bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dopamine release is impaired in a mouse model of DYT1 dystonia
Authors: Balcioglu Aygul , Kim Mee‐Ohk , Sharma Nutan , Cha Jang‐Ho , Breakefield Xandra O. , Standaert David G. 
Published: May 2007

AbstractEarly onset torsion dystonia, the most common form of hereditary primary dystonia, is caused by a mutation in the TOR1A gene, which codes for the protein torsinA. This form of dystonia is referred to as DYT1. We have used a transgenic mouse model of DYT1 dystonia [human mutant‐type (hMT)1 mice] to examine the effect of the mutant human torsinA protein on striatal dopaminergic function. Analysis of striatal tissue dopamine (DA) and metabolites using HPLC revealed no difference between hMT1 mice and their non‐transgenic littermates. Pre‐synaptic DA transporters were studied using in vitro autoradiography with [3H]mazindol, a ligand for the membrane DA transporter, and [3H]dihydrotetrabenazine, a ligand for the vesicular monoamine transporter. No difference in the density of striatal DA transporter or vesicular monoamine transporter binding sites was observed. Post‐synaptic receptors were studied using [3H]SCH‐23390, a ligand for D1 class receptors, [3H]YM‐09151‐2 and a ligand for D2 class receptors. There were again no differences in the density of striatal binding sites for these ligands. Using in vivo microdialysis in awake animals, we studied basal as well as amphetamine‐stimulated striatal extracellular DA levels. Basal extracellular DA levels were similar, but the response to amphetamine was markedly attenuated in the hMT1 mice compared with their non‐transgenic littermates (253 ± 71% vs. 561 ± 132%, p < 0.05, two‐way anova). These observations suggest that the mutation in the torsinA protein responsible for DYT1 dystonia may interfere with transport or release of DA, but does not alter pre‐synaptic transporters or post‐synaptic DA receptors. The defect in DA release as observed may contribute to the abnormalities in motor learning as previously documented in this transgenic mouse model, and may contribute to the clinical symptoms of the human disorder.
In vivo targeting of antibody fragments to the nervous system for Alzheimer’s disease immunotherapy and molecular imaging of amyloid plaques
Authors: Poduslo Joseph F. , Ramakrishnan Muthu , Holasek Silvina S. , Ramirez‐Alvarado Marina , Kandimalla Karunya K. , Gilles Emily J. , Curran Geoffry L. , Wengenack Thomas M. 
Published: May 2007

AbstractTargeting therapeutic or diagnostic proteins to the nervous system is limited by the presence of the blood–brain barrier. We report that a F(ab′)2 fragment of a monoclonal antibody against fibrillar human Aβ42 that is polyamine (p)‐modified has increased permeability at the blood–brain barrier, comparable binding to the antigen, and comparable in vitro binding to amyloid plaques in Alzheimer’s disease (AD) transgenic mouse brain sections. Intravenous injection of the pF(ab′)24.1 in the AD transgenic mouse demonstrated efficient targeting to amyloid plaques throughout the brain, whereas the unmodified fragment did not. Removal of the Fc portion of this antibody derivative will minimize the inflammatory response and cerebral hemorrhaging associated with passive immunization and provide increased therapeutic potential for treating AD. Coupling contrast agents/radioisotopes might facilitate the molecular imaging of amyloid plaques with magnetic resonance imaging/positron emission tomography. The efficient delivery of immunoglobulin G fragments may also have important applications to other neurodegenerative disorders or for the generalized targeting of nervous system antigens.
Agonist‐mediated regulation of presynaptic receptor function during development of rat septal neurons in culture
Authors: Ehret Andreas , Birthelmer Anja , Rutz Susanne , Riegert Céline , Rothmaier Anna Katharina , Jackisch Rolf 
Published: May 2007

