Sample records for improved long-term expression
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Unified pre- and postsynaptic long-term plasticity enables reliable and flexible learning.
Costa, Rui Ponte; Froemke, Robert C; Sjöström, P Jesper; van Rossum, Mark Cw
2015-08-26
Although it is well known that long-term synaptic plasticity can be expressed both pre- and postsynaptically, the functional consequences of this arrangement have remained elusive. We show that spike-timing-dependent plasticity with both pre- and postsynaptic expression develops receptive fields with reduced variability and improved discriminability compared to postsynaptic plasticity alone. These long-term modifications in receptive field statistics match recent sensory perception experiments. Moreover, learning with this form of plasticity leaves a hidden postsynaptic memory trace that enables fast relearning of previously stored information, providing a cellular substrate for memory savings. Our results reveal essential roles for presynaptic plasticity that are missed when only postsynaptic expression of long-term plasticity is considered, and suggest an experience-dependent distribution of pre- and postsynaptic strength changes.
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Recommendations for sexual expression management in long-term care: a qualitative needs assessment
Syme, Maggie L.; Lichtenberg, Peter; Moye, Jennifer
2017-01-01
Aims To conduct a qualitative needs assessment of Directors of Nursing regarding challenges and recommendations for addressing sexual expression and consent. Background Sexual expression management among long-term care residents is a complex issue for nursing home staff. Little guidance is available for those wanting to follow a person-centred approach. Policies and procedures are needed, and must be usable across long-term care settings. Design Qualitative design for in-depth exploration. Methods Semi-structured interviews were conducted with 20 Directors of Nursing in the spring and summer of 2013, representing a range of regions, facility sizes and resident populations. Interview questions prompted them to identify recommendations that address challenges to improving sexual expression management in long-term care settings. Results Comparative thematic analysis resulted in several codes, which were grouped into eight overall categories. Recommendation categories that addressed key challenges included: address the issue, make environmental changes, identify staff expertise, provide education and training, assess sexuality initially and recurrently, establish policies/procedures for sexual expression management, develop assessment tools for sexual expression and consent, and clarify legal issues. The recommendation to develop national guidelines was observed across categories. Discussion Directors of Nursing report several challenges to sexual expression management in their facilities, and perceive their current methods to be ad hoc. A proactive approach to policy and procedure development is needed. PMID:27188413
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Rengo, Giuseppe; Lymperopoulos, Anastasios; Zincarelli, Carmela; Donniacuo, Maria; Soltys, Stephen; Rabinowitz, Joseph E.; Koch, Walter J.
2009-01-01
Background The upregulation of G protein–coupled receptor kinase 2 in failing myocardium appears to contribute to dysfunctional β-adrenergic receptor (βAR) signaling and cardiac function. The peptide βARKct, which can inhibit the activation of G protein–coupled receptor kinase 2 and improve βAR signaling, has been shown in transgenic models and short-term gene transfer experiments to rescue heart failure (HF). This study was designed to evaluate long-term βARKct expression in HF with the use of stable myocardial gene delivery with adeno-associated virus serotype 6 (AAV6). Methods and Results In HF rats, we delivered βARKct or green fluorescent protein as a control via AAV6-mediated direct intramyocardial injection. We also treated groups with concurrent administration of the β-blocker metoprolol. We found robust and long-term transgene expression in the left ventricle at least 12 weeks after delivery. βARKct significantly improved cardiac contractility and reversed left ventricular remodeling, which was accompanied by a normalization of the neurohormonal (catecholamines and aldosterone) status of the chronic HF animals, including normalization of cardiac βAR signaling. Addition of metoprolol neither enhanced nor decreased βARKct-mediated beneficial effects, although metoprolol alone, despite not improving contractility, prevented further deterioration of the left ventricle. Conclusions Long-term cardiac AAV6-βARKct gene therapy in HF results in sustained improvement of global cardiac function and reversal of remodeling at least in part as a result of a normalization of the neurohormonal signaling axis. In addition, βARKct alone improves outcomes more than a β-blocker alone, whereas both treatments are compatible. These findings show that βARKct gene therapy can be of long-term therapeutic value in HF. PMID:19103992
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Korn, K T; Lemenager, R P; Claeys, M C; Waddell, J N; Engstrom, M; Schoonmaker, J P
2013-07-01
Two hundred and ten Angus × Simmental steers (initial BW 314 ± 11 kg) were separated into heavy and light BW blocks and allotted evenly by BW to 6 treatments (3 heavy and 2 light pens per treatment) to determine the effect of supplemental vitamin D3: 0 IU (no D), 250,000 IU for 165 d (long-term D), or 5 × 10(6) IU for 10 d (short-term D) on plasma and muscle calcium concentrations and gene expression in steers fed either 0 (NZ) or 8.38 mg/kg (ZH) zilpaterol hydrochloride (ZH) daily for 21 d. Placebo or ZH was added to the diet 24 d, and short-term D was added 13 d before slaughter. Treatments were removed from all diets 3 d before slaughter. Plasma total calcium (Ca(2+)) was determined at study initiation, start of ZH and short-term D feedings, and at vitamin D3 and ZH withdrawal. Both plasma total and ionic Ca(2+) were determined when animals were sent to harvest. Longissimus muscle total and ionic Ca(2+) were determined in meat aged 7 and 4 d postmortem, respectively. When ZH was fed, long-term D decreased plasma total Ca(2+) at slaughter (P < 0.04). Short-term D increased (P < 0.01) plasma total and ionic Ca(2+) at slaughter regardless of ZH inclusion in the diet. Long- and short-term D, with or without ZH, did not affect (P > 0.28) LM total Ca(2+); however, both long- and short-term D increased LM ionic Ca(2+) when ZH was not fed (P < 0.01). Long-term D reduced LM ionic Ca(2+) when ZH was fed (P < 0.02). Neither long- nor short-term D affected PPARα or δ gene expression (P = 0.19) whether or not ZH was fed. Expression of MYH1 and 2A (P < 0.05) but not 2X (P = 0.21) was decreased in steers fed ZH. Long-term D had no effect on MYH2A expression (P = 0.21). Short-term D increased MYH2A expression when ZH was not fed (P < 0.03). Calpain mRNA tended to be lower in steers fed ZH (P = 0.09), but was not affected by long- or short-term D regardless of whether or not ZH was fed (P = 0.39). Expression of calpastatin did not differ with vitamin D supplementation (P = 0.35). In conclusion, ZH decreased oxidative myosin expression, and when combined with long-term D, ZH decreased LM ionic Ca(2+). Moreover, vitamin D3 supplementation did not increase calpain mRNA. These results help explain why vitamin D3 does not improve tenderness in steers fed ZH.
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Staal, J. Bart; Heymans, Martijn W.; Harts, Chris C.; Hendriks, Erik J. M.; de Bie, Rob A.
2009-01-01
The objective of this study was to report on secondary analyses of a merged trial dataset aimed at exploring the potential importance of patient factors associated with clinically relevant improvements in non-acute, non-specific low back pain (LBP). From 273 predominantly male army workers (mean age 39 ± 10.5 years, range 20–56 years, 4 women) with LBP who were recruited in three randomized clinical trials, baseline individual patient factors, pain-related factors, work-related psychosocial factors, and psychological factors were evaluated as potential prognostic variables in a short-term (post-treatment) and a long-term logistic regression model (6 months after treatment). We found one dominant prognostic factor for improvement directly after treatment as well as 6 months later: baseline functional disability, expressed in Roland–Morris Disability Questionnaire scores. Baseline fear of movement, expressed in Tampa Scale for Kinesiophobia scores, had also significant prognostic value for long-term improvement. Less strongly associated with the outcome, but also included in our final models, were supervisor social support and duration of complaints (short-term model), and co-worker social support and pain radiation (long-term model). Information about initial levels of functional disability and fear-avoidance behaviour can be of value in the treatment of patient populations with characteristics comparable to the current army study population (e.g., predominantly male, physically active, working, moderate but chronic back problems). Individuals at risk for poor long-term LBP recovery, i.e., individuals with high initial level of disability and prominent fear-avoidance behaviour, can be distinguished that may need additional cognitive-behavioural treatment. PMID:20035358
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Schmelzer, Eva; Finoli, Anthony; Nettleship, Ian; Gerlach, Jörg C
2015-04-01
The construction and long-term maintenance of three-dimensional in vitro bone marrow models is of great interest but still quite challenging. Here we describe the use of a multi-compartment hollow-fiber membrane based three-dimensional perfusion bioreactor for long-term culture of whole human bone marrow mononuclear cells. We also investigated bioreactors with incorporated open-porous foamed hydroxyapatite scaffolds, mimicking the in vivo bone matrix. Cells in bioreactors with and without scaffolds were cultured to 6 weeks and compared to Petri dish controls. Cells were analyzed for gene expression, surface markers by flow cytometry, metabolic activity, hematopoietic potential, viability, and attachment by immunocytochemistry. Cells in bioreactors were metabolic active during long-term culture. The percentages of hematopoietic stem cell and mature endothelial cell fractions were maintained in bioreactors. The expression of most of the analyzed genes stabilized and increased after long-term culture of 6 weeks. Compared to Petri dish culture controls, bioreactor perfusion culture improved in both the short and long-term, the colony formation unit capacity of hematopoietic progenitors. Cells attached to the ample surface area provided by hydroxyapatite scaffolds. The implementation of a hydroxyapatite scaffold did not influence colony formation capacity, percentages of cell type specific fractions, gene expression, cell viability or metabolic turnover when compared to control cells cultured in bioreactors without scaffolds. In conclusion, three-dimensional perfusion bioreactor culture enables long-term maintenance of primary human bone marrow cells, with hydroxyapatite scaffolds providing an in vivo-like scaffold for three-dimensional culture. © 2015 Wiley Periodicals, Inc.
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Jackson, Robyn; Tilokee, Everad L; Latham, Nicholas; Mount, Seth; Rafatian, Ghazaleh; Strydhorst, Jared; Ye, Bin; Boodhwani, Munir; Chan, Vincent; Ruel, Marc; Ruddy, Terrence D; Suuronen, Erik J; Stewart, Duncan J; Davis, Darryl R
2015-09-11
Insulin-like growth factor 1 (IGF-1) activates prosurvival pathways and improves postischemic cardiac function, but this key cytokine is not robustly expressed by cultured human cardiac stem cells. We explored the influence of an enhanced IGF-1 paracrine signature on explant-derived cardiac stem cell-mediated cardiac repair. Receptor profiling demonstrated that IGF-1 receptor expression was increased in the infarct border zones of experimentally infarcted mice by 1 week after myocardial infarction. Human explant-derived cells underwent somatic gene transfer to overexpress human IGF-1 or the green fluorescent protein reporter alone. After culture in hypoxic reduced-serum media, overexpression of IGF-1 enhanced proliferation and expression of prosurvival transcripts and prosurvival proteins and decreased expression of apoptotic markers in both explant-derived cells and cocultured neonatal rat ventricular cardiomyocytes. Transplant of explant-derived cells genetically engineered to overexpress IGF-1 into immunodeficient mice 1 week after infarction boosted IGF-1 content within infarcted tissue and long-term engraftment of transplanted cells while reducing apoptosis and long-term myocardial scarring. Paracrine engineering of explant-derived cells to overexpress IGF-1 provided a targeted means of improving cardiac stem cell-mediated repair by enhancing the long-term survival of transplanted cells and surrounding myocardium. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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USDA-ARS?s Scientific Manuscript database
Long-term administration of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) mimics the effects of endurance exercise by activating AMP kinase and by increasing skeletal muscle expression of GLUT4 glucose transporter. AICAR is an intermediate in the purine de novo synthesis, and its tissue conc...
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Long-term academic stress enhances early processing of facial expressions.
Zhang, Liang; Qin, Shaozheng; Yao, Zhuxi; Zhang, Kan; Wu, Jianhui
2016-11-01
Exposure to long-term stress can lead to a variety of emotional and behavioral problems. Although widely investigated, the neural basis of how long-term stress impacts emotional processing in humans remains largely elusive. Using event-related brain potentials (ERPs), we investigated the effects of long-term stress on the neural dynamics of emotionally facial expression processing. Thirty-nine male college students undergoing preparation for a major examination and twenty-one matched controls performed a gender discrimination task for faces displaying angry, happy, and neutral expressions. The results of the Perceived Stress Scale showed that participants in the stress group perceived higher levels of long-term stress relative to the control group. ERP analyses revealed differential effects of long-term stress on two early stages of facial expression processing: 1) long-term stress generally augmented posterior P1 amplitudes to facial stimuli irrespective of expression valence, suggesting that stress can increase sensitization to visual inputs in general, and 2) long-term stress selectively augmented fronto-central P2 amplitudes for angry but not for neutral or positive facial expressions, suggesting that stress may lead to increased attentional prioritization to processing negative emotional stimuli. Together, our findings suggest that long-term stress has profound impacts on the early stages of facial expression processing, with an increase at the very early stage of general information inputs and a subsequent attentional bias toward processing emotionally negative stimuli. Copyright © 2016 Elsevier B.V. All rights reserved.
