697 research outputs found
Murine models of Alzheimer's disease and their use in developing immunotherapies
AbstractAlzheimer's disease (AD) is one of the categories of neurodegenerative diseases characterized by a conformational change of a normal protein into a pathological conformer with a high β-sheet content that renders it resistant to degradation and neurotoxic. In AD, the normal soluble amyloid β (sAβ) peptide is converted into oligomeric/fibrillar Aβ. The oligomeric forms of Aβ are thought to be the most toxic, while fibrillar Aβ becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. An additional important feature of AD is the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles. Many therapeutic interventions are under investigation to prevent and treat AD. The testing of these diverse approaches to ameliorate AD pathology has been made possible by the existence of numerous transgenic mouse models which each mirror specific aspects of AD pathology. None of the current murine models is a perfect match of the human disease. Perhaps the most exciting of the therapeutic approaches being developed is immunomodulation targeting the aggregating proteins, Aβ and tau. This type of AD therapy is currently being assessed in many transgenic mouse models, and promising findings have led to clinical trials. However, there is a discrepancy between results in murine models and ongoing clinical trials, which highlight the limitations of these models and also of our understanding of the underlying etiology and pathogenesis of AD. Because of these uncertainties, Tg models for AD are continuously being refined with the aim to better understand the disease and to enhance the predictive validity of potential treatments such as immunotherapies
Preventing β-amyloid fibrillization and deposition: β-sheet breakers and pathological chaperone inhibitors
Central to the pathogenesis of Alzheimer's disease (AD) is the conversion of normal, soluble β-amyloid (sAβ) to oligomeric, fibrillar Aβ. This process of conformational conversion can be influenced by interactions with other proteins that can stabilize the disease-associated state; these proteins have been termed 'pathological chaperones'. In a number of AD models, intervention that block soluble Aβ aggregation, including β-sheet breakers, and compounds that block interactions with pathological chaperones, have been shown to be highly effective. When combined with early pathology detection, these therapeutic strategies hold great promise as effective and relatively toxicity free methods of preventing AD related pathology
Carbonic anhydrase inhibition selectively prevents amyloid b neurovascular mitochondrial toxicity
Mounting evidence suggests that mitochondrial dysfunction plays a causal role in the etiology and progression of Alzheimer’s disease (AD). We recently showed that the carbonic anhydrase inhibitor (CAI) methazolamide (MTZ) prevents amyloid b (Ab)-mediated onset of apoptosis in the mouse brain. In this study, we used MTZ and, for the first time, the analog CAI acetazolamide (ATZ) in neuronal and cerebral vascular cells challenged with Ab, to clarify their protective effects and mitochondrial molecular mechanism of action. The CAIs selectively inhibited mitochondrial dysfunction pathways induced by Ab, without affecting metabolic function. ATZ was effective at concentrations 10 times lower than MTZ. Both MTZ and ATZ prevented mitochondrial membrane depolarization and H2O2 generation, with no effects on intracellular pH or ATP production. Importantly, the drugs did not primarily affect calcium homeostasis. This work suggests a new role for carbonic anhydrases (CAs) in the Ab-induced mitochondrial toxicity associated with AD and cerebral amyloid angiopathy (CAA), and paves the way to AD clinical trials for CAIs, FDA-approved drugs with a well-known profile of brain delivery
Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an alzheimer's disease model mouse
<p>Abstract</p> <p>Background</p> <p>Alzheimer's Disease (AD) is the most common of the conformational neurodegenerative disorders characterized by the conversion of a normal biological protein into a β-sheet-rich pathological isoform. In AD the normal soluble Aβ (sAβ) forms oligomers and fibrils which assemble into neuritic plaques. The most toxic form of Aβ is thought to be oligomeric. A recent study reveals the cellular prion protein, PrP<sup>C</sup>, to be a receptor for Aβ oligomers. Aβ oligomers suppress LTP signal in murine hippocampal slices but activity remains when pretreated with the PrP monoclonal anti-PrP antibody, 6D11. We hypothesized that targeting of PrP<sup>C </sup>to prevent Aβ oligomer-related cognitive deficits is a potentially novel therapeutic approach. APP/PS1 transgenic mice aged 8 months were intraperitoneally (i.p.) injected with 1 mg 6D11 for 5 days/week for 2 weeks. Two wild-type control groups were given either the same 6D11 injections or vehicle solution. Additional groups of APP/PS1 transgenic mice were given either i.p. injections of vehicle solution or the same dose of mouse IgG over the same period. The mice were then subjected to cognitive behavioral testing using a radial arm maze, over a period of 10 days. At the conclusion of behavioral testing, animals were sacrificed and brain tissue was analyzed biochemically or immunohistochemically for the levels of amyloid plaques, PrP<sup>C</sup>, synaptophysin, Aβ40/42 and Aβ oligomers.