Systemic Acrolein Elevations in Mice With Experimental Autoimmune Encephalomyelitis and Patients With Multiple Sclerosis

Demyelination and axonal injury are the key pathological processes in multiple sclerosis (MS), driven by inflammation and oxidative stress. Acrolein, a byproduct and instigator of oxidative stress, has been demonstrated as a neurotoxin in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, due to the invasive nature of acrolein detection using immunoblotting techniques, the investigation of acrolein in MS has been limited to animal models. Recently, detection of a specific acrolein-glutathione metabolite, 3-HPMA, has been demonstrated in urine, enabling the noninvasive quantification of acrolein for the first time in humans with neurological disorders. In this study, we have demonstrated similar elevated levels of acrolein in both urine (3-HPMA) and in spinal cord tissue (acrolein-lysine adduct) in mice with EAE, which can be reduced through systemic application of acrolein scavenger hydralazine. Furthermore, using this approach we have demonstrated an increase of 3-HPMA in both the urine and serum of MS patients relative to controls. It is expected that this noninvasive acrolein detection could facilitate the investigation of the role of acrolein in the pathology of MS in human. It may also be used to monitor putative therapies aimed at suppressing acrolein levels, reducing severity of symptoms, and slowing progression as previously demonstrated in animal studies

Software Metrics and Dashboard

Software metrics are a critical tool which provide continuous insight to products and processes and help build reliable software in mission critical environments. Using software metrics we can perform calculations that help assess the effectiveness of the underlying software or process. The two types of metrics relevant to our work is complexity metrics and in-process metrics. Complexity metrics tend to focus on intrinsic code properties like code complexity. In-process metrics focus on a higher-level view of software quality, measuring information that can provide insight into the underlying software development process. Our aim is to develop and evaluate a metrics dashboard to support Computational Science and Engineering (CSE) software development projects. This task requires us to perform the following activities: Assess how metrics are used and which general classes/types of metrics will be useful in CSE projects. Develop a metrics dashboard that will work for teams using sites like Github, Bitbucket etc. Assess the effectiveness of the dashboard in terms of project success and developer attitude towards metrics and process. Our current focus is on identifying requirements for the metrics dashboard which include the types of metrics that will help understand and improve the software quality. We have also started the development on the metrics dashboard based on the currently identified metrics types. We plan to provide a reliable metrics dashboard which could be used by the CSE development teams to improve their software quality, this will be done by instrumenting the metrics dashboard to gather usage statistics. In this way the dashboard evolves continuously

Association between hospital case volume and the use of bronchoscopy and esophagoscopy during head and neck cancer diagnostic evaluation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102212/1/cncr28379.pd

Individual differences in search and monitoring for color targets in dynamic visual displays

Many jobs now involve the monitoring visual representations of data that change over time. Monitoring dynamically changing displays for the onset of targets can be done in two ways: detecting targets directly post their onset or predicting their onset from the prior state of distractors. In the present study, participants? eye movements were measured as they monitored arrays of 108 colored squares whose colors changed systematically over time. Across three experiments, the data show that participants detected the onset of targets both directly and predictively. Experiments 1 and 2 showed that predictive detection was only possible when supported by sequential color changes that followed a scale ordered in color space. Experiment 3 included measures of individual differences in working memory capacity (WMC) and anxious affect and a manipulation of target prevalence in the search task. It found that predictive monitoring for targets, and decisions about target onsets, were influenced by interactions between individual differences in verbal and spatial WMC and intolerance of uncertainty, a characteristic that reflects worry about uncertain future events. The results have implications for the selection of individuals tasked with monitoring dynamic visual displays for target onsets

Genome-wide association study identifies _FUT8_ and _ESR2_ as co-regulators of a bi-antennary N-linked glycan A2 (GlcNAc~2~Man~3~GlcNAc~2~) in human plasma proteins

HPLC analysis of N-glycans quantified levels of the biantennary glycan (A2) in plasma proteins of 924 individuals. Subsequent genome-wide association study (GWAS) using 317,503 single nucleotide polymorphysms (SNP) identified two genetic loci influencing variation in A2: FUT 8 and ESR2. We demonstrate that human glycans are amenable to GWAS and their genetic regulation shows sex-specific effects with _FUT 8_ variants explaining 17.3% of the variance in pre-menopausal women, while _ESR2_ variants explained 6.0% of the variance in post-menopausal women

The 'Melanoma-enriched' microRNA miR-4731-5p acts as a tumour suppressor

We previously identified miR-4731-5p (miR-4731) as a melanoma-enriched microRNA following comparison of melanoma with other cell lines from solid malignancies. Additionally, miR-4731 has been found in serum from melanoma patients and expressed less abundantly in metastatic melanoma tissues from stage IV patients relative to stage III patients. As miR-4731 has no known function, we used biotin-labelled miRNA duplex pull-down to identify binding targets of miR-4731 in three melanoma cell lines (HT144, MM96L and MM253). Using the miRanda miRNA binding algorithm, all pulled-down transcripts common to the three cell lines (n=1092) had potential to be targets of miR-4731 and gene-set enrichment analysis of these (via STRING v9.1) highlighted significantly associated genes related to the ‘cell cycle’ pathway and the ‘melanosome’. Following miR-4731 overexpression, a selection (n=81) of pull-down transcripts underwent validation using a custom qRT-PCR array. These data revealed that miR-4731 regulates multiple genes associated with the cell cycle (e.g. CCNA2, ORC5L, and PCNA) and the melanosome (e.g. RAB7A, CTSD, and GNA13). Furthermore, members of the synovial sarcoma X breakpoint family (SSX) (melanoma growth promoters) were also down-regulated (e.g. SSX2, SSX4, and SSX4B) as a result of miR-4731 overexpression. Moreover, this down-regulation of mRNA expression resulted in ablation or reduction of SSX4 protein, which, in keeping with previous studies, resulted in loss of 2D colony formation. We therefore speculate that loss of miR-4731 expression in stage IV patient tumours supports melanoma growth by, in part; reducing its regulatory control of SSX expression levels

Uncovering Networks from Genome-Wide Association Studies via Circular Genomic Permutation

Genome-wide association studies (GWAS) aim to detect single nucleotide polymorphisms (SNP) associated with trait variation. However, due to the large number of tests, standard analysis techniques impose highly stringent significance thresholds, leaving potentially associated SNPs undetected, and much of the trait genetic variation unexplained. Pathway- and network-based methodologies applied to GWAS aim to detect associations missed by standard single-marker approaches. The complex and non-random architecture of the genome makes it a challenge to derive an appropriate testing framework for such methodologies. We developed a rapid and simple permutation approach that uses GWAS SNP association results to establish the significance of pathway associations while accounting for the linkage disequilibrium structure of SNPs and the clustering of functionally related elements in the genome. All SNPs used in the GWAS are placed in a “circular genome” according to their location. Then the complete set of SNP association P values are permuted by rotation with respect to the genomic locations of the SNPs. Once these “simulated” P values are assigned, the joint gene P values are calculated using Fisher’s combination test, and the association of pathways is tested using the hypergeometric test. The circular genomic permutation approach was applied to a human genome-wide association dataset. The data consists of 719 individuals from the ORCADES study genotyped for ∼300,000 SNPs and measured for 51 traits ranging from physical to biochemical measurements. KEGG pathways (n = 225) were used as the sets of pathways to be tested. Our results demonstrate that the circular genomic permutations provide robust association P values. The non-permuted hypergeometric analysis generates ∼1400 pathway-trait combination results with an association P value more significant than P ≤ 0.05, whereas applying circular genomic permutation reduces the number of significant results to a more credible 40% of that value. The circular permutation software (“genomicper”) is available as an R package at http://cran.r-project.org/

High Resolution mid-Infrared Imaging of SN 1987A

Using the Thermal-Region Camera and Spectrograph (T-ReCS) attached to the Gemini South 8m telescope, we have detected and resolved 10 micron emission at the position of the inner equatorial ring (ER) of supernova SN 1987A at day 6067. ``Hot spots'' similar to those found in the optical and near-IR are clearly present. The morphology of the 10 micron emission is globally similar to the morphology at other wavelengths from X-rays to radio. The observed mid-IR flux in the region of SN1987A is probably dominated by emission from dust in the ER. We have also detected the ER at 20 micron at a 4 sigma level. Assuming that thermal dust radiation is the origin of the mid-IR emission, we derive a dust temperature of 180^{+20}_{-10} K, and a dust mass of 1.- 8. 10^{-5} Mo for the ER. Our observations also show a weak detection of the central ejecta at 10 micron. We show that previous bolometric flux estimates (through day 2100) were not significantly contaminated by this newly discovered emission from the ER. If we assume that the energy input comes from radioactive decays only, our measurements together with the current theoretical models set a temperature of 90 leq T leq 100 K and a mass range of 10^{-4} - 2. 10^{-3} Mo for the dust in the ejecta. With such dust temperatures the estimated thermal emission is 9(+/-3) 10^{35} erg s^{-1} from the inner ring, and 1.5 (+/-0.5) 10^{36} erg s^{-1} from the ejecta. Finally, using SN 1987A as a template, we discuss the possible role of supernovae as major sources of dust in the Universe.Comment: aastex502, 14 pages, 4 figures; Accepted for publication in ApJ Content changed: new observations, Referee's comments and suggestion

Histologic and phenotypic factors and MC1R status associated with BRAF(V600E), BRAF(V600K), and NRAS mutations in a community-based sample of 414 cutaneous melanomas

Cutaneous melanomas arise through causal pathways involving interplay between exposure to UV radiation and host factors, resulting in characteristic patterns of driver mutations in BRAF, NRAS, and other genes. To gain clearer insights into the factors contributing to somatic mutation genotypes in melanoma, we collected clinical and epidemiologic data, performed skin examinations, and collected saliva and tumor samples from a community-based series of 414 patients aged 18 to 79, newly diagnosed with cutaneous melanoma. We assessed constitutional DNA for nine common polymorphisms in melanocortin-1 receptor gene (MC1R). Tumor DNA was assessed for somatic mutations in 25 different genes. We observed mutually exclusive mutations in BRAF (26%), BRAF (8%), BRAF (5%), and NRAS (9%). Compared to patients with BRAF wild-type melanomas, those with BRAF mutants were significantly younger, had more nevi but fewer actinic keratoses, were more likely to report a family history of melanoma, and had tumors that were more likely to harbor neval remnants. BRAF mutations were also associated with high nevus counts. Both BRAF and NRAS mutants were associated with older age but not with high sun exposure. We also found no association between MC1R status and any somatic mutations in this community sample of cutaneous melanomas, contrary to earlier reports