Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations

BACKGROUND: Previous studies investigating a genetic basis for idiopathic pulmonary fibrosis (IPF) have focused on resequencing single genes in IPF kindreds or cohorts to determine the genetic contributions to IPF. None has investigated interactions among the candidate genes. OBJECTIVE: To compare the frequencies and interactions of mutations in six IPF-associated genes in a cohort of 132 individuals with IPF with those of a disease-control cohort of 192 individuals with chronic obstructive pulmonary disease (COPD) and the population represented in the Exome Variant Server. METHODS: We resequenced the genes encoding surfactant proteins A2 (SFTPA2), and C (SFTPC), the ATP binding cassette member A3 (ABCA3), telomerase (TERT), thyroid transcription factor (NKX2-1) and mucin 5B (MUC5B) and compared the collapsed frequencies of rare (minor allele frequency <1%), computationally predicted deleterious variants in each cohort. We also genotyped a common MUC5B promoter variant that is over-represented in individuals with IPF. RESULTS: We found 15 mutations in 14 individuals (11%) in the IPF cohort: (SFTPA2 (n=1), SFTPC (n=5), ABCA3 (n=4) and TERT (n=5)). No individual with IPF had two different mutations, but one individual with IPF was homozygous for p.E292V, the most common ABCA3 disease-causing variant. We did not detect an interaction between any of the mutations and the MUC5B promoter variant. CONCLUSIONS: Rare mutations in SFTPA2, SFTPC and TERT are collectively over-represented in individuals with IPF. Genetic analysis and counselling should be considered as part of the IPF evaluation

Measurement of Jets and Jet Suppression in sqrt(s_NN)=2.76 TeV Lead-Lead Collisions with the ATLAS detector at the LHC

The first results of single jet observables in Pb+Pb collisions at sqrt(s_NN)=2.76 TeV measured with the ATLAS detector at the LHC are presented. Full jets are reconstructed with the anti-kt algorithm with R= 0.2 and 0.4, using an event-by-event subtraction procedure to correct for the effects of the underlying event including elliptic flow. The geometrically-scaled ratio of jet yields in central and peripheral events,Rcp, indicates a clear suppression of jets with ET >100 GeV. The transverse and longitudinal distributions of jet fragments is also presented. We find little no substantial change to the fragmentation properties and no significant change in the level of suppression when moving to the larger jet definition.Comment: 5 pages, 6 figures, proceedings for Quark Matter 2011, Annecy, France, May 23-28, 201

Early Structure Formation and Reionization in a Cosmological Model with a Running Primordial Power Spectrum

(abridged) We study high redshift structure formation and reionization in a LCDM universe under the assumption that the spectral power index of primordial density fluctuations is a function of length scale. We adopt a particular formulation of the running spectral index (RSI) model as suggested by the recent WMAP data. While early structure forms hierarchically in the RSI model, the reduced power on small scales causes a considerable delay in the formation epoch of low mass (~ 10^6 Msun) ``mini-halos'' compared to the LCDM model. The extremely small number of gas clouds in the RSI model indicates that reionization is initiated later than z<15, generally resulting in a smaller total Thomson optical depth than in the LCDM model. By carrying out radiative transfer calculations, we also study reionization by stellar populations formed in galaxies. Even with a top-heavy intial mass function representing an early population of massive stars and/or an extraordinarily high photon emission rate from galaxies, the total optical depth can only be as large as tau ~ 0.1 for reasonable models of early star-formation. The RSI model is thus in conflict with the large Thomson optical depth inferred by the WMAP satellite.Comment: Version accepted by ApJ. Visualizations are shown at http://cfa-www.harvard.edu/cpac/Reion/stars.htm

Preferential, enhanced breast cancer cell migration on biomimetic electrospun nanofiber ‘cell highways’