</p> <p>Results</p> <p>Behavioral testing showed a marked decrease in errors in 6D11 treated APP/PS1 Tg mice compared with the non-6D11 treated Tg groups (p < 0.0001). 6D11 treated APP/PS1 Tg mice behaved the same as wild-type controls indicating a recovery in cognitive learning, even after this short term 6D11 treatment. Brain tissue analysis from both treated and vehicle treated APP/PS1 groups indicate no significant differences in amyloid plaque burden, Aβ40/42, PrP<sup>C </sup>or Aβ oligomer levels. 6D11 treated APP/PS1 Tg mice had significantly greater synaptophysin immunoreactivity in the dentate gyrus molecular layer of the hippocampus compared to vehicle treated APP/PS1 Tg mice (p < 0.05).</p> <p>Conclusions</p> <p>Even short term treatment with monoclonal antibodies such as 6D11 or other compounds which block the binding of Aβ oligomers to PrP<sup>C </sup>can be used to treat cognitive deficits in aged AD transgenic mice.</p
Towards Space-like Photometric Precision from the Ground with Beam-Shaping Diffusers
We demonstrate a path to hitherto unachievable differential photometric
precisions from the ground, both in the optical and near-infrared (NIR), using
custom-fabricated beam-shaping diffusers produced using specialized
nanofabrication techniques. Such diffusers mold the focal plane image of a star
into a broad and stable top-hat shape, minimizing photometric errors due to
non-uniform pixel response, atmospheric seeing effects, imperfect guiding, and
telescope-induced variable aberrations seen in defocusing. This PSF reshaping
significantly increases the achievable dynamic range of our observations,
increasing our observing efficiency and thus better averages over
scintillation. Diffusers work in both collimated and converging beams. We
present diffuser-assisted optical observations demonstrating
ppm precision in 30 minute bins on a nearby bright star
16-Cygni A (V=5.95) using the ARC 3.5m telescope---within a factor of 2
of Kepler's photometric precision on the same star. We also show a transit of
WASP-85-Ab (V=11.2) and TRES-3b (V=12.4), where the residuals bin down to
ppm in 30 minute bins for WASP-85-Ab---a factor of 4 of
the precision achieved by the K2 mission on this target---and to 101ppm for
TRES-3b. In the NIR, where diffusers may provide even more significant
improvements over the current state of the art, our preliminary tests have
demonstrated ppm precision for a star on the 200"
Hale Telescope. These photometric precisions match or surpass the expected
photometric precisions of TESS for the same magnitude range. This technology is
inexpensive, scalable, easily adaptable, and can have an important and
immediate impact on the observations of transits and secondary eclipses of
exoplanets.Comment: Accepted for publication in ApJ. 30 pages, 20 figure
Probing for Exoplanets Hiding in Dusty Debris Disks: Disk Imaging, Characterization, and Exploration with HST/STIS Multi-Roll Coronagraphy
Spatially resolved scattered-light images of circumstellar (CS) debris in
exoplanetary systems constrain the physical properties and orbits of the dust
particles in these systems. They also inform on co-orbiting (but unseen)
planets, systemic architectures, and forces perturbing starlight-scattering CS
material. Using HST/STIS optical coronagraphy, we have completed the
observational phase of a program to study the spatial distribution of dust in
ten CS debris systems, and one "mature" protoplanetrary disk all with HST
pedigree, using PSF-subtracted multi-roll coronagraphy. These observations
probe stellocentric distances > 5 AU for the nearest stars, and simultaneously
resolve disk substructures well beyond, corresponding to the giant planet and
Kuiper belt regions in our Solar System. They also disclose diffuse very
low-surface brightness dust at larger stellocentric distances. We present new
results inclusive of fainter disks such as HD92945 confirming, and better
revealing, the existence of a narrow inner debris ring within a larger diffuse
dust disk. Other disks with ring-like sub-structures, significant asymmetries
and complex morphologies include: HD181327 with a posited spray of ejecta from
a recent massive collision in an exo-Kuiper belt; HD61005 suggested interacting
with the local ISM; HD15115 & HD32297, discussed also in the context of
environmental interactions. These disks, and HD15745, suggest debris system
evolution cannot be treated in isolation. For AU Mic's edge-on disk,
out-of-plane surface brightness asymmetries at > 5 AU may implicate one or more
planetary perturbers. Time resolved images of the MP Mus proto-planetary disk
provide spatially resolved temporal variability in the disk illumination. These
and other new images from our program enable direct inter-comparison of the
architectures of these exoplanetary debris systems in the context of our own
