Free energy and configurational entropy of liquid silica: fragile-to-strong crossover and polyamorphism

Recent molecular dynamics (MD) simulations of liquid silica, using the ``BKS'' model [Van Beest, Kramer and van Santen, Phys. Rev. Lett. {\bf 64}, 1955 (1990)], have demonstrated that the liquid undergoes a dynamical crossover from super-Arrhenius, or ``fragile'' behavior, to Arrhenius, or ``strong'' behavior, as temperature $T$ is decreased. From extensive MD simulations, we show that this fragile-to-strong crossover (FSC) can be connected to changes in the properties of the potential energy landscape, or surface (PES), of the liquid. To achieve this, we use thermodynamic integration to evaluate the absolute free energy of the liquid over a wide range of density and $T$. We use this free energy data, along with the concept of ``inherent structures'' of the PES, to evaluate the absolute configurational entropy $S_c$ of the liquid. We find that the temperature dependence of the diffusion coefficient and of $S_c$ are consistent with the prediction of Adam and Gibbs, including in the region where we observe the FSC to occur. We find that the FSC is related to a change in the properties of the PES explored by the liquid, specifically an inflection in the $T$ dependence of the average inherent structure energy. In addition, we find that the high $T$ behavior of $S_c$ suggests that the liquid entropy might approach zero at finite $T$, behavior associated with the so-called Kauzmann paradox. However, we find that the change in the PES that underlies the FSC is associated with a change in the $T$ dependence of $S_c$ that elucidates how the Kauzmann paradox is avoided in this system. Finally, we also explore the relation of the observed PES changes to the recently discussed possibility that BKS silica exhibits a liquid-liquid phase transition, a behavior that has been proposed to underlie the observed polyamorphism of amorphous solid silica.Comment: 14 pages, 18 figure

Clinical and haemodynamic correlates of heart rate turbulence as a non-invasive index of baroreflex sensitivity in chronic heart failure

HRT (heart rate turbulence), describing the heart rate changes following a premature ventricular contraction, has been regarded as an indirect index of baroreflex function. However, limited data are available on its relationship with invasive assessment by phenylephrine injection (Phe-slope). In the present study, we therefore compared these methodologies in a series of patients with HF (heart failure) in which both measures together with clinical and haemodynamic data were available. HRT parameters [TO (turbulence onset) and TS (turbulence slope)] were measured from 24-h Holter recordings obtained within 1 week of baroreflex sensitivity assessment and right heart haemodynamic evaluation (Swan-Ganz catheter). HRT was computable in 135 out of 157 (86%) patients who had both a phenylephrine test and haemodynamic evaluation. TO and TS significantly correlated with Phe-slope (r=−0.39, P<0.0001 and r=0.66, P<0.0001 respectively). Age, baseline heart rate, LVEF (left ventricular ejection fraction), PCP (pulmonary capillary pressure), CI (cardiac index) and sodium were significant and independent predictors of Phe-slope, accounting for 51% of its variability. Similarly, age, baseline heart rate and PCP, and NYHA (New York Heart Association) classes III–IV were independent predictors for TS and explained 48% of its variability, whereas only CI and LVEF were found to be significantly related to TO and explained a very limited proportion (20%) of the variability. In conclusion, these results suggest that HRT may be regarded as a surrogate measure of baroreflex sensitivity in clinical and prognostic evaluation in patients with HF

Global distribution and diversity of ovine-associated Staphylococcus aureus

Staphylococcus aureus is an important pathogen of many species, including sheep, and impacts on both human and animal health, animal welfare, and farm productivity. Here we present the widest global diversity study of ovine-associated S. aureus to date. We analysed 97 S. aureus isolates from sheep and sheep products from the UK, Turkey, France, Norway, Australia, Canada and the USA using multilocus sequence typing (MLST) and spa typing. These were compared with 196 sheep isolates from Europe (n = 153), Africa (n = 28), South America (n = 14) and Australia (n = 1); 172 bovine, 68 caprine and 433 human S. aureus profiles. Overall there were 59 STs and 87 spa types in the 293 ovine isolates; in the 97 new ovine isolates there were 22 STs and 37 spa types, including three novel MLST alleles, four novel STs and eight novel spa types. Three main CCs (CC133, CC522 and CC700) were detected in sheep and these contained 61% of all isolates. Four spa types (t002, t1534, t2678 and t3576) contained 31% of all isolates and were associated with CC5, CC522, CC133 and CC522 respectively. spa types were consistent with MLST CCs, only one spa type (t1403) was present in multiple CCs. The three main ovine CCs have different but overlapping patterns of geographical dissemination that appear to match the location and timing of sheep domestication and selection for meat and wool production. CC133, CC522 and CC700 remained ovine-associated following the inclusion of additional host species. Ovine isolates clustered separately from human and bovine isolates and those from sheep cheeses, but closely with caprine isolates. As with cattle isolates, patterns of clonal diversification of sheep isolates differ from humans, indicative of their relatively recent host-jump

Mapping Dynamic Histone Acetylation Patterns to Gene Expression in Nanog-depleted Murine Embryonic Stem Cells

