http://hdl.handle.net/1721.1/7628 http://hdl.handle.net/1721.1/46090 An investigation into a potential relationship between the rise in lanthanide usage and the increased prevalence of childhood asthma Puri, Charu Thesis (M.S.)--Massachusetts Institute of Technology, Division of Toxicology, 1997. Includes bibliographical references (leaves 69-71). http://hdl.handle.net/1721.1/45211 Symmetric signaling by an asymmetric 1 erythropoietin : 2 erythropoietin receptor complex Zhang, Yingxin One erythropoietin molecule binds asymmetrically to two identical receptor monomers via erythropoietin site 1 and site 2, although it is unclear how asymmetry affects receptor activation and signaling. Here we report the computational design and experimental validation of two mutant erythropoietin receptors: one that binds only to erythropoietin site 1 but not site 2, and one that binds only to site 2 but not site 1. Expression of either mutant receptor alone in Ba/F3 cells cannot elicit a signal in response to erythropoietin, but when co-expressed, there is a proliferative response and activation of the JAK2 Stat5 signaling pathway. A truncated erythropoietin receptor with only one cytosolic tyrosine (Y343), on only one receptor monomer is sufficient for signaling in response to erythropoietin, regardless of the monomer on which it is located. The same results apply to having only one conserved juxtamembrane hydrophobic L253 or W258 residue, essential for JAK2 activation, in the full-length receptor dimer. We conclude that despite asymmetry in the ligand-receptor dimer interaction, both sides are competent for signaling, and we suggest that the receptors signal equally. Thesis (M. Eng.)--Massachusetts Institute of Technology, Biological Engineering Division, 2008. Includes bibliographical references (p. 43-46). http://hdl.handle.net/1721.1/45210 Multi-scale analysis of cardiac myoarchitecture Wang, Teresa T The distribution and generation of force within the myocardium during normal contractility is dictated by the tissue's underlying 3D myoarchitecture. The presence of disordered myoarchitecture may in turn constitute the pathological basis of impaired cardiac mechanics in numerous clinical conditions, such as the remodeling heart following myocardial infarction and cardiomyopathies. To investigate the multi-scale nature of architectural disarray in the setting of myocardial disease, a dual imaging approach consisting of diffusion spectrum magnetic resonance imaging (DSI) and high-speed multislice two-photon microscopy (TPM) was used. DSI is a technique that derives fiber orientation from directionality of proton diffusion, whereas TPM derives cellular alignment from an autocorrelation of 3D resolved images of cells and subcellular structure. Mesoscale tract representations of myofiber orientation are generated from similarly aligned diffusion or autocorrelation vectors. These methods were applied to study induced myocardial infarction in the rat and hypertrophic cardiomyopathy associated with deletion of the gene for myosin binding protein C (cMyBP-C) in the mouse. Normal cardiac muscle fiber alignment within the ventricular wall was characterized by a series of helical tracts transitioning from a lefthanded orientation in the subepicardium to circumferential in the mid-myocardium to righthanded in the subendocardium. Infarcted hearts displayed a fiber void in the infarct zone and an extension of both subepicardial and subendocardial fibers beyond the border zone. It's hypothesized that the growth of fibers contributes to the remodeling process and provides tensile strength to the myocardium during contraction. (cont.) The hearts obtained from the cMyBP-C knockouts displayed significant myoarchitectural disarray characterized by a loss of voxel to voxel orientational coherence for fibers located from the mid-myocardium to subendocardium, resulting in a change in the transmural progression of remaining helical fibers. These observations suggest an association between cMyBP-C expression and cardiac fiber alignment, where variations in torsional rotation may constitute a mechanism for pump failure in hypertrophic cardiomyopathy. These results substantiate the use of multi-scale imaging methods to enhance understanding of molecular and cellular contributions to tissue mechanical function. Thesis (M. Eng.)--Massachusetts Institute of Technology, Biological Engineering Division, 2008. Includes bibliographical references (leaves 61-67). http://hdl.handle.net/1721.1/44882 Design and in vitro development of resorbable urologic drug delivery device Tobias, Irene S. (Irene Sophie) Implantable, controlled release drug delivery devices offer several advantages over systemic oral administration routes and immediate drug release treatments including direct therapy to target organ, more continuous maintenance of plasma and tissue drug levels and the potential for reduced side effects or toxicity. Urology has emerged as a unique field in which minimally invasive implantation techniques are available and such devices could provide improved beneficial therapies over conventional treatments. Urological indications for which localized drug therapy is already being advocated and investigated are highly suitable for treatment with implantable controlled release devices. This thesis describes the in vitro performance evaluation of an implantable, bio-resorbable device that can provide localized drug therapy of ciprofloxacin (CIP) to the seminal vesicle and nearby prostate gland for treatment of chronic prostatitis (CP). The device functions as an elementary osmotic pump (EOP) to release CIP for a period of 2-3 weeks after implantation in the seminal vesicle (SV) through transrectal needle injection or cystoscopic methods. The device is composed of an elastomeric, resorbable polymer cast in a tubular geometry with solid drug powder packed into its core and a micromachined release orifice drilled through its wall. Drug release experiments were performed to determine the effective release rate from a single orifice and the range of orifice size in which osmotic-controlled zero-order release was the dominant mechanism of drug delivery from the device. Device stability and function in an alkaline environment of similar pH to that of the SVs and infected prostate gland was also assessed in vitro. The device was found to function well in both de-ionized water and NaOH pH-8 solution with a sustained zero-order release rate of 2.47 ± 0.29 jtg/hr when fabricated with an orifice of diameter 100-150pm. Thesis (M. Eng.)--Massachusetts Institute of Technology, Biological Engineering Division, 2008. Includes bibliographical references (leaves 57-62).