Cellular & Molecular Mechanisms That Contribute to the Early Development of Skeletal Muscle & Systemic Insulin Resistance

Indiana University-Purdue University Indianapolis (IUPUI)Insulin resistance starts years before type 2 diabetes (T2D) diagnosis, even before recognition of prediabetes. Mice on a high fat diet have a similar early onset of insulin resistance, yet the mechanism remains unknown. Several studies have demonstrated that skeletal muscle insulin resistance resulting from obesity or high fat feeding does not stem from defects in proximal insulin signaling. Our lab discovered that excess plasma membrane cholesterol impairs insulin action. Excess cholesterol in the plasma membrane causes a loss of cortical actin filaments that are essential for glucose transporter GLUT4 regulation by insulin. Our cell studies further revealed that increased hexosamine biosynthesis pathway (HBP) activity increases O-linked N-acetylglucosamine modification of the transcription factor Sp1, leading to transcription of HMG-CoA reductase (HMGR), the rate-limiting enzyme in cholesterol biosynthesis. Our central hypothesis is that cholesterol accumulation mediated by HBP activity is an early reversible mechanism of high-fat diet-induced insulin resistance. We performed a series of studies and found that early high-fat feeding-induced insulin resistance is associated with a buildup of cholesterol in skeletal muscle membranes (SMM). Akin to the antidiabetic effect of caloric restriction, we found that high-fat diet removal fully mitigated SMM cholesterol accumulation and insulin resistance. Furthermore, using the cholesterol-binding agent methyl-β-cyclodextrin (MβCD), studies established causality between excess SMM cholesterol and insulin resistance. To begin to assess the role of the HBP/Sp1 in contributing to de novo cholesterol biosynthesis, SMM accumulation, and insulin resistance we treated high-fat fed mice with an Sp1 inhibitor, mithramycin. We found that mithramycin prevented SMM cholesterol accumulation and insulin resistance. This series of studies provide evidence that HBP/Sp1-mediated cholesterol accumulation in SMM is a causal, early and reversible mechanism of whole body insulin resistance

The Harlem Renaissance\u27s Hidden Figure

This project will seek to look at the Harlem Renaissance’s hidden figure, Jessie Fauset. Jessie Fauset was born to an A.M.E. minister and his wife as one of ten children in Camden County New Jersey and raised in Philadelphia. From there she got her college degree and began teaching all over the country. She has written four novels, There is Confusion, Plum Bun, The Chinaberry Tree, and Comedy: American Style, all of which I have read this summer. Each novel focuses on the early twentieth century black family. I will be analyzing these novels under the four themes of passing, acceptance, romance, and Paris/escape. I will also be mapping the characters in the novel on a QGIS system in order to indicate where the majority of the novel takes place and to see if certain characters have more movement than others. I will finally map Jessie Fauset’s life in order to see if her life parallels with the lives of her characters. Mapping consists of a close reading of the novel, identifying locations in the book, creating an excel spreadsheet, and plotting the spreadsheet onto an online map on QGIS

δ13C of aromatic compounds in sediments, oils and atmospheric emissions: A review

This review discusses major applications of stable carbon isotopic measurements of aromatic compounds, along with some specific technical aspects including purification of aromatic fractions for baseline separation. d13C measurements of organic matter (OM) in sediments and oils are routine in all fields of organic geochemistry, but they are predominantly done on saturated compounds. Aromatic compounds are important contributors to sedimentary organic matter, and provide indication of diagenetic processes, OM source, and thermal maturity. Studies have found evidence for a small13C-enrichment during diagenetic aromatisation of approximately 1–2‰, but the formation of polycyclic aromatic hydrocarbons (PAHs) from combustion and hydrothermal processes seems to produce no effect. Likewise, maturation and biodegradation also produce only small isotopic effects. An early application of d13C of aromatic compounds was in the classification of oil families by source. Bulk measurements have had some success in differentiating marine and terrigenous oils, but were not accurate in all settings. Compound-specific analyses measure certain aromatics with strong links to source, therefore allowing more accurate source identification. d13C measurements of individual aromatic compounds also allow identification of higher plant input in ancient sediments, even after severe diagenetic alteration or combustion to PAHs. Perylene, a PAH with a historically contentious origin, was assigned a source from wood-degrading fungi on the basis of its isotopic composition. Stable carbon isotopic measurements are also important in the analysis of organic matter from Chlorobiaceae, which is an important indicator of photic zone euxinic conditions in ancient sediments. A large range of aromatic products are formed from the carotenoid pigments of Chlorobiaceae, with an enriched carbon isotopic composition characteristic of the reverse tricarboxylic acid photosynthetic pathway employed by this family of organisms. In future, site-specific isotope analysis using techniques such as nuclear magnetic resonance spectrometry and high-resolution isotope ratio mass spectrometry may reveal more information about isotopic effects associated with aromatisation processes and maturation

Search Interfaces for Mathematicians

Access to mathematical knowledge has changed dramatically in recent years, therefore changing mathematical search practices. Our aim with this study is to scrutinize professional mathematicians' search behavior. With this understanding we want to be able to reason why mathematicians use which tool for what search problem in what phase of the search process. To gain these insights we conducted 24 repertory grid interviews with mathematically inclined people (ranging from senior professional mathematicians to non-mathematicians). From the interview data we elicited patterns for the user group "mathematicians" that can be applied when understanding design issues or creating new designs for mathematical search interfaces.Comment: conference article "CICM'14: International Conference on Computer Mathematics 2014", DML-Track: Digital Math Libraries 17 page

Synthesis and Studies of Cyclopentadienyl Molybdenum Complexes

The synthesis and electrochemical responses of [CpMo(CO)3]2, CpMo(CO)3I, CpMo(CO)3(OTf), and [CpMo(bpy)(CO)2] (Cp = cyclopentadienyl, bpy = 2,2’-bipyridine, OTf = trifluoromethansulfonate) in organic solvent are reported. Transition metal compounds such as Re(bpy)(CO)3Cl have been shown to be effective carbon dioxide reduction catalysts. The molybdenum metal complexes studied herein were examined under argon and carbon dioxide gas for the potential reduction of carbon dioxide. Proton Nuclear Magnetic Resonance (NMR) spectroscopy, infrared (IR) spectroscopy and an electrochemical method know as cyclic voltammetry were used to gather data on the complexes. Electrochemical response peaks under carbon dioxide were analyzed for the relative efficiency and potentials of the molybdenum catalysts. The addition of the bpy ligand to the molybdenum resulted in an unstable compound in solution. The molybdenum compounds studied were not found to be competent catalysts for the reduction of carbon dioxide

Novel Cascaded Ultra Bright Pulsed Source of Polarization Entangled Photons

A new ultra bright pulsed source of polarization entangled photons has been realized using type-II phase matching in spontaneous parametric down conversion process in two cascaded crystals. The optical axes of the crystals are aligned in such a way that the extraordinarily (ordinarily) polarized cone from one crystal overlaps with the ordinarily (extraordinarily) polarized cone from the second crystal. This spatial overlapping removes the association between the polarization and the output angle of the photons that exist in a single type-II down conversion process. Hence, entanglement of photons originating from any point on the output cones is possible if a suitable optical delay line is used. This delay line is particularly simple and easy to implement.Comment: 8 pages 8 figure

The recognition of ubiquitinated proteins by the proteasome.

The ability of ubiquitin to form up to eight different polyubiquitin chain linkages generates complexity within the ubiquitin proteasome system, and accounts for the diverse roles of ubiquitination within the cell. Understanding how each type of ubiquitin linkage is correctly interpreted by ubiquitin binding proteins provides important insights into the link between chain recognition and cellular fate. A major function of ubiquitination is to signal degradation of intracellular proteins by the 26S proteasome. Lysine-48 (K48) linked polyubiquitin chains are well established as the canonical signal for proteasomal degradation, but recent studies show a role for other ubiquitin linked chains in facilitating degradation by the 26S proteasome. Here, we review how different types of polyubiquitin linkage bind to ubiquitin receptors on the 26S proteasome, how they signal degradation and discuss the implications of ubiquitin chain linkage in regulating protein breakdown by the proteasome.JAN is supported by a Wellcome Trust Senior Clinical Research Fellowship (102770/Z/13/Z). The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (100140).This is the final published version. It first appeared from Springer via https://doi.org/10.1007/s00018-016-2255-

New aspects of cellular cholesterol regulation on blood glucose control- review and perspective on the impact of statin medications on metabolic health

Cholesterol is an essential component of cell membranes, and during the past several years, diabetes researchers have found that membrane cholesterol levels in adipocytes, skeletal muscle fibers and pancreatic beta cells influence insulin action and insulin secretion. Consequently, it is thought that dysregulated cell cholesterol homeostasis could represent a determinant of type 2 diabetes (T2D). Recent clinical findings compellingly add to this notion by finding increased T2D susceptibility in individuals with alterations in a variety of cholesterol metabolism genes. While it remains imperfectly understood how statins influence glucose metabolism, the fact that they display an influence on blood glucose levels and diabetes susceptibility seems to intensify the emerging importance of understanding cellular cholesterol in glucose metabolism. Taking this into account, this review first presents cell system and animal model findings that demonstrate the negative impact of cellular cholesterol accumulation or diminution on insulin action and insulin secretion. With this framework, a description of how changes in cholesterol metabolism genes are associated with T2D susceptibility will be presented. In addition, the connection between statins and T2D risk will be reviewed with expanded information on pitavastatin, a newer statin medication that displays actions favoring metabolic healt