Liquid filled canyons on Titan

In May 2013 the Cassini RADAR altimeter observed channels in Vid Flumina, a drainage network connected to Titan’s second largest hydrocarbon sea, Ligeia Mare. Analysis of these altimeter echoes shows that the channels are located in deep (up to ~570 m), steep-sided, canyons and have strong specular surface reflections that indicate they are currently liquid filled. Elevations of the liquid in these channels are at the same level as Ligeia Mare to within a vertical precision of about 0.7 m, consistent with the interpretation of drowned river valleys. Specular reflections are also observed in lower order tributaries elevated above the level of Ligeia Mare, consistent with drainage feeding into the main channel system

Analytical study of non Gaussian fluctuations in a stochastic scheme of autocatalytic reactions

A stochastic model of autocatalytic chemical reactions is studied both numerically and analytically. The van Kampen perturbative scheme is implemented, beyond the second order approximation, so to capture the non Gaussianity traits as displayed by the simulations. The method is targeted to the characterization of the third moments of the distribution of fluctuations, originating from a system of four populations in mutual interaction. The theory predictions agree well with the simulations, pointing to the validity of the van Kampen expansion beyond the conventional Gaussian solution.Comment: 15 pages, 8 figures, submitted to Phys. Rev.

Steady-state fluctuations of a genetic feedback loop:an exact solution

Genetic feedback loops in cells break detailed balance and involve bimolecular reactions; hence exact solutions revealing the nature of the stochastic fluctuations in these loops are lacking. We here consider the master equation for a gene regulatory feedback loop: a gene produces protein which then binds to the promoter of the same gene and regulates its expression. The protein degrades in its free and bound forms. This network breaks detailed balance and involves a single bimolecular reaction step. We provide an exact solution of the steady-state master equation for arbitrary values of the parameters, and present simplified solutions for a number of special cases. The full parametric dependence of the analytical non-equilibrium steady-state probability distribution is verified by direct numerical solution of the master equations. For the case where the degradation rate of bound and free protein is the same, our solution is at variance with a previous claim of an exact solution (Hornos et al, Phys. Rev. E {\bf 72}, 051907 (2005) and subsequent studies). We show explicitly that this is due to an unphysical formulation of the underlying master equation in those studies.Comment: 31 pages, 3 figures. Accepted for publication in the Journal of Chemical Physics (2012

Elastic constants of 3-, 4- and 6-connected chiral and anti-chiral honeycombs subject to uniaxial in-plane loading

Finite Element models are developed for the in-plane linear elastic constants of a family of honeycombs comprising arrays of cylinders connected by ligaments. Honeycombs having cylinders with 3, 4 and 6 ligaments attached to them are considered, with two possible configurations explored for each of the 3- (trichiral and anti-trichiral) and 4- (tetrachiral and anti-tetrachiral) connected systems. Honeycombs for each configuration have been manufactured using rapid prototyping and subsequently characterised for mechanical properties through in-plane uniaxial loading to verify the models. An interesting consequence of the family of 'chiral' honeycombs presented here is the ability to produce negative Poisson's ratio (auxetic) response. The deformation mechanisms responsible for auxetic functionality in such honeycombs are discussed

Multi-step self-guided pathways for shape-changing metamaterials

Multi-step pathways, constituted of a sequence of reconfigurations, are central to a wide variety of natural and man-made systems. Such pathways autonomously execute in self-guided processes such as protein folding and self-assembly, but require external control in macroscopic mechanical systems, provided by, e.g., actuators in robotics or manual folding in origami. Here we introduce shape-changing mechanical metamaterials, that exhibit self-guided multi-step pathways in response to global uniform compression. Their design combines strongly nonlinear mechanical elements with a multimodal architecture that allows for a sequence of topological reconfigurations, i.e., modifications of the topology caused by the formation of internal self-contacts. We realized such metamaterials by digital manufacturing, and show that the pathway and final configuration can be controlled by rational design of the nonlinear mechanical elements. We furthermore demonstrate that self-contacts suppress pathway errors. Finally, we demonstrate how hierarchical architectures allow to extend the number of distinct reconfiguration steps. Our work establishes general principles for designing mechanical pathways, opening new avenues for self-folding media, pluripotent materials, and pliable devices in, e.g., stretchable electronics and soft robotics.Comment: 16 pages, 3 main figures, 10 extended data figures. See https://youtu.be/8m1QfkMFL0I for an explanatory vide

Overexpression of Parkinson's Disease-Associated Mutation LRRK2 G2019S in Mouse Forebrain Induces Behavioral Deficits and alpha-Synuclein Pathology

Citation: Xiong, Y. L., Neifert, S., Karuppagounder, S. S., Stankowski, J. N., Lee, B. D., Grima, J. C., . . . Dawson, V. L. (2017). Overexpression of Parkinson's Disease-Associated Mutation LRRK2 G2019S in Mouse Forebrain Induces Behavioral Deficits and alpha-Synuclein Pathology. Eneuro, 4(2), 10. https://doi.org/10.1523/eneuro.0004-17.2017Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as an unambiguous cause of late-onset, autosomal-dominant familial Parkinson's disease (PD) and LRRK2 mutations are the strongest genetic risk factor for sporadic PD known to date. A number of transgenic mice expressing wild-type or mutant LRRK2 have been described with varying degrees of LRRK2-related abnormalities and modest pathologies. None of these studies directly addressed the role of the kinase domain in the changes observed and none of the mice present with robust features of the human disease. In an attempt to address these issues, we created a conditional LRRK2 G2019S (LRRK2 GS) mutant and a functionally negative control, LRRK2 G2019S/D1994A (LRRK2 GS/DA). Expression of LRRK2 GS or LRRK2 GS/DA was conditionally controlled using the tet-off system in which the presence of tetracycline-transactivator protein (tTA) with a CAMKII alpha promoter (CAMKII alpha-tTA) induced expression of TetP-LRRK2 GS or TetP-LRRK2 GS/DA in the mouse forebrain. Overexpression of LRRK2 GS in mouse forebrain induced behavioral deficits and alpha-synuclein pathology in a kinase-dependent manner. Similar to other genetically engineered LRRK2 GS mice, there was no significant loss of dopaminergic neurons. These mice provide an important new tool to study neurobiological changes associated with the increased kinase activity from the LRRK2 G2019S mutation, which may ultimately lead to a better understanding of not only the physiologic actions of LRRK2, but also potential pathologic actions that underlie LRRK2 GS-associated PD

Evaluation of rate law approximations in bottom-up kinetic models of metabolism.

BackgroundThe mechanistic description of enzyme kinetics in a dynamic model of metabolism requires specifying the numerical values of a large number of kinetic parameters. The parameterization challenge is often addressed through the use of simplifying approximations to form reaction rate laws with reduced numbers of parameters. Whether such simplified models can reproduce dynamic characteristics of the full system is an important question.ResultsIn this work, we compared the local transient response properties of dynamic models constructed using rate laws with varying levels of approximation. These approximate rate laws were: 1) a Michaelis-Menten rate law with measured enzyme parameters, 2) a Michaelis-Menten rate law with approximated parameters, using the convenience kinetics convention, 3) a thermodynamic rate law resulting from a metabolite saturation assumption, and 4) a pure chemical reaction mass action rate law that removes the role of the enzyme from the reaction kinetics. We utilized in vivo data for the human red blood cell to compare the effect of rate law choices against the backdrop of physiological flux and concentration differences. We found that the Michaelis-Menten rate law with measured enzyme parameters yields an excellent approximation of the full system dynamics, while other assumptions cause greater discrepancies in system dynamic behavior. However, iteratively replacing mechanistic rate laws with approximations resulted in a model that retains a high correlation with the true model behavior. Investigating this consistency, we determined that the order of magnitude differences among fluxes and concentrations in the network were greatly influential on the network dynamics. We further identified reaction features such as thermodynamic reversibility, high substrate concentration, and lack of allosteric regulation, which make certain reactions more suitable for rate law approximations.ConclusionsOverall, our work generally supports the use of approximate rate laws when building large scale kinetic models, due to the key role that physiologically meaningful flux and concentration ranges play in determining network dynamics. However, we also showed that detailed mechanistic models show a clear benefit in prediction accuracy when data is available. The work here should help to provide guidance to future kinetic modeling efforts on the choice of rate law and parameterization approaches

Multi-centre parallel arm randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based cognitive behavioural approach to managing fatigue in people with multiple sclerosis

Abstract (provisional) Background Fatigue is one of the most commonly reported and debilitating symptoms of multiple sclerosis (MS); approximately two-thirds of people with MS consider it to be one of their three most troubling symptoms. It may limit or prevent participation in everyday activities, work, leisure, and social pursuits, reduce psychological well-being and is one of the key precipitants of early retirement. Energy effectiveness approaches have been shown to be effective in reducing MS-fatigue, increasing self-efficacy and improving quality of life. Cognitive behavioural approaches have been found to be effective for managing fatigue in other conditions, such as chronic fatigue syndrome, and more recently, in MS. The aim of this pragmatic trial is to evaluate the clinical and cost-effectiveness of a recently developed group-based fatigue management intervention (that blends cognitive behavioural and energy effectiveness approaches) compared with current local practice. Methods This is a multi-centre parallel arm block-randomised controlled trial (RCT) of a six session group-based fatigue management intervention, delivered by health professionals, compared with current local practice. 180 consenting adults with a confirmed diagnosis of MS and significant fatigue levels, recruited via secondary/primary care or newsletters/websites, will be randomised to receive the fatigue management intervention or current local practice. An economic evaluation will be undertaken alongside the trial. Primary outcomes are fatigue severity, self-efficacy and disease-specific quality of life. Secondary outcomes include fatigue impact, general quality of life, mood, activity patterns, and cost-effectiveness. Outcomes in those receiving the fatigue management intervention will be measured 1 week prior to, and 1, 4, and 12 months after the intervention (and at equivalent times in those receiving current local practice). A qualitative component will examine what aspects of the fatigue management intervention participants found helpful/unhelpful and barriers to change. Discussion This trial is the fourth stage of a research programme that has followed the Medical Research Council guidance for developing and evaluating complex interventions. What makes the intervention unique is that it blends cognitive behavioural and energy effectiveness approaches. A potential strength of the intervention is that it could be integrated into existing service delivery models as it has been designed to be delivered by staff already working with people with MS. Service users will be involved throughout this research. Trial registration: Current Controlled Trials ISRCTN7651747

Mechanical Metamaterials with Negative Compressibility Transitions

When tensioned, ordinary materials expand along the direction of the applied force. Here, we explore network concepts to design metamaterials exhibiting negative compressibility transitions, during which a material undergoes contraction when tensioned (or expansion when pressured). Continuous contraction of a material in the same direction of an applied tension, and in response to this tension, is inherently unstable. The conceptually similar effect we demonstrate can be achieved, however, through destabilisations of (meta)stable equilibria of the constituents. These destabilisations give rise to a stress-induced solid-solid phase transition associated with a twisted hysteresis curve for the stress-strain relationship. The strain-driven counterpart of negative compressibility transitions is a force amplification phenomenon, where an increase in deformation induces a discontinuous increase in response force. We suggest that the proposed materials could be useful for the design of actuators, force amplifiers, micro-mechanical controls, and protective devices.Comment: Supplementary information available at http://www.nature.com/nmat/journal/v11/n7/abs/nmat3331.htm