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NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors
Hawk, Joshua D.; Bookout, Angie L.; Poplawski, Shane G.; Bridi, Morgan; Rao, Allison J.; Sulewski, Michael E.; Kroener, Brian T.; Manglesdorf, David J.; Abel, Ted
2012-01-01
The formation of a long-lasting memory requires a transcription-dependent consolidation period that converts a short-term memory into a long-term memory. Nuclear receptors compose a class of transcription factors that regulate diverse biological processes, and several nuclear receptors have been implicated in memory formation. Here, we examined the potential contribution of nuclear receptors to memory consolidation by measuring the expression of all 49 murine nuclear receptors after learning. We identified 13 nuclear receptors with increased expression after learning, including all 3 members of the Nr4a subfamily. These CREB-regulated Nr4a genes encode ligand-independent “orphan” nuclear receptors. We found that blocking NR4A activity in memory-supporting brain regions impaired long-term memory but did not impact short-term memory in mice. Further, expression of Nr4a genes increased following the memory-enhancing effects of histone deacetylase (HDAC) inhibitors. Blocking NR4A signaling interfered with the ability of HDAC inhibitors to enhance memory. These results demonstrate that the Nr4a gene family contributes to memory formation and is a promising target for improving cognitive function. PMID:22996661
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Dynamics of Hippocampal Protein Expression During Long-term Spatial Memory Formation*
Borovok, Natalia; Nesher, Elimelech; Levin, Yishai; Reichenstein, Michal; Pinhasov, Albert
2016-01-01
Spatial memory depends on the hippocampus, which is particularly vulnerable to aging. This vulnerability has implications for the impairment of navigation capacities in older people, who may show a marked drop in performance of spatial tasks with advancing age. Contemporary understanding of long-term memory formation relies on molecular mechanisms underlying long-term synaptic plasticity. With memory acquisition, activity-dependent changes occurring in synapses initiate multiple signal transduction pathways enhancing protein turnover. This enhancement facilitates de novo synthesis of plasticity related proteins, crucial factors for establishing persistent long-term synaptic plasticity and forming memory engrams. Extensive studies have been performed to elucidate molecular mechanisms of memory traces formation; however, the identity of plasticity related proteins is still evasive. In this study, we investigated protein turnover in mouse hippocampus during long-term spatial memory formation using the reference memory version of radial arm maze (RAM) paradigm. We identified 1592 proteins, which exhibited a complex picture of expression changes during spatial memory formation. Variable linear decomposition reduced significantly data dimensionality and enriched three principal factors responsible for variance of memory-related protein levels at (1) the initial phase of memory acquisition (165 proteins), (2) during the steep learning improvement (148 proteins), and (3) the final phase of the learning curve (123 proteins). Gene ontology and signaling pathways analysis revealed a clear correlation between memory improvement and learning phase-curbed expression profiles of proteins belonging to specific functional categories. We found differential enrichment of (1) neurotrophic factors signaling pathways, proteins regulating synaptic transmission, and actin microfilament during the first day of the learning curve; (2) transcription and translation machinery, protein trafficking, enhancement of metabolic activity, and Wnt signaling pathway during the steep phase of memory formation; and (3) cytoskeleton organization proteins. Taken together, this study clearly demonstrates dynamic assembly and disassembly of protein-protein interaction networks depending on the stage of memory formation engrams. PMID:26598641
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Nishijima, Takeshi; Kawakami, Masashi; Kita, Ichiro
2013-01-01
Physical exercise improves multiple aspects of hippocampal function. In line with the notion that neuronal activity is key to promoting neuronal functions, previous literature has consistently demonstrated that acute bouts of exercise evoke neuronal activation in the hippocampus. Repeated activating stimuli lead to an accumulation of the transcription factor ΔFosB, which mediates long-term neural plasticity. In this study, we tested the hypothesis that long-term voluntary wheel running induces ΔFosB expression in the hippocampus, and examined any potential region-specific effects within the hippocampal subfields along the dorso–ventral axis. Male C57BL/6 mice were housed with or without a running wheel for 4 weeks. Long-term wheel running significantly increased FosB/ΔFosB immunoreactivity in all hippocampal regions measured (i.e., in the DG, CA1, and CA3 subfields of both the dorsal and ventral hippocampus). Results confirmed that wheel running induced region-specific expression of FosB/ΔFosB immunoreactivity in the cortex, suggesting that the uniform increase in FosB/ΔFosB within the hippocampus is not a non-specific consequence of running. Western blot data indicated that the increased hippocampal FosB/ΔFosB immunoreactivity was primarily due to increased ΔFosB. These results suggest that long-term physical exercise is a potent trigger for ΔFosB induction throughout the entire hippocampus, which would explain why exercise can improve both dorsal and ventral hippocampus-dependent functions. Interestingly, we found that FosB/ΔFosB expression in the DG was positively correlated with the number of doublecortin-immunoreactive (i.e., immature) neurons. Although the mechanisms by which ΔFosB mediates exercise-induced neurogenesis are still uncertain, these data imply that exercise-induced neurogenesis is at least activity dependent. Taken together, our current results suggest that ΔFosB is a new molecular target involved in regulating exercise-induced hippocampal plasticity. PMID:24282574
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Mostajeran, M; Edvinsson, L; Warfvinge, K; Singh, R; Ansar, S
2017-04-01
Extracellular signal-regulated kinase (ERK) 1/2 is activated during acute phase of stroke and contributes to stroke pathology. We have found that acute treatment with MEK1/2 inhibitors decreases infarct size and neurological deficits 2 days after experimental stroke. However, it is not known whether benefits of this inhibition persist long-term. Therefore, the aim of this study was to assess neurological function, infarct size and recovery processes 14 days after stroke in male rats to determine long-term outcome following acute treatment with the MEK1/2 inhibitor U0126. Transient middle cerebral artery occlusion was induced in male rats. U0126 or vehicle was given at 0 and 24 h of reperfusion. Neurological function was assessed by staircase, 6-point and 28-point neuroscore tests up to 14 days after induction of stroke. At day 14, infarct volumes were determined and recovery processes were evaluated by measuring protein expression of the tyrosine kinase receptor Tie-2 and nestin. Levels of p-ERK1/2 protein were determined. Acute treatment with U0126 significantly improved long-term functional recovery, reduced infarct size, and enhanced Tie-2 and nestin protein expression at 14 days post-stroke. There was no residual blockade of p-ERK1/2 at this time point. It is demonstrated that benefits of early treatment with U0126 persist beyond subacute phase of ischaemic stroke in male rats. Prevention of ERK1/2 activation in the acute phase results in improved long-term functional outcome and enhances later-stage recovery processes. These results expand our understanding of the benefits and promise of using MEK1/2 inhibitors in stroke recovery. © 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.
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Zhu, G; Wang, Y; Li, J; Wang, J
2015-04-30
Ginseng serves as a potential candidate for the treatment of aging-related memory decline or memory loss. However, the related mechanism is not fully understood. In this study, we applied an intraperitoneal injection of ginsenoside Rg1, an active compound from ginseng in middle-aged mice and detected memory improvement and the underlying mechanisms. Our results showed that a period of 30-day administration of ginsenoside Rg1 enhanced long-term memory in the middle-aged animals. Consistent with the memory improvement, ginsenoside Rg1 administration facilitated weak theta-burst stimulation (TBS)-induced long-term potentiation (LTP) in acute hippocampal slices from middle-aged animals. Ginsenoside Rg1 administration increased the dendritic apical spine numbers and area in the CA1 region. In addition, ginsenoside Rg1 administration up-regulated the expression of hippocampal p-AKT, brain-derived neurotrophic factor (BDNF), proBDNF and glutamate receptor 1 (GluR1), but not p-ERK. Interestingly, the phosphatase and tensin homolog deleted on chromosome ten (PTEN) inhibitor (bpV) mimicked the ginsenoside Rg1 effects, including increasing p-AKT expression, promoting hippocampal basal synaptic transmission, LTP and memory. Taken together, our data suggest that ginsenoside Rg1 treatment improves memory in middle-aged mice possibly through regulating the PI3K/AKT pathway, altering apical spines and facilitating hippocampal LTP. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
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Upregulation of CREB-mediated transcription enhances both short- and long-term memory.
Suzuki, Akinobu; Fukushima, Hotaka; Mukawa, Takuya; Toyoda, Hiroki; Wu, Long-Jun; Zhao, Ming-Gao; Xu, Hui; Shang, Yuze; Endoh, Kengo; Iwamoto, Taku; Mamiya, Nori; Okano, Emiko; Hasegawa, Shunsuke; Mercaldo, Valentina; Zhang, Yue; Maeda, Ryouta; Ohta, Miho; Josselyn, Sheena A; Zhuo, Min; Kida, Satoshi
2011-06-15
Unraveling the mechanisms by which the molecular manipulation of genes of interest enhances cognitive function is important to establish genetic therapies for cognitive disorders. Although CREB is thought to positively regulate formation of long-term memory (LTM), gain-of-function effects of CREB remain poorly understood, especially at the behavioral level. To address this, we generated four lines of transgenic mice expressing dominant active CREB mutants (CREB-Y134F or CREB-DIEDML) in the forebrain that exhibited moderate upregulation of CREB activity. These transgenic lines improved not only LTM but also long-lasting long-term potentiation in the CA1 area in the hippocampus. However, we also observed enhanced short-term memory (STM) in contextual fear-conditioning and social recognition tasks. Enhanced LTM and STM could be dissociated behaviorally in these four lines of transgenic mice, suggesting that the underlying mechanism for enhanced STM and LTM are distinct. LTM enhancement seems to be attributable to the improvement of memory consolidation by the upregulation of CREB transcriptional activity, whereas higher basal levels of BDNF, a CREB target gene, predicted enhanced shorter-term memory. The importance of BDNF in STM was verified by microinfusing BDNF or BDNF inhibitors into the hippocampus of wild-type or transgenic mice. Additionally, increasing BDNF further enhanced LTM in one of the lines of transgenic mice that displayed a normal BDNF level but enhanced LTM, suggesting that upregulation of BDNF and CREB activity cooperatively enhances LTM formation. Our findings suggest that CREB positively regulates memory consolidation and affects memory performance by regulating BDNF expression.
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Musicki, Biljana; Champion, Hunter C; Becker, Robyn E; Liu, Tongyun; Kramer, Melissa F; Burnett, Arthur L
2005-07-01
Despite demonstrated clinical efficacy of sildenafil for the temporary treatment of erectile dysfunction, the possibility that sildenafil used long-term durably augments erectile ability remains unclear. We investigated whether continuous long-term administration of sildenafil at clinically relevant levels to aged rats "primes" the penis for improved erectile ability and involves nitric oxide (NO) or RhoA/Rho-kinase signaling pathways. In aged, but not young rats, sildenafil prolonged erection and increased the protein expressions of phosphorylated endothelial NO synthase (eNOS) at serine-1177 and phosphorylated Akt at serine-473 in penes. Only in the young rat penis, protein expressions of phosphodiesterase-5 and phosphomyosin phosphatase target subunit 1, a marker of Rho-kinase activity, were increased by sildenafil. Sildenafil inhibited phosphodiesterase-5 activity in penes of young and aged rats coincident with assayed free plasma levels of the drug equivalent to clinically therapeutic measurements. We conclude that erectile ability can be enhanced under preconditions of erectile impairment by long-term inhibition of phosphodiesterase-5 and that the effect is mediated by Akt-dependent eNOS phosphorylation. The lack of erectile ability enhancement in young rats by long-term phosphodiesterase-5 inhibition may relate to restrained NO signaling by phosphodiesterase-5 up-regulation, lack of incremental Akt and eNOS phosphorylation, and heightened Rho-kinase signaling in the penis.
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ERIC Educational Resources Information Center
Fritsch, Thomas; Kwak, Jung; Grant, Stacey; Lang, Josh; Montgomery, Rhonda R.; Basting, Anne D.
2009-01-01
Purpose: Creative expression (CE) programs are emerging interventions to improve the quality of care and life of persons with dementia (PWDs) in long-term care settings. However, limited empirical evidence exists to support the effectiveness of these programs. Here, we report the findings from an assessment of the impact of TimeSlips (TS), a group…
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Sun, Xiao-Juan; Pan, Shan-Shan
2014-07-01
To examine the role of calcitonin gene-related peptide (CGRP) in cardioprotection of short-term and long-term exercise preconditioning (EP). Male Sprague-Dawley rats were, respectively, subjected to continuous intermittent treadmill training 3 days or 3 weeks as short-term or long-term EP protocols. The myocardial injury induced by isoproterenol (ISO) was performed 24 hours after short-term and long-term EP. The myocardial injury was evaluated in terms of the serum cardiac troponin levels and the hematoxylin-basic fuchsin-picric acid staining. Additionally, serum CGRP levels, CGRP expression in the dorsal root ganglion (DRG), and heart were analyzed as possible mechanisms to explain short-term and long-term EP-induced cardioprotection. Both short-term and long-term EP markedly attenuated the isoproterenol-induced myocardial ischemia with lower serum cardiac troponin levels. Short-term EP does not alter serum CGRP levels and CGRP expression in the DRG and heart. Long-term EP significantly increases serum CGRP levels and CGRP expression in the DRG and heart. The results indicate that short-term EP does not increase the synthesis and release of CGRP. Therefore, the cardioprotective effect of short-term EP does not involve CGRP adaptation. Furthermore, long-term EP increases CGRP synthesis in the DRG and promotes CGRP release in the blood and heart. Hence, CGRP may play an important role in the cardioprotective effect of long-term EP.
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Synaptic Transmission Optimization Predicts Expression Loci of Long-Term Plasticity.
Costa, Rui Ponte; Padamsey, Zahid; D'Amour, James A; Emptage, Nigel J; Froemke, Robert C; Vogels, Tim P
2017-09-27
Long-term modifications of neuronal connections are critical for reliable memory storage in the brain. However, their locus of expression-pre- or postsynaptic-is highly variable. Here we introduce a theoretical framework in which long-term plasticity performs an optimization of the postsynaptic response statistics toward a given mean with minimal variance. Consequently, the state of the synapse at the time of plasticity induction determines the ratio of pre- and postsynaptic modifications. Our theory explains the experimentally observed expression loci of the hippocampal and neocortical synaptic potentiation studies we examined. Moreover, the theory predicts presynaptic expression of long-term depression, consistent with experimental observations. At inhibitory synapses, the theory suggests a statistically efficient excitatory-inhibitory balance in which changes in inhibitory postsynaptic response statistics specifically target the mean excitation. Our results provide a unifying theory for understanding the expression mechanisms and functions of long-term synaptic transmission plasticity. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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Retrovirus-based vectors for transient and permanent cell modification.
Schott, Juliane W; Hoffmann, Dirk; Schambach, Axel
2015-10-01
Retroviral vectors are commonly employed for long-term transgene expression via integrating vector technology. However, three alternative retrovirus-based platforms are currently available that allow transient cell modification. Gene expression can be mediated from either episomal DNA or RNA templates, or selected proteins can be directly transferred through retroviral nanoparticles. The different technologies are functionally graded with respect to safety, expression magnitude and expression duration. Improvement of the initial technologies, including modification of vector designs, targeted increase in expression strength and duration as well as improved safety characteristics, has allowed maturation of retroviral systems into efficient and promising tools that meet the technological demands of a wide variety of potential application areas. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Bonnafé, Elsa; Alayrangues, Julie; Hotier, Lucie; Massou, Isabelle; Renom, Allan; Souesme, Guillaume; Marty, Pierre; Allaoua, Marion; Treilhou, Michel; Armengaud, Catherine
2017-02-01
Bees are exposed in their environment to contaminants that can weaken the colony and contribute to bee declines. Monoterpenoid-based preparations can be introduced into hives to control the parasitic mite Varroa destructor. The long-term effects of monoterpenoids are poorly investigated. Olfactory conditioning of the proboscis extension reflex (PER) has been used to evaluate the impact of stressors on cognitive functions of the honeybee such as learning and memory. The authors tested the PER to odorants on bees after exposure to monoterpenoids in hives. Octopamine receptors, transient receptor potential-like (TRPL), and γ-aminobutyric acid channels are thought to play a critical role in the memory of food experience. Gene expression levels of Amoa1, Rdl, and trpl were evaluated in parallel in the bee brain because these genes code for the cellular targets of monoterpenoids and some pesticides and neural circuits of memory require their expression. The miticide impaired the PER to odors in the 3 wk following treatment. Short-term and long-term olfactory memories were improved months after introduction of the monoterpenoids into the beehives. Chronic exposure to the miticide had significant effects on Amoa1, Rdl, and trpl gene expressions and modified seasonal changes in the expression of these genes in the brain. The decrease of expression of these genes in winter could partly explain the improvement of memory. The present study has led to new insights into alternative treatments, especially on their effects on memory and expression of selected genes involved in this cognitive function. Environ Toxicol Chem 2017;36:337-345. © 2016 SETAC. © 2016 SETAC.
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Space Propulsion Synergy Group ETO technology assessments
NASA Astrophysics Data System (ADS)
Bray, James
There exists within the aerospace community a widely recognized need to improve future space launch systems. While these needs have been expressed by many national committees, potential solutions have not achieved consensus nor have they endured. Facing the challenge to remain competitive with limited national resources, the U.S. must improve its strategic planning efforts. A nationally accepted strategic plan for space would enable a focused research & development program. The Space Propulsion Synergy Group (SPSG), chartered to support long range strategic planning, has achieved several breakthroughs. First, using a broad industry/government team, the SPSG evaluated and achieved consensus on the vehicles, propulsion systems, and propulsion technologies that have the best long term potential for achieving desired system attributes. The breakthrough that enabled broad consensus was developing criteria that are measurable a-priori. Second, realizing that systems having the best long term payoffs can loose support when constraints are tight, the SPSG invented a dual prioritization approach that balances long term strategic thrusts with current programmatic constraints. This breakthrough enables individual program managers to make decisions based on both individual project needs and long term strategic needs. Results indicate that a SSTO using an integrated modular engine has the best long term potential for a 20 Klb class vehicle and that health monitoring and control technologies rank among the highest dual priority liquid rocket technologies.
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Kennedy, Bruce C; Dimova, Jiva G; Siddappa, Asha J M; Tran, Phu V; Gewirtz, Jonathan C; Georgieff, Michael K
2014-11-01
Gestational iron deficiency in humans and rodents produces long-term deficits in cognitive and socioemotional function and alters expression of plasticity genes in the hippocampus that persist despite iron treatment. Prenatal choline supplementation improves cognitive function in other rodent models of developmental insults. The objective of this study was to determine whether prenatal choline supplementation prevents the long-term effects of fetal-neonatal iron deficiency on cognitive and social behaviors and hippocampal gene expression. Pregnant rat dams were administered an iron-deficient (2-6 g/kg iron) or iron-sufficient (IS) (200 g/kg iron) diet from embryonic day (E) 3 to postnatal day (P) 7 with or without choline supplementation (5 g/kg choline chloride, E11-18). Novel object recognition (NOR) in the test vs. acquisition phase, social approach (SA), and hippocampal mRNA expression were compared at P65 in 4 male adult offspring groups: formerly iron deficient (FID), FID with choline supplementation (FID-C), IS, and IS with choline supplementation. Relative to the intact NOR in IS rats (acquisition: 47.9%, test: 60.2%, P < 0.005), FID adult rats had impaired recognition memory at the 6-h delay (acquisition: 51.4%, test: 55.1%, NS), accompanied by a 15% reduction in hippocampal expression of brain-derived neurotrophic factor (Bdnf) (P < 0.05) and myelin basic protein (Mbp) (P < 0.05). Prenatal choline supplementation in FID rats restored NOR (acquisition: 48.8%, test: 64.4%, P < 0.0005) and increased hippocampal gene expression (FID-C vs. FID group: Bdnf, Mbp, P < 0.01). SA was also reduced in FID rats (P < 0.05 vs. IS rats) but was only marginally improved by prenatal choline supplementation. Deficits in recognition memory, but not social behavior, resulting from gestational iron deficiency are attenuated by prenatal choline supplementation, potentially through preservation of hippocampal Bdnf and Mbp expression. Prenatal choline supplementation may be a promising adjunct treatment for fetal-neonatal iron deficiency. © 2014 American Society for Nutrition.
