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Brain ischemia results from cardiac arrest, stroke or head trauma. These conditions can cause severe brain damage and are a leading cause of death and long-term disability. Neurons are far more susceptible to ischemic damage than neighboring astrocytes, but astrocytes have diverse and important functions in many aspects of ischemic brain damage. Here we review three main roles of astrocytes in ischemic brain damage. First, we consider astrocyte glycogen stores, which can defend the brain against hypoglycemic brain damage but may aggravate brain damage during ischemia due to enhanced lactic acidosis. Second, we review recent breakthroughs in understanding astrocytic mechanisms of transmitter release, particularly for those transmitters with known roles in ischemic brain damage: glutamate, D -serine, ATP and adenosine. Third, we discuss the role of gap-junctionally connected networks of astrocytes in mediating the spread of damaging molecules to healthy 'bystanders' during infarct expansion in stroke.

Phosphatidylinositol-3,4,5-trisphosphate (PIP₃) has been proposed to modulate the odorant sensitivity of olfactory sensory neurons by inhibiting activation of cyclic nucleotide-gated (CNG) channels in the cilia. When applied to the intracellular face of excised patches, PIP₃ has been shown to inhibit activation of heteromeric olfactory CNG channels, composed of CNGA2, CNGA4, and CNGB1b subunits, and homomeric CNGA2 channels. In contrast, we discovered that channels formed by CNGA3 subunits from cone photoreceptors were unaffected by PIP₃. Using chimeric channels and a deletion mutant, we determined that residues 61-90 within the N terminus of CNGA2 are necessary for PIP₃ regulation, and a biochemical \"pulldown\" assay suggests that PIP₃ directly binds this region. The N terminus of CNGA2 contains a previously identified calcium-calmodulin (Ca²⁺/CaM)-binding domain (residues 68-81) that mediates Ca²⁺/CaM inhibition of homomeric CNGA2 channels but is functionally silent in heteromeric channels. We discovered, however, that this region is required for PIP₃ regulation of both homomeric and heteromeric channels. Furthermore, PIP₃ occluded the action of Ca²⁺/CaM on both homomeric and heteromeric channels, in part by blocking Ca²⁺/CaM binding. Our results establish the importance of the CNGA2 N terminus for PIP₃ inhibition of olfactory CNG channels and suggest that PIP₃ inhibits channel activation by disrupting an autoexcitatory interaction between the N and C termini of adjacent subunits. By dramatically suppressing channel currents, PIP₃ may generate a shift in odorant sensitivity that does not require prior channel activity.

Cyclic nucleotide-gated (CNG) ion channels play a central role in vision and olfaction, generating the electrical responses to light in photoreceptors and to odorants in olfactory receptors. These channels have been detected in many other tissues where their functions are largely unclear. The use of gene knockouts and other methods have yielded some information, but there is a pressing need for potent and specific pharmacological agents directed at CNG channels. To date there has been very little systematic effort in this direction - most of what can be termed CNG channel pharmacology arose from testing reagents known to target protein kinases or other ion channels, or by accident when researchers were investigating other intracellular pathways that may regulate the activity of CNG channels. Predictably, these studies have not produced selective agents. However, taking advantage of emerging structural information and the increasing knowledge of the biophysical properties of these channels, some promising compounds and strategies have begun to emerge. In this review we discuss progress on two fronts, cyclic nucleotide analogs as both activators and competitive inhibitors, and inhibitors that target the pore or gating machinery of the channel. We also discuss the potential of these compounds for treating certain forms of retinal degeneration.

ABSTRACTErwinia amylovora is the causal agent of fire blight, a devastating disease affecting some plants of the Rosaceae family. We isolated bacteriophages from samples collected from infected apple and pear trees along the Wasatch Front in Utah. We announce 19 high-quality complete genome sequences of E. amylovora bacteriophages.

