86 research outputs found
Chronic Intranasal Treatment with an Anti-Aβ30-42 scFv Antibody Ameliorates Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease
Amyloid-beta peptide (Aβ)-directed active and passive immunization therapeutic strategies reduce brain levels of Aβ, decrease the severity of beta-amyloid plaque pathology and reverse cognitive deficits in mouse models of Alzheimer's disease (AD). As an alternative approach to passive immunization with full IgG molecules, single-chain variable fragment (scFv) antibodies can modulate or neutralize Aβ-related neurotoxicity and inhibit its aggregation in vitro. In this study, we characterized a scFv derived from a full IgG antibody raised against the C-terminus of Aβ, and studied its passage into the brains of APP transgenic mice, as well as its potential to reduce Aβ-related pathology. We found that the scFv entered the brain after intranasal application, and that it bound to beta-amyloid plaques in the cortex and hippocampus of APP transgenic mice. Moreover, the scFv inhibited Aβ fibril formation and Aβ-mediated neurotoxicity in vitro. In a preventative therapeutic approach chronic intranasal treatment with scFv reduced congophilic amyloid angiopathy (CAA) and beta-amyloid plaque numbers in the cortex of APPswe/PS1dE9 mice. This reduction of CAA and plaque pathology was associated with a redistribution of brain Aβ from the insoluble fraction to the soluble peptide pool. Due to their lack of the effector domain of full IgG, scFv may represent an alternative tool for the treatment of Aβ-related pathology without triggering Fc-mediated effector functions. Additionally, our observations support the possibility that Aβ-directed immunotherapy can reduce Aβ deposition in brain vessels in transgenic mice
Characterization of non-uniform InGaN alloys: spatial localization of carriers and optical properties
Tight binding parameterization through particle swarm optimization algorithm
The tight binding (TB) approach represents a good trade-off between accuracy and computational burden. For this reason, it is widely used for device simulations. However, a proper description of a physical system by means of TB requires an accurate parameterization of the Hamiltonian matrix elements (HME), that is usually done by fitting over suitable properties that can be measured or computed with first-principles approaches. We show that the particle swarm optimization algorithm is a powerful tool for the parameterization of the TB HME, using the density functional theory band dispersions of bulk reference materials as a target. We discuss the results obtained for bulk MAPbI(3) perovskite in its high temperature cubic phase
InGaN/GaN multi‐quantum‐well solar cells under high solar concentration and elevated temperatures for hybrid solar thermal‐photovoltaic power plants
Induction of Metallothionein I by Arsenic via Metal-activated Transcription Factor 1: CRITICAL ROLE OF C-TERMINAL CYSTEINE RESIDUES IN ARSENIC SENSING
Metal-activated transcription factor 1 (MTF1) mediates the induction of
metallothioneins I and II by zinc and stress signals. The mechanism of MTF1
activation has not been well understood. We analyzed the interaction between
arsenic (As3+) and MTF1 for Mt1 induction. As3+
potently induces Mt1 mRNA expression in mouse hepa1c1c7 cells.
Induction is dependent upon functional MTF1 as induction is lost in
Mtf1 knockout cells but is restored upon reconstitution with
Mtf1; moreover, As3+ induces the binding of MTF1 to the
metal response elements of endogenous Mt1. Induction is not affected
by modulating zinc concentrations but is markedly enhanced by cycloheximide.
Phenylarsine oxide (PAO), which covalently binds to vicinal protein cysteine
thiol groups, induces Mt1 with a magnitude of higher potency than
that of As3+. PAO affinity beads effectively pulls down the
carboxyl half of MTF1 (MTF1321–675) by binding to a cluster
of five cysteine residues near the terminus. Preincubation with
As3+, Cd2+, Co2+, Ni2+,
Ag+, Hg2+, and Bi3+ blocks pulldown of
MTF1321–675 by PAO beads in vitro and in
vivo, indicating that binding of the metal inducers to the same
C-terminal cysteine cluster as PAO occurs. Deletion of the C-terminal cysteine
cluster or mutation of the cysteine residues abolishes or markedly reduces the
transcription activation activity of MTF1 and the ability of MTF1 to restore
Mt1 induction in Mtf1 knockout cells. The findings
demonstrate a critical role of the C-terminal cysteine cluster of MTF1 in
arsenic sensing and gene transcription via arsenic-cysteine thiol
interaction
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