Connexin-dependent neuroglial networking as a new therapeutic target

Astrocytes and neurons dynamically interact during physiological processes, and it is now widely accepted that they are both organized in plastic and tightly regulated networks. Astrocytes are connected through connexin-based gap junction channels, with brain region specificities, and those networks modulate neuronal activities, such as those involved in sleep-wake cycle, cognitive, or sensory functions. Additionally, astrocyte domains have been involved in neurogenesis and neuronal differentiation during development; they participate in the "tripartite synapse" with both pre-synaptic and post-synaptic neurons by tuning down or up neuronal activities through the control of neuronal synaptic strength. Connexin-based hemichannels are also involved in those regulations of neuronal activities, however, this feature will not be considered in the present review. Furthermore, neuronal processes, transmitting electrical signals to chemical synapses, stringently control astroglial connexin expression, and channel functions. Long-range energy trafficking toward neurons through connexin-coupled astrocytes and plasticity of those networks are hence largely dependent on neuronal activity. Such reciprocal interactions between neurons and astrocyte networks involve neurotransmitters, cytokines, endogenous lipids, and peptides released by neurons but also other brain cell types, including microglial and endothelial cells. Over the past 10 years, knowledge about neuroglial interactions has widened and now includes effects of CNS-targeting drugs such as antidepressants, antipsychotics, psychostimulants, or sedatives drugs as potential modulators of connexin function and thus astrocyte networking activity. In physiological situations, neuroglial networking is consequently resulting from a two-way interaction between astrocyte gap junction-mediated networks and those made by neurons. As both cell types are modulated by CNS drugs we postulate that neuroglial networking may emerge as new therapeutic targets in neurological and psychiatric disorders

The connexin43 mimetic peptide Gap19 inhibits hemichannels without altering gap junctional communication in astrocytes

In the brain, astrocytes represent the cellular population that expresses the highest amount of connexins (Cxs). This family of membrane proteins is the molecular constituent of gap junction channels and hemichannels that provide pathways for direct cytoplasm-to-cytoplasm and inside-out exchange, respectively. Both types of Cx channels are permeable to ions and small signaling molecules allowing astrocytes to establish dynamic interactions with neurons. So far, most pharmacological approaches currently available do not distinguish between these two channel functions, stressing the need to develop new specific molecular tools. In astrocytes two major Cxs are expressed, Cx43 and Cx30, and there is now evidence indicating that at least Cx43 operates as a gap junction channel as well as a hemichannel in these cells. Based on studies in primary cultures as well as in acute hippocampal slices, we report here that Gap 19, a nonapeptide derived from the cytoplasmic loop of Cx43, inhibits astroglial Cx43 hemichannels in a dose-dependent manner, without affecting gap junction channels. This peptide, which not only selectively inhibits hemichannels but is also specific for Cx43, can be delivered in vivo in mice as TAT-Gap19, and displays penetration into the brain parenchyma. As a result, Gap 19 combined with other tools opens up new avenues to decipher the role of Cx43 hemichannels in interactions between astrocytes and neurons in physiological as well as pathological situations

Final report of comprehensive testing program for concrete at elevated temperatures

The objective of this program was to define the variations in physical (thermal) and mechanical (strength) properties of limestone aggregate concrete and lightweight insulating concrete exposed to elevated temperatures that could occur as a result of a postulated large sodium spill in a lined LMFBR equipment cell. To meet this objective, five test series were conducted: (1) unconfined compression, (2) shear, (3) rebar bond, (4) sustained loading (creep), and (5) thermal properties. Mechanical property results are presented for concretes subjected to temperature up to 621{sup 0}C (1150{sup 0}F)

The Role of Final State Interactions in Quasielastic 56^{56}Fe(e,e′)(e,e') Reactions at large ∣q⃗∣|\vec q|

A relativistic finite nucleus calculation using a Dirac optical potential is used to investigate the importance of final state interactions [FSI] at large momentum transfers in inclusive quasielastic electronuclear reactions. The optical potential is derived from first-order multiple scattering theory and then is used to calculate the FSI in a nonspectral Green's function doorway approach. At intermediate momentum transfers excellent predictions of the quasielastic $^{56}$Fe$(e,e')$ experimental data for the longitudinal response function are obtained. In comparisons with recent measurements at $|{\vec q|}=1.14$~GeV/c the theoretical calculations of $R_L$ give good agreement for the quasielastic peak shape and amplitude, but place the position of the peak at an energy transfer of about $40$~MeV higher than the data.Comment: 13 pages typeset using revtex 3.0 with 6 postscript figures in accompanying uuencoded file; submitted to Phys. Rev.

