2,279 research outputs found
C9orf72-Associated FTD/ALS: When Less Is More
Hexanucleotide repeat expansions in C9ORF72 cause neurodegeneration in FTD and ALS by unknown mechanisms. A new report, by Donnelly et al. (2013), finds that these repeats trigger a pathogenic gain-of-function cascade that can be corrected by suppressing expression of the repeat transcript, paving the way for therapeutic strategies aimed at eliminating the toxic RNA
RNA-mediated neurodegeneration in repeat expansion disorders
Most neurodegenerative disorders are thought to result primarily from the accumulation of misfolded proteins, which interfere with protein homeostasis in neurons. For a subset of diseases, however, noncoding regions of RNAs assume a primary toxic gain-of-function, leading to degeneration in many tissues, including the nervous system. Here we review a series of proposed mechanisms by which noncoding repeat expansions give rise to nervous system degeneration and dysfunction. These mechanisms include transcriptional alterations and the generation of antisense transcripts, sequestration of mRNA-associated protein complexes that lead to aberrant mRNA splicing and processing, and alterations in cellular processes, including activation of abnormal signaling cascades and failure of protein quality control pathways. We place these potential mechanisms in the context of known RNA-mediated disorders, including the myotonic dystrophies and fragile X tremor ataxia syndrome, and discuss recent results suggesting that mRNA toxicity may also play a role in some presumably protein-mediated neurodegenerative disorders. Lastly, we comment on recent progress in therapeutic development for these RNA-dominant diseases. ANN NEUROL 2010;67:291â300Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69199/1/21948_ftp.pd
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Estimation after subpopulation selection in adaptive seamless trials
During the development of new therapies, it is not uncommon to test whether a new treatment works better than the existing treatment for all patients who suffer from a condition (full population) or for a subset of the full population (subpopulation). One approach that may be used for this objective is to have two separate trials, where in the first trial, data are collected to determine if the new treatment benefits the full population or the subpopulation. The second trial is a confirmatory trial to test the new treatment in the population selected in the first trial. In this paper, we consider the more efficient two-stage adaptive seamless designs (ASDs), where in stage 1, data are collected to select the population to test in stage 2. In stage 2, additional data are collected to perform confirmatory analysis for the selected population. Unlike the approach that uses two separate trials, for ASDs, stage 1 data are also used in the confirmatory analysis. Although ASDs are efficient, using stage 1 data both for selection and confirmatory analysis introduces selection bias and consequently statistical challenges in making inference. We will focus on point estimation for such trials. In this paper, we describe the extent of bias for estimators that ignore multiple hypotheses and selecting the population that is most likely to give positive trial results based on observed stage 1 data. We then derive conditionally unbiased estimators and examine their mean squared errors for different scenarios
Repeatâassociated nonâAUG translation from antisense CCG repeats in fragile X tremor/ataxia syndrome
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135162/1/ana24800_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135162/2/ana24800.pd
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Point and interval estimation in two-stage adaptive designs with time to event data and biomarker-driven subpopulation selection
In personalized medicine, it is often desired to determine if all patients or only a subset of them benefit from a treatment. We consider estimation in twoâstage adaptive designs that in stage 1 recruit patients from the full population. In stage 2, patient recruitment is restricted to the part of the population, which, based on stage 1 data, benefits from the experimental treatment. Existing estimators, which adjust for using stage 1 data for selecting the part of the population from which stage 2 patients are recruited, as well as for the confirmatory analysis after stage 2, do not consider time to event patient outcomes. In this work, for time to event data, we have derived a new asymptotically unbiased estimator for the log hazard ratio and a new interval estimator with good coverage probabilities and probabilities that the upper bounds are below the true values. The estimators are appropriate for several selection rules that are based on a single or multiple biomarkers, which can be categorical or continuous
Repeat-Associated Non-AUG (RAN) Translation and Other Molecular Mechanisms in Fragile X Tremor Ataxia Syndrome
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset inherited neurodegenerative disorder characterized by progressive intention tremor, gait ataxia and dementia associated with mild brain atrophy. The cause of FXTAS is a premutation expansion, of 55 to 200 CGG repeats localized within the 5âČUTR of FMR1. These repeats are transcribed in the sense and antisense directions into mutants RNAs, which have increased expression in FXTAS. Furthermore, CGG sense and CCG antisense expanded repeats are translated into novel proteins despite their localization in putatively non-coding regions of the transcript. Here we focus on two proposed disease mechanisms for FXTAS: 1) RNA gain-of-function, whereby the mutant RNAs bind specific proteins and preclude their normal functions, and 2) repeat-associated non-AUG (RAN) translation, whereby translation through the CGG or CCG repeats leads to the production of toxic homopolypeptides, which in turn interfere with a variety of cellular functions. Here, we analyze the data generated to date on both of these potential molecular mechanisms and lay out a path forward for determining which factors drive FXTAS pathogenicity