BACKGROUND: Aggressive metastatic breast cancer cells seemingly evade surgical resection and current therapies, leading to colonization in distant organs and tissues and poor patient prognosis. Therefore, high-throughput in vitro tools allowing rapid, accurate, and novel anti-metastatic drug screening are grossly overdue. Conversely, aligned nanofiber constitutes a prominent component of the late-stage breast tumor margin extracellular matrix. This parallel suggests that the use of a synthetic ECM in the form of a nanoscale model could provide a convenient means of testing the migration potentials of cancer cells to achieve a long-term goal of providing clinicians an in vitro platform technology to test the efficacy of novel experimental anti-metastatic compounds. METHODS: Electrospinning produces highly aligned, cell-adhesive nanofiber matrices by applying a strong electric field to a polymer-containing solution. The resulting fibrous microstructure and morphology closely resembles in vivo tumor microenvironments suggesting their use in analysis of migratory potentials of metastatic cancer cells. Additionally, a novel interface with a gel-based delivery system creates CXCL12 chemotactic gradients to enhance CXCR4-expressing cell migration. RESULTS: Cellular dispersions of MCF-10A normal mammary epithelial cells or human breast cancer cells (MCF-7 and MDA-MB-231) seeded on randomly-oriented nanofiber exhibited no significant differences in total or net distance traveled as a result of the underlying topography. Cells traveled ~2-5 fold greater distances on aligned fiber. Highly-sensitive MDA-MB-231 cells displayed an 82% increase in net distance traversed in the presence of a CXCL12 gradient. In contrast, MCF-7 cells exhibited only 31% increase and MCF-10A cells showed no statistical difference versus control or vehicle conditions. MCF-10A cells displayed little sensitivity to CXCL12 gradients, while MCF-7 cells displayed early sensitivity when CXCL12 concentrations were higher. MDA-MB-231 cells displayed low relative expression levels of CXCR4, but high sensitivity resulting in 55-fold increase at late time points due to CXCL12 gradient dissipation. CONCLUSIONS: This model could create clinical impact as an in vitro diagnostic tool for rapid assessment of tumor needle biopsies to confirm metastatic tumors, their invasiveness, and allow high-throughput drug screening providing rapid development of personalized therapies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2407-14-825) contains supplementary material, which is available to authorized users

A Revised Model for the Formation of Disk Galaxies: Low Spin and Dark-Halo Expansion

We use observed rotation velocity-luminosity (VL) and size-luminosity (RL) relations to single out a specific scenario for disk galaxy formation in the LCDM cosmology. Our model involves four independent log-normal random variables: dark-halo concentration c, disk spin lam_gal, disk mass fraction m_gal, and stellar mass-to-light ratio M/L_I. A simultaneous match of the VL and RL zero points with adiabatic contraction requires low-c halos, but this model has V_2.2~1.8 V_vir (where V_2.2 and V_vir are the circular velocity at 2.2 disk scale lengths and the virial radius, respectively) which will be unable to match the luminosity function (LF). Similarly models without adiabatic contraction but standard c also predict high values of V_2.2/V_vir. Models in which disk formation induces an expansion rather than the commonly assumed contraction of the dark-matter halos have V_2.2~1.2 V_vir which allows a simultaneous fit of the LF. This may result from non-spherical, clumpy gas accretion, where dynamical friction transfers energy from the gas to the dark matter. This model requires low lam_gal and m_gal values, contrary to naive expectations. However, the low lam_gal is consistent with the notion that disk galaxies predominantly survive in halos with a quiet merger history, while a low m_gal is also indicated by galaxy-galaxy lensing. The smaller than expected scatter in the RL relation, and the lack of correlation between the residuals of the VL and RL relations, respectively, imply that the scatter in lam_gal and in c need to be smaller than predicted for LCDM halos, again consistent with the idea that disk galaxies preferentially reside in halos with a quiet merger history.Comment: 28 pages, 16 figures, ApJ accepted, minor changes from unpublished version, uses emulateapj.cls, high-resolution version available at http://www.ucolick.org/~dutton/65200/hi-res-version/ms.dutton.v2_hr.p

The spatial and velocity bias of linear density peaks and proto-haloes in the Lambda cold dark matter cosmology

We use high resolution N-body simulations to investigate the Lagrangian bias of cold dark matter haloes within the LCDM cosmology. Our analysis focuses on "proto-haloes", which we identify in the simulation initial conditions with the subsets of particles belonging to individual redshift-zero haloes. We then calculate the number-density and velocity-divergence fields of proto-haloes and estimate their auto spectral densities. We also measure the corresponding cross spectral densities with the linear matter distribution. We use our results to test a Lagrangian-bias model presented by Desjacques and Sheth which is based on the assumption that haloes form out of local density maxima of a specific height. Our comparison validates the predicted functional form for the scale-dependence of the bias for both the density and velocity fields. We also show that the bias coefficients are accurately predicted for the velocity divergence. On the contrary, the theoretical values for the density bias parameters do not accurately match the numerical results as a function of halo mass. This is likely due to the simplistic assumptions that relate virialized haloes to density peaks of a given height in the model. We also detect appreciable stochasticity for the Lagrangian density bias, even on very large scales. These are not included in the model at leading order but correspond to higher order corrections.Comment: 10 pages, 4 figures. Matches version accepted for publication in MNRA

The formation of CDM haloes I: Collapse thresholds and the ellipsoidal collapse model

