Examinations into the Calcium Hypothesis of Alzheimer\u27s Disease

Alzheimer\u27s disease (AD) is devastating to the patient, their family and friends, and represents a significant fiscal burden to our society. Currently available therapeutics provide only mild symptomatic relief and do not alter the course of the disease. Developing the next generation of disease modifying therapies requires an understanding of the early cellular changes responsible for AD. A hindrance to progress is the fact that most patients develop AD sporadically. However, mutations in the presenilin (PS) homologs cause dominantly inherited, early-onset AD. These mutations provide an important tool for understanding the cellular changes that cause AD. One consequence of PS mutations is exaggerated intracellular Ca2+ ([Ca2+]i) signaling. However, the mechanisms underlying this phenomenon remain controversial and its role in AD pathogenesis is unknown. Presented here are data indicating that exaggerated [Ca2+]i signaling is dependent upon the inositol 1,4,5-trisphosphate receptor (InsP3R) and contributes to AD pathogenesis in vivo. We began our studies by testing multiple proposed mechanisms for exaggerated [Ca2+]i signaling. To do this we employed multiple Ca2+ imaging protocols and Ca2+ indicators to directly measure ER Ca2+ dynamics in several cell systems. We found that decreasing InsP3R protein level rescues exaggerated [Ca2+]i signaling in primary cortical neurons and hippocampal slices from mutant PS1 expressing mice. We then determined the contribution of exaggerated [Ca2+]i signaling to AD pathogenesis. Using a combination of genetic, biochemical, electrophysiological and behavioral techniques, we found that rescue of exaggerated [Ca2+]i signaling dramatically attenuates mild cognitive impairment and AD phenotypes in AD mouse models. Reduction of InsP3R1 protein level in PS1M146V-KIN mice rescued enhanced hippocampal ryanodine receptor protein level, enhanced hippocampal synaptic potentiation, and constitutive activation of the CaMKIV-CREB transcriptional pathway. In 3xTg mice, reduced InsP3R1 protein level attenuated Aβ and phospho-tau accumulation and hippocampal electrophysiology and memory impairments. Together, these results reveal that mutant PS-associated exaggerated [Ca2+]i signaling is InsP3R1-dependent, a proximal event, and contributes to the development of AD in vivo. These findings advance our understanding of the pathological role of exaggerated [Ca2+]i signaling in AD and identify several novel targets for the development of disease modifying therapeutics

A Simulation Analysis of the Relationship between Retail Sales and Shopping Center Rents

This article examines the variation in rents per square foot among regional shopping centers in the United States in response to variation in retail sales per square foot. The analysis breaks new ground by treating base and percentage rents as endogenous functions of retail sales. The analysis further distinguishes between de facto, if not de jure, fixed and percentage leases, and between new versus existing leases. Simulation results suggest that shopping center rents can easily increase in the short-run as retail sales decrease, or they can easily decrease as retail sales increase. In addition, the results suggest that shopping center rents per square foot generally react more aggressively to an increase in retail sales per square foot over time than to a decrease in retail sales per square foot, all else equal.

Method for delivering drugs soluble in a vaporization vehicle

This invention relates to a method for delivering drugs sublimable in a vaporization vehicle. The method involves combining a sufficient amount of a vaporization vehicle to sublime the drug and the drug to be delivered, heating the vaporization vehicle to substantially its boiling point and administering the vapor by inhalation to a subject

Droplet activation, separation, and compositional analysis: laboratory studies and atmospheric measurements [Discussion paper]

Droplets produced in a cloud condensation nucleus chamber as a function of supersaturation have been separated from unactivated aerosol particles using counterflow virtual impaction. Residual material after droplets were evaporated was chemically analyzed with an Aerodyne Aerosol Mass Spectrometer and the Particle Analysis by Laser Mass Spectrometry instrument. Experiments were initially conducted to verify activation conditions for monodisperse ammonium sulfate particles and to determine the resulting droplet size distribution as a function of supersaturation. Based on the observed droplet size, the counterflow virtual impactor cut-size was set to differentiate droplets from unactivated interstitial particles. Validation experiments were then performed to verify that only droplets with sufficient size passed through the counterflow virtual impactor for subsequent analysis. A two-component external mixture of monodisperse particles was also exposed to a supersaturation which would activate one of the types (ammonium sulfate) but not the other (polystyrene latex spheres). The mass spectrum observed after separation indicated only the former, validating separation of droplets from unactivated particles. Results from atmospheric measurements using this technique indicate that aerosol particles often activate predominantly as a function of particle size. Chemical composition is not irrelevant, however, and we observed enhancement of sulfate in droplet residuals using single particle analysis

Droplet activation, separation, and compositional analysis: laboratory studies and atmospheric measurements