AbstractPresynaptic receptors modulating the release of acetylcholine (ACh) were studied in fetal septal neurons cultured in a growth medium to which various drugs were added from day 3 in vitro (DIV 3) to DIV 14. The influence of these drugs on the function of the presynaptic muscarinic (M‐) autoreceptor was determined at DIV 14 by measuring the inhibitory effect of the M‐agonist oxotremorine on the electrically‐evoked release of [³H]ACh from cultures pre‐incubated with [³H]choline. The presence of the M‐agonists oxotremorine (100 μmol/L) or carbachol (100 μmol/L) from DIV 3 to DIV 14, or from DIV 13 to DIV 14, abolished M‐autoreceptor function at DIV 14, whereas the presence of the M‐antagonist atropine (10 μmol/L from DIV 3 to DIV 14) during growth left M‐autoreceptor function unaltered. Inhibition of ACh esterase by donepezil (1 μmol/L from DIV 3 to DIV 14) weakly decreased M‐autoreceptor function at DIV 14; inhibition of neuronal firing by 0.1 tetrodotoxin (0.1 μmol/L from DIV 3 to DIV 14) did not tend to affect M‐autoreceptor function at DIV 14. Co‐cultivation of fetal septal and raphe neurons for 2 weeks yielded cell cultures containing both vesicular ACh transporter‐ and tryptophan hydroxylase‐immunopositive cells. From these cultures, the release of both [³H]ACh and [³H]5‐HT could be induced by electrical field stimulation. In co‐cultured neurons versus septal‐only ones the inhibitory effect of oxotremorine on the evoked release of [³H]ACh appeared almost normal, whereas that of the selective 5‐HT1B agonist 3‐(1,2,5,6‐tetrahydropyrid‐4‐yl)pyrrollo[3,2‐b]pyrid‐5‐one (CP‐93,129) was completely abolished. The effects of CP‐93,129 were also absent on DIV 14 in septal mono‐cultures grown in the presence of CP‐93,129 (10 μmol/L) from DIV 3 to DIV 14. It is therefore concluded that the regulation of presynaptic receptor function strongly depends on the concentrations of endogenous transmitters in the neuronal environment.
An alternatively spliced cytochrome P4501A1 in human brain fails to bioactivate polycyclic aromatic hydrocarbons to DNA‐reactive metabolites
Authors: Kommaddi Reddy P. , Turman Cheri M. , Moorthy Bhagavatula , Wang Lihua , Strobel Henry W. , Ravindranath Vijayalakshmi 
Published: May 2007

Abstract CYP1A1, a cytochrome P450 enzyme, metabolizes polycyclic aromatic hydrocarbons to genotoxic metabolite(s) that bind to DNA and initiate carcinogenesis. RT‐PCR amplification of the complete open reading frame of CYP1A1 generated an amplicon of 1593 bp having deletion of 87 bp of exon‐6 that translated into functional P450 enzyme. Unlike wild type CYP1A1, exon 6 del CYP1A1 did not metabolize polycyclic aromatic hydrocarbons such as, benzo(a)pyrene to genotoxic, ultimate carcinogens that form DNA adducts. Exon 6 del CYP1A1 metabolized ethoxyresorufin (the classical substrate for CYP1A1) less efficiently compared with wild type CYP1A1 while pentoxy and benzyloxyresorufin (classical substrates for CYP2B) were dealkylated more efficiently. In silico docking showed alteration of the substrate access channel in exon 6 del CYP1A1 such that benzo(a)pyrene does not bind in any orientation that would permit the formation of carcinogenic metabolites. Genotyping revealed that the splice variant was not generated due to differences in genomic DNA sequence and the variant was present only in brain but not in liver, kidney, lung, or heart from the same individual. We provide evidence that unique P450 enzymes, generated by alternate splicing in a histiospecific manner can modify genotoxic potential of carcinogens such as benzo(a)pyrene by altering their biotransformation pathway.
Constitutively active calcineurin mediates delayed neuronal death through Fas‐ligand expression via activation of NFAT and FKHR transcriptional activities in mouse brain ischemia
Authors: Shioda Norifumi , Han Feng , Moriguchi Shigeki , Fukunaga Kohji 
Published: May 2007

AbstractWe recently demonstrated that a constitutively active form of calcineurin (CaN) is generated by calpain‐mediated limited proteolysis following brain ischemia. The calpain‐induced CaN activation mediated delayed neuronal death through translocation of nuclear factor of activated T‐cells (NFAT) into nuclei after brain ischemia. We also previously demonstrated that activation of forkhead in rhabdomyosarcoma (FKHR), a forkhead transcription factor and substrate of protein kinase‐B (Akt), mediated ischemia‐induced neuronal death through Fas‐ligand expression in gerbil hippocampus. FKHR activation occurred through decreased Akt activity and concomitant dephosphorylation mediated by undefined phosphatases. In this study, we show that phosphorylated Ser‐256 of FKHR is dephosphorylated by constitutively active CaN and that in turn FKHR forms a complex with CaN that is translocated into nuclei after brain ischemia. After nuclear translocation of NFAT and FKHR, both NFAT and FKHR stimulated expression of Fas‐ligand by binding to its promoter region. Consistent with activation of the Fas‐ligand promoter by FKHR dephosphorylation, Fas‐ligand expression increased 2 days after ischemia/reperfusion, and treatment with the CaN inhibitor FK506 inhibited that expression. These results suggest that FKHR is a downstream target of CaN and that constitutively active CaN mediates delayed neuronal death through Fas‐ligand expression via up‐regulation of both NFAT and FKHR transcriptional activity in brain ischemia.
Contrasting roles of neuronal Msk1 and Rsk2 in Bad phosphorylation and feedback regulation of Erk signalling
Authors: Clark C. J. , McDade D. M. , O’Shaughnessy C. T. , Morris B. J. 
Published: May 2007

AbstractActivated extracellular‐signal‐regulated kinase (Erk) phosphorylates and activates downstream kinases including ribosomal S6 kinase 2 (Rsk2/RPS6KA3) and mitogen‐ and stress‐activated kinase 1 (Msk1, RPS6KA5). Rsk2 plays an important role in neuronal plasticity, as patients with Coffin–Lowry syndrome, where Rsk2 is dysfunctional, have impaired cognitive function. However, the relative role of neuronal Rsk2 and Msk1 in activating proteins downstream of Erk is unclear. In PC12 cells and in cortical neurones, the calcium ionophore A23187‐induced phosphorylation of Erk, Msk1, Rsk2 and also the Bcl‐2‐associated death protein (Bad), which protects against neurotoxicity. Specific knockdown of Msk1 with small interfering RNA reduced the ability of A23187 to induce Bad phosphorylation in both PC12 cells and cortical neurones. Conversely, specific knockdown of Rsk2 potentiated Bad phosphorylation following A23187 treatment, and also elevated Erk phosphorylation in both cell types. This indicates that Msk1 rather than Rsk2 mediates neuronal Bad phosphorylation following Ca2+ influx and implicates Rsk2 in a negative‐feedback regulation of Erk activity.
Inhibition of protein phosphatases induces transport deficits and axonopathy
Authors: Yang Ying , Yang Xi‐Fei , Wang Yi‐Peng , Tian Qing , Wang Xiao‐Chuan , Li Hong‐Lian , Wang Qun , Wang Jian‐Zhi 
Published: May 2007

