Comparison of WTC dust size on macrophage inflammatory cytokine release in vivo and in vitro

Background

The WTC collapse exposed over 300,000 people to high concentrations of WTC-PM; particulates up to ∼50 mm were recovered from rescue workers’ lungs. Elevated MDC and GM-CSF independently predicted subsequent lung injury in WTC-PM-exposed workers. Our hypotheses are that components of WTC dust strongly induce GM-CSF and MDC in AM; and that these two risk factors are in separate inflammatory pathways.

Methodology/Principal Findings

Normal adherent AM from 15 subjects without WTC-exposure were incubated in media alone, LPS 40 ng/mL, or suspensions of WTC-PM_10–53 or WTC-PM_2.5 at concentrations of 10, 50 or 100 µg/mL for 24 hours; supernatants assayed for 39 chemokines/cytokines. In addition, sera from WTC-exposed subjects who developed lung injury were assayed for the same cytokines. In the in vitro studies, cytokines formed two clusters with GM-CSF and MDC as a result of PM_10–53 and PM_2.5. GM-CSF clustered with IL-6 and IL-12(p70) at baseline, after exposure to WTC-PM_10–53 and in sera of WTC dust-exposed subjects (n = 70) with WTC lung injury. Similarly, MDC clustered with GRO and MCP-1. WTC-PM_10–53 consistently induced more cytokine release than WTC-PM_2.5 at 100 µg/mL. Individual baseline expression correlated with WTC-PM-induced GM-CSF and MDC.

Conclusions

WTC-PM_10–53 induced a stronger inflammatory response by human AM than WTC-PM_2.5. This large particle exposure may have contributed to the high incidence of lung injury in those exposed to particles at the WTC site. GM-CSF and MDC consistently cluster separately, suggesting a role for differential cytokine release in WTC-PM injury. Subject-specific response to WTC-PM may underlie individual susceptibility to lung injury after irritant dust exposure.     

Evaluation of p53 genotype on gene expression in the testis, liver, and heart from male C57BL/6 mice

Our laboratory is conducting experiments designed to characterize the role of p53 in gene expression in the TSG-p53? mouse model. In the study reported here, gene expression levels in tissue derived from the testis, liver, and heart of male, 8–9 week old, p53 wild-type (WT), heterozygous (HET) or knockout (KO) mice were determined utilizing a targeted qPCR 84-gene array. The heart, liver and testis were selected because of the unique function and rate of cell division of each tissue. The genes on the arrays were categorized into three Functional Gene Groups, Apoptosis, Cell-Cycle and DNA Repair. Differences in expression of the functional groups were determined by multivariate analysis of variance (MANOVA) and significant (P < 0.05) differences in their expression were found among the heart, liver and testis. Further, the expression of the Functional Gene Groups in each of these tissues was also significantly affected by p53 genotype. These data indicate that gene expression in unperturbed tissue is influenced by the status of p53 genotype, and relates, at least partially, to the function of the tissue.     

Long-Term Occupancy Trends in a Data-Poor Dugong Population in the Andaman and Nicobar Archipelago

Prioritizing efforts for conserving rare and threatened species with limited past data and lacking population estimates is predicated on robust assessments of their occupancy rates. This is particularly challenging for elusive, long-lived and wide-ranging marine mammals. In this paper we estimate trends in long-term (over 50years) occupancy, persistence and extinction of a vulnerable and data-poor dugong (Dugong dugon) population across multiple seagrass meadows in the Andaman and Nicobar archipelago (India). For this we use hierarchical Bayesian dynamic occupancy models accounting for false negatives (detection probability<1), persistence and extinction, to two datasets: a) fragmentary long-term occurrence records from multiple sources (1959–2004, n = 40 locations), and b) systematic detection/non-detection data from current surveys (2010–2012, n = 57). Dugong occupancy across the archipelago declined by 60% (from 0.45 to 0.18) over the last 20 years and present distribution was largely restricted to sheltered bays and channels with seagrass meadows dominated by Halophila and Halodule sp. Dugongs were not found in patchy meadows with low seagrass cover. In general, seagrass habitat availability was not limiting for dugong occupancy, suggesting that anthropogenic factors such as entanglement in gillnets and direct hunting may have led to local extinction of dugongs from locations where extensive seagrass meadows still thrive. Effective management of these remnant dugong populations will require a multi-pronged approach, involving 1) protection of areas where dugongs still persist, 2) monitoring of seagrass habitats that dugongs could recolonize, 3) reducing gillnet use in areas used by dugongs, and 4) engaging with indigenous/settler communities to reduce impacts of hunting.     

Iron-sulphur proteins: Their possible place in the origin of life and the development of early metabolic systems

A review is made of certain features of the biology and chemistry of the iron-sulphur proteins which suggests that these proteins may be descended from an ancestral form or form swhich arose very early in the development of biological metabolic systems (the origin of life). If this hypothesis is correct it would suggest that this class of proteins developed during the epoch in which the Earth's atmosphere was reducing in nature and that the relative facility with which the active site of certain contemporary iron-sulphur proteins is experimentally reconstituted may have played a part in their evolutionary development.     

Local processes strongly influence post-bleaching benthic recovery in the Lakshadweep Islands

The atoll reefs of the Lakshadweep, in the Indian Ocean suffered a catastrophic mortality of hard coral in the wake of the El Niño event of 1998. This study tracked changes to coral and other benthic elements in three atolls in the Lakshadweep from 2000 to 2003. The recovery of coral was highly site-specific, and appeared to be driven by differences in post-settlement survival of coral recruits, that were in turn, influenced by the local hydrodynamics of the atolls. Post bleaching recovery was highest on west-facing reefs, while recovery on east-facing reefs was very limited. However, no ‘phase-shift’ to macroalgal dominated reefs was evident. High herbivore pressures were perhaps the most important control of macroalgae. Five years after the mass mortality, the genera that showed the maximum gains represented a mix of different susceptibilities to bleaching, while some genera that were not particularly susceptible to bleaching showed significant declines. These results suggest that decline or recovery of coral is likely dependent on individual life history strategies, post-recruitment survival, and contingency.     

Novel, potent, selective, and orally bioavailable human betaII-tryptase inhibitors

The synthesis of novel [1,2,4]oxadiazoles and their structure-activity relationship (SAR) for the inhibition of tryptase and related serine proteases is presented. Elaboration of the P'-side afforded potent, selective, and orally bioavailable tryptase inhibitors.     

(−)-Dibromophakellin: An α2B adrenoceptor agonist isolated from the Australian marine sponge,Acanthella costata

Bioassay-guided fractionation of the organic extract from the marine sponge Acanthella costata resulted in the isolation of the known natural product, (?)-dibromophakellin (1). Using a fluorescence imaging plate reader (FLIPR) based assay, compound 1 was identified as displaying agonist activity against the α_2B adrenoceptor, with an EC₅₀ of 4.2 μM. Debromination and Suzuki–Miyaura coupling reactions were undertaken in order to provide structure activity data about the pyrrole ring of this marine metabolite. These synthetic studies generated the known natural product analogues, (?)-phakellin (2), and (?)-monobromophakellin (3), along with the new synthetic derivatives (?)-4-bromo-5-phenylphakellin (5) and (?)-4,5-diphenylphakellin (6). Substitution of the C-5 Br of 1 with H (2 and 3) or phenyl (5 and 6) resulted in loss of activity indicating that Br at C-5 is required for agonist activity.     

Use of linear mixed models for genetic evaluation of gestation length and birth weight allowing for heavy-tailed residual effects

Background

The distribution of residual effects in linear mixed models in animal breeding applications is typically assumed normal, which makes inferences vulnerable to outlier observations. In order to mute the impact of outliers, one option is to fit models with residuals having a heavy-tailed distribution. Here, a Student''s-t model was considered for the distribution of the residuals with the degrees of freedom treated as unknown. Bayesian inference was used to investigate a bivariate Student''s-t (BSt) model using Markov chain Monte Carlo methods in a simulation study and analysing field data for gestation length and birth weight permitted to study the practical implications of fitting heavy-tailed distributions for residuals in linear mixed models.

Methods

In the simulation study, bivariate residuals were generated using Student''s-t distribution with 4 or 12 degrees of freedom, or a normal distribution. Sire models with bivariate Student''s-t or normal residuals were fitted to each simulated dataset using a hierarchical Bayesian approach. For the field data, consisting of gestation length and birth weight records on 7,883 Italian Piemontese cattle, a sire-maternal grandsire model including fixed effects of sex-age of dam and uncorrelated random herd-year-season effects were fitted using a hierarchical Bayesian approach. Residuals were defined to follow bivariate normal or Student''s-t distributions with unknown degrees of freedom.

Results

Posterior mean estimates of degrees of freedom parameters seemed to be accurate and unbiased in the simulation study. Estimates of sire and herd variances were similar, if not identical, across fitted models. In the field data, there was strong support based on predictive log-likelihood values for the Student''s-t error model. Most of the posterior density for degrees of freedom was below 4. Posterior means of direct and maternal heritabilities for birth weight were smaller in the Student''s-t model than those in the normal model. Re-rankings of sires were observed between heavy-tailed and normal models.

Conclusions

Reliable estimates of degrees of freedom were obtained in all simulated heavy-tailed and normal datasets. The predictive log-likelihood was able to distinguish the correct model among the models fitted to heavy-tailed datasets. There was no disadvantage of fitting a heavy-tailed model when the true model was normal. Predictive log-likelihood values indicated that heavy-tailed models with low degrees of freedom values fitted gestation length and birth weight data better than a model with normally distributed residuals.Heavy-tailed and normal models resulted in different estimates of direct and maternal heritabilities, and different sire rankings. Heavy-tailed models may be more appropriate for reliable estimation of genetic parameters from field data.