Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele

Training dual-task walking in community-dwelling adults within 1 year of stroke: A protocol for a single-blind randomized controlled trial

Background: Community ambulation is a highly complex skill requiring the ability to adapt to increased environmental complexity and perform multiple tasks simultaneously. After stroke, individuals demonstrate a diminished ability to perform dual-tasks. Current evidence suggests that conventional rehabilitation does not adequately address gait-related dual-task impairments after stroke, which may be contributing to low levels of participation and physical inactivity in community-dwelling stroke survivors. The objective of this study is to investigate the efficacy of dual-task gait training in community-dwelling adults within 1 year of stroke. Specifically, we will compare the effects of dual-task gait training and single-task gait training on cognitive-motor interference during walking at preferred speed and at fastest comfortable speed (Aim 1), locomotor control during obstacle negotiation (Aim 2), and spontaneous physical activity (Aim 3). Methods/design: This single-blind randomized controlled trial will involve 44 individuals within 12 months of stroke. Following baseline evaluation, participants will be randomly allocated to single- or dual-task gait training. Both groups will receive 12, 30-minute sessions provided one-on-one over 4–6 weeks in an outpatient therapy setting. Single-task gait training involves practice of gait activities incorporating motor relearning principles. Dual-task gait training involves an identical gait training protocol; the critical difference being that the dual-task gait training group will practice the gait activities while simultaneously performing a cognitive task for 75% of the repetitions. Blinded assessors will measure outcomes at baseline, post-intervention, and 6 months after completion of the intervention. The primary outcome measure will be dual-task effects on gait speed and cognition during unobstructed walking. Secondary outcomes include spatiotemporal and kinetic gait parameters during unobstructed single- and dual-task walking at preferred and fastest comfortable walking speeds, gait parameters during high and low obstacle crossing, spontaneous physical activity, executive function, lower extremity motor function, Timed Up and Go, balance self-efficacy, number of falls, and stroke-related disability. Hypotheses for each aim will be tested using an intention-to-treat analysis with repeated measures ANOVA design. Discussion: This trial will provide evidence to help clinicians make decisions about the types of activities to include in rehabilitation to improve dual-task walking after stroke

Intravenous magnesium prevents atrial fibrillation after coronary artery bypass grafting: a meta-analysis of 7 double-blind, placebo-controlled, randomized clinical trials

<p>Abstract</p> <p>Background</p> <p>Postoperative atrial fibrillation (POAF) is the most common complication after coronary artery bypass grafting (CABG). The preventive effect of magnesium on POAF is not well known. This meta-analysis was undertaken to assess the efficacy of intravenous magnesium on the prevention of POAF after CABG.</p> <p>Methods</p> <p>Eligible studies were identified from electronic databases (Medline, Embase, and the Cochrane Library). The primary outcome measure was the incidence of POAF. The meta-analysis was performed with the fixed-effect model or random-effect model according to heterogeneity.</p> <p>Results</p> <p>Seven double-blind, placebo-controlled, randomized clinical trials met the inclusion criteria including 1,028 participants. The pooled results showed that intravenous magnesium reduced the incidence of POAF by 36% (RR 0.64; 95% confidence interval (CI) 0.50-0.83; <it>P </it>= 0.001; with no heterogeneity between trials (heterogeneity <it>P </it>= 0.8, <it>I</it>²= 0%)).</p> <p>Conclusions</p> <p>This meta-analysis indicates that intravenous magnesium significantly reduces the incidence of POAF after CABG. This finding encourages the use of intravenous magnesium as an alternative to prevent POAF after CABG. But more high quality randomized clinical trials are still need to confirm the safety.</p

Enzymatic Depilation of Animal Hide: Identification of Elastase (LasB) from Pseudomonas aeruginosa MCM B-327 as a Depilating Protease

Conventional leather processing involving depilation of animal hide by lime and sulphide treatment generates considerable amounts of chemical waste causing severe environmental pollution. Enzymatic depilation is an environmentally friendly process and has been considered to be a viable alternative to the chemical depilation process. We isolated an extracellular protease from Pseudomonas aeruginosa strain MCM B-327 with high depilation activity using buffalo hide as a substrate. This 33 kDa protease generated a peptide mass fingerprint and de novo sequence that matched perfectly with LasB (elastase), of Pseudomonas aeruginosa. In support of this data a lasB mutant of MCM B-327 strain lacked depilatory activity and failed to produce LasB. LasB heterologously over-produced and purified from Escherichia coli also exhibited high depilating activity. Moreover, reintroduction of the lasB gene to the P. aeruginosa lasB mutant via a knock-in strategy also successfully restored depilation activity thus confirming the role of LasB as the depilating enzyme

Structural shape optimization using Cartesian grids and automatic h-adaptive mesh projection

[EN] We present a novel approach to 3D structural shape optimization that leans on an Immersed Boundary Method. A boundary tracking strategy based on evaluating the intersections between a fixed Cartesian grid and the evolving geometry sorts elements as internal, external and intersected. The integration procedure used by the NURBS-Enhanced Finite Element Method accurately accounts for the nonconformity between the fixed embedding discretization and the evolving structural shape, avoiding the creation of a boundary-fitted mesh for each design iteration, yielding in very efficient mesh generation process. A Cartesian hierarchical data structure improves the efficiency of the analyzes, allowing for trivial data sharing between similar entities or for an optimal reordering of thematrices for the solution of the system of equations, among other benefits. Shape optimization requires the sufficiently accurate structural analysis of a large number of different designs, presenting the computational cost for each design as a critical issue. The information required to create 3D Cartesian h- adapted mesh for new geometries is projected from previously analyzed geometries using shape sensitivity results. Then, the refinement criterion permits one to directly build h-adapted mesh on the new designs with a specified and controlled error level. Several examples are presented to show how the techniques here proposed considerably improve the computational efficiency of the optimization process.The authors wish to thank the Spanish Ministerio de Economia y Competitividad for the financial support received through the project DPI2013-46317-R and the FPI program (BES-2011-044080), and the Generalitat Valenciana through the project PROMETEO/2016/007.Marco, O.; Ródenas, J.; Albelda Vitoria, J.; Nadal, E.; Tur Valiente, M. (2017). Structural shape optimization using Cartesian grids and automatic h-adaptive mesh projection. Structural and Multidisciplinary Optimization. 1-21. https://doi.org/10.1007/s00158-017-1875-1S121MATLAB version 8.3.0.532 (R2014a) (2014) Documentation. The Mathworks, Inc., Natick, MassachusettsAbel JF, Shephard MS (1979) An algorithm for multipoint constraints in finite element analysis. Int J Numer Methods Eng 14(3):464–467Amestoy P, Davis T, Duff I (1996) An approximate minimum degree ordering algorithm. SIAM J Matrix Anal Appl 17(4):886–905Barth W, Stürzlinger W (1993) Efficient ray tracing for Bezier and B-spline surfaces. Comput Graph 17 (4):423–430Bennett J A, Botkin M E (1985) Structural shape optimization with geometric problem description and adaptive mesh refinement. AIAA J 23(3):459–464Braibant V, Fleury C (1984) Shape optimal design using b-splines. Comput Methods Appl Mech Eng 44 (3):247–267Bugeda G, Oliver J (1993) A general methodology for structural shape optimization problems using automatic adaptive remeshing. Int J Numer Methods Eng 36(18):3161–3185Bugeda G, Ródenas J J, Oñate E (2008) An integration of a low cost adaptive remeshing strategy in the solution of structural shape optimization problems using evolutionary methods. Comput Struct 86(13–14):1563–1578Chang K, Choi K K (1992) A geometry-based parameterization method for shape design of elastic solids. Mech Struct Mach 20(2):215–252Cho S, Ha S H (2009) Isogeometric shape design optimization: exact geometry and enhanced sensitivity. Struct Multidiscip Optim 38(1):53–70Belegundu D, Zhang YMS, Salagame R (1991) The natural approach for shape optimization with mesh distortion control. Tech. rep., Penn State UniversityDavis T A, Gilbert J R, Larimore S, Ng E (2004) An approximate column minimum degree ordering algorithm. ACM Trans Math Softw 30(3):353–376Doctor L J, Torborg J G (1981) Display techniques for octree-encoded objects. IEEE Comput Graph Appl 1(3):29–38Dunning P D, Kim H A, Mullineux G (2011) Investigation and improvement of sensitivity computation using the area-fraction weighted fixed grid FEM and structural optimization. Finite Elem Anal Des 47(8):933–941Düster A, Parvizian J, Yang Z, Rank E (2008) The finite cell method for three-dimensional problems of solid mechanics. Comput Methods Appl Mech Eng 197(45-48):3768–3782Escobar J M, Montenegro R, Rodríguez E, Cascón J M (2014) The meccano method for isogeometric solid modeling and applications. Eng Comput 30(3):331–343Farhat C, Lacour C, Rixen D (1998) Incorporation of linear multipoint constraints in substructure based iterative solvers. Part 1: a numerically scalable algorithm. Int J Numer Methods Eng 43(6):997–1016Fries T P, Omerović S (2016) Higher-order accurate integration of implicit geometries. Int J Numer Methods Eng 106(5):323–371Fuenmayor F J, Oliver J L (1996) Criteria to achieve nearly optimal meshes in the h-adaptive finite element mehod. Int J Numer Methods Eng 39(23):4039–4061Fuenmayor F J, Oliver J L, Ródenas J J (1997) Extension of the Zienkiewicz-Zhu error estimator to shape sensitivity analysis. Int J Numer Methods Eng 40(8):1413–1433García-Ruíz M J, Steven G P (1999) Fixed grid finite elements in elasticity problems. Eng Comput 16 (2):145–164Gill P, Murray W, Saunders M, Wright M (1984) Procedures for optimization problems with a mixture of bounds and general linear constraints. ACM Trans Math Software 10:282–298González-Estrada O A, Nadal E, Ródenas J J, Kerfriden P, Bordas S P A, Fuenmayor F J (2014) Mesh adaptivity driven by goal-oriented locally equilibrated superconvergent patch recovery. Comput Mech 53(5):957–976Ha S H, Choi K K, Cho S (2010) Numerical method for shape optimization using T-spline based isogeometric method. Struct Multidiscip Optim 42(3):417–428Haftka R T, Grandhi R V (1986) Structural shape optimization: A survey. Comput Methods Appl Mech Eng 57(1):91–106Haslinger J, Jedelsky D (1996) Genetic algorithms and fictitious domain based approaches in shape optimization. Struc Optim 12:257–264Hughes T J R, Cottrell J A, Bazilevs Y (2005) Isogeometric Analysis: CAD, Finite Elements, NURBS, Exact Geometry, and Mesh Refinement. Comput Methods Appl Mech Eng 194:4135–4195Jackins C L, Tanimoto S L (1980) Oct-tree and their use in representing three-dimensional objects. Comput Graphics Image Process 14(3):249–270Kajiya J T (1982) Ray Tracing Parametric Patches. SIGGRAPH Comput Graph 16(3):245–254van Keulen F, Haftka R T, Kim N (2005) Review of options for structural design sensitivity analysis. Part I: linear systems. Comput Methods Appl Mech Eng 194(30-33):3213–3243Kibsgaard S (1992) Sensitivity analysis-the basis for optimization. Int J Numer Methods Eng 34(3):901–932Kikuchi N, Chung K Y, Torigaki T, Taylor J E (1986) Adaptive finite element methods for shape optimization of linearly elastic structures. Comput Methods Appl Mech Eng 57(1):67–89Kim N H, Chang Y (2005) Eulerian shape design sensitivity analysis and optimization with a fixed grid. Comput Methods Appl Mech Eng 194(30–33):3291–3314Kudela L, Zander N, Kollmannsberger S, Rank E (2016) Smart octrees: Accurately integrating discontinuous functions in 3d. Comput Methods Appl Mech Eng 306(1):406–426Kunisch K, Peichl G (1996) Numerical gradients for shape optimization based on embedding domain techniques. Comput Optim 18:95–114Li K, Qian X (2011) Isogeometric analysis and shape optimization via boundary integral. Computer-Aided Design 43(11):1427–1437Lian H, Kerfriden P, Bordas S P A (2016) Implementation of regularized isogeometric boundary element methods for gradient-based shape optimization in two-dimensional linear elasticity. Int J Numer Methods Eng 106 (12):972–1017Liu L, Zhang Y, Hughes T J R, Scott M A, Sederberg T W (2014) Volumetric T-spline Construction using Boolean Operations. Eng Comput 30(4):425–439Marco O, Sevilla R, Zhang Y, Ródenas J J, Tur M (2015) Exact 3D boundary representation in finite element analysis based on Cartesian grids independent of the geometry. Int J Numer Methods Eng 103:445–468Marco O, Ródenas J J, Fuenmayor FJ, Tur M (2017a) An extension of shape sensitivity analysis to an immersed boundary method based on cartesian grids. Computational Mechanics SubmittedMarco O, Ródenas J J, Navarro-Jiménez JM, Tur M (2017b) Robust h-adaptive meshing strategy for arbitrary cad geometries in a cartesian grid framework. Computers & Structures SubmittedMeagher D (1980) Octree Encoding: A New Technique for the Representation, Manipulation and Display of Arbitrary 3-D Objects by Computer. Tech. Rep. IPL-TR-80-11 I, Rensselaer Polytechnic InstituteMoita J S, Infante J, Mota C M, Mota C A (2000) Sensitivity analysis and optimal design of geometrically non-linear laminated plates and shells. Comput Struct 76(1–3):407–420Nadal E (2014) Cartesian Grid FEM (cgFEM): High Performance h-adaptive FE Analysis with Efficient Error Control. Application to Structural Shape Optimization. PhD Thesis. Universitat Politècnica de ValènciaNadal E, Ródenas J J, Albelda J, Tur M, Tarancón J E, Fuenmayor F J (2013) Efficient finite element methodology based on cartesian grids: application to structural shape optimization. Abstr Appl Anal 2013:1–19Najafi A R, Safdari M, Tortorelli D A, Geubelle P H (2015) A gradient-based shape optimization scheme using an interface-enriched generalized FEM. Comput Methods Appl Mech Eng 296:1–17Nguyen V P, Anitescu C, Bordas S P A, Rabczuk T (2015) Isogeometric analysis: An overview and computer implementation aspects. Math Comput Simul 117:89–116Nishita T, Sederberg TW, Kakimoto M (1990) Ray Tracing Trimmed Rational Surface Patches. SIGGRAPH Comput Graph 24(4):337–345Nocedal J, Wright SJ (2006) Numerical optimization, 2nd edn. Springer-Verlag, New YorkPandey P C, Bakshi P (1999) Analytical response sensitivity computation using hybrid finite elements. Comput Struct 71(5):525–534Parvizian J, Düster A, Rank E (2007) Finite Cell Method: h- and p- Extension for Embedded Domain Methods in Solid Mechanics. Comput Mech 41(1):121–133Peskin C S (1977) Numerical Analysis of Blood Flow in the Heart. J Comput Phys 25:220–252Poldneff M J, Rai I S, Arora J S (1993) Implementation of design sensitivity analysis for nonlinear structures. AIAA J 31(11):2137–2142Powell M (1983) Variable metric methods for constrained optimization. In: Bachem A, Grotschel M, Korte B (eds) Mathematical Programming: The State of the Art, Springer, Berlin, Heidelberg, pp 288–311Qian X (2010) Full analytical sensitivities in NURBS based isogeometric shape optimization. Comput Methods Appl Mech Eng 199(29–32):2059–2071Riehl S, Steinmann