Mechanisms of impaired red blood cell ATP release in older adults: implications for altered vascular control with age

2018 Summer.Includes bibliographical references.The following dissertation is comprised of a series of experiments with the overall aim of determining the mechanisms of impaired ATP release from red blood cells (RBCs) of healthy older adults in response to hemoglobin deoxygenation and identifying a potential role of this impairment in the declines in vascular control of peripheral blood flow with advancing age. Advancing age is the primary risk factor for cardiovascular disease (CVD), which is the leading cause of death in societies today and is strongly associated with arterial dysfunction. Furthermore, impairments in vascular control and the subsequent regulation of tissue blood flow and oxygen delivery contribute to vascular pathologies such as atherosclerosis and ischemic disease, as well as the age-associated declines in functional capacity, exercise tolerance, and overall quality of life. Thus, understanding the mechanisms of the age-related impairments in vascular control and identifying potential therapeutic targets holds significant potential for reducing the healthcare burden associated with a rapidly aging population. Accordingly, the ultimate goal of this dissertation is to determine if an in vivo pharmacological approach can be utilized to treat the age-related declines in RBC ATP release, thereby restoring circulating ATP responses and subsequent vascular control during the physiological stimuli of hypoxia and exercise in healthy older adults. The key novel findings of this dissertation are that (i) age-associated declines in RBC deformability are the primary mechanism of impaired deoxygenation-induced ATP release from RBCs of healthy older adults; (ii) primary (healthy) aging is not associated with a global decline in RBC function given that inhibition of cyclic AMP hydrolysis by phosphodiesterase 3 did not improve deoxygenation-induced ATP release from RBCs of older adults and that the cellular responses to Gi protein activation remained intact with age; and (iii) that systemic Rho-kinase inhibition via administration of fasudil improves the age-related impairments in vascular control and circulating ATP during systemic hypoxia and exercise, which may be related to enhanced RBC ATP release and NO bioavailability. These findings are the first to identify a role for Rho-kinase inhibition in improving these physiological responses in healthy older adults and are therefore clinically significant for aging population in which impaired vascular control contributes to elevations in cardiovascular disease risk and declines in exercise tolerance, functional independence and overall quality of life

Post-Newtonian factorized multipolar waveforms for spinning, non-precessing black-hole binaries

We generalize the factorized resummation of multipolar waveforms introduced by Damour, Iyer and Nagar to spinning black holes. For a nonspinning test-particle spiraling a Kerr black hole in the equatorial plane, we find that factorized multipolar amplitudes which replace the residual relativistic amplitude f_{l m} with its l-th root, \rho_{l m} = f_{l m}^{1/l}, agree quite well with the numerical amplitudes up to the Kerr-spin value q \leq 0.95 for orbital velocities v \leq 0.4. The numerical amplitudes are computed solving the Teukolsky equation with a spectral code. The agreement for prograde orbits and large spin values of the Kerr black hole can be further improved at high velocities by properly factoring out the lower-order post-Newtonian contributions in \rho_{l m}. The resummation procedure results in a better and systematic agreement between numerical and analytical amplitudes (and energy fluxes) than standard Taylor-expanded post-Newtonian approximants. This is particularly true for higher-order modes, such as (2,1), (3,3), (3,2), and (4,4) for which less spin post-Newtonian terms are known. We also extend the factorized resummation of multipolar amplitudes to generic mass-ratio, non-precessing, spinning black holes. Lastly, in our study we employ new, recently computed, higher-order post-Newtonian terms in several subdominant modes, and compute explicit expressions for the half and one-and-half post-Newtonian contributions to the odd-parity (current) and even-parity (odd) multipoles, respectively. Those results can be used to build more accurate templates for ground-based and space-based gravitational-wave detectors.Comment: 37 pages, 11 figures; Typos in Sec.IV Eqs.(38-42) fixe

Hubble distancing: Focusing on distance measurements in cosmology

The Hubble-Lemaitre tension is currently one of the most important questions in cosmology. Most of the focus so far has been on reconciling the Hubble constant value inferred from detailed cosmic microwave background measurement with that from the local distance ladder. This emphasis on one number -- namely $H_0$ -- misses the fact that the tension fundamentally arises from disagreements of distance measurements. To be successful, a proposed cosmological model must accurately fit these distances rather than simply infer a given value of $H_0$. Using the newly developed likelihood package `distanceladder', which integrates the local distance ladder into MontePython, we show that focusing on $H_0$ at the expense of distances can lead to the spurious detection of new physics in models which change late-time cosmology. As such, we encourage the observational cosmology community to make their actual distance measurements broadly available to model builders instead of simply quoting their derived Hubble constant values.Comment: 21 pages, 8 figure

