Characterization of Bone Material Properties and Microstructure in Osteogenesis Imperfecta/Brittle Bone Disease

Osteogenesis imperfecta (OI) is a genetic disorder primarily associated with mutations to type I collagen and resulting in mild to severe bone fragility. To date, there is very little data quantifying OI cortical bone mechanics. The purpose of this dissertation was to investigate bone microstructure, mineralization, and mechanical properties in adolescents with OI. Characterization studies were performed on small osteotomy specimens obtained from the extremities during routine corrective surgeries. Nanoindentation was used to examine the longitudinal elastic modulus and hardness at the material level for mild OI type I vs. severe OI type III. Both modulus and hardness were significantly higher (by 7% and 8%, respectively) in mild OI cortical bone compared to the more severe phenotype. Lamellar microstructure also affected these properties, as the younger bone material immediately surrounding osteons showed decreased modulus (13%) and hardness (11%) compared to the older interstitial material. A high resolution micro-computed tomography system utilizing synchrotron radiation (SRµCT) was described and used to analyze the microscale vascular porosity, osteocyte lacunar morphometry, and bone mineral density in OI vs. healthy individuals. Vascular porosity, canal diameter, and osteocyte lacunar density were all two to six times higher in OI cortical bone. Osteocytes were also more spherical in shape. Finally, three-point bending techniques were used to evaluate the microscale mechanical properties of OI cortical bone in two different orientations. Elastic modulus, flexural yield strength, ultimate strength, and crack-growth toughness were three to six times higher in specimens whose pore structure was primarily oriented parallel vs. perpendicular to the long bone axis. There was also a strong negative correlation between the elevated vascular porosity of OI cortical bone and its elastic modulus, flexural yield strength, and ultimate strength. This relationship was independent of osteocyte lacunar density and tissue mineral density. In summary, these findings highlight new material and microstructural changes within OI cortical bone that help contribute to its fragility. They also underscore a deep connection between bone structure and mechanical integrity at multiple length scales

Micro-CT Characterization of Human Trabecular Bone in Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a genetic syndrome affecting collagen synthesis and assembly. Its symptoms vary widely but commonly include bone fragility, reduced stature, and bone deformity. Because of the small size and paucity of human specimens, there is a lack of biomechanical data for OI bone. Most literature has focused on histomorphometric analyses, which rely on assumptions to extrapolate 3-D properties. In this study, a micro-computed tomography (μCT) system was used to directly measure structural and mineral properties in pediatric OI bone collected during routine surgical procedures. Surface renderings suggested a poorly organized, plate-like orientation. Patients with a history of bone-augmenting drugs exhibited increased bone volume fraction (BV/TV), trabecular number (Tb.N), and connectivity density (Eu.Conn.D). The latter two parameters appeared to be related to OI severity. Structural results were consistently higher than those reported in a previous histomorphometric study, but these differences can be attributed to factors such as specimen collection site, drug therapy, and assumptions associated with histomorphometry. Mineral testing revealed strong correlations with several structural parameters, highlighting the importance of a dual approach in trabecular bone testing. This study reports some of the first quantitative μCT data of human OI bone, and it suggests compelling possibilities for the future of OI bone assessment

Neptunism and transformism:Robert Jameson and other evolutionary theorists in early nineteenth-century Scotland

This paper sheds new light on the prevalence of evolutionary ideas in Scotland in the early nineteenth century and establish what connections existed between the espousal of evolutionary theories and adherence to the directional history of the earth proposed by Abraham Gottlob Werner and his Scottish disciples. A possible connection between Wernerian geology and theories of the transmutation of species in Edinburgh in the period when Charles Darwin was a medical student in the city was suggested in an important 1991 paper by James Secord. This study aims to deepen our knowledge of this important episode in the history of evolutionary ideas and explore the relationship between these geological and evolutionary discourses. To do this it focuses on the circle of natural historians around Robert Jameson, Wernerian geologist and professor of natural history at the University of Edinburgh from 1804 to 1854. From the evidence gathered here there emerges a clear confirmation that the Wernerian model of geohistory facilitated the acceptance of evolutionary explanations of the history of life in early nineteenth-century Scotland. As Edinburgh was at this time the most important center of medical education in the English-speaking world, this almost certainly influenced the reception and development of evolutionary ideas in the decades that followed.</p

