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Subduction-zone metamorphism is considered to be a major chemical filter for both the arc magmatism and mantle compositional heterogeneity. To understand the element transport during this process, we conducted a petrographic and geochemical study of the bulk-rock blueschists and eclogites from the western Tianshan ultrahigh-pressure metamorphic belt, northwest China. By examining correlations among incompatible elements, we show that high field strength elements (HFSEs), rare earth elements (REEs), Th, and U are relatively immobile, whereas Pb and Sr are mobile in both basaltic and sedimentary protoliths during subduction-zone metamorphism. K, Rb, Cs, and Ba are mobile in rocks of basaltic protolith but immobile in rocks of sedimentary protolith because of the presence and persistent stability of white mica throughout their petrologic history. The commonly observed enrichment of some immobile elements (e.g., U, light [L] REEs) in arc magmas may thus not be caused by subduction-zone aqueous fluids. The lack of Rb/Sr-Sm/Nd correlation in these metamorphosed rocks is inconsistent with the observed first-order Sr-Nd isotope correlation in oceanic basalts, suggesting that the residual ocean crust that has undergone subduction-zone metamorphism cannot be the major source material for oceanic basalts, as widely believed, although it can contribute to mantle compositional heterogeneity in general. [ABSTRACT FROM AUTHOR]

Calorie restriction [CR; ~40% below ad libitum (AL) intake] improves the health of many species, including rats, by mechanisms that may be partly related to enhanced insulin sensitivity for glucose disposal by skeletal muscle. Excessive activation of several mitogen-activated protein kinases (MAPKs), including JNK1/2, p38, and ERK1/2 has been linked to insulin resistance. Although insulin can activate ERK1/2, this effect is not required for insulin-mediated glucose uptake. We hypothesized that skeletal muscle from male 9-mo-old Fischer 344/Brown Norway rats CR (35-40% beginning at 3 mo old) versus AL rats would have 1) attenuated activation of JNK1/2, p38, and ERK1/2 under basal conditions; and 2) no difference for insulin-induced ERK1/2 activation. In contrast to our hypothesis, there were significant CR-related increases in the phosphorylation of p38 (epitrochlearis, soleus, and gastrocnemius), JNK1 (epitrochlearis and soleus), and JNK2 (gastrocnemius). Consistent with our hypothesis, CR did not alter insulin-mediated ERK1/2 activation. The greater JNK1/2 and p38 phosphorylation with CR was not attributable to diet effects on muscle oxidative stress (assessed by protein carbonyls and 4-hydroxynonenal protein conjugates). In muscles from the same rats used for the present study, we previously reported a CR-related increase in insulin-mediated glucose uptake by the epitrochlearis and the soleus (Sharma N, Arias EB, Bhat AD, Sequea DA, Ho S, Croff KK, Sajan MP, Farese RV, Cartee GD. Am J Physiol Endocrinol Metab 300: E966-E978, 2011). The present results indicate that the improved insulin sensitivity with CR is not attributable to attenuated MAPK phosphorylation in skeletal muscle. [ABSTRACT FROM AUTHOR]

Familial benign chronic pemphigus or Hailey-Hailey disease (OMIM 169600) is an autosomal-dominant blistering disease. Here we present a rare case of familial benign chronic pemphigus in a Chinese infant. The 5-month-old proband, who showed diffusely distributed skin lesions, is the youngest patient of Hailey-Hailey disease ever reported. The detection of an ATP2C1 gene mutation in this infant confirmed the diagnosis. His mother carried the same mutation, but with no history of skin lesions. [ABSTRACT FROM AUTHOR]

To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel–Haenzel P values = 1 × 10−5 to 4 × 10−3), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion–extravasation–migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk. [ABSTRACT FROM PUBLISHER]

