Functional modulation of the transient outward current Ito by KCNE beta-subunits and regional distribution in human non-failing and failing hearts

Objectives: The function of Kv4.3 (KCND3) channels, which underlie the transient outward current I,, in human heart, can be modulated by several accessory subunits such as KChIP2 and KCNE1-KCNE5. Here we aimed to determine the regional expression of Kv4.3, KChIP2, and KCNE mRNAs in non-failing and failing human hearts and to investigate the functional consequences of subunit coexpression in heterologous expression systems. Methods: We quantified mRNA levels for two Kv4.3 isoforms, Kv4.3-S and Kv4.3-L, and for KChIP2 as well as KCNE1-KCNE5 with real-time RT-PCR. We also studied the effects of KCNEs on Kv4.3 + KChIP2 current characteristics in CHO cells with the whole-cell voltage-clamp method. Results: In non-failing hearts, low expression was found for KCNE1, KCNE3, and KCNE5, three times higher expression for KCNE2, and 60 times higher for KCNE4. Transmural gradients were detected only for KChIP2 in left and right ventricles. Compared to non-failing tissue, failing hearts showed higher expression of Kv4.3-L and KCNE1 and lower of Kv4.3-S, KChIP2, KCNE4, and KCNE5. In CHO cells, Kv4.3 + KChIP2 currents were differentially modified by co-expressed KCNEs: time constants of inactivation were shorter with KCNE1 and KCNE3-5 while time-to-peak was decreased, and V-0.5 of steady-state inactivation was shifted to more negative potentials by all KCNE subunits. Importantly, KCNE2 induced a unique and prominent 'overshoot' of peak current during recovery from inactivation similar to that described for human I-to while other KCNE subunits induced little (KCNE4,5) or no overshoot. Conclusions: All KCNEs are expressed in the human heart at the transcript level. Compared to It. in native human myocytes, none of the combination of KChIP2 and KCNE produced an ideal congruency in current characteristics, suggesting that additional factors contribute to the regulation of the native I-to channel

The LeChatelier principle: The long and the short of it

Using ordinary calculus techniques, we investigate the conditions under which LeChatelier effects are signable for finite changes in parameter values. We show, for example, that the short run demand for a factor is always less responsive to price changes than the long run demand, provided that the factor of production and the fixed factor do not switch from being substitutes to being complements (or vice versa) over the relevant range of the price change. The absence of a sign change in the complementarity/substitutability relation holds under conditions that are considerably more general than supermodularity of the production function.postprin

Jet array impingement flow distributions and heat transfer characteristics. Effects of initial crossflow and nonuniform array geometry

Two-dimensional arrays of circular air jets impinging on a heat transfer surface parallel to the jet orifice plate are considered. The jet flow, after impingement, is constrained to exit in a single direction along the channel formed by the jet orifice plate and the heat transfer surface. The configurations considered are intended to model those of interest in current and contemplated gas turbine airfoil midchord cooling applications. The effects of an initial crossflow which approaches the array through an upstream extension of the channel are considered. Flow distributions as well as heat transfer coefficients and adiabatic wall temperatures resolved to one streamwise hole spacing were measured as a function of the initial crossflow rate and temperature relative to the jet flow rate and temperature. Both Nusselt number profiles and dimensionless adiabatic wall temperature (effectiveness) profiles are presented and discussed. Special test results which show a significant reduction of jet orifice discharge coefficients owing to the effect of a confined crossflow are also presented, along with a flow distribution model which incorporates those effects. A nonuniform array flow distribution model is developed and validated

Further SEASAT SAR coastal ocean wave analysis

Analysis techniques used to exploit SEASAT synthetic aperture radar (SAR) data of gravity waves are discussed and the SEASAT SAR's ability to monitor large scale variations in gravity wave fields in both deep and shallow water is evaluated. The SAR analysis techniques investigated included motion compensation adjustments and the semicausal model for spectral analysis of SAR wave data. It was determined that spectra generated from fast Fourier transform analysis (FFT) of SAR wave data were not significantly altered when either range telerotation adjustments or azimuth focus shifts were used during processing of the SAR signal histories, indicating that SEASAT imagery of gravity waves is not significantly improved or degraded by motion compensation adjustments. Evaluation of the semicausal (SC) model using SEASAT SAR data from Rev. 974 indicates that the SC spectral estimates were not significantly better than the FFT results

Equivariant orbifold structures on the projective line and integrable hierarchies

AbstractLet CP1k,m be the orbifold structure on CP1 obtained via uniformizing the neighborhoods of 0 and ∞ respectively by z↦zk and w↦wm. The diagonal action of the torus T=(S1)2 on CP1 induces naturally an action on the orbifold CP1k,m. In this paper we prove that if k and m are co-prime then Givental's prediction of the equivariant total descendent Gromov–Witten potential of CP1k,m satisfies certain Hirota Quadratic Equations (HQE for short). We also show that after an appropriate change of the variables, similar to Getzler's change in the equivariant Gromov–Witten theory of CP1, the putative Gromov–Witten potential turns into tau-function of a new integrable hierarchy, which we call the equivariant bi-graded Toda hierarchy. The Hamiltonian description of this hierarchy will be investigated in a future article

Calcium-permeable AMPA receptors in the VTA and nucleus accumbens after cocaine exposure: when, how, and why?

In animal models of drug addiction, cocaine exposure has been shown to increase levels of calcium-permeable AMPA receptors (CP-AMPARs) in two brain regions that are critical for motivation and reward—the ventral tegmental area (VTA) and the nucleus accumbens (NAc). This review compares CP-AMPAR plasticity in the two brain regions and addresses its functional significance. In VTA dopamine neurons, cocaine exposure results in synaptic insertion of high conductance CP-AMPARs in exchange for lower conductance calcium-impermeable AMPARs (CI-AMPARs). This plasticity is rapid in onset (hours), GluA2-dependent, and can be observed with a single cocaine injection. Whereas it is short-lived after experimenter-administered cocaine, it persists for months after cocaine self-administration. In addition to strengthening synapses and altering Ca2+ signaling, CP-AMPAR insertion alters subsequent induction of plasticity at VTA synapses. However, CP-AMPAR insertion is unlikely to mediate the increased DA cell activity that occurs during early withdrawal from cocaine exposure. Metabotropic glutamate receptor 1 (mGluR1) exerts a negative influence on CP-AMPAR accumulation in the VTA. Acutely, mGluR1 stimulation elicits a form of LTD resulting from CP-AMPAR removal and CI-AMPAR insertion. In medium spiny neurons (MSNs) of the NAc, extended access cocaine self-administration is required to increase CP-AMPAR levels. This is first detected after approximately a month of withdrawal and then persists. Once present in NAc synapses, CP-AMPARs mediate the expression of incubation of cue-induced cocaine craving. The mechanism of their accumulation may be GluA1-dependent, which differs from that observed in the VTA. However, similar to VTA, mGluR1 stimulation removes CP-AMPARs from MSN synapses. Loss of mGluR1 tone during cocaine withdrawal may contribute to CP-AMPAR accumulation in the NAc. Thus, results in both brain regions point to the possibility of using positive modulators of mGluR1 as treatments for cocaine addiction