Folding and Hydrodynamics of a DNA i-Motif from the c-MYC Promoter Determined by Fluorescent Cytidine Analogs

AbstractThe four-stranded i-motif (iM) conformation of cytosine-rich DNA has importance to a wide variety of biochemical systems that range from their use in nanomaterials to potential roles in oncogene regulation. The iM structure is formed at slightly acidic pH, where hemiprotonation of cytosine results in a stable C-C+ basepair. Here, we performed fundamental studies to examine iM formation from a C-rich strand from the promoter of the human c-MYC gene. We used a number of biophysical techniques to characterize both the hydrodynamic properties and folding kinetics of a folded iM. Our hydrodynamic studies using fluorescence anisotropy decay and analytical ultracentrifugation show that the iM structure has a compact size in solution and displays the rigidity of a double strand. By studying the rates of circular dichroism spectral changes and quenching of fluorescent cytidine analogs, we also established a mechanism for the folding of a random coil oligo into the iM. In the course of determining this folding pathway, we established that the fluorescent dC analogs tC° and PdC can be used to monitor individual residues of an iM structure and to determine the pKa of an iM. We established that the C-C+ hydrogen bonding of certain bases initiates the folding of the iM structure. We also showed that substitutions in the loop regions of iMs give a distinctly different kinetic signature during folding compared with bases that are intercalated. Our data reveal that the iM passes through a distinct intermediate form between the unfolded and folded forms. Taken together, our results lay the foundation for using fluorescent dC analogs to follow structural changes during iM formation. Our technique may also be useful for examining folding and structural changes in more complex iMs

Observation of Parametric Instability in Advanced LIGO

Parametric instabilities have long been studied as a potentially limiting effect in high-power interferometric gravitational wave detectors. Until now, however, these instabilities have never been observed in a kilometer-scale interferometer. In this work we describe the first observation of parametric instability in an Advanced LIGO detector, and the means by which it has been removed as a barrier to progress

Near and Mid-IR Photometry of the Pleiades, and a New List of Substellar Candidate Members

We make use of new near and mid-IR photometry of the Pleiades cluster in order to help identify proposed cluster members. We also use the new photometry with previously published photometry to define the single-star main sequence locus at the age of the Pleiades in a variety of color-magnitude planes. The new near and mid-IR photometry extend effectively two magnitudes deeper than the 2MASS All-Sky Point Source catalog, and hence allow us to select a new set of candidate very low mass and sub-stellar mass members of the Pleiades in the central square degree of the cluster. We identify 42 new candidate members fainter than Ks =14 (corresponding to 0.1 Mo). These candidate members should eventually allow a better estimate of the cluster mass function to be made down to of order 0.04 solar masses. We also use new IRAC data, in particular the images obtained at 8 um, in order to comment briefly on interstellar dust in and near the Pleiades. We confirm, as expected, that -- with one exception -- a sample of low mass stars recently identified as having 24 um excesses due to debris disks do not have significant excesses at IRAC wavelengths. However, evidence is also presented that several of the Pleiades high mass stars are found to be impacting with local condensations of the molecular cloud that is passing through the Pleiades at the current epoch.Comment: Accepted to ApJS; data tables and embedded-figure version available at http://spider.ipac.caltech.edu/staff/stauffer/pleiades07

Modernism, class and colonialism in Robert Noonan’s The Ragged Trousered Philanthropists

This essay explores Robert Noonan’s 1914 novel, The Ragged Trousered Philanthropists, as a work of Irish modernist fiction. Reading its fragmented narrative as a reflection of the author’s subaltern position as an Irish republican and socialist, it interprets Noonan’s work as the product of the anticolonial and class struggles in which he was involved. Its critique of capitalist and imperial hegemony and the assertions that suffering, injustice and violence are normal, natural or inevitable phenomena reflects the author’s frustration, anger and desperation. In this way the novel counters and decentres the bourgeois-imperial dynamic that was reflected in the textual stability of Victorian realism. The Ragged Trousered Philanthropists is an uneasy text that is at once ruptured and uncertain of its own aesthetic status and conveys, through its shifting, episodic plot, the precariousness of a working-class existence permanently poised “on the brink of destitution.” © 2018 Informa UK Limited, trading as Taylor & Francis Grou

Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis