410 research outputs found
alpha(7) Nicotinic acetylcholine receptor activation prevents behavioral and molecular changes induced by repeated phencyclidine treatment
No full textUdgivelsesdato: 2009 May-JunThe core features of schizophrenia include deficits in cognitive processes, such as attention and working memory, subserved by the prefrontal cortex (PFC). These deficits are believed to involve deficient neurotransmission through NMDA receptors, particularly on parvalbumin-containing interneurons, and administration of the NMDA-antagonist phencyclidine (PCP) in rodents is a well validated model of such cognitive deficits. Here we show that repeated PCP treatment (10 mg/kg/day for 10 days) decreased the expression of parvalbumin and synaptophysin mRNA in the mouse PFC, which corresponds to changes seen in patients with schizophrenia. In addition, PCP increased the basal mRNA expression in the PFC of the activity-regulated cytoskeleton-associated protein (Arc), a molecule involved in synaptic plasticity. These molecular changes produced by PCP were accompanied by a behavioral impairment as determined in a modified Y-maze test. Polymorphisms in the alpha(7) nicotinic acetylcholine receptor (nAChR) gene have been linked to schizophrenia. Here we demonstrate that acute administration of the selective alpha(7) nAChR partial agonist SSR180711 dose-dependently reversed the behavioral impairment induced by PCP. Importantly, repeated co-administration of SSR180711 (3 mg/kg) with PCP prevented both the changes in parvalbumin, synaptophysin, and Arc mRNA expression in the PFC, and the behavioral impairment induced by PCP. These results are the first to demonstrate prevention of the deleterious effects induced by repeated PCP treatment. The behavioral and molecular effects of alpha(7) nAChR agonism in this model, particularly the prevention of a decline in parvalbumin mRNA expression, suggest an involvement of the alpha(7) nAChR not only in the symptomatic relief, but also the pathophysiology, of schizophrenia
Axonal degeneration in an Alzheimer mouse model is PS1 gene dose dependent and linked to intraneuronal Aß accumulation
No full textAbnormalities and impairments in axonal transport are suggested to strongly contribute to the pathological alterations underlying AD. The exact mechanisms leading to axonopathy are currently unclear, but it was recently suggested that APP expression itself triggers axonal degeneration. We used APP transgenic mice and crossed them on a hemi- or homozygous PS1 knock-in background (APP/PS1KI). Depending on the mutant PS1 dosage, we demonstrate a clear aggravation in both plaque-associated and plaque-distant axonal degeneration, despite of an unchanged APP expression level. Amyloid-ß (Aβ) peptides were found to accumulate in axonal swellings as well as in axons and apical dendrites proximate to neurons accumulating intraneuronal Aβ in their cell bodies. This suggests that Aβ can be transported within neurites thereby contributing to axonal deficits. In addition, diffuse extracellular Aβ deposits were observed in the close vicinity of axonal spheroids accumulating intracellular Aβ, which might be indicative of a local Aβ release from sites of axonal damage
Accumulation of intraneuronal Aβ correlates with ApoE4 genotype
No full textIn contrast to extracellular plaque and intracellular tangle pathology, the presence and relevance of intraneuronal Aβ in Alzheimer’s disease (AD) is still a matter of debate. Human brain tissue offers technical challenges such as post-mortem delay and uneven or prolonged tissue fixation that might affect immunohistochemical staining. In addition, previous studies on intracellular Aβ accumulation in human brain often used antibodies targeting the C-terminus of Aβ and differed strongly in the pretreatments used. To overcome these inconsistencies, we performed extensive parametrical testing using a highly specific N-terminal Aβ antibody detecting the aspartate at position 1, before developing an optimal staining protocol for intraneuronal Aβ detection in paraffin-embedded sections from AD patients. To rule out that this antibody also detects the β-cleaved APP C-terminal fragment (β-CTF, C99) bearing the same epitope, paraffin-sections of transgenic mice overexpressing the C99-fragment were stained without any evidence for cross-reactivity in our staining protocol. The staining intensity of intraneuronal Aβ in cortex and hippocampal tissue of 10 controls and 20 sporadic AD cases was then correlated to patient data including sex, Braak stage, plaque load, and apolipoprotein E (ApoE) genotype. In particular, the presence of one or two ApoE4 alleles strongly correlated with an increased accumulation of intraneuronal Aβ peptides. Given that ApoE4 is a major genetic risk factor for AD and is involved in neuronal cholesterol transport, it is tempting to speculate that perturbed intracellular trafficking is involved in the increased intraneuronal Aβ aggregation in AD
NORMAL COORDINATES FOR VINYL FLUORIDE AND THE SEVEN DEUTEROVINYL FLUORIDES
