ALBERT

Description: Background: Social plasticity is a pervasive feature of animal behavior. Animals adjust the expression of their social behavior to the daily changes in social life and to transitions between life-history stages, and this ability has an impact in their Darwinian fitness. This behavioral plasticity may be achieved either by rewiring or by biochemically switching nodes of the neural network underlying social behavior in response to perceived social information. Independent of the proximate mechanisms, at the neuromolecular level social plasticity relies on the regulation of gene expression, such that different neurogenomic states emerge in response to different social stimuli and the switches between states are orchestrated by signaling pathways that interface the social environment and the genotype. Here, we test this hypothesis by characterizing the changes in the brain profile of gene expression in response to social odors in the Mozambique Tilapia, Oreochromis mossambicus. This species has a rich repertoire of social behaviors during which both visual and chemical information are conveyed to conspecifics. Specifically, dominant males increase their urination frequency during agonist encounters and during courtship to convey chemical information reflecting their dominance status. Results: We recorded electro-olfactograms to test the extent to which the olfactory epithelium can discriminate between olfactory information from dominant and subordinate males as well as from pre- and post-spawning females. We then performed a genome-scale gene expression analysis of the olfactory bulb and the olfactory cortex homolog in order to identify the neuromolecular systems involved in processing these social stimuli. Conclusions: Our results show that different olfactory stimuli from conspecifics’ have a major impact in the brain transcriptome, with different chemical social cues eliciting specific patterns of gene expression in the brain. These results confirm the role of rapid changes in gene expression in the brain as a genomic mechanism underlying behavioral plasticity and reinforce the idea of an extensive transcriptional plasticity of cichlid genomes, especially in response to rapid changes in their social environment.