AbstractThe activity of protein phosphatase (PP)‐2A and PP‐1 decreased in the brains of Alzheimer’s disease and inhibition of the phosphatases led to spatial memory deficit in rats. However, the molecular basis underlying memory impairment of the phosphatase inhibition is elusive. In the present study, we observed a selective inhibition of PP‐2A and PP‐1 with Calyculin A (CA) not only caused hyperphosphorylation of cytoskeletal proteins, but also impaired the transport of pEGFP‐labeled neurofilament‐M subunit in the axon‐like processes of neuroblastoma N2a cells and resulted in accumulation of neurofilament in the cell bodies. To analyze the morphological alteration of the cells during inhibition of the phosphatases, we established a cell model showing steady outgrowth of axon‐like cell processes and employed a stereological system to analyze the retraction of the processes. We found CA treatment inhibited outgrowth of the cell processes and prolonged treatment with CA caused retraction of the processes and meanwhile, the early neurodegenerative varicosities were also obvious in the CA‐treated cells. We conclude suppression of PP‐2A and PP‐1 by CA not only damages intracellular transport but also leads to cell degeneration, which may serve as the functional and structural elements for the memory deficits induced by suppression of the phosphatases.
The lipophilic metal chelators DP‐109 and DP‐460 are neuroprotective in a transgenic mouse model of amyotrophic lateral sclerosis
Authors: Petri Susanne , Calingasan Noel Y. , Alsaied Osama A. , Wille Elizabeth , Kiaei Mahmoud , Friedman Jonathan E. , Baranova Oxana , Chavez Juan C. , Beal M. Flint 
Published: May 2007

AbstractOne of the hypotheses for the development of familial amyotrophic lateral sclerosis (ALS) is that mutations in the superoxide dismutase 1 enzyme lead to aberrant properties of the copper within the active site of the enzyme which then causes increased oxidative damage. The lipophilic metal chelators DP‐109 and DP‐460 which chelate calcium, copper, and zinc were tested in the G93A‐transgenic ALS mouse model. Both compounds significantly extended survival, DP‐109 (5 mg/kg/day) by 10%, DP‐460 (10 mg/kg/day) by 9%. While the effect on survival was relatively small, chelator treatment also improved motor performance, dramatically reduced cell loss in the lumbar spinal cord and decreased reactive astrocytosis and microgliosis. Markers of oxidative damage, tumor necrosis factor (TNF)‐αand α‐synuclein were reduced in the lumbar spinal cord of G93A mice treated with DP‐109 or DP‐460 as compared with vehicle‐treated animals. Furthermore, the treatment induced protein expression of the transcription factor hypoxia inducible factor‐1α and mRNA levels of vascular endothelial growth factor as a corresponding target gene. In line with previous studies using metal chelators in the G93A animal model, our results suggest that these compounds have neuroprotective capacities in ALS.
Brain‐derived neurotrophic factor stimulates the transcriptional and neuroprotective activity of myocyte‐enhancer factor 2C through an ERK1/2‐RSK2 signaling cascade
Authors: Wang Yupeng , Liu Lidong , Xia Zhengui 
Published: May 2007

AbstractNeurotrophin activation of myocyte‐enhancer factor (MEF) 2C is one of the strongest pro‐survival signaling pathways in developing neurons. To date, neurotrophin stimulation of MEF2C has been largely attributed to its direct phosphorylation by extracellular signal‐regulated kinase (ERK) 5. Because MEF2C is not directly phosphorylated by ERK1/2 in vitro, it is generally assumed that the ERK1/2 signaling cascade does not regulate MEF2C. Surprisingly, we discovered that ERK1/2 are required for both the transcriptional and neuroprotective activity of MEF2C in cortical neurons stimulated by brain‐derived neurotrophic factor. ERK1/2 stimulation of MEF2C is mediated by p90 ribosomal S6 kinase 2 (RSK2), a Ser/Thr protein kinase downstream of ERK1/2. RSK2 strongly phosphorylates purified recombinant MEF2C protein in vitro. Furthermore, RSK2 can directly phosphorylate MEF2C on S192, a consensus RSK2‐phosphorylation site located in the transactivation domain of MEF2C. Substitution of S192 with a non‐phosphorylatable alanine diminishes both the transcriptional and neuroprotective activity of MEF2C to an extent similar to mutation on S387, an established activating phosphorylation site. Together, our data identifies ERK1/2‐RSK2 signaling as a novel mechanism by which neurotrophins activate MEF2C and promote neuronal survival.
Isolation and characterization of microsatellite loci in the finless porpoise (Neophocaena phocaenoides)
Authors: CHEN L. , BRUFORD M. , YANG G. 
Published: May 2007

