ELISA analysis of β-secretase cleavage of the Swedish amyloid precursor protein in the secretory and endocytic pathways

Limiting beta amyloid (Aβ) production could become an important therapeutic target in Alzheimer's disease (AD). Aβ is derived by the sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases. A double missense mutation in APP found in a Swedish pedigree (APPsw) elevates Aβ40 and Aβ42 production. Aβ production and, therefore, β-secretase cleavage of APPsw reportedly occur in the endoplasmic reticulum (ER), Golgi and endocytic compartments. However, the relative contribution of β-secretase cleavage occurring in each compartment has not been determined. Experiments described here use a novel ELISA to measure the β-cleaved product, APPswβ. Using this ELISA, we provide new information regarding the relative amount of β-secretase cleavage of APPsw that occurs in secretory and endocytic pathways. Using a dilysine retrieval motif to retain APPsw in the ER, we discovered that less than 15% of the β-secretase cleavage was still detected. Experiments utilizing endocytosis-impaired mutants of APPsw revealed that little or no β-secretase cleavage of APPsw appears to take place through endocytosis. Surprisingly, deletion of the entire cytoplasmic tail increased both APPswβ and Aβ secretion, suggesting that protein interactions with this region normally impede β-secretase cleavage. These results suggest that APPsw is cleaved by β-secretase late in the secretory pathway.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66393/1/j.0022-3042.2002.00764.x.pd

Making a financial time machine:a multitouch application to enable interactive 3-D visualization of distant savings goals

Financial planning and decision making for the general public continues to vex and perplex in equal measure. Whilst the tools presented by a typical desktop computer should make the task easier, the recent financial crisis confirms the increasing difficulty that people have in calculating the benefits of deferring consumption for future gains (i.e. Saving). We present an interactive concept demonstration for Microsoft SurfaceTM that tackles two of the key barriers to saving decision making. Firstly we show an interface that avoid the laborious writing down or inputting of data and instead embodies the cognitive decision of allocation of resources in a physical gesture based interface, where the scale of the investment or expenditure correlates with the scale of the gesture. Second we show how a fast-forward based animation can demonstrate the impact of small increments in savings to a long term savings goal in a strategy game-based, interactive format. The platform uses custom software (XNATM format) as opposed to the more usual WPFTM format found on Surface applications. This enables dynamic 3-D graphical icons to be used to maximize the interactive appeal of the interface. Demonstration and test trial feedback indicates that this platform can be adapted to suit the narrative of individual purchasing decisions to inform educate diverse user groups about the long term consequences of small financial decisions

Evaluation of exercises designed to improve children's use of descriptive words in oral language

Thesis (Ed.M.)--Boston Universit

The curious nonexistence of Gaussian 2-designs

2-designs -- ensembles of quantum pure states whose 2nd moments equal those of the uniform Haar ensemble -- are optimal solutions for several tasks in quantum information science, especially state and process tomography. We show that Gaussian states cannot form a 2-design for the continuous-variable (quantum optical) Hilbert space L2(R). This is surprising because the affine symplectic group HWSp (the natural symmetry group of Gaussian states) is irreducible on the symmetric subspace of two copies. In finite dimensional Hilbert spaces, irreducibility guarantees that HWSp-covariant ensembles (such as mutually unbiased bases in prime dimensions) are always 2-designs. This property is violated by continuous variables, for a subtle reason: the (well-defined) HWSp-invariant ensemble of Gaussian states does not have an average state because the averaging integral does not converge. In fact, no Gaussian ensemble is even close (in a precise sense) to being a 2-design. This surprising difference between discrete and continuous quantum mechanics has important implications for optical state and process tomography.Comment: 9 pages, no pretty figures (sorry!

UMass Amherst Framework Principles for Provider Agreements

Rationale and 14 principles to guide investments and agreements with providers for services, infrastructure and content. Produced by the Framework for Provider Agreements Task Force

Probing Unstable Massive Neutrinos with Current Cosmic Microwave Background Observations

The pattern of anisotropies in the Cosmic Microwave Background depends upon the masses and lifetimes of the three neutrino species. A neutrino species of mass greater than 10 eV with lifetime between 10^{13} sec and 10^{17} sec leaves a very distinct signature (due to the integrated Sachs-Wolfe effect): the anisotropies at large angles are predicted to be comparable to those on degree scales. Present data exclude such a possibility and hence this region of parameter space. For $m_\nu \simeq 30$ eV, $\tau \simeq 10^{13}$ sec, we find an interesting possibility: the Integrated Sachs Wolfe peak produced by the decaying neutrino in low-$\Omega$ models mimics the acoustic peak expected in an $\Omega = 1$ model.Comment: 5 pages, 4 figure

Cost–Benefit Analysis of Coyote Removal as a Management Option in Texas Cattle Ranching

