The chemical evolution of the solar neighbourhood

Recent models of galactic chemical evolution account for updated evolutionary models of massive stars (with special emphasis on stellar winds) and for the effects of intermediate mass and massive binaries. The results are summarised. We also present a critical discussion on possible effects of stellar rotation on overall galactic chemical evolutionary simulations.Comment: 12 pages, 3 figures, Pacific Rim Conference, Xi'an, China, 11-17 July 200

Measuring and explaining mortality in Dutch hospitals; The Hospital Standardized Mortality Rate between 2003 and 2005

Background. Indicators of hospital quality, such as hospital standardized mortality ratios (HSMR), have been used increasingly to assess and improve hospital quality. Our aim has been to describe and explain variation in new HSMRs for the Netherlands. Methods. HSMRs were estimated using data from the complete population of discharged patients during 2003 to 2005. We used binary logistic regression to indirectly standardize for differences in case-mix. Out of a total of 101 hospitals 89 hospitals remained in our explanatory analysis. In this analysis we explored the association between HSMRs and determinants that can and cannot be influenced by hospitals. For this analysis we used a two-level hierarchical linear regression model to explain variation in yearly HSMRs. Results. The average HSMR decreased yearly with more than eight

Clinical risk stratification of paediatric renal transplant recipients using C1q and C3d fixing of de novo donor-specific antibodies

Introduction: We have previously shown that children who developed de novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) had greater decline in allograft function. We hypothesised that patients with complement-activating DSA would have poorer renal allograft outcomes. Methods: A total of 75 children developed DSA in the original study. The first positive DSA sample was subsequently tested for C1q and C3d fixing. The primary event was defined as 50% reduction from baseline estimated glomerular filtration rate and was analysed using the Kaplan–Meier estimator. Results: Of 65 patients tested, 32 (49%) and 23 (35%) tested positive for C1q and C3d fixing, respectively. Of the 32 C1q-positive (c1q+) patients, 13 (41%) did not show concomitant C3d fixing. The mean fluorescence intensity values of the original immunoglobulin G DSA correlated poorly with complement-fixing positivity (C1q: adjusted R2 0.072; C3d: adjusted R2 0.11; p < 0.05). C1q+ antibodies were associated with acute tubulitis [0.75 ± 0.18 (C1q+) vs. 0.25 ± 0.08 (C1q−) episodes per patient (mean ± standard error of the mean; p < 0.05] but not with worse long-term renal allograft dysfunction (median time to primary event 5.9 (C1q+) vs. 6.4 (C1q−) years; hazard ratio (HR) 0.74; 95% confidence ratio (CI) 0.30–1.81; p = 0.58]. C3d-positive (C3d+) antibodies were associated with positive C4d histological staining [47% (C3d+) vs. 20% (C3d−); p = 0.04] and with significantly worse long-term allograft dysfunction [median time to primary event: 5.6 (C3d+) vs. 6.5 (C3d−) years; HR 0.38; 95% CI 0.15–0.97; p = 0.04]. Conclusion: Assessment of C3d fixing as part of prospective HLA monitoring can potentially aid stratification of patients at the highest risk of long-term renal allograft dysfunction

A Conserved PHD Finger Protein and Endogenous RNAi Modulate Insulin Signaling in Caenorhabditis elegans

Insulin signaling has a profound effect on longevity and the oxidative stress resistance of animals. Inhibition of insulin signaling results in the activation of DAF-16/FOXO and SKN-1/Nrf transcription factors and increased animal fitness. By studying the biological functions of the endogenous RNA interference factor RDE-4 and conserved PHD zinc finger protein ZFP-1 (AF10), which regulate overlapping sets of genes in Caenorhabditis elegans, we identified an important role for these factors in the negative modulation of transcription of the insulin/PI3 signaling-dependent kinase PDK-1. Consistently, increased expression of pdk-1 in zfp-1 and rde-4 mutants contributed to their reduced lifespan and sensitivity to oxidative stress and pathogens due to the reduction in the expression of DAF-16 and SKN-1 targets. We found that the function of ZFP-1 in modulating pdk-1 transcription was important for the extended lifespan of the age-1(hx546) reduction-of-function PI3 kinase mutant, since the lifespan of the age-1; zfp-1 double mutant strain was significantly shorter compared to age-1(hx546). We further demonstrate that overexpression of ZFP-1 caused an increased resistance to oxidative stress in a DAF-16–dependent manner. Our findings suggest that epigenetic regulation of key upstream signaling components in signal transduction pathways through chromatin and RNAi may have a large impact on the outcome of signaling and expression of numerous downstream genes.Leukemia & Lymphoma Society of America (3260-07 Special Fellow Award)Arnold and Mabel Beckman Foundation (Young Investigator Award)United States. National Institutes of Health (Director's New Innovator Award (1 DP2 OD006412-01))United States. National Institutes of Health (grant GM66269)modENCODE (grant U01 HG004270)United States. National Institutes of Health (training grant 5T32 GM07088-34

Definitions, Foundations and Associations of Physical Literacy: A Systematic Review

Background: The concept of physical literacy has stimulated increased research attention in recent years—being deployed in physical education, sport participation, and the promotion of physical activity. Independent research groups currently operationalize the construct differently. Objective The purpose of this systematic review was to conduct a systematic review of the physical literacy construct,as reflected in contemporary research literature. Methods: Five databases were searched using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines for systematic reviews. Inclusion criteria were English language, peer reviewed, published by March 2016, and seeking to conceptualize physical literacy. Articles that met these criteria were analysed in relation to three core areas: properties/attributes, philosophicalfoundations and theoretical associations with other constructs. A total of 50 published articles met the inclusion criteria and were analysed qualitatively using inductive thematic analysis.Results: The thematic analysis addressed the three core areas. Under definitions, core attributes that define physical literacy were identified, as well as areas of conflict between different approaches currently being adopted. One relatively clear philosophical approach was prominent in approximately half of the papers, based on a monist/holistic ontology and phenomenological epistemology. Finally, theanalysis identified a number of theoretical associations, including health, physical activity and academic performance.Conclusions: Current literature contains different representations of the physical literacy construct. The costs and benefits of adopting an exclusive approach versus pluralism are considered. Recommendations for both researchers and practitioners focus on identifying and clearly articulating the definitions, philosophical assumptions and expected outcomes prior to evaluating the effectiveness of this emerging concept

Computational solutions for omics data

High-throughput experimental technologies are generating increasingly massive and complex genomic data sets. The sheer enormity and heterogeneity of these data threaten to make the arising problems computationally infeasible. Fortunately, powerful algorithmic techniques lead to software that can answer important biomedical questions in practice. In this Review, we sample the algorithmic landscape, focusing on state-of-the-art techniques, the understanding of which will aid the bench biologist in analysing omics data. We spotlight specific examples that have facilitated and enriched analyses of sequence, transcriptomic and network data sets.National Institutes of Health (U.S.) (Grant GM081871

A Homolog of Subtilisin-Like Proprotein Convertase 7 Is Essential to Anterior Neural Development in Xenopus

BACKGROUND: Subtilisin-like Proprotein Convertase 7 (SPC7) is a member of the subtilisin/kexin family of pro-protein convertases. It cleaves many pro-proteins to release their active proteins, including members of the bone morphogenetic protein (BMP) family of signaling molecules. Other SPCs are known to be required during embryonic development but corresponding data regarding SPC7 have not been reported previously. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that Xenopus SPC7 (SPC7) was expressed predominantly in the developing brain and eye, throughout the neural plate initially, then more specifically in the lens and retina primordia as development progressed. Since no prior functional information has been reported for SPC7, we used gain- and loss-of-function experiments to investigate the possibility that it may also convey patterning or tissue specification information similarly to Furin, SPC4, and SPC6. Overexpression of SPC7 was without effect. In contrast, injection of SPC7 antisense morpholino oligonucleotides (MO) into a single blastomere at the 2- or 4-cell stage produced marked disruption of head structures; anophthalmia was salient. Bilateral injections suppressed head and eye formation completely. In parallel with suppression of eye and brain development by SPC7 knockdown, expression of early anterior neural markers (Sox2, Otx2, Rx2, and Pax6) and late eye-specific markers (β-Crystallin and Opsin), and of BMP target genes such as Tbx2 and Tbx3, was reduced or eliminated. Taken together, these findings suggest a critical role for SPC7-perhaps, at least in part, due to activation of one or more BMPs-in early patterning of the anterior neural plate and its derivatives. CONCLUSION/SIGNIFICANCE: SPC7 is required for normal development of the eye and brain, possibly through processing BMPs, though other potential substrates cannot be excluded

Spontaneous preterm labor is associated with an increase in the proinflammatory signal transducer TLR4 receptor on maternal blood monocytes

<p>Abstract</p> <p>Background</p> <p>Localized inflammation and increased expression of TLR4 receptors within the uterus has been implicated in the pathogenesis of preterm labor. It remains unclear whether intrauterine inflammatory responses activate the maternal peripheral circulatory system. Therefore we determined whether increased TLR4 expression is present in the peripheral maternal white blood cells of women with spontaneous preterm labor.</p> <p>Methods</p> <p>This is a cross-sectional study of 41 preterm labor cases and 41 non-preterm controls. For each case and control sample, RNA was purified from white blood cells and TLR4 mRNA pool size was evaluated by quantitative PCR. Protein expression levels were determined by flow cytometry. Statistical evaluation using multiple linear regressions was used to determine any significant differences between the cases and controls. The purpose was to determine association prevalence of TLR4 levels and preterm labor.</p> <p>Results</p> <p>Adjusted mean TLR4 mRNA levels of 0.788 ± 0.037 (standard error) for preterm labor and 0.348 ± 0.038 for the corresponding pregnant control women were statistically significantly different <it>(P </it>= 0.002). Using the lower 95% confidence interval of the mean expression level in PTL subjects (0.7) as a cutoff value for elevated TLR4 mRNA levels, 25/41 (60.9%) of PTL patients expressed elevated TLR4 mRNA as compared to 0/41 (0%) in control subjects. The TLR4 receptor levels in the granulocyte fraction of white blood cells from preterm labor and pregnant controls were similar. However, TLR4⁺/CD14⁺monocytes were 2.3 times more frequent (70% vs. 30%) and TLR4 also had a 2.6-fold higher density (750 vs. 280 molecules per cell) in preterm labor women compared with pregnant controls. There was no difference in the levels of TLR4 in patients at term.</p> <p>Conclusions</p> <p>Patients with preterm labor exhibited elevated levels of CD14⁺maternal blood monocytes each bearing enhanced expression of TLR4, indicating that the peripheral circulatory system is activated in patients with preterm labor. Elevated leukocyte TLR4 levels may be a useful biomarker associated with preterm labor.</p

Evaluation of methods for detection of fluorescence labeled subcellular objects in microscope images

<p>Abstract</p> <p>Background</p> <p>Several algorithms have been proposed for detecting fluorescently labeled subcellular objects in microscope images. Many of these algorithms have been designed for specific tasks and validated with limited image data. But despite the potential of using extensive comparisons between algorithms to provide useful information to guide method selection and thus more accurate results, relatively few studies have been performed.</p> <p>Results</p> <p>To better understand algorithm performance under different conditions, we have carried out a comparative study including eleven spot detection or segmentation algorithms from various application fields. We used microscope images from well plate experiments with a human osteosarcoma cell line and frames from image stacks of yeast cells in different focal planes. These experimentally derived images permit a comparison of method performance in realistic situations where the number of objects varies within image set. We also used simulated microscope images in order to compare the methods and validate them against a ground truth reference result. Our study finds major differences in the performance of different algorithms, in terms of both object counts and segmentation accuracies.</p> <p>Conclusions</p> <p>These results suggest that the selection of detection algorithms for image based screens should be done carefully and take into account different conditions, such as the possibility of acquiring empty images or images with very few spots. Our inclusion of methods that have not been used before in this context broadens the set of available detection methods and compares them against the current state-of-the-art methods for subcellular particle detection.</p

Offspring of Mothers Fed a High Fat Diet Display Hepatic Cell Cycle Inhibition and Associated Changes in Gene Expression and DNA Methylation

The association between an adverse early life environment and increased susceptibility to later-life metabolic disorders such as obesity, type 2 diabetes and cardiovascular disease is described by the developmental origins of health and disease hypothesis. Employing a rat model of maternal high fat (MHF) nutrition, we recently reported that offspring born to MHF mothers are small at birth and develop a postnatal phenotype that closely resembles that of the human metabolic syndrome. Livers of offspring born to MHF mothers also display a fatty phenotype reflecting hepatic steatosis and characteristics of non-alcoholic fatty liver disease. In the present study we hypothesised that a MHF diet leads to altered regulation of liver development in offspring; a derangement that may be detectable during early postnatal life. Livers were collected at postnatal days 2 (P2) and 27 (P27) from male offspring of control and MHF mothers (n = 8 per group). Cell cycle dynamics, measured by flow cytometry, revealed significant G0/G1 arrest in the livers of P2 offspring born to MHF mothers, associated with an increased expression of the hepatic cell cycle inhibitor Cdkn1a. In P2 livers, Cdkn1a was hypomethylated at specific CpG dinucleotides and first exon in offspring of MHF mothers and was shown to correlate with a demonstrable increase in mRNA expression levels. These modifications at P2 preceded observable reductions in liver weight and liver∶brain weight ratio at P27, but there were no persistent changes in cell cycle dynamics or DNA methylation in MHF offspring at this time. Since Cdkn1a up-regulation has been associated with hepatocyte growth in pathologic states, our data may be suggestive of early hepatic dysfunction in neonates born to high fat fed mothers. It is likely that these offspring are predisposed to long-term hepatic dysfunction