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Combined Analyses of hENT1, TS, and DPD Predict Outcomes of Borderline-resectable Pancreatic Cancer.
Yabushita, Yasuhiro; Mori, Ryutaro; Taniguchi, Koichi; Matsuyama, Ryusei; Kumamoto, Takafumi; Sakamaki, Kentaro; Kubota, Kensuke; Endo, Itaru
2017-05-01
Predicting chemosensitivity to neoadjuvant chemoradiotherapy (NACRT) in pancreatic cancer is desired. The present study aimed to examine the relationship between intratumoral expression of human equilibrative nucleoside transporter 1 (hENT1), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) and the outcomes of NACRT with gemcitabine (GEM) combined with S-1 in patients with borderline-resectable pancreatic cancer (BRPC). Forty-seven patients who underwent NACRT with GEM plus S-1, following curative surgery, were recruited in our Institution between 2009 and 2012. Immunohistochemical expressions of hENT1, TS, and DPD in fine-needle aspiration (FNA) biopsies and resected specimens were examined. The correlation between these enzyme expressions and long-term outcome was analyzed. In 21 FNA specimens, no relationship between clinical responses to NACRT and long-term survival was found. However, in 47 resected specimens, patients were classified according to the number of favorable hENT1, TS, and DPD expression factors (hENT1 positive/TS negative/DPD negative). The presence of three favorable factors was strongly associated with improved partial response rates to NACRT (p=0.002). Patients with 2 or more favorable factors showed a significantly longer overall survival than the other patients (p=0.002). Combined expression analyses of hENT1, TS, and DPD may predict long-term outcomes in patients with BRPC after NACRT. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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Maejima, Hiroshi; Kanemura, Naohiko; Kokubun, Takanori; Murata, Kenji; Takayanagi, Kiyomi
2018-02-05
Aerobic exercise is known to increase expression of neurotrophins, particularly brain-derived neurotrophic factor (BDNF), in the hippocampus and to improve cognitive function. Exercise exerts neuroprotective effects in the hippocampus by inducing epigenetic changes, which play crucial roles in aging and neurodegenerative diseases. Specifically, the activity levels of histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate histone acetylation and modulate gene transcription. The objective of the present study was to assess the interactive effects of exercise and aging on cognitive function, expression of neurotrophins (BDNF and neurotrophin-4) and their receptors (tyrosine receptor kinase B and p75), and epigenetic regulations, including the activity of HATs and HADCs in the hippocampus. We used the senescence-accelerated mouse (SAM) model, specifically 13-month-old SAM resistant 1(SAMR1) and SAM prone 1 (SAMP1) lines. Mice were distributed into four groups based on accelerated senescence and exercise status. Mice in the exercise groups exercised on a treadmill for approximately 60min a day, 5days a week. Aerobic exercise for 4 weeks improved cognitive function, accompanied by an increase in BDNF expression and a decrease in p75 transcription in both SAMR1 and SAMP1. In addition, the exercise regimen activated both HAT and HDAC in the hippocampus. Therefore, the present study reveals that despite accelerated senescence, long-term exercise improved cognitive function, upregulated the expression of BDNF, and downregulated p75, a receptor involved in apoptotic signaling. Furthermore, long-term exercise enhanced activity of both HAT and HDAC, which may contribute to the transcriptional regulation underlying the improvement of cognitive function. Copyright © 2017 Elsevier B.V. All rights reserved.
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Retention of gene expression in porcine islets after agarose encapsulation and long-term culture
DOE Office of Scientific and Technical Information (OSTI.GOV)
Dumpala, Pradeep R., E-mail: pdumpala@rixd.org; Holdcraft, Robert W.; Martis, Prithy C.
Agarose encapsulation of porcine islets allows extended in vitro culture, providing ample time to determine the functional capacity of the islets and conduct comprehensive microbiological safety testing prior to implantation as a treatment for type 1 diabetes mellitus. However, the effect that agarose encapsulation and long-term culture may have on porcine islet gene expression is unknown. The aim of the present study was to compare the transcriptome of encapsulated porcine islets following long-term in vitro culture against free islets cultured overnight. Global gene expression analysis revealed no significant change in the expression of 98.47% of genes. This indicates that the gene expressionmore » profile of free islets is highly conserved following encapsulation and long-term culture. Importantly, the expression levels of genes that code for critical hormones secreted by islets (insulin, glucagon, and somatostatin) as well as transcripts encoding proteins involved in their packaging and secretion are unchanged. While a small number of genes known to play roles in the insulin secretion and insulin signaling pathways are differentially expressed, our results show that overall gene expression is retained following islet isolation, agarose encapsulation, and long-term culture. - Highlights: • Effect of agarose encapsulation and 8 week culture on porcine islets was analyzed. • Transcriptome analysis revealed no significant change in a majority (98%) of genes. • Agarose encapsulation allows for long-term culture of porcine islets. • Islet culture allows for functional and microbial testing prior to clinical use.« less
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Wu, Yiming; Peng, Jun; Campbell, Kenneth B; Labeit, Siegfried; Granzier, Henk
2007-01-01
Because long-term hypothyroidism results in diastolic dysfunction, we investigated myocardial passive stiffness in hypothyroidism and focused on the possible role of titin, an important determinant of diastolic stiffness. A rat model of hypothyroidism was used, obtained by administering propylthiouracil (PTU) for times that varied from 1 month (short-term) to 4 months (long-term). Titin expression was determined by transcript analysis, gel electrophoresis and immunoelectron microscopy. Diastolic function was measured at the isolated heart, skinned muscle, and cardiac myocyte levels. We found that hypothyroidism resulted in expression of a large titin isoform, the abundance of which gradually increased with time to become the most dominant isoform in long-term hypothyroid rats. This isoform co-migrates on high-resolution gels with fetal cardiac titin. Transcript analysis on myocardium of long-term PTU rats, provided evidence for expression of additional PEVK and Ig domain exons, similar to what has been described in fetal myocardium. Consistent with the expression of a large titin isoform, titin-based restoring and passive forces were significantly reduced in single cardiac myocytes and muscle strips of long-term hypothyroid rats. Overall muscle stiffness and LV diastolic wall stiffness were increased, however, due to increased collagen-based stiffness. We conclude that long term hypothyroidism triggers expression of a large cardiac titin isoform and that the ensuing reduction in titin-based passive stiffness functions as a compensatory mechanism to reduce LV wall stiffness.
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Månsson, K N T; Frick, A; Boraxbekk, C-J; Marquand, A F; Williams, S C R; Carlbring, P; Andersson, G; Furmark, T
2015-03-17
Cognitive behavior therapy (CBT) is an effective treatment for social anxiety disorder (SAD), but many patients do not respond sufficiently and a substantial proportion relapse after treatment has ended. Predicting an individual's long-term clinical response therefore remains an important challenge. This study aimed at assessing neural predictors of long-term treatment outcome in participants with SAD 1 year after completion of Internet-delivered CBT (iCBT). Twenty-six participants diagnosed with SAD underwent iCBT including attention bias modification for a total of 13 weeks. Support vector machines (SVMs), a supervised pattern recognition method allowing predictions at the individual level, were trained to separate long-term treatment responders from nonresponders based on blood oxygen level-dependent (BOLD) responses to self-referential criticism. The Clinical Global Impression-Improvement scale was the main instrument to determine treatment response at the 1-year follow-up. Results showed that the proportion of long-term responders was 52% (12/23). From multivariate BOLD responses in the dorsal anterior cingulate cortex (dACC) together with the amygdala, we were able to predict long-term response rate of iCBT with an accuracy of 92% (confidence interval 95% 73.2-97.6). This activation pattern was, however, not predictive of improvement in the continuous Liebowitz Social Anxiety Scale-Self-report version. Follow-up psychophysiological interaction analyses revealed that lower dACC-amygdala coupling was associated with better long-term treatment response. Thus, BOLD response patterns in the fear-expressing dACC-amygdala regions were highly predictive of long-term treatment outcome of iCBT, and the initial coupling between these regions differentiated long-term responders from nonresponders. The SVM-neuroimaging approach could be of particular clinical value as it allows for accurate prediction of treatment outcome at the level of the individual.
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Ferris, Robert L; Blumenschein, George; Fayette, Jerome; Guigay, Joel; Colevas, A Dimitrios; Licitra, Lisa; Harrington, Kevin J; Kasper, Stefan; Vokes, Everett E; Even, Caroline; Worden, Francis; Saba, Nabil F; Docampo, Lara Carmen Iglesias; Haddad, Robert; Rordorf, Tamara; Kiyota, Naomi; Tahara, Makoto; Lynch, Mark; Jayaprakash, Vijayvel; Li, Li; Gillison, Maura L
2018-06-01
We report 2-year results from CheckMate 141 to establish the long-term efficacy and safety profile of nivolumab and outcomes by tumor PD-L1 expression in patients with recurrent or metastatic (R/M),platinum-refractory squamous cell carcinoma of the head and neck (SCCHN). Patients with R/M SCCHN with tumor progression/recurrence within 6 months of platinum therapy were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks or investigator's choice (IC). Primary endpoint: overall survival (OS). Data cutoff: September 2017. With 24.2 months' minimum follow-up, nivolumab (n = 240) continued to improve OS vs IC (n = 121), hazard ratio (HR) = 0.68 (95% CI 0.54-0.86). Nivolumab nearly tripled the estimated 24-month OS rate (16.9%) vs IC (6.0%), and demonstrated OS benefit across patients with tumor PD-L1 expression ≥1% (HR [95% CI] = 0.55 [0.39-0.78]) and < 1% (HR [95% CI] = 0.73 [0.49-1.09]), and regardless of tumor HPV status. Estimated OS rates at 18, 24, and 30 months with nivolumab were consistent irrespective of PD-L1 expression (<1%/≥1%). In the nivolumab arm, there were no observed differences in baseline characteristics or safety profile between long-term survivors and the overall population. Grade 3-4 treatment-related adverse event rates were 15.3% and 36.9% for nivolumab and IC, respectively. Nivolumab significantly improved OS at the primary analysis and demonstrated prolonged OS benefit vs IC and maintenance of a manageable and consistent safety profile with 2-year follow-up. OS benefit was observed with nivolumab irrespective of PD-L1 expression and HPV status. (Clinicaltrials.gov: NCT02105636). Copyright © 2018. Published by Elsevier Ltd.
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Improve T Cell Therapy in Neuroblastoma
2012-07-01
Epstein - Barr - virus (EBV)-specific cytotoxic T lymphocytes (EBV-CTLs) genetically modified to express a chimeric antigen receptor (CAR-GD2) targeting the...A. Krance, M. K. Brenner, and C. M. Rooney. 1996. Long-term restoration of immunity against Epstein - Barr virus infection by adoptive transfer of gene... Barr - virus (EBV)- specific cytotoxic T l ymphocytes (EBV-CTLs) genetically modified to express a c himeric antigen receptor (CAR-GD2) targeting the GD2
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Aneja, Manish Kumar; Geiger, Johannes; Imker, Rabea; Uzgun, Senta; Kormann, Michael; Hasenpusch, Guenther; Maucksch, Christof; Rudolph, Carsten
2009-12-31
phi C31 integrase has emerged as a potent tool for achieving long-term gene expression in different tissues. The present study aimed at optimizing elements of phi C31 integrase system for alveolar type II cells. Luciferase and beta-galactosidase activities were measured at different time points post transfection. 5-Aza-2'deoxycytidine (AZA) and trichostatin A (TSA) were used to inhibit DNA methyltransferase and histone deacetylase complex (HDAC) respectively. In A549 cells, expression of the integrase using a CMV promoter resulted in highest integrase activity, whereas in MLE12 cells, both CAG and CMV promoter were equally effective. Effect of polyA site was observed only in A549 cells, where replacement of SV40 polyA by bovine growth hormone (BGH) polyA site resulted in an enhancement of integrase activity. Addition of a C-terminal SV40 nuclear localization signal (NLS) did not result in any significant increase in integrase activity. Long-term expression studies with AZA and TSA, provided evidence for post-integrative gene silencing. In MLE12 cells, both DNA methylases and HDACs played a significant role in silencing, whereas in A549 cells, it could be attributed majorly to HDAC activity. Donor plasmids comprising cellular promoters ubiquitin B (UBB), ubiquitin C (UCC) and elongation factor 1 alpha (EF1 alpha) in an improved backbone prevented post-integrative gene silencing. In contrast to A549 and MLE12 cells, no silencing could be observed in human bronchial epithelial cells, BEAS-2B. Donor plasmid coding for murine erythropoietin under the EF1 alpha promoter when combined with phi C31 integrase resulted in higher long-term erythropoietin expression and subsequently higher hematocrit levels in mice after intravenous delivery to the lungs. These results provide evidence for cell specific post integrative gene silencing with C31 integrase and demonstrate the pivotal role of donor plasmid in long-term expression attained with this system.
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Cattavarayane, Sandhanakrishnan; Palovuori, Riitta; Tanjore Ramanathan, Jayendrakishore; Manninen, Aki
2015-02-27
The growth properties and self-renewal capacity of embryonic stem (ES) cells are regulated by their immediate microenvironment such as the extracellular matrix (ECM). Integrins, a central family of cellular ECM receptors, have been implicated in these processes but their specific role in ES cell self-renewal remains unclear. Here we have studied the effects of different ECM substrates and integrins in mouse ES cells in the absence of Leukemia Inhibitory Factor (LIF) using short-term assays as well as long-term cultures. Removal of LIF from ES cell culture medium induced morphological differentiation of ES cells into polarized epistem cell-like cells. These cells maintained epithelial morphology and expression of key stemness markers for at least 10 passages in the absence of LIF when cultured on laminin, fibronectin or collagen IV substrates. The specific functional roles of α6-, αV- and β1-integrin subunits were dissected using stable lentivirus-mediated RNAi methodology. β1-integrins were required for ES cell survival in long-term cultures and for the maintenance of stem cell marker expression. Inhibition of α6-integrin expression compromised self-renewal on collagen while αV-integrins were required for robust ES cell adhesion on laminin. Analysis of the stemness marker expression revealed subtle differences between α6- and αV-depleted ES cells but the expression of both was required for optimal self-renewal in long-term ES cell cultures. In the absence of LIF, long-term ES cell cultures adapt an epistem cell-like epithelial phenotype and retain the expression of multiple stem cell markers. Long-term maintenance of such self-renewing cultures depends on the expression of β1-, α6- and αV-integrins.
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Yu, Tae Jun; Hong, Kyung-Han; Choi, Hyun-Gyug; Sung, Jae Hee; Choi, Il Woo; Ko, Do-Kyeong; Lee, Jongmin; Kim, Junwon; Kim, Dong Eon; Nam, Chang Hee
2007-06-25
We demonstrate a long-term operation with reduced phase noise in the carrier-envelope-phase (CEP) stabilization process by employing a double feedback loop and an improved signal detection in the direct locking technique [Opt. Express 13, 2969 (2005)]. A homodyne balanced detection method is employed for efficiently suppressing the dc noise in the f-2f beat signal, which is converted into the CEP noise in the direct locking loop working at around zero carrier-envelope offset frequency (f(ceo)). In order to enhance the long-term stability, we have used the double feedback scheme that modulates both the oscillator pump power for a fast control and the intracavity-prism insertion depth for a slow and high-dynamic-range control. As a result, the in-loop phase jitter is reduced from 50 mrad of the previous result to 29 mrad, corresponding to 13 as in time scale, and the long-term stable operation is achieved for more than 12 hours.
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Creep-rupture reliability analysis
NASA Technical Reports Server (NTRS)
Peralta-Duran, A.; Wirsching, P. H.