Description: Journal of Medicinal Chemistry DOI: 10.1021/jm301096s

Description: Objective: A comprehensive website review was conducted to assess the quality, content and readability of online information for teens with sickle cell anemia (SCA). Methods. Key words relevant to SCA were searched across the five most commonly used search engine domains. Websites that contained information about the diagnosis and management of SCA were reviewed. Quality of the information was appraised using the validated DISCERN tool. Two physicians rated website content completeness and accuracy independently. Readability of the sites was documented using SMOG scores and the Flesch Reading ease scoring system. Results. Search results yielded more than 600 sites of which 25 websites met the criteria for DISCERN quality review. The majority of sites targeted parents and only 5/25 (20%) were specific to teens with SCA. The overall quality of the website information was "fair", with the average DISCERN quality rating score being 50.1 (± 9.3, range 31.0-67.5). Only 12/25(48%)of the websites had DISCERN scores above 50 (mean 57.37 + 4.93, range 52.17-67.50). The average completeness score of the sites was 20 out of 29 (±5; range 12-27) and accuracy was consistently rated 4/4, indicating high accuracy with moderate completeness. The average SMOG score was 12.44 (±2.01; range 10.21-16.08), and the mean Flesch Reading Ease score was 46.45 (±13.22; range 17.50-66.10) indicating that the material was written well above the acceptable level for patient education materials. Conclusion. Given the paucity of high quality Internet health information at an appropriate reading level for teens with SCA, there is a critical need for the development of Internet programs to meet their unique self-management needs. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) encompasses a heterogeneous and poorly understood group of neoplasms with poor responses to therapy and grave clinical outcomes in both canine and human patients. Because PTCL-NOS is relatively uncommon in human patients, an appropriate model is needed to facilitate elucidation of the underlying pathobiology and identification of novel therapeutic targets. A canine model of PTCL has the added potential to provide a large animal veterinary population for pre-clinical therapeutic trials and subsequent translation into human patients. Marked breed-specific predilection for this disease suggests that genetic risk factors may also be explored using the dog model. PTCL is the second most common type of lymphoma diagnosed in dogs. Similar to human patients, dogs with PTCL are usually middle-aged to older animals and typically present with peripheral lymph node involvement but systemic disease is not uncommon. Canine PTCLs are most commonly CD4-positive, often lose expression of CD5, and exhibit a histomorphology similar to that described in humans. The Boxer breed is significantly over-represented in the population of dogs that develop PTCL. Objective: In this study, we aimed to characterize the gene expression profile of canine PTCL and evaluate the molecular similarity to PTCL-NOS in human patients. Methods: RNA-sequencing was performed on lymph node aspirates from six dogs (3 Boxers and 3 non-Boxers) diagnosed with CD4+ PTCL and sorted CD4+ T-cells from control dogs. Gene expression was compared between neoplastic and non-neoplastic T cells. Gene set enrichment analysis was used to compare the gene expression profile of canine PTCL to a gene list created from a similarly designed, publically available, microarray study of human PTCL-NOS. The gene list was comprised of the top upregulated and downregulated genes in 28 cases of human PTCL-NOS when compared to sorted human control CD4+ T-cells. Results: Canine PTCL was significantly enriched for the gene set representative of human PTCL-NOS. Furthermore, similar to humans, canine PTCL upregulated pathways were involved in proliferation, cell adhesion, extracellular matrix modification, and signal transduction. Canine cases overexpressed GATA3 and CCR4; two markers which characterize a distinct subset of human PTCL-NOS associated with worse clinical outcomes. Canine cases also exhibit significant enrichment for the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) induced gene signatures, consistent with the GATA3 subgroup. Overexpression of platelet derived growth factors (PDGFRs) was conserved across both human and canine cases and has been suggested as a potential therapeutic target. GATA3 and PDGFR-alpha expression in canine cases was corroborated by immunohistochemistry. Boxers and non-Boxers exhibited markedly similar patterns of gene expression, with the exception that lymphomas from all three Boxers significantly upregulated ROS1 compared to non-Boxers. Conclusions: From this work we conclude that canine CD4+ PTCL is molecularly similar to an aggressive subset of human PTCL-NOS and may serve as a useful model to further investigate the molecular drivers of this aggressive and poorly understood disease. Disclosures No relevant conflicts of interest to declare.

Description: Key Points Glucose metabolism enhances hematopoietic stem cell formation and function in the vertebrate embryo Glucose metabolism modulates hif1α activity via mitochondrial generation of reactive oxygen species to impact HSC-relevant gene expression

