Gravin orchestrates protein kinase A and 2-adrenergic receptor signaling critical for synaptic plasticity and memory

A kinase-anchoring proteins (AKAPs) organize compartmentalized pools of protein kinase A (PKA) to enable localized signaling events within neurons. However, it is unclear which of the many expressed AKAPs in neurons target PKA to signaling complexes important for long-lasting forms of synaptic plasticity and memory storage. In the forebrain, the anchoring protein gravin recruits a signaling complex containing PKA, PKC, calmodulin, and PDE4D (phosphodiesterase 4D) to the β2-adrenergic receptor. Here, we show that mice lacking the α-isoform of gravin have deficits in PKA-dependent long-lasting forms of hippocampal synaptic plasticity including β2-adrenergic receptor-mediated plasticity, and selective impairments of long-term memory storage. Furthermore, both hippocampal β2-adrenergic receptor phosphorylation by PKA, and learning-induced activation of ERK in the CA1 region of the hippocampus are attenuated in mice lacking gravin-α. We conclude that gravin compartmentalizes a significant pool of PKA that regulates learning-induced β2-adrenergic receptor signaling and ERK activation in the hippocampus in vivo, thereby organizing molecular interactions between glutamatergic and noradrenergic signaling pathways for long-lasting synaptic plasticity, and memory storage

Maximum Running Speed of Captive Bar-Headed Geese Is Unaffected by Severe Hypoxia

While bar-headed geese are renowned for migration at high altitude over the Himalayas, previous work on captive birds suggested that these geese are unable to maintain rates of oxygen consumption while running in severely hypoxic conditions. To investigate this paradox, we re-examined the running performance and heart rates of bar-headed geese and barnacle geese (a low altitude species) during exercise in hypoxia. Bar-headed geese (n = 7) were able to run at maximum speeds (determined in normoxia) for 15 minutes in severe hypoxia (7% O2; simulating the hypoxia at 8500 m) with mean heart rates of 466±8 beats min�1. Barnacle geese (n = 10), on the other hand, were unable to complete similar trials in severe hypoxia and their mean heart rate (316 beats.min�1) was significantly lower than bar-headed geese. In bar-headed geese, partial pressures of oxygen and carbon dioxide in both arterial and mixed venous blood were significantly lower during hypoxia than normoxia, both at rest and while running. However, measurements of blood lactate in bar-headed geese suggested that anaerobic metabolism was not a major energy source during running in hypoxia. We combined these data with values taken from the literature to estimate (i) oxygen supply, using the Fick equation and (ii) oxygen demand using aerodynamic theory for bar-headed geese flying aerobically, and under their own power, at altitude. This analysis predicts that the maximum altitude at which geese can transport enough oxygen to fly without environmental assistance ranges from 6,800 m to 8,900 m altitude, depending on the parameters used in the model but that such flights should be rare

Enhanced Cellular Transduction of Nanoparticles Resistant to Rapidly Forming Plasma Protein Coronas

Nanoparticles (NPs) are increasingly being developed as biomedical platforms for drug/nucleic acid delivery and imaging. However, in biological fluids, NPs interact with a wide range of proteins that form a coating known as protein corona. Coronae can critically influence self-interaction and binding of other molecules, which can affect toxicity, promote cell activation, and inhibit general or specific cellular uptake. Glycosaminoglycan (GAG)-binding enhanced transduction (GET) is developed to efficiently deliver a variety of cargoes intracellularly; employing GAG-binding peptides, which promote cell targeting, and cell penetrating peptides (CPPs) which enhance endocytotic cell internalization. Herein, it is demonstrated that GET peptide coatings can mediate sustained intracellular transduction of magnetic NPs (MNPs), even in the presence of serum or plasma. NP colloidal stability, physicochemical properties, toxicity and cellular uptake are investigated. Using label-free snapshot proteomics, time-resolved profiles of human plasma coronas formed on functionalized GET-MNPs demonstrate that coronae quickly form (<1 min), with their composition relatively stable but evolving. Importantly GET-MNPs present a subtly different corona composition to MNPs alone, consistent with GAG-binding activities. Understanding how NPs interact with biological systems and can retain enhanced intracellular transduction will facilitate novel drug delivery approaches for cell-type specific targeting of new nanomaterials

Singular solutions of fully nonlinear elliptic equations and applications

We study the properties of solutions of fully nonlinear, positively homogeneous elliptic equations near boundary points of Lipschitz domains at which the solution may be singular. We show that these equations have two positive solutions in each cone of $\mathbb{R}^n$, and the solutions are unique in an appropriate sense. We introduce a new method for analyzing the behavior of solutions near certain Lipschitz boundary points, which permits us to classify isolated boundary singularities of solutions which are bounded from either above or below. We also obtain a sharp Phragm\'en-Lindel\"of result as well as a principle of positive singularities in certain Lipschitz domains.Comment: 41 pages, 2 figure

Numerical evidence for `multi-scalar stars'

We present a class of general relativistic soliton-like solutions composed of multiple minimally coupled, massive, real scalar fields which interact only through the gravitational field. We describe a two-parameter family of solutions we call ``phase-shifted boson stars'' (parameterized by central density rho_0 and phase delta), which are obtained by solving the ordinary differential equations associated with boson stars and then altering the phase between the real and imaginary parts of the field. These solutions are similar to boson stars as well as the oscillating soliton stars found by Seidel and Suen [E. Seidel and W.M. Suen, Phys. Rev. Lett. 66, 1659 (1991)]; in particular, long-time numerical evolutions suggest that phase-shifted boson stars are stable. Our results indicate that scalar soliton-like solutions are perhaps more generic than has been previously thought.Comment: Revtex. 4 pages with 4 figures. Submitted to Phys. Rev.

Self-trapping transition for nonlinear impurities embedded in a Cayley tree

The self-trapping transition due to a single and a dimer nonlinear impurity embedded in a Cayley tree is studied. In particular, the effect of a perfectly nonlinear Cayley tree is considered. A sharp self-trapping transition is observed in each case. It is also observed that the transition is much sharper compared to the case of one-dimensional lattices. For each system, the critical values of $\chi$ for the self-trapping transitions are found to obey a power-law behavior as a function of the connectivity $K$ of the Cayley tree.Comment: 6 pages, 7 fig

ColliderBit: a GAMBIT module for the calculation of high-energy collider observables and likelihoods

We describe ColliderBit, a new code for the calculation of high energy collider observables in theories of physics beyond the Standard Model (BSM). ColliderBit features a generic interface to BSM models, a unique parallelised Monte Carlo event generation scheme suitable for large-scale supercomputer applications, and a number of LHC analyses, covering a reasonable range of the BSM signatures currently sought by ATLAS and CMS. ColliderBit also calculates likelihoods for Higgs sector observables, and LEP searches for BSM particles. These features are provided by a combination of new code unique to ColliderBit, and interfaces to existing state-of-the-art public codes. ColliderBit is both an important part of the GAMBIT framework for BSM inference, and a standalone tool for efficiently applying collider constraints to theories of new physics