bluuebunny/crossref_metadata_2025 huggingface dataset:
Dendritic cells and their role in tumor immunosurveillance
Authors: Strioga Marius , Schijns Virgil , Powell Daniel J , Pasukoniene Vita , Dobrovolskiene Neringa , Michalek Jaroslav
Published: June 2012

Dendritic cells (DCs) comprise a heterogeneous population of cells that play a key role in initiating, directing and regulating adaptive immune responses, including those critically involved in tumor immunosurveillance. As a riposte to the central role of DCs in the generation of antitumor immune responses, tumors have developed various mechanisms which impair the immunostimulatory functions of DCs or even instruct them to actively contribute to tumor growth and progression. In the first part of this review we discuss general aspects of DC biology, including their origin, subtypes, immature and mature states, and functional plasticity which ensures a delicate balance between active immune response and immune tolerance. In the second part of the review we discuss the complex interactions between DCs and the tumor microenvironment, and point out the challenges faced by DCs during the recognition of tumor Ags. We also discuss the role of DCs in tumor angiogenesis and vasculogenesis.
Porphyromonas gingivalis LPS stimulates the expression of LPS-binding protein in human oral keratinocytes in vitro
Authors: Ding Pei-Hui , Wang Cun-Yu , Darveau Richard P , Jin Lijian
Published: June 2012

LPS-binding protein (LBP) functions as a crucial molecule in innate immune responses to bacterial challenge. Our study has shown the expression of LBP in human gingiva and its significant association with periodontal health and disease. Porphyromonas gingivalis is a key pathogen of periodontal disease. P. gingivalis LPS as a main virulence factor is strongly involved in periodontal pathogenesis and it displays a significant lipid A structural heterogeneity. Currently, it remains unknown whether, and to what extent, the lipid A structural heterogeneity of P. gingivalis LPS affects LBP expression. The present study investigated the expression profile of LBP in human oral keratinocytes (HOKs) stimulated by two isoforms of P. gingivalis LPS [tetra- (LPS1435/1449) and penta-acylated (LPS1690)] and Escherichia coli LPS, and the involvement of TLRs in LBP expression. The results showed that the expression of LBP mRNA and peptide was significantly up-regulated by P. gingivalis LPS1690 and E. coli LPS, while P. gingivalis LPS1435/1449 did not affect LBP expression. Blocking assay and siRNA gene silencing revealed that P. gingivalis LPS1690-induced LBP expression was through both TLR2 and TLR4. This in vitro study demonstrates that P. gingivalis LPS with a lipid A structural heterogeneity differentially modulates LBP expression in HOKs.
Effect of solute Mg on grain size of aluminium alloys
Authors: Birol Y
Published: June 2012

The effect of solute Mg on grain size in Al–Mg alloys was investigated. Mg provides a grain refining effect for aluminium alloys that is retained until the eutectic point. While the inverse relationship between the grain size and the growth restriction factor is confirmed for hypoeutectic Mg concentrations, the monotonic increase of the latter even when the growth restriction effect gradually deteriorates evidences a rather poor correlation with the grain size in Al–Mg alloys. The correlation between the grain size and the solidification interval in Al–Mg alloys is not a good one, either. Hence, the solute effect depends on the system and appears to be too complex to be accounted for by a single parameter.
Characterisation and quantification of microstructural banding in dual-phase steels Part 2 – case study extending to 3D
Authors: McGarrity K S , Sietsma J , Jongbloed G
Published: June 2012

Two dual phase steels with markedly different microstructural banding have been serial sectioned for characterisation and quantification of the banding in three dimension (3D). Two parameters, bounded on a scale of zero to one, have been defined to quantify the amount of microstructural banding in two dimension (2D). The band continuity index Cb quantifies the continuity of each band within the band. The perpendicular continuity index Cp describes the continuity between adjacent bands. In the present work, these parameters are extended and applied to full 3D bands. The results show that while the connectivity of bands in 3D is different than what is observed in 2D, the quantification of banding with these parameters in 2D is sufficient to accurately represent the banding in 3D, thus validating these newly defined parameters.
High speed rolling of Mg–3Al–1Zn alloy: Texture and microstructure analysis
Authors: Sanjari M , Farzadfar S A , Utsunomiya H , Sakai T , Essadiqi E , Yue S
Published: June 2012

High speed rolling (HSR) of 1000 m min−1 was employed to successfully roll AZ31 alloy in one pass with 65 reduction in thickness at 300 and 450°C. The rollability, texture and microstructure after HSR, in comparison with low speed rolling (15 m min−1), improved significantly. It is suggested that the double peak and weaker basal texture obtained after HSR are attributed to the activation of compression and double twins. After annealing, the double peak basal texture is replaced by a single peak one, which may be due to preferential grain growth of basal grains.
Grain refinement of solidified Mg–Al alloys by limited angular oscillation
Authors: Guo H-M , Sheng Y-Y , Liu D-D , Xie W , Ge Z-P , Yang X-J
Published: June 2012

