The role of fibrocytes in fibrotic diseases of the lungs and heart

Fibrosis is the end result of a complex series of events that follow tissue injury and inflammation. Pathophysiologic fibrosis results in permanent scar formation, and can impair organ function. Fibrocytes are circulating, bone-marrow-derived progenitor cells that traffic from the bone marrow to the injured organ via the bloodstream, where they differentiate into fibroblasts and myofibroblasts, and play a pivotal role in both physiologic and aberrant fibrosis. In this review, we focus on the contribution of fibrocytes to fibrotic diseases of the lungs and the heart, including interstitial lung diseases, asthma, pulmonary hypertension, atherosclerosis and ischemic cardiomyopathy

Sn-modification of Pt7/alumina model catalysts: Suppression of carbon deposition and enhanced thermal stability.

An atomic layer deposition process is used to modify size-selected Pt7/alumina model catalysts by Sn addition, both before and after Pt7 cluster deposition. Surface science methods are used to probe the effects of Sn-modification on the electronic properties, reactivity, and morphology of the clusters. Sn addition, either before or after cluster deposition, is found to strongly affect the binding properties of a model alkene, ethylene, changing the number and type of binding sites, and suppressing decomposition leading to carbon deposition and poisoning of the catalyst. Density functional theory on a model system, Pt4Sn3/alumina, shows that the Sn and Pt atoms are mixed, forming alloy clusters with substantial electron transfer from Sn to Pt. The presence of Sn also makes all the thermally accessible structures closed shell, such that ethylene binds only by π-bonding to a single Pt atom. The Sn-modified catalysts are quite stable in repeated ethylene temperature programmed reaction experiments, suggesting that the presence of Sn also reduces the tendency of the sub-nano-clusters to undergo thermal sintering

The Relationship between resistance exercise induced testosterone and cortisol responses and steroid receptor phosphorylation

The precise contribution of hormones to resistance training adaptations remains unclear. Recently, resistance exercise (RE) has been shown to change phosphorylation of androgen (pAR) & glucocorticoid receptors (pGR). Examining the relationships between the hormonal responses & steroid receptor phosphorylation may elucidate the role of acute hormonal responses to training adaptations. PURPOSE: The purpose of this study was to examine relationships between exercise-induced hormonal responses and pGR & pAR. METHODS: Resistance trained (RT) (n = 10; age = 21.3±1.7yrs, ht = 175.8±6.8cm, bodymass = 84.5±13.5kg) & untrained (UT) (n = 9; age = 20.8±3.1yrs, ht = 178.7±8.9cm, bodymass = 81.0±14.0kg) men completed an acute RE session of 6 sets of 10 reps, & 4 sets of 10 reps at 75% 1RM of barbell back squats, & knee extension, respectively. Muscle biopsies were obtained at rest, 10+, 30+, 60+, & 180+ minutes post-exercise & analyzed for total AR, pAR at ser81, ser213, ser515, ser650, total GR, and pGR at ser134, ser211, ser226. Testosterone & cortisol samples were obtained before, & up to 45 minutes post-exercise. Pearson correlations were performed to determine relationships between endocrine responses (area-under-curve [AUC]) & changes in total & phosphorylated AR & GR. Significance was determined at p≤0.05. RESULTS: The change in total AR at 180+ was correlated with cortisol (Pooled: r = -0.668, p = 0.002) & was strongest in RT subjects (RT: r = -0.767, p = 0.010). Cortisol was correlated with pARser81 at 60+ (r = 0.601, p = 0.006) & 180+ (r = 0.537, p = 0.018). Cortisol was correlated with the change in pARser650 at 180+ (r = 0.724, p = 0.018) in RT subjects. In UT the changes in pGRser134 & pGRser226 were correlated at 10+ (r = 0.987, p = 0.001) & 30+ (r = 0.943, p = 0.001). CONCLUSION: Cortisol responses were related to AR content, & changes in phosphorylation at sites regulating AR ligand sensitivity, & AR localization. There was a training status-specific relationship in UT subjects between pGR sites that regulate receptor localization, & GR sensitivity to cellular stress. Individualized cortisol responses are strongly related to AR activity and may explain the discrepancy in studies that solely investigated anabolic hormones & training adaptations, since these relationships also appear to be specific to different training statuses

