The selectivity, voltage-dependence and acid sensitivity of the tandem pore potassium channel TASK-1 : contributions of the pore domains

We have investigated the contribution to ionic selectivity of residues in the selectivity filter and pore helices of the P1 and P2 domains in the acid sensitive potassium channel TASK-1. We used site directed mutagenesis and electrophysiological studies, assisted by structural models built through computational methods. We have measured selectivity in channels expressed in Xenopus oocytes, using voltage clamp to measure shifts in reversal potential and current amplitudes when Rb+ or Na+ replaced extracellular K+. Both P1 and P2 contribute to selectivity, and most mutations, including mutation of residues in the triplets GYG and GFG in P1 and P2, made channels nonselective. We interpret the effects of these—and of other mutations—in terms of the way the pore is likely to be stabilised structurally. We show also that residues in the outer pore mouth contribute to selectivity in TASK-1. Mutations resulting in loss of selectivity (e.g. I94S, G95A) were associated with slowing of the response of channels to depolarisation. More important physiologically, pH sensitivity is also lost or altered by such mutations. Mutations that retained selectivity (e.g. I94L, I94V) also retained their response to acidification. It is likely that responses both to voltage and pH changes involve gating at the selectivity filter

A class of efficient high-order iterative methods with memory for nonlinear equations and their dynamics

[EN] In this paper we obtain some theoretical results about iterative methods with memory for nonlinear equations. The class of algorithms we consider focus on incorporating memory without increasing the computational cost of the algorithm. This class uses for the predictor step of each iteration a quantity that has already been calculated in the previous iteration, typically the quantity governing the slope from the previous corrector step. In this way we do not introduce any extra computation, and more importantly, we avoid new function evaluations, allowing us to obtain high-order iterative methods in a simple way. A specific class of methods of this type is introduced, and we prove the convergence order is 2(n) + 2(n-2) with n + 1 function evaluations. An exhaustive efficiency study is performed to show the competitiveness of these methods. Finally, we test some specific examples and explore the effect that this predictor may have on the convergence set by setting a dynamical study.Ministerio de Economia y Competitividad de Espana, Grant/Award Number: MTM2014-52016-C2-2-P; Generalitat Valenciana Prometeo, Grant/Award Number: /2016/089Howk, CL.; Hueso, J.; Martínez Molada, E.; Teruel-Ferragud, C. (2018). A class of efficient high-order iterative methods with memory for nonlinear equations and their dynamics. Mathematical Methods in the Applied Sciences. 41(17):7263-7282. https://doi.org/10.1002/mma.4821S72637282411

Multidimensional Homeier's generalized class and its application to planar 1D Bratu problem

[EN] In this paper, a parametric family of iterative methods for solving nonlinear systems, including Homeier’s scheme is presented, proving its third-order of convergence. The numerical section is devoted to obtain an estimation of the solution of the classical Bratu problem by transforming it in a nonlinear system by using finite differences, and solving it with different elements of the iterative family.This research was supported by Ministerio de Economía y Competitividad MTM2014-52016-C02-02.Cordero Barbero, A.; Franqués García, AM.; Torregrosa Sánchez, JR. (2015). Multidimensional Homeier's generalized class and its application to planar 1D Bratu problem. Journal of the Spanish Society of Applied Mathematics. 70(1):1-10. https://doi.org/10.1007/s40324-015-0037-xS110701Abad, M. F., Cordero, A., Torregrosa, J. R.: Fourth-and fifth-order for solving nonlinear systems of equations: an application to the global positioning system, Abstr. Appl. Anal. (2013) (Article ID 586708)Andreu, C., Cambil, N., Cordero, A., Torregrosa, J.R.: Preliminary orbit determination of artificial satellites: a vectorial sixth-order approach, Abstr. Appl. Anal. (2013) (Article ID 960582)Awawdeh, F.: On new iterative method for solving systems of nonlinear equations. Numer. Algorithms 54, 395–409 (2010)Boyd, J.P.: One-point pseudospectral collocation for the one-dimensional Bratu equation. Appl. Math. Comput. 217, 5553–5565 (2011)Bratu, G.: Sur les equation integrals non-lineaires. Bull. Math. Soc. France 42, 113–142 (1914)Buckmire, R.: Applications of Mickens finite differences to several related boundary value problems. In: Mickens, R.E. (ed.) Advances in the Applications of Nonstandard Finite Difference Schemes, pp. 47–87. World Scientific Publishing, Singapore (2005)Cordero, A., Hueso, J.L., Martínez, E., Torregrosa, J.R.: A modified Newton-Jarratt’s composition. Numer. Algorithms 55, 87–99 (2010)Gelfand, I.M.: Some problems in the theory of quasi-linear equations. Trans. Am. Math. Soc. Ser. 2, 295–381 (1963)Homeier, H.H.H.: On Newton-tyoe methods with cubic convergence. J. Comput. Appl. Math. 176, 425–432 (2005)Jacobsen, J., Schmitt, K.: The Liouville-Bratu-Gelfand problem for radial operators. J. Differ. Equ. 184, 283–298 (2002)Jalilian, R.: Non-polynomial spline method for solving Bratu’s problem. Comput. Phys. Comm. 181, 1868–1872 (2010)Kanwar, V., Kumar, S., Behl, R.: Several new families of Jarratts method for solving systems of nonlinear equations. Appl. Appl. Math. 8(2), 701–716 (2013)Mohsen, A.: A simple solution of the Bratu problem. Comput. Math. with Appl. 67, 26–33 (2014)Petković, M., Neta, B., Petković, L., Džunić, J.: Multipoint Methods for Solving Nonlinear Equations. Academic Press, Amsterdam (2013)Sharma, J.R., Guna, R.K., Sharma, R.: An efficient fourth order weighted-Newton method for systems of nonlinear equations. Numer. Algorithms 62, 307–323 (2013)Sharma, J.R., Arora, H.: On efficient weighted-Newton methods for solving systems of nonlinear equations. Appl. Math. Comput. 222, 497–506 (2013)Traub, J.F.: Iterative Methods for the Solution of Equations. Chelsea Publishing Company, New York (1982)Wan, Y.Q., Guo, Q., Pan, N.: Thermo-electro-hydrodynamic model for electrospinning process. Int. J. Nonlinear Sci. Numer. Simul. 5, 5–8 (2004

Flavour physics from an approximate U(2)^3 symmetry

The quark sector of the Standard Model exhibits an approximate U(2)^3 flavour symmetry. This symmetry, broken in specific directions dictated by minimality, can explain the success of the Cabibbo-Kobayashi-Maskawa picture of flavour mixing and CP violation, confirmed by the data so far, while allowing for observable deviations from it, as expected in most models of ElectroWeak Symmetry Breaking. Building on previous work in the specific context of supersymmetry, we analyze the expected effects and we quantify the current bounds in a general Effective Field Theory framework. As a further relevant example we then show how the U(2)^3 symmetry and its breaking can be implemented in a generic composite Higgs model and we make a first analysis of its peculiar consequences. We also discuss how some partial extension of U(2)^3 to the lepton sector can arise, both in general and in composite Higgs models. An optimistic though conceivable interpretation of the considerations developed in this paper gives reasons to think that new physics searches in the flavour sector may be about to explore an interesting realm of phenomena.Comment: 29 pages, 5 figure

Enhanced Characterization of the Smell of Death by Comprehensive Two-Dimensional Gas Chromatography-Time-of-Flight Mass Spectrometry (GCxGC-TOFMS)

Soon after death, the decay process of mammalian soft tissues begins and leads to the release of cadaveric volatile compounds in the surrounding environment. The study of postmortem decomposition products is an emerging field of study in forensic science. However, a better knowledge of the smell of death and its volatile constituents may have many applications in forensic sciences. Domestic pigs are the most widely used human body analogues in forensic experiments, mainly due to ethical restrictions. Indeed, decomposition trials on human corpses are restricted in many countries worldwide. This article reports on the use of comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GCxGC-TOFMS) for thanatochemistry applications. A total of 832 VOCs released by a decaying pig carcass in terrestrial ecosystem, i.e. a forest biotope, were identified by GCxGC-TOFMS. These postmortem compounds belong to many kinds of chemical class, mainly oxygen compounds (alcohols, acids, ketones, aldehydes, esters), sulfur and nitrogen compounds, aromatic compounds such as phenolic molecules and hydrocarbons. The use of GCxGC-TOFMS in study of postmortem volatile compounds instead of conventional GC-MS was successful

Artificial Modulation of the Gating Behavior of a K+ Channel in a KvAP-DNA Chimera

We present experiments where the gating behavior of a voltage-gated ion channel is modulated by artificial ligand binding. We construct a channel-DNA chimera with the KvAP potassium channel reconstituted in an artificial membrane. The channel is functional and the single channel ion conductivity unperturbed by the presence of the DNA. However, the channel opening probability vs. bias voltage, i.e., the gating, can be shifted considerably by the electrostatic force between the charges on the DNA and the voltage sensing domain of the protein. Different hybridization states of the chimera DNA thus lead to different response curves of the channel

Non-equivalent role of TM2 gating hinges in heteromeric Kir4.1/Kir5.1 potassium channels

Comparison of the crystal structures of the KcsA and MthK potassium channels suggests that the process of opening a K+ channel involves pivoted bending of the inner pore-lining helices at a highly conserved glycine residue. This bending motion is proposed to splay the transmembrane domains outwards to widen the gate at the “helix-bundle crossing”. However, in the inwardly rectifying (Kir) potassium channel family, the role of this “hinge” residue in the second transmembrane domain (TM2) and that of another putative glycine gating hinge at the base of TM2 remain controversial. We investigated the role of these two positions in heteromeric Kir4.1/Kir5.1 channels, which are unique amongst Kir channels in that both subunits lack a conserved glycine at the upper hinge position. Contrary to the effect seen in other channels, increasing the potential flexibility of TM2 by glycine substitutions at the upper hinge position decreases channel opening. Furthermore, the contribution of the Kir4.1 subunit to this process is dominant compared to Kir5.1, demonstrating a non-equivalent contribution of these two subunits to the gating process. A homology model of heteromeric Kir4.1/Kir5.1 shows that these upper “hinge” residues are in close contact with the base of the pore α-helix that supports the selectivity filter. Our results also indicate that the highly conserved glycine at the “lower” gating hinge position is required for tight packing of the TM2 helices at the helix-bundle crossing, rather than acting as a hinge residue

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders