1,335 research outputs found
Fiber-Flux Diffusion Density for White Matter Tracts Analysis: Application to Mild Anomalies Localization in Contact Sports Players
We present the concept of fiber-flux density for locally quantifying white
matter (WM) fiber bundles. By combining scalar diffusivity measures (e.g.,
fractional anisotropy) with fiber-flux measurements, we define new local
descriptors called Fiber-Flux Diffusion Density (FFDD) vectors. Applying each
descriptor throughout fiber bundles allows along-tract coupling of a specific
diffusion measure with geometrical properties, such as fiber orientation and
coherence. A key step in the proposed framework is the construction of an FFDD
dissimilarity measure for sub-voxel alignment of fiber bundles, based on the
fast marching method (FMM). The obtained aligned WM tract-profiles enable
meaningful inter-subject comparisons and group-wise statistical analysis. We
demonstrate our method using two different datasets of contact sports players.
Along-tract pairwise comparison as well as group-wise analysis, with respect to
non-player healthy controls, reveal significant and spatially-consistent FFDD
anomalies. Comparing our method with along-tract FA analysis shows improved
sensitivity to subtle structural anomalies in football players over standard FA
measurements
Bridging Time Scales in Cellular Decision Making with a Stochastic Bistable Switch
Cellular transformations which involve a significant phenotypical change of
the cell's state use bistable biochemical switches as underlying decision
systems. In this work, we aim at linking cellular decisions taking place on a
time scale of years to decades with the biochemical dynamics in signal
transduction and gene regulation, occuring on a time scale of minutes to hours.
We show that a stochastic bistable switch forms a viable biochemical mechanism
to implement decision processes on long time scales. As a case study, the
mechanism is applied to model the initiation of follicle growth in mammalian
ovaries, where the physiological time scale of follicle pool depletion is on
the order of the organism's lifespan. We construct a simple mathematical model
for this process based on experimental evidence for the involved genetic
mechanisms. Despite the underlying stochasticity, the proposed mechanism turns
out to yield reliable behavior in large populations of cells subject to the
considered decision process. Our model explains how the physiological time
constant may emerge from the intrinsic stochasticity of the underlying gene
regulatory network. Apart from ovarian follicles, the proposed mechanism may
also be of relevance for other physiological systems where cells take binary
decisions over a long time scale.Comment: 14 pages, 4 figure
A deletion of FGFR2 creating a chimeric IIIb/IIIc exon in a child with Apert syndrome
<p>Abstract</p> <p>Background</p> <p>Signalling by fibroblast growth factor receptor type 2 (FGFR2) normally involves a tissue-specific alternative splice choice between two exons (IIIb and IIIc), which generates two receptor isoforms (FGFR2b and FGFR2c respectively) with differing repertoires of FGF-binding specificity. Here we describe a unique chimeric IIIb/c exon in a patient with Apert syndrome, generated by a non-allelic homologous recombination event.</p> <p>Case Presentation</p> <p>We present a child with Apert syndrome in whom routine genetic testing had excluded the <it>FGFR2 </it>missense mutations commonly associated with this disorder. The patient was found to harbour a heterozygous 1372 bp deletion between <it>FGFR2 </it>exons IIIb and IIIc, apparently originating from recombination between 13 bp of identical DNA sequence present in both exons. The rearrangement was not present in the unaffected parents.</p> <p>Conclusions</p> <p>Based on the known pathogenesis of Apert syndrome, the chimeric FGFR2 protein is predicted to act in a dominant gain-of-function manner. This is likely to result from its expression in mesenchymal tissues, where retention of most of the residues essential for FGFR2b binding activity would result in autocrine activation. This report adds to the repertoire of rare cases of Apert syndrome for which a pathogenesis based on atypical <it>FGFR2 </it>rearrangements can be demonstrated.</p
Intervention to enhance skilled arm and hand movements after stroke: A feasibility study using a new virtual reality system
