Fast Genome-Wide QTL Association Mapping on Pedigree and Population Data

Since most analysis software for genome-wide association studies (GWAS) currently exploit only unrelated individuals, there is a need for efficient applications that can handle general pedigree data or mixtures of both population and pedigree data. Even data sets thought to consist of only unrelated individuals may include cryptic relationships that can lead to false positives if not discovered and controlled for. In addition, family designs possess compelling advantages. They are better equipped to detect rare variants, control for population stratification, and facilitate the study of parent-of-origin effects. Pedigrees selected for extreme trait values often segregate a single gene with strong effect. Finally, many pedigrees are available as an important legacy from the era of linkage analysis. Unfortunately, pedigree likelihoods are notoriously hard to compute. In this paper we re-examine the computational bottlenecks and implement ultra-fast pedigree-based GWAS analysis. Kinship coefficients can either be based on explicitly provided pedigrees or automatically estimated from dense markers. Our strategy (a) works for random sample data, pedigree data, or a mix of both; (b) entails no loss of power; (c) allows for any number of covariate adjustments, including correction for population stratification; (d) allows for testing SNPs under additive, dominant, and recessive models; and (e) accommodates both univariate and multivariate quantitative traits. On a typical personal computer (6 CPU cores at 2.67 GHz), analyzing a univariate HDL (high-density lipoprotein) trait from the San Antonio Family Heart Study (935,392 SNPs on 1357 individuals in 124 pedigrees) takes less than 2 minutes and 1.5 GB of memory. Complete multivariate QTL analysis of the three time-points of the longitudinal HDL multivariate trait takes less than 5 minutes and 1.5 GB of memory

Degranulating mast cells in fibrotic regions of human tumors and evidence that mast cell heparin interferes with the growth of tumor cells through a mechanism involving fibroblasts

BACKGROUND: The purpose of this study was to test the hypothesis that mast cells that are present in fibrotic regions of cancer can suppress the growth of tumor cells through an indirect mechanism involving peri-tumoral fibroblasts. METHODS: We first immunostained a wide variety of human cancers for the presence of degranulated mast cells. In a subsequent series of controlled in vitro experiments, we then co-cultured UACC-812 human breast cancer cells with normal fibroblasts in the presence or absence of different combinations and doses of mast cell tryptase, mast cell heparin, a lysate of the human mast cell line HMC-1, and fibroblast growth factor-7 (FGF-7), a powerful, heparin-binding growth factor for breast epithelial cells. RESULTS: Degranulating mast cells were localized predominantly in the fibrous tissue of every case of breast cancer, head and neck cancer, lung cancer, ovarian cancer, non-Hodgkin's lymphoma, and Hodgkin's disease that we examined. Mast cell tryptase and HMC-1 lysate had no significant effect on the clonogenic growth of cancer cells co-cultured with fibroblasts. By contrast, mast cell heparin at multiple doses significantly reduced the size and number of colonies of tumor cells co-cultured with fibroblasts, especially in the presence of FGF-7. Neither heparin nor FGF-7, individually or in combination, produced any significant effect on the clonogenic growth of breast cancer cells cultured without fibroblasts. CONCLUSION: Degranulating mast cells are restricted to peri-tumoral fibrous tissue, and mast cell heparin is a powerful inhibitor of clonogenic growth of tumor cells co-cultured with fibroblasts. These results may help to explain the well-known ability of heparin to inhibit the growth of primary and metastatic tumors

A New Algorithm for Protein Design

We apply a new approach to the reverse protein folding problem. Our method uses a minimization function in the design process which is different from the energy function used for folding. For a lattice model, we show that this new approach produces sequences that are likely to fold into desired structures. Our method is a significant improvement over previous attempts which used the energy function for designing sequences.Comment: 10 pages latex 2.09 no figures. Use uufiles to decod

Systematic design of single-mode coupled-resonator optical waveguides in photonic crystals

By establishing a direct relation between the dispersion and the field profile of a coupled-resonator optical waveguide (CROW) and those of its constituent cavities, we present a systematic method for the design of a single-mode CROW and for control of its dispersion. The procedure includes the design of a single-mode cavity and control of its frequency by engineering its structure. Then, by chaining these cavities in the proper direction and at an appropriate distance, we achieve the desired dispersion for the CROW

Recalling a Witnessed Event Increases Eyewitness Suggestibility The Reversed Testing Effect

People\u27s later memory of an event can be altered by exposure to misinformation about that event. The typical misinformation paradigm, however, does not include a recall test prior to the introduction of misinformation, contrary to what real-life eyewitnesses encounter when they report to a 911 operator or crime-scene officer. Because retrieval is a powerful memory enhancer (the testing effect), recalling a witnessed event prior to receiving misinformation about it should reduce eyewitness suggestibility. We show, however, that immediate cued recall actually exacerbates the later misinformation effect for both younger and older adults. The reversed testing effect we observed was based on two mechanisms: First, immediate cued recall enhanced learning of the misinformation; second, the initially recalled details became particularly susceptible to interference from later misinformation, a finding suggesting that even human episodic memory may undergo a reconsolidation process. These results show that real-life eyewitness memory may be even more susceptible to misinformation than is currently envisioned

Accounting for the association of family conflict and heavy alcohol use among adolescent girls: the role of depressed mood