Phosphatidylinositol-3,4,5-trisphosphate (PIP^sub 3^) has been proposed to modulate the odorant sensitivity of olfactory sensory neurons by inhibiting activation of cyclic nucleotide-gated (CNG) channels in the cilia. When applied to the intracellular face of excised patches, PIP^sub 3^ has been shown to inhibit activation of heteromeric olfactory CNG channels, composed of CNGA2, CNGA4, and CNGBlb subunits, and homomeric CNGA2 channels. In contrast, we discovered that channels formed by CNGA3 subunits from cone photoreceptors were unaffected by PIP^sub 3^. Using chimeric channels and a deletion mutant, we determined that residues 61-90 within the N terminus of CNGA2 are necessary for PIP^sub 3^ regulation, and a biochemical \"pulldown\" assay suggests that PIP^sub 3^ directly binds this region. The N terminus of CNGA2 contains a previously identified calcium-calmodulin (Ca2+/CaM)-binding domain (residues 68-81) that mediates Ca2+/CaM inhibition of homomeric CNGA2 channels but is functionally silent in heteromeric channels. We discovered, however, that this region is required for PIP^sub 3^ regulation of both homomeric and heteromeric channels. Furthermore, PIP^sub 3^ occluded the action of Ca2+/CaM on both homomeric and heteromeric channels, in part by blocking Ca2+/CaM binding. Our results establish the importance of the CNGA2 N terminus for PIP^sub 3^ inhibition of olfactory CNG channels and suggest that PIP^sub 3^ inhibits channel activation by disrupting an autoexcitatory interaction between the N and C termini of adjacent subunits. By dramatically suppressing channel currents, PIP^sub 3^ may generate a shift in odorant sensitivity that does not require prior channel activity. [PUBLICATION ABSTRACT]

Phosphatidylinositol-3,4,5-trisphosphate (PIP 3 ) has been proposed to modulate the odorant sensitivity of olfactory sensory neurons by inhibiting activation of cyclic nucleotide-gated (CNG) channels in the cilia. When applied to the intracellular face of excised patches, PIP 3 has been shown to inhibit activation of heteromeric olfactory CNG channels, composed of CNGA2, CNGA4, and CNGB1b subunits, and homomeric CNGA2 channels. In contrast, we discovered that channels formed by CNGA3 subunits from cone photoreceptors were unaffected by PIP 3 . Using chimeric channels and a deletion mutant, we determined that residues 61–90 within the N terminus of CNGA2 are necessary for PIP 3 regulation, and a biochemical “pulldown” assay suggests that PIP 3 directly binds this region. The N terminus of CNGA2 contains a previously identified calcium–calmodulin (Ca 2+ /CaM)-binding domain (residues 68–81) that mediates Ca 2+ /CaM inhibition of homomeric CNGA2 channels but is functionally silent in heteromeric channels. We discovered, however, that this region is required for PIP 3 regulation of both homomeric and heteromeric channels. Furthermore, PIP 3 occluded the action of Ca 2+ /CaM on both homomeric and heteromeric channels, in part by blocking Ca 2+ /CaM binding. Our results establish the importance of the CNGA2 N terminus for PIP 3 inhibition of olfactory CNG channels and suggest that PIP 3 inhibits channel activation by disrupting an autoexcitatory interaction between the N and C termini of adjacent subunits. By dramatically suppressing channel currents, PIP 3 may generate a shift in odorant sensitivity that does not require prior channel activity.

Phosphatidylinositol-3,4,5-trisphosphate (PIP sub(3)) has been proposed to modulate the odorant sensitivity of olfactory sensory neurons by inhibiting activation of cyclic nucleotide-gated (CNG) channels in the cilia. When applied to the intracellular face of excised patches, PIP sub(3) has been shown to inhibit activation of heteromeric olfactory CNG channels, composed of CNGA2, CNGA4, and CNGB1b subunits, and homomeric CNGA2 channels. In contrast, we discovered that channels formed by CNGA3 subunits from cone photoreceptors were unaffected by PIP sub(3). Using chimeric channels and a deletion mutant, we determined that residues 61-90 within the N terminus of CNGA2 are necessary for PIP sub(3) regulation, and a biochemical \"pulldown\" assay suggests that PIP sub(3) directly binds this region. The N terminus of CNGA2 contains a previously identified calcium-calmodulin (Ca super(2+)/CaM)-binding domain (residues 68-81) that mediates Ca super(2+)/CaM inhibition of homomeric CNGA2 channels but is functionally silent in heteromeric channels. We discovered, however, that this region is required for PIP sub(3) regulation of both homomeric and heteromeric channels. Furthermore, PIP sub(3) occluded the action of Ca super(2+)/CaM on both homomeric and heteromeric channels, in part by blocking Ca super(2+)/CaM binding. Our results establish the importance of the CNGA2 N terminus for PIP sub(3) inhibition of olfactory CNG channels and suggest that PIP sub(3) inhibits channel activation by disrupting an autoexcitatory interaction between the N and C termini of adjacent subunits. By dramatically suppressing channel currents, PIP sub(3) may generate a shift in odorant sensitivity that does not require prior channel activity.

Editor Post: When the joint resolution to confer the rank of Lieutenant General on the present Commanding General of the United States Army was introduced, it was well understood that there would be vigorous opposition to the same.

[Editor of The Tribune.]--The impartial observer of the political situation in Virginia must, from an examination of the record, be forcibly struck with the falsity of the charge constantly made that all the Federal officeholders in Virginia were the appointees of Senator Mahone. Another equally erroneous opinion generally...