Short-Term Exercise In Mice Increases Tibial Post-Yield Mechanical Properties While Two Weeks of Latency Following Exercise Increases Tissue-Level Strength

We have previously shown that exercise during growth increases post-yield deformation in C57BL6/129 (B6;129) male tibiae at the expense of reduced pre-yield deformation and structural and tissue strength. Other research in the literature indicates that increased mineral content, cross-sectional geometry and structural strength due to exercise can be maintained or increased after exercise ends for as long as 14 weeks. It was therefore hypothesized that after our exercise protocol ended, effects of exercise on mechanical properties would persist, resulting in increased post-yield behavior and rescued strength versus age-matched control mice. Beginning at 8 weeks of age, exercise consisted of running on a treadmill (30 min/day, 12 m/min, 5° incline) for 21 consecutive days. At the end of running and 2 weeks later, in the cortical bone of the tibial mid-diaphyses of B6;129 male mice, changes due to exercise and latency following exercise were assayed by mechanical tests and analyses of cross-sectional geometry. Exercise increased structural post-yield deformation compared with weight-matched control mice, without changes in bone size or shape, suggesting that exercised-induced changes in pre-existing bone quality were responsible. Over the 2-week latency period, no growth-related changes were noted in control mice, but exercise-induced changes resulted in increased tissue stiffness and strength versus mice sacrificed immediately after exercise ended. Our data indicate that periods of exercise followed by latency can alter strength, stiffness, and ductility of bone independent of changes in size or shape, suggesting that exercise may be a practical way to increase the quality of the bone extracellular matrix

Investigating the Inbred Strain-Specific Response to Biglycan-Deficiency and Exercise: A Study in Genetically-Mediated Skeletal Adaptation.

Bone is an exquisitely evolved connective tissue that serves structural and metabolic roles in the body. Bone fragility leading to fracture is a significant medical and economic burden facing our society. Each year, 1.5 million Americans suffer an age-related fracture, resulting in direct-care expenditures of 18 billion dollars a year and often leading to decreased quality of life or even death. Animals with targeted mutations in a bone matrix protein (KO) are utilized to study the protein’s roles in regulating extracellular matrix (ECM) deposition and architecture and understanding how these functions relate to bone disease and fracture etiology. The importance of skeletal loading for the maintenance/increase of bone mass was suggested as early as 1892. In addition to increased size, mechanical loading influences bone ECM quality. Since many diseases influence the mechanical integrity of bone through altered tissue quality, mechanical stimulation may be a practical way to prevent/treat ECM deficiencies. Mouse inbred strain-specific responses in bone have been demonstrated following mechanical stimulation and bone regeneration. No study has demonstrated that the response to a genetic deletion can exhibit inbred-strain-specific characteristics, or that phenotypic changes can be modulated with mechanical stimulation. It was hypothesized that the response to a genetic deletion (the bone matrix protein biglycan, bgn), mechanical stimulation (running) and a combination of these two variables would display inbred-strain-specific characteristics in the tibiae of C57BL6/129 (B6;129) and C3H/He (C3H) male mice. This dissertation establishes for the first time that an inbred strain-specific response to genetic deletion exists, further develops the roles that biglycan plays in regulating collagen and mineral in vivo and links these in vivo roles with mechanical integrity. Without addition of new bone, exercise altered the pre-existing ECM which influenced tissue quality and mechanical integrity. In B6;129 KO, exercise-induced changes in tissue composition compensated for tissue-level mechanical deficiencies, suggesting that mechanical stimulation may be effective as a therapeutic intervention for diseases associated with deficiencies in bone quality. These studies provide new insights into inbred strain research which has important implications to the proper interpretation of investigations into the effects of genetic deficiencies and loading on the skeleton.Ph.D.Biomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/57673/2/jmwallac_1.pd

Inbred Strain-Specific Response to Biglycan Deficiency in the Cortical Bone of C57BL6/129 and C3H/He Mice

Inbred strain-specific differences in mice exist in bone cross-sectional geometry, mechanical properties, and indices of bone formation. Inbred strain-specific responses to external stimuli also exist, but the role of background strain in response to genetic deletion is not fully understood. Biglycan (bgn) deficiency impacts bone through negative regulation of osteoblasts, resulting in extracellular matrix alterations and decreased mechanical properties. Because osteoblasts from C3H/He (C3H) mice are inherently more active versus osteoblasts from other inbred strains, and the bones of C3H mice are less responsive to other insults, it was hypothesized that C3H mice would be relatively more resistant to changes associated with bgn deficiency compared with C57BL6/129 (B6;129) mice. Changes in mRNA expression, tissue composition, mineral density, bone formation rate, cross-sectional geometry, and mechanical properties were studied at 8 and 11 wk of age in the tibias of male wildtype and bgn-deficient mice bred on B6;129 and C3H background strains. Bgn deficiency altered collagen cross-linking and gene expression and the amount and composition of mineral in vivo. In bgn's absence, changes in collagen were independent of mouse strain. Bgn-deficiency increased the amount of mineral in both strains, but changes in mineral composition, cross-sectional geometry, and mechanical properties were dependent on genetic background. Bgn deficiency influenced the amount and composition of bone in mice from both strains at 8 wk, but C3H mice were better able to maintain properties close to wildtype (WT) levels. By 11 wk, most properties from C3H knockout (KO) bones were equal to or greater than WT levels, whereas phenotypic differences persisted in B6;129 KO mice. This is the first study into mouse strain-specific changes in a small leucine-rich proteoglycan gene disruption model in properties across the bone hierarchy and is also one of the first to relate these changes to mechanical competence. This study supports the importance of genetic factors in determining the response to a gene deletion and defines biglycan's importance to collagen and mineral composition in vivo

Ultrastructural elastic deformation of cortical bone tissue probed by NIR Raman spectroscopy

Raman spectroscopy is used as a probe of ultrastructural (molecular) changes in both the mineral and matrix (protein and glycoprotein, predominantly type I collagen) components of murine cortical bone as it responds to loading in the elastic regime. At the ultrastructural level, crystal structure and protein secondary structure distort as the tissue is loaded. These structural changes are followed as perturbations to tissue spectra. We load tissue in a custom-made dynamic mechanical tester that fits on the stage of a Raman microprobe and can accept hydrated tissue specimens. As the specimen is loaded in tension and/or compression, the shifts in mineral P-O4v 1 and relative band heights in the Amide III band envelope are followed with the microprobe. Average load is measured using a load cell while the tissue is loaded under displacement control. Changes occur in both the mineral and matrix components of bone as a response to elastic deformation. We propose that the mineral apatitic crystal lattice is deformed by movement of calcium and other ions. The matrix is proposed to respond by deformation of the collagen backbone. Raman microspectroscopy shows that bone mineral is not a passive contributor to tissue strength. The mineral active response to loading may function as a local energy storage and dissipation mechanism, thus helping to protect tissue from catastrophic damage

Science camera calibration for extreme adaptive optics

The nascent field of planet detection has yielded a host of extra-solar planet detections. To date, these detections have been the result of indirect techniques: the planet is inferred by precisely measuring its effect on the host star. Direct observation of extra-solar planets remains a challenging yet compelling goal. In this vein, the Center for Adaptive Optics has proposed a ground-based, high-actuator density extreme AO system (XAOPI), for a large (~10 m) telescope whose ultimate goal is to directly evidence a specific class of these objects: young and massive planets. Detailed system wave-front error budgets suggest that this system is a feasible, if not an ambitious, proposition. One key element in this error budget is the calibration and maintenance of the science camera wave front with respect to the wave-front sensor which currently has an allowable contribution of ~ 5 nanometers rms. This talk first summarizes the current status of calibration on existing ground-based AO systems, the magnitude of this effect in the system error budget and current techniques for mitigation. Subsequently, we will explore the nature of this calibration error term, it’s source in the non-commonality between the science camera and wave front sensor, and the effect of the temporal evolution of non-commonality. Finally, we will describe preliminary plans for sensing and controlling this error term. The sensing techniques include phase retrieval, phase contrast and external metrology. To conclude, a calibration scenario that meets the stringent requirement for XAOPI will be discussed

Inbred Strain-Specific Effects of Exercise in Wild Type and Biglycan Deficient Mice

Biglycan (bgn)-deficient mice (KO) have defective osteoblasts which lead to changes in the amount and quality of bone. Altered tissue strength in C57BL6/129 (B6;129) KO mice, a property which is independent of tissue quantity, suggests that deficiencies in tissue quality are responsible. However, the response to bgn-deficiency is inbred strain-specific. Mechanical loading influences bone matrix quality in addition to any increase in bone mass or change in bone formation activity. Since many diseases influence the mechanical integrity of bone through altered tissue quality, loading may be a way to prevent and treat extracellular matrix deficiencies. C3H/He (C3H) mice consistently have a less vigorous response to mechanical loading vs. other inbred strains. It was therefore hypothesized that the bones from both wild type (WT) and KO B6;129 mice would be more responsive to exercise than the bones from C3H mice. To test these hypotheses at 11 weeks of age, following 21 consecutive days of exercise, we investigated cross-sectional geometry, mechanical properties, and tissue composition in the tibiae of male mice bred on B6;129 and C3H backgrounds. This study demonstrated inbred strain-specific compositional and mechanical changes following exercise in WT and KO mice, and showed evidence of genotype-specific changes in bone in response to loading in a gene disruption model. This study further shows that exercise can influence bone tissue composition and/or mechanical integrity without changes in bone geometry. Together, these data suggest that exercise may represent a possible means to alter tissue quality and mechanical deficiencies caused by many diseases of bone

A cluster randomized controlled trial of a modified vaccination clinical reminder for primary care providers

Objective: Adult vaccination rates in the United States fall short of national goals, and rates are particularly low for Black Americans. We tested a provider-focused vaccination uptake intervention: a modified electronic health record clinical reminder that bundled together three adult vaccination reminders, presented patient vaccination history, and included talking points for providers to address vaccine hesitancy. Method: Primary care teams at the Atlanta Veterans Affairs Medical Center, who saw 28,941 patients during this period, were randomly assigned to receive either the modified clinical reminder (N = 44 teams) or the status quo (N = 40 teams). Results: Uptake of influenza and other adult vaccinations was 1.6 percentage points higher in the intervention group, which was not statistically significant (CI = [-1.3, 4.4], p = 0.28). The intervention had similar effects on Black and White patients and did not reduce the disparity in vaccination rates between these groups. Conclusion: Provider-focused interventions are a promising way to address vaccine hesitancy, but they may need to be more intensive than a modified clinical reminder to have appreciable effects on vaccination uptake

Homo Æqualis: A Cross-Society Experimental Analysis of Three Bargaining Games

Data from three bargaining games-the Dictator Game, the Ultimatum Game, and the Third-Party Punishment Game-played in 15 societies are presented. The societies range from US undergraduates to Amazonian, Arctic, and African hunter-gatherers. Behaviour within the games varies markedly across societies. The paper investigates whether this behavioural diversity can be explained solely by variations in inequality aversion. Combining a single parameter utility function with the notion of subgame perfection generates a number of testable predictions. While most of these are supported, there are some telling divergences between theory and data: uncertainty and preferences relating to acts of vengeance may have influenced play in the Ultimatum and Third-Party Punishment Games; and a few subjects used the games as an opportunity to engage in costly signalling.

High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids.

BackgroundPatients with systemic lupus erythematosus (SLE) are at increased risk of atherosclerosis, even after accounting for traditional risk factors. High levels of leptin and low levels of adiponectin are associated with both atherosclerosis and immunomodulatory functions in the general population.ObjectiveTo examine the association between these adipokines and subclinical atherosclerosis in SLE, and also with other known inflammatory biomarkers of atherosclerosis.MethodsCarotid ultrasonography was performed in 250 women with SLE and 122 controls. Plasma leptin and adiponectin levels were measured. Lipoprotein a (Lp(a)), oxidised phospholipids on apoB100 (OxPL/apoB100), paraoxonase, apoA-1 and inflammatory high-density lipoprotein (HDL) function were also assessed.ResultsLeptin levels were significantly higher in patients with SLE than in controls (23.7±28.0 vs 13.3±12.9 ng/ml, p<0.001). Leptin was also higher in the 43 patients with SLE with plaque than without plaque (36.4±32.3 vs 20.9±26.4 ng/ml, p=0.002). After multivariate analysis, the only significant factors associated with plaque in SLE were leptin levels in the highest quartile (≥29.5 ng/ml) (OR=2.8, p=0.03), proinflammatory HDL (piHDL) (OR=12.8, p<0.001), age (OR=1.1, p<0.001), tobacco use (OR=7.7, p=0.03) and hypertension (OR=3.0, p=0.01). Adiponectin levels were not significantly associated with plaque in our cohort. A significant correlation between leptin and piHDL function (p<0.001), Lp(a) (p=0.01) and OxPL/apoB100 (p=0.02) was also present.ConclusionsHigh leptin levels greatly increase the risk of subclinical atherosclerosis in SLE, and are also associated with an increase in inflammatory biomarkers of atherosclerosis such as piHDL, Lp(a) and OxPL/apoB100. High leptin levels may help to identify patients with SLE at risk of atherosclerosis

Double-Peaked Broad Emission Lines in NGC 4450 and Other LINERs

Spectra taken with HST reveal that NGC 4450 emits Balmer emission lines with displaced double peaks and extremely high-velocity wings. This characteristic line profile, previously seen in a few nearby LINERs and in a small fraction of broad-line radio galaxies, can be interpreted as a kinematic signature of a relativistic accretion disk. We can reproduce the observed profile with a model for a disk with a radial range of 1000-2000 gravitational radii and inclined by 27 degrees along the line of sight. The small-aperture HST data also allow us to detect, for the first time, the featureless continuum at optical wavelengths in NGC 4450; the nonstellar nucleus is intrinsically very faint, with M_B = -11.2 mag for D = 16.8 Mpc. We have examined the multiwavelength properties of NGC 4450 collectively with those of other low-luminosity active nuclei which possess double-peaked broad lines and find a number of common features. These objects are all classified spectroscopically as "type 1" LINERs or closely related objects. The nuclear luminosities are low, both in absolute terms and relative to the Eddington rates. All of them have compact radio cores, whose strength relative to the optical nuclear emission places them in the league of radio-loud active nuclei. The broad-band spectral energy distributions of these sources are most notable for their deficit of ultraviolet emission compared to those observed in luminous Seyfert 1 nuclei and quasars. The double-peaked broad-line radio galaxies Arp 102B and Pictor A have very similar attributes. We discuss how these characteristics can be understood in the context of advection-dominated accretion onto massive black holes.Comment: To appear in The Astrophysical Journal. Latex, 15 pages, embedded figures and tabl