AbstractEight dinucleotide microsatellite loci were isolated from the finless porpoise (Neophocaena phocaenoides). Analysis of 30 individuals showed the number of alleles ranged from four to 21 with observed heterozygosity ranging from 0.300 to 0.833, and expected heterozygosity ranging from 0.437 to 0.932. Cross‐species amplification was tested in four other cetacean species. These microsatellite markers would be valuable tools for population genetic studies of finless porpoises and other cetacean species.
Habitat selection by Marsh Tits Poecile palustris in the UK
Authors: HINSLEY SHELLEY A. , CARPENTER JANE E. , BROUGHTON RICHARD K. , BELLAMY PAUL E. , ROTHERY PETER , AMAR ARJUN , HEWSON CHRIS M. , GOSLER ANDREW G. 
Published: May 2007

The Marsh Tit Poecile palustris is a small, hole‐nesting woodland passerine whose national population in the UK has declined by more than 50% in the last 25 years. To investigate possible causes for the species long‐term decline, we examined habitat selection by Marsh Tits at three scales. For individual foraging birds, winter time budgets and foraging behaviour, recorded using instantaneous sampling, differed little between Marsh and Blue Tits Cyanistes caeruleus, but Marsh Tits spent more time in the understorey and more time lower down in both the woodland canopy and the understorey. At the scale of breeding territories, the characteristics (numbers by size class, vegetation density, species richness) of trees and shrubs were compared using 100 × 10‐m sample transects of ten territories in each of four woods. The characteristics of the trees differed significantly between woods whilst those of the shrubs did not, suggesting that the characteristics of shrubs were more important in territory selection by Marsh Tits than were those of trees. Furthermore, in one of the four woods (Wytham Woods, Oxfordshire), Marsh Tits were largely absent from areas with dense tree canopy, but poor shrub cover. On a national scale, using data from 157 of the woodlands surveyed by the RSPB/BTO Repeat Woodland Bird Survey, Marsh Tit abundance in 2003/04 was found to be positively related to vegetation cover at heights corresponding to the shrub layer, especially at 2–4 m. These relationships were not apparent in data for the same woods for the 1980s, but shrub cover had increased substantially by 2003/04 and Marsh Tit abundance had increased in woods with the most cover in 2003/04. Thus, factors damaging the shrub layer, such as overgrazing by deer, shading out by canopy closure and managed clearance of shrub cover, may reduce the suitability of woodland for Marsh Tits. Habitat use by a closely related species, Willow Tit Poecile montanus, is also discussed.
The ecology of clutch size variation in Darwin's Small Ground FinchGeospiza fuliginosa: comparison between lowland and highland habitats
Authors: KLEINDORFER S. 
Published: May 2007

This study examines the ecology of clutch size variation between two contiguous populations of Small Ground FinchGeospiza fuliginosathat breed in geographically distinct habitats (lowlands, highlands) on Santa Cruz Island of the Galapagos Archipelago. Small clutch size is considered an adaptive response to high predation risk (to reduce behavioural conspicuousness at the nest and lower the energetic costs of re‐nesting), whereas high food abundance is predicted to favour large clutch size. This study has two main objectives: (1) to present descriptive data on clutch size variation inG. fuliginosabetween habitats, and (2) to test life‐history predictions for clutch size variation based on food abundance and nest predation hypotheses. The highlands on Santa Cruz Island were characterized by high nest predation (52%), high annual rainfall and high insect abundance across the year, whereas the lowlands were characterized by low nest predation (5%), seasonal rainfall and high insect abundance during the breeding season. The highland birds had smaller clutch size and a shorter re‐nesting interval. Patterns of nest attendance differed significantly between habitats. The percentage of time incubating per hour was comparable between habitats, but the mean duration per incubation event was longer in the highlands (with fewer events per hour), which is consistent with the prediction of reduced behavioural conspicuousness at nests under conditions of high predation risk. There were no significant differences in nestling feeding levels between habitats, probably becauseG. fuliginosais a multiple prey loader.
Compensation for light loss due to filtering by macular pigment: relation to hue cancellation
Authors: Stringham James M. , Hammond Billy R. 
Published: May 2007