Albert algebras over Z and other rings

Albert algebras, a specific kind of Jordan algebra, are naturally distinguished objects among commutative non-associative algebras and also arise naturally in the context of simple affine group schemes of type $F_4$, $E_6$, or $E_7$. We study these objects over an arbitrary base ring $R$, with particular attention to the case of the integers. We prove in this generality results previously in the literature in the special case where $R$ is a field of characteristic different from 2 and 3.Comment: v2: section 12 on number of generators is new, Theorem 13.5 now holds for semi-local rings (and even a somewhat wider class

When True Recognition Suppresses False Recognition: Evidence from Amnesic Patients

False recognition occurs when people mistakenly claim that a novel item is familiar. After studying lists of semantically related words, healthy controls show extraordinarily high levels of false recognition to nonstudied lures that are semantic associates of study list words. In previous experiments, we found that both Korsakoff and non-Korsakoff amnesic patients show reduced levels of false recognition to semantic associates, implying that the medial temporal/diencephalic structures that are damaged in amnesic patients are involved in the encoding and/or retrieval of information that underlies false recognition. These data contrast with earlier results indicating greater false recognition in Korsakoff amnesics than in control subjects. The present experiment tests the hypothesis that greater or lesser false recognition of semantic associates in amnesic patients, relative to normal controls, can be demonstrated by creating conditions that are more or less conducive to allowing true recognition to suppress false recognition. With repeated presentation and testing of lists of semantic associates, control subjects and both Korsakoff and non-Korsakoff amnesics showed increasing levels of true recognition across trials. However, control subjects exhibited decreasing levels of false recognition across trials, whereas Korsakoff amnesic patients showed increases across trials and non-Korsakoff amnesics showed a fluctuating pattern. Consideration of signal detection analyses and differences between the two types of amnesic patients provides insight into how mechanisms of veridical episodic memory can be used to suppress false recognition.Psycholog

Analysis of spin precession in binary black hole systems including quadrupole-monopole interaction

We analyze in detail the spin precession equations in binary black hole systems, when the tidal torque on a Kerr black hole due to quadrupole-monopole coupling is taken into account. We show that completing the precession equations with this term reveals the existence of a conserved quantity at 2PN order when averaging over orbital motion. This quantity allows one to solve the (orbit-averaged) precession equations exactly in the case of equal masses and arbitrary spins, neglecting radiation reaction. For unequal masses, an exact solution does not exist in closed form, but we are still able to derive accurate approximate analytic solutions. We also show how to incorporate radiation reaction effects into our analytic solutions adiabatically, and compare the results to solutions obtained numerically. For various configurations of the binary, the relative difference in the accumulated orbital phase computed using our analytic solutions versus a full numerical solution vary from about 0.3% to 1.8% over the 80 - 140 orbital cycles accumulated while sweeping over the orbital frequency range 20 - 300 Hz. This typically corresponds to a discrepancy of order 5-6 radians. While this may not be accurate enough for implementation in LIGO template banks, we still believe that our new solutions are potentially quite useful for comparing numerical relativity simulations of spinning binary black hole systems with post-Newtonian theory. They can also be used to gain more understanding of precession effects, with potential application to the gravitational recoil problem, and to provide semi-analytical templates for spinning, precessing binaries.Comment: version published in Phys. Rev. D, with improved figures and more detailed discussion of cubic anharmonic oscillato

Treatment of endometriosis by aromatase inhibitors: efficacy and side effects

The recent demonstration that aromatase is expressed at higher levels in endometriosis implants than in normal endometrium has led to pilot studies using inhibitor aromatasis in patients with endometriosis. We conducted a systematic review of the literature and studied the efficacy of aromatase inhibitors on endometriosis. There were seventeen studies (case reports/series) evaluating outcomes of aromatase inhibitors. Studies suggest that aromatase inhibitors alone or co-administered with progestins, oral contraceptives or gonadotrophin releasing hormone (GnRH) agonist could reduce pain and endometriosis. There is only one randomized controlled trial comparing aromatase inhibitor+GnRH agonist and GnRH agonist and one study with eighty patients. Side-effects profiles of aromatase inhibitor regimens are favorable; it does not appear a significant bone loss. Aromatase inhibitors seem to have a promising effect on endometriosis but randomized controlled trials are needed to prove their effects and their safety