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Search Results: 1 - 10 of 301238 matches for " Amanda J. Roberts "
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Neurobiological Signatures of Alcohol Dependence Revealed by Protein Profiling
Giorgio Gorini, Amanda J. Roberts, R. Dayne Mayfield
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082656
Abstract: Alcohol abuse causes dramatic neuroadaptations in the brain, which contribute to tolerance, dependence, and behavioral modifications. Previous proteomic studies in human alcoholics and animal models have identified candidate alcoholism-related proteins. However, recent evidences suggest that alcohol dependence is caused by changes in co-regulation that are invisible to single protein-based analysis. Here, we analyze global proteomics data to integrate differential expression, co-expression networks, and gene annotations to unveil key neurobiological rearrangements associated with the transition to alcohol dependence modeled by a Chronic Intermittent Ethanol (CIE), two-bottle choice (2BC) paradigm. We analyzed cerebral cortices (CTX) and midbrains (MB) from male C57BL/6J mice subjected to a CIE, 2BC paradigm, which induces heavy drinking and represents one of the best available animal models for alcohol dependence and relapse drinking. CIE induced significant changes in protein levels in dependent mice compared with their non-dependent controls. Multiple protein isoforms showed region-specific differential regulation as a result of post-translational modifications. Our integrative analysis identified modules of co-expressed proteins that were highly correlated with CIE treatment. We found that modules most related to the effects of CIE treatment coordinate molecular imbalances in endocytic- and energy-related pathways, with specific proteins involved, such as dynamin-1. The qRT-PCR experiments validated both differential and co-expression analyses, and the correspondence among our data and previous genomic and proteomic studies in humans and rodents substantiates our findings. The changes identified above may play a key role in the escalation of ethanol consumption associated with dependence. Our approach to alcohol addiction will advance knowledge of brain remodeling mechanisms and adaptive changes in response to drug abuse, contribute to understanding of organizational principles of CTX and MB proteomes, and define potential new molecular targets for treating alcohol addiction. The integrative analysis employed here highlight the advantages of systems approaches in studying the neurobiology of alcohol addiction.
CCL2-ethanol interactions and hippocampal synaptic protein expression in a transgenic mouse model
Donna L. Gruol,Jennifer G. Bray,Amanda J. Roberts
Frontiers in Integrative Neuroscience , 2014, DOI: 10.3389/fnint.2014.00029
Abstract: Chronic exposure to ethanol produces a number of detrimental effects on behavior. Neuroadaptive changes in brain structure or function underlie these behavioral effects and may be transient or persistent in nature. Central to the functional changes are alterations in the biology of neuronal and glial cells of the brain. Recent data show that ethanol induces glial cells of the brain to produce elevated levels of neuroimmune factors including CCL2, a key innate immune chemokine. Depending on the conditions of ethanol exposure, the upregulated levels of CCL2 can be transient or persistent and outlast the period of ethanol exposure. Importantly, results indicate that the upregulated levels of CCL2 may lead to CCL2-ethanol interactions that mediate or regulate the effects of ethanol on the brain. Glial cells are in close association with neurons and regulate many neuronal functions. Therefore, effects of ethanol on glial cells may underlie some of the effects of ethanol on neurons. To investigate this possibility, we are studying effects of chronic ethanol on hippocampal synaptic function in a transgenic mouse model that expresses elevated levels of CCL2 in the brain through enhanced glial expression, a situation know to occur in alcoholics. Both CCL2 and ethanol have been reported to alter synaptic function in the hippocampus. In the current study, we determined if interactions are evident between CCL2 and ethanol at the level of hippocampal synaptic proteins. Two ethanol exposure paradigms were used; the first involved ethanol exposure by drinking and the second involved ethanol exposure in a paradigm that combines drinking plus ethanol vapor. The first paradigm does not produce dependence on ethanol, whereas the second paradigm is commonly used to produce ethanol dependence. Results show modest effects of both ethanol exposure paradigms on the level of synaptic proteins in the hippocampus of CCL2 transgenic mice compared with their non-transgenic littermate controls, consistent with ethanol-CCL2 interactions. No evidence of toxic effects of CCL2 or CCL2-ethanol interactions was observed. Taken together, these results support the idea that ethanol induced astrocyte production of CCL2 can result in neuroadaptive changes that interact with the actions of ethanol.
Anxiolytic-Like Effects of Antisauvagine-30 in Mice Are Not Mediated by CRF2 Receptors
Eric P. Zorrilla, Amanda J. Roberts, Jean E. Rivier, George F. Koob
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063942
Abstract: The role of brain corticotropin-releasing factor type 2 (CRF2) receptors in behavioral stress responses remains controversial. Conflicting findings suggest pro-stress, anti-stress or no effects of impeding CRF2 signaling. Previous studies have used antisauvagine-30 as a selective CRF2 antagonist. The present study tested the hypotheses that 1) potential anxiolytic-like actions of intracerebroventricular (i.c.v.) administration of antisauvagine-30 also are present in mice lacking CRF2 receptors and 2) potential anxiolytic-like effects of antisauvagine-30 are not shared by the more selective CRF2 antagonist astressin2-B. Cannulated, male CRF2 receptor knockout (n = 22) and wildtype littermate mice (n = 21) backcrossed onto a C57BL/6J genetic background were tested in the marble burying, elevated plus-maze, and shock-induced freezing tests following pretreatment (i.c.v.) with vehicle, antisauvagine-30 or astressin2-B. Antisauvagine-30 reduced shock-induced freezing equally in wildtype and CRF2 knockout mice. In contrast, neither astressin2-B nor CRF2 genotype influenced shock-induced freezing. Neither CRF antagonist nor CRF2 genotype influenced anxiety-like behavior in the plus-maze or marble burying tests. A literature review showed that the typical antisauvagine-30 concentration infused in previous intracranial studies (~1 mM) was 3 orders greater than its IC50 to block CRF1-mediated cAMP responses and 4 orders greater than its binding constants (Kd, Ki) for CRF1 receptors. Thus, increasing, previously used doses of antisauvagine-30 also exert non-CRF2-mediated effects, perhaps via CRF1. The results do not support the hypothesis that brain CRF2 receptors tonically promote anxiogenic-like behavior. Utilization of CRF2 antagonists, such as astressin2-B, at doses that are more subtype-selective, can better clarify the significance of brain CRF2 systems in stress-related behavior.
IL-6 Mediated Degeneration of Forebrain GABAergic Interneurons and Cognitive Impairment in Aged Mice through Activation of Neuronal NADPH Oxidase
Laura L. Dugan, Sameh S. Ali, Grigoriy Shekhtman, Amanda J. Roberts, Jacinta Lucero, Kevin L. Quick, M. Margarita Behrens
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005518
Abstract: Background Multiple studies have shown that plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) are elevated in patients with important and prevalent adverse health conditions, including atherosclerosis, diabetes, obesity, obstructive sleep apnea, hypertension, and frailty. Higher plasma levels of IL-6, in turn, increase the risk of many conditions associated with aging including age-related cognitive decline. However, the mechanisms underlying this association between IL-6 and cognitive vulnerability remain unclear. Methods and Findings We investigated the role of IL-6 in brain aging in young (4 mo) and aged (24 mo) wild-type C57BL6 and genetically-matched IL-6?/? mice, and determined that IL-6 was necessary and sufficient for increased neuronal expression of the superoxide-producing immune enzyme, NADPH-oxidase, and this was mediated by non-canonical NFκB signaling. Furthermore, superoxide production by NADPH-oxidase was directly responsible for age-related loss of parvalbumin (PV)-expressing GABAergic interneurons, neurons essential for normal information processing, encoding, and retrieval in hippocampus and cortex. Targeted deletion of IL-6 or elimination of superoxide by chronic treatment with a superoxide-dismutase mimetic prevented age-related loss of PV-interneurons and reversed age-related cognitive deficits on three standard tests of spatial learning and recall. Conclusions Present results indicate that IL-6 mediates age-related loss of critical PV-expressing GABAergic interneurons through increased neuronal NADPH-oxidase-derived superoxide production, and that rescue of these interneurons preserves cognitive performance in aging mice, suggesting that elevated peripheral IL-6 levels may be directly and mechanistically linked to long-lasting cognitive deficits in even normal older individuals. Further, because PV-interneurons are also selectively affected by commonly used anesthetic agents and drugs, our findings imply that IL-6 levels may predict adverse CNS effects in older patients exposed to these compounds through specific derangements in inhibitory interneurons, and that therapies directed at lowering IL-6 may have cognitive benefits clinically.
