Time-Course Analysis of Brain Regional Expression Network Responses to Chronic Intermittent Ethanol and Withdrawal: Implications for Mechanisms Underlying Excessive Ethanol Consumption

Long lasting abusive consumption, dependence, and withdrawal are characteristic features of alcohol use disorders (AUD). Mechanistically, persistent changes in gene expression are hypothesized to contribute to brain adaptations leading to ethanol toxicity and AUD. We employed repeated chronic intermittent ethanol (CIE) exposure by vapor chamber as a mouse model to simulate the cycles of ethanol exposure and withdrawal commonly seen with AUD. This model has been shown to induce progressive ethanol consumption in rodents. Brain CIE-responsive expression networks were identified by microarray analysis across five regions of the mesolimbic dopamine system and extended amygdala with tissue harvested from 0-hours to 7-days following CIE. Weighted Gene Correlated Network Analysis (WGCNA) was used to identify gene networks over-represented for CIE-induced temporal expression changes across brain regions. Differential gene expression analysis showed that long-lasting gene regulation occurred 7-days after the final cycle of ethanol exposure only in prefrontal cortex (PFC) and hippocampus. Across all brain regions, however, ethanol-responsive expression changes occurred mainly within the first 8-hours after removal from ethanol. Bioinformatics analysis showed that neuroinflammatory responses were seen across multiple brain regions at early time-points, whereas co-expression modules related to neuroplasticity, chromatin remodeling, and neurodevelopment were seen at later time-points and in specific brain regions (PFC or HPC). In PFC a module containing Bdnf was identified as highly CIE responsive in a biphasic manner, with peak changes at 0 hours and 5 days following CIE, suggesting a possible role in mechanisms underlying long-term molecular and behavioral response to CIE. Bioinformatics analysis of this network and several other modules identified Let-7 family microRNAs as potential regulators of gene expression changes induced by CIE. Our results suggest a complex temporal and regional pattern of widespread gene network responses involving neuroinflammatory and neuroplasticity related genes as contributing to physiological and behavioral responses to chronic ethanol

Association of invasion-promoting tenascin-C additional domains with breast cancers in young women

Introduction: Tenascin-C (TNC) is a large extracellular matrix glycoprotein that shows prominent stromal expression in many solid tumours. The profile of isoforms expressed differs between cancers and normal breast, with the two additional domains AD1 and AD2 considered to be tumour associated. The aim of the present study was to investigate expression of AD1 and AD2 in normal, benign and malignant breast tissue to determine their relationship with tumour characteristics and to perform in vitro functional assays to investigate the role of AD1 in tumour cell invasion and growth. Methods: Expression of AD1 and AD2 was related to hypoxanthine phosphoribosyltransferase 1 as a housekeeping gene in breast tissue using quantitative RT-PCR, and the results were related to clinicopathological features of the tumours. Constructs overexpressing an AD1-containing isoform (TNC-14/AD1/16) were transiently transfected into breast carcinoma cell lines (MCF-7, T-47 D, ZR-75-1, MDA-MB-231 and GI-101) to assess the effect in vitro on invasion and growth. Statistical analysis was performed using a nonparametric Mann-Whitney test for comparison of clinicopathological features with levels of TNC expression and using Jonckheere-Terpstra trend analysis for association of expression with tumour grade. Results: Quantitative RT-PCR detected AD1 and AD2 mRNA expression in 34.9% and 23.1% of 134 invasive breast carcinomas, respectively. AD1 mRNA was localised by in situ hybridisation to tumour epithelial cells, and more predominantly to myoepithelium around associated normal breast ducts. Although not tumour specific, AD1 and AD2 expression was significantly more frequent in carcinomas in younger women (age ≤40 years; P < 0.001) and AD1 expression was also associated with oestrogen receptor-negative and grade 3 tumours (P < 0.05). AD1 was found to be incorporated into a tumour-specific isoform, not detected in normal tissues. Overexpression of the TNC-14/AD1/16 isoform significantly enhanced tumour cell invasion (P < 0.01) and growth (P < 0.01) over base levels. Conclusions: Together these data suggest a highly significant association between AD-containing TNC isoforms and breast cancers in younger women (age ≤40 years), which may have important functional significance in vivo

Exploring Participants’ Representations and Shifting Sensitivities in a Hackathon for Dementia

Recent HCI research has addressed emerging approaches for public engagement. One such public-facing method which has gained popularity over the previous decade have been open design events, or hackathons. In this paper we report on DemVR, a hackathon event that invited designers, technologists, and students of these disciplines to design Virtual Reality (VR) environments for people with dementia and their care partners. While our event gained reasonable attraction from designers and developers, this paper unpacks the challenges in representing and involving people with dementia in these events, which had multiple knock-on effects on participant's outputs. Our analysis presents insights into participants’ motivations, challenges participants faced when constructing their ‘absent user’, and the design features teams developed to address the social context of the user. We conclude the paper by proposing a set of commitments for collaborative design events, community building through design, and reification in design

Adaptation of a RAS pathway activation signature from FF to FFPE tissues in colorectal cancer

