Exome sequencing helped the fine diagnosis of two siblings afflicted with atypical Timothy syndrome (TS2)

BACKGROUND: Long-QT syndrome (LQTS) causes a prolongation of the QT-interval in the ECG leading to life threatening tachyarrhythmia and ventricular fibrillation. One atypical form of LQTS, Timothy syndrome (TS), is associated with syndactyly, immune deficiency, cognitive and neurological abnormalities as well as distinct cranio-facial abnormalities. CASE PRESENTATION: On a family with both children diagnosed with clinical LQTS, we performed whole exome sequencing to comprehensively screen for causative mutations after a targeted candidate gene panel screen for Long-QT syndrome target genes failed to identify any underlying genetic defect. Using exome sequencing, we identified in both affected children, a p.402G > S mutation in exon 8 of the CACNA1C gene, a voltage-dependent Ca2+ channel. The mutation was inherited from their father, a mosaic mutation carrier. Based on this molecular finding and further more careful clinical examination, we refined the diagnosis to be Timothy syndrome (TS2) and thereby were able to present new therapeutic approaches. CONCLUSIONS: Our study highlights the difficulties in accurate diagnosis of patients with rare diseases, especially those with atypical clinical manifestation. Such challenge could be addressed with the help of comprehensive and unbiased mutation screening, such as exome sequencing

Outcomes of patients with atypical haemolytic uraemic syndrome with native and transplanted kidneys treated with eculizumab: a pooled post hoc analysis

Atypical hemolytic uremic syndrome (aHUS) often leads to end-stage renal disease (ESRD) and kidney transplantation; graft loss rates are high due to disease recurrence. A post hoc analysis of four prospective clinical trials in aHUS was performed to evaluate eculizumab, a terminal complement inhibitor, in patients with native or transplanted kidneys. The trials included 26-week treatment and extension periods. Dialysis, transplant, and graft loss were evaluated. Study endpoints included complete thrombotic microangiopathy (TMA) response, TMA event-free status, hematologic and renal parameters, and adverse events. Of 100 patients, 74 had native kidneys and 26 in the transplant subgroup had a collective history of 38 grafts. No patients lost grafts and only one with preexisting ESRD received a transplant on treatment. Efficacy endpoints were achieved similarly in both subgroups. After 26 weeks, mean absolute estimated glomerular filtration rate increased from baseline to 61 and 37 mL/min/1.73 m2 in native (n=71; P<0.0001) and transplanted kidney (n=25; P=0.0092) subgroups. Two patients (one/subgroup) developed meningococcal infections; both recovered, one continued therapy. Eculizumab was well tolerated. Eculizumab improved hematologic and renal outcomes in both subgroups. In patients with histories of multiple graft losses, eculizumab protected kidney function. (ClinicalTrials. gov numbers : NCT00844545, NCT00844844, NCT00838513, NCT00844428, NCT01193348, and NCT01194973) This article is protected by copyright. All rights reserved

Controlled assembly of SNAP-PNA-fluorophore systems on DNA templates to produce fluorescence resonance energy transfer

The SNAP protein is a widely used self-labeling tag that can be used for tracking protein localization and trafficking in living systems. A model system providing controlled alignment of SNAP-tag units can provide a new way to study clustering of fusion proteins. In this work, fluorescent SNAP-PNA conjugates were controllably assembled on DNA frameworks forming dimers, trimers, and tetramers. Modification of peptide nucleic acid (PNA) with the O6-benzyl guanine (BG) group allowed the generation of site-selective covalent links between PNA and the SNAP protein. The modified BG-PNAs were labeled with fluorescent Atto dyes and subsequently chemo-selectively conjugated to SNAP protein. Efficient assembly into dimer and oligomer forms was verified via size exclusion chromatography (SEC), electrophoresis (SDS-PAGE), and fluorescence spectroscopy. DNA directed assembly of homo- and hetero-dimers of SNAP-PNA constructs induced homo- and hetero-FRET, respectively. Longer DNA scaffolds controllably aligned similar fluorescent SNAP-PNA constructs into higher oligomers exhibiting homo-FRET. The combined SEC and homo-FRET studies indicated the 1:1 and saturated assemblies of SNAP-PNA-fluorophore:DNA formed preferentially in this system. This suggested a kinetic/stoichiometric model of assembly rather than binomially distributed products. These BG-PNA-fluorophore building blocks allow facile introduction of fluorophores and/or assembly directing moieties onto any protein containing SNAP. Template directed assembly of PNA modified SNAP proteins may be used to investigate clustering behavior both with and without fluorescent labels which may find use in the study of assembly processes in cells

A new fireworm (Amphinomidae) from the Cretaceous of Lebanon identified from three-dimensionally preserved myoanatomy

© 2015 Parry et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. The attached file is the published version of the article

A fast sparse block circulant matrix vector product

In the context of computed tomography (CT), iterative image reconstruction techniques are gaining attention because high-quality images are becoming computationally feasible. They involve the solution of large systems of equations, whose cost is dominated by the sparse matrix vector product (SpMV). Our work considers the case of the sparse matrices being block circulant, which arises when taking advantage of the rotational symmetry in the tomographic system. Besides the straightforward storage saving, we exploit the circulant structure to rewrite the poor-performance SpMVs into a high-performance product between sparse and dense matrices. This paper describes the implementations developed for multi-core CPUs and GPUs, and presents experimental results with typical CT matrices. The presented approach is up to ten times faster than without exploiting the circulant structure.Romero Alcalde, E.; Tomás Domínguez, AE.; Soriano Asensi, A.; Blanquer Espert, I. (2014). A fast sparse block circulant matrix vector product. En Euro-Par 2014 Parallel Processing. Springer. 548-559. doi:10.1007/978-3-319-09873-9_46S548559Bian, J., Siewerdsen, J.H., Han, X., Sidky, E.Y., Prince, J.L., Pelizzari, C.A., Pal, X.: Evaluation of sparse-view reconstruction from flat-panel-detector cone-beam ct. Physics in Medicine and Biology 55, 6575–6599 (2010)Dalton, S., Bell, N.: CUSP: A C++ templated sparse matrix library version 0.4.0 (2014), http://cusplibrary.github.com/Feldkamp, L., Davis, L., Kress, J.: Practical cone-beam algorithm. Journal of the Optical Society of America 1, 612–619 (1984)Ganine, V., Legrand, M., Michalska, H., Pierre, C.: A sparse preconditioned iterative method for vibration analysis of geometrically mistuned bladed disks. Computers & Structures 87(5-6), 342–354 (2009)Hara, A.K., Paden, R.G., Silva, A.C., Kujak, J.L., Lawder, H.J., Pavlicek, W.: Iterative reconstruction technique for reducing body radiation dose at CT: Feasibility study. American Journal of Roentgenology 193, 764–771 (2009)Heroux, M.A., Bartlett, R.A., Howle, V.E., Hoekstra, R.J., Hu, J.J., Kolda, T.G., Lehoucq, R.B., Long, K.R., Pawlowski, R.P., Phipps, E.T., Salinger, A.G., Thornquist, H.K., Tuminaro, R.S., Willenbring, J.M., Williams, A., Stanley, K.S.: An overview of the Trilinos project. ACM Trans. Math. Softw. 31(3), 397–423 (2005)Im, E.J., Yelick, K., Vuduc, R.: Sparsity: Optimization framework for sparse matrix kernels. International Journal of High Performance Computing Applications 18(1), 135–158 (2004)Jones, E., Oliphant, T., Peterson, P., et al.: SciPy: Open source scientific tools for Python (2001), http://www.scipy.org/Kaveh, A., Rahami, H.: Block circulant matrices and applications in free vibration analysis of cyclically repetitive structures. Acta Mechanica 217(1-2), 51–62 (2011)Kourtis, K., Goumas, G., Koziris, N.: Optimizing sparse matrix-vector multiplication using index and value compression. In: Proceedings of the 5th Conference on Computing Frontiers, CF 2008, pp. 87–96. ACM, New York (2008)Krotkiewski, M., Dabrowski, M.: Parallel symmetric sparse matrix–vector product on scalar multi-core CPUs. Parallel Computing 36(4), 181–198 (2010)Lee, B., Vuduc, R., Demmel, J., Yelick, K.: Performance models for evaluation and automatic tuning of symmetric sparse matrix-vector multiply. In: International Conference on Parallel Processing, ICPP 2004, vol. 1, pp. 169–176 (2004)Leroux, J.D., Selivanov, V., Fontaine, R., Lecomte, R.: Accelerated iterative image reconstruction methods based on block-circulant system matrix derived from a cylindrical image representation. In: Nuclear Science Symposium Conference Record, NSS 2007, vol. 4, pp. 2764–2771. IEEE (2007)NVIDIA: CUSPARSE library (2014), https://developer.nvidia.com/cusparsePan, X., Sidky, E.Y., Vannier, M.: Why do commercial CT scanners still employ traditional, filtered back-projection for image reconstruction? Inverse Problems 25, 123009 (2008)Rodríguez-Alvarez, M.J., Soriano, A., Iborra, A., Sánchez, F., González, A.J., Conde, P., Hernández, L., Moliner, L., Orero, A., Vidal, L.F., Benlloch, J.M.: Expectation maximization (EM) algorithms using polar symmetries for computed tomography CT image reconstruction. Computers in Biology and Medicine 43(8), 1053–1061 (2013)Sheep, L., Vardi, Y.: Maximum likelihood reconstruction for emmision tomography. IEEE Transactions on Medical Imaging 1, 113–122 (1982)Sidky, E.Y., Pan, X.: Image reconstruction in circular cone-beam computed tomography by constrained, total-variation minimization. Physics in Medicine and Biology 53, 4777–4807 (2008)Soriano, A., Rodríguez-Alvarez, M.J., Iborra, A., Sánchez, F., Carles, M., Conde, P., González, A.J., Hernández, L., Moliner, L., Orero, A., Vidal, L.F., Benlloch, J.M.: EM tomographic image reconstruction using polar voxels. Journal of Instrumentation 8, C01004 (2013)Thibaudeau, C., Leroux, J.D., Pratte, J.F., Fontaine, R., Lecomte, R.: Cylindrical and spherical ray-tracing for ct iterative reconstruction. In: 2011 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC), pp. 4378–4381 (2011)Vuduc, R., Demmel, J.W., Yelick, K.A.: OSKI: A library of automatically tuned sparse matrix kernels. Journal of Physics: Conference Series 16(1), 521 (2005)Vuduc, R.W., Moon, H.-J.: Fast sparse matrix-vector multiplication by exploiting variable block structure. In: Yang, L.T., Rana, O.F., Di Martino, B., Dongarra, J. (eds.) HPCC 2005. LNCS, vol. 3726, pp. 807–816. Springer, Heidelberg (2005)Williams, S., Oliker, L., Vuduc, R., Shalf, J., Yelick, K., Demmel, J.: Optimization of sparse matrix-vector multiplication on emerging multicore platforms. Parallel Computing 35(3), 178–194 (2009

Programmable in situ amplification for multiplexed imaging of mRNA expression

In situ hybridization methods enable the mapping of mRNA expression within intact biological samples. With current approaches, it is challenging to simultaneously map multiple target mRNAs within whole-mount vertebrate embryos, representing a significant limitation in attempting to study interacting regulatory elements in systems most relevant to human development and disease. Here, we report a multiplexed fluorescent in situ hybridization method based on orthogonal amplification with hybridization chain reactions (HCR). With this approach, RNA probes complementary to mRNA targets trigger chain reactions in which fluorophore-labeled RNA hairpins self-assemble into tethered fluorescent amplification polymers. The programmability and sequence specificity of these amplification cascades enable multiple HCR amplifiers to operate orthogonally at the same time in the same sample. Robust performance is achieved when imaging five target mRNAs simultaneously in fixed whole-mount and sectioned zebrafish embryos. HCR amplifiers exhibit deep sample penetration, high signal-to-background ratios and sharp signal localization

Multiplicity dependence of jet-like two-particle correlations in p-Pb collisions at sNN\sqrt{s_{NN}} = 5.02 TeV

Two-particle angular correlations between unidentified charged trigger and associated particles are measured by the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV. The transverse-momentum range 0.7 $< p_{\rm{T}, assoc} < p_{\rm{T}, trig} <$ 5.0 GeV/$c$ is examined, to include correlations induced by jets originating from low momen\-tum-transfer scatterings (minijets). The correlations expressed as associated yield per trigger particle are obtained in the pseudorapidity range $|\eta|<0.9$. The near-side long-range pseudorapidity correlations observed in high-multiplicity p-Pb collisions are subtracted from both near-side short-range and away-side correlations in order to remove the non-jet-like components. The yields in the jet-like peaks are found to be invariant with event multiplicity with the exception of events with low multiplicity. This invariance is consistent with the particles being produced via the incoherent fragmentation of multiple parton--parton scatterings, while the yield related to the previously observed ridge structures is not jet-related. The number of uncorrelated sources of particle production is found to increase linearly with multiplicity, suggesting no saturation of the number of multi-parton interactions even in the highest multiplicity p-Pb collisions. Further, the number scales in the intermediate multiplicity region with the number of binary nucleon-nucleon collisions estimated with a Glauber Monte-Carlo simulation.Comment: 23 pages, 6 captioned figures, 1 table, authors from page 17, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/161