Darcin: a male pheromone that stimulates female memory and sexual attraction to an individual male's odour
Sarah A Roberts, Deborah M Simpson, Stuart D Armstrong, Amanda J Davidson, Duncan H Robertson, Lynn McLean, Robert J Beynon, Jane L Hurst
BMC Biology , 2010, DOI: 10.1186/1741-7007-8-75
Abstract: Using wild-stock house mice to ensure natural responses that generalize across individual genomes, we identify a single atypical male-specific major urinary protein (MUP) of mass 18893Da that invokes a female's inherent sexual attraction to male compared to female urinary scent. Attraction to this protein pheromone, which we named darcin, was as strong as the attraction to intact male urine. Importantly, contact with darcin also stimulated a strong learned attraction to the associated airborne urinary odour of an individual male, such that, subsequently, females were attracted to the airborne scent of that specific individual but not to that of other males.This involatile protein is a mammalian male sex pheromone that stimulates a flexible response to individual-specific odours through associative learning and memory, allowing female sexual attraction to be inherent but selective towards particular males. This 'darcin effect' offers a new system to investigate the neural basis of individual-specific memories in the brain and give new insights into the regulation of behaviour in complex social mammals.See associated Commentary http://www.biomedcentral.com/1741-7007/8/71 webcitePheromones are specific chemical signals, produced for communication between individuals of the same species, that trigger a specific natural behaviour or physiological process [1]. Signals can be single compounds or combinations of compounds in a precise ratio, detected either by smell or taste [2]. Ubiquitous among invertebrates, pheromones are used to coordinate many aspects of social behaviour, including sexual recognition and attraction to bring opposite sex conspecifics together for mating [3]. Vertebrates also make widespread use of chemical scent signals for within-species communication. However, the more complex individual-specific odours of mammals, combined with variable responses to scents that often depend on context and learning, have led many to suggest that mammalian scent signa
Abnormal Oxidative Stress Responses in Fibroblasts from Preeclampsia Infants
Penghua Yang, Aihua Dai, Andrei P. Alexenko, Yajun Liu, Amanda J. Stephens, Laura C. Schulz, Danny J. Schust, R. Michael Roberts, Toshihiko Ezashi
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0103110
Abstract: Background Signs of severe oxidative stress are evident in term placentae of infants born to mothers with preeclampsia (PE), but it is unclear whether this is a cause or consequence of the disease. Here fibroblast lines were established from umbilical cords (UC) delivered by mothers who had experienced early onset PE and from controls with the goal of converting these primary cells to induced pluripotent stem cells and ultimately trophoblast. Contrary to expectations, the oxidative stress responses of these non-placental cells from PE infants were more severe than those from controls. Methods and Findings Three features suggested that UC-derived fibroblasts from PE infants responded less well to oxidative stressors than controls: 1) While all UC provided outgrowths in 4% O2, success was significantly lower for PE cords in 20% O2; 2) PE lines established in 4% O2 proliferated more slowly than controls when switched to 20% O2; 3) PE lines were more susceptible to the pro-oxidants diethylmaleate and tert-butylhydroquinone than control lines, but, unlike controls, were not protected by glutathione. Transcriptome profiling revealed only a few genes differentially regulated between PE lines and controls in 4% O2 conditions. However, a more severely stressed phenotype than controls, particularly in the unfolded protein response, was evident when PE lines were switched suddenly to 20% O2, thus confirming the greater sensitivity of the PE fibroblasts to acute changes in oxidative stress. Conclusions UC fibroblasts derived from PE infants are intrinsically less able to respond to acute oxidative stress than controls, and this phenotype is retained over many cell doublings. Whether the basis of this vulnerability is genetic or epigenetic and how it pertains to trophoblast development remains unclear, but this finding may provide a clue to the basis of the early onset, usually severe, form of PE.
