Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing.

BACKGROUND: Elevated TCRαß+CD4-CD8- double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U). OBJECTIVE: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway-related genes could explain these cases. METHODS: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway-related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH). RESULTS: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous "loss-of-expression" FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH. CONCLUSION: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing.

S-Leaping: An Adaptive, Accelerated Stochastic Simulation Algorithm, Bridging [Formula: see text]-Leaping and R-Leaping.

We propose the S-leaping algorithm for the acceleration of Gillespie's stochastic simulation algorithm that combines the advantages of the two main accelerated methods; the [Formula: see text]-leaping and R-leaping algorithms. These algorithms are known to be efficient under different conditions; the [Formula: see text]-leaping is efficient for non-stiff systems or systems with partial equilibrium, while the R-leaping performs better in stiff system thanks to an efficient sampling procedure. However, even a small change in a system's set up can critically affect the nature of the simulated system and thus reduce the efficiency of an accelerated algorithm. The proposed algorithm combines the efficient time step selection from the [Formula: see text]-leaping with the effective sampling procedure from the R-leaping algorithm. The S-leaping is shown to maintain its efficiency under different conditions and in the case of large and stiff systems or systems with fast dynamics, the S-leaping outperforms both methods. We demonstrate the performance and the accuracy of the S-leaping in comparison with the [Formula: see text]-leaping and R-leaping on a number of benchmark systems involving biological reaction networks.

Numerical assessment of wake-based estimation of instantaneous lift in flapping flight of large birds.

Experimental characterization of bird flight without instrumenting the animal requires measuring the flow behind the bird in a wind tunnel. Models are used to link the measured velocities to the corresponding aerodynamic forces. Widely-used models can, however, prove inconsistent when evaluating the instantaneous lift. Yet, accurately estimating variations of lift is critical in order to reverse-engineer flapping flight. In this work, we revisit mathematical models of lift based on the conservation of momentum in a control volume around a bird. Using a numerical framework to represent a flapping bird wing and compute the flow around it, we mimic the conditions of a wind tunnel and produce realistic wakes, which we compare to experimental data. Providing ground truth measurements of the flow everywhere around the simulated bird, we assess the validity of several lift estimation techniques. We observe that the circulation-based component of the instantaneous lift can be retrieved from measurements of velocity in a single plane behind a bird, with a latency that is found to depend directly on the free-stream velocity. We further show that the lift contribution of the added-mass effect cannot be retrieved from such measurements and quantify the level of approximation due to ignoring this contribution in instantaneous lift estimation.

On the role of tail in stability and energetic cost of bird flapping flight.

Migratory birds travel over impressively long distances. Consequently, they have to adopt flight regimes being both efficient-in order to spare their metabolic resources-and robust to perturbations. This paper investigates the relationship between both aspects, i.e., energetic performance and stability, in flapping flight of migratory birds. Relying on a poly-articulated wing morphing model and a tail-like surface, several families of steady flight regime have been identified and analysed. These families differ by their wing kinematics and tail opening. A systematic parametric search analysis has been carried out, in order to evaluate power consumption and cost of transport. A framework tailored for assessing limit cycles, namely Floquet theory, is used to numerically study flight stability. Our results show that under certain conditions, an inherent passive stability of steady and level flight can be achieved. In particular, we find that progressively opening the tail leads to passively stable flight regimes. Within these passively stable regimes, the tail can produce either upward or downward lift. However, these configurations entail an increase of cost of transport at high velocities penalizing fast forward flight regimes. Our model-based predictions suggest that long range flights require a furled tail configuration, as confirmed by field observations, and consequently need to rely on alternative mechanisms to stabilize the flight.

Model coupling biomechanics and fluid dynamics for the simulation of controlled flapping flight.

This paper proposes a multiphysics computational framework coupling biomechanics and aerodynamics for the simulation of bird flight. It features a biomechanical model based on the anatomy of a bird, which models the bones and feathers of the wing. The aerodynamic solver relies on a vortex particle-mesh method and represents the wing through an immersed lifting line, acting as a source of vorticity in the flow. An application of the numerical tool is presented in the modeling of the flight of a northern bald ibis (Geronticus eremita). The wing kinematics are imposed based on biological observations and controllers are developed to enable stable flight in a closed loop. Their design is based on a linearized model of flapping flight dynamics. The controller solves an underdetermination in the control parameters through minimization. The tool and the controllers are used in two simulations: one where the bird has to trim itself at a given flight speed, and another where it has to accelerate from a trimmed state to another at a higher speed. The bird wake is accurately represented. It is analyzed and compared to the widespread frozen-wake assumption, highlighting phenomena that the latter cannot capture. The method also allows the computation of the aerodynamic forces experienced by the flier, either through the lifting line method or through control-volume analysis. The computed power requirements at several flight speeds exhibit an order of magnitude and dependency on velocity in agreement with the literature.

An exact accelerated stochastic simulation algorithm.

An exact method for stochastic simulation of chemical reaction networks, which accelerates the stochastic simulation algorithm (SSA), is proposed. The present "ER-leap" algorithm is derived from analytic upper and lower bounds on the multireaction probabilities sampled by SSA, together with rejection sampling and an adaptive multiplicity for reactions. The algorithm is tested on a number of well-quantified reaction networks and is found experimentally to be very accurate on test problems including a chaotic reaction network. At the same time ER-leap offers a substantial speedup over SSA with a simulation time proportional to the 23 power of the number of reaction events in a Galton-Watson process.

Prosody Predicts Contest Outcome in Non-Verbal Dialogs.

Non-verbal communication has important implications for inter-individual relationships and negotiation success. However, to what extent humans can spontaneously use rhythm and prosody as a sole communication tool is largely unknown. We analysed human ability to resolve a conflict without verbal dialogs, independently of semantics. We invited pairs of subjects to communicate non-verbally using whistle sounds. Along with the production of more whistles, participants unwittingly used a subtle prosodic feature to compete over a resource (ice-cream scoops). Winners can be identified by their propensity to accentuate the first whistles blown when replying to their partner, compared to the following whistles. Naive listeners correctly identified this prosodic feature as a key determinant of which whistler won the interaction. These results suggest that in the absence of other communication channels, individuals spontaneously use a subtle variation of sound accentuation (prosody), instead of merely producing exuberant sounds, to impose themselves in a conflict of interest. We discuss the biological and cultural bases of this ability and their link with verbal communication. Our results highlight the human ability to use non-verbal communication in a negotiation process.

Evaluation of chitooligosaccharide application on mineral accumulation and plant growth in Phaseolus vulgaris.

Chitooligosaccharides (COS) - water soluble derivatives from chitin, are an interesting group of molecules for several biological applications, for they can enter plant cells and bind negatively charged molecules. Several studies reported an enhanced plant growth and higher crop yield due to chitosan application in soil grown plants, but no studies have looked on the effect of COS application on plant mineral nutrient dynamics in hydroponically grown plants. In this study, Phaseolus vulgaris was grown in hydroponic culture and the effect of three different concentrations of COS on plant growth and mineral accumulation was assessed. There were significant changes in mineral allocations for Mo, B, Zn, P, Pb, Cd, Mn, Fe, Mg, Ca, Cu, Na, Al and K among treatments. Plant morphology was severely affected in high doses of COS, as well as lignin concentration in the stem and the leaves, but not in the roots. Chlorophyll A, B and carotenoid concentrations did not change significantly among treatments, suggesting that even at higher concentrations, COS application did not affect photosynthetic pigment accumulation. Plants grown at high COS levels had shorter shoots and roots, suggesting that COS can be phytotoxic to the plant. The present study is the first detailed report on the effect of COS application on mineral nutrition in plants, and opens the door for future studies that aim at utilizing COS in biofortification or phytoremediation programs.

Multiresolution stochastic simulations of reaction-diffusion processes.

Stochastic simulations of reaction-diffusion processes are used extensively for the modeling of complex systems in areas ranging from biology and social sciences to ecosystems and materials processing. These processes often exhibit disparate scales that render their simulation prohibitive even for massive computational resources. The problem is resolved by introducing a novel stochastic multiresolution method that enables the efficient simulation of reaction-diffusion processes as modeled by many-particle systems. The proposed method quantifies and efficiently handles the associated stiffness in simulating the system dynamics and its computational efficiency and accuracy are demonstrated in simulations of a model problem described by the Fisher-Kolmogorov equation. The method is general and can be applied to other many-particle models of physical processes.

R-leaping: accelerating the stochastic simulation algorithm by reaction leaps.

A novel algorithm is proposed for the acceleration of the exact stochastic simulation algorithm by a predefined number of reaction firings (R-leaping) that may occur across several reaction channels. In the present approach, the numbers of reaction firings are correlated binomial distributions and the sampling procedure is independent of any permutation of the reaction channels. This enables the algorithm to efficiently handle large systems with disparate rates, providing substantial computational savings in certain cases. Several mechanisms for controlling the accuracy and the appearance of negative species are described. The advantages and drawbacks of R-leaping are assessed by simulations on a number of benchmark problems and the results are discussed in comparison with established methods.

Reconnection of colliding vortex rings.

We investigate numerically the Navier-Stokes dynamics of reconnecting vortex rings at small Reynolds number for a variety of configurations. We find that reconnections are dissipative due to the smoothing of vorticity gradients at reconnection kinks and to the formation of secondary structures of stretched antiparallel vorticity which transfer kinetic energy to small scales where it is subsequently dissipated efficiently. In addition, the relaxation of the reconnection kinks excites Kelvin waves which due to strong damping are of low wave number and affect directly only large scale properties of the flow.