By introducing limited angular oscillation (LAO) during the initial stages of solidification, experiments were conducted to examine the potency of LAO for grain refining of commercial Mg–Al alloys. Significant grain refinement has been successfully achieved at oscillation intensities above the critical value. The refinement effect by solute content occurs across the oscillation intensity range examined and is more pronounced under the conditions of weak oscillation intensity. The refinement effectiveness for Mg–Al alloys is AZ31>AZ61>AZ91. Oscillation intensity plays a more important role in determining the extent of grain refining than the solute content. Theoretical discussions provide new clues to understanding of the mechanism of grain refinement by LAO.
Prediction of cutting forces and surface roughness using artificial neural network (ANN) and support vector regression (SVR) in turning 4140 steel
Authors: Asilturk İ , Kahramanli H , Mounayri H El
Published: June 2012

In the present study, the prediction of cutting forces and surface roughness was carried out using neural networks and support vector regression (SVR) with six inputs, namely, three axis vibrations of the tool holder and cutting speed, feedrate and depth of cut. The data obtained by experimentation are used to construct predictive models. A feedforward backpropagation neural network and SVR have been selected for modelling. The coefficient of determination ( R2), mean absolute prediction error and root mean square error were calculated for each method, and these values served as a measure of prediction precision. We carried out comparison of the prediction accuracy of artificial neural networks and SVR. Comparison of the two models indicates that both models have successful performance. Experimental results are provided to confirm the effectiveness of this approach.
Structure and properties of TiO2 coatings on biomedical NiTi alloy by microarc oxidation
Authors: Wang H R , Liu F , Song Y , Wang F P
Published: June 2012

A porous TiO2 coating was prepared on NiTi alloys by microarc oxidation (MAO) in a titania sol containing solution at constant current density. The surface of the TiO2 coating displays a rough and porous structure. The roughness and thickness of the MAO coating depend on the applied voltage for MAO treatment. X-ray photoelectron spectroscopy (XPS) analysis reveals that the elements of the coatings mainly contain Ti, O, P and Ni elements, and the Ni content is significantly lower in the coating than in the NiTi substrate. Thin film X-ray diffraction shows that the MAO coating is composed of amorphous titanium oxide. The coatings are tightly adhesive to the substrates. Potentiodynamic polarisation curves indicate that the corrosion resistance of the MAO coating is better than that of uncoated NiTi. The MAO coating prepared on the NiTi has been soaked in a simulated body fluid (SBF) to investigate the biomimetic deposition of apatite on the surface of the MAO coating. It is found that the MAO coating shows an excellent apatite forming ability after soaking in a SBF for 14 days.
The consistency for estimator of nonparametric regression model based on NOD errors
Authors: Yang Wenzhi , Wang Xuejun , Wang Xinghui , Hu Shuhe
Published: June 2012

By using some inequalities for NOD random variables, we give its application to investigate the nonparametric regression model based on these errors. Some consistency results for the estimator ofg(x) are presented, including the mean convergence, uniform convergence, almost sure convergence and convergence rate. We generalize some related results and as an example of designed assumptions for weight functions, we give the nearest neighbor weights.

AMS Mathematical Subject Classification 2000: 62G05; 62G08.
Phosphoinositide-3-kinase/akt - dependent signaling is required for maintenance of [Ca2+]i,ICa, and Ca2+ transients in HL-1 cardiomyocytes
Authors: Graves Bridget M , Simerly Thomas , Li Chuanfu , Williams David L , Wondergem Robert
Published: June 2012

The phosphoinositide 3-kinases (PI3K/Akt) dependent signaling pathway plays an important role in cardiac function, specifically cardiac contractility. We have reported that sepsis decreases myocardial Akt activation, which correlates with cardiac dysfunction in sepsis. We also reported that preventing sepsis induced changes in myocardial Akt activation ameliorates cardiovascular dysfunction. In this study we investigated the role of PI3K/Akt on cardiomyocyte function by examining the role of PI3K/Akt-dependent signaling on [Ca2+]i, Ca2+ transients and membrane Ca2+ current, I
Ca, in cultured murine HL-1 cardiomyocytes. LY294002 (1–20 μM), a specific PI3K inhibitor, dramatically decreased HL-1 [Ca2+]i, Ca2+ transients and I
Ca. We also examined the effect of PI3K isoform specific inhibitors, i.e. α (PI3-kinase α inhibitor 2; 2–8 nM); β (TGX-221; 100 nM) and γ (AS-252424; 100 nM), to determine the contribution of specific isoforms to HL-1 [Ca2+]i regulation. Pharmacologic inhibition of each of the individual PI3K isoforms significantly decreased [Ca2+]i, and inhibited Ca2+ transients. Triciribine (1–20 μM), which inhibits AKT downstream of the PI3K pathway, also inhibited [Ca2+]i, and Ca2+ transients and I
Ca. We conclude that the PI3K/Akt pathway is required for normal maintenance of [Ca2+]i in HL-1 cardiomyocytes. Thus, myocardial PI3K/Akt-PKB signaling sustains [Ca2+]i required for excitation-contraction coupling in cardiomyoctyes.
Natural diterpenes from coffee, cafestol and kahweol induce apoptosis through regulation of specificity protein 1 expression in human malignant pleural mesothelioma
Authors: Lee Kyung-Ae , Chae Jung-Il , Shim Jung-Hyun
Published: June 2012

Background

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a very poor prognosis. Several clinical studies such as immunotherapy, gene therapy and molecular targeting agents have been tried for treatment of malignant mesothelioma, however, there is no application for effective clinical treatment. Coffee has various biological functions such as anti-oxidant, anti-inflammatory, anti-mutagenic and anti-carcinogenic activities. The therapeutic activities of the bioactive compounds in coffee was sugested to influence intracellular signaling of MPM. Regarding to the cancer-related functions, In this study, suppression of Sp1 protein level followed by induction of MSTO-211H cell apoptosis by cafestol and kahweol were investigated in oreder to determine Sp1's potential as a significant target for human MPM therapy as well.