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On the need to adjust for multiplicity in confirmatory clinical trials with master protocols
Pulp and Papermaking Properties of A Hybrid Poplar Clone Grown Under Four Management Strategies and Two Soil Sites
A study was undertaken to evaluate the pulp and papermaking properties of short rotation intensive culture (SRIC), three-year-old, Populus hybrid grown under four management strategies (control, irrigation, fertilization, and fertilization/irrigation) on two sites with either favorable or unfavorable inherent conditions for high biomass yields. No large differences in total pulp yields were observed with management strategy, although the fertilization/irrigation growth strategy produced debarked chips that gave slightly higher total pulp yields with lower permanganate numbers than did debarked chips obtained from the other three growth strategies. In addition, no significant differences (P †0.05) in total kraft pulp yields were observed between sites. As expected, the wood/bark chip mixture for each management strategy and site produced significantly lower pulp yields with higher permanganate numbers compared to the debarked chips.Handsheet strength evaluation studies were conducted using these pulps, and no statistical differences in handsheet breaking length, tear, burst, and M.I.T. fold were measured among management strategies or sites. However, longer fibers were measured from wood obtained from trees grown on the Basher (favorable) site. No statistical differences in handsheet properties were measured between debarked and total tree pulps. Results of this study indicated that neither the growth management strategy nor the soil site influenced handsheet strength properties for three-year-old Populus hybrid. These observations imply that the silviculturalist should grow SRIC Populus trees that produce the highest biomass yield at lowest possible cost
Blooms of Dinoflagellate Mixotrophs in a Lower Chesapeake Bay Tributary: Carbon and Nitrogen Uptake over Diurnal, Seasonal, and Interannual Timescales
A multi-year study was conducted in the eutrophic Lafayette River, a sub-tributary of the lower Chesapeake Bay during which uptake of inorganic and organic nitrogen (N) and C compounds was measured during multiple seasons and years when different dinoflagellate species were dominant. Seasonal dinoflagellate blooms included a variety of mixotrophic dinoflagellates including Heterocapsa triquetra in the late winter, Prorocentrum minimum in the spring, Akashiwo sanguinea in the early summer, and Scrippsiella trochoidea and Cochlodinium polykrikoides in late summer and fall. Results showed that no single N source fueled algal growth, rather rates of N and C uptake varied on seasonal and diurnal timescales, and within blooms as they initiated and developed. Rates of photosynthetic C uptake were low yielding low assimilation numbers during much of the study period and the ability to assimilate dissolved organic carbon augmented photosynthetic C uptake during bloom and non-bloom periods. The ability to use dissolved organic C during the day and night may allow mixotrophic bloom organisms a competitive advantage over co-occurring phytoplankton that are restricted to photoautotrophic growth, obtaining N and C during the day and in well-lit surface waters
Novel model for end-neuroma formation in the amputated rabbit forelimb
<p>Abstract</p> <p>Background</p> <p>The forelimb amputee poses many reconstructive challenges in the clinical setting, and there is a paucity of established surgical models for study. To further elucidate the pathogenic process in amputation neuroma formation, we created a reproducible, well-tolerated rabbit forelimb amputation model.</p> <p>Methods</p> <p>Upon approval from the Institutional Animal Care and Use Committee, 5 New Zealand White rabbits underwent left forelimb amputation. During this initial surgery, the median, radial and ulnar nerves were transected 1.6-2.5 (mean 2.0) cm distal to the brachial plexus, transposed onto the anterior chest wall and preserved at length. Six weeks subsequent to the amputation, the distal 5 mm of each neuroma was excised, and the remaining stump underwent histomorphometric analysis.</p> <p>Results</p> <p>The nerve cross sectional areas increased by factors of 1.99, 3.17, and 2.59 in the median (p = 0.077), radial (p < 0.0001) and the ulnar (p = 0.0026) nerves, respectively. At the axonal level, the number and cross-sectional area of myelinated fibers demonstrated an inverse relationship whereby the number of myelinated fibers in the median, radial and ulnar nerves increased by factors of 5.13 (p = 0.0043), 5.25 (p = 0.0056) and 5.59 (p = 0.0027), and the cross-sectional areas of these myelinated fibers decreased by factors of 4.62 (p < 0.001), 3.51 (p < 0.01), and 4.29 (p = 0.0259), respectively.</p> <p>Conclusion</p> <p>Given that the surgical model appears well-tolerated by the rabbits and that patterns of morphologic change are consistent and reproducible, we are encouraged to further investigate the utility of this model in the pathogenesis of neuroma formation.</p
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