<p>Abstract</p> <p>Background</p> <p>Rehabilitation programs designed to develop skill in upper extremity (UE) function after stroke require progressive practice that engage and challenge the learner. Virtual realty (VR) provides a unique environment where the presentation of stimuli can be controlled systematically for optimal challenge by adapting task difficulty as performance improves. We describe four VR tasks that were developed and tested to improve arm and hand movement skills for individuals with hemiparesis.</p> <p>Methods</p> <p>Two participants with chronic post-stroke paresis and different levels of motor severity attended 12 training sessions lasting 1 to 2 hours each over a 3-week period. Behavior measures and questionnaires were administered pre-, mid-, and post-training.</p> <p>Results</p> <p>Both participants improved VR task performance across sessions. The less impaired participant averaged more time on task, practiced a greater number of blocks per session, and progressed at a faster rate over sessions than the more impaired participant. Impairment level did not change but both participants improved functional ability after training. The less impaired participant increased the number of blocks moved on the Box & Blocks test while the more impaired participant achieved 4 more items on the Functional Test of the Hemiparetic UE.</p> <p>Conclusion</p> <p>Two participants with differing motor severity were able to engage in VR based practice and improve performance over 12 training sessions. We were able to successfully provide individualized, progressive practice based on each participant's level of movement ability and rate of performance improvement.</p
Bright ligand-activatable fluorescent protein for high-quality multicolor live-cell super-resolution microscopy
We introduce UnaG as a green-to-dark photoswitching fluorescent protein capable of high-quality super-resolution imaging with photon numbers equivalent to the brightest photoswitchable red protein. UnaG only fluoresces upon binding of a fluorogenic metabolite, bilirubin, enabling UV-free reversible photoswitching with easily controllable kinetics and low background under Epi illumination. The on- and off-switching rates are controlled by the concentration of the ligand and the excitation light intensity, respectively, where the dissolved oxygen also promotes the off-switching. The photo-oxidation reaction mechanism of bilirubin in UnaG suggests that the lack of ligand-protein covalent bond allows the oxidized ligand to detach from the protein, emptying the binding cavity for rebinding to a fresh ligand molecule. We demonstrate super-resolution single-molecule localization imaging of various subcellular structures genetically encoded with UnaG, which enables facile labeling and simultaneous multicolor imaging of live cells. UnaG has the promise of becoming a default protein for high-performance super-resolution imaging. Photoconvertible proteins occupy two color channels thereby limiting multicolour localisation microscopy applications. Here the authors present UnaG, a new green-to-dark photoswitching fluorescent protein for super-resolution imaging, whose activation is based on a noncovalent binding with bilirubin
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Transcription Factor NF-κB Is Transported to the Nucleus via Cytoplasmic Dynein/Dynactin Motor Complex in Hippocampal Neurons
Mikenberg I, Widera D, Kaus A, Kaltschmidt B, Kaltschmidt C. Transcription Factor NF-kappa B Is Transported to the Nucleus via Cytoplasmic Dynein/Dynactin Motor Complex in Hippocampal Neurons. PLOS ONE. 2007;2(7):e589.Background. Long-term changes in synaptic plasticity require gene transcription, indicating that signals generated at the synapse must be transported to the nucleus. Synaptic activation of hippocampal neurons is known to trigger retrograde transport of transcription factor NF-kappa B. Transcription factors of the NF-kappa B family are widely expressed in the nervous system and regulate expression of several genes involved in neuroplasticity, cell survival, learning and memory. Principal Findings. In this study, we examine the role of the dynein/dynactin motor complex in the cellular mechanism targeting and transporting activated NF-kappa B to the nucleus in response to synaptic stimulation. We demonstrate that overexpression of dynamitin, which is known to dissociate dynein from microtubules, and treatment with microtubule-disrupting drugs inhibits nuclear accumulation of NF-kappa B p65 and reduces NF-kappa B-dependent transcription activity. In this line, we show that p65 is associated with components of the dynein/dynactin complex in vivo and in vitro and that the nuclear localization sequence (NLS) within NF-kappa B p65 is essential for this binding. Conclusion. This study shows the molecular mechanism for the retrograde transport of activated NF-kappa B from distant synaptic sites towards the nucleus