Methods

Cells were treated separately with final concentration of cafestol and kahweol and the results were analyzed by MTS assay, DAPI staining, PI staining, luciferase assay, RT-PCR, and immunoblotting.

Results

Viability of MSTO-211H and H28 cells were decreased, and apoptotic cell death was increased in MSTO-211H as a result of cafestol and kahweol treatment. Cafestol and kahweol increased Sub-G1 population and nuclear condensation in MSTO-211H cells. Roles of Sp1 in cell proliferation and apoptosis of the MSTO-211H cells by the Sp1 inhibitor of Mithramycin A were previously confirmed. Cafestol and kahweol significantly suppressed Sp1 protein levels. Kahweol slightly attenuated Sp1 mRNA, while Cafestol did not affect in MSTO-211H cells. Cafestol and kahweol modulated the promoter activity and protein expression level of the Sp1 regulatory genes including Cyclin D1, Mcl-1, and Survivin in mesothelioma cells. Apoptosis signaling cascade was activated by cleavages of Bid, Caspase-3, and PARP with cafestol and by upregulation of Bax, and downregulation of Bcl-xl by kahweol.

Conclusions

Sp1 can be a novel molecular target of cafestol and kahweol in human MPM.
Sufficient virus-neutralizing antibody in the central nerve system improves the survival of rabid rats
Authors: Liao Pi-Hung , Yang Hui-Hua , Chou Ping-Tse , Wang Ming-Hseng , Chu Po-Chun , Liu Hao-Li , Chen Li-Kuang
Published: June 2012

Background

Rabies is known to be lethal in human. Treatment with passive immunity for the rabies is effective only when the patients have not shown the central nerve system (CNS) signs. The blood–brain barrier (BBB) is a complex functional barrier that may compromise the therapeutic development in neurological diseases. The goal of this study is to determine the change of BBB integrity and to assess the therapeutic possibility of enhancing BBB permeability combined with passive immunity in the late stage of rabies virus infection.

Methods

The integrity of BBB permeability in rats was measured by quantitative ELISA for total IgG and albumin levels in the cerebrospinal fluid (CSF) and by exogenously applying Evans blue as a tracer. Western blotting of occludin and ZO-1, two tight junction proteins, was used to assess the molecular change of BBB structure.

The breakdown of BBB with hypertonic arabinose, recombinant tumor necrosis factor-alpha (rTNF-γ), and focused ultrasound (FUS) were used to compare the extent of BBB disruption with rabies virus infection. Specific humoral immunity was analyzed by immunofluorescent assay and rapid fluorescent focus inhibition test. Virus-neutralizing monoclonal antibody (mAb) 8-10E was administered to rats with hypertonic breakdown of BBB as a passive immunotherapy to prevent the death from rabies.

Results

The BBB permeability was altered on day 7 post-infection. Increased BBB permeability induced by rabies virus infection was observed primarily in the cerebellum and spinal cord. Occludin was significantly decreased in both the cerebral cortex and cerebellum. The rabies virus-specific antibody was not strongly elicited even in the presence of clinical signs. Disruption of BBB had no direct association with the lethal outcome of rabies. Passive immunotherapy with virus-neutralizing mAb 8-10E with the hypertonic breakdown of BBB prolonged the survival of rabies virus-infected rats.

Conclusions

We demonstrated that the BBB permeability was altered in a rat model with rabies virus inoculation. Delivery of neutralizing mAb to the infected site in brain combined with effective breakdown of BBB could be an aggressive but feasible therapeutic mode in rabies when the CNS infection has been established.
Bios2mds: an R package for comparing orthologous protein families by metric multidimensional scaling
Authors: Pelé Julien , Bécu Jean-Michel , Abdi Hervé , Chabbert Marie
Published: June 2012

Background

The distance matrix computed from multiple alignments of homologous sequences is widely used by distance-based phylogenetic methods to provide information on the evolution of protein families. This matrix can also be visualized in a low dimensional space by metric multidimensional scaling (MDS). Applied to protein families, MDS provides information complementary to the information derived from tree-based methods. Moreover, MDS gives a unique opportunity to compare orthologous sequence sets because it can add supplementary elements to a reference space.

Results

The R package bios2mds (from BIOlogical Sequences to MultiDimensional Scaling) has been designed to analyze multiple sequence alignments by MDS. Bios2mds starts with a sequence alignment, builds a matrix of distances between the aligned sequences, and represents this matrix by MDS to visualize a sequence space. This package also offers the possibility of performing K-means clustering in the MDS derived sequence space. Most importantly, bios2mds includes a function that projects supplementary elements (a.k.a. “out of sample” elements) onto the space defined by reference or “active” elements. Orthologous sequence sets can thus be compared in a straightforward way. The data analysis and visualization tools have been specifically designed for an easy monitoring of the evolutionary drift of protein sub-families.