1984-01-01
A probabilistic approach to the correlation and extrapolation of creep-rupture data is presented. Time temperature parameters (TTP) are used to correlate the data, and an analytical expression for the master curve is developed. The expression provides a simple model for the statistical distribution of strength and fits neatly into a probabilistic design format. The analysis focuses on the Larson-Miller and on the Manson-Haferd parameters, but it can be applied to any of the TTP's. A method is developed for evaluating material dependent constants for TTP's. It is shown that optimized constants can provide a significant improvement in the correlation of the data, thereby reducing modelling error. Attempts were made to quantify the performance of the proposed method in predicting long term behavior. Uncertainty in predicting long term behavior from short term tests was derived for several sets of data. Examples are presented which illustrate the theory and demonstrate the application of state of the art reliability methods to the design of components under creep.
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Kim, Young-Je; Choi, Myung-Sook; Woo, Je Tae; Jeong, Mi Ji; Kim, Sang Ryong; Jung, Un Ju
2017-08-01
We evaluated the long-term effect of low-dose nobiletin (NOB), a polymethoxylated flavone, on diet-induced obesity and related metabolic disturbances. C57BL/6J mice were fed a high-fat diet (HFD, 45 kcal% fat) with or without NOB (0.02%, w/w) for 16 weeks. NOB did not alter food intake or body weight. Despite increases in fatty acid oxidation-related genes expression and enzymes activity in adipose tissue, NOB did not affect adipose tissue weight due to simultaneous increases in lipogenic genes expression and fatty acid synthase activity. However, NOB significantly decreased not only pro-inflammatory genes expression in adipose tissue but also proinflammatory cytokine levels in plasma. NOB-supplemented mice also showed improved glucose tolerance and insulin resistance, along with decreased levels of plasma insulin, free fatty acids, total cholesterol, non-HDL-cholesterol, and apolipoprotein B. In addition, NOB caused significant decreases in hepatic lipid droplet accumulation and triglyceride content by activating hepatic fatty acid oxidation-related enzymes. Hepatic proinflammatory TNF-α mRNA expression, collagen accumulation, and plasma levels of aminotransferases, liver damage indicators, were also significantly lower in NOB-supplemented mice. These findings suggest that long-term supplementation with low-dose NOB can protect against HFD-induced inflammation, insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease, without ameliorating adiposity. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Niedoszytko, Marek; Bruinenberg, Marcel; de Monchy, Jan; Weersma, Rinse K; Wijmenga, Cisca; Jassem, Ewa; Elberink, Joanne N G Oude
2011-06-01
Insect venom immunotherapy (VIT) is the only causative treatment of insect venom allergy (IVA). The immunological mechanism(s) responsible for long-term protection achieved by VIT are largely unknown. A better understanding is relevant for improving the diagnosis, prediction of anaphylaxis, and monitoring and simplifying treatment of IVA. To find genes that are differentially expressed during the maintenance phase of VIT and after stopping, to get clues about the pathways involved in the long-term protective effect of immunotherapy. Whole genome gene expression analysis was performed on RNA samples from 50 patients treated with VIT and 43 healthy controls. Patients were divided into three groups: (1) before the start of VIT; (2) on maintenance phase of VIT for at least 3 years still receiving injections; and (3) after VIT. Of all 48,804 probes present in the array, 48,773 transcripts had sufficient data for further analysis. The list of genes that were differentially expressed (at least log2 FC > 2; P < .05 corrected for multiple testing) during the maintenance phase of VIT as well as after successful VIT contains 89 entities. The function of these genes affects cell signaling, cell differentiation, and ion transport. This study shows that a group of genes is differentially expressed both during and after VIT in comparison with gene expression in patients before VIT. Although the results of this study should be confirmed prospectively, the relevance of these findings is supported by the fact that they are related to putative mechanisms of immunotherapy. Copyright © 2011 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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Viability of long-term gene therapy in the cochlea.
Atkinson, Patrick J; Wise, Andrew K; Flynn, Brianna O; Nayagam, Bryony A; Richardson, Rachael T
2014-04-22
Gene therapy has been investigated as a way to introduce a variety of genes to treat neurological disorders. An important clinical consideration is its long-term effectiveness. This research aims to study the long-term expression and effectiveness of gene therapy in promoting spiral ganglion neuron survival after deafness. Adenoviral vectors modified to express brain derived neurotrophic factor or neurotrophin-3 were unilaterally injected into the guinea pig cochlea one week post ototoxic deafening. After six months, persistence of gene expression and significantly greater neuronal survival in neurotrophin-treated cochleae compared to the contralateral cochleae were observed. The long-term gene expression observed indicates that gene therapy is potentially viable; however the degeneration of the transduced cells as a result of the original ototoxic insult may limit clinical effectiveness. With further research aimed at transducing stable cochlear cells, gene therapy may be an efficacious way to introduce neurotrophins to promote neuronal survival after hearing loss.
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Does stress remove the HDAC brakes for the formation and persistence of long-term memory?
White, André O; Wood, Marcelo A
2014-07-01
It has been known for numerous decades that gene expression is required for long-lasting forms of memory. In the past decade, the study of epigenetic mechanisms in memory processes has revealed yet another layer of complexity in the regulation of gene expression. Epigenetic mechanisms do not only provide complexity in the protein regulatory complexes that control coordinate transcription for specific cell function, but the epigenome encodes critical information that integrates experience and cellular history for specific cell functions as well. Thus, epigenetic mechanisms provide a unique mechanism of gene expression regulation for memory processes. This may be why critical negative regulators of gene expression, such as histone deacetylases (HDACs), have powerful effects on the formation and persistence of memory. For example, HDAC inhibition has been shown to transform a subthreshold learning event into robust long-term memory and also generate a form of long-term memory that persists beyond the point at which normal long-term memory fails. A key question that is explored in this review, from a learning and memory perspective, is whether stress-dependent signaling drives the formation and persistence of long-term memory via HDAC-dependent mechanisms. Copyright © 2013 Elsevier Inc. All rights reserved.
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Does stress remove the HDAC brakes for the formation and persistence of long-term memory?
White, André O.; Wood, Marcelo A.
2013-01-01
It has been known for numerous decades that gene expression is required for long-lasting forms of memory. In the past decade, the study of epigenetic mechanisms in memory processes has revealed yet another layer of complexity in the regulation of gene expression. Epigenetic mechanisms do not only provide complexity in the protein regulatory complexes that control coordinate transcription for specific cell function, but the epigenome encodes critical information that integrates experience and cellular history for specific cell functions as well. Thus, epigenetic mechanisms provide a unique mechanism of gene expression regulation for memory processes. This may be why critical negative regulators of gene expression, such as histone deacetylases (HDACs), have powerful effects on the formation and persistence of memory. For example, HDAC inhibition has been shown to transform a subthreshold learning event into robust long-term memory and also generate a form of long-term memory that persists beyond the point at which normal long-term memory fails. A key question that is explored in this review, from a learning and memory perspective, is whether stress-dependent signaling drives the formation and persistence of long-term memory via HDAC-dependent mechanisms. PMID:24149059
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Zhou, Zhike; Liu, Tingting; Sun, Xiaoyu; Mu, Xiaopeng; Zhu, Gang; Xiao, Ting; Zhao, Mei; Zhao, Chuansheng
2017-03-30
It has been showed that enriched environment (EE) enhances the hippocampal neurogenesis and improves the cognitive impairments, accompanied by the increased expressions of stromal cell-derived factor-1 (SDF-1) in adult rats of temporal lobe epilepsy (TLE). We examined whether the enhanced neurogenesis and improved cognitive functions induced by EE following seizures were mediated by SDF-1/CXCR4 pathway. Therefore, we investigated the effects of the EE combined with CXCR4 antagonist AMD3100 on neurogenesis, cognitive functions and the long-term seizure activity in the TLE model. Adult rats were randomly assigned as control rats, rats treated with EE, rats subjected to status epilepticus (SE), post-SE rats treated with EE, AMD3100 or EE combined with AMD3100 respectively. We used immunofluorescence staining to analyze the hippocampal neurogenesis and Nissl staining to evaluate hippocampal damage. Electroencephalography was used to measure the frequency and mean duration of spontaneous seizures. Cognitive function was evaluated by Morris water maze test. EE treatment significantly, as well as improved cognitive impairments and decreased long-term seizure activity, and that these effects might be mediated through SDF-1/CXCR4 pathway during the chronic stage of TLE. Although AMD3100 reversed the effect of EE on neurogenesis, it did not abolish the cognitive improvement induced by EE following seizures. More importantly, EE combined with AMD3100 treatment significantly suppressed long-term seizure activity, which provided promising evidences to treat TLE. Copyright © 2017 Elsevier B.V. All rights reserved.
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Kennedy, Bruce C.; Dimova, Jiva G.; Siddappa, Asha J. M.; Tran, Phu V.; Gewirtz, Jonathan C.; Georgieff, Michael K.
2014-01-01
Background: Gestational iron deficiency in humans and rodents produces long-term deficits in cognitive and socioemotional function and alters expression of plasticity genes in the hippocampus that persist despite iron treatment. Prenatal choline supplementation improves cognitive function in other rodent models of developmental insults. Objective: The objective of this study was to determine whether prenatal choline supplementation prevents the long-term effects of fetal-neonatal iron deficiency on cognitive and social behaviors and hippocampal gene expression. Methods: Pregnant rat dams were administered an iron-deficient (2–6 g/kg iron) or iron-sufficient (IS) (200 g/kg iron) diet from embryonic day (E) 3 to postnatal day (P) 7 with or without choline supplementation (5 g/kg choline chloride, E11–18). Novel object recognition (NOR) in the test vs. acquisition phase, social approach (SA), and hippocampal mRNA expression were compared at P65 in 4 male adult offspring groups: formerly iron deficient (FID), FID with choline supplementation (FID-C), IS, and IS with choline supplementation. Results: Relative to the intact NOR in IS rats (acquisition: 47.9%, test: 60.2%, P < 0.005), FID adult rats had impaired recognition memory at the 6-h delay (acquisition: 51.4%, test: 55.1%, NS), accompanied by a 15% reduction in hippocampal expression of brain-derived neurotrophic factor (Bdnf) (P < 0.05) and myelin basic protein (Mbp) (P < 0.05). Prenatal choline supplementation in FID rats restored NOR (acquisition: 48.8%, test: 64.4%, P < 0.0005) and increased hippocampal gene expression (FID-C vs. FID group: Bdnf, Mbp, P < 0.01). SA was also reduced in FID rats (P < 0.05 vs. IS rats) but was only marginally improved by prenatal choline supplementation. Conclusions: Deficits in recognition memory, but not social behavior, resulting from gestational iron deficiency are attenuated by prenatal choline supplementation, potentially through preservation of hippocampal Bdnf and Mbp expression. Prenatal choline supplementation may be a promising adjunct treatment for fetal-neonatal iron deficiency. PMID:25332485
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Zanin, M P; Hellström, M; Shepherd, R K; Harvey, A R; Gillespie, L N
2014-09-26
Spiral ganglion neurons (SGNs), the target cells of the cochlear implant, undergo gradual degeneration following loss of the sensory epithelium in deafness. The preservation of a viable population of SGNs in deafness can be achieved in animal models with exogenous application of neurotrophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3. For translation into clinical application, a suitable delivery strategy that provides ongoing neurotrophic support and promotes long-term SGN survival is required. Cell-based neurotrophin treatment has the potential to meet the specific requirements for clinical application, and we have previously reported that Schwann cells genetically modified to express BDNF can support SGN survival in deafness for 4 weeks. This study aimed to investigate various parameters important for the development of a long-term cell-based neurotrophin treatment to support SGN survival. Specifically, we investigated different (i) cell types, (ii) gene transfer methods and (iii) neurotrophins, in order to determine which variables may provide long-term neurotrophin expression and which, therefore, may be the most effective for supporting long-term SGN survival in vivo. We found that fibroblasts that were nucleofected to express BDNF provided the most sustained neurotrophin expression, with ongoing BDNF expression for at least 30 weeks. In addition, the secreted neurotrophin was biologically active and elicited survival effects on SGNs in vitro. Nucleofected fibroblasts may therefore represent a method for safe, long-term delivery of neurotrophins to the deafened cochlea to support SGN survival in deafness. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
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Kim, Jennifer E; Patel, Mira A; Mangraviti, Antonella; Kim, Eileen S; Theodros, Debebe; Velarde, Esteban; Liu, Ann; Sankey, Eric W; Tam, Ada; Xu, Haiying; Mathios, Dimitrios; Jackson, Christopher M; Harris-Bookman, Sarah; Garzon-Muvdi, Tomas; Sheu, Mary; Martin, Allison M; Tyler, Betty M; Tran, Phuoc T; Ye, Xiaobu; Olivi, Alessandro; Taube, Janis M; Burger, Peter C; Drake, Charles G; Brem, Henry; Pardoll, Drew M; Lim, Michael
2017-01-01
Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme. Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes (TIL) can express multiple checkpoints, and expression of ≥2 checkpoints corresponds to a more exhausted T-cell phenotype. We investigate TIM-3 expression in a glioma model and the antitumor efficacy of TIM-3 blockade alone and in combination with anti-PD-1 and SRS. C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (i) control, (ii) SRS, (iii) anti-PD-1 antibody, (iv) anti-TIM-3 antibody, (v) anti-PD-1 + SRS, (vi) anti-TIM-3 + SRS, (vii) anti-PD-1 + anti-TIM-3, and (viii) anti-PD-1 + anti-TIM-3 + SRS. Survival and immune activation were assessed. Dual therapy with anti-TIM-3 antibody + SRS or anti-TIM-3 + anti-PD-1 improved survival compared with anti-TIM-3 antibody alone. Triple therapy resulted in 100% overall survival (P < 0.05), a significant improvement compared with other arms. Long-term survivors demonstrated increased immune cell infiltration and activity and immune memory. Finally, positive staining for TIM-3 was detected in 7 of 8 human GBM samples. This is the first preclinical investigation on the effects of dual PD-1 and TIM-3 blockade with radiation. We also demonstrate the presence of TIM-3 in human glioblastoma multiforme and provide preclinical evidence for a novel treatment combination that can potentially result in long-term glioma survival and constitutes a novel immunotherapeutic strategy for the treatment of glioblastoma multiforme. Clin Cancer Res; 23(1); 124-36. ©2016 AACR. ©2016 American Association for Cancer Research.
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Iso, Yoshitaka; Spees, Jeffrey L.; Serrano, Claudia; Bakondi, Benjamin; Pochampally, Radhika; Song, Yao-Hua; Sobel, Burton E.; Delafontaine, Patrick; Prockop, Darwin J.
2007-01-01
The aim of this study was to determine whether intravenously-administered multipotent stromal cells from human bone marrow (hMSCs) can improve cardiac function after myocardial infarction (MI) without long-term engraftment and therefore whether transitory paracrine effects or secreted factors are responsible for the benefit conferred. hMSCs were injected systemically into immunodeficient mice with acute MI. Cardiac function and fibrosis after MI in the hMSC-treated group was significantly improved compared with that in controls. However, despite the cardiac improvement, there was no evident hMSC engraftment in the heart 3 weeks after MI. Microarray assays and ELISAs demonstrated that multiple protective factors were expressed and secreted from the hMSCs in culture. Factors secreted by hMSCs prevented cell death of cultured cardiomyocytes and endothelial cells under conditions that mimicked tissue ischemia. The favorable effects of hMSCs appear to reflect the impact of secreted factors rather than engraftment, differentiation, or cell fusion. PMID:17257581
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Paradiso, A; Rabinovich, M; Vallejo, C; Machiavelli, M; Romero, A; Perez, J; Lacava, J; Cuevas, M A; Rodriquez, R; Leone, B; Sapia, M G; Simone, G; De Lena, M
1996-12-20
In a series of 71 patients with advanced colorectal cancer treated with biochemically modulated 5-fluorouracil (5-FU) and methotrexate (MTX), we investigated the relationship between the proliferating-cell nuclear antigen (PCNA) (PC10) and p53 (Pab1801) primary-tumor immunohistochemical expression with respect to clinical response and long-term prognosis. Nuclear p53 expression was demonstrated in 44% of samples (any number of positive tumor cells) while all tumors showed a certain degree of PCNA immunostaining. PCNA immunostaining was correlated with histopathologic grade and p53 expression, while p53 was not correlated with any of the parameters considered. The probability of clinical response to biochemically modulated 5-FU was independent of p53 and PCNA expression. p53 expression (all cut-off values) was not associated with short- or long-term clinical prognosis, whereas patients with higher PCNA primary-tumor expression showed longer survival from treatment and survival from diagnosis, according to univariate and multivariate analysis, particularly in the sub-set of colon-cancer patients. We conclude that the clinical response of advanced-colorectal-cancer patients to biochemically modulated 5-FU and MTX cannot be predicted by PCNA and p53 primary-tumor expression, but high PCNA expression appears to be independently related to long-term prognosis.