Although thiazolidinediones (TZDs) are potent promoters of adipogenesis in the preadipocyte, they induce apoptosis in several other cell types, such as cancer cells, endothelial cells and T-lymphocytes. In this study, we investigated the proapoptotic effect of TZDs in mature 3T3-L1 adipocytes, which express high levels of the peroxisome proliferator-activated receptor-γ (PPARγ) protein. Apoptosis was induced in mature 3T3-L1 adipocytes by treatment with troglitazone, pioglitazone or prostaglandin J2, and could be blocked by the PPARγ antagonist GW9662. Treatment with PPARγ agonists also decreased Akt-1 protein and phosphorylation levels without affecting phosphoinositide 3-kinase and PTEN. Further analysis indicated that in troglitazone-treated 3T3-L1 adipocytes, Bad phosphorylation and Bcl-2 protein levels were reduced, and Bax translocation to the mitochondria was increased. Subsequently, cytochrome c release and caspase-3 cleavage were observed. TZD-induced adipocyte apoptosis could be blocked by the caspase-3 inhibitor Ac-DEVD-CHO or by overexpression of Bcl2. In cultured rat primary adipocytes, similar apoptosis-inducing effects of troglitazone were also observed. Thus, TZDs promote apoptosis in adipocytes through a PPARγ-dependent pathway. This apoptosis is mediated by the inhibition of Akt-1, which decreases Bad phosphorylation and activates the mitochondrial apoptotic pathway. [ABSTRACT FROM AUTHOR]

The causes of glioblastoma and other gliomas remain obscure. To discover new candidate genes influencing glioma susceptibility, we conducted a principal component–adjusted genome-wide association study (GWAS) of 275,895 autosomal variants among 692 adult high-grade glioma cases (622 from the San Francisco Adult Glioma Study (AGS) and 70 from the Cancer Genome Atlas (TCGA)) and 3,992 controls (602 from AGS and 3,390 from Illumina iControlDB (iControls)). For replication, we analyzed the 13 SNPs with P < 10−6 using independent data from 176 high-grade glioma cases and 174 controls from the Mayo Clinic. On 9p21, rs1412829 near CDKN2B had discovery P = 3.4 × 10−8, replication P = 0.0038 and combined P = 1.85 × 10−10. On 20q13.3, rs6010620 intronic to RTEL1 had discovery P = 1.5 × 10−7, replication P = 0.00035 and combined P = 3.40 × 10−9. For both SNPs, the direction of association was the same in discovery and replication phases. [ABSTRACT FROM AUTHOR]

Signaling through the T cell antigen receptor (TCR) is important for the homeostasis of naïve and memory CD4+ T cells. The significance of TCR signaling in regulatory T (Treg) cells has not been systematically addressed. Using an Ox40-cre allele that is prominently expressed in Treg cells, and a conditional null allele of the gene encoding p56Lck, we have examined the importance of TCR signaling in Treg cells. Inactivation of p56Lck resulted in abnormal Treg homeostasis characterized by impaired turnover, preferential redistribution to the lymph nodes, loss of suppressive function, and striking changes in gene expression. Abnormal Treg cell homeostasis and function did not reflect the involvement of p56Lck in CD4 function because these effects were not observed when CD4 expression was inactivated by Ox40-cre.The results make clear multiple aspects of Treg cell homeostasis and phenotype that are dependent on a sustained capacity to signal through the TCR. [ABSTRACT FROM AUTHOR]

The recent availability of whole-genome scale data sets that investigate complementary and diverse aspects of transcriptional regulation has spawned an increased need for new and effective computational approaches to analyze and integrate these large scale assays. Here, we propose a novel algorithm, based on random forest methodology, to relate gene expression (as derived from expression microarrays) to sequence features residing in gene promoters (as derived from DNA motif data) and transcription factor binding to gene promoters (as derived from tiling microarrays). We extend the random forest approach to model a multivariate response as represented, for example, by time-course gene expression measures. An analysis of the multivariate random forest output reveals complex regulatory networks, which consist of cohesive, condition-dependent regulatory cliques. Each regulatory clique features homogeneous gene expression profiles and common motifs or synergistic motif groups. We apply our method to several yeast physiological processes: cell cycle, sporulation, and various stress conditions. Our technique displays excellent performance with regard to identifying known regulatory motifs, including high order interactions. In addition, we present evidence of the existence of an alternative MCBbinding pathway, which we confirm using data from two independent cell cycle studies and two other physioloigical processes. Finally, we have uncovered elaborate transcription regulation refinement mechanisms involving PAC and mRRPE motifs that govern essential rRNA processing. These include intriguing instances of differing motif dosages and differing combinatorial motif control that promote regulatory specificity in rRNA metabolism under differing physiological processes. [ABSTRACT FROM AUTHOR]