Description: Abstract 1266 During development, the embryo is exposed to rapidly changing metabolic conditions and demands. The impact of elevated glucose levels on the developing hematopoietic system is not well characterized. Intriguingly, children born to mothers with gestational diabetes as well as those diagnosed with diabetes themselves have a higher risk of developing childhood leukemia, suggesting increased blood sugar concentrations may have lasting impact on hematopoiesis. To evaluate the consequences of elevated glucose levels on hematopoietic stem cell (HSC) development, zebrafish embryos were exposed to glucose and modifiers of glucose metabolism during embryonic blood cell specification from 12 to 36 hours post fertilization (hpf). HSCs in the Aorta-Gonad-Mesonephros (AGM) region were analyzed by in situ hybridization for the conserved markers runx1 and cmyb (n≥25–50 embryos/condition). D-glucose expanded HSCs in a dose-responsive manner, while the metabolically inactive enantiomer L-glucose did not affect HSCs. Quantitation by qPCR and FACS analysis of fluorescent HSC reporter embryos runx1:eGFP, cmyb:eGFP and CD41:GFP revealed a ∼3-fold increase in HSCs. Enhanced cellular proliferation (BrdU) was detected in the AGM in response to increased glucose levels. The effects of glucose on HSCs were sustained without any block in differentiation potential in larvae, and in adults after marrow injury. AGM time course analysis and ultrastructural assessment by electron microscopy (EM) revealed accelerated runx1 expression and hematopoietic cluster formation. EM and in situ hybridization for scl, gata1, and globin also demonstrated enhanced red cell numbers in response to elevated glucose levels. Genetic and chemical modulations of the metabolic hormone insulin did not alter the effects of glucose on HSC number. Activity of the glucose transporter glut1 was required to observe enhanced HSC induction, and glucose exposure increased glucose, ATP and lactate concentrations in the embryo. Additionally, incubation with inhibitors of glycolysis (lonidamine, ethyl-3-bromopyruvate) and oxidative phosphorylation (cyanide, oxaloacetate) reversed the beneficial effects of glucose, demonstrating that glucose affects HSCs specifically through energy metabolism. Enhanced oxidative phosphorylation produces excess reactive oxygen species (ROS), which can directly serve as hematopoietic signaling factors; treatment with the antioxidants N-acetylcysteine and MitoQ decreased HSC formation and blocked the effect of concomitant glucose exposure, while H2O2 expanded HSCs. Similarly, genetic enhancement of ROS levels by knockdown of peroxiredoxin 1 increased HSCs. ROS were visualized in vivo in erythrocytes and CD41+ cells using the fluorescent sensor peroxyfluorescein 2; increased glucose levels significantly enhanced ROS in the AGM as determined by FACS analysis of the lmo2:dsRed hematopoietic precursor and vascular reporter. ROS directly affects the stability of the cellular hypoxia sensor, hypoxia inducible factor 1α (hif1α), which can regulate expression of hematopoietic genes, such as vegf and epo. Stabilization of hif1α by cobalt chloride or morpholino knockdown of vhl enhanced HSCs and rescued the block in HSC induction following inhibition of energy metabolism or ROS production. Furthermore, by microarray and qPCR gene expression analysis, glucose exposure greatly impacted hematopoietic related transcripts, in addition to eliciting significant changes in the hif1α gene network: glucose increased expression of epo and epor during the primitive wave of hematopoiesis, confirming the effects on erythrocytes seen in vivo. In addition to vegf, nos and igf were induced during the definitive wave of hematopoiesis in a dose- and time-dependent fashion, providing signals to support HSC induction and expansion. These data indicate that fluctuations in glucose levels, and subsequent metabolic activity initially occurring in the dorsal aorta, are sensed by hif1α, which then functions to genetically enhance hematopoietic supply in advance of the anticipated demands of the growing organism during development. Our work provides direct evidence that the developing embryo responds dynamically to metabolic challenges by accelerating and expanding blood formation and demonstrates a connection between glucose metabolism and hif1α signaling in regulating HSC induction. Disclosures: Vander Heiden: Agios Pharmaceuticals: Consultancy, Equity Ownership. Goessling:Fate Therapeutics: Consultancy. North:Fate Therapeutics: Consultancy.

Description: Behaviour problems are amongst the most common reasons given for relinquishing dogs to rehoming centres. Some behaviour problems may be amenable to being tackled pre-emptively with classes educating owners on basic dog training and understanding behaviour; however, it is recognised that people with low socio-economic status (SES) may face barriers to attending classes such as affordability, variable working hours, and limited access to transport and childcare. The current study piloted free-to-use dog training and owner education classes in areas with high levels of economic deprivation, both in the traditional face-to-face format and online. It was hypothesised that providing an online dog training course may help people overcome practical barriers by allowing them to complete training modules in their own time. High dropout rates were observed in both formats (online: 100%, face-to-face: 43% dropout). A course of paid dog training classes running in the same area saw a comparatively low dropout rate (24%). Participants who completed the face-to-face classes had significantly higher household incomes and were less likely to receive means-tested benefits than participants who dropped out (household income p = 0.049; benefits status p = 0.017). This evidence suggests that people with low SES may face non-course fee-related barriers to attending dog training classes. Future research should include a qualitative investigation of people’s reasons for not continuing with dog training courses. Study findings can support the development of training and behaviour advice delivery that is accessible to people with varied socio-economic backgrounds.