The monetary value of livestock losses attributed to coyote (Canis latrans) predation in North America has increased during the past 20 years. In Texas, USA alone in 2011, these loses were estimated at $6.9 million. To mitigate coyote-related livestock losses, several lethal and nonlethal control methods have been developed. However, there remains a need for better information to guide management decisions regarding cost-effective predator control strategies for livestock production systems. We acquired data, which was used in the model, from published literature from 1960 to present day, subject matter experts, and anecdotal information on coyote ecology. We developed a systems dynamics simulation model to evaluate the economic impact of coyote control on an average-sized cattle (Bos spp.) operation (1,000 ha) for a conceptual 10-year period in Texas. We conducted a sensitivity analyses to validate the model and identify the most sensitive parameters. We tested 88 scenarios using common coyote management methods (i.e., aerial gunning, M-44 devices, snares, livestock guard animals (LGAs), calling and shooting, and foothold traps), combinations of multiple management methods, and number of applications per year (once per year, twice per year, continuous). Several management methods were cost effective at reducing calf predation when applied sparingly and under assumptions of skillful and dedicated application of coyote control methods. The most cost-effective method of coyote control to reduce calf depredation was the combined use of snares and LGAs. When applied 1 month prior to the primary calving month, the snare/LGA combination showed an 81% decrease in overall costs of calf loss and predator management during the 10-year period, respectively. Cost effectiveness of methods deteriorated as the number of applications per year increased. While these are useful results, the intangible values of coyotes through grazing benefits (i.e., fewer prey species such as lagomorphs on the landscape to compete for forage with cattle) and ecological benefits (i.e., mitigation of meso-predator release) were not included in the model. However, these benefits should be considered by ranchers before implementing lethal coyote management

A Preliminary Mass Balance Model of Primary Productivity and Dissolved Oxygen in the Mississippi River Plume/Inner Gulf Shelf Region

A deterministic, mass balance model for phytoplankton, nutrients, and dissolved oxygen was applied to the Mississippi River Plume/Inner Gulf Shelf (MRP/IGS) region. The model was calibrated to a comprehensive set of field data collected during July 1990 at over 200 sampling stations in the northern Gulf of Mexico. The spatial domain of the model is represented by a three-dimensional, 21-segment water-column .grid extending from the Mississippi River Delta west to the Louisiana-Texas border, and from the shoreline seaward to the 30-60 m bathymetric contours. Diagnostic analyses and numerical experiments were conducted with the calibrated model to better understand the environmental processes controlling primary productivity and dissolved oxygen dynamics in the MRP/IGS region. Underwater light attenuation appears relatively more important than nutrient limitation in controlling rates of primary productivity. Chemical-biological processes appear relatively more important than advective-dispersive transport processes in controlling bottom-water dissolved oxygen dynamics. Oxidation of carbonaceous material in the water column, phytoplankton respiration, and sediment oxygen demand all appear to contribute significantly to total oxygen depletion rates in bottom waters. The estimated contribution of sediment oxygen demand to total oxygen-depletion rates in bottom waters ranges from 22% to 30%. Primary productivity appears to he an important source of dissolved oxygen to bottom waters in the region of the Atchafalaya River discharge and further west along the Louisiana Inner Shelf. Dissolved oxygen concentrations appear very sensitive to changes in underwater light attenuation due to strong coupling between dissolved oxygen and primary productivity in bottom waters. The Louisiana Inner Shelf in the area of the Atchafalaya River discharge and further west to the Texas border appears to be characterized by significantly different light attent, ation-depth-primary productivity relationships than the area immediately west of the Mississippi Delta. Nutrient remineralization in the water column appears to contribute significantly to maintaining chlorophyll concentrations on the Louisiana Inner Shelf

Understanding living with tracheostomy ventilation for motor neuron disease and the implications for quality of life: a qualitative study protocol

Introduction: Home mechanical ventilation can be used to manage symptoms of breathlessness and sustain life for people living with motor neuron disease (plwMND). In the UK, less than 1% of plwMND use tracheostomy ventilation (TV). This contrasts with some other countries, where rates are much higher. Due to a lack of evidence about its feasibility, cost-effectiveness or outcomes, TV is not covered in the UK National Institute for Health and Care Excellence guidance. Most plwMND receiving TV in the UK do so as an unplanned crisis intervention, which can lead to a prolonged hospital stay while a complex care package is arranged. There is insufficient literature addressing the burdens and benefits of TV, how it should be initiated and delivered, and how future care choices for plwMND can be supported. The aim of this research is to provide new understandings of the experiences of plwMND using TV, and those of family members and healthcare professionals (HCPs) involved in their care.Methods and analysis: A UK-wide qualitative study with two workstreams: (1) Patient focused case studies (n=6) including plwMND, family members and HCPs to focus on experiences and tasks of daily living from multiple perspectives. (2) Interviews with plwMND (n=10), family members, including bereaved family members (n=10) and HCPs (n=20) on broader experiences and issues relating to use of TV, such as ethical considerations and decision making.Ethics and dissemination: Ethical approval has been granted by the Leicester South Research Ethics Committee (22/EM/0256). All participants will be asked to provide electronic, written and/or audio recorded informed consent. Study findings will be disseminated in peer-reviewed journals and conference presentations and used to develop new resources for teaching and public information