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1.
Shreaya Chakroborty Clark Briggs Megan B. Miller Ivan Goussakov Corinne Schneider Joyce Kim Jaime Wicks Jill C. Richardson Vincent Conklin Benjamin G. Cameransi Grace E. Stutzmann 《PloS one》2012,7(12)
Alzheimer’s disease (AD) is a devastating neurodegenerative condition with no known cure. While current therapies target late-stage amyloid formation and cholinergic tone, to date, these strategies have proven ineffective at preventing disease progression. The reasons for this may be varied, and could reflect late intervention, or, that earlier pathogenic mechanisms have been overlooked and permitted to accelerate the disease process. One such example would include synaptic pathology, the disease component strongly associated with cognitive impairment. Dysregulated Ca2+ homeostasis may be one of the critical factors driving synaptic dysfunction. One of the earliest pathophysiological indicators in mutant presenilin (PS) AD mice is increased intracellular Ca2+ signaling, predominantly through the ER-localized inositol triphosphate (IP3) and ryanodine receptors (RyR). In particular, the RyR-mediated Ca2+ upregulation within synaptic compartments is associated with altered synaptic homeostasis and network depression at early (presymptomatic) AD stages. Here, we offer an alternative approach to AD therapeutics by stabilizing early pathogenic mechanisms associated with synaptic abnormalities. We targeted the RyR as a means to prevent disease progression, and sub-chronically treated AD mouse models (4-weeks) with a novel formulation of the RyR inhibitor, dantrolene. Using 2-photon Ca2+ imaging and patch clamp recordings, we demonstrate that dantrolene treatment fully normalizes ER Ca2+ signaling within somatic and dendritic compartments in early and later-stage AD mice in hippocampal slices. Additionally, the elevated RyR2 levels in AD mice are restored to control levels with dantrolene treatment, as are synaptic transmission and synaptic plasticity. Aβ deposition within the cortex and hippocampus is also reduced in dantrolene-treated AD mice. In this study, we highlight the pivotal role of Ca2+ aberrations in AD, and propose a novel strategy to preserve synaptic function, and thereby cognitive function, in early AD patients. 相似文献
2.
Axial ligands of chloroplast cytochrome b-559: identification and requirement for a heme-cross-linked polypeptide structure 总被引:5,自引:0,他引:5
Optical, resonance Raman, and electron paramagnetic resonance spectroscopies have been used to characterize the ligands and spin state of the chloroplast cytochrome b-559. The protein was isolated from both maize and spinach in a low-potential form. The spectroscopic data indicate that the heme iron in both ferric and ferrous cytochrome b-559 is in its low-spin state and ligated in its fifth and sixth coordination positions by histidine nitrogens. Electron paramagnetic resonance data for the purified spinach cytochrome are in good agreement with those determined by Bergstr?m and V?nng?rd [Bergstr?m, J., & V?nng?rd, T. (1982) Biochim. Biophys. Acta 682, 452-456] for a low-potential membrane-bound form of cytochrome b-559. The g values of high-potential cytochrome b-559 are shifted from those of its low-potential forms; this shift is interpreted as arising from a deviation of the planes of the two axial histidine imidazole rings from a parallel orientation. The model is consistent with the physical data and may also account for the facility with which cytochrome b-559 can be converted between low- and high-potential forms. Recent biochemical and molecular biological data [Widger, W. R., Cramer, W. A., Hermodson, M., Meyer, D., & Gullifor, M. (1984) J. Biol. Chem. 259, 3870-3876; Herrmann, R. G., Alt, J., Schiller, D., Cramer, W. A., & Widger, W. R. (1984) FEBS Lett. 179, 239-244] have shown that two polypeptides, one with 83 residues and a second with 39 residues, most likely constitute the protein of the cytochrome.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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4.
Cation-exchange displacement chromatography of proteins with protamine displacers: effect of induced salt gradients. 总被引:2,自引:0,他引:2
Protamine was investigated for its utility as a protein displacer in cation-exchange systems. Although the protamine solution contained several variants of the molecule, the high affinity of all of the components in this heterogeneous biopolymer enabled it to act as an efficient protein displacer. To facilitate parameter estimation of the protamine, a preliminary purification was carried out by preparative elution chromatography. Chromatographic parameters of both the feed proteins and protamine displacer were obtained for use in a multicomponent steric mass action ion-exchange displacement model. Model simulations were compared to displacement results under both moderate and intense induced salt gradient conditions. In both cases, excellent agreement was obtained between the displacement experiments and theoretical predictions. In addition, these studies serve to dramatize the importance of induced salt gradients in ion-exchange displacement systems. 相似文献
5.
Steven I. Higgins Robert B. O’Hara Olga Bykova Michael D. Cramer Isabelle Chuine Eva‐Maria Gerstner Thomas Hickler Xavier Morin Michael R. Kearney Guy F. Midgley Simon Scheiter 《Journal of Biogeography》2012,39(12):2132-2145
Aim To develop a physiologically based model of the plant niche for use in species distribution modelling. Location Europe. Methods We link the Thornley transport resistance (TTR) model with functions which describe how the TTR’s model parameters are influenced by abiotic environmental factors. The TTR model considers how carbon and nutrient uptake, and the allocation of these assimilates, influence growth. We use indirect statistical methods to estimate the model parameters from a high resolution data set on tree distribution for 22 European tree species. Results We infer, from distribution data and abiotic forcing data, the physiological niche dimensions of 22 European tree species. We found that the model fits were reasonable (AUC: 0.79–0.964). The projected distributions were characterized by a false positive rate of 0.19 and a false negative rate 0.12. The fitted models are used to generate projections of the environmental factors that limit the range boundaries of the study species. Main conclusions We show that physiological models can be used to derive physiological niche dimensions from species distribution data. Future work should focus on including prior information on physiological rates into the parameter estimation process. Application of the TTR model to species distribution modelling suggests new avenues for establishing explicit links between distribution and physiology, and for generating hypotheses about how ecophysiological processes influence the distribution of plants. 相似文献
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7.
L Levine M N Sawka B E Joyce B S Cadarette K B Pandolf 《European journal of applied physiology and occupational physiology》1984,53(1):12-16
Comparisons of physiological responses to 0, 0.5, 1, and 2 mg atropine (IM) were made in seven males (X +/- SD: age, 24 +/- 3 years; ht, 174 +/- 12 cm; wt, 76 +/- 3 kg) while they exercised (approximately 390 W) in a hot-dry (40 degrees C, 20% rh) environment. Responses to 4 mg, as well as repeatability of responses to 2 mg, were studied in two and six of these subjects, respectively. On 8 test days an intramuscular injection of atropine or saline control was administered 20 min before subjects walked on a treadmill for two 50-min bouts. Heart rate (HR) during exercise did not change in the control trial but by min 50 increased during all atropine trials (P less than 0.01). Rectal temperature (Tre) increased (P less than 0.01) in all trials by min 50 and continued increasing (P less than 0.01) in the 2-mg trial during the second exercise bout. For the two subjects tested with all dosages (0.5 - 4 mg atropine), the change in HR and Tre between the atropine and control trials at 50 min of exercise was regressed against the various atropine dosages. The relationship (r = 0.92) for HR was curvilinear while the relationship (r = 0.99) for Tre was linear. Mean weighted skin temperature (Tsk) was relatively constant during exercise and was warmer (P less than 0.05) with increasing atropine dosage. In a repeat 2 mg trial, HR was 6 bt . min-1 lower (P less than 0.05) on the second exposure but Tre was the same (P greater than 0.05) on both days. For subjects walking in the heat, three new observations were: 1) 0.5 mg of atropine resulted in increased HR and Tsk compared to control values; 2) HR was elevated but the magnitude of change decreased with increasing dosage, while the elevation in Tre was consistent with increasing dosage; and 3) rectal temperatures (in trials with and without atropine) were unaffected by previous days of atropine administration. 相似文献
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9.
Influx of na, k, and ca into roots of salt-stressed cotton seedlings : effects of supplemental ca
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High Na+ concentrations may disrupt K+ and Ca2+ transport and interfere with growth of many plant species, cotton (Gossypium hirsutum L.) included. Elevated Ca2+ levels often counteract these consequences of salinity. The effect of supplemental Ca2+ on influx of Ca2+, K+, and Na+ in roots of intact, salt-stressed cotton seedlings was therefore investigated. Eight-day-old seedlings were exposed to treatments ranging from 0 to 250 millimolar NaCl in the presence of nutrient solutions containing 0.4 or 10 millimolar Ca2+. Sodium influx increased proportionally to increasing salinity. At high external Ca2+, Na+ influx was less than at low Ca2+. Calcium influx was complex and exhibited two different responses to salinity. At low salt concentrations, influx decreased curvilinearly with increasing salt concentration. At 150 to 250 millimolar NaCl, 45Ca2+ influx increased in proportion to salt concentrations, especially with high Ca2+. Potassium influx declined significantly with increasing salinity, but was unaffected by external Ca2+. The rate of K+ uptake was dependent upon root weight, although influx was normalized for root weight. We conclude that the protection of root growth from salt stress by supplemental Ca2+ is related to improved Ca-status and maintenance of K+/Na+ selectivity. 相似文献
10.
Light-regulated methylation of chloroplast proteins 总被引:2,自引:0,他引:2
Protein carboxyl methyltransferases, which catalyze transfer of methyl groups from S-adenosyl-L-methionine to the free carboxyl groups of acidic amino acids in proteins, can be divided into two classes based on several characteristics, such as the stoichiometry of substrate protein methylation, base stability of the incorporated methyl group, specificity for substrate, and participation in a regulatory system with which methylesterases are associated. The presence of such an enzyme in a photosynthetic system was demonstrated in the present work. The extent of methylation of chloroplast proteins was stimulated 30% by light and then decreased by the same amount in the presence of the electron transport inhibitor 3-(3',4'-dichlorophenyl)-1', 1'-dimethylurea or uncouplers of phosphorylation, indicating a dependence of the methyltransferase activity on photosynthetic electron transport and the trans-membrane delta pH. The light-independent, as well as the light-dependent, activity is probably of chloroplast origin since the extent of light stimulation in the purified thylakoid membranes and the stromal fraction was similar, and at low concentrations of S-adenosyl-L-methionine the small subunit of ribulose-1,5-bisphosphate carboxylase:oxygenase was found to be the predominant substrate. The labeling pattern of chloroplast proteins and labeling of an exogenous nonchloroplast protein indicated that the methyltransferase activity was not substrate-specific, although at low concentrations of the methyl donor, the small subunit of ribulose-1,5-bisphosphate carboxylase:oxygenase was labeled almost exclusively. Based on the low stoichiometry (less than 100 pmol/mg protein) of the methylation, its base lability, irreversibility, and the lack of substrate specificity except at very low concentrations of methyl donor, it was inferred that the chloroplast methyltransferase is best classified as a class II system that may function as part of a repair mechanism to replace racemized amino acids. 相似文献