West Nile Virus Neuroinvasive Disease: Lessons From Two Cases.

BACKGROUND AND OBJECTIVE: West Nile neuroinvasive disease (WNND) displays a wide range of clinical manifestations due to its involvement of various structures within the central nervous system and peripheral nervous system, often including prolonged unresponsiveness as the presenting symptom. METHODS AND RESULTS: We describe 2 patients presenting with coma and bilateral thalamic lesions on brain magnetic resonance imaging, found to have WNND after extensive workup. These cases illustrate some of the challenges associated with evaluating coma in general and specifically in diagnosing WNND. CONCLUSION: The clinical diagnosis of WNND requires a high index of suspicion, particularly in immunocompromised and elderly patients. Brain and spine magnetic resonance imaging findings can help narrow down the differential diagnosis, although other diseases may manifest similarly. Serological studies on the cerebrospinal fluid are essential to confirm the diagnosis but have inherent limitations. Given these challenges, WNND should be considered in all patients living in endemic areas who present with unexplained altered mental status during the late summer and early fall seasons.

Long-Term Potentiation Requires a Rapid Burst of Dendritic Mitochondrial Fission during Induction.

Synaptic transmission is bioenergetically demanding, and the diverse processes underlying synaptic plasticity elevate these demands. Therefore, mitochondrial functions, including ATP synthesis and Ca2+ handling, are likely essential for plasticity. Although axonal mitochondria have been extensively analyzed, LTP is predominantly induced postsynaptically, where mitochondria are understudied. Additionally, though mitochondrial fission is essential for their function, signaling pathways that regulate fission in neurons remain poorly understood. We found that NMDAR-dependent LTP induction prompted a rapid burst of dendritic mitochondrial fission and elevations of mitochondrial matrix Ca2+. The fission burst was triggered by cytosolic Ca2+ elevation and required CaMKII, actin, and Drp1, as well as dynamin 2. Preventing fission impaired mitochondrial matrix Ca2+ elevations, structural LTP in cultured neurons, and electrophysiological LTP in hippocampal slices. These data illustrate a novel pathway whereby synaptic activity controls mitochondrial fission and show that dynamic control of fission regulates plasticity induction, perhaps by modulating mitochondrial Ca2+ handling.

Identification of a minimal region of the HIV-1 5'-leader required for RNA dimerization, NC binding, and packaging.

Assembly of human immunodeficiency virus type 1 (HIV-1) particles is initiated in the cytoplasm by the formation of a ribonucleoprotein complex comprising the dimeric RNA genome and a small number of viral Gag polyproteins. Genomes are recognized by the nucleocapsid (NC) domains of Gag, which interact with packaging elements believed to be located primarily within the 5'-leader (5'-L) of the viral RNA. Recent studies revealed that the native 5'-L exists as an equilibrium of two conformers, one in which dimer-promoting residues and NC binding sites are sequestered and packaging is attenuated, and one in which these sites are exposed and packaging is promoted. To identify the elements within the dimeric 5'-L that are important for packaging, we generated HIV-1 5'-L RNAs containing mutations and deletions designed to eliminate substructures without perturbing the overall structure of the leader and examined effects of the mutations on RNA dimerization, NC binding, and packaging. Our findings identify a 159-residue RNA packaging signal that possesses dimerization and NC binding properties similar to those of the intact 5'-L and contains elements required for efficient RNA packaging.

NMR detection of structures in the HIV-1 5'-leader RNA that regulate genome packaging.

The 5'-leader of the HIV-1 genome regulates multiple functions during viral replication via mechanisms that have yet to be established. We developed a nuclear magnetic resonance approach that enabled direct detection of structural elements within the intact leader (712-nucleotide dimer) that are critical for genome packaging. Residues spanning the gag start codon (AUG) form a hairpin in the monomeric leader and base pair with residues of the unique-5' region (U5) in the dimer. U5:AUG formation promotes dimerization by displacing and exposing a dimer-promoting hairpin and enhances binding by the nucleocapsid (NC) protein, which is the cognate domain of the viral Gag polyprotein that directs packaging. Our findings support a packaging mechanism in which translation, dimerization, NC binding, and packaging are regulated by a common RNA structural switch.