Paper presented at the 4th Strathmore International Mathematics Conference (SIMC 2017), 19 - 23 June 2017, Strathmore University, Nairobi, Kenya.Background: The KRAS gene is mutated in about 40 % of colorectal cancer (CRC) cases, which has been clinically validated as a predictive mutational marker of intrinsic resistance to anti-EGFR inhibitor (EGFRi) therapy. Since nearly 60 % of patients with a wild type KRAS fail to respond to EGFRicombination therapies, there is a need to develop more reliable molecular signatures to better predict response. Here we address the challenge of adapting a gene expression signature predictive of RAS pathway activation, created using fresh frozen (FF) tissues, for use with more widely available formalinfixed paraffin-embedded (FFPE) tissues. Methods: In this study, we evaluated the translation of an 18-gene RAS pathway signature score from FF to FFPE in 54 CRC cases, using a head-to- head comparison of five technology platforms. FFPE-based technologies included the Affymetrix Gene Chip (Affy), NanoString nCounter™ (NanoS),Illumina whole genome RNASeq (RNA-Acc), Illumina targeted RNASeq (t-RNA), and Illuminastranded Total RNA-rRNA- depletion (rRNA). Results: Using Affy_FF as the “gold” standard, initial analysis of the 18-gene RAS scores on all 54samples shows varying pairwise Spearman correlations, with (1) Affy_FFPE (r= 0.233, p = 0.090); (2)NanoS_FFPE (r= 0.608, p &lt; 0.0001); (3) RNA-Acc_FFPE (r= 0.175, p = 0.21); (4) t-RNA_FFPE (r=−0.237, p = 0.085); (5) and t-RNA (r= −0.012, p = 0.93). These results suggest that only NanoString has successful FF to FFPE translation. The subsequentremoval of identified “problematic” samples (n= 15) and genes (n= 2) further improves the correlations of Affy_FF with three of the five technologies: Affy_FFPE (r= 0.672, p &lt; 0.0001); NanoS_FFPE (r= 0.738, p &lt; 0.0001); and RNA-Acc_FFPE (r= 0.483, p = 0.002). Conclusions: Of the five technology platforms tested, Nano String technology provides a more faithful translation of the RAS pathway gene expression signature from FF to FFPE than the Affymetrix GeneChip and multiple RNASeq technologies. Moreover, Nano String was the most forgiving technology in the analysis of samples with presumably poor RNA quality. Using this approach, the RAS signature score may now be reasonably applied to FFPE clinical samples

The Vehicle, Fall 1994

Table of Contents Poetry Noah\u27s WifeJennifer Moropage 8-9 The Intensity of a BreathHeather Anne Winterspage 10-11 When I Was RainNicole Moonpage 11 Wreckage at Low Tide, After a Storm On Cape FearMatt Parkspage 12-14 two belowKeith Spearpage 16 HeatScott Langrenpage 17 Plastic Shard WordsMatthew J. Nelsonpage 18 Mr. Snowplow ManMartin Paul Brittpage 19 Carpe DiemMichael Lairpage 19 untitledWalt Howardpage 20 The GameKellie J. Olsenpage 21 AT PEACEJennifer Surmanpage 22 SawdustSue Songerpage 23 Photography Unbound RealitiesKris Quiriconipage 26 untitled Mark Porter page 27 untitled Mark Porter page 28 untitled Mark Porter page 29 Prose I am Here...RememberingJ. Dylan McNeillpage 32-34 RecognitionSue Songerpage 35-36 SACCADICSteve Beinpage 37-40 The BurnBryan Levekpage 41-45 Biographiespage 46-48https://thekeep.eiu.edu/vehicle/1063/thumbnail.jp

The Vehicle, Fall 1994

Table of Contents Poetry Noah\u27s WifeJennifer Moropage 8-9 The Intensity of a BreathHeather Anne Winterspage 10-11 When I Was RainNicole Moonpage 11 Wreckage at Low Tide, After a Storm On Cape FearMatt Parkspage 12-14 two belowKeith Spearpage 16 HeatScott Langrenpage 17 Plastic Shard WordsMatthew J. Nelsonpage 18 Mr. Snowplow ManMartin Paul Brittpage 19 Carpe DiemMichael Lairpage 19 untitledWalt Howardpage 20 The GameKellie J. Olsenpage 21 AT PEACEJennifer Surmanpage 22 SawdustSue Songerpage 23 Photography Unbound RealitiesKris Quiriconipage 26 untitled Mark Porter page 27 untitled Mark Porter page 28 untitled Mark Porter page 29 Prose I am Here...RememberingJ. Dylan McNeillpage 32-34 RecognitionSue Songerpage 35-36 SACCADICSteve Beinpage 37-40 The BurnBryan Levekpage 41-45 Biographiespage 46-48https://thekeep.eiu.edu/vehicle/1063/thumbnail.jp

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Discriminating between primary school students with high and low self-esteem.

From an initial sample of 747 primary school students, the top 16 percent (n =116) with high self-esteem (HSE) and the bottom 15 percent (n = I1 I) with low selfesteem (LSE) were se/eeted. These two groups were then compared on personal and classroom variables. Significant differences were found for all personal (self-talk, selfconcepts) and classroom (teacher feedback, praise, teacher-student relationship, and classroom environment) variables. Students with HSE scored more highly on all variables. Discriminant Function Analysis (DFA) was then used to determine which variables discriminated between these two groups of students. Learner self-concept, positive and negative self-talk, classroom environment, and effort feedback were the best discriminators of students with high and low self-esteem. Implications for educational psychologists and teachers are discussed