Rational Design, Preparation, and Analysis of Chemical Reagents for Investigating Multiple Pathological Factors in Alzheimer???s Disease

School of Molecular Sciences(Chemistry)Alzheimer???s disease (AD) is the most common form of neurodegenerative disease that is currently affecting over 28 million people worldwide. Even after more than a century of research, there still is no cure or even effective, long-term therapeutics for AD. As a result, AD continues to increase in prevalence and presents a major socioeconomic burden for today???s society. The absence of a cure is most certainly a result of our limited understanding of the cause(s) of AD. For example, due to the involvement of many pathological factors, such as misfolded and aggregated proteins, dysregulated metal ions, and overproduced reactive oxygen species, it is very difficult to unravel and identify the most up-stream causative factors of AD to which a drug can be designed to correct. Therefore, it is clear that in order to begin to determine the underlying cause of AD, we first must develop tools that can be used to probe and investigate the interconnections between these pathological facets. The work presented in this dissertation highlights our efforts toward this goal. Following a detailed introduction given in Chapter 1, a structure-reactivity study is presented in Chapter 2 to determine key pharmacophores that have potential applications for the development of multifunctional chemical tools for AD. In Chapter 3, a small, compact redox-active molecule is identified as a potential anti-amyloidogenic agent for AD that relies on the formation of intramolecular ligand???peptide crosslinks and represents a novel strategy for amyloid management. The applicability of transition metal complexes to control the self-assembly of amyloid-?? (A??) peptides is further probed in Chapter 4 with the use of tetramethylcyclam metal complexes which are shown to hydrolytically cleave amide bonds of A?? peptides. Finally, Appendix A proposes a novel method to synthetically generate specific diastereomers of our tetramethylcyclam metal complexes based on a newly identified anion effect. Overall, our findings presented herein offer significant contributions toward advancing the development of chemical tools and therapeutics for AD, and our particular emphasis on establishing reaction mechanisms and biological applicability gives us further directions to improve our next-generation reagents.ope

Design Principles for Special Purpose, Embodied, Conversational Intelligence with Environmental Sensors (SPECIES) Agents

As information systems increase their ability to gather and analyze data from the natural environment and as computational power increases, the next generation of human-computer interfaces will be able to facilitate more lifelike and natural interactions with humans. This can be accomplished by using sensors to non-invasively gather information from the user, using artificial intelligence to interpret this information to perceive users’ emotional and cognitive states, and using customized interfaces and responses based on embodied-conversational-agent (avatar) technology to respond to the user. We refer to this novel and unique class of intelligent agents as Special Purpose Embodied Conversational Intelligence with Environmental Sensors (SPECIES) agents. In this paper, we build on interpersonal communication theory to specify four essential design principles of all SPECIES agents. We also share findings of initial research that demonstrates how SPECIES agents can be deployed to augment human tasks. Results of this paper organize future research efforts in collectively studying and creating more robust, influential, and intelligent SPECIES agents

Plasmodium vivax chloroquine resistance links to pvcrt transcription in a genetic cross

Mainstay treatment for Plasmodium vivax malaria has long relied on chloroquine (CQ) against blood-stage parasites plus primaquine against dormant liver-stage forms (hypnozoites), however drug resistance confronts this regimen and threatens malaria control programs. Understanding the basis of P. vivax chloroquine resistance (CQR) will inform drug discovery and malaria control. Here we investigate the genetics of P. vivax CQR by a cross of parasites differing in drug response. Gametocytogenesis, mosquito infection, and progeny production are performed with mixed parasite populations in nonhuman primates, as methods for P. vivax cloning and in vitro cultivation remain unavailable. Linkage mapping of progeny surviving \u3e 15 mg/kg CQ identifies a 76 kb region in chromosome 1 including pvcrt, an ortholog of the Plasmodium falciparum CQR transporter gene. Transcriptional analysis supports upregulated pvcrt expression as a mechanism of CQR

