Blood lipid profiles and peripheral blood mononuclear cell cholesterol metabolism gene expression in patients with and without methotrexate treatment

<p>Abstract</p> <p>Background</p> <p>Methotrexate (MTX) is the most commonly prescribed disease-modifying antirheumatic drug (DMARD) in rheumatoid arthritis. ATP-binding cassette transporter-A1 (ABCA1) and 27-Hydroxylase (HY27) are known antiatherogenic proteins that promote cellular cholesterol efflux. In THP-1 macrophages, MTX can promote the reversal of cholesterol transport, limit foam cell formation and also reverse COX-2 inhibitor-mediated downregulation of ABCA1. Despite its antiatherogenic potential <it>in vitro</it>, the impact of clinical use of low-dose MTX on cholesterol metabolism in humans is unknown. Objective of the study was to examine whether clinical MTX use is associated with altered blood lipids and/or <it>ABCA1/HY27 </it>expressions.</p> <p>Methods</p> <p>In all, 100 rheumatoid arthritis subjects were recruited from a medical center in central Taiwan. Plasma lipid profiles and peripheral blood mononuclear cell <it>HY27 </it>and <it>ABCA1 </it>expressions were compared between subjects taking MTX (MTX+) and other disease-modifying antirheumatic drugs (DMARDs) (MTX-). Dietary intake was assessed by a registered dietician.</p> <p>Results</p> <p>Though no difference observed in the blood lipids between MTX+ and MTX- subjects, the expressions of <it>ABCA1 </it>and <it>HY27 </it>were significantly elevated in MTX+ subjects (n = 67) compared to MTX- subjects (n = 32, p < 0.05). ABCA expression correlated with MTX doses (r = 0.205, p = 0.042), and MTX+ subjects are more likely to have increased <it>HY27 </it>compared to MTX- subjects (OR = 2.5, p = 0.038). Prevalence of dyslipidemia and overweight, and dietary fat/cholesterol intake were lower than that of the age-matched population. Although no differences were observed in the blood lipids, the potential impacts of MTX on cholesterol metabolism should not be overlooked and the atheroprotective effects from MTX induced <it>HY27 </it>and <it>ABCA1 </it>expressions may still be present in those persons with pre-existing dyslipidemia.</p> <p>Conclusions</p> <p>We demonstrated novel findings on the increased gene expressions of atheroprotective protein <it>HY27 </it>and <it>ABCA1 </it>in human peripheral blood mononuclear cells (PBMCs) with clinical use of low-dose MTX. Whether MTX induced <it>HY27 </it>and <it>ABCA1 </it>expressions can protect against cardiovascular disease in patients with chronic inflammation through the facilitation of cholesterol export remains to be established. Further studies on the impacts of low-dose MTX on hypercholesterolemic patients are underway.</p

Modelling reef hydrodynamics and sediment mobility under sea level rise in atoll reef island systems

This is the author accepted manuscript. The final version is available on open access from Elsevier via the DOI in this record. Low-lying coral reef islands will be significantly impacted by future sea level rise (SLR). It is generally expected that SLR will destabilise reef islands because increasing reef submergence allows larger waves, and therefore greater energy transmission, across reef flats. However, the impact of SLR on altering both reef flat sediment transport and sediment delivery to island shorelines is poorly understood. Here, we use the currents of removal approach (coupling two-dimensional wave modelling with settling velocity data from 186 benthic sediment samples) to model shifts in both reef hydrodynamics and benthic sediment transport under scenarios of mean reef submergence (MRS = +0 m, +0.5 m, +1 m) at two atoll rim reef sites in the Maldives. Under contemporary conditions (MRS = +0 m), we found that benthic sediment transport is likely occurring, consistent with active reef-to-island sediment connectivity. Under conditions of increased MRS, shifts in wave velocities, and in turn sediment potential mobility, were both non-linear and non-uniform. Significant between-site differences were found in the magnitude of projected shifts in sediment mobility under scenarios of increased MRS, which implies that morphological responses to increases in MRS are likely to be diverse, even over local scales. Under increased MRS, the largest increases in sediment mobility were projected on the inner reef flat, whereas lagoonal zones remained as sinks for sediment deposition. We thus hypothesize that while reef islands will persist as sedimentary landforms under projected rates of MRS, lagoonward reef island migration is likely to occur. Findings have implications for predicting the future adaptive capacity of atoll nations. The challenge is to incorporate such potential increases in island mobility and intra-regional diversity in reef system geomorphic responses to sea level rise into national-scale vulnerability assessments.NER