Assessment of a novel commercial large field of view phantom for comprehensive MR imaging quality assurance of a 0.35T MRgRT system

Consistent quality assurance (QA) programs are vital to MR-guided radiotherapy (MRgRT), for ensuring treatment is delivered accurately and the onboard MRI system is providing the expected image quality. However, daily imaging QA with a dedicated phantom is not common at many MRgRT centers, especially with large phantoms that cover a field of view (FOV), similar to the human torso. This work presents the first clinical experience with a purpose-built phantom for large FOV daily and periodic comprehensive quality assurance (QUASAR™ MRgRT Insight Phantom (beta)) from Modus Medical Devices Inc. (Modus QA) on an MRgRT system. A monthly American College of Radiology (ACR) QA phantom was also imaged for reference. Both phantoms were imaged on a 0.35T MR-Linac, a 1.5T Philips wide bore MRI, and a 3.0T Siemens MRI, with T1-weighted and T2-weighted acquisitions. The Insight phantom was imaged in axial and sagittal orientations. Image quality tests including geometric accuracy, spatial resolution accuracy, slice thickness accuracy, slice position accuracy, and image intensity uniformity were performed on each phantom, following their respective instruction manuals. The geometric distortion test showed similar distortions of -1.7 mm and -1.9 mm across a 190 mm and a 283 mm lengths for the ACR and MRgRT Insight phantoms, respectively. The MRgRT Insight phantom utilized a modulation transform function (MTF) for spatial resolution evaluation, which showed decreased performance on the lower

Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains

The design of compounds that can discriminate between closely related target proteins remains a central challenge in drug discovery. Specific therapeutics targeting the highly conserved myosin motor family are urgently needed as mutations in at least six of its members cause numerous diseases. Allosteric modulators, like the myosin-II inhibitor blebbistatin, are a promising means to achieve specificity. However, it remains unclear why blebbistatin inhibits myosin-II motors with different potencies given that it binds at a highly conserved pocket that is always closed in blebbistatin-free experimental structures. We hypothesized that the probability of pocket opening is an important determinant of the potency of compounds like blebbistatin. To test this hypothesis, we used Markov state models (MSMs) built from over 2 ms of aggregate molecular dynamics simulations with explicit solvent. We find that blebbistatin\u27s binding pocket readily opens in simulations of blebbistatin-sensitive myosin isoforms. Comparing these conformational ensembles reveals that the probability of pocket opening correctly identifies which isoforms are most sensitive to blebbistatin inhibition and that docking against MSMs quantitatively predicts blebbistatin binding affinities (

Neural Correlates of Verb Argument Structure Processing

This fMRI study examined the neural correlates of verbs controlled for argument structure complexity and nouns controlled for semantic class. Participants showed activation of left inferior frontal and posterior temporal regions for verbs as compared to nouns, and more widespread, non-perisylvian activation for nouns as compared to verbs. Verbs with more complex argument structure entries activated posterior temporal regions bilaterally. These findings suggest that posterior perisylvian regions are crucial for processing the argument structure information associated with verbs

Comparative analysis of Mycobacterium tuberculosis pe and ppe genes reveals high sequence variation and apparent absence of selective constraints

CITATION: McEvoy, C. R. E. et al. 2012. Comparative analysis of Mycobacterium tuberculosis pe and ppe genes reveals high sequence variation and apparent absence of selective constraints. PLoS ONE, 7(4): e30593, doi:10.1371/journal.pone.0030593.The original publication is available at http://journals.plos.org/plosoneMycobacterium tuberculosis complex (MTBC) genomes contain 2 large gene families termed pe and ppe. The function of pe/ppe proteins remains enigmatic but studies suggest that they are secreted or cell surface associated and are involved in bacterial virulence. Previous studies have also shown that some pe/ppe genes are polymorphic, a finding that suggests involvement in antigenic variation. Using comparative sequence analysis of 18 publicly available MTBC whole genome sequences, we have performed alignments of 33 pe (excluding pe_pgrs) and 66 ppe genes in order to detect the frequency and nature of genetic variation. This work has been supplemented by whole gene sequencing of 14 pe/ppe (including 5 pe_pgrs) genes in a cohort of 40 diverse and well defined clinical isolates covering all the main lineages of the M. tuberculosis phylogenetic tree. We show that nsSNP's in pe (excluding pgrs) and ppe genes are 3.0 and 3.3 times higher than in non-pe/ppe genes respectively and that numerous other mutation types are also present at a high frequency. It has previously been shown that non-pe/ppe M. tuberculosis genes display a remarkably low level of purifying selection. Here, we also show that compared to these genes those of the pe/ppe families show a further reduction of selection pressure that suggests neutral evolution. This is inconsistent with the positive selection pressure of “classical” antigenic variation. Finally, by analyzing such a large number of genes we were able to detect large differences in mutation type and frequency between both individual genes and gene sub-families. The high variation rates and absence of selective constraints provides valuable insights into potential pe/ppe function. Since pe/ppe proteins are highly antigenic and have been studied as potential vaccine components these results should also prove informative for aspects of M. tuberculosis vaccine design.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030593Publisher's versio