Polyimide based amorphous silicon solar modules

Requirements for space power are increasingly emphasizing lower costs and higher specific powers. This results from new fiscal constraints, higher power requirements for larger applications, and the evolution toward longer distance missions such as a Lunar or Mars base. The polyimide based a-Si modules described are being developed to meet these needs. The modules consist of tandem a-Si solar cell material deposited directly on a roll of polyimide. A laser scribing/printing process subdivides the deposition into discrete cell strips which are series connected to produce the required voltage without cutting the polymer backing. The result is a large, monolithic, blanket type module approximately 30 cm wide and variable in length depending on demand. Current production modules have a specific power slightly over 500 W/Kg with room for significant improvement. Costs for the full blanket modules range from $30/Watt to$150/Watt depending on quantity and engineering requirements. Work to date focused on the modules themselves and adjusting them for the AMO spectrum. Work is needed yet to insure that the modules are suitable for the space environment

Optimizing Network Connectivity for Mobile Health Technologies in sub-Saharan Africa

Background: Mobile health (mHealth) technologies hold incredible promise to improve healthcare delivery in resource-limited settings. Network reliability across large catchment areas can be a major challenge. We performed an analysis of network failure frequency as part of a study of real-time adherence monitoring in rural Uganda. We hypothesized that the addition of short messaging service (SMS+GPRS) to the standard cellular network modality (GPRS) would reduce network disruptions and improve transmission of data. Methods: Participants were enrolled in a study of real-time adherence monitoring in southwest Uganda. In June 2011, we began using Wisepill devices that transmit data each time the pill bottle is opened. We defined network failures as medication interruptions of >48 hours duration that were transmitted when network connectivity was re-established. During the course of the study, we upgraded devices from GPRS to GPRS+SMS compatibility. We compared network failure rates between GPRS and GPRS+SMS periods and created geospatial maps to graphically demonstrate patterns of connectivity. Results: One hundred fifty-seven participants met inclusion criteria of seven days of SMS and seven days of SMS+GPRS observation time. Seventy-three percent were female, median age was 40 years (IQR 33–46), 39% reported >1-hour travel time to clinic and 17% had home electricity. One hundred one had GPS coordinates recorded and were included in the geospatial maps. The median number of network failures per person-month for the GPRS and GPRS+SMS modalities were 1.5 (IQR 1.0–2.2) and 0.3 (IQR 0–0.9) respectively, (mean difference 1.2, 95%CI 1.0–1.3, p-value<0.0001). Improvements in network connectivity were notable throughout the region. Study costs increased by approximately $1USD per person-month. Conclusions: Addition of SMS to standard GPRS cellular network connectivity can significantly reduce network connection failures for mobile health applications in remote areas. Projects depending on mobile health data in resource-limited settings should consider this upgrade to optimize mHealth applications

Hop to It! The Relationship Between Hop Tests and The Anterior Cruciate Ligament – Return to Sport Index After Anterior Cruciate Ligament Reconstruction in NCAA Division 1 Collegiate Athletes

# Background Outcomes after anterior cruciate ligament reconstruction (ACLR) may not be optimal, with poor physical and psychological function potentially affecting return to sport (RTS) ability. Understanding the relationship between commonly used hop tests and the Anterior Cruciate Ligament -- Return to Sport Index (ACL-RSI) may improve rehabilitation strategies and optimize patient outcomes. # Hypothesis/Purpose The purpose of this study was to examine the relationship between ACL-RSI scores and limb symmetry index (LSI) for the single hop for distance (SHD), triple hop for distance (THD), crossover hop for distance (CHD), timed 6-meter hop (T6H), and single leg vertical hop (SLVH) in a cohort of National Collegiate Athletic Association (NCAA) Division 1 collegiate athletes after ACLR. The hypothesis was that SLVH LSI would be more highly correlated with ACL-RSI score than all horizontal hop tests. # Study design Cross-Sectional Study # Methods Twenty-one National Collegiate Athletic Association (NCAA) Division 1 collegiate athletes (7 males, 14 females) at 6.62 ± 1.69 months after ACLR were included in this retrospective study. Primary outcomes were ACL-RSI score and LSI for SHD, THD, CHD, T6H, and SLVH. The relationship between ACL-RSI scores and performance on hop tests (LSIs) was evaluated using correlation analysis and step-wise linear regression (p ≤ 0.05). # Results There were significant correlations found when comparing ACL-RSI and the LSI for SHD (r~s~ = 0.704, p \< 0.001), THD (r~s~ = 0.617, p = 0.003), CHD (r~s~ = 0.580, p = 0.006), and SLVH (r~s~ = 0.582, p = 0.006). The CHD explained 66% (R^2^ value of 0.660) of the variance in the ACL-RSI, while the other hop tests did not add to the predictive model. # Conclusions Physical function has the capacity to influence psychological status after ACLR. Clinicians should recognize that SLVH, SHD, THD, and CHD are correlated with ACL-RSI and improvements in physical function during rehabilitation may improve psychological status and optimize RTS after ACLR. # Level of evidence Level

Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer???s disease

The absence of effective therapeutics against Alzheimer???s disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-?? (A??), metal-A??, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets??? reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.ope

Human Alcohol-Microbiota Mice have Increased Susceptibility to Bacterial Pneumonia

Preclinical studies have shown that chronic alcohol abuse leads to alterations in the gastrointestinal microbiota that are associated with behavior changes, physiological alterations, and immunological effects. However, such studies have been limited in their ability to evaluate the direct effects of alcohol-associated dysbiosis. To address this, we developed a humanized alcoholmicrobiota mouse model to systematically evaluate the immunological effects of chronic alcohol abuse mediated by intestinal dysbiosis. Germ-free mice were colonized with human fecal microbiota from individuals with high and low Alcohol Use Disorders Identification Test (AUDIT) scores and bred to produce human alcohol-associated microbiota or human control-microbiota F1 progenies. F1 offspring colonized with fecal microbiota from individuals with high AUDIT scores had increased susceptibility to Klebsiella pneumoniae and Streptococcus pneumoniae pneumonia, as determined by increased mortality rates, pulmonary bacterial burden, and post-infection lung damage. These findings highlight the importance of considering both the direct effects of alcohol and alcohol-induced dysbiosis when investigating the mechanisms behind alcohol-related disorders and treatment strategies

GOES-17 Magnetometer On-Orbit Calibration Design and Results

The Geostationary Operational Environmental Satellite-R (GOES-R) is a series of four NOAA weather satellites. Each spacecraft flies a Magnetometer instrument which includes two boom mounted fluxgate sensors located 6.3 and 8.5 meters from the spacecraft. Sensor readings are corrupted by both internal (bias and scale factor) and external (spacecraft emitted fields and misalignments) error sources. In order to estimate the bias, an on-orbit calibration is performed, slewing the spacecraft about multiple axes and then performing a fit of the data to determine zero offset and misalignment terms. The first satellite in the series, GOES-16 was launched in November 2016. Its magnetometer calibration maneuver was found to be inadequate providing insufficient rotation about orthogonal axes. The uncertainty in the estimated biases was found to be in the 3-5 nanotesla range, exceeding the magnetometer accuracy requirement of 1.0 nanotesla. Based on lessons learned, the maneuver was redesigned to provide multiple 360 degree rotations about two orthogonal axes, providing optimal visibility into bias and misalignment. Varying ambient fields over the duration of the calibration maneuvers, corrupts the ability to accurately determine parameters of interest. To address this issue, rather than assuming a constant field for the duration of the maneuver, a non-linear least squares filter was employed that uses a series of spline functions to better fit the ambient field. The number of splines can be varied to minimize the least squares filter residuals. Simulations were performed using 360 days of GOES-16 data to bound the uncertainty in the biases for given residuals of the fit to the ambient field. Following the launch of the second satellite in the series, GOES-17 in March 2018, the new calibration maneuver and enhanced bias estimation algorithm were exercised twice. Based on the residuals of the fit, the uncertainty of the estimated zero offset was reduced by an order of magnitude from 3-5 nanotesla to approximately 0.4 nanotesla per axis. This paper provides details of the maneuver design and the innovative algorithm used to estimate the GOES-17 biases and misalignments