Splicing is an important process for regulation of gene expression in eukaryotes, and it has important functional links to other steps of gene expression. Two examples of these linkages include Ceg1, a component of the mRNA capping enzyme, and the chromatin elongation factors Spt4-5, both of which have recently been shown to play a role in the normal splicing of several genes in the yeast Saccharomyces cerevisiae. Using a genomic approach to characterize the roles of Spt4-5 in splicing, we used splicing-sensitive DNA microarrays to identify specific sets of genes that are mis-spliced in ceg1, spt4, and spt5 mutants. In the context of a complex, nested, experimental design featuring 22 dye-swap array hybridizations, comprising both biological and technical replicates, we applied five appropriate statistical models for assessing differential expression between wild-type and the mutants. To refine selection of differential expression genes, we then used a robust model-synthesizing approach, Differential Expression via Distance Synthesis, to integrate all five models. The resultant list of differentially expressed genes was then further analyzed with regard to select attributes: we found that highly transcribed genes with long introns were most sensitive to spt mutations. QPCR confirmation of differential expression was established for the limited number of genes evaluated. In this paper, we showcase splicing array technology, as well as powerful, yet general, statistical methodology for assessing differential expression, in the context of a real, complex experimental design. Our results suggest that the Spt4-Spt5 complex may help coordinate splicing with transcription under conditions that present kinetic challenges to spliceosome assembly or function. [ABSTRACT FROM AUTHOR]

Identification of peptides binding to Major Histocompatibility Complex (MHC) molecules is important for accelerating vaccine development and improving immunotherapy. Accordingly, a wide variety of prediction methods have been applied in this context. In this paper, we introduce (tree-based) ensemble classifiers for such problems and contrast their predictive performance with forefront existing methods for both MHC class I and class II molecules. In addition, we investigate the impact of differing peptide representation schemes on performance. Finally, classifier predictions are used to conduct genomewide scans of a diverse collection of HIV-1 strains, enabling assessment of epitope conservation. We investigated all combinations of six classification methods (classification trees, artificial neural networks, support vector machines, as well as the more recently devised ensemble methods (bagging, random forests, boosting) with four peptide representation schemes (amino acid sequence, select biophysical properties, select quantitative structure-activity relationship (QSAR) descriptors, and the combination of the latter two) in predicting peptide binding to an MHC class I molecule (HLA-A2) and MHC class II molecule (HLA-DR4). Our results show that the ensemble methods are consistently more accurate than the other three alternatives. Furthermore, they are robust with respect to parameter tuning. Among the four representation schemes, the amino acid sequence representation gave consistently (across classifiers) best results. This finding obviates the need for feature selection strategies incurred by use of biophysical and/or QSAR properties. We obtained, and aligned, a diverse set of 32 HIV-1 genomes and pursued genomewide HLA-DR4 epitope profiling by querying with respect to classifier predictions, as obtained under each of the four peptide representation schemes. We validated those epitopes conserved across strains against known T-cell epitopes. Once again, amino acid sequence representation was at least as effective as using properties. Assessment of novel epitope predictions awaits experimental verification. [ABSTRACT FROM PUBLISHER]

Intensities measurements of spotted microarrays embody many undesirable systematic variations. Very commonly, varying amounts and types of such variations are observed in different arrays. Although various normalization methods have been proposed to remove such systematic effects, it has not been well studied how to assess or select the most appropriate method for different arrays and data sets. To address this issue, we present a novel normalization technique, STEPNORM, for data-dependent and adaptive normalization of two-channel spotted microarrays. STEPNORM performs a stepwise interrogation of a range of different normalization models and selects the appropriate method based on formal model selection criteria. In addition, we evaluate the effectiveness of STEPNORM and other commonly used normalization methods utilizing a set of specially constructed splicing arrays. [ABSTRACT FROM AUTHOR]

Background: Microarray technology is a powerful methodology for identifying differentially expressed genes. However, when thousands of genes in a microarray data set are evaluated simultaneously by fold changes and significance tests, the probability of detecting false positives rises sharply. In this first microarray study of brachial plexus injury, we applied and compared the performance of two recently proposed algorithms for tackling this multiple testing problem, Significance Analysis of Microarrays (SAM) and Westfall and Young step down adjusted p values, as well as t-statistics and Welch statistics, in specifying differential gene expression under different biological states. Results: Using SAM based on t statistics, we identified 73 significant genes, which fall into different functional categories, such as cytokines / neurotrophin, myelin function and signal transduction. Interestingly, all but one gene were down-regulated in the patients. Using Welch statistics in conjunction with SAM, we identified an additional set of up-regulated genes, several of which are engaged in transcription and translation regulation. In contrast, the Westfall and Young algorithm identified only one gene using a conventional significance level of 0.05. Conclusion: In coping with multiple testing problems, Family-wise type I error rate (FWER) and false discovery rate (FDR) are different expressions of Type I error rates. The Westfall and Young algorithm controls FWER. In the context of this microarray study, it is, seemingly, too conservative. In contrast, SAM, by controlling FDR, provides a promising alternative. In this instance, genes selected by SAM were shown to be biologically meaningful. [ABSTRACT FROM AUTHOR]

