1,469 research outputs found
Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model
The amyloid-β (Aβ) peptide, the primary constituent of amyloid plaques found in Alzheimer’s disease (AD) brains, is derived from sequential proteolytic processing of the Amyloid Precursor Protein (APP). However, the contribution of different cell types to Aβ deposition has not yet been examined in an in vivo, non-overexpression system. Here, we show that endogenous APP is highly expressed in a heterogeneous subset of GABAergic interneurons throughout various laminae of the hippocampus, suggesting that these cells may have a profound contribution to AD plaque pathology. We then characterized the laminar distribution of amyloid burden in the hippocampus of an APP knock-in mouse model of AD. To examine the contribution of GABAergic interneurons to plaque pathology, we blocked Aβ production specifically in these cells using a cell type-specific knock-out of BACE1. We found that during early stages of plaque deposition, interneurons contribute to approximately 30% of the total plaque load in the hippocampus. The greatest contribution to plaque load (75%) occurs in the stratum pyramidale of CA1, where plaques in human AD cases are most prevalent and where pyramidal cell bodies and synaptic boutons from perisomatic-targeting interneurons are located. These findings reveal a crucial role of GABAergic interneurons in the pathology of AD. Our study also highlights the necessity of using APP knock-in models to correctly evaluate the cellular contribution to amyloid burden since APP overexpressing transgenic models drive expression in cell types according to the promoter and integration site and not according to physiologically relevant expression mechanisms
An Open-System Quantum Simulator with Trapped Ions
The control of quantum systems is of fundamental scientific interest and
promises powerful applications and technologies. Impressive progress has been
achieved in isolating the systems from the environment and coherently
controlling their dynamics, as demonstrated by the creation and manipulation of
entanglement in various physical systems. However, for open quantum systems,
engineering the dynamics of many particles by a controlled coupling to an
environment remains largely unexplored. Here we report the first realization of
a toolbox for simulating an open quantum system with up to five qubits. Using a
quantum computing architecture with trapped ions, we combine multi-qubit gates
with optical pumping to implement coherent operations and dissipative
processes. We illustrate this engineering by the dissipative preparation of
entangled states, the simulation of coherent many-body spin interactions and
the quantum non-demolition measurement of multi-qubit observables. By adding
controlled dissipation to coherent operations, this work offers novel prospects
for open-system quantum simulation and computation.Comment: Pre-review submission to Nature. For an updated and final version see
publication. Manuscript + Supplementary Informatio
Advancing Tests of Relativistic Gravity via Laser Ranging to Phobos
Phobos Laser Ranging (PLR) is a concept for a space mission designed to
advance tests of relativistic gravity in the solar system. PLR's primary
objective is to measure the curvature of space around the Sun, represented by
the Eddington parameter , with an accuracy of two parts in ,
thereby improving today's best result by two orders of magnitude. Other mission
goals include measurements of the time-rate-of-change of the gravitational
constant, and of the gravitational inverse square law at 1.5 AU
distances--with up to two orders-of-magnitude improvement for each. The science
parameters will be estimated using laser ranging measurements of the distance
between an Earth station and an active laser transponder on Phobos capable of
reaching mm-level range resolution. A transponder on Phobos sending 0.25 mJ, 10
ps pulses at 1 kHz, and receiving asynchronous 1 kHz pulses from earth via a 12
cm aperture will permit links that even at maximum range will exceed a photon
per second. A total measurement precision of 50 ps demands a few hundred
photons to average to 1 mm (3.3 ps) range precision. Existing satellite laser
ranging (SLR) facilities--with appropriate augmentation--may be able to
participate in PLR. Since Phobos' orbital period is about 8 hours, each
observatory is guaranteed visibility of the Phobos instrument every Earth day.
Given the current technology readiness level, PLR could be started in 2011 for
launch in 2016 for 3 years of science operations. We discuss the PLR's science
objectives, instrument, and mission design. We also present the details of
science simulations performed to support the mission's primary objectives.Comment: 25 pages, 10 figures, 9 table
Evaluating the use of the Child and Adolescent Intellectual Disability Screening Questionnaire (CAIDS-Q) to estimate IQ in children with low intellectual ability
In situations where completing a full intellectual assessment is not possible or desirable the clinician or researcher may require an alternative means of accurately estimating intellectual functioning. There has been limited research in the use of proxy IQ measures in children with an intellectual disability or low IQ. The present study aimed to provide a means of converting total scores from a screening tool (the Child and Adolescent Intellectual Disability Screening Questionnaire: CAIDS-Q) to an estimated IQ. A series of linear regression analyses were conducted on data from 428 children and young people referred to clinical services, where FSIQ was predicted from CAIDS-Q total scores. Analyses were conducted for three age groups between ages 6 and 18 years. The study presents a conversion table for converting CAIDS-Q total scores to estimates of FSIQ, with corresponding 95% prediction intervals to allow the clinician or researcher to estimate FSIQ scores from CAIDS-Q total scores. It is emphasised that, while this conversion may offer a quick means of estimating intellectual functioning in children with a below average IQ, it should be used with caution, especially in children aged between 6 and 8 years old
A formally verified compiler back-end
This article describes the development and formal verification (proof of
semantic preservation) of a compiler back-end from Cminor (a simple imperative
intermediate language) to PowerPC assembly code, using the Coq proof assistant
both for programming the compiler and for proving its correctness. Such a
verified compiler is useful in the context of formal methods applied to the
certification of critical software: the verification of the compiler guarantees