Zoonotic Mycobacterium bovis : induced tuberculosis in humans

CITATION: Muller, B. 2013. Zoonotic Mycobacterium bovis : induced tuberculosis in humans. Emerging Infectious Diseases, 19(6):899-908, doi:10.3201/eid1906.120543.The original publication is available at http://wwwnc.cdc.gov/eidWe aimed to estimate the global occurrence of zoonotic tuberculosis (TB) caused by Mycobacterium bovis or M. caprae infections in humans by performing a multilingual, systematic review and analysis of relevant scientific literature of the last 2 decades. Although information from many parts of the world was not available, data from 61 countries suggested a low global disease incidence. In regions outside Africa included in this study, overall median proportions of zoonotic TB of ≤1.4% in connection with overall TB incidence rates ≤71/100,000 population/year suggested low incidence rates. For countries of Africa included in the study, we multiplied the observed median proportion of zoonotic TB cases of 2.8% with the continental average overall TB incidence rate of 264/100,000 population/year, which resulted in a crude estimate of 7 zoonotic TB cases/100,000 population/year. These generally low incidence rates notwithstanding, available data indicated substantial consequences of this disease for some population groups and settings.http://wwwnc.cdc.gov/eid/article/19/6/12-0543_articlePublisher's versio

Prevalence of prenatal zinc deficiency and its association with socio-demographic, dietary and health care related factors in Rural Sidama, Southern Ethiopia: A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Several studies witnessed that prenatal zinc deficiency (ZD) predisposes to diverse pregnancy complications. However, scientific evidences on the determinants of prenatal ZD are scanty and inconclusive. The purpose of the present study was to assess the prevalence and determinants of prenatal ZD in Sidama zone, Southern Ethiopia.</p> <p>Methods</p> <p>A community based, cross-sectional study was conducted in Sidama zone in January and February 2011. Randomly selected 700 pregnant women were included in the study. Data on potential determinants of ZD were gathered using a structured questionnaire. Serum zinc concentration was measured using Atomic Absorption Spectrometry. Statistical analysis was done using logistic regression and linear regression.</p> <p>Results</p> <p>The mean serum zinc concentration was 52.4 (+/-9.9) μg/dl (95% CI: 51.6-53.1 μg/dl). About 53.0% (95% CI: 49.3-56.7%) of the subjects were zinc deficient. The majority of the explained variability of serum zinc was due to dietary factors like household food insecurity level, dietary diversity and consumption of animal source foods. The risk of ZD was 1.65 (95% CI: 1.02-2.67) times higher among women from maize staple diet category compared to <it>Enset </it>staple diet category. Compared to pregnant women aged 15-24 years, those aged 25-34 and 35-49 years had 1.57 (95% CI: 1.04-2.34) and 2.18 (95% CI: 1.25-3.63) times higher risk of ZD, respectively. Women devoid of self income had 1.74 (95% CI: 1.11-2.74) time increased risk than their counterparts. Maternal education was positively associated to zinc status. Grand multiparas were 1.74 (95% CI: 1.09-3.23) times more likely to be zinc deficient than nulliparas. Frequency of coffee intake was negatively association to serum zinc level. Positive association was noted between serum zinc and hemoglobin concentrations. Altitude, history of iron supplementation, maternal workload, physical access to health service, antenatal care and nutrition education were not associated to zinc status.</p> <p>Conclusion</p> <p>ZD is of public health concern in the area. The problem must be combated through a combination of short, medium and long-term strategies. This includes the use of household based phytate reduction food processing techniques, agricultural based approaches and livelihood promotion strategies.</p