Design of a three-dimensional in vitro model to elucidate the influence of integrin beta 1 and matrix metalloproteinases in breast cancer remodeling of collagen I

Every year there are nearly two million new cases of invasive breast cancer worldwide and over 500,000 deaths, the majority from metastatic sites. While cellular changes during tumorigenesis and progression have been studied, our understanding of extracellular matrix remodeling, at the fiber level, by individual and collective cellular cohorts remains limited. Furthermore, recent studies suggest that there is a correlation between the organization of collagen I fibers perpendicular to the tumor and patient survival. However, the underlying mechanism of this alignment remains unknown. The central hypothesis proposed in this dissertation is that breast cancer tumors reorganize collagen I fibers perpendicular to the tumor surface via integrin β1 and matrix metalloproteinases (MMPs). To investigate this hypothesis, we developed a novel in vitro assay that replicates collagen I fiber alignment previously reported in vivo and a new quantitative collagen I fiber orientation algorithm. Our studies using multicellular aggregates, derived from the triple negative breast cancer cell line MDA-MB-231, embedded into collagen I matrices and confocal reflectance microscopy provide novel insights into how the local microenvironment is affected and into local orientation of the collagen I fibers near the spheroid-collagen I interface. These results agree well with our computational studies. Furthermore, the viability of the algorithm is demonstrated using both in silico and in vitro derived images, and shows that this algorithm is more accurate than similar algorithms previously published. Using the developed in vitro assay and computational algorithm it is also demonstrated that knocking down integrin β1 reduces the amount of collagen I aligned perpendicularly to the tumor surface, while inhibiting MMP activity using the broad spectrum MMP inhibitor GM6001 increases the amount of collagen I aligned perpendicularly to the tumor surface at early time points. The work presented here has implications in three-dimensional multicellular assays, accurate fiber orientation analysis, and understanding the role of integrins in matrix reorganization and cancer cell metastasis.2019-08-09T00:00:00

Hadronic transitions Υ(2\u3ci\u3eS\u3c/i\u3e)→Υ(1\u3ci\u3eS\u3c/i\u3e)

Using a 73.6 pb-1 data sample of Υ(2S) events collected with the CLEO II detector at the Cornell Electron Storage Ring, we have investigated the hadronic transitions between the Υ(2S) and the Υ(1S). The dipion transition Υ(2S) → Υ(1S) π+π- was studied using two different analysis techniques. Selecting events in which Υ(1S) → e+e-, μ+μ- (‘‘exclusive’’ analysis), and using the Υ(1S) leptonic branching fractions world averages from the PDG review, we obtained Ɓ(Υ(2S) → Υ(1S) π+π-) =0.189±0.004±0.010, while using a method allowing Υ(1S) → anything (‘‘inclusive’’ analysis) we obtained Ɓ(Υ(2S) → Υ(1S) π+π-) = 0.196 ±0.002±0.010. The appropriate weighted average of the two measurements gives Ɓ(Υ(2S) → Υ(1S) π+π-) = 0.192±0.002±0.010. Combining the exclusive and inclusive results we derive the Υ(1S) leptonic branching fractions Bee = 0.0229±0.0008±0.0011 and Bμμ = 0.0249±0.0008±0.0013. We also studied Υ(2S) → Υ(1S) π0π0 and obtained Ɓ(Υ(2S) → Υ(1S) π0π0) = 0.092±0.006±0.008. Parameters of the π π system (dipion invariant mass spectra, angular distributions) were analyzed and found to be consistent with current theoretical models. Lastly, we searched for the η and single π0 transitions and obtained the 90% confidence level upper limits Ɓ(Υ(2S) → Υ(1S) η) \u3c 0.0028 and Ɓ(Υ(2S) → Υ(1S) π0) \u3c 0.0011

Into the Multiverse: Methods for Studying Developmental Neuroscience

One major challenge in developmental neuroscience research is the sheer number of choices researchers face when addressing even a single research question. Even once data collection is complete, the journey from raw data to interpretation of findings may depend on numerous decisions. To address this issue, this dissertation explores “multiverse” analysis techniques for following many analytical paths at once in the same dataset. In chapter 1, multiverses are used to examine which analyses of age-related change in amygdala-medial prefrontal cortex circuitry are robust versus sensitive to researcher decisions. Chapter 2 uses multiverse analysis to identify optimal solutions for mitigating breathing-induced artifacts in resting-state functional magnetic resonance imaging data. Chapter 3 uses a variety of model specifications to characterize simultaneous reward learning strategies in youth contingent on both visual task cues and spatial-motor information. Despite varied approaches and goals, each of the three studies highlight the benefits of conducting multiple parallel analyses for both addressing questions in developmental neuroscience and deepening understanding of the methods used to address them

Loss of AND-34/BCAR3 Expression in Mice Results in Rupture of the Adult Lens

PURPOSE. AND-34/BCAR3 (Breast Cancer Anti-Estrogen Resistance 3) associates with the focal adhesion adaptor protein, p130CAS/BCAR1. Expression of AND-34 regulates epithelial cell growth pattern, motility, and growth factor dependence. We sought to establish the effects of the loss of AND-34 expression in a mammalian organism. METHODS. AND-34−/− mice were generated by homologous recombination. Histopathology, in situ hybridization, and western blotting were performed on murine tissues. RESULTS. Western analyses confirmed total loss of expression in AND-34−/− splenic lymphocytes. Mice lacking AND-34 are fertile and have normal longevity. While AND-34 is widely expressed in wild type mice, histologic analysis of multiple organs in AND-34−/− mice is unremarkable and analyses of lymphocyte development show no overt changes. A small percentage of AND-34−/− mice show distinctive small white eye lesions resulting from the migration of ruptured cortical lens tissue into the anterior chamber. Following initial vacuolization and liquefaction of the lens cortex first observed at postnatal day three, posterior lens rupture occurs in all AND-34−/− mice, beginning as early as three weeks and seen in all mice at three months. Western blot analysis and in situ hybridization confirmed the presence of AND-34 RNA and protein in lens epithelial cells, particularly at the lens equator. Prior data link AND-34 expression to the activation of Akt signaling. While Akt Ser 473 phosphorylation was readily detectable in AND-34+/+ lens epithelial cells, it was markedly reduced in the AND-34−/− lens epithelium. Basal levels of p130Cas phosphorylation were higher in AND-34+/+ than in AND-34−/− lens epithelium. CONCLUSIONS. These results demonstrate the loss of AND-34 dysregulates focal adhesion complex signaling in lens epithelial cells and suggest that AND-34-mediated signaling is required for maintenance of the structural integrity of the adult ocular lens.National Institutes of Health (RO1 CA114094); Logica Foundatio

The diffusion of disruptive technologies

We identify novel technologies using textual analysis of patents, job postings, and earnings calls. Our approach enables us to identify and document the diffusion of 29 disruptive technologies across firms and labor markets in the U.S. Five stylized facts emerge from our data. First, the locations where technologies are developed that later disrupt businesses are geographically highly concentrated, even more so than overall patenting. Second, as the technologies mature and the number of new jobs related to them grows, they gradually spread across space. While initial hiring is concentrated in high-skilled jobs, over time the mean skill level in new positions associated with the technologies declines, broadening the types of jobs that adopt a given technology. At the same time, the geographic diffusion of low-skilled positions is significantly faster than higher-skilled ones, so that the locations where initial discoveries were made retain their leading positions among high-paying positions for decades. Finally, these technology hubs are more likely to arise in areas with universities and high skilled labor pools

Compact object coalescence rate estimation from short gamma-ray burst observations

Recent observational and theoretical results suggest that Short-duration Gamma-Ray Bursts (SGRBs) are originated by the merger of compact binary systems of two neutron stars or a neutron star and a black hole. The observation of SGRBs with known redshifts allows astronomers to infer the merger rate of these systems in the local universe. We use data from the SWIFT satellite to estimate this rate to be in the range $\sim 500$-1500 Gpc$^{-3}$yr$^{-1}$. This result is consistent with earlier published results which were obtained through alternative approaches. We estimate the number of coincident observations of gravitational-wave signals with SGRBs in the advanced gravitational-wave detector era. By assuming that all SGRBs are created by neutron star-neutron star (neutron star-black hole) mergers, we estimate the expected rate of coincident observations to be in the range $\simeq 0.2$ to 1 ($\simeq 1$ to 3) yr$^{-1}$.Comment: 23 pages, 3 figures, version accepted for publicatio

P-Type Silicon Strip Sensors for the new CMS Tracker at HL-LHC

The upgrade of the LHC to the High-Luminosity LHC (HL-LHC) is expected to increase the LHC design luminosity by an order of magnitude. This will require silicon tracking detectors with a significantly higher radiation hardness. The CMS Tracker Collaboration has conducted an irradiation and measurement campaign to identify suitable silicon sensor materials and strip designs for the future outer tracker at the CMS experiment. Based on these results, the collaboration has chosen to use n-in-p type silicon sensors and focus further investigations on the optimization of that sensor type. This paper describes the main measurement results and conclusions that motivated this decision

X-ray phase contrast imaging of biological specimens with tabletop synchrotron radiation

Since their discovery in 1896, x-rays have had a profound impact on science, medicine and technology. Here we show that the x-rays from a novel tabletop source of bright coherent synchrotron radiation can be applied to phase contrast imaging of biological specimens, yielding superior image quality and avoiding the need for scarce or expensive conventional sources