Conclusions

The bios2mds package provides the tools for a complete integrated pipeline aimed at the MDS analysis of multiple sets of orthologous sequences in the R statistical environment. In addition, as the analysis can be carried out from user provided matrices, the projection function can be widely used on any kind of data.
Variation of presence/absence genes among Arabidopsis populations
Authors: Tan Shengjun , Zhong Yan , Hou Huan , Yang Sihai , Tian Dacheng
Published: June 2012

Background

Gene presence/absence (P/A) polymorphisms are commonly observed in plants and are important in individual adaptation and species differentiation. Detecting their abundance, distribution and variation among individuals would help to understand the role played by these polymorphisms in a given species. The recently sequenced 80 Arabidopsis genomes provide an opportunity to address these questions.

Results

By systematically investigating these accessions, we identified 2,407 P/A genes (or 8.9%) absent in one or more genomes, averaging 444 absent genes per accession. 50.6% of P/A genes belonged to multi-copy gene families, or 31.0% to clustered genes. However, the highest proportion of P/A genes, outnumbered in singleton genes, was observed in the regions near centromeres. In addition, a significant correlation was observed between the P/A gene frequency among the 80 accessions and the diversity level at P/A loci. Furthermore, the proportion of P/A genes was different among functional gene categories. Finally, a P/A gene tree showed a diversified population structure in the worldwide Arabidopsis accessions.

Conclusions

An estimate of P/A genes and their frequency distribution in the worldwide Arabidopsis accessions was obtained. Our results suggest that there are diverse mechanisms to generate or maintain P/A genes, by which individuals and functionally different genes can selectively maintain P/A polymorphisms for a specific adaptation.
Divergent gene expression in the conserved dauer stage of the nematodes Pristionchus pacificus and Caenorhabditis elegans
Authors: Sinha Amit , Sommer Ralf J , Dieterich Christoph
Published: June 2012

Background

An organism can respond to changing environmental conditions by adjusting gene regulation and by forming alternative phenotypes. In nematodes, these mechanisms are coupled because many species will form dauer larvae, a stress-resistant and non-aging developmental stage, when exposed to unfavorable environmental conditions, and execute gene expression programs that have been selected for the survival of the animal in the wild. These dauer larvae represent an environmentally induced, homologous developmental stage across many nematode species, sharing conserved morphological and physiological properties. Hence it can be expected that some core components of the associated transcriptional program would be conserved across species, while others might diverge over the course of evolution. However, transcriptional and metabolic analysis of dauer development has been largely restricted to Caenorhabditis elegans. Here, we use a transcriptomic approach to compare the dauer stage in the evolutionary model system Pristionchus pacificus with the dauer stage in C. elegans.

Results

We have employed Agilent microarrays, which represent 20,446 P. pacificus and 20,143 C. elegans genes to show an unexpected divergence in the expression profiles of these two nematodes in dauer and dauer exit samples. P. pacificus and C. elegans differ in the dynamics and function of genes that are differentially expressed. We find that only a small number of orthologous gene pairs show similar expression pattern in the dauers of the two species, while the non-orthologous fraction of genes is a major contributor to the active transcriptome in dauers. Interestingly, many of the genes acquired by horizontal gene transfer and orphan genes in P. pacificus, are differentially expressed suggesting that these genes are of evolutionary and functional importance.

Conclusion

Our data set provides a catalog for future functional investigations and indicates novel insight into evolutionary mechanisms. We discuss the limited conservation of core developmental and transcriptional programs as a common aspect of animal evolution.
Hypoglycemic and antioxidant effects of leaf essential oil of Pelargonium graveolens L’Hér. in alloxan induced diabetic rats
Authors: Boukhris Maher , Bouaziz Mohamed , Feki Ines , Jemai Hedya , El Feki Abdelfattah , Sayadi Sami
Published: June 2012

Background

Rose-scented geranium (Pelargonium graveolens L’Hér.), which is used in traditional Tunisian folk medicine for the treatment of hyperglycaemia, is widely known as one of the medicinal herbs with the highest antioxidant activity. The present paper is conducted to test the hypoglycemic and antioxidative activities of the leaf essential oil of P. graveolens.

Methods

The essential oil P. graveolens was administered daily and orally to the rats at two doses of 75 mg/kg and 150 mg/kg body weight (b.w.) for 30 days. The chemical composition of P. graveolens essential oil, body weight, serum glucose, hepatic glycogen, thiobarbituric acid-reactive substances (TBARS), the components of hepatic, and renal and serum antioxidant systems were evaluated. The hypoglycemic effect of rose-scented geranium was compared to that of the known anti-diabetic drug glibenclamide (600 μg/kg b.w.).

Results

After the administration of two doses of essential oil of Pelargonium graveolens L’Hér. together with glibenclamide which is known by its antidiabetic activities and used as reference (600 μg/kg b.w.), for four weeks, the serum glucose significantly decreased and antioxidant perturbations were restored. The hypoglycemic effect of P. graveolens at the dose of 150 mg/kg b.w. was significantly (p< 0.05) more effective than that of glibenclamide. It is through the histological findings in hepatic and renal tissues of diabetic rats that these beneficial effects of geranium oils were confirmed.

