Speech Communication

Contains reports on two research projects.United States Air Force, Electronic Systems Division (Contract AF19(628)-3325)National Science Foundation (Grant G-16526)National Institutes of Health (Grant MH-04737-03 and Grant NB-04332-01)National Aeronautics and Space Administration (Grant NsG-496

PhosFox: a bioinformatics tool for peptide-level processing of LC-MS/MS-based phosphoproteomic data

Background: It is possible to identify thousands of phosphopeptides and -proteins in a single experiment with mass spectrometry-based phosphoproteomics. However, a current bottleneck is the downstream data analysis which is often laborious and requires a number of manual steps.Results: Toward automating the analysis steps, we have developed and implemented a software, PhosFox, which enables peptide-level processing of phosphoproteomic data generated by multiple protein identification search algorithms, including Mascot, Sequest, and Paragon, as well as cross-comparison of their identification results. The software supports both qualitative and quantitative phosphoproteomics studies, as well as multiple between-group comparisons. Importantly, PhosFox detects uniquely phosphorylated peptides and proteins in one sample compared to another. It also distinguishes differences in phosphorylation sites between phosphorylated proteins in different samples. Using two case study examples, a qualitative phosphoproteome dataset from human keratinocytes and a quantitative phosphoproteome dataset from rat kidney inner medulla, we demonstrate here how PhosFox facilitates an efficient and in-depth phosphoproteome data analysis. PhosFox was implemented in the Perl programming language and it can be run on most common operating systems. Due to its flexible interface and open source distribution, the users can easily incorporate the program into their MS data analysis workflows and extend the program with new features. PhosFox source code, implementation and user instructions are freely available from https://bitbucket.org/phintsan/phosfox.Conclusions: PhosFox facilitates efficient and more in-depth comparisons between phosphoproteins in case-control settings. The open source implementation is easily extendable to accommodate additional features for widespread application use cases

RELATIONSHIP BETWEEN ATOPIC DERMATITIS AND IMMUNOGLOBULIN E

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66225/1/j.1365-4362.1976.tb00705.x.pd

A beta 2-Integrin/MRTF-A/SRF Pathway Regulates Dendritic Cell Gene Expression, Adhesion, and Traction Force Generation

beta 2-integrins are essential for immune system function because they mediate immune cell adhesion and signaling. Consequently, a loss of beta(2)-integrin expression or function causes the immunodeficiency disorders, Leukocyte Adhesion Deficiency (LAD) type I and III. LAD-III is caused by mutations in an important integrin regulator, kindlin-3, but exactly how kindlin-3 regulates leukocyte adhesion has remained incompletely understood. Here we demonstrate that mutation of the kindlin-3 binding site in the beta 2-integrin (TTT/AAA-beta 2-integrin knock-in mouse/KI) abolishes activation of the actin-regulated myocardin related transcription factor A/serum response factor (MRTF-A/SRF) signaling pathway in dendritic cells and MRTF-A/SRF-dependent gene expression. We show that Ras homolog gene family, member A (RhoA) activation and filamentous-actin (F-actin) polymerization is abolished in murine TTT/AAA-beta 2-integrin KI dendritic cells, which leads to a failure of MRTF-A to localize to the cell nucleus to coactivate genes together with SRF. In addition, we show that dendritic cell gene expression, adhesion and integrin-mediated traction forces on ligand coated surfaces is dependent on the MRTF-A/SRF signaling pathway. The participation of beta 2-integrin and kindlin-3-mediated cell adhesion in the regulation of the ubiquitous MRTF-A/SRF signaling pathway in immune cells may help explain the role of beta 2-integrin and kindlin-3 in integrin-mediated gene regulation and immune system function

A high-powered replication study finds no effect of starting or stopping hormonal contraceptive use on relationship quality

A number of recent studies have implicated that incongruent use of hormonal contraceptives (HCs) negatively affects various aspects of women’s romantic relationships. It has been suggested that women with incongruent HC use (a discrepancy in HC use status between when they first met their current partner and the time of study participation) report less sexual satisfaction and higher jealousy scores compared to women with congruent HC use. A similar effect has also been hypothesized for general relationship satisfaction, and recent findings suggest that the association between HC incongruency and general relationship satisfaction is moderated by women’s perceived facial attractiveness of male partners. Using a large convenience sample (N = 948) of Finnish women, we attempted to replicate previously reported findings but found no support for the HC congruency hypothesis, despite excellent statistical power (≥98.7%) to detect previously reported effect sizes. Instead, after dividing our sample into four groups based on HC congruency/incongruency, we found that the largest differences in jealousy, sexual satisfaction, and relationship satisfaction scores tended to be found between women who were consistent HC users and consistent non-users (i.e., between women with different kinds of congruent HC use). We also detected a significant main effect of current HC use on jealousy. We conclude that, as the effect size of the HC incongruency effect reported in previous studies was small, unequal distributions of current HC users within congruent and incongruent HC user groups may give rise to spurious HC incongruency effects in studies using small samples

