The Camac Street Project : Operation Yellow Brick Road

This report chronicles the author's experiences as he completed his studies at the School of Community Economic Development. (Library-derived description)Caesar, J. A. (1992). The Camac Street Project: Operation Yellow Brick Road. Retrieved from http://academicarchive.snhu.eduMaster of Science (M.S.)School of Community Economic Developmen

The effects of peripheral and central high insulin on brain insulin signaling and amyloid-β in young and old APP/PS1 mice

Hyperinsulinemia is a risk factor for late-onset Alzheimer's disease (AD). In vitro experiments describe potential connections between insulin, insulin signaling, and amyloid-β (Aβ), but in vivo experiments are needed to validate these relationships under physiological conditions. First, we performed hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in young, awake, behaving APP(swe)/PS1(dE9) transgenic mice. Both a postprandial and supraphysiological insulin clamp significantly increased interstitial fluid (ISF) and plasma Aβ compared with controls. We could detect no increase in brain, ISF, or CSF insulin or brain insulin signaling in response to peripheral hyperinsulinemia, despite detecting increased signaling in the muscle. Next, we delivered insulin directly into the hippocampus of young APP/PS1 mice via reverse microdialysis. Brain tissue insulin and insulin signaling was dose-dependently increased, but ISF Aβ was unchanged by central insulin administration. Finally, to determine whether peripheral and central high insulin has differential effects in the presence of significant amyloid pathology, we repeated these experiments in older APP/PS1 mice with significant amyloid plaque burden. Postprandial insulin clamps increased ISF and plasma Aβ, whereas direct delivery of insulin to the hippocampus significantly increased tissue insulin and insulin signaling, with no effect on Aβ in old mice. These results suggest that the brain is still responsive to insulin in the presence of amyloid pathology but increased insulin signaling does not acutely modulate Aβ in vivo before or after the onset of amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma Aβ in young and old mice, independent of neuronal insulin signaling. SIGNIFICANCE STATEMENT The transportation of insulin from blood to brain is a saturable process relevant to understanding the link between hyperinsulinemia and AD. In vitro experiments have found direct connections between high insulin and extracellular Aβ, but these mechanisms presume that peripheral high insulin elevates brain insulin significantly. We found that physiological hyperinsulinemia in awake, behaving mice does not increase CNS insulin to an appreciable level yet modestly increases extracellular Aβ. We also found that the brain of aged APP/PS1 mice was not insulin resistant, contrary to the current state of the literature. These results further elucidate the relationship between insulin, the brain, and AD and its conflicting roles as both a risk factor and potential treatment

Investigations into mechanisms of complement regulation and bacterial evasion of the innate immune response

The complement system is a major mechanism of the innate immune system, providing a first line of defence against infection. Many pathogens have evolved mechanisms of evading the complement response by recruitment of complement components onto their surface. Presented here is characterisation of the interface between a complement regulator, factor H, and a protein from Neisseria meningitidis, factor H binding protein (fHbp), which increases complement evasion by the meningococcus. The affinity of the interaction has been measured and experiments have been performed showing that fHbp mimics the glycosaminoglycans found on the surface of host cells. The atomic resolution structure of a mutant form of fHbp that ablates factor H binding is also presented which is a potential vaccine candidate. Borrelia burgdorferi evades complement by recruitment of factor H mediated by the complement regulator acquiring surface protein (CRASP) family of proteins. Investigations into a member of this family, CspA, has revealed that a dimeric form of the protein binds the complement regulator in a high-affinity interaction that utilises a binding site that has been mapped to domains five to seven of factor H. The atomic resolution structure of another member of the CRASP family, ErpC, has been determined that displays a different architecture to fHbp and CspA, yet experiments show that it is capable of binding factor H domains five through seven with an identical affinity. It is hypothesised that the multiple members of the CRASP family enable complement evasion across the range of reservoir hosts and throughout the different stages of the life-cycle of the zoonotic bacterium. Complement requires tight regulation on order to prevent damage to host cells. The structure of the oligomerisation domains from a complement regulator, C4bp, and a homologue from Gallus gallus, are presented providing the first examples of homoheptameric coiled-coil formation found in nature. Rationalisation of the different C4bp isoforms has also been achieved suggesting that only 7α0β and 7α1β species exist. A new model for incorporation of the beta chain is presented. The function of the complement factor H related (CFHR) family of proteins has never been reliably elucidated. Presented here is the structure of the N-terminus of CFHR-1 and data showing that CFHR-1, CFHR-2 and CFHR-5 form homo and heterodimeric species which behave as competitive antagonists towards factor H. This results in deregulation of complement, increasing the levels of activation and helping to maintain the homeostatic balance of complement regulation on the surface of host-cells. Rationalisation of the links between complement related diseases and polymorphisms within the CFHR family of proteins is also provided

Sweetheart Time

Contains advertisements and/or short musical examples of pieces being sold by publisher.https://digitalcommons.library.umaine.edu/mmb-vp/7153/thumbnail.jp

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment