Passage through International Straits: Free or Innocent? The Interests at Stake

The purpose of this Article is to examine interests involved in the straits question, with emphasis on the interests of the coastal states, and to propose a solution to the conflict. A proposal will be made regarding the question of submerged passage by submarines through international straits. Two assumptions are made. First, the Conference will settle on a territorial sea breadth of twelve miles, and second, that neither group will consider its position on the straits issue so important that it will allow the Conference to fail without making a serious attempt at a compromise

Doctor of Philosophy

dissertationIntracortical microelectrode arrays create a direct interface between the brain and external devices. This “brain-machine interface” has found clinical application by allowing patients with tetraplegia to control computer cursors and robotic limbs. Unfortunately, use of intracortical microelectrode array technology is currently limited by its inconsistent ability to record neural signals over time. It is widely believed that the foreign body response (FBR) contributes to recording inconsistency. Most characterizations of the FBR to intracortical microelectrodes have been in the rat using devices with simple architecture, while the only device currently used in humans, the Utah Electrode Array (UEA), is much larger and more complex. In this work, we characterized the FBR to the UEA and found that, unlike with simpler devices, implantation of a UEA results in extensive vascular injury and loss of cortical tissue. We also sought to determine which features of the FBR correlated with recording inconsistency and found that biomarkers of astrogliosis, blood-brain barrier leakage, and tissue loss were associated with decreased recording performance. Next, since a significant portion of potential brain-machine interface recipients are aged, we applied similar methods in an aged cohort of rats in order to understand the effect of aging on the FBR and recording performance. We found that, surprisingly, recording performance was superior in the aged cohort. Astrogliosis was again associated with decreased recording performance in the aged cohort. Finally, we continued our development and validation of a finite element model of cytokine diffusion to assist in designing next-generation devices with a reduced FBR. Taken as a whole, this work provides meaningful insights into the mechanisms of inconsistent recording performance and discusses several promising avenues for overcoming them

Preclinical translation of exosomes derived from mesenchymal stem/stromal cells.

Exosomes are nanovesicles secreted by virtually all cells. Exosomes mediate the horizontal transfer of various macromolecules previously believed to be cell-autonomous in nature, including nonsecretory proteins, various classes of RNA, metabolites, and lipid membrane-associated factors. Exosomes derived from mesenchymal stem/stromal cells (MSCs) appear to be particularly beneficial for enhancing recovery in various models of disease. To date, there have been more than 200 preclinical studies of exosome-based therapies in a number of different animal models. Despite a growing number of studies reporting the therapeutic properties of MSC-derived exosomes, their underlying mechanism of action, pharmacokinetics, and scalable manufacturing remain largely outstanding questions. Here, we review the global trends associated with preclinical development of MSC-derived exosome-based therapies, including immunogenicity, source of exosomes, isolation methods, biodistribution, and disease categories tested to date. Although the in vivo data assessing the therapeutic properties of MSC-exosomes published to date are promising, several outstanding questions remain to be answered that warrant further preclinical investigation

Cross-Power Spectrum and Its Application on Window Functions in the WMAP data

Cross-power spectrum is a quadratic estimator between two maps that can provide unbiased estimate of the underlying power spectrum of the correlated signals, which is therefore used for extracting the power spectrum in the WMAP data. In this paper we discuss the limit of cross-power spectrum and derive the residual from uncorrelated signal, which is the source of error in power spectrum extraction. We employ the estimator to extract window functions by crossing pairs of extragalactic point sources. We desmonstrate its usefulness in WMAP Difference Assembly maps where the window functions are measured via Jupiter and then extract the window functions of the 5 WMAP frequency band maps.Comment: added the part of applying cross power spectrum on WMAP DA maps and frequency band maps and submitted to Ap

Foreground removal from WMAP 5yr temperature maps using an MLP neural network

One of the main obstacles for extracting the cosmic microwave background (CMB) signal from observations in the mm/sub-mm range is the foreground contamination by emission from Galactic component: mainly synchrotron, free-free, and thermal dust emission. The statistical nature of the intrinsic CMB signal makes it essential to minimize the systematic errors in the CMB temperature determinations. The feasibility of using simple neural networks to extract the CMB signal from detailed simulated data has already been demonstrated. Here, simple neural networks are applied to the WMAP 5yr temperature data without using any auxiliary data. A simple \emph{multilayer perceptron} neural network with two hidden layers provides temperature estimates over more than 75 per cent of the sky with random errors significantly below those previously extracted from these data. Also, the systematic errors, i.e.\ errors correlated with the Galactic foregrounds, are very small. With these results the neural network method is well prepared for dealing with the high - quality CMB data from the ESA Planck Surveyor satellite.Comment: 6 pages, 13 figure

Human Myoblast and Mesenchymal Stem Cell Interactions Visualized by Videomicroscopy.

Muscle-derived progenitor cell (myoblast) therapy has promise for the treatment of denervated, weakened, and fibrotic muscle. The best methods for injecting myoblasts to promote fusion and retention have yet to be determined, however. Mesenchymal stem/stromal cells have also been reported to have beneficial effects in restoring damaged tissue, through increasing vascularization and reducing inflammation. The interactions between human primary skeletal myoblasts and bone marrow-derived mesenchymal stem/stromal cells were examined using time-lapse images put into video format. Of interest, there is a high degree of cell-to-cell interaction with microparticles transferring between both cell types, and formation of nanotubules to bridge cytoplasmic contents between the two types of cell. This model provides an in vitro platform for examining mechanisms for cell-to-cell interaction preceding myoblast fusion

Endothelial cells derived from patients' induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia A.

Hemophilia A (HA) is a bleeding disorder characterized by spontaneous and prolonged hemorrhage. The disease is caused by mutations in the coagulation factor 8 gene (F8) leading to factor VIII (FVIII) deficiency. Since FVIII is primarily produced in endothelial cells (ECs) in a non-diseased human being, ECs hold great potential for development as a cell therapy for HA. We showed that HA patient-specific induced pluripotent stem cells (HA-iPSCs) could provide a renewable supply of ECs. The HA-iPSC-derived ECs were transduced with lentiviral vectors to stably express the functional B domain deleted F8 gene, the luciferase gene, and the enhanced green fluorescent protein gene (GFP). When transplanted intramuscularly into neonatal and adult immune deficient mice, the HA-iPSC-derived ECs were retained in the animals for at least 10-16 weeks and maintained their expression of FVIII, GFP, and the endothelial marker CD31, as demonstrated by bioluminescence imaging and immunostaining, respectively. When transplanted into HA mice, these transduced HA-iPSC-derived ECs significantly reduced blood loss in a tail-clip bleeding test and produced therapeutic plasma levels (11.2%-369.2%) of FVIII. Thus, our studies provide proof-of-concept that HA-iPSC-derived ECs can serve as a factory to deliver FVIII for the treatment of HA not only in adults but also in newborns

Shifting the Universe: Early Dark Energy and Standard Rulers

The presence of dark energy at high redshift influences both the cosmic sound horizon and the distance to last scattering of the cosmic microwave background. We demonstrate that through the degeneracy in their ratio, early dark energy can lie hidden in the CMB temperature and polarization spectra, leading to an unrecognized shift in the sound horizon. If the sound horizon is then used as a standard ruler, as in baryon acoustic oscillations, then the derived cosmological parameters can be nontrivially biased. Fitting for the absolute ruler scale (just as supernovae must be fit for the absolute candle magnitude) removes the bias but decreases the leverage of the BAO technique by a factor 2.Comment: 6 pages, 3 figure