Modulation of human macrophage responses to mycobacterium tuberculosis by silver nanoparticles of different size and surface modification

Exposure to silver nanoparticles (AgNP) used in consumer products carries potential health risks including increased susceptibility to infectious pathogens. Systematic assessments of antimicrobial macrophage immune responses in the context of AgNP exposure are important because uptake of AgNP by macrophages may lead to alterations of innate immune cell functions. In this study we examined the effects of exposure to AgNP with different particle sizes (20 and 110 nm diameters) and surface chemistry (citrate or polyvinlypyrrolidone capping) on cellular toxicity and innate immune responses against Mycobacterium tuberculosis (M.tb) by human monocyte-derived macrophages (MDM). Exposures of MDM to AgNP significantly reduced cellular viability, increased IL8 and decreased IL10 mRNA expression. Exposure of M.tb-infected MDM to AgNP suppressed M.tb-induced expression of IL1B, IL10, and TNFA mRNA. Furthermore, M.tb-induced IL-1β, a cytokine critical for host resistance to M.tb, was inhibited by AgNP but not by carbon black particles indicating that the observed immunosuppressive effects of AgNP are particle specific. Suppressive effects of AgNP on the M.tb-induced host immune responses were in part due to AgNP-mediated interferences with the TLR signaling pathways that culminate in the activation of the transcription factor NF-κB. AgNP exposure suppressed M.tb-induced expression of a subset of NF-κB mediated genes (CSF2, CSF3, IFNG, IL1A, IL1B, IL6, IL10, TNFA, NFKB1A). In addition, AgNP exposure increased the expression of HSPA1A mRNA and the corresponding stress-induced Hsp72 protein. Up-regulation of Hsp72 by AgNP can suppress M.tb-induced NF-κB activation and host immune responses. The observed ability of AgNP to modulate infectious pathogen-induced immune responses has important public health implications

Respiratory and cardiovascular responses to walking down a traffic-polluted road compared with walking in a traffic-free area in participants aged 60 years and older with chronic lung or heart disease and age-matched healthy controls: a randomised, crossover study

Background Long-term exposure to pollution can lead to an increase in the rate of decline of lung function, especially in older individuals and in those with chronic obstructive pulmonary disease (COPD), whereas shorter-term exposure at higher pollution levels has been implicated in causing excess deaths from ischaemic heart disease and exacerbations of COPD. We aimed to assess the effects on respiratory and cardiovascular responses of walking down a busy street with high levels of pollution compared with walking in a traffic-free area with lower pollution levels in older adults. Methods In this randomised, crossover study, we recruited men and women aged 60 years and older with angiographically proven stable ischaemic heart disease or stage 2 Global initiative for Obstructive Lung Disease (GOLD) COPD who had been clinically stable for 6 months, and age-matched healthy volunteers. Individuals with ischaemic heart disease or COPD were recruited from existing databases or outpatient respiratory and cardiology clinics at the Royal Brompton & Harefield NHS Foundation Trust and age-matched healthy volunteers using advertising and existing databases. All participants had abstained from smoking for at least 12 months and medications were taken as recommended by participants' doctors during the study. Participants were randomly assigned by drawing numbered disks at random from a bag to do a 2 h walk either along a commercial street in London (Oxford Street) or in an urban park (Hyde Park). Baseline measurements of participants were taken before the walk in the hospital laboratory. During each walk session, black carbon, particulate matter (PM) concentrations, ultrafine particles, and nitrogen dioxide (NO2) concentrations were measured. Findings Between October, 2012, and June, 2014, we screened 135 participants, of whom 40 healthy volunteers, 40 individuals with COPD, and 39 with ischaemic heart disease were recruited. Concentrations of black carbon, NO2, PM10, PM2.5, and ultrafine particles were higher on Oxford Street than in Hyde Park. Participants with COPD reported more cough (odds ratio [OR] 1·95, 95% CI 0·96–3·95; p<0·1), sputum (3·15, 1·39–7·13; p<0·05), shortness of breath (1·86, 0·97–3·57; p<0·1), and wheeze (4·00, 1·52–10·50; p<0·05) after walking down Oxford Street compared with Hyde Park. In all participants, irrespective of their disease status, walking in Hyde Park led to an increase in lung function (forced expiratory volume in the first second [FEV1] and forced vital capacity [FVC]) and a decrease in pulse wave velocity (PWV) and augmentation index up to 26 h after the walk. By contrast, these beneficial responses were attenuated after walking on Oxford Street. In participants with COPD, a reduction in FEV1 and FVC, and an increase in R5–20 were associated with an increase in during-walk exposure to NO2, ultrafine particles and PM2.5, and an increase in PWV and augmentation index with NO2 and ultrafine particles. In healthy volunteers, PWV and augmentation index were associated both with black carbon and ultrafine particles. Interpretation Short-term exposure to traffic pollution prevents the beneficial cardiopulmonary effects of walking in people with COPD, ischaemic heart disease, and those free from chronic cardiopulmonary diseases. Medication use might reduce the adverse effects of air pollution in individuals with ischaemic heart disease. Policies should aim to control ambient levels of air pollution along busy streets in view of these negative health effects

Three-year follow-up and event rates in the international REduction of Atherothrombosis for Continued Health Registry

To determine 3-year event rates in outpatients with vascular disease enrolled in the REduction of Atherothrombosis for Continued Health (REACH) Registry. Methods and results REACH enrolled 67 888 outpatients with atherothrombosis [ established coronary artery disease (CAD), cerebrovascutar disease, or peripheral arterial disease (PAD)], or with at least three atherothrombotic risk factors, from 44 countries . Among the 55 499 patients at baseline with symptomatic disease, 39 675 were eligible for 3-year follow-up, and 32 247 had data available (81% retention rate). Among the symptomatic patients at 3 years, 92% were taking an antithrombotic agent, 91% an anti hypertensive, and 76% were on Upid- lowering therapy. For myocardial infarction (Ml)/ stroke/vascutar death, 1 - and 3-year event rates for all patients were 4.2 and 11.0%, respectively. Event rates (MI/ stroke/vascutar death) were significantly higher for patients with symptomatic disease vs. those with risk factors only at 1 year (4.7 vs. 2.3%, P < 0.001) and at 3 years (12.0 vs. 6.0%, P < 0.001). One and 3-year rates of MI /stroke/vascular cleath/ rehospitatization were 14.4 and 28.4 %, respectively, for patients with symptomatic disease. Rehospitalization for a vascular event other than Mi/ stroke/ vascular death was common at 3 years (19.0% overall; 33.6% for PAD ; 23.0% for CAD). For patients with symptomatic vascular disease in one vascular bed vs. multiple vascular beds, 3-year event rates for MI/stroke/ vascular death/ rehospitalization were 25.5 vs. 40.5% (P < 0.001). Conclusion Despite contemporary therapy, outpatients with symptomatic atherothrombotic vascular disease experience high rates of recurrent vascular events and rehospitalizations

Rate versus rhythm control and outcomes in patients with atrial fibrillation and chronic kidney disease: Data from the GUSTO-III Trial

Background: Atrial fi brillation (AF) and chronic kidney disease (CKD) have both beenshown to portend worse outcomes after acute myocardial infarction (MI); however, the benefi tof a rhythm control strategy in patients with CKD post-MI is unclear.Methods: We prospectively studied 985 patients with new-onset AF post-MI in theGUSTO-III trial, of whom 413 (42%) had CKD (creatinine clearance &lt; 60 mL/min).A rhythm control strategy, defi ned as the use of an antiarrhythmic medication and/orelectrical cardioversion, was used in 346 (35%) of patients.Results: A rhythm control strategy was used in 34% of patients with CKD and 36% of patientswith no CKD. At hospital discharge, sinus rhythm was present in 487 (76%) of patients treatedwith a rate control strategy, vs. 276 (80%) in those treated with rhythm control (p = 0.20). CKDwas associated with a lower odds of sinus rhythm at discharge (unadjusted OR 0.56, 95% CI0.38–0.84, p &lt; 0.001). However, in multivariable analyses, treatment with a rhythm controlstrategy was not associated with discharge rhythm (HR 1.068, 95% CI 0.69–1.66, p = 0.77),30-day mortality (HR 0.78, 95% CI 0.54–1.12, p = 0.18) or mortality from day 30 to 1 year(HR 1.00, 95% CI 0.59–1.69, p = 0.99). CKD status did not signifi cantly impact the relationshipbetween rhythm control and outcomes.Conclusions: Treatment with a rhythm or rate control strategy does not signifi cantly impactshort-term or long-term mortality in patients with post-MI AF, regardless of kidney disease status.Future studies to investigate the optimal management of AF in CKD patients are needed