119— The Role of Post-Encoding Retrieval on Cognitive and Neural Representations of Spatial Environments

Spatial memory is an important ability for navigating around one’s surrounding environment. However, due to the challenges of developing experimental paradigms that utilize large scale, real-world environments, little research has analyzed, in detail, the development of cognitive maps over time. Past research in rodents has shown that hippocampal place-cells replay during periods of quiet wakefulness, suggesting that mental replay of recent spatial experiences is tied to the development of cognitive maps. In humans, we hypothesize that the development of cognitive maps could therefore be manipulated by having participants selectively recall recent navigational experiences. We analyzed the development of cognitive maps for novel, real-world spatial environments in two groups, a spatial sequencing group (SSG) and rote-retrieval group (RRG), over a period of 2 weeks using Google Street View software. After navigating through the environment, participants’ spatial memories were tested with either rote retrieval or spatial sequencing recognition tests. Our preliminary results suggest the RRG was more successful navigating previously learned routes than the SSG with more practice on the trained routes, whereas the SSG may have developed some ability to discover shortcuts by being encouraged to think more broadly about the routes they were learning, and not rely on memorization

Non-coding RNAs underlie genetic predisposition to breast cancer

Funder: National Breast Cancer Foundation; doi: http://dx.doi.org/10.13039/501100001026Abstract: Background: Genetic variants identified through genome-wide association studies (GWAS) are predominantly non-coding and typically attributed to altered regulatory elements such as enhancers and promoters. However, the contribution of non-coding RNAs to complex traits is not clear. Results: Using targeted RNA sequencing, we systematically annotated multi-exonic non-coding RNA (mencRNA) genes transcribed from 1.5-Mb intervals surrounding 139 breast cancer GWAS signals and assessed their contribution to breast cancer risk. We identify more than 4000 mencRNA genes and show their expression distinguishes normal breast tissue from tumors and different breast cancer subtypes. Importantly, breast cancer risk variants, identified through genetic fine-mapping, are significantly enriched in mencRNA exons, but not the promoters or introns. eQTL analyses identify mencRNAs whose expression is associated with risk variants. Furthermore, chromatin interaction data identify hundreds of mencRNA promoters that loop to regions that contain breast cancer risk variants. Conclusions: We have compiled the largest catalog of breast cancer-associated mencRNAs to date and provide evidence that modulation of mencRNAs by GWAS variants may provide an alternative mechanism underlying complex traits

Epigenome erosion and SOX10 drive neural crest phenotypic mimicry in triple-negative breast cancer

Intratumoral heterogeneity is caused by genomic instability and phenotypic plasticity, but how these features co-evolve remains unclear. SOX10 is a neural crest stem cell (NCSC) specifier and candidate mediator of phenotypic plasticity in cancer. We investigated its relevance in breast cancer by immunophenotyping 21 normal breast and 1860 tumour samples. Nuclear SOX10 was detected in normal mammary luminal progenitor cells, the histogenic origin of most TNBCs. In tumours, nuclear SOX10 was almost exclusive to TNBC, and predicted poorer outcome amongst cross-sectional (p = 0.0015, hazard ratio 2.02, n = 224) and metaplastic (p = 0.04, n = 66) cases. To understand SOX10’s influence over the transcriptome during the transition from normal to malignant states, we performed a systems-level analysis of co-expression data, de-noising the networks with an eigen-decomposition method. This identified a core module in SOX10’s normal mammary epithelial network that becomes rewired to NCSC genes in TNBC. Crucially, this reprogramming was proportional to genome-wide promoter methylation loss, particularly at lineage-specifying CpG-island shores. We propose that the progressive, genome-wide methylation loss in TNBC simulates more primitive epigenome architecture, making cells vulnerable to SOX10-driven reprogramming. This study demonstrates potential utility for SOX10 as a prognostic biomarker in TNBC and provides new insights about developmental phenotypic mimicry—a major contributor to intratumoral heterogeneity

An Informational Theory of Midterm Elections: The Impact of Iraq War Deaths on the

Reves, and several more I am sure I am forgetting for their constant reality checks when I started to lose sight of my goals. If I have left anyone out who feels they were slighted, I offer my humblest apologies for the omission. Finally I must thank the many different locations throughout Denton where this paper was written, including the UNT library, Banter and Jupiter House coffee shops, the bench in front of the public admin department in Wooten Hall, now sadly gone, all provided the workspace I needed to complete this paper, and I must give them my thanks. iii 1962 1966 1970 1974 1978 1982 1986 1990 1994 1998 for the highest offices on the ballot. In doing so I hope to illustrate the scholastic background I will be drawing upon for this paper. I also include some research on vote

Mixed ductal-lobular carcinomas: evidence for progression from ductal to lobular morphology

Mixed ductal-lobular carcinomas (MDL) display both ductal and lobular morphology, and are an archetypal example of intra-tumour morphological heterogeneity. The mechanisms underlying coexistence of these different morphologic entities are poorly understood, although theories include that these components either represent 'collision' of independent tumours or evolve from a common ancestor. We performed comprehensive clinico-pathological analysis of a cohort of 82 MDLs and found: i) MDLs more frequently co-exist with ductal carcinoma in situ (DCIS) than lobular carcinoma in situ (LCIS); ii) the E-cadherin-catenin complex was normal in the ductal component in 77.6% of tumours; iii) in the lobular component, E-cadherin was almost always aberrantly located to the cytoplasm in contrast to Invasive Lobular Carcinoma (ILC), where E-cadherin is typically absent. Comparative Genomic Hybridisation (CGH) and multi-region whole exome sequencing (WES) of four representative cases revealed that all morphologically distinct components within an individual case were clonally related. Mutations identified varied between cases; those associated with common clonal ancestry included BRCA2, TBX3, TP53, while those associated with clonal divergence included CDH1, ESR1. Together, these data support a model in which separate morphological components of MDLs arise from a common ancestor, and that lobular morphology can arise via a 'ductal' pathway of tumour progression. In MDLs that present with LCIS and DCIS, the clonal divergence likely occurs early, and is frequently associated with complete loss of E-cadherin expression, as in ILC. While in the majority of MDLs, which present with DCIS but not LCIS, direct clonal divergence from ductal to the lobular phenotype occurs late in tumour evolution and is associated with aberrant expression of E-cadherin. The mechanisms driving the phenotypic change may involve E-cadherin-catenin complex deregulation, but are yet to be fully elucidated, as there is significant inter-tumour heterogeneity and each case may employ unique molecular mechanisms

Association analysis identifies 65 new breast cancer risk loci.

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention

Association analysis identifies 65 new breast cancer risk loci.

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention