MONITORING OF MESENCHYMAL BASED CONSTRUCTS USING MAGNETIC RESONANCE ELASTOGRAPHY

Evaluating the functionality of an engineered material lies in the proper characterization of its material and functional properties. In the treatment of musculoskeletal disorders, engineered bone or fat tissue must behave as an adequate replacement else failure of the material could result in discomfort and further surgical procedures. A significant material characteristic that reflects tissue development is the mechanical properties (i.e. shear strength and viscosity). Shear strength and viscosity provide an indication of how efficient the material is in dissipating energy. Energy dissipation occurs naturally in many tissues including fat and can prevent damage to deeper tissues. Many of the techniques for determining a material’s shear modulus result in the destruction of the construct. However, few methods exist that can assess this property by evaluating a noninvasive cross-section of the construct. As a result a need exists for the development of a nondestructive way to assess the biomechanical properties of engineered materials both before and after they have been implanted. In an effort to improve the quality of constructs being produced, a recently developed magnetic resonance imaging (MRI) technique termed magnetic resonance elastography (MRE) was applied to evaluate the development of adipogenic (fat) and osteogenic (bone) tissue constructs derived from mesenchymal stem cells. MRE is a technique in which motion from a mechanical actuator is synchronized to a phase contrast imaging pulse sequence and used to measure the generated displacement. The captured displacement is displayed in shear wave images from which the properties of shear stiffness can be derived. For differentiation of the bone marrow-derived mesenchymal stems cells, the use of differentiation media kits was applied. Change in stiffness was observed over the four weeks of in vitro growth. Constructs initially measured at approximately 3 kPa developed into 22 kPa osteogenic and 1 kPa adipogenic tissues. Following four weeks in vitro growth, constructs were implanted in athymic mice and assessed with an MRE system custom built for animal imaging. The following thesis demonstrates the application of MRE to evaluate the mechanical properties of engineered constructs through in vitro growth and in vivo regeneration in an animal model. Advisor: Shadi F. Othma

Curcumin-loaded magnetic nanoparticles for breast cancer therapeutics and imaging applications

Breast cancer is a commonly diagnosed cancer among women in the United States. It is estimated that 230,480 women were diagnosed with, and 39,520 women died from, breast cancer in 2011 in the United States.1 Basal-like breast cancer accounts for 15% of all breast cancers and has a poor prognosis. The majority of these cancers are referred to as triple-negative breast cancers because they do not over express estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2.2,3 Chemotherapy is an effective option to treat such cancers; however, chemotherapy is always associated with several sets of side effects.4–7 To overcome/avoid issues with side effects, natural compounds which are used as daily food ingredients may be an alternative option

Antioxidant Theranostic Copolymer-Mediated Reduction In Oxidative Stress Following Traumatic Brain Injury Improves Outcome In A Mouse Model

Following a traumatic brain injury (TBI), excess reactive oxygen species (ROS) and lipid peroxidation products (LPOx) are generated and lead to secondary injury beyond the primary insult. A major limitation of current treatments is poor target engagement, which has prevented success in clinical trials. Thus, nanoparticle-based treatments have received recent attention because of their ability to increase accumulation and retention in damaged brain. Theranostic neuroprotective copolymers (NPC3) containing thiol functional groups can neutralize ROS and LPOx. Immediate administration of NPC3 following injury in a controlled cortical impact (CCI) mouse model provides a therapeutic window in reducing ROS levels at 2.08–20.83 mg kg−1 in males and 5.52–27.62 mg kg−1 in females. This NPC3-mediated reduction in oxidative stress improves spatial learning and memory in males, while females show minimal improvement. Notably, NPC3-mediated reduction in oxidative stress prevents the bilateral spread of necrosis in male mice, which is not observed in female mice and likely accounts for the sex-based spatial learning and memory differences. Overall, these findings suggest sex-based differences to oxidative stress scavenger nanoparticle treatments, and a possible upper threshold of antioxidant activity that provides therapeutic benefit in injured brain since female mice benefit from NPC3 treatment to a lesser extent than male mice

Restoration of normal blood flow in atherosclerotic arteries promotes plaque stabilization

Blood flow is a key regulator of atherosclerosis. Disturbed blood flow promotes atherosclerotic plaque development, whereas normal blood flow protects against plaque development. We hypothesized that normal blood flow is also therapeutic, if it were able to be restored within atherosclerotic arteries. Apolipoprotein E-deficient (ApoE-/-) mice were initially instrumented with a blood flow-modifying cuff to induce plaque development and then five weeks later the cuffwas removed to allowrestoration of normal blood flow. Plaques in decuffed mice exhibited compositional changes that indicated increased stability compared to plaques in mice with the cuff maintained. The therapeutic benefit of decuffingwas comparable to atorvastatin and the combination had an additive effect. In addition, decuffing allowed restoration of lumen area, blood velocity, and wall shear stress to near baseline values, indicating restoration of normal blood flow. Our findings demonstrate that the mechanical effects of normal blood flow on atherosclerotic plaques promote stabilization

Smooth muscle cells affect differential nanoparticle accumulation in disturbed blood flow-induced murine atherosclerosis