Accretion Disc Theory: From the Standard Model Until Advection

Accretion disc theory was first developed as a theory with the local heat balance, where the whole energy produced by a viscous heating was emitted to the sides of the disc. One of the most important new invention of this theory was a phenomenological treatment of the turbulent viscosity, known as ''alpha'' prescription, when the (r$\phi$) component of the stress tensor was approximated by ($\alpha$ P) with a unknown constant $\alpha$. This prescription played the role in the accretion disc theory as well important as the mixing-length theory of convection for stellar evolution. Sources of turbulence in the accretion disc are discussed, including nonlinear hydrodynamical turbulence, convection and magnetic field role. In parallel to the optically thick geometrically thin accretion disc models, a new branch of the optically thin accretion disc models was discovered, with a larger thickness for the same total luminosity. The choice between these solutions should be done of the base of a stability analysis. The ideas underlying the necessity to include advection into the accretion disc theory are presented and first models with advection are reviewed. The present status of the solution for a low-luminous optically thin accretion disc model with advection is discussed and the limits for an advection dominated accretion flows (ADAF) imposed by the presence of magnetic field are analysed.Comment: Roceeding of the Int. Workshop "Observational Evidence for Black Holes in the Universe". Calcutta, 11-17 January 1998. Kluwer Acad. Pu

Genetic analysis of a major international collection of cultivated apple varieties reveals previously unknown historic heteroploid and inbred relationships

Domesticated apple (Malus x domestica Borkh.) is a major global crop and the genetic diversity held within the pool of cultivated varieties is important for the development of future cultivars. The aim of this study was to investigate the diversity held within the domesticated form, through the analysis of a major international germplasm collection of cultivated varieties, the UK National Fruit Collection, consisting of over 2,000 selections of named cultivars and seedling varieties. We utilised Diversity Array Technology (DArT) markers to assess the genetic diversity within the collection. Clustering attempts, using the software STRUCTURE revealed that the accessions formed a complex and historically admixed group for which clear clustering was challenging. Comparison of accessions using the Jaccard similarity coefficient allowed us to identify clonal and duplicate material as well as revealing pairs and groups that appeared more closely related than a standard parent-offspring or full-sibling relations. From further investigation, we were able to propose a number of new pedigrees, which revealed that some historically important cultivars were more closely related than previously documented and that some of them were partially inbred. We were also able to elucidate a number of parent-offspring relationships that had resulted in a number of important polyploid cultivars. This included reuniting polyploid cultivars that in some cases dated as far back as the 18th century, with diploid parents that potentially date back as far as the 13th century

Disparities and risks of sexually transmissible infections among men who have sex with men in China: a meta-analysis and data synthesis.

BACKGROUND: Sexually transmitted infections (STIs), including Hepatitis B and C virus, are emerging public health risks in China, especially among men who have sex with men (MSM). This study aims to assess the magnitude and risks of STIs among Chinese MSM. METHODS: Chinese and English peer-reviewed articles were searched in five electronic databases from January 2000 to February 2013. Pooled prevalence estimates for each STI infection were calculated using meta-analysis. Infection risks of STIs in MSM, HIV-positive MSM and male sex workers (MSW) were obtained. This review followed the PRISMA guidelines and was registered in PROSPERO. RESULTS: Eighty-eight articles (11 in English and 77 in Chinese) investigating 35,203 MSM in 28 provinces were included in this review. The prevalence levels of STIs among MSM were 6.3% (95% CI: 3.5-11.0%) for chlamydia, 1.5% (0.7-2.9%) for genital wart, 1.9% (1.3-2.7%) for gonorrhoea, 8.9% (7.8-10.2%) for hepatitis B (HBV), 1.2% (1.0-1.6%) for hepatitis C (HCV), 66.3% (57.4-74.1%) for human papillomavirus (HPV), 10.6% (6.2-17.6%) for herpes simplex virus (HSV-2) and 4.3% (3.2-5.8%) for Ureaplasma urealyticum. HIV-positive MSM have consistently higher odds of all these infections than the broader MSM population. As a subgroup of MSM, MSW were 2.5 (1.4-4.7), 5.7 (2.7-12.3), and 2.2 (1.4-3.7) times more likely to be infected with chlamydia, gonorrhoea and HCV than the broader MSM population, respectively. CONCLUSION: Prevalence levels of STIs among MSW were significantly higher than the broader MSM population. Co-infection of HIV and STIs were prevalent among Chinese MSM. Integration of HIV and STIs healthcare and surveillance systems is essential in providing effective HIV/STIs preventive measures and treatments. TRIAL REGISTRATION: PROSPERO NO: CRD42013003721

Accelerated search for biomolecular network models to interpret high-throughput experimental data