Conclusions

It suggests that administration of essential oil of P. graveolens may be helpful in the prevention of diabetic complications associated with oxidative stress. Our results, therefore, suggest that the rose-scented geranium could be used as a safe alternative antihyperglycemic drug for diabetic patients.
Adipose derived mesenchymal stem cells transplantation via portal vein improves microcirculation and ameliorates liver fibrosis induced by CCl4 in rats
Authors: Wang Yu , Lian Fan , Li Jiaping , Fan Wenzhe , Xu Hanshi , Yang Xiuyan , Liang Liuqin , Chen Wei , Yang Jianyong
Published: June 2012

Introduction

Adipose derived mesenchymal stem cells (ADMSCs), carrying the similar characteristics to bone marrow mesenchymal stem cells, only much more abundant and easier to obtain, may be a promising treatment for liver fibrosis. We aim to investigate the therapeutic potential of ADMSCs transplantation in liver fibrosis caused by carbon tetrachloride (CCl4) in rats as well as its underlying mechanism, and to further explore the appropriate infusion pathway.

Methods

ADMSCs were isolated, cultured and identified. Placebo and ADMSCs were transplanted via portal vein and tail vein respectively into carbon tetrachloride (CCl4)-induced liver fibrosis rats. Computed tomography (CT) perfusion scan and microvessel counts were performed to measure the alteration of liver microcirculation after therapy. Liver function tests and histological findings were estimated.

Results

CT perfusion scan shown significant decrease of hepatic arterial perfusion index, significant increased portal vein perfusion, total liver perfusion in rats receiving ADMSCs from portal vein, and Factor VIII (FVIII) immunohistochemical staining shown significant decrease of microvessels in rats receiving ADMSCs from portal vein, indicating microcirculation improvement in portal vein group. Vascular endothelial growth Factor (VEGF) was significantly up-regulated in fibrosis models, and decreased after ADMSCs intraportal transplantation. A significant improvement of liver functional test and histological findings in portal vein group were observed. No significance was found in rats receiving ADMSCs from tail vein.

Conclusions

ADMSCs have a therapeutic effect against CCl4-mediated liver fibrosis. ADMSCs may benefit the fibrotic liver through alteration of microcirculation, evidenced by CT perfusion scan and down-regulation of VEGF. Intraportal transplantation is a better pathway than tail vein transplantation.
Synthesis of size-controlled monodisperse Pd nanoparticles via a non-aqueous seed-mediated growth
Authors: Zhang Lei , Wang Lin , Jiang Zhiyuan , Xie Zhaoxiong
Published: June 2012

We demonstrated that stepwise seed-mediated growth could be extended in non-aqueous solution (solvothermal synthesis) and improved as an effective method for controlling the uniform size of palladium nanoparticles (Pd NPs) in a wide range. The monodisperse Pd NPs with the size of about 5 nm were synthesized by simply reducing Pd(acac)2 with formaldehyde in different organic amine solvents. By an improved stepwise seed-mediated synthesis, the size of the monodisperse Pd NPs can be precisely controlled from approximately 5 to 10 nm. The as-prepared Pd NPs could self assemble to well-shaped superlattice crystal without size selection process.
Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population
Authors: Ellis James K , Athersuch Toby J , Thomas Laura DK , Teichert Friederike , Pérez-Trujillo Miriam , Svendsen Claus , Spurgeon David J , Singh Rajinder , Järup Lars , Bundy Jacob G , Keun Hector C
Published: June 2012

Background

The 'exposome' represents the accumulation of all environmental exposures across a lifetime. Top-down strategies are required to assess something this comprehensive, and could transform our understanding of how environmental factors affect human health. Metabolic profiling (metabonomics/metabolomics) defines an individual's metabolic phenotype, which is influenced by genotype, diet, lifestyle, health and xenobiotic exposure, and could also reveal intermediate biomarkers for disease risk that reflect adaptive response to exposure. We investigated changes in metabolism in volunteers living near a point source of environmental pollution: a closed zinc smelter with associated elevated levels of environmental cadmium.

Methods

High-resolution 1H NMR spectroscopy (metabonomics) was used to acquire urinary metabolic profiles from 178 human volunteers. The spectral data were subjected to multivariate and univariate analysis to identify metabolites that were correlated with lifestyle or biological factors. Urinary levels of 8-oxo-deoxyguanosine were also measured, using mass spectrometry, as a marker of systemic oxidative stress.

Results

Six urinary metabolites, either associated with mitochondrial metabolism (citrate, 3-hydroxyisovalerate, 4-deoxy-erythronic acid) or one-carbon metabolism (dimethylglycine, creatinine, creatine), were associated with cadmium exposure. In particular, citrate levels retained a significant correlation to urinary cadmium and smoking status after controlling for age and sex. Oxidative stress (as determined by urinary 8-oxo-deoxyguanosine levels) was elevated in individuals with high cadmium exposure, supporting the hypothesis that heavy metal accumulation was causing mitochondrial dysfunction.

Conclusions

This study shows evidence that an NMR-based metabolic profiling study in an uncontrolled human population is capable of identifying intermediate biomarkers of response to toxicants at true environmental concentrations, paving the way for exposome research.
Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia
Authors: Püntener Ursula , Booth Steven G , Perry V Hugh , Teeling Jessica L
Published: June 2012

Background

Systemic infection leads to generation of inflammatory mediators that result in metabolic and behavioural changes. Repeated or chronic systemic inflammation leads to a state of innate immune tolerance: a protective mechanism against overactivity of the immune system. In this study, we investigated the immune adaptation of microglia and brain vascular endothelial cells in response to systemic inflammation or bacterial infection.