Atherosclerosis is a lipid-driven chronic inflammatory disease that leads to the formation of plaques in the inner lining of arteries. Plaques form over a range of phenotypes, the most severe of which is vulnerable to rupture and causes most of the clinically significant events. In this study, we evaluated the efficacy of nanoparticles (NPs) to differentiate between two plaque phenotypes based on accumulation kinetics in a mouse model of atherosclerosis. This model uses a perivascular cuff to induce two regions of disturbed wall shear stress (WSS) on the inner lining of the instrumented artery, low (upstream) and multidirectional (downstream), which, in turn, cause the development of an unstable and stable plaque phenotype, respectively. To evaluate the influence of each WSS condition, in addition to the final plaque phenotype, in determining NP uptake, mice were injected with NPs at intermediate and fully developed stages of plaque growth. The kinetics of artery wall uptake were assessed in vivo using dynamic contrast-enhanced magnetic resonance imaging. At the intermediate stage, there was no difference in NP uptake between the two WSS conditions, although both were different from the control arteries. At the fully-developed stage, however, NP uptake was reduced in plaques induced by low WSS, but not multidirectional WSS. Histological evaluation of plaques induced by low WSS revealed a significant inverse correlation between the presence of smooth muscle cells and NP accumulation, particularly at the plaque-lumen interface, which did not exist with other constituents (lipid and collagen) and was not present in plaques induced by multidirectional WSS. These findings demonstrate that NP accumulation can be used to differentiate between unstable and stable murine atherosclerosis, but accumulation kinetics are not directly influenced by the WSS condition. This tool could be used as a diagnostic to evaluate the efficacy of experimental therapeutics for atherosclerosis

The 2012 Hubble Ultra Deep Field (UDF12): Observational Overview

We present the 2012 Hubble Ultra Deep Field campaign (UDF12), a large 128 orbit Cycle 19 Hubble Space Telescope program aimed at extending previous Wide Field Camera 3 (WFC3)/IR observations of the UDF by quadrupling the exposure time in the F105W filter, imaging in an additional F140W filter, and extending the F160W exposure time by 50%, as well as adding an extremely deep parallel field with the Advanced Camera for Surveys (ACS) in the F814W filter with a total exposure time of 128 orbits. The principal scientific goal of this project is to determine whether galaxies reionized the universe; our observations are designed to provide a robust determination of the star formation density at z ≳ 8, improve measurements of the ultraviolet continuum slope at z ~ 7-8, facilitate the construction of new samples of z ~ 9-10 candidates, and enable the detection of sources up to z ~ 12. For this project we committed to combining these and other WFC3/IR imaging observations of the UDF area into a single homogeneous dataset to provide the deepest near-infrared observations of the sky. In this paper we present the observational overview of the project and describe the procedures used in reducing the data as well as the final products that were produced. We present the details of several special procedures that we implemented to correct calibration issues in the data for both the WFC3/IR observations of the main UDF field and our deep 128 orbit ACS/WFC F814W parallel field image, including treatment for persistence, correction for time-variable sky backgrounds, and astrometric alignment to an accuracy of a few milliarcseconds. We release the full, combined mosaics comprising a single, unified set of mosaics of the UDF, providing the deepest near-infrared blank-field view of the universe currently achievable, reaching magnitudes as deep as AB ~ 30 mag in the near-infrared, and yielding a legacy dataset on this field

Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy

Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n = 152) and 3, 311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P = 1.42 x 10(-12)),8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472;P = 3.41 x 10(-8)),and 2p22 at SOS1 (rs963731;P = 1.76 x 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22;rs1768208;P = 2.07 x 10(-7)) and MAPT H1c (17q21;rs242557;P = 7.91 x 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein)

Using State Space Exploration to Determine How Gene Regulatory Networks Constrain Mutation Order in Cancer Evolution

Cancer develops via the progressive accumulation of somatic mutations, which subvert the normal operation of the gene regulatory network of the cell. However, little is known about the order in which mutations are acquired in successful clones. A particular sequence of mutations may confer an early selective advantage to a clone by increasing survival or proliferation, or lead to negative selection by triggering cell death. The space of allowed sequences of mutations is therefore constrained by the gene regulatory network. Here, we introduce a methodology for the systematic exploration of the effect of every possible sequence of oncogenic mutations in a cancer cell modelled as a qualitative network. Our method uses attractor identification using binary decision diagrams and can be applied to both synchronous and asynchronous systems. We demonstrate our method using a recently developed model of ER-negative breast cancer. We show that there are differing levels of constraint in the order of mutations for different combinations of oncogenes, and that the effects of ErbB2/HER2 over-expression depend on the preceding mutations

Advancements in decadal climate predictability: the role of nonoceanic drivers

We review recent progress in understanding the role of sea ice, land surface, stratosphere, and aerosols in decadal-scale predictability and discuss the perspectives for improving the predictive capabilities of current Earth system models (ESMs). These constituents have received relatively little attention because their contribution to the slow climatic manifold is controversial in comparison to that of the large heat capacity of the oceans. Furthermore, their initialization as well as their representation in state-of-the-art climate models remains a challenge. Numerous extraoceanic processes that could be active over the decadal range are proposed. Potential predictability associated with the aforementioned, poorly represented, and scarcely observed constituents of the climate system has been primarily inspected through numerical simulations performed under idealized experimental settings. The impact, however, on practical decadal predictions, conducted with realistically initialized full-fledged climate models, is still largely unexploited. Enhancing initial-value predictability through an improved model initialization appears to be a viable option for land surface, sea ice, and, marginally, the stratosphere. Similarly, capturing future aerosol emission storylines might lead to an improved representation of both global and regional short-term climatic changes. In addition to these factors, a key role on the overall predictive ability of ESMs is expected to be played by an accurate representation of processes associated with specific components of the climate system. These act as “signal carriers,” transferring across the climatic phase space the information associated with the initial state and boundary forcings, and dynamically bridging different (otherwise unconnected) subsystems. Through this mechanism, Earth system components trigger low-frequency variability modes, thus extending the predictability beyond the seasonal scale