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Krukowski, Karen; Feng, Xi; Paladini, Maria Serena; Chou, Austin; Sacramento, Kristen; Grue, Katherine; Riparip, Lara-Kirstie; Jones, Tamako; Campbell-Beachler, Mary; Nelson, Gregory; Rosi, Susanna
2018-05-18
Microglia are the main immune component in the brain that can regulate neuronal health and synapse function. Exposure to cosmic radiation can cause long-term cognitive impairments in rodent models thereby presenting potential obstacles for astronauts engaged in deep space travel. The mechanism/s for how cosmic radiation induces cognitive deficits are currently unknown. We find that temporary microglia depletion, one week after cosmic radiation, prevents the development of long-term memory deficits. Gene array profiling reveals that acute microglia depletion alters the late neuroinflammatory response to cosmic radiation. The repopulated microglia present a modified functional phenotype with reduced expression of scavenger receptors, lysosome membrane protein and complement receptor, all shown to be involved in microglia-synapses interaction. The lower phagocytic activity observed in the repopulated microglia is paralleled by improved synaptic protein expression. Our data provide mechanistic evidence for the role of microglia in the development of cognitive deficits after cosmic radiation exposure.
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Barmeyer, Christian; Schumann, Michael; Meyer, Tim; Zielinski, Christina; Zuberbier, Torsten; Siegmund, Britta; Schulzke, Jörg-Dieter; Daum, Severin; Ullrich, Reiner
2017-01-01
Irritable bowel syndrome (IBS) is common but therapies are unsatisfactory. Food is often suspected as cause by patients, but diagnostic procedures, apart from allergy testing, are limited. Based on the hypothesis of non-celiac wheat sensitivity (WS) in a subgroup of IBS patients, we tested the long-term response to a gluten-free diet (GFD) and investigated HLA-DQ2 or -DQ8 expression as a diagnostic marker for WS in diarrhea-dominant (IBS-D) and mixed-type IBS (IBS-M). The response to a GFD served as reference test for WS and HLA-DQ2/8 expression was determined as index test. Patients were classified as responders if they reported complete or considerable relief of IBS symptoms on at least 75 % of weeks over a 4-month period of gluten-free diet. Established questionnaires (IBS-Quality of Life (IBS-QoL), IBS Symptom Severity Scale (IBS-SSS), European Quality of Life-5 Dimensions (EQ-5D)) were used for secondary outcome measures. Thirty-five patients finished the study. Of these, 12 (34 %) were responders and classified as having WS (95 % CI 21-51 %). HLA-DQ2/8 expression had a specificity of 52 % (95 % CI 33-71 %) and sensitivity of 25 % (95 % CI 8-54 %) for WS. Responders showed improvement in quality of life and symptom scores. At 1-year follow-up, all responders and 55 % of non-responders were still on GFD and reported symptom relief. Using strict criteria as recommended for IBS studies, about one third of patients with IBS-D or IBS-M are wheat sensitive, with a similar proportion in both IBS types. Expression of HLA-DQ2/8 is not useful as diagnostic marker for WS. Long-term adherence to a GFD is high and can sustain symptomatic improvement.
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Choi, Myung-Sook; Park, Hyo Jin; Kim, Sang Ryong; Kim, Do Yeon; Jung, Un Ju
2017-12-01
This study evaluated whether long-term supplementation with dietary yerba mate has beneficial effects on adiposity and its related metabolic dysfunctions in diet-induced obese mice. C57BL/6J mice were randomly divided into two groups and fed their respective experimental diets for 16 weeks as follows: (1) control group fed with high-fat diet (HFD) and (2) mate group fed with HFD plus yerba mate. Dietary yerba mate increased energy expenditure and thermogenic gene mRNA expression in white adipose tissue (WAT) and decreased fatty acid synthase (FAS) mRNA expression in WAT, which may be linked to observed decreases in body weight, WAT weight, epididymal adipocyte size, and plasma leptin level. Yerba mate also decreased levels of plasma lipids (free fatty acids, triglycerides, and total cholesterol) and liver aminotransferase enzymes, as well as the accumulation of hepatic lipid droplets and lipid content by inhibiting the activities of hepatic lipogenic enzymes, such as FAS and phosphatidate phosphohydrolase, and increasing fecal lipid excretion. Moreover, yerba mate decreased the levels of plasma insulin as well as the homeostasis model assessment of insulin resistance, and improved glucose tolerance. Circulating levels of gastric inhibitory polypeptide and resistin were also decreased in the mate group. These findings suggest that long-term supplementation of dietary yerba mate may be beneficial for improving diet-induced adiposity, insulin resistance, dyslipidemia, and hepatic steatosis.
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Catterson, James H; Khericha, Mobina; Dyson, Miranda C; Vincent, Alec J; Callard, Rebecca; Haveron, Steven M; Rajasingam, Arjunan; Ahmad, Mumtaz; Partridge, Linda
2018-06-04
Intermittent fasting (IF) can improve function and health during aging in laboratory model organisms, but the mechanisms at work await elucidation. We subjected fruit flies (Drosophila melanogaster) to varying degrees of IF and found that just one month of a 2-day fed:5-day fasted IF regime at the beginning of adulthood was sufficient to extend lifespan. This long-lasting, beneficial effect of early IF was not due to reduced fecundity. Starvation resistance and resistance to oxidative and xenobiotic stress were increased after IF. Early-life IF also led to higher lipid content in 60-day-old flies, a potential explanation for increased longevity. Guts of flies 40 days post-IF showed a significant reduction in age-related pathologies and improved gut barrier function. Improved gut health was also associated with reduced relative bacterial abundance. Early IF thus induced profound long-term changes. Pharmacological and genetic epistasis analysis showed that IF acted independently of the TOR pathway because rapamycin and IF acted additively to extend lifespan, and global expression of a constitutively active S6K did not attenuate the IF-induced lifespan extension. We conclude that short-term IF during early life can induce long-lasting beneficial effects, with robust increase in lifespan in a TOR-independent manner, probably at least in part by preserving gut health. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.
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Hellmich, Helen L.; Eidson, Kristine; Cowart, Jeremy; Crookshanks, Jeanna; Boone, Deborah K.; Shah, Syed; Uchida, Tatsuo; DeWitt, Douglas S.; Prough, Donald S.
2008-01-01
Increases of synaptically released zinc and intracellular accumulation of zinc in hippocampal neurons after traumatic or ischemic brain injury is neurotoxic and chelation of zinc has been shown to reduce neurodegeneration. Although our previous studies showed that zinc chelation in traumatically brain-injured rats correlated with an increase in whole-brain expression of several neuroprotective genes and reduced numbers of apoptotic neurons, the effect on functional outcome has not been determined, and the question of whether this treatment may actually be clinically relevant has not been answered. In the present study, we show that treatment of TBI rats with the zinc chelator calcium EDTA reduces the numbers of injured, Fluoro-Jade- positive neurons in the rat hippocampus 24 hours after injury but does not improve neurobehavioral outcome (spatial memory deficits) two weeks post-injury. Our data suggest that zinc chelation, despite providing short-term histological neuroprotection, fails to improve long-term functional outcome, perhaps because long-term disruptions in homeostatic levels of zinc adversely influence hippocampus-dependent spatial memory. PMID:18556117
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Lee, Min-Young; Yu, Ji Hea; Kim, Ji Yeon; Seo, Jung Hwa; Park, Eun Sook; Kim, Chul Hoon; Kim, Hyongbum; Cho, Sung-Rae
2013-01-01
Housing animals in an enriched environment (EE) enhances behavioral function. However, the mechanism underlying this EE-mediated functional improvement and the resultant changes in gene expression have yet to be elucidated. We attempted to investigate the underlying mechanisms associated with long-term exposure to an EE by evaluating gene expression patterns. We housed 6-week-old CD-1 (ICR) mice in standard cages or an EE comprising a running wheel, novel objects, and social interaction for 2 months. Motor and cognitive performances were evaluated using the rotarod test and passive avoidance test, and gene expression profile was investigated in the cerebral hemispheres using microarray and gene set enrichment analysis (GSEA). In behavioral assessment, an EE significantly enhanced rotarod performance and short-term working memory. Microarray analysis revealed that genes associated with neuronal activity were significantly altered by an EE. GSEA showed that genes involved in synaptic transmission and postsynaptic signal transduction were globally upregulated, whereas those associated with reuptake by presynaptic neurotransmitter transporters were downregulated. In particular, both microarray and GSEA demonstrated that EE exposure increased opioid signaling, acetylcholine release cycle, and postsynaptic neurotransmitter receptors but decreased Na+ / Cl- -dependent neurotransmitter transporters, including dopamine transporter Slc6a3 in the brain. Western blotting confirmed that SLC6A3, DARPP32 (PPP1R1B), and P2RY12 were largely altered in a region-specific manner. An EE enhanced motor and cognitive function through the alteration of synaptic activity-regulating genes, improving the efficient use of neurotransmitters and synaptic plasticity by the upregulation of genes associated with postsynaptic receptor activity and downregulation of presynaptic reuptake by neurotransmitter transporters.
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Romero, Roberto; Tarca, Adi L; Chaemsaithong, Piya; Miranda, Jezid; Chaiworapongsa, Tinnakorn; Jia, Hui; Hassan, Sonia S; Kalita, Cynthia A; Cai, Juan; Yeo, Lami; Lipovich, Leonard
2014-09-01
To identify differentially expressed long non-coding RNA (lncRNA) genes in human myometrium in women with spontaneous labor at term. Myometrium was obtained from women undergoing cesarean deliveries who were not in labor (n = 19) and women in spontaneous labor at term (n = 20). RNA was extracted and profiled using an Illumina® microarray platform. We have used computational approaches to bound the extent of long non-coding RNA representation on this platform, and to identify co-differentially expressed and correlated pairs of long non-coding RNA genes and protein-coding genes sharing the same genomic loci. We identified co-differential expression and correlation at two genomic loci that contain coding-lncRNA gene pairs: SOCS2-AK054607 and LMCD1-NR_024065 in women in spontaneous labor at term. This co-differential expression and correlation was validated by qRT-PCR, an experimental method completely independent of the microarray analysis. Intriguingly, one of the two lncRNA genes differentially expressed in term labor had a key genomic structure element, a splice site, that lacked evolutionary conservation beyond primates. We provide, for the first time, evidence for coordinated differential expression and correlation of cis-encoded antisense lncRNAs and protein-coding genes with known as well as novel roles in pregnancy in the myometrium of women in spontaneous labor at term.
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Soulé, Jonathan; Penke, Zsuzsa; Kanhema, Tambudzai; Alme, Maria Nordheim; Laroche, Serge; Bramham, Clive R.
2008-01-01
Long-term recognition memory requires protein synthesis, but little is known about the coordinate regulation of specific genes. Here, we examined expression of the plasticity-associated immediate early genes (Arc, Zif268, and Narp) in the dentate gyrus following long-term object-place recognition learning in rats. RT-PCR analysis from dentate gyrus tissue collected shortly after training did not reveal learning-specific changes in Arc mRNA expression. In situ hybridization and immunohistochemistry were therefore used to assess possible sparse effects on gene expression. Learning about objects increased the density of granule cells expressing Arc, and to a lesser extent Narp, specifically in the dorsal blade of the dentate gyrus, while Zif268 expression was elevated across both blades. Thus, object-place recognition triggers rapid, blade-specific upregulation of plasticity-associated immediate early genes. Furthermore, Western blot analysis of dentate gyrus homogenates demonstrated concomitant upregulation of three postsynaptic density proteins (Arc, PSD-95, and α-CaMKII) with key roles in long-term synaptic plasticity and long-term memory. PMID:19190776
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Molecular brake pad hypothesis: pulling off the brakes for emotional memory
Vogel-Ciernia, Annie
2015-01-01
Under basal conditions histone deacetylases (HDACs) and their associated co-repressor complexes serve as molecular ‘brake pads’ to prevent the gene expression required for long-term memory formation. Following a learning event, HDACs and their co-repressor complexes are removed from a subset of specific gene promoters, allowing the histone acetylation and active gene expression required for long-term memory formation. Inhibition of HDACs increases histone acetylation, extends gene expression profiles, and allows for the formation of persistent long-term memories for training events that are otherwise forgotten. We propose that emotionally salient experiences have utilized this system to form strong and persistent memories for behaviorally significant events. Consequently, the presence or absence of HDACs at a selection of specific gene promoters could serve as a critical barrier for permitting the formation of long-term memories. PMID:23096102
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Tsai, Sheng-Feng; Ku, Nai-Wen; Wang, Tzu-Feng; Yang, Yan-Hsiang; Shih, Yao-Hsiang; Wu, Shih-Ying; Lee, Chu-Wan; Yu, Megan; Yang, Ting-Ting; Kuo, Yu-Min
2018-05-07
Aging impairs hippocampal neuroplasticity and hippocampus-related learning and memory. In contrast, exercise training is known to improve hippocampal neuronal function. However, whether exercise is capable of restoring memory function in old animals is less clear. Here, we investigated the effects of exercise on the hippocampal neuroplasticity and memory functions during aging. Young (3 months), middle-aged (9-12 months), and old (18 months) mice underwent moderate-intensity treadmill running training for 6 weeks, and their hippocampus-related learning and memory, and the plasticity of their CA1 neurons was evaluated. The memory performance (Morris water maze and novel object recognition tests), and dendritic complexity (branch and length) and spine density of their hippocampal CA1 neurons decreased as their age increased. The induction and maintenance of high-frequency stimulation-induced long-term potentiation in the CA1 area and the expressions of neuroplasticity-related proteins were not affected by age. Treadmill running increased CA1 neuron long-term potentiation and dendritic complexity in all three age groups, and it restored the learning and memory ability in middle-aged and old mice. Furthermore, treadmill running upregulated the hippocampal expressions of brain-derived neurotrophic factor and monocarboxylate transporter-4 in middle-aged mice, glutamine synthetase in old mice, and full-length TrkB in middle-aged and old mice. The hippocampus-related memory function declines from middle age, but long-term moderate-intensity running effectively increased hippocampal neuroplasticity and memory in mice of different ages, even when the memory impairment had progressed to an advanced stage. Thus, long-term, moderate intensity exercise training might be a way of delaying and treating aging-related memory decline. © 2018 S. Karger AG, Basel.
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Liu, Xiangrong; Liu, Jia; Zhao, Shangfeng; Zhang, Haiyue; Cai, Wei; Cai, Mengfei; Ji, Xunming; Leak, Rehana K; Gao, Yanqin; Chen, Jun; Hu, Xiaoming
2016-02-01
Interleukin-4 (IL-4) is a unique cytokine that may contribute to brain repair by regulating microglia/macrophage functions. Thus, we examined the effect of IL-4 on long-term recovery and microglia/macrophage polarization in 2 well-established stroke models. Transient middle cerebral artery occlusion or permanent distal middle cerebral artery occlusion was induced in wild-type and IL-4 knockout C57/BL6 mice. In a separate cohort of wild-type animals, IL-4 (60 ng/d for 7 days) or vehicle was infused into the cerebroventricle after transient middle cerebral artery occlusion. Behavioral outcomes were assessed by the Rotarod, corner, foot fault, and Morris water maze tests. Neuronal tissue loss was verified by 2 independent neuron markers. Markers of classically activated (M1) and alternatively activated (M2) microglia were assessed by real-time polymerase chain reaction, immunofluorescence, and flow cytometry. Loss of IL-4 exacerbated sensorimotor deficits and impaired cognitive functions ≤21 days post injury. In contrast to the delayed deterioration of neurological functions, IL-4 deficiency increased neuronal tissue loss only in the acute phase (5 days) after stroke and had no impact on neuronal tissue loss 14 or 21 days post injury. Loss of IL-4 promoted expression of M1 microglia/macrophage markers and impaired expression of M2 markers at 5 and 14 days post injury. Administration of IL-4 into the ischemic brain also enhanced long-term functional recovery. The cytokine IL-4 improves long-term neurological outcomes after stroke, perhaps through M2 phenotype induction in microglia/macrophages. These results are the first to suggest that immunomodulation with IL-4 is a promising approach to promote long-term functional recovery after stroke. © 2016 American Heart Association, Inc.