Methods

Mice were given repeated doses of lipopolysaccharide (LPS) or a single injection of liveSalmonella typhimurium. Inflammatory cytokines were measured in serum, spleen and brain, and microglial phenotype studied by immunohistochemistry. To assess priming of the innate immune response in the brain, mice were infected withSalmonella typhimuriumand subsequently challenged with a focal unilateral intracerebral injection of LPS.

Results

Repeated systemic LPS challenges resulted in increased brain IL-1β, TNF-α and IL-12 levels, despite attenuated systemic cytokine production. Each LPS challenge induced significant changes in burrowing behaviour. In contrast, brain IL-1β and IL-12 levels inSalmonella typhimurium-infected mice increased over three weeks, with high interferon-γ levels in the circulation. Behavioural changes were only observed during the acute phase of the infection. Microglia and cerebral vasculature display an activated phenotype, and focal intracerebral injection of LPS four weeks after infection results in an exaggerated local inflammatory response when compared to non-infected mice.

Conclusions

These studies reveal that the innate immune cells in the brain do not become tolerant to systemic infection, but are primed instead. This may lead to prolonged and damaging cytokine production that may have a profound effect on the onset and/or progression of pre-existing neurodegenerative disease.
Live sequence charts to model medical information
Authors: Aslakson Eric , Szekely Smadar , Vernon Suzanne D , Bateman Lucinda , Baumbach Jan , Setty Yaki
Published: June 2012

Background

Medical records accumulate data concerning patient health and the natural history of disease progression. However, methods to mine information systematically in a form other than an electronic health record are not yet available. The purpose of this study was to develop an object modeling technique as a first step towards a formal database of medical records.

Method

Live Sequence Charts (LSC) were used to formalize the narrative text obtained during a patient interview. LSCs utilize a visual scenario-based programming language to build object models. LSC extends the classical language of UML message sequence charts (MSC), predominantly through addition of modalities and providing executable semantics. Inter-object scenarios were defined to specify natural history event interactions and different scenarios in the narrative text.

Result

A simulated medical record was specified into LSC formalism by translating the text into an object model that comprised a set of entities and events. The entities described the participating components (i.e., doctor, patient and record) and the events described the interactions between elements. A conceptual model is presented to illustrate the approach. An object model was generated from data extracted from an actual new patient interview, where the individual was eventually diagnosed as suffering from Chronic Fatigue Syndrome (CFS). This yielded a preliminary formal designated vocabulary for CFS development that provided a basis for future formalism of these records.

Conclusions

Translation of medical records into object models created the basis for a formal database of the patient narrative that temporally depicts the events preceding disease, the diagnosis and treatment approach. The LSCs object model of the medical narrative provided an intuitive, visual representation of the natural history of the patient’s disease.
Patterns of failure after multimodal treatments for high-grade glioma: effectiveness of MIB-1 labeling index
Authors: Uehara Kazuyuki , Sasayama Takashi , Miyawaki Daisuke , Nishimura Hideki , Yoshida Kenji , Okamoto Yoshiaki , Mukumoto Naritoshi , Akasaka Hiroaki , Nishihara Masamitsu , Fujii Osamu , Soejima Toshinori , Sugimura Kazuro , Kohmura Eiji , Sasaki Ryohei
Published: June 2012

Background

The purpose of the present study was to analyze the recurrence pattern of high-grade glioma treated with a multimodal treatment approach and to evaluate whether the MIB-1 labeling index (LI) could be a useful marker for predicting the pattern of failure in glioblastoma (GB).

Methods and materials

We evaluated histologically confirmed 131 patients with either anaplastic astrocytoma (AA) or GB. A median dose was 60 Gy. Concomitant and adjuvant chemotherapy were administered to 111 patients. MIB-1 LI was assessed by immunohistochemistry. Recurrence patterns were categorized according to the areas of recurrence as follows: central failure (recurrence in the 95% of 60 Gy); in-field (recurrence in the high-dose volume of 50 Gy; marginal (recurrence outside the high-dose volume) and distant (recurrence outside the RT field).

Results

The median follow-up durations were 13 months for all patients and 19 months for those remaining alive. Among AA patients, the 2-year progression-free and overall survival rates were 23.1% and 39.2%, respectively, while in GB patients, the rates were 13.3% and 27.6%, respectively. The median survival time was 20 months for AA patients and 15 months for GB patients. Among AA patients, recurrences were central in 68.7% of patients; in-field, 18.8%; and distant, 12.5%, while among GB patients, 69.0% of recurrences were central, 15.5% were in-field, 12.1% were marginal, and 3.4% were distant. The MIB-1 LI medians were 18.2% in AA and 29.8% in GB. Interestingly, in patients with GB, the MIB-1 LI had a strong effect on the pattern of failure (P = 0.014), while the extent of surgical removal (P = 0.47) and regimens of chemotherapy (P = 0.57) did not.