No full text B. Bak and D. Christensen, Spectrochim, Acta 12, 355 (1958). J. R. Scherer and W. J. Potts, J. Chem Phys. 31, 1691 (1959).Author Institution: Department of Chemistry, Thermodynamic Research Center Texas A\&M UniversityAnnual coordinate calculation was carried out for these eight isotopic molecules based mainly on the experimental data reported by Bak and A perturbation program was used and the most general quadratic valence force potential function was assumed. A six-constant potential function did reproduce very closely the 24 out-of-plane vibrations. The results agree very well with those of Scherer and A least-squares fit of the 72 calculated to the observed in-plane frequencies was obtained using a 45-constant potential function. On the basis of these calculations, the in-plane fundamental vibrational assignments of Bak and Christensen were reexamined and modified. The new assignments as well as the final set of potential functions will be presented and discussed
University of Florida Potato Variety Trials Spotlight: Atlantic
No full text‘Atlantic’ is a white-skinned potato, being the standard variety for chiping commonly cultivated in Florida (Figure 1). The cultivar was released as a white mutant of the USDA breeding program. It was selected from a cross of Wauseon and Lenape (UDSA seedling B5141-6). ‘Atlantic’ was released in July 1976 by the Agricultural Research Service of the USDA, the Florida Agricultural Experiment Station, the Virginia Truck and Ornamentals Research Station, the New Jersey Agricultural Experiment Station, and the Maine Agricultural Experiment Station (Webb et al. 1978). Production and quality results provided in this spotlight are summarized from various trials conducted by the University of Florida over the past 22 years.
https://edis.ifas.ufl.edu/hs1278
This is a minor revision with an added author. Originally published 3/2016:
Mwatuwa, Rodrick, Christian Christensen, and Lincoln Zotarelli. 2020. “University of Florida Potato Variety Trials Spotlight: Atlantic”. EDIS 2016 (3), 3. https://doi.org/10.32473/edis-hs1278-2016
An antibody raised against a pathogenic serpin variant induces mutant-like behaviour in the wild-type protein.
No full textA monoclonal antibody (mAb) that binds to a transient intermediate may act as a catalyst for the corresponding reaction; here we show this principle can extend on a macro-molecular scale to the induction of mutant-like oligomerisation in a wild-type protein. Using the common, pathogenic Glu342Lys (Z) variant of α1-antitrypsin as antigen - whose native state is susceptible to the formation of a proto-oligomeric intermediate - we have produced a mAb (5E3) that increases the rate of oligomerisation of the wild-type (M) variant. Employing ELISA, gel shift, thermal stability and FRET time-course experiments, we show that mAb5E3 does not bind to the native state of α1-antitrypsin, but recognises a cryptic epitope in the vicinity of the post-helix A loop and strand 4C that is revealed upon transition to the polymerisation intermediate, and which persists in the ensuing oligomer. This epitope is not shared by loop-inserted monomeric conformations. We show the increased amenity to polymerisation by either the pathogenic Glu342Lys mutation or the binding of mAb5E3 occurs without affecting energetic barrier to polymerisation. As mAb5E3 also does not alter the relative stability of the monomer to intermediate, it acts in a manner similar to the Glu342Lys mutation, by facilitating the conformational interchange between these two states
Reduced basal and novelty-induced levels of activity-regulated cytoskeleton associated protein (Arc) and c-Fos mRNA in the cerebral cortex and hippocampus of APPswe/PS1ΔE9 transgenic mice
No full textActivity-regulated cytoskeletal-associated protein (Arc) and c-Fos are immediate early gene (IEG) products induced by novelty in the hippocampus and involved in the consolidation of synaptic plasticity and long-term memory. We investigated whether induction of arc and c-fos after exposure to a novel open field environment was compromised in different neocortical areas and the hippocampal formation in APP/PS1ΔE9 transgenic mice characterized by pronounced accumulation and deposition of beta amyloid (Aβ). Notably, the basal level of Arc and c-fos mRNA in the neocortex was significantly lower in APP/PS1ΔE9 compared to wild-type mice. Novelty exposure induced an increase in Arc and c-Fos mRNA in the medial prefrontal cortex (mPFC), parietal cortex, and hippocampal formation in both APP/PS1ΔE9 transgenic and wild-type mice. However, novelty-induced IEG expression did not reach the same levels in APP/PS1ΔE9 as in the wild-type mice. In contrast, synaptophysin levels did not differ between mutant and wild type mice, suggesting that the observed effect was not due to a general decrease in the number of presynapses. These data suggest a reduction in basal and novelty-induced neuronal activity in a transgenic mouse model of Alzheimer's disease, which is most pronounced in cortical regions, indicating that a decreased functional response in IEG expression could be partly responsible for the cognitive deficits observed in patients with Alzheimer's disease
P1‐026: Intracellular Aβ triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer's disease
No full textCross-Plane Stereo PIV Measurements of a Turbulent Boundary Layer Overlying Irregular Roughness