<p>Abstract</p> <p>Background</p> <p>The functions of human cells are carried out by biomolecular networks, which include proteins, genes, and regulatory sites within DNA that encode and control protein expression. Models of biomolecular network structure and dynamics can be inferred from high-throughput measurements of gene and protein expression. We build on our previously developed fuzzy logic method for bridging quantitative and qualitative biological data to address the challenges of noisy, low resolution high-throughput measurements, i.e., from gene expression microarrays. We employ an evolutionary search algorithm to accelerate the search for hypothetical fuzzy biomolecular network models consistent with a biological data set. We also develop a method to estimate the probability of a potential network model fitting a set of data by chance. The resulting metric provides an estimate of both model quality and dataset quality, identifying data that are too noisy to identify meaningful correlations between the measured variables.</p> <p>Results</p> <p>Optimal parameters for the evolutionary search were identified based on artificial data, and the algorithm showed scalable and consistent performance for as many as 150 variables. The method was tested on previously published human cell cycle gene expression microarray data sets. The evolutionary search method was found to converge to the results of exhaustive search. The randomized evolutionary search was able to converge on a set of similar best-fitting network models on different training data sets after 30 generations running 30 models per generation. Consistent results were found regardless of which of the published data sets were used to train or verify the quantitative predictions of the best-fitting models for cell cycle gene dynamics.</p> <p>Conclusion</p> <p>Our results demonstrate the capability of scalable evolutionary search for fuzzy network models to address the problem of inferring models based on complex, noisy biomolecular data sets. This approach yields multiple alternative models that are consistent with the data, yielding a constrained set of hypotheses that can be used to optimally design subsequent experiments.</p

Mining Unknown Porcine Protein Isoforms by Tissue-Based Map of Proteome Enhances the Pig Genome Annotation

A lack of the complete pig proteome has left a gap in our knowledge of the pig genome and has restricted the feasibility of using pigs as a biomedical model. In this study, we developed a tissue-based proteome map using 34 major normal pig tissues. A total of 5841 unknown protein isoforms were identified and systematically characterized, including 2225 novel protein isoforms, 669 protein isoforms from 460 genes symbolized beginning with LOC, and 2947 protein isoforms without clear NCBI annotation in the current pig reference genome. These newly identified protein isoforms were functionally annotated through profiling the pig transcriptome with high-throughput RNA sequencing of the same pig tissues, further improving the genome annotation of the corresponding protein-coding genes. Combining the well-annotated genes that have parallel expression pattern and subcellular witness, we predicted the tissue-related subcellularlocations and potential functions for these unknown proteins. Finally, we mined 3081 orthologous genes for 52.7% of unknown protein isoforms across multiple species, referring to 68 KEGG pathways as well as 23 disease signaling pathways. These findings provide valuable insights and a rich resource for enhancing studies of pig genomics and biology, as well as biomedical model application to human medicine

Constructing Biological Pathways by a Two-Step Counting Approach

Networks are widely used in biology to represent the relationships between genes and gene functions. In Boolean biological models, it is mainly assumed that there are two states to represent a gene: on-state and off-state. It is typically assumed that the relationship between two genes can be characterized by two kinds of pairwise relationships: similarity and prerequisite. Many approaches have been proposed in the literature to reconstruct biological relationships. In this article, we propose a two-step method to reconstruct the biological pathway when the binary array data have measurement error. For a pair of genes in a sample, the first step of this approach is to assign counting numbers for every relationship and select the relationship with counting number greater than a threshold. The second step is to calculate the asymptotic p-values for hypotheses of possible relationships and select relationships with a large p-value. This new method has the advantages of easy calculation for the counting numbers and simple closed forms for the p-value. The simulation study and real data example show that the two-step counting method can accurately reconstruct the biological pathway and outperform the existing methods. Compared with the other existing methods, this two-step method can provide a more accurate and efficient alternative approach for reconstructing the biological network

Persistent Cell Motion in the Absence of External Signals: A Search Strategy for Eukaryotic Cells

Eukaryotic cells are large enough to detect signals and then orient to them by differentiating the signal strength across the length and breadth of the cell. Amoebae, fibroblasts, neutrophils and growth cones all behave in this way. Little is known however about cell motion and searching behavior in the absence of a signal. Is individual cell motion best characterized as a random walk? Do individual cells have a search strategy when they are beyond the range of the signal they would otherwise move toward? Here we ask if single, isolated, Dictyostelium and Polysphondylium amoebae bias their motion in the absence of external cues. We placed single well-isolated Dictyostelium and Polysphondylium cells on a nutrient-free agar surface and followed them at 10 sec intervals for ~10 hr, then analyzed their motion with respect to velocity, turning angle, persistence length, and persistence time, comparing the results to the expectation for a variety of different types of random motion. We find that amoeboid behavior is well described by a special kind of random motion: Amoebae show a long persistence time (~10 min) beyond which they start to lose their direction; they move forward in a zig-zag manner; and they make turns every 1-2 min on average. They bias their motion by remembering the last turn and turning away from it. Interpreting the motion as consisting of runs and turns, the duration of a run and the amplitude of a turn are both found to be exponentially distributed. We show that this behavior greatly improves their chances of finding a target relative to performing a random walk. We believe that other eukaryotic cells may employ a strategy similar to Dictyostelium when seeking conditions or signal sources not yet within range of their detection system.Comment: 15 pages, 11 figures, accepted for publication in PLOS On