Conclusions

MIB-1 LI predominantly affected the pattern of failure in GB patients treated with a multimodal approach, and it might be a useful tool for the management of the disease.
Rediscovering the chick embryo as a model to study retinal development
Authors: Vergara M Natalia , Canto-Soler M Valeria
Published: June 2012

The embryonic chick occupies a privileged place among animal models used in developmental studies. Its rapid development and accessibility for visualization and experimental manipulation are just some of the characteristics that have made it a vertebrate model of choice for more than two millennia. Until a few years ago, the inability to perform genetic manipulations constituted a major drawback of this system. However, the completion of the chicken genome project and the development of techniques to manipulate gene expression have allowed this classic animal model to enter the molecular age. Such techniques, combined with the embryological manipulations that this system is well known for, provide a unique toolkit to study the genetic basis of neural development. A major advantage of these approaches is that they permit targeted gene misexpression with extremely high spatiotemporal resolution and over a large range of developmental stages, allowing functional analysis at a level, speed and ease that is difficult to achieve in other systems. This article provides a general overview of the chick as a developmental model focusing more specifically on its application to the study of eye development. Special emphasis is given to the state of the art of the techniques that have made gene gain- and loss-of-function studies in this model a reality. In addition, we discuss some methodological considerations derived from our own experience that we believe will be beneficial to researchers working with this system.
A generalizable pre-clinical research approach for orphan disease therapy
Authors: Beaulieu Chandree L , Samuels Mark E , Ekins Sean , McMaster Christopher R , Edwards Aled M , Krainer Adrian R , Hicks Geoffrey G , Frey Brendan J , Boycott Kym M , MacKenzie Alex E
Published: June 2012

With the advent of next-generation DNA sequencing, the pace of inherited orphan disease gene identification has increased dramatically, a situation that will continue for at least the next several years. At present, the numbers of such identified disease genes significantly outstrips the number of laboratories available to investigate a given disorder, an asymmetry that will only increase over time. The hope for any genetic disorder is, where possible and in addition to accurate diagnostic test formulation, the development of therapeutic approaches. To this end, we propose here the development of a strategic toolbox and preclinical research pathway for inherited orphan disease. Taking much of what has been learned from rare genetic disease research over the past two decades, we propose generalizable methods utilizing transcriptomic, system-wide chemical biology datasets combined with chemical informatics and, where possible, repurposing of FDA approved drugs for pre-clinical orphan disease therapies. It is hoped that this approach may be of utility for the broader orphan disease research community and provide funding organizations and patient advocacy groups with suggestions for the optimal path forward. In addition to enabling academic pre-clinical research, strategies such as this may also aid in seeding startup companies, as well as further engaging the pharmaceutical industry in the treatment of rare genetic disease.
Identifying MicroRNA-mRNA regulatory network in colorectal cancer by a combination of expression profile and bioinformatics analysis
Authors: Fu Jihong , Tang Wentao , Du Peng , Wang Guanghui , Chen Wei , Li Jingming , Zhu Yunxiang , Gao Jun , Cui Long
Published: June 2012

Background

MicroRNAs (miRNAs) are involved in carcinogenesis and tumor progression by regulating post-transcriptional gene expression. However, the miRNA-mRNA regulatory network is far from being fully understood. The objective of this study is to identify the colorectal cancer (CRC) specific miRNAs and their target mRNAs using a multi-step approach.

Results

A multi-step approach combining microarray miRNA and mRNA expression profile and bioinformatics analysis was adopted to identify the CRC specific miRNA-mRNA regulatory network. First, 32 differentially expressed miRNAs and 2916 mRNAs from CRC samples and their corresponding normal epithelial tissues were identified by miRNA and mRNA microarray, respectively. Secondly, 22 dysregulated miRNAs and their 58 target mRNAs (72 miRNA-mRNA pairs) were identified by a combination of Pearson’s correlation analysis and prediction by databases TargetScan and miRanda. Bioinformatics analysis revealed that these miRNA-mRNAs pairs were involved in Wnt signaling pathway. Additionally, 6 up-regulated miRNAs (mir-21, mir-223, mir-224, mir-29a, mir-29b, and mir-27a) and 4 down-regulated predicted target mRNAs (SFRP1, SFRP2, RNF138, and KLF4) were selected to validate the expression level and their anti-correlationship in an extended cohort of CRC patients by qRT-PCR. Except for mir-27a, the differential expression and their anti-correlationship were proven. Finally, a transfection assay was performed to validate a regulatory relationship between mir-29a and KLF4 at both RNA and protein levels.

Conclusions

Seventy-two miRNA-mRNA pairs combined by 22 dysregulated miRNAs and their 58 target mRNAs identified by the multi-step approach appear to be involved in CRC tumorigenesis. The results in our study were worthwhile to further investigation via a functional study to fully understand the underlying regulatory mechanisms of miRNA in CRC.
An approach for jatropha improvement using pleiotropic QTLs regulating plant growth and seed yield
Authors: Sun Fei , Liu Peng , Ye Jian , Lo Loong Chuan , Cao Suying , Li Lei , Yue Gen Hua , Wang Chun Ming
Published: June 2012

Background

Higher seed yield is one of the objectives of jatropha breeding. However, genetic analysis of the yield traits has not been done in jatropha. Quantitative trait loci (QTL) mapping was conducted to identify genetic factors controlling growth and seed yield in jatropha, a promising biofuel crop.