The role of plant physiology in hydrology: looking backwards and forwards
J. Roberts
Hydrology and Earth System Sciences (HESS) & Discussions (HESSD) , 2007,
Abstract: The implementation of plant physiological studies at the Institute of Hydrology focussed both on examining and understanding the physiological controls of transpiration as well as evaluating the value of using physiological methods to measure transpiration. Transpiration measurement by physiological methods would be particularly valuable where this could not be achieved by micrometeorological and soil physics methods. The principal physiological measurements used were determinations of leaf stomatal conductance and leaf water relations to monitor plant water stress. In this paper the value of these approaches is illustrated by describing a few case studies in which plant physiological insight, provided both as new measurements and existing knowledge, would aid in the interpretation of the hydrological behaviour of important vegetation. Woody vegetation figured largely in these studies, conducted in the UK and overseas. Each of these case studies is formulated as a quest to answer a particular question. A collaborative comparison of conifer forest transpiration in Thetford forest using micrometeorological and soil physics techniques exhibited a substantially larger (~1 mm day 1) estimate from the micrometeorological approach. So the question – Why is there a disagreement in the estimates of forest transpiration made using micrometeorological and soil physics approaches? A range of physiological studies followed that suggested that there was no one simple answer but that the larger estimate from the micrometeorology technique might include contributions of water taken up by deep roots, from shallow-rooted vegetation and possibly also from water previously stored in trees. These sources of water were probably not included in the soil physics estimate of transpiration. The annual transpiration from woodlands in NW Europe shows a low magnitude and notable similarity between different sites raising the question – Why is transpiration from European forests low and conservative? An important contribution both to the similar and low transpiration is the likely reduction of stomatal conductance of the foliage associated with increasing air humidity deficit. A greater response is usually found when initial conductances are highest. Also contributing to similarities in transpiration from forest stands would be a compensatory role of understories and that deficits in soil moisture may not come into play until severe soil water deficits occur. Physiological studies have been conducted in many locations overseas. The modest transpiration of tropical rainforest is intriguing – Why is tropical rainforest transpiration so low? In common with temperate trees the reduction of stomatal conductance of tropical trees in association with increasing air humidity deficit will limit transpiration. In addition the high leaf area index of tropical rainforest creates conditions in the lower canopy layers that mean transpiration from those layers is much reduced from what migh
Identifying Protein Function—A Call for Community Action
Richard J. Roberts
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0020042
Multi-objective calibration of the land surface scheme TERRA/LM using LITFASS-2003 data
J. Roberts ,P. Rosier
Hydrology and Earth System Sciences (HESS) & Discussions (HESSD) , 2005,
Abstract: The possible effects of broadleaved woodland on recharge to the UK Chalk aquifer have led to a study of evaporation and transpiration from beech woodland (Black Wood) and pasture (Bridgets Farm), growing in shallow soils above chalk in Hampshire. Eddy correlation measurements of energy balance components above both the forest and the grassland enabled calculation of latent heat flux (evaporation and transpiration) as a residual. Comparative measurements of soil water content and soil water potential in 9 m profiles under both forest and grassland found changes in soil water content down to 6 m at both sites; however, the soil water potential measurements showed upward movement of water only above a depth of about 2 m. Below this depth, water continued to drain and the soil water potential measurements showed downward movement of water at both sites, notwithstanding significant negative soil water potentials in the chalk and soil above. Seasonal differences occur in the soil water content profiles under broadleaved woodland and grass. Before the woodland foliage emerges, greater drying beneath the grassland is offset in late spring and early summer by increased drying under the forest. Yet, when the change in soil water profiles is at a maximum, in late summer, the profiles below woodland and grass are very similar. A comparison of soil water balances for Black Wood and Bridgets Farm using changes in soil water contents, local rainfall and evaporation measured by the energy balance approach allowed drainage to be calculated at each site. Although seasonal differences occurred, the difference in cumulative drainage below broadleaved woodland and grass was small.
The impact of broadleaved woodland on water resources in lowland UK: II. Evaporation estimates from sensible heat flux measurements over beech woodland and grass on chalk sites in Hampshire
J. Roberts ,P. Rosier
Hydrology and Earth System Sciences (HESS) & Discussions (HESSD) , 2005,
Abstract: In the United Kingdom the planting of broadleaved woodland has led to concerns about the impact on water resources. Comparative studies, typically using soil water measurements, have been established to compare water use of broadleaved woodland and grassland. The diversity of outcomes from these studies makes it difficult to make any consistent prediction of the hydrological impact of afforestation. Most studies have shown greater drying of soils under broadleaved woodland than under grass. However, two studies in a beech wood growing on shallow soils above chalk at Black Wood, Micheldever, Hampshire showed little overall difference between broadleaved woodland and grass, either in soil water abstraction or in evaporation. Two factors are thought to contribute to the different results from Black Wood. It is known that evaporation can be considerably enhanced at the edges of woodlands or in small areas of woodlands. The studies at Black Wood were made well within a large area of fairly uniform woodland. Other studies in which a difference occurred in soil drying between broadleaved woodland and grass used measurements made in small areas of woodlands or at woodland edges. Another important difference between comparison of woodland at Black Wood and grassland growing nearby, also on shallow soils above Chalk, compared to other broadleaved woodland/grass comparisons, growing on other geologies, is the influence of the Chalk. Although vegetation such as grass (and woodland) does not populate the chalk profusely with roots, water can be removed from the Chalk by the roots which proliferate at the soil/chalk interface and which can generate upward water movement within the Chalk. Published work showed that only in a very dry summer did the evaporation from grass growing on shallow soils above chalk fall below potential. In broadleaved woodland/grass comparisons on non-chalky soils it is possible that moisture deficits in the soil below the grass may reach critical levels and reduce evaporation below that of the woodland with which it is being compared.
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