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Van Lierde, K M; Mortier, G; Huysman, E; Vermeersch, H
2010-03-01
The purpose of the present case study was to determine the long-term impact of partial glossectomy (using the keyhole technique) on overall speech intelligibility and articulation in a Dutch-speaking child with Beckwith-Wiedemann syndrome (BWS). Furthermore the present study is meant as a contribution to the further delineation of the phonation, resonance, articulation and language characteristics and oral behaviour in a child with BWS. Detailed information on the speech and language characteristics of children with BWS may lead to better guidance of pediatric management programs. The child's speech was assessed 9 years after partial glossectomy with regard to ENT characteristics, overall intelligibility (perceptual consensus evaluation), articulation (phonetic and phonological errors), voice (videostroboscopy, vocal quality), resonance (perceptual, nasometric assessment), language (expressive and receptive) and oral behaviour. A class III malocclusion, an anterior open bite, diastema, overangulation of lower incisors and an enlarged but normal symmetric shaped tongue were present. The overall speech intelligibility improved from severely impaired (presurgical) to slightly impaired (5 months post-glossectomy) to normal (9 years postoperative). Comparative phonetic inventory showed a remarkable improvement of articulation. Nine years post-glossectomy three types of distortions seemed to predominate: a rhotacism and sigmatism and the substitution of the alveolar /z/. Oral behaviour, vocal characteristics and resonance were normal, but problems with expressive syntactic abilities were present. The long-term impact of partial glossectomy, using the keyhole technique (preserving the vascularity and the nervous input of the remaining intrinsic tongue muscles), on speech intelligibility, articulation, and oral behaviour in this Dutch-speaking child with congenital macroglossia can be regarded as successful. It is not clear how these expressive syntactical problems demonstrated in this child can be explained. Certainly they are not part of a more general developmental delay, hearing problems or cognitive malfunctioning. To what extent the presence of expressive syntactical problems is a possible aspect of the phenotypic spectrum of children with BWS is subject for further research. Multiple variables, both known and unknown can affect the long-term outcome after partial glossectomy in a child with BWS. The timing and type of the surgical technique, hearing and cognitive functioning are known variables in this study. But variables such as children's motivation, the contribution of the motor-oriented speech therapy, the parental articulation input and stimulation and other family, school and community factors are unknown and are all factors which can influence speech outcome after partial glossectomy. Detailed analyses in a greater number of subjects with BWS may help further illustrate the long-term impact of partial glossectomy. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.
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Mantha, Katarzyna; Laufer, Benjamin I; Singh, Shiva M
2014-01-01
Fetal alcohol spectrum disorder (FASD) is an umbrella term that refers to a wide range of behavioral and cognitive deficits resulting from prenatal alcohol exposure. It involves changes in brain gene expression that underlie lifelong FASD symptoms. How these changes are achieved from immediate to long-term effects, and how they are maintained, is unknown. We have used the C57BL/6J mouse to assess the dynamics of genomic alterations following binge alcohol exposure. Ethanol-exposed fetal (short-term effect) and adult (long-term effect) brains were assessed for gene expression and microRNA (miRNA) changes using Affymetrix mouse arrays. We identified 48 and 68 differentially expressed genes in short- and long-term groups, respectively. No gene was common between the 2 groups. Short-term (immediate) genes were involved in cellular compromise and apoptosis, which represent ethanol's toxic effects. Long-term genes were involved in various cellular functions, including epigenetics. Using quantitative RT-PCR, we confirmed the downregulation of long-term genes: Camk1g, Ccdc6, Egr3, Hspa5, and Xbp1. miRNA arrays identified 20 differentially expressed miRNAs, one of which (miR-302c) was confirmed. miR-302c was involved in an inverse relationship with Ccdc6. A network-based model involving altered genes illustrates the importance of cellular redox, stress and inflammation in FASD. Our results also support a critical role of apoptosis in FASD, and the potential involvement of miRNAs in the adaptation of gene expression following prenatal ethanol exposure. The ultimate molecular footprint involves inflammatory disease, neurological disease and skeletal and muscular disorders as major alterations in FASD. At the cellular level, these processes represent abnormalities in redox, stress and inflammation, with potential underpinnings to anxiety. © 2014 S. Karger AG, Basel.
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Doroudchi, M Mehdi; Greenberg, Kenneth P; Liu, Jianwen; Silka, Kimberly A; Boyden, Edward S; Lockridge, Jennifer A; Arman, A Cyrus; Janani, Ramesh; Boye, Shannon E; Boye, Sanford L; Gordon, Gabriel M; Matteo, Benjamin C; Sampath, Alapakkam P; Hauswirth, William W; Horsager, Alan
2011-01-01
Previous work established retinal expression of channelrhodopsin-2 (ChR2), an algal cation channel gated by light, restored physiological and behavioral visual responses in otherwise blind rd1 mice. However, a viable ChR2-based human therapy must meet several key criteria: (i) ChR2 expression must be targeted, robust, and long-term, (ii) ChR2 must provide long-term and continuous therapeutic efficacy, and (iii) both viral vector delivery and ChR2 expression must be safe. Here, we demonstrate the development of a clinically relevant therapy for late stage retinal degeneration using ChR2. We achieved specific and stable expression of ChR2 in ON bipolar cells using a recombinant adeno-associated viral vector (rAAV) packaged in a tyrosine-mutated capsid. Targeted expression led to ChR2-driven electrophysiological ON responses in postsynaptic retinal ganglion cells and significant improvement in visually guided behavior for multiple models of blindness up to 10 months postinjection. Light levels to elicit visually guided behavioral responses were within the physiological range of cone photoreceptors. Finally, chronic ChR2 expression was nontoxic, with transgene biodistribution limited to the eye. No measurable immune or inflammatory response was observed following intraocular vector administration. Together, these data indicate that virally delivered ChR2 can provide a viable and efficacious clinical therapy for photoreceptor disease-related blindness. PMID:21505421
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Early pathologic findings and long-term improvement in anti-Ma2-associated encephalitis.
Blumenthal, D T; Salzman, K L; Digre, K B; Jensen, R L; Dunson, W A; Dalmau, J
2006-07-11
A 67-year-old man sequentially developed anti-Ma2-associated paraneoplastic encephalitis (PNE) and contralateral herpes simplex encephalitis (HSE). Brain biopsy 1 month before HSE revealed extensive infiltrates of T cells, B cells, and plasma cells. Most T cells expressed the cytotoxic granule-associated protein TIA-1 and the membranolytic protein granzyme-B. Although recovery was thought to be unlikely, treatment of the PNE with corticosteroids and resection of the associated lung cancer resulted in dramatic improvement for 21 months.
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Jaén, Maria Luisa; Vilà, Laia; Elias, Ivet; Jimenez, Veronica; Rodó, Jordi; Maggioni, Luca; Ruiz-de Gopegui, Rafael; Garcia, Miguel; Muñoz, Sergio; Callejas, David; Ayuso, Eduard; Ferré, Tura; Grifoll, Iris; Andaluz, Anna; Ruberte, Jesus; Haurigot, Virginia; Bosch, Fatima
2017-09-15
Diabetes is a complex metabolic disease that exposes patients to the deleterious effects of hyperglycemia on various organs. Achievement of normoglycemia with exogenous insulin treatment requires the use of high doses of hormone, which increases the risk of life-threatening hypoglycemic episodes. We developed a gene therapy approach to control diabetic hyperglycemia based on co-expression of the insulin and glucokinase genes in skeletal muscle. Previous studies proved the feasibility of gene delivery to large diabetic animals with adeno-associated viral (AAV) vectors. Here, we report the long-term (∼8 years) follow-up after a single administration of therapeutic vectors to diabetic dogs. Successful, multi-year control of glycemia was achieved without the need of supplementation with exogenous insulin. Metabolic correction was demonstrated through normalization of serum levels of fructosamine, triglycerides, and cholesterol and remarkable improvement in the response to an oral glucose challenge. The persistence of vector genomes and therapeutic transgene expression years after vector delivery was documented in multiple samples from treated muscles, which showed normal morphology. Thus, this study demonstrates the long-term efficacy and safety of insulin and glucokinase gene transfer in large animals and especially the ability of the system to respond to the changes in metabolic needs as animals grow older.
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Transient HIF2A inhibition promotes satellite cell proliferation and muscle regeneration.
Xie, Liwei; Yin, Amelia; Nichenko, Anna S; Beedle, Aaron M; Call, Jarrod A; Yin, Hang
2018-06-01
The remarkable regeneration capability of skeletal muscle depends on the coordinated proliferation and differentiation of satellite cells (SCs). The self-renewal of SCs is critical for long-term maintenance of muscle regeneration potential. Hypoxia profoundly affects the proliferation, differentiation, and self-renewal of cultured myoblasts. However, the physiological relevance of hypoxia and hypoxia signaling in SCs in vivo remains largely unknown. Here, we demonstrate that SCs are in an intrinsic hypoxic state in vivo and express hypoxia-inducible factor 2A (HIF2A). HIF2A promotes the stemness and long-term homeostatic maintenance of SCs by maintaining their quiescence, increasing their self-renewal, and blocking their myogenic differentiation. HIF2A stabilization in SCs cultured under normoxia augments their engraftment potential in regenerative muscle. Conversely, HIF2A ablation leads to the depletion of SCs and their consequent regenerative failure in the long-term. In contrast, transient pharmacological inhibition of HIF2A accelerates muscle regeneration by increasing SC proliferation and differentiation. Mechanistically, HIF2A induces the quiescence and self-renewal of SCs by binding the promoter of the Spry1 gene and activating Spry1 expression. These findings suggest that HIF2A is a pivotal mediator of hypoxia signaling in SCs and may be therapeutically targeted to improve muscle regeneration.
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Mury, Fábio B; da Silva, Weber C; Barbosa, Nádia R; Mendes, Camila T; Bonini, Juliana S; Sarkis, Jorge Eduardo Souza; Cammarota, Martin; Izquierdo, Ivan; Gattaz, Wagner F; Dias-Neto, Emmanuel
2016-10-01
Phospholipase A2 (Pla2) is required for memory retrieval, and its inhibition in the hippocampus has been reported to impair memory acquisition in rats. Moreover, cognitive decline and memory deficits showed to be reduced in animal models after lithium treatment, prompting us to evaluate possible links between Pla2, lithium and memory. Here, we evaluated the possible modulation of Pla2 activity by a long-term treatment of rats with low doses of lithium and its impact in memory. Wistar rats were trained for the inhibitory avoidance task, treated with lithium for 100 days and tested for perdurability of long-term memory. Hippocampal samples were used for quantifying the expression of 19 brain-expressed Pla2 genes and for evaluating the enzymatic activity of Pla2 using group-specific radio-enzymatic assays. Our data pointed to a significant perdurability of long-term memory, which correlated with increased transcriptional and enzymatic activities of certain members of the Pla2 family (iPla2 and sPla2) after the chronic lithium treatment. Our data suggest new possible targets of lithium, add more information on its pharmacological activity and reinforce the possible use of low doses of lithium for the treatment of neurodegenerative conditions such as the Alzheimer's disease.
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HDAC3 Is a Critical Negative Regulator of Long-Term Memory Formation
McQuown, Susan C.; Barrett, Ruth M.; Matheos, Dina P.; Post, Rebecca J.; Rogge, George A.; Alenghat, Theresa; Mullican, Shannon E.; Jones, Steven; Rusche, James R.; Lazar, Mitchell A.; Wood, Marcelo A.
2011-01-01
Gene expression is dynamically regulated by chromatin modifications on histone tails, such as acetylation. In general, histone acetylation promotes transcription, whereas histone deacetylation negatively regulates transcription. The interplay between histone acetyl-transerases and histone deacetylases (HDACs) is pivotal for the regulation of gene expression required for long-term memory processes. Currently, very little is known about the role of individual HDACs in learning and memory. We examined the role of HDAC3 in long-term memory using a combined genetic and pharmacologic approach. We used HDAC3–FLOX genetically modified mice in combination with adeno-associated virus-expressing Cre recombinase to generate focal homozygous deletions of Hdac3 in area CA1 of the dorsal hippocampus. To complement this approach, we also used a selective inhibitor of HDAC3, RGFP136 [N-(6-(2-amino-4-fluorophenylamino)-6-oxohexyl)-4-methylbenzamide]. Immunohistochemistry showed that focal deletion or intrahippocampal delivery of RGFP136 resulted in increased histone acetylation. Both the focal deletion of HDAC3 as well as HDAC3 inhibition via RGFP136 significantly enhanced long-term memory in a persistent manner. Next we examined expression of genes implicated in long-term memory from dorsal hippocampal punches using quantitative reverse transcription-PCR. Expression of nuclear receptor subfamily 4 group A, member 2 (Nr4a2) and c-fos was significantly increased in the hippocampus of HDAC3–FLOX mice compared with wild-type controls. Memory enhancements observed in HDAC3–FLOX mice were abolished by intrahippocampal delivery of Nr4a2 small interfering RNA, suggesting a mechanism by which HDAC3 negatively regulates memory formation. Together, these findings demonstrate a critical role for HDAC3 in the molecular mechanisms underlying long-term memory formation. PMID:21228185
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Montastier, Emilie; Déjean, Sébastien; Le Gall, Caroline; Saris, Wim H M; Langin, Dominique; Viguerie, Nathalie
2014-01-01
Weight loss reduces risk factors associated with obesity. However, long-term metabolic improvement remains a challenge. We investigated quantitative gene expression of subcutaneous adipose tissue in obese individuals and its relationship with low calorie diet and long term weight maintenance induced changes in insulin resistance. Three hundred eleven overweight and obese individuals followed a dietary protocol consisting of an 8-week low calorie diet followed by a 6-month ad libitum weight-maintenance diet. Individuals were clustered according to insulin resistance trajectories assessed using homeostasis model assessment of insulin resistance (HOMA-IR) index. Adipose tissue mRNA levels of 267 genes selected for regulation according to obesity, metabolic status and response to dieting was assessed using high throughput RT-qPCR. A combination of discriminant analyses was used to identify genes with regulation according to insulin resistance trajectories. Partial correlation was used to control for change in body mass index. Three different HOMA-IR profile groups were determined. HOMA-IR improved during low calorie diet in the 3 groups. At the end of the 6-month follow-up, groups A and B had reduced HOMA-IR by 50%. In group C, HOMA-IR had returned to baseline values. Genes were differentially expressed in the adipose tissue of individuals according to groups but a single gene, CIDEA, was common to all phases of the dietary intervention. Changes in adipose tissue CIDEA mRNA levels paralleled variations in insulin sensitivity independently of change in body mass index. Overall, CIDEA was up-regulated in adipose tissue of individuals with successful long term insulin resistance relapse and not in adipose tissue of unsuccessful individuals. The concomitant change in adipose tissue CIDEA mRNA levels and insulin sensitivity suggests a beneficial role of adipose tissue CIDEA in long term glucose homeostasis, independently of weight variation. ClinicalTrials.gov NCT00390637.
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Vuica, Ana; Ferhatović Hamzić, Lejla; Vukojević, Katarina; Jerić, Milka; Puljak, Livia; Grković, Ivica; Filipović, Natalija
2015-12-01
Diabetes mellitus (DM) is a metabolic disorder associated with serious liver complications. As a metabolic chronic disease, DM is very common in the elderly. Recent studies suggest ameliorating effects of vitamin D on metabolic and oxidative stress in the liver tissue in an experimental model of DM. The aim of this study was to investigate the expression of vitamin D receptors (VDRs) and 1α-hydroxylase, the key enzyme for the production of active vitamin D form (calcitriol) in the liver during long-term diabetes mellitus type 1 (DM1) in aging rats. We performed immunohistochemical analysis of liver expression of 1α-hydroxylase and VDRs during aging in long-term streptozotocin-induced DM1. 1α-Hydroxylase was identified in the monocyte/macrophage system of the liver. In addition to the nuclear expression, we also observed the expression of VDR in membranes of lipid droplets within hepatocytes. Aging and long-term DM1 resulted in significant increases in the number of 1α-hydroxylase immunoreactive cells, as well as the percentage of strongly positive VDR hepatocytes. In conclusion, the liver has the capacity for active vitamin D synthesis in its monocyte/macrophage system that is substantially increased in aging and long-term diabetes mellitus. These conditions are also characterized by significant increases in vitamin D receptor expression in hepatocytes. The present study suggests that VDR signaling system could be a potential target in prevention of liver complications caused by diabetes and aging. Copyright © 2015 Elsevier Inc. All rights reserved.