Results

A linkage map was constructed consisting of 105 SSR (simple sequence repeat) markers converged into 11 linkage groups. With this map, we identified a total of 28 QTLs for 11 growth and seed traits using a population of 296 backcrossing jatropha trees. Two QTLs qTSW-5 and qTSW-7 controlling seed yield were mapped on LGs 5 and 7 respectively, where two QTL clusters controlling yield related traits were detected harboring five and four QTLs respectively. These two QTL clusters were critical with pleiotropic roles in regulating plant growth and seed yield. Positive additive effects of the two QTLs indicated higher values for the traits conferred by the alleles from J. curcas, while negative additive effects of the five QTLs on LG6, controlling plant height, branch number (in the 4th and 10th months post seed germination), female flower number and fruit number respectively, indicated higher values conferred by the alleles from J. integerrima. Therefore favored alleles from both the parents could be expected to be integrated into elite jatropha plant by further backcrossing and marker assisted selection. Efficient ways to improve the seed yield by applying the two QTL clusters are discussed.

Conclusion

This study is the first report on genetic analysis of growth and seed traits with molecular markers in jatropha. An approach for jatropha improvement is discussed using pleiotropic QTLs, which will be likely to lead to initiation of molecular breeding in jatropha by integrating more markers in the QTL regions.
MicroRNA expression signature in human abdominal aortic aneurysms
Authors: Pahl Matthew C , Derr Kimberly , Gäbel Gabor , Hinterseher Irene , Elmore James R , Schworer Charles M , Peeler Thomas C , Franklin David P , Gray John L , Carey David J , Tromp Gerard , Kuivaniemi Helena
Published: June 2012

Background

Abdominal aortic aneurysm (AAA) is a dilatation of the aorta affecting most frequently elderly men. Histologically AAAs are characterized by inflammation, vascular smooth muscle cell apoptosis, and extracellular matrix degradation. The mechanisms of AAA formation, progression, and rupture are currently poorly understood. A previous mRNA expression study revealed a large number of differentially expressed genes between AAA and non-aneurysmal control aortas. MicroRNAs (miRNAs), small non-coding RNAs that are post-transcriptional regulators of gene expression, could provide a mechanism for the differential expression of genes in AAA.

Methods

To determine differences in miRNA levels between AAA (n = 5) and control (n = 5) infrarenal aortic tissues, a microarray study was carried out. Results were adjusted using Benjamini-Hochberg correction (adjustedp < 0.05). Real-time quantitative RT-PCR (qRT-PCR) assays with an independent set of 36 AAA and seven control tissues were used for validation. Potential gene targets were retrieved from miRNA target prediction databases Pictar, TargetScan, and MiRTarget2. Networks from the target gene set were generated and examined using the network analysis programs, CytoScape® and Ingenuity Pathway Core Analysis®.

Results

A microarray study identified eight miRNAs with significantly different expression levels between AAA and controls (adjustedp < 0.05). Real-time qRT-PCR assays validated the findings for five of the eight miRNAs. A total of 222 predicted miRNA target genes known to be differentially expressed in AAA based on a prior mRNA microarray study were identified. Bioinformatic analyses revealed that several target genes are involved in apoptosis and activation of T cells.

Conclusions

Our genome-wide approach revealed several differentially expressed miRNAs in human AAA tissue suggesting that miRNAs play a role in AAA pathogenesis.
Network analysis identifies a putative role for the PPAR and type 1 interferon pathways in glucocorticoid actions in asthmatics
Authors: Diez Diego , Goto Susumu , Fahy John V , Erle David J , Woodruff Prescott G , Wheelock Åsa M , Wheelock Craig E
Published: June 2012

Background

Asthma is a chronic inflammatory airway disease influenced by genetic and environmental factors that affects ~300 million people worldwide, leading to ~250,000 deaths annually. Glucocorticoids (GCs) are well-known therapeutics that are used extensively to suppress airway inflammation in asthmatics. The airway epithelium plays an important role in the initiation and modulation of the inflammatory response. While the role of GCs in disease management is well understood, few studies have examined the holistic effects on the airway epithelium.

Methods

Gene expression data were used to generate a co-transcriptional network, which was interrogated to identify modules of functionally related genes. In parallel, expression data were mapped to the human protein-protein interaction (PPI) network in order to identify modules with differentially expressed genes. A common pathways approach was applied to highlight genes and pathways functionally relevant and significantly altered following GC treatment.

Results

Co-transcriptional network analysis identified pathways involved in inflammatory processes in the epithelium of asthmatics, including the Toll-like receptor (TLR) and PPAR signaling pathways. Analysis of the PPI network identified RXRA, PPARGC1A, STAT1 and IRF9, among others genes, as differentially expressed. Common pathways analysis highlighted TLR and PPAR signaling pathways, providing a link between general inflammatory processes and the actions of GCs. Promoter analysis identified genes regulated by the glucocorticoid receptor (GCR) and PPAR pathways as well as highlighted the interferon pathway as a target of GCs.

Conclusions

Network analyses identified known genes and pathways associated with inflammatory processes in the airway epithelium of asthmatics. This workflow illustrated a hypothesis generating experimental design that integrated multiple analysis methods to produce a weight-of-evidence based approach upon which future focused studies can be designed. In this case, results suggested a mechanism whereby GCs repress TLR-mediated interferon production via upregulation of the PPAR signaling pathway. These results highlight the role of interferons in asthma and their potential as targets of future therapeutic efforts.