Objective: Heavy alcohol use increases dramatically at age 14, and there is emerging cross-sectional evidence that when girls experience family conflict at younger ages (11-13 years) the risk of alcohol use and misuse is high. This study evaluated the role of family conflict and subsequent depressed mood in predicting heavy alcohol use among adolescent girls. Method: This was a three-wave longitudinal study with annual assessments (modal ages 12, 13, and 14 years). The participants (N = 886, 57% female) were from 12 metropolitan schools in Victoria, Australia, and participants completed questionnaires during school class time. The key measures were based on the Communities That Care Youth Survey and included family conflict (Wave 1), depressed mood (Wave 2), and heavy alcohol use (Wave 3). Control variables included school commitment, number of peers who consumed alcohol, whether parents were living together, and ethnic background. Results: With all controls in the model, depressed mood at Wave 2 was predicted by family conflict at Wave 1. The interaction of family conflict with gender was significant, with girls showing a stronger association of family conflict and depressed mood. Depressed mood at Wave 2 predicted heavy alcohol use at Wave 3. Conclusions: Girls may be especially vulnerable to family conflict, and subsequent depressed mood increases the risk of heavy alcohol use. The results support the need for gender-sensitive family-oriented prevention programs delivered in late childhood and early adolescence. (J. Stud. Alcohol Drugs, 74, 396-405, 2013

High scale impact in alignment and decoupling in two-Higgs doublet models

The two-Higgs doublet model (2HDM) provides an excellent benchmark to study physics beyond the Standard Model (SM). In this work we discuss how the behaviour of the model at high energy scales causes it to have a scalar with properties very similar to those of the SM -- which means the 2HDM can be seen to naturally favor a decoupling or alignment limit. For a type II 2HDM, we show that requiring the model to be theoretically valid up to a scale of 1 TeV, by studying the renormalization group equations (RGE) of the parameters of the model, causes a significant reduction in the allowed magnitude of the quartic couplings. This, combined with $B$-physics bounds, forces the model to be naturally decoupled. As a consequence, any non-decoupling limits in type II, like the wrong-sign scenario, are excluded. On the contrary, even with the very constraining limits for the Higgs couplings from the LHC, the type I model can deviate substantially from alignment. An RGE analysis similar to that made for type II shows, however, that requiring a single scalar to be heavier than about 500 GeV would be sufficient for the model to be decoupled. Finally, we show that not only a 2HDM where the lightest of the CP-even scalars is the 125 GeV one does not require new physics to be stable up to the Planck scale but this is also true when the heavy CP-even Higgs is the 125 GeV and the theory has no decoupling limit for the type I model.Comment: 28 pages, 19 figure

Secretome Analysis of Skeletal Myogenesis Using SILAC and Shotgun Proteomics

Myogenesis, the formation of skeletal muscle, is a multistep event that commences with myoblast proliferation, followed by cell-cycle arrest, and finally the formation of multinucleated myotubes via fusion of mononucleated myoblasts. Each step is orchestrated by well-documented intracellular factors, such as cytoplasmic signalling molecules and nuclear transcription factors. Regardless, the key step in getting a more comprehensive understanding of the regulation of myogenesis is to explore the extracellular factors that are capable of eliciting the downstream intracellular factors. This could further provide valuable insight into the acute cellular response to extrinsic cues in maintaining normal muscle development. In this paper, we survey the intracellular factors that respond to extracellular cues that are responsible for the cascades of events during myogenesis: myoblast proliferation, cell-cycle arrest of myoblasts, and differentiation of myoblasts into myotubes. This focus on extracellular perspective of muscle development illustrates our mass spectrometry-based proteomic approaches to identify differentially expressed secreted factors during skeletal myogenesis

Visual Outcomes, Quality of Vision, and Quality of Life of Diffractive Multifocal Intraocular Lens Implantation after Myopic Laser In Situ Keratomileusis: A Prospective, Observational Case Series

Purpose. To report visual performance and quality of life after implantation of a bifocal diffractive multifocal intraocular lens (MIOL) in postmyopic laser in situ keratomileusis (LASIK) patients. Methods. Prospective, observational case series. Patients with prior myopic LASIK who had implantation of Tecnis ZMA00/ZMB00 MIOL (Abbott Medical Optics) at Hong Kong Sanatorium and Hospital were included. Postoperative examinations included monocular and binocular distance, intermediate and near visual acuity (VA), and contrast sensitivity; visual symptoms (0–5); satisfaction (1–5); spectacle independence rate; and quality of life. Results. Twenty-three patients (27 eyes) were included. No intraoperative complications developed. Mean monocular uncorrected VA at distance, intermediate, and near were 0.13±0.15 (standard deviation), 0.22±0.15, and 0.16±0.15, respectively. Corresponding mean values for binocular uncorrected VA were 0.00±0.10, 0.08±0.13, and 0.13±0.10, respectively. No eyes lost >1 line of corrected distance VA. Contrast sensitivity at different spatial frequencies between operated and unoperated eyes did not differ significantly (all P>0.05). Mean score for halos, night glare, starbursts, and satisfaction were 1.46±1.62, 1.85±1.69, 0.78±1.31, and 3.50±1.02, respectively. Eighteen patients (78%) reported complete spectacle independence. Mean composite score of the quality-of-life questionnaire was 90.31±8.50 out of 100. Conclusions. Implantation of the MIOL after myopic LASIK was safe and achieved good visual performance