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Effects of Ibuprofen on Cognition and NMDA Receptor Subunit Expression Across Aging
Loza, Alejandra Márquez; Elias, Valerie; Wong, Carmen P.; Ho, Emily; Bermudez, Michelle; Magnusson, Kathy R.
2017-01-01
Age-related declines in long- and short-term memory show relationships to decreases in N-methyl-D-aspartate (NMDA) receptor expression, which may involve inflammation. This study was designed to determine effects of an anti-inflammatory drug, ibuprofen, on cognitive function and NMDA receptor expression across aging. Male C57BL/6 mice (ages 5, 14, 20, and 26 months) were fed ibuprofen (375 ppm) in NIH31 diet or diet alone for 6 weeks prior to testing. Behavioral testing using the Morris water maze showed that older mice performed significantly worse than younger in spatial long-term memory, reversal, and short-term memory tasks. Ibuprofen enhanced overall performance in the short-term memory task, but this appeared to be more related to improved executive function than memory. Ibuprofen induced significant decreases over all ages in the mRNA densities for GluN2B subunit, all GluN1 splice variants, and GluN1-1 splice forms in the frontal cortex and in protein expression of GluN2A, GluN2B and GluN1 C2′ cassettes in the hippocampus. GluN1-3 splice form mRNA and C2′ cassette protein were significantly increased across ages in frontal lobes of ibuprofen-treated mice. Ibuprofen did not alter expression of pro-inflammatory cytokines IL-1β and TNFα, but did reduce the area of reactive astrocyte immunostaining in frontal cortex of aged mice. Enhancement in executive function showed a relationship to increased GluN1-3 mRNA and decreased gliosis. These findings suggest that inflammation may play a role in executive function declines in aged animals, but other effects of ibuprofen on NMDA receptors appeared to be unrelated to aging or inflammation. PMID:28057539
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Peripheral laser assisted angioplasty: results, complications and follow-up.
Owen, E R; Moussa, S A; Lewis, J D; Wilkins, R A
1990-04-01
Detailed results including complications and ultimate outcome of 24 laser assisted angioplasties in 22 patients are presented. Despite the enthusiasm expressed in other published reports, we remain sceptical of the value of laser using a 1.5 mm 'hot-tip' probe for assisting angioplasty of peripheral occlusions. The tendency for this type of probe to damage the vessel wall and in so doing prohibit the use of subsequent balloon dilatation is a major problem. In this small series the long-term patency was not improved compared with conventional angioplasty. We have established the relative safety of this laser technique and further advances in probe design may lead to greater success in crossing long lesions. Long-term maintenance of patency in these diseased arteries will need further advances in technique and assessment preferably by a controlled trial.
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Transgenic Mice Expressing an Inhibitory Truncated Form of p300 Exhibit Long-Term Memory Deficits
ERIC Educational Resources Information Center
Oliveira, Ana M. M.; Wood, Marcelo A.; McDonough, Conor B.; Abel, Ted
2007-01-01
The formation of many forms of long-term memory requires several molecular mechanisms including regulation of gene expression. The mechanisms directing transcription require not only activation of individual transcription factors but also recruitment of transcriptional coactivators. CBP and p300 are transcriptional coactivators that interact with…
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VEGF improves survival of mesenchymal stem cells in infarcted hearts
DOE Office of Scientific and Technical Information (OSTI.GOV)
Pons, Jennifer; Huang Yu; Arakawa-Hoyt, Janice
2008-11-14
Bone marrow-derived mesenchymal stem cells (MSC) are a promising source for cell-based treatment of myocardial infarction (MI), but existing strategies are restricted by low cell survival and engraftment. We examined whether vascular endothelial growth factor (VEGF) improve MSC viability in infracted hearts. We found long-term culture increased MSC-cellular stress: expressing more cell cycle inhibitors, p16{sup INK}, p21 and p19{sup ARF}. VEGF treatment reduced cellular stress, increased pro-survival factors, phosphorylated-Akt and Bcl-xL expression and cell proliferation. Co-injection of MSCs with VEGF to MI hearts increased cell engraftment and resulted in better improvement of cardiac function than that injected with MSCs ormore » VEGF alone. In conclusion, VEGF protects MSCs from culture-induce cellular stress and improves their viability in ischemic myocardium, which results in improvements of their therapeutic effect for the treatment of MI.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Yu, Cheng-Chia; School of Dentistry, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
Cigarette smoking is one of the major risk factors in the development and further progression of tumorigenesis, including oral squamous cell carcinoma (OSCC). Recent studies suggest that interplay cancer stem-like cells (CSCs) and epithelial−mesenchymal transdifferentiation (EMT) properties are responsible for the tumor maintenance and metastasis in OSCC. The aim of the present study was to investigate the effects of long-term exposure with nicotine, a major component in cigarette, on CSCs and EMT characteristics. The possible reversal regulators were further explored in nicotine-induced CSCs and EMT properties in human oral epithelial (OE) cells. Long-term exposure with nicotine was demonstrated to up-regulatemore » ALDH1 population in normal gingival and primary OSCC OE cells dose-dependently. Moreover, long-term nicotine treatment was found to enhance the self-renewal sphere-forming ability and stemness gene signatures expression and EMT regulators in OE cells. The migration/cell invasiveness/anchorage independent growth and in vivo tumor growth by nude mice xenotransplantation assay was enhanced in long-term nicotine-stimulated OE cells. Knockdown of Snail in long-term nicotine-treated OE cells was found to reduce their CSCs properties. Therapeutic delivery of Si-Snail significantly blocked the xenograft tumorigenesis of long-term nicotine-treated OSCC cells and largely significantly improved the recipient survival. The present study demonstrated that the enrichment of CSCs coupled EMT property in oral epithelial cells induced by nicotine is critical for the development of OSCC tumorigenesis. Targeting Snail might offer a new strategy for the treatment of OSCC patients with smoking habit. -- Highlights: ► Sustained nicotine treatment induced CSCs properties of oral epithelial cells. ► Long-term nicotine treatment enhance EMT properties of oral epithelial cells. ► Long-term nicotine exposure increased tumorigenicity of oral epithelial cells. ► Si-Snail blocked xenograft tumorigenesis of long-term nicotine-treated OSCC cells.« less
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Lebas, Benoît; Galley, Julien; Renaud-Gabardos, Edith; Pujol, Françoise; Lenfant, Françoise; Garmy-Susini, Barbara; Chaufour, Xavier; Prats, Anne-Catherine
2017-04-01
Critical leg ischemia (CLI) represents the ultimate stage of peripheral arterial disease. Despite current surgery advances, patients with CLI have limited therapeutic options. Therapeutic angiogenesis thus appears as a powerful approach, aiming to stimulate vessel formation by angiogenic molecules administration. In this context, combined gene therapy has been proved to be the most efficient. The present study aims to compare, in a preclinical mouse model, the therapeutic benefit of a combination of 2 angiogenic factors fibroblast growth factor 2 (FGF2) and Cyr61 using plasmid and viral vectors, able to generate short- or long-term transgene expression in the leg, respectively. Two therapeutic genes, FGF2 and Cyr61, were introduced into internal ribosome entry site-based expression vectors (FGFiCyr) allowing co-expression of the 2 transgenes. The proangiogenic plasmid pC-FGFiCyr was assessed by intramuscular administration followed by electrotransfer into ischemic legs. To generate long-term transgene expression, the FGFiCyr bicistronic cassette was introduced into an adenoassociated virus-derived vector (rAAV). The rAAV treatment was performed either before or immediately after surgery. Therapeutic effects were analyzed by laser Doppler imaging, clinical score, and angiography. The plasmid pC-FGFiCyr improved revascularization, reperfusion, and clinical score. Surprisingly, when AAV-FGFiCyr was injected 21 or 28 days before surgery, the proangiogenic rAAV was drastically deleterious on all measured parameters. In contrast, when administrated shortly after surgery, AAV-FGFiCyr generated therapeutic benefits, with a significantly better clinical score than after treatment with the plasmid. Therapeutic effects of the angiogenic combination FGF2-Cyr61 is observed with short-term transgene expression, but the treatment is significantly more efficient when a long-term expression viral vector is used. However, the rAAV-FGFiCyr generated therapeutic benefit only when injected in an ischemic leg, whereas the same dose of rAAV exhibited deleterious effects when administrated to healthy animals. These data may contribute to the understanding of the moderate success of proangiogenic treatments in CLI gene therapy clinical assays. Copyright © 2016 Elsevier Inc. All rights reserved.
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Mehta, Vineet; Singh, Tiratha Raj; Udayabanu, Malairaman
2017-12-01
Chronic stress is associated with impaired neurogenesis, neurodegeneration and behavioral dysfunction, whereas the mechanism underlying stress-mediated neurological complications is still not clear. In the present study, we aimed to investigate whether chronic unpredicted stress (CUS) mediated neurological alterations are associated with impaired hippocampal insulin signaling or not, and studied the effect of quercetin in this scenario. Male Swiss albino mice were subjected to 21day CUS, during which 30mg/kg quercetin treatment was given orally. After 21days, behavioral functions were evaluated in terms of locomotor activity (Actophotometer), muscle coordination (Rota-rod), depression (Tail Suspension Test (TST), Forced Swim Test (FST)) and memory performance (Passive-avoidance step-down task (PASD)). Further, hippocampal insulin signaling was evaluated in terms of protein expression of insulin, insulin receptor (IR) and glucose transporter 4 (GLUT-4) and neurogenesis was evaluated in terms of doublecortin (DCX) expression. 21day CUS significantly impaired locomotion and had no effect on muscle coordination. Stressed animals were depressed and showed markedly impaired memory functions. Quercetin treatment significantly improvement stress-mediated behavior dysfunction as indicated by improved locomotion, lesser immobility time and greater frequency of upward turning in TST and FST and increased transfer latency on the day 2 (short-term memory) and day 5 (long-term memory) in PASD test. We observed significantly higher IR expression and significantly lower GLUT-4 expression in the hippocampus of stressed animals, despite of nonsignificant difference in insulin levels. Further, chronic stress impaired hippocampal neurogenesis, as indicated by the significantly reduced levels of hippocampal DCX expression. Quercetin treatment significantly lowered insulin and IR expression and significantly enhanced GLUT-4 and DCX expression in the hippocampus, when compared to CUS. In conclusion, quercetin treatment efficiently alleviated stress mediated behavioral dysfunction by modulating hippocampal insulin signaling and neurogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.
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Mathias, Brittany; Delmas, Amber L; Ozrazgat-Baslanti, Tezcan; Vanzant, Erin L; Szpila, Benjamin E; Mohr, Alicia M; Moore, Frederick A; Brakenridge, Scott C; Brumback, Babette A; Moldawer, Lyle L; Efron, Philip A
2017-04-01
We hypothesized that after sepsis in humans, MDSCs will be persistently increased, functionally immunosuppressive, and associated with adverse clinical outcomes. Cancer and sepsis have surprisingly similar immunologic responses and equally dismal long term consequences. In cancer, increased myeloid-derived suppressor cells (MDSCs) induce detrimental immunosuppression, but little is known about the role of MDSCs after sepsis. Blood was obtained from 74 patients within 12 hours of severe sepsis/septic shock (SS/SS), and at set intervals out to 28 days, and also in 18 healthy controls. MDSCs were phenotyped for cell surface receptor expression and enriched by cell sorting. Functional and genome-wide expression analyses were performed. Multiple logistic regression analysis was conducted to determine if increased MDSC appearance was associated with in-hospital and long-term outcomes. After SS/SS, CD33CD11bHLA-DR MDSCs were dramatically increased out to 28 days (P < 0.05). When co-cultured with MDSCs from SS/SS patients, antigen-driven T-cell proliferation and TH1/TH2 cytokine production were suppressed (P < 0.05). Additionally, septic MDSCs had suppressed HLA gene expression and up-regulated ARG1 expression (P < 0.05). Finally, SS/SS patients with persistent increased percentages of blood MDSCs had increased nosocomial infections, prolonged intensive care unit stays, and poor functional status at discharge (P < 0.05). After SS/SS in humans, circulating MDSCs are persistently increased, functionally immunosuppressive, and associated with adverse outcomes. This novel observation warrants further studies. As observed in cancer immunotherapy, MDSCs could be a novel component in multimodality immunotherapy targeting detrimental inflammation and immunosuppression after SS/SS to improve currently observed dismal long-term outcomes.
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Differential functions of NR2A and NR2B in short-term and long-term memory in rats.
Jung, Ye-Ha; Suh, Yoo-Hun
2010-08-23
N-methyl-D-aspartate receptors (NMDARs) are glutamate receptors implicated in synaptic plasticity and memory function. The specific functions of NMDA receptor subunits NR2A and NR2B have not yet been fully determined in the different types of memory. Nine Wistar rats (8-weeks-old) were subjected to the Morris water maze task to evaluate the memory behaviorally. Quantitative analysis of NR1, NR2A, and NR2B levels in the right and left forebrain of rats was performed and subunit associations with different types of memory were investigated using the Morris water maze task. Right forebrain NR2A expression was significantly increased and correlated with faster escape time onto a hidden platform, indicating involvement of short-term memory, because of the training time interval. Right forebrain NR2B expression was positively associated with long-term memory lasting 24-h (h). In the left forebrain, NR2B expression was positively related to 72-h long-term memory. In conclusion, the functions of NR2A and NR2B receptors were differentially specialized in short-term and long-term memory, depending on the right or left forebrain.
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Design of compact long-period gratings imprinted in optimized photonic crystal fibers
NASA Astrophysics Data System (ADS)
Seraji, F. E.; Chehreghani Anzabi, L.; Farsinezhad, S.
2009-10-01
To imprint a long-period grating (LPG) in a photonic crystal fiber (PCF) with an optimum response, first the parameters of the PCF should be optimized. In this paper, by using a semi-analytical enhanced improved vectorial effective index method, the optimized PCF parameters are determined by dividing the single-mode operation of the PCF into two regions in terms of air-hole spacing Λ ( Λ>3 μm and Λ≤3 μm). For each region appropriate expressions are suggested to evaluate the PCF parameters. By calculating the effective refractive index difference between the optimized core and cladding of the PCF under a phase-matching condition, the optimum grating period in terms of the PCF parameters is obtained.
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Nordentoft, I; Jeppesen, P B; Hong, J; Abudula, R; Hermansen, K
2008-06-25
High content isoflavone soy protein (SBP) (Abalon) has been found in animal studies to possess beneficial effects on a number of the characteristic features of the insulin resistance syndrome. The aim of this study was to investigate whether SBP exerts beneficial effects on metabolism in the diabetic KKAy-mouse. Furthermore, we investigated the long-term in vivo effect of SBP on the expression profile in islets of key insulin regulatory genes. Twenty KKAy-mice, aged 5 weeks, were divided into 2 groups and treated for 9 weeks with either (A) standard chow diet (control) or (B) chow + 50% SBP. Twenty normal C57BL-mice fed with standard chow diet served as nondiabetic controls (C). Blood samples were collected and analyzed before and after intervention. Gene expression was determined in islets by quantitative real-time RT-PCR and Affymetrix microarray. It was demonstrated that long-term treatment with SBP improves glucose homeostasis, increases insulin sensitivity, and lowers plasma triglycerides in diabetic KKAy-mice. SBP reduces fasting plasma glucose, insulin, triglycerides, and total cholesterol. Furthermore, SBP markedly changes the gene expression profile of key insulin regulatory genes GLUT2, GLUT3, Ins1, Ins2, IGF1, Beta2/Neurod1, cholecystokinin, and LDLr, and proliferative genes in islets isolated from KKAy-mice. After 9 weeks of treatment with SBP, plasma glucose and insulin homeostasis was normalized compared to start levels. The results indicate that SBP improves glucose and insulin sensitivity and up-regulates the expression of key insulin regulatory genes.
