CaMKII regulation of astrocytic glutamate uptake

Indiana University-Purdue University Indianapolis (IUPUI)Glutamate clearance by astrocytes is an essential part of physiological excitatory neurotransmission. Failure to adapt or maintain low levels of glutamate in the central nervous system is associated with multiple acute and chronic neurodegenerative diseases. The primary excitatory amino acid transporters (EAATs) in human astrocytes are EAAT1 and EAAT2 (GLAST and GLT-1 respectively in rodents). While the inhibition of a ubiquitously-expressed serine/threonine protein kinase, the calcium/calmodulindependent kinase (CaMKII) results in diminished glutamate uptake in cultured primary rodent astrocytes, the molecular mechanism underlying this regulation is unknown. In order to delineate this mechanism, we use a heterologous expression model to explore CaMKII regulation of EAAT1 and EAAT2. In transiently transfected HEK293T cells, pharmacological inhibition of CaMKII and overexpression of a dominant-negative version of CaMKII (Asp136Asn) reduces [3H]-glutamate uptake by EAAT1, without altering EAAT2 mediated glutamate uptake. Surprisingly, overexpression of a constitutively active autophosphorylation mutant (Thr287Asp) to increase autonomous CaMKII activity and a mutant incapable of autophosphorylation (Thr287Val) had no effect on either EAAT1 or EAAT2 mediated glutamate uptake. Pulldown of FLAGtagged glutamate transporters suggests CaMKII does not interact with EAAT1 or EAAT2. SPOTS peptide arrays and recombinant GST-fusion proteins of the intracellular N- and C-termini of EAAT1 identified two potential phosphorylation sites at residues Thr26 and Thr37 in the N-terminus. Introducing an Ala (a non-phospho mimetic) but not an Asp (phosphomimetic) at Thr37 diminished EAAT1-mediated glutamate uptake, suggesting that the phosphorylation state of this residue is important for constitutive EAAT1 function. In sum, this is the first report of a glutamate transporter being identified as a direct CaMKII substrate. These findings indicate that CaMKII signaling is a critical driver of homeostatic glutamate uptake by EAAT1. Aberrations in basal CaMKII activity disrupt glutamate uptake, which can perpetuate glutamate-mediated excitotoxicity and result in cellular death

Stability of Service under Time-of-Use Pricing

We consider "time-of-use" pricing as a technique for matching supply and demand of temporal resources with the goal of maximizing social welfare. Relevant examples include energy, computing resources on a cloud computing platform, and charging stations for electric vehicles, among many others. A client/job in this setting has a window of time during which he needs service, and a particular value for obtaining it. We assume a stochastic model for demand, where each job materializes with some probability via an independent Bernoulli trial. Given a per-time-unit pricing of resources, any realized job will first try to get served by the cheapest available resource in its window and, failing that, will try to find service at the next cheapest available resource, and so on. Thus, the natural stochastic fluctuations in demand have the potential to lead to cascading overload events. Our main result shows that setting prices so as to optimally handle the {\em expected} demand works well: with high probability, when the actual demand is instantiated, the system is stable and the expected value of the jobs served is very close to that of the optimal offline algorithm.Comment: To appear in STOC'1

Space-charge transport limits of ion beams in periodic quadrupole focusing channels

It has been empirically observed in both experiments and particle-in-cell simulations that space-charge-dominated beams suffer strong growth in statistical phase-space area (degraded quality) and particle losses in alternating gradient quadrupole transport channels when the undepressed phase advance sigma_0 increases beyond about 85 degrees per lattice period. Although this criterion has been used extensively in practical designs of strong focusing intense beam transport lattices, the origin of the limit has not been understood. We propose a mechanism for the transport limit resulting from classes of halo particle resonances near the core of the beam that allow near-edge particles to rapidly increase in oscillation amplitude when the space-charge intensity and the flutter of the matched beam envelope are both sufficiently large. When coupled with a diffuse beam edge and/or perturbations internal to the beam core that can drive particles outside the edge, this mechanism can result in large and rapid halo-driven increases in the statistical phase-space area of the beam, lost particles, and degraded transport. A core-particle model is applied to parametrically analyze this process. Extensive self-consistent particle in cell simulations are employed to better quantify space-charge limit and verify core-particle model predictions.Comment: 17 pages, 5 figures. Submitted to Nuclear Instruments and Methods A. Includes a long version of a conference talk (trans_limits_talk.pdf) presented on the topic at the "Coulomb'05 -- High Intensity Beam Dynamics" workshop (Senigallia, Italy, 12-16 September 2005). This talk presents further supporting information/plots not included in the abbreviated, draft-format manuscrip

A fourth-order spline method for singular two-point boundary-value problems

AbstractThis paper describes two methods for the solution of (weakly) singular two-point boundary-value problems: Consider the uniform mesh xi = ih, h = 1/N, i = 0(1)N. Define the linear functionals Li(y) = y(xi) and Mi(y) = (x−α(xαy′)′\xv;x=xi. In both these methods a piecewise ‘spline’ solution is obtained in the form s(x) = si(x), x\wE; [xi−1, xi], i = 1(1)N, where in each subinterval si(x) is in the linear span of a certain set of (non-polynomial) basis functions in the representation of the solution y(x) of the two-point boundary value problem and satisfies the interpolation conditions: Li−1(s) = Li−1(y), Li(y), Mi−1(s) = Mi−1(y), Mi(s) = Mi(y). By construction s and x−α(xαs′)′ \wE; C[0,1]. Conditions of continuity are derived to ensure that xαs′ \wE; C[0, 1]. It follows that the unknown parameters yi and Mi(y), i = 1(1)N − 1, must satisfy conditions of the form: The first method consists in replacing Mi(y) by fnof(xi, yi) and solving (*) to obtain the values yi; this method is generalization of the idea of Bickley [2] for the case of (weakly) singular two-point boundary-value problems and provides order h2 uniformly convergent approximations over [0, 1]. As a modification of the above method, in the second method we generate the solution yi at the nodal points by adapting the fourth-order method of Chawla [3] and then use the conditions of continuity (*) to obtain the corresponding smoothed approximations for Mi(y) needed for the construction of the spline solution. We show that the resulting new spline method provides order h4 uniformly convergent approximations over [0, 1]. The second-order and the fourth-order methods are illustrated computationally

High temperature carrier controlled ferromagnetism in alkali doped ZnO nanorods

Recent efforts in developing spintronic and magneto-optoelectric material for applications have relied on the use of magnetic semiconductors doped with transition metals and have met with limited success. Using a fresh synthesis approach using alkali ions we demonstrate that alkali doped zinc oxide can provide high temperature magnetic semiconductors. We report studies on nanocrystalline powder and pellets of p-type ZnO:Li and ZnO:Na that exhibit ferromagnetism up to 554 K. The ferromagnetic behavior was confirmed from magnetic hysteresis, ferromagnetic resonance, magnetic force microscopy, and explained by a model where substitutional Li+/Na+ in cation site induce local magnetic moments on oxygen atoms. Optimum dopant concentrations enable ferromagnetic exchange interaction leading to high Curie temperature

Recurrent acute pancreatitis due to a santorinicele in a young patient

A cystic dilatation of the terminal portion of the minor pancreatic duct (duct of Santorini) is referred to as a santorinicele. It is usually associated with pancreas divisum and has been suggested to be a cause of relative stenosis of the minor papilla, often leading to recurrent pancreatitis. While this anomaly has been reported in the paediatric population, it is more commonly found in the elderly. We present a 27-year-old woman with recurrent acute pancreatitis attributed to a santorinicele with a dorsal duct-exclusive pancreatic drainage