Solar System.Comment: 109 pages, 43 figures, accepted for publication in the Astronomical
Journa
Resolution of the type material of the Asian elephant, Elephas maximus Linnaeus, 1758 (Proboscidea, Elephantidae)
The understanding of Earth’s biodiversity depends critically on the accurate identification and nomenclature of
species. Many species were described centuries ago, and in a surprising number of cases their nomenclature or type
material remain unclear or inconsistent. A prime example is provided by Elephas maximus, one of the most iconic
and well-known mammalian species, described and named by Linnaeus (1758) and today designating the Asian
elephant. We used morphological, ancient DNA (aDNA), and high-throughput ancient proteomic analyses to
demonstrate that a widely discussed syntype specimen of E. maximus, a complete foetus preserved in ethanol, is
actually an African elephant, genus Loxodonta. We further discovered that an additional E. maximus syntype,
mentioned in a description by John Ray (1693) cited by Linnaeus, has been preserved as an almost complete skeleton
at the Natural History Museum of the University of Florence. Having confirmed its identity as an Asian elephant
through both morphological and ancient DNA analyses, we designate this specimen as the lectotype of E. maximus
Differences in the gas and dust distribution in the transitional disk of a sun-like young star, PDS 70
We present ALMA 0.87 mm continuum, HCO+ J=4--3 emission line, and CO J=3--2
emission line data of the disk of material around the young, Sun-like star PDS
70. These data reveal the existence of a possible two component transitional
disk system with a radial dust gap of 0."2 +/- 0."05, an azimuthal gap in the
HCO+ J=4--3 moment zero map, as well as two bridge-like features in the gas
data. Interestingly these features in the gas disk have no analogue in the dust
disk making them of particular interest. We modeled the dust disk using the
Monte Carlo radiative transfer code HOCHUNK3D (Whitney et al. 2013) using a two
disk components. We find that there is a radial gap that extends from 15-60 au
in all grain sizes which differs from previous work
An evaluation of Cochrane Crowd found that crowdsourcing produced accurate results in identifying randomised trials
BACKGROUND: Filtering the deluge of new research to facilitate evidence synthesis has proven to be unmanageable using current paradigms of search and retrieval. Crowdsourcing, a way of harnessing the collective effort of a 'crowd' of people, has the potential to support evidence synthesis by addressing this information overload created by the exponential growth in primary research outputs. Cochrane Crowd, Cochrane's citizen science platform, offers a range of tasks aimed at identifying studies related to healthcare. Accompanying each task are brief, interactive training modules and agreement algorithms that help ensure accurate collective decision-making. OUR OBJECTIVES WERE: (1) to evaluate the performance of Cochrane Crowd in terms of its accuracy, capacity and autonomy; and (2) to examine contributor engagement across three tasks aimed at identifying randomised trials. STUDY DESIGN: Crowd accuracy was evaluated by measuring the sensitivity and specificity of crowd screening decisions on a sample of titles and abstracts, compared with 'quasi gold-standard' decisions about the same records using the conventional methods of dual screening. Crowd capacity, in the form of output volume, was evaluated by measuring the number of records processed by the crowd, compared with baseline. Crowd autonomy, the capability of the crowd to produce accurate collectively-derived decisions without the need for expert resolution, was measured by the proportion of records that needed resolving by an expert. RESULTS: The Cochrane Crowd community currently has 18,897 contributors from 163 countries. Collectively, the Crowd has processed 1,021,227 records, helping to identify 178,437 reports of randomised trials (RCTs) for Cochrane's Central Register of Controlled Trials. The sensitivity for each task was 99.1% for the randomised controlled trial identification task (RCT ID), 99.7% for the randomised controlled trial identification task of trial from ClinicalTrials.gov (CT ID) and 97.7% for identification of randomised controlled trials from the International Clinical Trials Registry Platform (ICTRP ID). The specificity for each task was 99% for RCT ID, 98.6% for CT ID and 99.1% for ICTRP ID. The capacity of the combined Crowd and machine learning workflow has increased five-fold in six years, compared with baseline. The proportion of records requiring expert resolution across the tasks ranged from 16.6% to 19.7%. CONCLUSION: Cochrane Crowd is sufficiently accurate and scalable to keep pace with the current rate of publication (and registration) of new primary studies. It has also proved to be a popular, efficient and accurate way for a large number of people to play an important voluntary role in health evidence production. Cochrane Crowd is now an established part of Cochrane's effort to manage the deluge of primary research being produced
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