Chitosan encapsulation modulates the effect of capsaicin on the tight junctions of MDCK cells
Capsaicin has known pharmacological effects including the ability to reversibly open cellular tight junctions, among others. The aim of this study was to develop a strategy to enhance the paracellular transport of a substance with low permeability (FITC-dextran) across an epithelial cell monolayer via reversible opening of cellular tight junctions using a nanosystem comprised by capsaicin and of chitosan. We compared the biophysical properties of free capsaicin and capsaicin-loaded chitosan nanocapsules, including their cytotoxicity towards epithelial MDCK-C7 cells and their effect on the integrity of tight junctions, membrane permeability and cellular uptake. The cytotoxic response of MDCK-C7 cells to capsaicin at a concentration of 500 μM, which was evident for the free compound, is not observable following its encapsulation. The interaction between nanocapsules and the tight junctions of MDCK-C7 cells was investigated by impedance spectroscopy, digital holographic microscopy and structured illumination fluorescence microscopy. The nanocapsules modulated the interaction between capsaicin and tight junctions as shown by the different time profile of trans-epithelial electrical resistance and the enhanced permeability of monolayers incubated with FITC-dextran. Structured illumination fluorescence microscopy showed that the nanocapsules were internalized by MDCK-C7 cells. The capsaicin-loaded nanocapsules could be further developed as drug nanocarriers with enhanced epithelial permeability
Improved Weighted Random Forest for Classification Problems
Several studies have shown that combining machine learning models in an
appropriate way will introduce improvements in the individual predictions made
by the base models. The key to make well-performing ensemble model is in the
diversity of the base models. Of the most common solutions for introducing
diversity into the decision trees are bagging and random forest. Bagging
enhances the diversity by sampling with replacement and generating many
training data sets, while random forest adds selecting a random number of
features as well. This has made the random forest a winning candidate for many
machine learning applications. However, assuming equal weights for all base
decision trees does not seem reasonable as the randomization of sampling and
input feature selection may lead to different levels of decision-making
abilities across base decision trees. Therefore, we propose several algorithms
that intend to modify the weighting strategy of regular random forest and
consequently make better predictions. The designed weighting frameworks include
optimal weighted random forest based on ac-curacy, optimal weighted random
forest based on the area under the curve (AUC), performance-based weighted
random forest, and several stacking-based weighted random forest models. The
numerical results show that the proposed models are able to introduce
significant improvements compared to regular random forest
Pseudo-acetylation of multiple sites on human Tau proteins alters Tau phosphorylation and microtubule binding, and ameliorates amyloid beta toxicity
Tau is a microtubule-associated protein that is highly soluble and natively unfolded. Its dysfunction is involved in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease (AD), where it aggregates within neurons. Deciphering the physiological and pathogenic roles of human Tau (hTau) is crucial to further understand the mechanisms leading to its dysfunction in vivo. We have used a knock-out/knock-in strategy in Drosophila to generate a strain with hTau inserted into the endogenous fly tau locus and expressed under the control of the endogenous fly tau promoter, thus avoiding potential toxicity due to genetic over-expression. hTau knock-in (KI) proteins were expressed at normal, endogenous levels, bound to fly microtubules and were post-translationally modified, hence displaying physiological properties. We used this new model to investigate the effects of acetylation on hTau toxicity in vivo. The simultaneous pseudo-acetylation of hTau at lysines 163, 280, 281 and 369 drastically decreased hTau phosphorylation and significantly reduced its binding to microtubules in vivo. These molecular alterations were associated with ameliorated amyloid beta toxicity. Our results indicate acetylation of hTau on multiple sites regulates its biology and ameliorates amyloid beta toxicity in vivo
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