The off-shell electromagnetic form factors of pions and kaons in chiral perturbation theory

The off-shell electromagnetic vertex of a (pseudo-) scalar particle contains, in general, two form factors F and G which depend, in addition to the squared momentum transfer, on the invariant masses associated with the initial and final legs of the vertex. Chiral perturbation theory to one loop is used to calculate the off-shell form factors of pions and kaons. The formalism of Gasser and Leutwyler, which was previously used to calculate the on-shell limit of the form factor F, is extended to accommodate the most general form for off-shell Green's functions in the pseudoscalar meson sector. We find that chiral symmetry predicts that the form factors F of the charged pions and kaons go off-shell in the same way, i.e., the off-shell slope at the real photon point is given by the same new phenomenological constant $\beta_1$. Furthermore, it is shown that at order $p^4$ the form factor F of the $K^0$ does not show any off-shell dependence. The form factors G are all related to the form factors F in the correct fashion as required by the Ward-Takahashi identity. Numerical results for different off-shell kinematics are presented.Comment: TRIUMF preprint TRI-PP-94-4, 25 pages in LaTeX + 10 figures (uufile'd, compressed PostScript file appended at end, hardcopy available from authors

The role of the gap junction protein connexin43 in B lymphocyte motility and migration

AbstractThe gap junction family of proteins is widely expressed in mammalian cells and form intercellular channels between adjacent cells, as well as hemichannels, for transport of molecules between the cell and the surrounding environment. In addition, gap junction proteins have recently been implicated as important for the regulation of cell adhesion and migration in a variety of cell types. The gap junction protein connexin43 (Cx43) regulates B lymphocyte adhesion, BCR- and LFA-1-mediated activation of the GTPase Rap1, and cytoskeletal rearrangements resulting in changes to cell shape and membrane spreading. We demonstrate here that the actin cytoskeleton is important for the distribution of Cx43 in the B cell plasma membrane and for other cell processes involving the cytoskeleton. Using shRNA knockdown of Cx43 in B lymphoma cells we show that Cx43 is also necessary for chemokine-mediated Rap 1 activation, motility, CXCL12-directed migration, and movement across an endothelial cell monolayer. These results demonstrate that in addition to its role in B cell spreading, Cx43 is an important regulator of B-cell motility and migration, processes essential for normal B-cell development and immune responses

Off-shell pion electromagnetic form factor from a gauge-invariant Nambu-Jona-Lasinio model

The off--shell electromagnetic vertex function of pions and kaons is studied in a bosonized Nambu--Jona-Lasinio model with a gauge--invariant proper--time cutoff. The slope of the pion form factor with respect to the pion 4--momentum is found to be equal to the on--shell pion charge radius in the chiral limit. The off--shell slope of the $K^0$ form factor is zero, that of the $K^\pm$ about 15\% smaller than that of the pion. We compare our results with those of a recent calculation in chiral perturbation theory.Comment: (9 p., standard LaTeX, 1 PostScript figure appended) UNITUE-THEP-7/9

Gauge-invariant theory of pion photoproduction with dressed hadrons

Based on an effective field theory of hadrons in which quantum chromodynamics is assumed to provide the necessary bare cutoff functions, a gauge-invariant theory of pion photoproduction with fully dressed nucleons is developed. The formalism provides consistent dynamical descriptions of pi-N --> pi-N scattering and Gamma-N --> pi-N production mechanisms in terms of nonlinear integral equations for fully dressed hadrons. Defining electromagnetic currents via the gauging of hadronic n-point Green's functions, dynamically detailed currents for dressed nucleons are introduced. The dressed hadron currents and the pion photoproduction current are explicitly shown to satisfy gauge invariance in a self-consistent manner. Approximations are discussed that make the nonlinear formalism manageable in practice and yet preserve gauge invariance. This is achieved by recasting the gauge conditions for all contributing interaction currents as continuity equations with ``surface'' terms for the individual particle legs coming into or going out of the hadronic interaction region. General procedures are given that approximate any type of (global) interaction current in a gauge-invariance preserving manner as a sum of single-particle ``surface'' currents. It is argued that these prescriptions carry over to other reactions, irrespective of the number or type of contributing hadrons or hadronic systems.Comment: 33 pages, RevTeX; includes 8 postscript figures (requires psfig.sty). This version corrects some minor errors, etc.; contains updated references. Accepted for publication in Phys. Rev. C56 (Oct. 97

Gauge-invariant tree-level photoproduction amplitudes with form factors

We show how the gauge-invariance formulation given by Haberzettl is implemented in practice for photoproduction amplitudes at the tree level with form factors describing composite nucleons. We demonstrate that, in contrast to Ohta's gauge-invariance prescription, this formalism allows electric current contributions to be multiplied by a form factor, i.e., it does not require that they be treated like bare currents. While different in detail, this nevertheless lends support to previous ad hoc approaches which multiply the Born amplitudes by an overall form factor. Numerical results for kaon photoproduction off the nucleon are given. They show that the gauge procedure by Haberzettl leads to much improved $\chi^2$ values as compared to Ohta's prescription.Comment: 5 pages, RevTeX, two eps figure