Embryonic stem cells (ESC) have the potential to self-renew indefinitely and to differentiate into any of the three germ layers. The molecular mechanisms for self-renewal, maintenance of pluripotency and lineage specification are poorly understood, but recent results point to a key role for epigenetic mechanisms. In this study, we focus on quantifying the impact of histone 3 acetylation (H3K9,14ac) on gene expression in murine embryonic stem cells. We analyze genome-wide histone acetylation patterns and gene expression profiles measured over the first five days of cell differentiation triggered by silencing Nanog, a key transcription factor in ESC regulation. We explore the temporal and spatial dynamics of histone acetylation data and its correlation with gene expression using supervised and unsupervised statistical models. On a genome-wide scale, changes in acetylation are significantly correlated to changes in mRNA expression and, surprisingly, this coherence increases over time. We quantify the predictive power of histone acetylation for gene expression changes in a balanced cross-validation procedure. In an in-depth study we focus on genes central to the regulatory network of Mouse ESC, including those identified in a recent genome-wide RNAi screen and in the PluriNet, a computationally derived stem cell signature. We find that compared to the rest of the genome, ESC-specific genes show significantly more acetylation signal and a much stronger decrease in acetylation over time, which is often not reflected in an concordant expression change. These results shed light on the complexity of the relationship between histone acetylation and gene expression and are a step forward to dissect the multilayer regulatory mechanisms that determine stem cell fate.Comment: accepted at PLoS Computational Biolog

Transcriptome analyses of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways

INTRODUCTION: Molecular characterization of the normal epithelial cell types that reside in the mammary gland is an important step toward understanding pathways that regulate self-renewal, lineage commitment, and differentiation along the hierarchy. Here we determined the gene expression signatures of four distinct subpopulations isolated from the mouse mammary gland. The epithelial cell signatures were used to interrogate mouse models of mammary tumorigenesis and to compare with their normal human counterpart subsets to identify conserved genes and networks. METHODS: RNA was prepared from freshly sorted mouse mammary cell subpopulations (mammary stem cell (MaSC)-enriched, committed luminal progenitor, mature luminal and stromal cell) and used for gene expression profiling analysis on the Illumina platform. Gene signatures were derived and compared with those previously reported for the analogous normal human mammary cell subpopulations. The mouse and human epithelial subset signatures were then subjected to Ingenuity Pathway Analysis (IPA) to identify conserved pathways. RESULTS: The four mouse mammary cell subpopulations exhibited distinct gene signatures. Comparison of these signatures with the molecular profiles of different mouse models of mammary tumorigenesis revealed that tumors arising in MMTV-Wnt-1 and p53-/- mice were enriched for MaSC-subset genes, whereas the gene profiles of MMTV-Neu and MMTV-PyMT tumors were most concordant with the luminal progenitor cell signature. Comparison of the mouse mammary epithelial cell signatures with their human counterparts revealed substantial conservation of genes, whereas IPA highlighted a number of conserved pathways in the three epithelial subsets. CONCLUSIONS: The conservation of genes and pathways across species further validates the use of the mouse as a model to study mammary gland development and highlights pathways that are likely to govern cell-fate decisions and differentiation. It is noteworthy that many of the conserved genes in the MaSC population have been considered as epithelial-mesenchymal transition (EMT) signature genes. Therefore, the expression of these genes in tumor cells may reflect basal epithelial cell characteristics and not necessarily cells that have undergone an EMT. Comparative analyses of normal mouse epithelial subsets with murine tumor models have implicated distinct cell types in contributing to tumorigenesis in the different models

Lymphocyte subsets and the role of Th1/Th2 balance in stressed chronic pain patients

Background: The complex regional pain syndrome (CRPS) and fibromyalgia (FM) are chronic pain syndromes occurring in highly stressed individuals. Despite the known connection between the nervous system and immune cells, information on distribution of lymphocyte subsets under stress and pain conditions is limited. Methods: We performed a comparative study in 15 patients with CRPS type I, 22 patients with FM and 37 age- and sex-matched healthy controls and investigated the influence of pain and stress on lymphocyte number, subpopulations and the Th1/Th2 cytokine ratio in T lymphocytes. Results: Lymphocyte numbers did not differ between groups. Quantitative analyses of lymphocyte subpopulations showed a significant reduction of cytotoxic CD8+ lymphocytes in both CRPS (p < 0.01) and FM (p < 0.05) patients as compared with healthy controls. Additionally, CRPS patients were characterized by a lower percentage of IL-2-producing T cell subpopulations reflecting a diminished Th1 response in contrast to no changes in the Th2 cytokine profile. Conclusions: Future studies are warranted to answer whether such immunological changes play a pathogenetic role in CRPS and FM or merely reflect the consequences of a pain-induced neurohumoral stress response, and whether they contribute to immunosuppression in stressed chronic pain patients. Copyright (c) 2008 S. Karger AG, Basel

Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis.

The linear ubiquitin chain assembly complex (LUBAC) is essential for innate immunity in mice and humans, yet its role in adaptive immunity is unclear. Here we show that the LUBAC components HOIP, HOIL-1 and SHARPIN have essential roles in late thymocyte differentiation, FOXP3(+) regulatory T (Treg)-cell development and Treg cell homeostasis. LUBAC activity is not required to prevent TNF-induced apoptosis or necroptosis but is necessary for the transcriptional programme of the penultimate stage of thymocyte differentiation. Treg cell-specific ablation of HOIP causes severe Treg cell deficiency and lethal immune pathology, revealing an ongoing requirement of LUBAC activity for Treg cell homeostasis. These data reveal stage-specific requirements for LUBAC in coordinating the signals required for T-cell differentiation

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study.

National Coordinating Centre for Research Methodology; Medical Research Council, UK Department of Health; Chief Scientist OfficeNot peer reviewedPublisher PD