No full textThe structural attributes of turbulent flow over a complex roughness topography are explored with both low and high frame-rate stereo particle-image velocimetry (sPIV) measurements in a wall-normal\u96spanwise measurement plane (y - z). Particular attention is paid on the structures of the outer layer and well as within the roughness sublayer. The roughness under consideration was replicated from a turbine blade damaged by deposition of foreign materials and contains a broad range of topographical scales arranged in a highly irregular manner. This roughness was reproduced over a long streamwise fetch in a boundary-layer wind tunnel and measurements were performed at a momentum thickness Reynolds number of 14,000. Instantaneous velocity fields from the low-frame-rate measurements revealed structural attributes qualitatively consistent with smooth-wall flow structure, particularly patterns consistent with large-scale motions termed hairpin vortex packets. However, single-point turbulence statistics revealed significant statistical heterogeneity in the form of low- and high-momentum flow pathways marked by enhanced Reynolds stresses and turbulent kinetic energy. The low-momentum flow pathways were also marked by intense vortical activity along their spanwise boundaries, indicating that these pathways could represent preferential \u93channeling\u94 of large-scale motions due to the roughness below or the generation of trains of vortical structures shed from the roughness that advect downstream along a common path. In addition, some of these flow pathways were found to extend well into the outer layer of the flow. The high-frame-rate sPIV measurements in the spanwise\u96wall-normal plane were conducted at a lower momentum thickness Reynolds number of 4500 and revealed the dynamical nature of the flow both in the outer region and in the roughness sublayer.The structural attributes of turbulent flow over a complex roughness topography are explored with both low and high frame-rate stereo particle-image velocimetry (sPIV) measurements in a wall-normal\u96spanwise measurement plane (y - z). Particular attention is paid on the structures of the outer layer and well as within the roughness sublayer. The roughness under consideration was replicated from a turbine blade damaged by deposition of foreign materials and contains a broad range of topographical scales arranged in a highly irregular manner. This roughness was reproduced over a long streamwise fetch in a boundary-layer wind tunnel and measurements were performed at a momentum thickness Reynolds number of 14,000. Instantaneous velocity fields from the low-frame-rate measurements revealed structural attributes qualitatively consistent with smooth-wall flow structure, particularly patterns consistent with large-scale motions termed hairpin vortex packets. However, single-point turbulence statistics revealed significant statistical heterogeneity in the form of low- and high-momentum flow pathways marked by enhanced Reynolds stresses and turbulent kinetic energy. The low-momentum flow pathways were also marked by intense vortical activity along their spanwise boundaries, indicating that these pathways could represent preferential \u93channeling\u94 of large-scale motions due to the roughness below or the generation of trains of vortical structures shed from the roughness that advect downstream along a common path. In addition, some of these flow pathways were found to extend well into the outer layer of the flow. The high-frame-rate sPIV measurements in the spanwise\u96wall-normal plane were conducted at a lower momentum thickness Reynolds number of 4500 and revealed the dynamical nature of the flow both in the outer region and in the roughness sublayer
Repeated administration of α7 nicotinic acetylcholine receptor (nAChR) agonists, but not positive allosteric modulators, increases α7 nAChR levels in the brain
No full textThe alpha7 nicotinic acetylcholine receptor (nAChR) is an important target for treatment of cognitive deficits in schizophrenia and Alzheimer's disease. However, the receptor desensitizes rapidly in vitro, which has led to concern regarding its applicability as a clinically relevant drug target. Here we investigate the effects of repeated agonism on alpha7 nAChR receptor levels and responsiveness in vivo in rats. Using [(125)I]-alpha-bungarotoxin (BTX) autoradiography we show that acute or repeated administration with the selective alpha7 nAChR agonist A-582941 increases the number of alpha7 nAChR binding sites in several brain regions, particularly in the prefrontal cortex. The alpha7 nAChR agonists SSR180711 and PNU-282987 also increase [(125)I]-BTX binding, suggesting that this is a general consequence of alpha7 nAChR agonism. Interestingly, the alpha7 nAChR positive allosteric modulators PNU-120596 and NS1738 do not increase [(125)I]-BTX binding. Furthermore, A-582941-induced increase in Arc and c-fos mRNA expression in the prefrontal cortex is enhanced and unaltered, respectively, after repeated administration, demonstrating that the alpha7 nAChRs remain responsive. Contrarily, A-582941-induced phosphorylation of Erk2 in the prefrontal cortex occurs following acute, but not repeated administration. Our results demonstrate that repeated agonist administration increases the number of alpha7 nAChRs in the brain, and leads to coupling versus uncoupling of specific intracellular signaling pathways. Additionally, our data suggest a fundamental difference between the sequelae of repeated administration with agonists and allosteric modulators of the alpha7 nAChR
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