AbstractBackground:  A long‐standing question in colour vision research is how the visual system is able to correct for the significant absorbance of short wave light by the crystalline lens and macular pigment (MP). Such compensation must be required in order to maintain colour constancy across the retina where MP levels are changing quickly and dramatically.Objective:  We studied this compensation mechanism by measuring MP spatial density profiles and hue cancellation functions across the central retina in a sample of six young healthy subjects.Method:  Yellow (Y, 575 nm)/blue (B, 440 nm) and red (R, 600 nm)/green (G, 501 nm) cancellation functions were obtained at 0, 1, 1.75, 3 and 7° eccentricity. The MP optical density at 460 nm was measured at these same eccentricities using heterochromatic flicker photometry. One subject was assessed repeatedly over a 4‐month period during daily supplementation with 30 mg of lutein (L).Results:  Hue cancellation values for the Y/B system did not change across the retina (r = 0.09). In contrast, R/G sensitivity changed as a direct function of MP absorbance (r = 0.99). The Y/B values did not change in the one subject supplemented with 30 mg L daily, despite increases in MP of about 50% over 4 months.Conclusions:  Despite large variations in MP across the retina, hue cancellation values for the Y‐B system across the central retina were constant. For example, one subject's MP density declined from a central peak of 0.99 to near zero at 7° (near 90% transmission difference) yet thresholds for the Y/B system were unaffected. In contrast, the G lobe of the R/G system was directly correlated with MP density. Taken together, these results confirm that the Y/B system compensates for MP density, but the R/G system does not.
Objective refraction from monochromatic wavefront aberrations via Zernike power polynomials
Authors: Robert Iskander D. , Davis Brett A. , Collins Michael J. , Franklin Ross 
Published: May 2007

AbstractWith the increased popularity of wavefront sensor devices there has been significant interest in relating the subjectively measured sphero‐cylindrical refractive error to the objectively measured wavefront aberrations. We investigate the applicability of four different measures for objective refraction assessment that are derived from a set of estimated Zernike wavefront coefficients. Two of the measures are based on the second‐ and higher‐order Zernike polynomials while the other two measures are based on the estimated dioptric power representations. For the latter, closed‐form expressions for dioptric powers based on the estimated focal length and the wavefront curvature are derived. We call these two new representations the ‘refractive Zernike power polynomials’ and ‘curvature Zernike power polynomials’. Data from 120 eyes from 60 normal subjects were used to assess the correlation between the subjective and objective refractions. The results indicate that the objective sphero‐cylindrical refraction calculated from the estimated refractive power map via the Zernike power polynomials is superior to the other considered representations and achieves best correlation with subjective sphero‐cylindrical refraction.
Changes in astigmatism with accommodation
Authors: Radhakrishnan Hema , Charman W. Neil 
Published: May 2007

AbstractAn experiment is described in which changes in ocular astigmatism were recorded over an accommodation stimulus range of 0–4 D, in the right eyes of a group of 31 normal subjects aged 17–37 years. The visual axes were horizontal and the observation conditions were monocular. Although subjects had a range of spherical ametropia, all had initial astigmatism of 1.0 DC or less. It was found that, for most subjects in the group, astigmatism changed in the with‐the‐rule direction, the mean change being −0.036 DC at axis 176 deg for each dioptre of accommodation response. It is speculated that these changes might reflect increases in lens tilt about a horizontal axis, caused by the combined effects of a slacker zonule and gravity.