Electrophysiological Mechanisms of Gastrointestinal Arrhythmogenesis: Lessons from the Heart.

This is the final published version. It first appeared at http://journal.frontiersin.org/article/10.3389/fphys.2016.00230/full.Disruptions in the orderly activation and recovery of electrical excitation traveling through the heart and the gastrointestinal (GI) tract can lead to arrhythmogenesis. For example, cardiac arrhythmias predispose to thromboembolic events resulting in cerebrovascular accidents and myocardial infarction, and to sudden cardiac death. By contrast, arrhythmias in the GI tract are usually not life-threatening and much less well characterized. However, they have been implicated in the pathogenesis of a number of GI motility disorders, including gastroparesis, dyspepsia, irritable bowel syndrome, mesenteric ischaemia, Hirschsprung disease, slow transit constipation, all of which are associated with significant morbidity. Both cardiac and gastrointestinal arrhythmias can broadly be divided into non-reentrant and reentrant activity. The aim of this paper is to compare and contrast the mechanisms underlying arrhythmogenesis in both systems to provide insight into the pathogenesis of GI motility disorders and potential molecular targets for future therapy

Stretching and squeezing of sessile dielectric drops by the optical radiation pressure

We study numerically the deformation of sessile dielectric drops immersed in a second fluid when submitted to the optical radiation pressure of a continuous Gaussian laser wave. Both drop stretching and drop squeezing are investigated at steady state where capillary effects balance the optical radiation pressure. A boundary integral method is implemented to solve the axisymmetric Stokes flow in the two fluids. In the stretching case, we find that the drop shape goes from prolate to near-conical for increasing optical radiation pressure whatever the drop to beam radius ratio and the refractive index contrast between the two fluids. The semi-angle of the cone at equilibrium decreases with the drop to beam radius ratio and is weakly influenced by the index contrast. Above a threshold value of the radiation pressure, these "optical cones" become unstable and a disruption is observed. Conversely, when optically squeezed, the drop shifts from an oblate to a concave shape leading to the formation of a stable "optical torus". These findings extend the electrohydrodynamics approach of drop deformation to the much less investigated "optical domain" and reveal the openings offered by laser waves to actively manipulate droplets at the micrometer scale

In-vivo heterogeneous functional and residual strains in human aortic valve leaflets

Residual and physiological functional strains in soft tissues are known to play an important role in modulating organ stress distributions. Yet, no known comprehensive information on residual strains exist, or non-invasive techniques to quantify in-vivo deformations for the aortic valve (AV) leaflets. Herein we present a completely non-invasive approach for determining heterogeneous strains – both functional and residual – in semilunar valves and apply it to normal human AV leaflets. Transesophageal 3D echocardiographic (3DE) images of the AV were acquired from open-heart transplant patients, with each AV leaflet excised after heart explant and then imaged in a flattened configuration ex-vivo. Using an established spline parameterization of both 3DE segmentations and digitized ex-vivo images (Aggarwal et al., 2014), surface strains were calculated for deformation between the ex-vivo and three in-vivo configurations: fully open, just-coapted, and fully-loaded. Results indicated that leaflet area increased by an average of 20% from the ex-vivo to in-vivo open states, with a highly heterogeneous strain field. The increase in area from open to just-coapted state was the highest at an average of 25%, while that from just-coapted to fully-loaded remained almost unaltered. Going from the ex-vivo to in-vivo mid-systole configurations, the leaflet area near the basal attachment shrank slightly, whereas the free edge expanded by ~10%. This was accompanied by a 10° −20° shear along the circumferential-radial direction. Moreover, the principal stretches aligned approximately with the circumferential and radial directions for all cases, with the highest stretch being along the radial direction. Collectively, these results indicated that even though the AV did not support any measurable pressure gradient in the just-coapted state, the leaflets were significantly pre-strained with respect to the excised state. Furthermore, the collagen fibers of the leaflet were almost fully recruited in the just-coapted state, making the leaflet very stiff with marginal deformation under full pressure. Lastly, the deformation was always higher in the radial direction and lower along the circumferential one, the latter direction made stiffer by the preferential alignment of collagen fibers. These results provide significant insight into the distribution of residual strains and the in-vivo strains encountered during valve opening and closing in AV leaflets, and will form an important component of the tool that can evaluate valve׳s functional properties in a non-invasive manner

SIRAC: Supervised Identification of Regions of Aberration in aCGH datasets

<p>Abstract</p> <p>Background</p> <p>Array comparative genome hybridization (aCGH) provides information about genomic aberrations. Alterations in the DNA copy number may cause the cell to malfunction, leading to cancer. Therefore, the identification of DNA amplifications or deletions across tumors may reveal key genes involved in cancer and improve our understanding of the underlying biological processes associated with the disease.</p> <p>Results</p> <p>We propose a supervised algorithm for the analysis of aCGH data and the identification of regions of chromosomal alteration (SIRAC). We first determine the DNA-probes that are important to distinguish the classes of interest, and then evaluate in a systematic and robust scheme if these relevant DNA-probes are closely located, i.e. form a region of amplification/deletion. SIRAC does not need any preprocessing of the aCGH datasets, and requires only few, intuitive parameters.</p> <p>Conclusion</p> <p>We illustrate the features of the algorithm with the use of a simple artificial dataset. The results on two breast cancer datasets show promising outcomes that are in agreement with previous findings, but SIRAC better pinpoints the dissimilarities between the classes of interest.</p