Droplets produced in a cloud condensation nuclei chamber (CCNC) as a function of supersaturation have been separated from unactivated aerosol particles using counterflow virtual impaction. Residual material after droplets were evaporated was chemically analyzed with an Aerodyne Aerosol Mass Spectrometer (AMS) and the Particle Analysis by Laser Mass Spectrometry (PALMS) instrument. Experiments were initially conducted to verify activation conditions for monodisperse ammonium sulfate particles and to determine the resulting droplet size distribution as a function of supersaturation. Based on the observed droplet size, the counterflow virtual impactor cut-size was set to differentiate droplets from unactivated interstitial particles. Validation experiments were then performed to verify that only droplets with sufficient size passed through the counterflow virtual impactor for subsequent analysis. A two-component external mixture of monodisperse particles was also exposed to a supersaturation which would activate one of the types (hygroscopic salts) but not the other (polystyrene latex spheres or adipic acid). The mass spectrum observed after separation indicated only the former, validating separation of droplets from unactivated particles. Results from ambient measurements using this technique and AMS analysis were inconclusive, showing little chemical differentiation between ambient aerosol and activated droplet residuals, largely due to low signal levels. When employing as single particle mass spectrometer for compositional analysis, however, we observed enhancement of sulfate in droplet residuals

Aging and the Law

https://digitalcommons.nyls.edu/fac_books/1138/thumbnail.jp

Modeling kinetic partitioning of secondary organic aerosol and size distribution dynamics: representing effects of volatility, phase state, and particle-phase reaction

This paper describes and evaluates a new framework for modeling kinetic gas-particle partitioning of secondary organic aerosol (SOA) that takes into account diffusion and chemical reaction within the particle phase. The framework uses a combination of (a) an analytical quasi-steady-state treatment for the diffusion–reaction process within the particle phase for fast-reacting organic solutes, and (b) a two-film theory approach for slow- and nonreacting solutes. The framework is amenable for use in regional and global atmospheric models, although it currently awaits specification of the various gas- and particle-phase chemistries and the related physicochemical properties that are important for SOA formation. Here, the new framework is implemented in the computationally efficient Model for Simulating Aerosol Interactions and Chemistry (MOSAIC) to investigate the competitive growth dynamics of the Aitken and accumulation mode particles. Results show that the timescale of SOA partitioning and the associated size distribution dynamics depend on the complex interplay between organic solute volatility, particle-phase bulk diffusivity, and particle-phase reactivity (as exemplified by a pseudo-first-order reaction rate constant), each of which can vary over several orders of magnitude. In general, the timescale of SOA partitioning increases with increase in volatility and decrease in bulk diffusivity and rate constant. At the same time, the shape of the aerosol size distribution displays appreciable narrowing with decrease in volatility and bulk diffusivity and increase in rate constant. A proper representation of these physicochemical processes and parameters is needed in the next generation models to reliably predict not only the total SOA mass, but also its composition- and number-diameter distributions, all of which together determine the overall optical and cloud-nucleating properties

Working with patients and members of the public: informing health economics in child health research

This paper considers patient and public involvement (PPI) in health economics research and how this might be facilitated. PPI refers to research carried out ‘with’ or ‘by’ members of the public and is now an important aspect of health research policies internationally. Patients and members of the public can be involved in all stages of the research cycle, from establishing whether the topic is important to influencing details of study design, wording of patient-facing documentation and interpretation and dissemination of findings. PPI has become commonplace in health services research. In the context of clinical trials, it has become imperative, with, for example, patients and members of the public informing the selection of outcome measures and recruitment methods, and qualitative research is frequently steered by PPI input regarding the content of interview topic guides and the interpretation of study findings. It is less common for PPI to be explicitly reported in the economic components of health services research. However, we argue that involvement is no less important in this area. The fundamental rationale for involving people in research is that it promotes democratic principles, research quality and relevance to service users. These arguments equally apply to health economics as to other health research disciplines. Our overarching aim in this paper is to show how health economic research might be informed by PPI. We report our experiences of PPI via case studies in child health, reflect on our learnings, and make suggestions for future research practice

Assessment of Scientific Payload Carrying Spirulina Onboard Blue Origin’s New Shepard Vehicle

The research team at ERAU and UTHSCSA analyzed the effects of suborbital flight stressors and various light conditions (red, white, no light) on the Arthrospira platensis (Spirulina), onboard Blue Origin’s New Shepard vehicle. Commercially available cyanobacterium species were cultivated and closely monitored in mother colonies several months before the suborbital flight mission. The aim of this study was to estimate the biomass production and growth as a potential dietary alternative for prospective human spaceflight\u27s life support system. Spirulina samples were flown in a NanoLab with adjacent avionics supporting the light conditions and sensors to monitor the temperature, relative humidity, and accelerations. The various flight parameters measured in the NanoLab were validated with the flight data gathered by Nanoracks, the flight integrator. Thus, we also assessed the effect of microgravity and different light conditions on the gene expression. Our data indicates that the Spirulina samples onboard the rocket had significant (p \u3c 0.01-0.0001) downregulation of majority of the gene expression

Who the hell was that? Stories, bodies and actions in the world

This article explores a two-way relationship between stories and the experiential actions of bodies in the world. Through an autoethnographic approach, the article presents a series of interlinked story fragments in an effort to show and evoke a feel for the ways in which stories, bodies, and actions influence and shape each other over time. It offers some reflections on the experiences the stories portray from the perspective of a social constructionist conception of narrative theory and suggest that while stories exert a powerful influence on the actions of our bodies, our bodies intrude on or ‘talk back’ to this process because bodies have an existence beyond stories