers ( n = 22) and never smokers ( n = 21) with asthma performed exhaled nitric oxide measurements and spirometry before and after two weeks of oral dexamethasone (6 mg/1.74 m2 /day). Linear and non-linear nitric oxide analysis was performed to derive estimates for alveolar nitric oxide (Calv ) and nitric oxide flux (J′aw ) for each subject. Results FENO50 was significantly lower in smokers with asthma and did not change significantly in response to dexamethasone. Calv derived by linear modelling was lower in smokers with asthma and did not change significantly in response in either group. J′aw was substantially lower in smokers with asthma (smokers (median (IQR)); 573 pl/s (217, 734), non-smoker; 1535 pl/s (785, 3496), p = 0.001) and was reduced in both groups following dexamethasone (non-smokers change (mean (95% CI)); −743.3 pl/s (−1710, −163), p = 0.005, smokers; −293 pl/s (−572, −60), p = 0.016). Correction for axial flow did not substantially change the derived results. Conclusions Bronchial NO flux appears to be sensitive to oral dexamethasone and may provide a useful exploratory endpoint for the analysis of novel anti-inflammatory therapies in smokers with asthma.
Cerebrovascular disease remains a significant public health burden with its greatest impact on the elderly population. Advances in neuroimaging techniques allow detailed and sophisticated evaluation ...of many manifestations of cerebrovascular disease in the brain parenchyma as well as in the intracranial and extracranial vasculature. These tools continue to contribute to our understanding of the multifactorial processes that occur in the age-dependent development of cerebrovascular disease. Structural abnormalities related to vascular disease in the brain and vessels have been well characterized with CT and MRI based techniques. We review some of the pathophysiologic mechanisms in the aging brain and cerebral vasculature and the related structural abnormalities detectable on neuroimaging, including evaluation of age-related white matter changes, atherosclerosis of the cerebral vasculature, and cerebral infarction. In addition, newer neuroimaging techniques, such as diffusion tensor imaging, perfusion techniques, and assessment of cerebrovascular reserve, are also reviewed, as these techniques can detect physiologic alterations which complement the morphologic changes that cause cerebrovascular disease in the aging brain.Further investigation of these advanced imaging techniques has potential application to the understanding and diagnosis of cerebrovascular disease in the elderly.
African species of Oxyscelio (Hymenoptera: Platygastridae s.l.) are revised. A total of 14 species are recognized, 13 of which are described as new: Oxyscelio absentiae Burks, sp. n., Oxyscelio ...galeri Burks, sp. n., Oxyscelio gyri Burks, sp. n., Oxyscelio idoli Burks, sp. n., Oxyscelio intensionis Burks, sp. n., Oxyscelio io Burks, sp. n., Oxyscelio kylix Burks, sp. n., Oxyscelio lunae Burks, sp. n., Oxyscelio nemesis Burks, sp. n., Oxyscelio pulveris Burks, sp. n., Oxyscelio quassus Burks, sp. n., Oxyscelio teli Burks, sp. n. and Oxyscelio xenii Burks, sp. n. The genus Freniger Szabó, syn. n. is recognized as part of an endemic African species group of Oxyscelio with incomplete hind wing venation, and Oxyscelio bicolor (Szabó), comb. n. is therefore recognized as the only previously described species of Oxyscelio from Africa. The Oxyscelio crateris and Oxyscelio cuculli species groups, previously known from southeast Asia, are represented in Africa by seven and one species respectively.
•VCSEL Wafer diameters on GaAs were initially developed at 100 mm and rapidly expanded to 150 mm.•Improved uniformity in reflectivity, thickness and composition.•150 mm VCSELs on GaAs were qualified ...from a newly constructed state-of-the-art epi-foundry.•New substrate material was considered – Ge demonstrated significantly reduced wafer bow, zero EPD substrate with minimal slip.•Growth of VCSELs on 200 mm wafers.
III-V Compound Semiconductors (CS) such as Gallium Arsenide (GaAs), Indium Phosphide (InP) and more latterly, Gallium Nitride (GaN) are critical Key Enabling Technologies, fundamentally underpinning several recent major technology revolutions. Two major current and likely-future markets within the burgeoning photonics industry ($7 billion) are 3D imaging and sensing and LIDAR applications, with high predicted market growth. Datacom and industrial markets add considerable further momentum to this market growth. Evidence of such expansion is provided in the manufacturing of VCSEL-based devices, which have in recent years, entered a rapid growth phase. For the mass-manufacturing of for example, GaAs/AlGaAs-based VCSEL MOVPE epitaxy, many areas require addressing in key underlying R&D, such as cost-reduction and in thickness and wavelength uniformity. In addition, scalability, (e.g. to 150 mm wafers), automation and in-situ process control will impact yield and throughput improvements.
We will demonstrate the preparations for mass-manufacturing, through improvements implemented across the evolution of the VCSEL epiwafers from smaller diameters, through 100 mm and on to 150 mm wafers. More recently however, further developments have led to even larger diameter VCSEL wafer epitaxy, on both GaAs and Ge 200 mm substrates. Challenges in growing on such large diameter wafers will be presented from the epitaxy (layer uniformity and wafer bow) and device fabrication perspective. We will demonstrate how these improvements impact on the manufacturing readiness of production VCSEL wafers.
Allele expression (AE) analysis robustly measures cis-regulatory effects. Here, we present and demonstrate the utility of a vast AE resource generated from the GTEx v8 release, containing 15,253 ...samples spanning 54 human tissues for a total of 431 million measurements of AE at the SNP level and 153 million measurements at the haplotype level. In addition, we develop an extension of our tool phASER that allows effect sizes of cis-regulatory variants to be estimated using haplotype-level AE data. This AE resource is the largest to date, and we are able to make haplotype-level data publicly available. We anticipate that the availability of this resource will enable future studies of regulatory variation across human tissues.
Abstract Background Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also ...associated with other diseases or traits. Objectives This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. Methods In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. Results We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 ( KCNJ13-GIGYF2 ), 6p21 ( C2 ), 11p15 ( MRVI1-CTR9 ), 12q13 ( LRP1 ), 12q24 ( SCARB1 ), and 16q13 ( CETP ). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10−4 with a range of other diseases/traits. Conclusions We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
The platygastroid wasp Echthrodesis lamorali has been of considerable interest since its description in 1968, primarily because of its highly modified, densely pilose, wingless body, its distribution ...and unusual biology. The species is endemic to the Cape Peninsula, South Africa, where it is an endoparasitoid of eggs of the marine spiders Desis formidabilis (Desidae) and Amaurobioides africanus (Anyphaenidae) in the intertidal region. Although a highly aberrant monospecific genus, the phylogenetic relationships of Echthrodesis are confused, in part due to convergence in body form across numerous unrelated platygastroid genera. We used sequence data from the nuclear 28S rRNA and 18S rDNA genes, and the mitochondrial cytochrome oxidase 1 (CO1) gene, to determine the phylogenetic affinities of E. lamorali. We present a revised taxonomic description for the genus and species, as well as new morphological information on the structure of its mouthparts and ovipositor system. Phylogenetic analyses of molecular data place E. lamorali within one of two independent clades of platygastroid wasps that use spider eggs as hosts. Echthrodesis is sister to a group of three genera: Neobaeus (New Zealand; host unconfirmed); Mirobaeoides (Australia; spider eggs); and Embidobia (near cosmopolitan; embiid eggs). Details on the biology, behaviour and morphological adaptations of E. lamorali are provided.
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