P (2014) An integrated approach to shape optimization and mesh adaptivity based on material residual forces. Comput Methods Appl Mech Eng 278:640–663Riehl S, Steinmann P (2016) On structural shape optimization using an embedding domain discretization technique. Int J Numer Methods Eng 109(9):1315–1343Ródenas J J, Tarancón J E, Albelda J, Roda A, Fuenmayor F J (2005) Hierarchical Properties in Elements Obtained by Subdivision: a Hierarquical h-adaptivity Program. In: Díez P, Wiberg N E (eds) Adaptive Modeling and Simulation, p 2005Ródenas J J, Corral C, Albelda J, Mas J, Adam C (2007a) Nested domain decomposition direct and iterative solvers based on a hierarchical h-adaptive finite element code. In: Runesson K, Díez P (eds) Adaptive Modeling and Simulation 2007, Internacional Center for Numerical Methods in Engineering (CIMNE), pp 206–209Ródenas J J, Tur M, Fuenmayor F J, Vercher A (2007b) Improvement of the superconvergent patch recovery technique by the use of constraint equations: the SPR-C technique. Int J Numer Methods Eng 70(6):705–727Ródenas J J, Bugeda G, Albelda J, Oñate E (2011) On the need for the use of error-controlled finite element analyses in structural shape optimization processes. Int J Numer Methods Eng 87(11):1105–1126Schillinger D, Ruess M (2015) The finite cell method: A review in the context of higher-order structural analysis of cad and image-based geometric models. Arch Comput Meth Eng 22(3):391– 455Sevilla R, Fernández-Méndez S, Huerta A (2011a) 3D-NURBS-enhanced Finite Element Method (NEFEM). Int J Numer Methods Eng 88(2):103–125Sevilla R, Fernández-Méndez S, Huerta A (2011b) Comparison of High-order Curved Finite Elements. Int J Numer Methods Eng 87(8):719–734Sevilla R, Fernández-Méndez S, Huerta A (2011c) NURBS-enhanced Finite Element Method (NEFEM): A Seamless Bridge Between CAD and FEM. Arch Comput Meth Eng 18(4):441–484Sweeney M, Bartels R (1986) Ray tracing free-form b-spline surfaces. IEEE Comput Graph Appl 6(2):41–49Toth D L (1985) On Ray Tracing Parametric Surfaces. SIGGRAPH Comput Graph 19(3):171–179Tur M, Albelda J, Nadal E, Ródenas J J (2014) Imposing dirichlet boundary conditions in hierarchical cartesian meshes by means of stabilized lagrange multipliers. Int J Numer Methods Eng 98(6):399–417Tur M, Albelda J, Marco O, Ródenas J J (2015) Stabilized Method to Impose Dirichlet Boundary Conditions using a Smooth Stress Field. Comput Methods Appl Mech Eng 296:352–375Yao T, Choi KK (1989) 3-d shape optimal design and automatic finite element regridding. Int J Numer Methods Eng 28(2):369–384Zhang L, Gerstenberger A, Wang X, Liu W K (2004) Immersed Finite Element Method. Comput Methods Appl Mech Eng 293(21):2051–2067Zhang Y, Wang W, Hughes T J R (2013) Conformal Solid T-spline Construction from Boundary T-spline Representations. Comput Mech 6(51):1051–1059Zienkiewicz O C, Zhu J Z (1987) A Simple Error Estimator and Adaptive Procedure for Practical Engineering Analysis. Int J Numer Methods Eng 24(2):337–35

Modulating RNA structure and catalysis: lessons from small cleaving ribozymes

RNA is a key molecule in life, and comprehending its structure/function relationships is a crucial step towards a more complete understanding of molecular biology. Even though most of the information required for their correct folding is contained in their primary sequences, we are as yet unable to accurately predict both the folding pathways and active tertiary structures of RNA species. Ribozymes are interesting molecules to study when addressing these questions because any modifications in their structures are often reflected in their catalytic properties. The recent progress in the study of the structures, the folding pathways and the modulation of the small ribozymes derived from natural, self-cleaving, RNA motifs have significantly contributed to today’s knowledge in the field