that the safety properties proved on the source code hold for the executable
compiled code as well
Pupil Size in Spider Eyes Is Linked to Post-Ecdysal Lens Growth
In this study we describe a distinctive pigment ring that appears in spider eyes after ecdysis and successively decreases in size in the days thereafter. Although pigment stops in spider eyes are well known, size variability is, to our knowledge, reported here for the first time. Representative species from three families (Ctenidae, Sparassidae and Lycosidae) are investigated and, for one of these species (Cupiennius salei, Ctenidae), the progressive increase in pupil diameter is monitored. In this species the pupil occupies only a fourth of the total projected lens surface after ecdysis and reaches its final size after approximately ten days. MicroCT images suggest that the decrease of the pigment ring is linked to the growth of the corneal lens after ecdysis. The pigment rings might improve vision in the immature eye by shielding light rays that would otherwise enter the eye via peripheral regions of the cornea, beside the growing crystalline lens
Development of the infant foot as a load bearing structure : study protocol for a longitudinal evaluation (the Small Steps study)
Background
An improved understanding of the structural and functional development of the paediatric foot is fundamental to a strong theoretical framework for health professionals and scientists. An infant’s transition from sitting, through crawling and cruising, to walking is when the structures and function of the foot must adapt to bearing load. The adaptation of skin and other hard and soft tissue, and foot and gait biomechanics, during this time is poorly understood. This is because data characterising the foot tissue and loading pre-walking onset does not exist. Of the existing kinematic and plantar pressure data, few studies have collected data which reflects the real-life activities of infants with modern equipment.
Methods
This is a longitudinal study and part of the Great Foundations Initiative, a collaborative project between the University of Brighton and the University of Salford, which is seeking to improve foot health in children. Two cohorts of 50 infants will be recruited at the two sites (University of Brighton, Eastbourne, UK and University of Salford, Salford, UK). Infants will be recruited when they first reach for their feet and attend four laboratory visits at milestones related to foot loading, with experienced independent walking being the final milestone. Data collection will include tissue characteristics (skin thickness, texture, elasticity, pH and tendon thickness and cross-sectional area), plantar pressures and kinematics captured during real world locomotion tasks.
Discussion
This study will provide a database characterising the development of the infant foot as it becomes a weight bearing structure. The data will allow effective comparison and quantification of changes in structure and function due to maturation and loading by measuring pre and post established walking. Additional variables which impact on the development of the foot (gender, ethnicity and body weight) will also be factored into our analysis. This will help us to advance understanding of the determinants of foot development in early childhood
Transmission Selects for HIV-1 Strains of Intermediate Virulence: A Modelling Approach
Recent data shows that HIV-1 is characterised by variation in viral virulence factors that is heritable between infections, which suggests that viral virulence can be naturally selected at the population level. A trade-off between transmissibility and duration of infection appears to favour viruses of intermediate virulence. We developed a mathematical model to simulate the dynamics of putative viral genotypes that differ in their virulence. As a proxy for virulence, we use set-point viral load (SPVL), which is the steady density of viral particles in blood during asymptomatic infection. Mutation, the dependency of survival and transmissibility on SPVL, and host effects were incorporated into the model. The model was fitted to data to estimate unknown parameters, and was found to fit existing data well. The maximum likelihood estimates of the parameters produced a model in which SPVL converged from any initial conditions to observed values within 100–150 years of first emergence of HIV-1. We estimated the 1) host effect and 2) the extent to which the viral virulence genotype mutates from one infection to the next, and found a trade-off between these two parameters in explaining the variation in SPVL. The model confirms that evolution of virulence towards intermediate levels is sufficiently rapid for it to have happened in the early stages of the HIV epidemic, and confirms that existing viral loads are nearly optimal given the assumed constraints on evolution. The model provides a useful framework under which to examine the future evolution of HIV-1 virulence
Structural and Functional Analysis of Phytotoxin Toxoflavin-Degrading Enzyme
Pathogenic bacteria synthesize and secrete toxic low molecular weight compounds as virulence factors. These microbial toxins play essential roles in the pathogenicity of bacteria in various hosts, and are emerging as targets for antivirulence strategies. Toxoflavin, a phytotoxin produced by Burkholderia glumae BGR1, has been known to be the key factor in rice grain rot and wilt in many field crops. Recently, toxoflavin-degrading enzyme (TxDE) was identified from Paenibacillus polymyxa JH2, thereby providing a possible antivirulence strategy for toxoflavin-mediated plant diseases. Here, we report the crystal structure of TxDE in the substrate-free form and in complex with toxoflavin, along with the results of a functional analysis. The overall structure of TxDE is similar to those of the vicinal oxygen chelate superfamily of metalloenzymes, despite the lack of apparent sequence identity. The active site is located at the end of the hydrophobic channel, 9 Ã… in length, and contains a Mn(II) ion interacting with one histidine residue, two glutamate residues, and three water molecules in an octahedral coordination. In the complex, toxoflavin binds in the hydrophobic active site, specifically the Mn(II)-coordination shell by replacing a ligating water molecule. A functional analysis indicated that TxDE catalyzes the degradation of toxoflavin in a manner dependent on oxygen, Mn(II), and the reducing agent dithiothreitol. These results provide the structural features of TxDE and the early events in catalysis
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