Objective •This study aimed to investigate the effectiveness and safety of intravitreal conbercept injections with or without focal macular photocoagulation in the treatment of diabetic macular edema (DME). Methods • This retrospective study included 60 DME patients (60 eyes) divided into two treatment groups. The conbercept group received monthly intravitreal injections for 5 consecutive sessions, while the combination therapy group received intravitreal injections and focal macular photocoagulation. Changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT) were observed before and at months 1, 3, 6, 9, and 12 after treatment in both groups, along with the number of intravitreal conbercept injections administered. Results • At 1, 3, 6, 9, and 12 months after treatment, both the conbercept and combined treatment groups showed improvement in best-corrected visual acuity (BCVA) and decrease in central macular thickness (CMT) compared to before treatment, with statistical significant differences (P < .05). However, the differences in BCVA and CMT between the two groups at each time point after treatment were not significant (P>.05). During the 1-year follow-up period, the mean number of injections in the combined treatment group was 6.3±0.8, which was less than that in the conbercept treatment group (7.6 ± 0.9), with a significant difference (t=5.556, P<.001). The incidence of subconjunctival hemorrhage was 10.9% and 10.5% in the two groups, respectively, with no significant inter-group difference (χ² = 0.013, P = .908). None of the patients exhibited serious treatment-related ocular and systemic complications during the treatment period. Conclusions • Treatment of DME with intravitreal conbercept injections, whether with or without focal macular photocoagulation, is safe and effective in improving the patients’ visual acuity and retinal anatomy. However, patients who receive combined treatment require fewer intravitreal injections than those who receive conbercept treatment alone. [ABSTRACT FROM AUTHOR]

Motivation: Modern strategies for mapping disease loci require efficient genotyping of a large number of known polymorphic sites in the genome. The sensitive and high-throughput nature of hybridization-based DNA microarray technology provides an ideal platform for such an application by interrogating up to hundreds of thousands of single nucleotide polymorphisms (SNPs) in a single assay. Similar to the development of expression arrays, these genotyping arrays pose many data analytic challenges that are often platform specific. Affymetrix SNP arrays, e.g. use multiple sets of short oligonucleotide probes for each known SNP, and require effective statistical methods to combine these probe intensities in order to generate reliable and accurate genotype calls. Results: We developed an integrated multi-SNP, multi-array genotype calling algorithm for Affymetrix SNP arrays, MAMS, that combines single-array multi-SNP (SAMS) and multi-array, single-SNP (MASS) calls to improve the accuracy of genotype calls, without the need for training data or computation-intensive normalization procedures as in other multi-array methods. The algorithm uses resampling techniques and model-based clustering to derive single array based genotype calls, which are subsequently refined by competitive genotype calls based on (MASS) clustering. The resampling scheme caps computation for single-array analysis and hence is readily scalable, important in view of expanding numbers of SNPs per array. The MASS update is designed to improve calls for atypical SNPs, harboring allele-imbalanced binding affinities, that are difficult to genotype without information from other arrays. Using a publicly available data set of HapMap samples from Affymetrix, and independent calls by alternative genotyping methods from the HapMap project, we show that our approach performs competitively to existing methods. Availability: R functions are available upon request from the authors. Contact: yxiao@itsa.ucsf.edu and rufang@biostat.ucsf.edu Supplementary information: Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We have reported in a mouse model of transfusion-related acute lung injury (TRALI) that the mechanism of lung injury is dependent on the neutrophil. We have now analyzed the whole lung response in this model using a DNA microarray approach. METHODS: BALB/c mice were challenged with either MHC 1 mAb (n=3) or isotype control mAb (n=3). The lungs were removed after two hours. RNA was isolated and transcript expression in TRALI and control animals was compared using MEEBO arrays, which include probes for nearly all known mouse genes. Selected ELISA assays were also done using mouse plasma. RESULTS: Microarray analysis revealed 310 transcripts that were increased or decreased by at least 2-fold in TRALI and reached statistical significance (log-odds ratio > 0). Many of the most highly induced transcripts encode neutrophil-derived chemokines (Table). Gene products chemotactic for neutrophils (CXCL1, CXCL2, Calgranulin A & B, CCL3, CXCR2) and other cell types were identified. DCIP-1 is a novel neutrophil chemokine produced by dendritic cells that has not previously been associated with lung injury. Plasma levels of several of the highest differentially expressed genes were also elevated (Table, mean ± sd, *p<0.01 TRALI vs. control). CONCLUSIONS: A mouse model of TRALI is characterized by robust increases in neutrophil-derived chemokine mRNA transcripts and proteins in the lung. [ABSTRACT FROM AUTHOR]