In the excursion set approach to structure formation initially spherical regions of the linear density field collapse to form haloes of mass $M$ at redshift $z_{\rm id}$ if their linearly extrapolated density contrast, averaged on that scale, exceeds some critical threshold, $\delta_{\rm c}(z_{\rm id})$. The value of $\delta_{\rm c}(z_{\rm id})$ is often calculated from the spherical or ellipsoidal collapse model, which provide well-defined predictions given auxiliary properties of the tidal field at a given location. We use two cosmological simulations of structure growth in a $\Lambda$ cold dark matter scenario to quantify $\delta_{\rm c}(z_{\rm id})$, its dependence on the surrounding tidal field, as well as on the shapes of the Lagrangian regions that collapse to form haloes at $z_{\rm id}$. Our results indicate that the ellipsoidal collapse model provides an accurate description of the mean dependence of $\delta_{\rm c}(z_{\rm id})$ on both the strength of the tidal field and on halo mass. However, for a given $z_{\rm id}$, $\delta_{\rm c}(z_{\rm id})$ depends strongly on the halo's characteristic formation redshift: the earlier a halo forms, the higher its initial density contrast. Surprisingly, the majority of haloes forming $today$ fall below the ellipsoidal collapse barrier, contradicting the model predictions. We trace the origin of this effect to the non-spherical shapes of Lagrangian haloes, which arise naturally due to the asymmetry of the linear tidal field. We show that a modified collapse model, that accounts for the triaxial shape of protohaloes, provides a more accurate description of the measured minimum overdensities of recently collapsed objects.Comment: MNRAS in pres

Calcium II Triplet Spectroscopy of LMC Red Giants. I. Abundances and Velocities for a Sample of Populous Clusters

Abridged Abstract - Utilizing the FORS2 instrument on the VLT, we have obtained near infrared spectra for more than 200 stars in 28 populous LMC clusters. This cluster sample spans a large range of ages (~ 1-13 Gyr) and metallicities (-0.3 > [Fe/H] > -2.0) and has good areal coverage of the LMC disk. The strong absorption lines of the Calcium II triplet are used to derive cluster radial velocities and abundances. We determine mean cluster velocities to typically 1.6 km/s and mean metallicities to 0.04 dex (random error). For eight of these clusters, we report the first spectroscopically determined metallicities based on individual cluster stars, and six of these eight have no published radial velocity measurements. (continued in paper)Comment: 26 pages of text plus 14 figures and 6 tables. Accepted for publication in AJ. Scheduled for Vol. 132, No. 4 (October 2006

Thermal stability of heterotrimeric pMHC proteins as determined by circular dichroism spectroscopy

T cell receptor (TCR) recognition of foreign peptide fragments, presented by peptide major histocompatibility complex (pMHC), governs T-cell mediated protection against pathogens and cancer. Many factors govern T-cell sensitivity, including the affinity of the TCR-pMHC interaction and the stability of pMHC on the surface of antigen presenting cells. These factors are particularly relevant for the peptide vaccination field, in which more stable pMHC interactions could enable more effective protection against disease. Here, we discuss a method for the determination of pMHC stability that we have used to investigate HIV immune escape, T-cell sensitivity to cancer antigens and mechanisms leading to autoimmunity

Engagement intervention versus treatment as usual for young adults with serious mental illness: a randomized pilot trial

Background: Young adults have elevated rates of mental health disorders, yet they often do not receive consistent care. The challenge of continuing to engage young adults has been pervasive worldwide. Few engagement interventions have been designed for young adults with serious mental illness. Just Do You is a theoretically guided engagement intervention. It uses innovative modalities (i.e., technology, expressive arts activities, narrative expression, mentoring) to engage participants in conversations about services and how they work, while simultaneously orienting them to treatment. Methods/design: This pilot and feasibility study utilizes a hybrid research design, examining feasibility, acceptability, and preliminary impact, alongside implementation. The study combines qualitative methods, a small pilot randomized trial, and a small cost-benefit analysis. Respondents are clinic staff and young adults who have made initial contact with the Personalized Recovery Oriented Services (PROS) program. Quantitative survey data are collected at baseline, 2 weeks (post-intervention), 1 month, and 3 months. The assessments focus on measuring feasibility, acceptability, engagement, and mental health outcomes. Medical record extraction will be used to triangulate self-report data. We will conduct single degree of freedom contrasts to examine whether Just Do You leads to improved outcomes relative to Treatment-As-Usual using robust regression for each outcome measure. We will examine whether changes in the proposed mediating variables occur across groups using a similar contrast strategy. In addition, we will use structural equation modeling to examine the contribution of mediators to ultimate outcomes. Finally, we will use constant comparison coding techniques for qualitative analyses. Discussion: The aim of this study is to examine the feasibility of a young adult engagement meta-intervention through an intensive preliminary pilot trial, learning through collaboration with stakeholders. Just Do You has the potential to fill a gap in the service system for young adults with serious mental illnesses, improving the seemingly intractable problem of disengagement. The program uses culturally responsive strategies, is recovery-oriented, and builds upon the best evidence to date. Our efforts align with local and national health care reform efforts embedding people with lived experience. Trial registration: This trial was registered with ClinicalTrials.gov (Identifier: NCT03423212) on April 18, 2018, as Protocol Record R34 MH111861-01, New York University, as the Just Do You Program for Young Adults with Serious Mental Illness