Polarization of Upsilon(nS) at the Tevatron

The polarization of inclusive Upsilon(nS) at the Fermilab Tevatron is calculated within the nonrelativistic QCD factorization framework. We use a recent determination of the NRQCD matrix elements from fitting the CDF data on bottomonium production from Run IB of the Tevatron. The result for the polarization of Upsilon(1S) integrated over the transverse momentum bin 8 < p_T < 20 GeV is consistent with a recent measurement by the CDF Collaboration. The transverse polarization of Upsilon(1S) is predicted to increase steadily for p_T greater than about 10 GeV. The Upsilon(2S) and Upsilon(3S) are predicted to have significantly larger transverse polarizations than Upsilon(1S).Comment: 15 pages, 3 figure

Regulated dicing of pre-mir-144 via reshaping of its terminal loop.

Although the route to generate microRNAs (miRNAs) is often depicted as a linear series of sequential and constitutive cleavages, we now appreciate multiple alternative pathways as well as diverse strategies to modulate their processing and function. Here, we identify an unusually profound regulatory role of conserved loop sequences in vertebrate pre-mir-144, which are essential for its cleavage by the Dicer RNase III enzyme in human and zebrafish models. Our data indicate that pre-mir-144 dicing is positively regulated via its terminal loop, and involves the ILF3 complex (NF90 and its partner NF45/ILF2). We provide further evidence that this regulatory switch involves reshaping of the pre-mir-144 apical loop into a structure that is appropriate for Dicer cleavage. In light of our recent findings that mir-144 promotes the nuclear biogenesis of its neighbor mir-451, these data extend the complex hierarchy of nuclear and cytoplasmic regulatory events that can control the maturation of clustered miRNAs

A model-based circular binary segmentation algorithm for the analysis of array CGH data

<p>Abstract</p> <p>Background</p> <p>Circular Binary Segmentation (CBS) is a permutation-based algorithm for array Comparative Genomic Hybridization (aCGH) data analysis. CBS accurately segments data by detecting change-points using a maximal-<it>t </it>test; but extensive computational burden is involved for evaluating the significance of change-points using permutations. A recent implementation utilizing a hybrid method and early stopping rules (hybrid CBS) to improve the performance in speed was subsequently proposed. However, a time analysis revealed that a major portion of computation time of the hybrid CBS was still spent on permutation. In addition, what the hybrid method provides is an approximation of the significance upper bound or lower bound, not an approximation of the significance of change-points itself.</p> <p>Results</p> <p>We developed a novel model-based algorithm, extreme-value based CBS (eCBS), which limits permutations and provides robust results without loss of accuracy. Thousands of aCGH data under null hypothesis were simulated in advance based on a variety of non-normal assumptions, and the corresponding maximal-<it>t </it>distribution was modeled by the Generalized Extreme Value (GEV) distribution. The modeling results, which associate characteristics of aCGH data to the GEV parameters, constitute lookup tables (eXtreme model). Using the eXtreme model, the significance of change-points could be evaluated in a constant time complexity through a table lookup process.</p> <p>Conclusions</p> <p>A novel algorithm, eCBS, was developed in this study. The current implementation of eCBS consistently outperforms the hybrid CBS 4× to 20× in computation time without loss of accuracy. Source codes, supplementary materials, supplementary figures, and supplementary tables can be found at <url>http://ntumaps.cgm.ntu.edu.tw/eCBSsupplementary</url>.</p

Cerebrospinal fluid biomarkers of Alzheimer\u27s disease in a cohort of adults with Down syndrome

Introduction: Virtually all individuals with Down syndrome (DS) will develop Alzheimer\u27s disease (AD) pathology by age 40. Cerebrospinal fluid (CSF) biomarkers have characterized AD pathology in cohorts of late-onset AD (LOAD) and autosomal-dominant AD (ADAD). Few studies have evaluated such biomarkers in adults with DS. Methods: CSF concentrations of amyloid beta (Aβ)40, Aβ42, tau, phospho-tau181 (p-tau), neurofilament light chain (NfL), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase-3-like protein 1 (YKL-40), alpha synuclein (αSyn), neurogranin (Ng), synaptosomal-associated protein 25 (SNAP-25), and visinin-like protein 1 (VILIP-1) were assessed in CSF from 44 adults with DS from the Alzheimer\u27s Biomarker Consortium-Down Syndrome study. Biomarker levels were evaluated by cognitive status, age, and apolipoprotein E gene ( Results: Biomarker abnormalities indicative of amyloid deposition, tauopathy, neurodegeneration, synaptic dysfunction, and neuroinflammation were associated with increased cognitive impairment. Age and Discussion: The profile of many established and emerging CSF biomarkers of AD in a cohort of adults with DS was similar to that reported in LOAD and ADAD, while some differences were observed

Optimizing Use of Multistream Influenza Sentinel Surveillance Data

We applied time-series methods to multivariate sentinel surveillance data recorded in Hong Kong during 1998–2007. Our study demonstrates that simultaneous monitoring of multiple streams of influenza surveillance data can improve the accuracy and timeliness of alerts compared with monitoring of aggregate data or of any single stream alone