Background: Published studies examining the association between childhood maltreatment (CM) and self-harm (SH) among adolescents have been accumulated. It is possible that resilience serves as a moderator or mediator in CM-SH association, nevertheless, this topic has never been thoroughly investigated.Methods: In this population-based cross-sectional study, we surveyed 3146 students aged 10-17 in southwest China. The Childhood Trauma Questionnaire (CTQ), the Modified version of Adolescents Self-Harm Scale (MASHS), and the Resilience Scale for Chinese Adolescents (RSCA) were used to measure CM, SH, and resilience. Correlational analyses, hierarchical multivariate linear regression, and structural equation modeling (SEM) were performed to test the moderation and mediation of resilience in CM-SH association.Results: Findings revealed that, resilience with its five dimensions, CM, and SH were significantly correlated with each other. Resilience partially moderated and mediated the association between CM and SH. Besides, among all dimensions of resilience, emotion regulation, interpersonal assistance, and family support presented the strongest mediation in CM-SH association.Conclusions: Our results highlight the importance of resilience in CM related SH among Chinese teenagers. Resilience-oriented intervention could be considered in SH intervention measures for adolescents who had experienced CM. [ABSTRACT FROM AUTHOR]

Disruption of the body clock has been recognized as a risk factor for cardiovascular disease. How the circadian pacemaker interacts with the genetic factors associated with plasma lipid traits remains poorly understood. Recent genome-wide association studies have identified an expanding list of genetic variants that influence plasma cholesterol and triglyceride levels. Here we analyzed circadian regulation of lipid-associated candidate genes in the liver and identified two distinct groups exhibiting rhythmic and non-rhythmic patterns of expression during light-dark cycles. Liver-specific inactivation of Bmal1 led to elevated plasma LDL/VLDL cholesterol levels as a consequence of the disruption of the PCSK9/LDL receptor regulatory axis. Ablation of the liver clock perturbed diurnal regulation of lipid-associated genes in the liver and markedly reduced the expression of the non-rhythmically expressed gene Trib1. Adenovirus- mediated rescue of Trib1 expression lowered plasma PCSK9 levels, increased LDL receptor protein expression, and restored plasma cholesterol homeostasis in mice lacking a functional liver clock. These results illustrate an unexpected mechanism through which the biological clock regulates cholesterol homeostasis through its regulation of non-rhythmic genes in the liver. [ABSTRACT FROM AUTHOR]

Squamous metaplasia (SM) is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether SM actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry, and fibroblast culture of lung samples from COPD patients; genome-wide analysis of an in vitro model of SM; and in vitro modeling of human airway epithelial-mesenchymal interactions, we provide evidence that SM, through the increased secretion of IL-1beta, induces a fibrotic response in adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-beta activation in amplifying SM and driving IL-1beta-dependent profibrotic mesenchymal responses. Finally, we show that SM correlates with increased severity of COPD and that fibroblast expression of the integrin alpha(v)beta(8), which is the major mediator of airway fibroblast TGF-beta activation, correlated with disease severity and small airway wall thickening in COPD. Our findings have identified TGF-beta as a potential therapeutic target for COPD. [ABSTRACT FROM AUTHOR]

de Winter syndrome is a special equivalent of anterior ST-segment elevation myocardial infarction (STEMI) characterized by the absence of overt ST-elevation with upsloping ST-segment depression followed by tall symmetrical T-waves in the precordial leads, often associated with total occlusion of the proximal left anterior descending coronary artery. Herein we present a case of de Winter syndrome in a 63-year-old man, whose initial ECG showed no ST-segment elevation, but subsequent coronary angiography confirmed total occlusion of the proximal LAD coronary artery. The patient was successfully treated via mechanical reperfusion therapy and stenting through percutaneous coronary intervention (PCI). de Winter syndrome is associated with a high mortality often due to insufficient awareness of this condition by clinicians. Immediate reperfusion therapy by PCI is the life-saving treatment for the patients diagnosed with this syndrome, and prompt recognition of the ECG pattern is critical to ensure the timely administration of the therapy.