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Zebrafish VEGF Receptors: A Guideline to Nomenclature
Stem Cell and Regenerative Biolog
Structural and functional analysis of the middle segment of hsp90: implications for ATP hydrolysis and client protein and cochaperone interactions
Activation of client proteins by the Hsp90 molecular chaperone is dependent on binding and hydrolysis of ATP, which drives a molecular clamp via transient dimerization of the N-terminal domains. The crystal structure of the middle segment of yeast Hsp90 reveals considerable evolutionary divergence from the equivalent regions of other GHKL protein family members such as MutL and GyrB, including an additional domain of new fold. Using the known structure of the N-terminal nucleotide binding domain, a model for the Hsp90 dimer has been constructed. From this structure, residues implicated in the ATPase-coupled conformational cycle and in interactions with client proteins and the activating cochaperone Aha1 have been identified, and their roles functionally characterized in vitro and in vivo
Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer’s disease
Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer’s disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month after compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD
Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection
Glial glutamate transporter EAAT2 plays a major role in glutamate clearance in synaptic clefts. Several lines of evidence indicate that strategies designed to increase EAAT2 expression have potential for preventing excitotoxicity, which contributes to neuronal injury and death in neurodegenerative diseases. We previously discovered several classes of compounds that can increase EAAT2 expression through translational activation. Here, we present efficacy studies of the compound LDN/OSU-0212320, which is a pyridazine derivative from one of our lead series. In a murine model, LDN/OSU-0212320 had good potency, adequate pharmacokinetic properties, no observed toxicity at the doses examined, and low side effect/toxicity potential. Additionally, LDN/OSU-0212320 protected cultured neurons from glutamate-mediated excitotoxic injury and death via EAAT2 activation. Importantly, LDN/OSU-0212320 markedly delayed motor function decline and extended lifespan in an animal model of amyotrophic lateral sclerosis (ALS). We also found that LDN/OSU-0212320 substantially reduced mortality, neuronal death, and spontaneous recurrent seizures in a pilocarpine-induced temporal lobe epilepsy model. Moreover, our study demonstrated that LDN/OSU-0212320 treatment results in activation of PKC and subsequent Y-box–binding protein 1 (YB-1) activation, which regulates activation of EAAT2 translation. Our data indicate that the use of small molecules to enhance EAAT2 translation may be a therapeutic strategy for the treatment of neurodegenerative diseases
Measurements of electron-proton elastic cross sections for
We report on precision measurements of the elastic cross section for
electron-proton scattering performed in Hall C at Jefferson Lab. The
measurements were made at 28 unique kinematic settings covering a range in
momentum transfer of 0.4 5.5 . These measurements
represent a significant contribution to the world's cross section data set in
the range where a large discrepancy currently exists between the ratio of
electric to magnetic proton form factors extracted from previous cross section
measurements and that recently measured via polarization transfer in Hall A at
Jefferson Lab.Comment: 17 pages, 18 figures; text added, some figures replace
Nuclear transparency from quasielastic A(e,e'p) reactions uo to Q^2=8.1 (GeV/c)^2
The quasielastic (e,ep) reaction was studied on targets of
deuterium, carbon, and iron up to a value of momentum transfer of 8.1
(GeV/c). A nuclear transparency was determined by comparing the data to
calculations in the Plane-Wave Impulse Approximation. The dependence of the
nuclear transparency on and the mass number was investigated in a
search for the onset of the Color Transparency phenomenon. We find no evidence
for the onset of Color Transparency within our range of . A fit to the
world's nuclear transparency data reflects the energy dependence of the free
proton-nucleon cross section.Comment: 11 pages, 6 figure
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