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Nakamoto, Hirotaka; Hamada, Chieko; Shimaoka, Tetsutaro; Sekiguchi, Yoshimi; Io, Hiroaki; Kaneko, Kayo; Horikoshi, Satoshi; Tomino, Yasuhiko
2014-03-01
Characteristics of pathological alterations in long-term peritoneal dialysis (PD) are thickening of submesothelial compact (SMC) zone, small-vessel vasculopathy, and loss of mesothelial cells. Bioincompatible PD fluid plays crucial roles in peritoneal injury. Encapsulating peritoneal sclerosis (EPS), a rare and serious complication, occurred in patients on long-term PD or frequent peritonitis episodes, and ~50 % of EPS developed after PD cessation. We hypothesized that PD-related peritoneal injury factors induced by bioincompatible PD fluid accumulated in the peritoneum and might induce EPS. We therefore examined the accumulation of advanced glycation end products (AGE) and beta 2-microglobulin (β2M) in peritoneum and evaluated the relationship between their accumulation, clinical parameters, and outcome after PD cessation. Forty-five parietal peritoneal specimens were obtained from 28 PD patients, 14 uremic patients, and three patients with normal kidney function. The peritoneal equilibration test was used for peritoneal function. AGE- and β2M-expressing areas were found in vascular walls, perivascular areas, and the deep layer of the SMC in short-term PD patients and extended over the entire SMC in long-term patients. Peritonitis and prolonged PD treatment aggravated peritoneal thickening and the proportion of AGE-expressing areas. The proportion of β2M-expressing areas was increased in long-term PD patients. Thickening of the SMC and the proportions of AGE- and β2M-expressing areas were not related to ascites or EPS after PD withdrawal. It appears that the increased proportion of AGE and β2M deposition induced by long-term exposure of PD fluid may be a marker of peritoneal injury.
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Astrocyte-neuron lactate transport is required for long-term memory formation
Suzuki, Akinobu; Stern, Sarah A.; Bozdagi, Ozlem; Huntley, George W.; Walker, Ruth H.; Magistretti, Pierre J.; Alberini, Cristina M.
2011-01-01
SUMMARY We report that in the rat hippocampus learning leads to a significant increase in extracellular lactate levels, which derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in-vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation. PMID:21376239
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Long- and short-term effects of boron excess to root form and function in two tomato genotypes.
Princi, Maria Polsia; Lupini, Antonio; Longo, Caterina; Miller, Anthony J; Sunseri, Francesco; Abenavoli, Maria Rosa
2016-12-01
Boron (B) is an essential plant nutrient, but when present in excess it is toxic. Morphological measurements were made to assess the impact of B toxicity on the growth of two different tomato hybrids, Losna and Ikram. Contrasting long and short-term B responses in these tomato hybrids, were observed. Losna showed less toxicity symptoms, maintaining higher growth and showing much less B content in both root and shoot tissues compared to Ikram. Root morphological differences did not explain the tolerance between the two hybrids. Under excess B supply, a significant inhibition on net nitrate uptake rate was observed in Ikram, but not in Losna. This effect may be explained by a decrease of nitrate transporter transcripts in Ikram, which was not measured in Losna. There was a different pattern of B transporter expression in two tomatoes and this can explain the contrasting tolerance observed. Indeed, Losna may be able to exclude or efflux B resulting in less accumulation in the shoot. Particularly, SlBOR4 expression showed significant differences between the tomato hybrids, with higher expression in Losna explaining the improved B-tolerance. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
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Autologous mesenchymal stem cell–derived dopaminergic neurons function in parkinsonian macaques
Hayashi, Takuya; Wakao, Shohei; Kitada, Masaaki; Ose, Takayuki; Watabe, Hiroshi; Kuroda, Yasumasa; Mitsunaga, Kanae; Matsuse, Dai; Shigemoto, Taeko; Ito, Akihito; Ikeda, Hironobu; Fukuyama, Hidenao; Onoe, Hirotaka; Tabata, Yasuhiko; Dezawa, Mari
2012-01-01
A cell-based therapy for the replacement of dopaminergic neurons has been a long-term goal in Parkinson’s disease research. Here, we show that autologous engraftment of A9 dopaminergic neuron-like cells induced from mesenchymal stem cells (MSCs) leads to long-term survival of the cells and restoration of motor function in hemiparkinsonian macaques. Differentiated MSCs expressed markers of A9 dopaminergic neurons and released dopamine after depolarization in vitro. The differentiated autologous cells were engrafted in the affected portion of the striatum. Animals that received transplants showed modest and gradual improvements in motor behaviors. Positron emission tomography (PET) using [11C]-CFT, a ligand for the dopamine transporter (DAT), revealed a dramatic increase in DAT expression, with a subsequent exponential decline over a period of 7 months. Kinetic analysis of the PET findings revealed that DAT expression remained above baseline levels for over 7 months. Immunohistochemical evaluations at 9 months consistently demonstrated the existence of cells positive for DAT and other A9 dopaminergic neuron markers in the engrafted striatum. These data suggest that transplantation of differentiated autologous MSCs may represent a safe and effective cell therapy for Parkinson’s disease. PMID:23202734
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Gamé, Xavier; Allard, Julien; Escourrou, Ghislaine; Gourdy, Pierre; Tack, Ivan; Rischmann, Pascal; Arnal, Jean-François; Malavaud, Bernard
2008-03-01
Estrogens are known to modulate lower urinary tract (LUT) trophicity and neuronal nitric oxide synthase (nNOS) expression in several organs. The aim of this study was to explore the effects of endogenous and supraestrus levels of 17beta-estradiol (E2) on LUT and urethral nNOS expression and function. LUT function and histology and urethral nNOS expression were studied in adult female mice subjected either to sham surgery, surgical castration, or castration plus chronic E2 supplementation (80 microg.kg(-1).day(-1), i.e., pregnancy level). The micturition pattern was profoundly altered by long-term supraestrus levels of E2 with decreased frequency paralleled by increased residual volumes higher than those of ovariectomized mice. Urethral resistance was increased twofold in E2-treated mice, with no structural changes in urethra, supporting a pure tonic mechanism. Acute nNOS inhibition by 7-nitroindazole decreased frequency and increased residual volumes in ovariectomized mice but had no additive effect on the micturition pattern of long-term supraestrus mice, showing that long-term supraestrus E2 levels and acute inhibition of nNOS activity had similar functional effects. Finally, E2 decreased urethral nNOS expression in ovariectomized mice. Long-term supraestrus levels of E2 increased urethral tone through inhibition of nNOS expression, whereas physiological levels of E2 had no effect.
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Liu, Daojie; Yin, Jiming; Qiao, Luxin; Shi, Ying; Dong, Yaowu; Li, Ning; Zhang, Fujie; Chen, Dexi
2013-01-01
As the backbone of highly active antiretroviral therapy (HAART), nucleoside reverse transcriptase inhibitors (NRTIs) have effectively improved outcomes for HIV-infected patients. However, long-term treatment with NRTIs can cause a series of pathologies associated with mitochondrial toxicity. To date, the status and mechanism of mitochondrial toxicity induced by NRTIs are still not clear, especially in HIV-infected children. As part of the national pediatric HAART program in China, our study focused on mitochondrial toxicity and its potential mechanism in HIV-1-infected children who were divided into two groups based on their duration of treatment with NRTIs: one group received treatment for less than 36 months and one group was treated for 36 to 72 months. The control group comprised age-matched non-HIV-infected children. Blood lactic acid and ATP levels in peripheral blood mononuclear cells (PBMCs) were measured to evaluate mitochondrial function, and mtDNA copies and mutations in PBMCs were determined for detecting mtDNA lesions. Simultaneously, TK2 and P53R2 gene expression in PBMC was measured. As compared with the control group, blood lactic acid levels in both NRTI treatment groups were significantly higher, whereas ATP levels and mtDNA mutation rates in PBMCs did not differ between the control and the two NRTI treatment groups. Both NRTI treatment groups exhibited significant mtDNA loss. N Moreover, we found that P53R2 mRNA expression and protein levels were significantly reduced in both treatment groups and that TK2 mRNA expression and protein levels were induced in the long-term NRTI treatment group. These results suggest that mitochondrial toxicity occurs in long-term HAART patients and that P53R2 and TK2 levels in PBMCs are useful biomarkers for detecting mitochondrial toxicity in patients on long-term treatment with NRTIs. PMID:23468942
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Luckey, Chance John; Bhattacharya, Deepta; Goldrath, Ananda W.; Weissman, Irving L.; Benoist, Christophe; Mathis, Diane
2006-01-01
The only cells of the hematopoietic system that undergo self-renewal for the lifetime of the organism are long-term hematopoietic stem cells and memory T and B cells. To determine whether there is a shared transcriptional program among these self-renewing populations, we first compared the gene-expression profiles of naïve, effector and memory CD8+ T cells with those of long-term hematopoietic stem cells, short-term hematopoietic stem cells, and lineage-committed progenitors. Transcripts augmented in memory CD8+ T cells relative to naïve and effector T cells were selectively enriched in long-term hematopoietic stem cells and were progressively lost in their short-term and lineage-committed counterparts. Furthermore, transcripts selectively decreased in memory CD8+ T cells were selectively down-regulated in long-term hematopoietic stem cells and progressively increased with differentiation. To confirm that this pattern was a general property of immunologic memory, we turned to independently generated gene expression profiles of memory, naïve, germinal center, and plasma B cells. Once again, memory-enriched and -depleted transcripts were also appropriately augmented and diminished in long-term hematopoietic stem cells, and their expression correlated with progressive loss of self-renewal function. Thus, there appears to be a common signature of both up- and down-regulated transcripts shared between memory T cells, memory B cells, and long-term hematopoietic stem cells. This signature was not consistently enriched in neural or embryonic stem cell populations and, therefore, appears to be restricted to the hematopoeitic system. These observations provide evidence that the shared phenotype of self-renewal in the hematopoietic system is linked at the molecular level. PMID:16492737
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Ellis, J L; Hindrichsen, I K; Klop, G; Kinley, R D; Milora, N; Bannink, A; Dijkstra, J
2016-09-01
Inoculants of lactic acid bacteria (LAB) are used to improve silage quality and prevent spoilage via increased production of lactic acid and other organic acids and a rapid decline in silage pH. The addition of LAB inoculants to silage has been associated with increases in silage digestibility, dry matter intake (DMI), and milk yield. Given the potential change in silage and rumen fermentation conditions accompanying these silage additives, the aim of this study was to investigate the effect of LAB silage inoculants on DMI, digestibility, milk yield, milk composition, and methane (CH4) production from dairy cows in vivo. Eight mid-lactation Holstein-Friesian dairy cows were grouped into 2 blocks of 4 cows (multiparous and primiparous) and used in a 4×4 double Latin square design with 21-d periods. Methane emissions were measured by indirect calorimetry. Treatments were grass silage (mainly ryegrass) with no inoculant (GS), with a long-term inoculant (applied at harvest; GS+L), with a short-term inoculant (applied 16h before feeding; GS+S), or with both long and short-term inoculants (GS+L+S). All diets consisted of grass silage and concentrate (75:25 on a dry matter basis). The long-term inoculant consisted of a 10:20:70 mixture of Lactobacillus plantarum, Lactococcus lactis, and Lactobacillus buchneri, and the short-term inoculant was a preparation of Lc. lactis. Dry matter intake was not affected by long-term or short-term silage inoculation, nor was dietary neutral detergent fiber or fat digestibility, or N or energy balance. Milk composition (except milk urea) and fat and protein-corrected milk yield were not affected by long- or short-term silage inoculation, nor was milk microbial count. However, milk yield tended to be greater with long-term silage inoculation. Methane expressed in units of grams per day, grams per kilogram of DMI, grams per kilogram of milk, or grams per kilogram of fat and protein-corrected milk yield was not affected by long- or short-term silage inoculation. However, CH4 expressed in units of kilojoules per kilogram of metabolic body weight per day tended to be greater with long-term silage inoculation. Results of this study indicate minimal responses in animal performance to both long- and short-term inoculation of grass silage with LAB. Strain and dose differences as well as different basal silages and ensiling conditions are likely responsible for the lack of significant effects observed here, although positive effects have been observed in other studies. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.
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Application of a partnership model for transformative and sustainable international development.
Powell, Dorothy L; Gilliss, Catherine L; Hewitt, Hermi H; Flint, Elizabeth P
2010-01-01
There are differences of intent and impact between short-term and long-term engagement of U.S. academic institutions with communities of need in developing nations. Global health programs that produce long-term transformative change rather than transient relief are more likely to be sustainable and in ethical harmony with expressed needs of a region or community. This article explores characteristics of successful ethical partnerships in global health and the challenges that threaten them, introducing a consensus community engagement model as a framework for building relationships, evolving an understanding of needs, and collaboratively developing solutions and responses to priority health needs in underserved regions of the world. The community engagement model is applied to a case study of an initiative by a U.S. school of nursing to establish long-term relationships with the nursing community in the Caribbean region with the goal of promoting transformative change through collaborative development of programs and services addressing health care needs of the region's growing elderly population and the increasing prevalence of noncommunicable chronic diseases. Progress of this ongoing long-term relationship is analyzed in the context of the organizational, philosophical, ethical, and resource commitments embodied in this approach to initiation of transformative and sustainable improvements in public health.
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Bozkaya, F; Atli, M O; Guzeloglu, A; Kayis, S A; Yildirim, M E; Kurar, E; Yilmaz, R; Aydilek, N
2017-08-01
The aim was to investigate the effects of long-term heat stress and dietary restriction on the expression of certain genes involving in steroidogenic pathway and small heat-shock proteins (sHSPs) in rat testis. Sprague Dawley rats (n = 24) were equally divided into four groups. Group I and II were kept at an ambient temperature of 22°C, while Groups III and IV were reared at 38°C for 9 weeks. Feed was freely available for Group I and Group III, while Group II and Group IV were fed 60% of the diet consumed by their ad libitum counterparts. At the end of 9 weeks, testicles were collected under euthanasia. Total RNA was isolated from testis tissue samples. Expression profiles of the genes encoding androgen-binding protein, follicle-stimulating hormone receptor, androgen receptor, luteinising hormone receptor, steroidogenic acute regulatory protein (StAR), cyclooxygenase-2 and sHSP genes were assessed at mRNA levels using qPCR. Long-term heat stress decreased the expression of StAR and HspB10 genes while dietary restriction upregulated StAR gene expression. The results suggested that long-term heat stress negatively affected the expression of StAR and HspB10 genes and the dietary restriction was able to reverse negative effect of heat stress on the expression of StAR gene in rat testis. © 2016 Blackwell Verlag GmbH.
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Kroeze, Y; Peeters, D; Boulle, F; van den Hove, D L A; van Bokhoven, H; Zhou, H; Homberg, J R
2015-01-01
The selective serotonin reuptake inhibitor (SSRI) fluoxetine is widely prescribed for the treatment of symptoms related to a variety of psychiatric disorders. After chronic SSRI treatment, some symptoms remediate on the long term, but the underlying mechanisms are not yet well understood. Here we studied the long-term consequences (40 days after treatment) of chronic fluoxetine exposure on genome-wide gene expression. During the treatment period, we measured body weight; and 1 week after treatment, cessation behavior in an SSRI-sensitive anxiety test was assessed. Gene expression was assessed in hippocampal tissue of adult rats using transcriptome analysis and several differentially expressed genes were validated in independent samples. Gene ontology analysis showed that upregulated genes induced by chronic fluoxetine exposure were significantly enriched for genes involved in myelination. We also investigated the expression of myelination-related genes in adult rats exposed to fluoxetine at early life and found two myelination-related genes (Transferrin (Tf) and Ciliary neurotrophic factor (Cntf)) that were downregulated by chronic fluoxetine exposure. Cntf, a neurotrophic factor involved in myelination, showed regulation in opposite direction in the adult versus neonatally fluoxetine-exposed groups. Expression of myelination-related genes correlated negatively with anxiety-like behavior in both adult and neonatally fluoxetine-exposed rats. In conclusion, our data reveal that chronic fluoxetine exposure causes on the long-term changes in expression of genes involved in myelination, a process that shapes brain connectivity and contributes to symptoms of psychiatric disorders. PMID:26393488
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Interest in Long-Term Care among Health Services Administration Students
ERIC Educational Resources Information Center
Temple, April; Thompson, Jon M.
2011-01-01
The aging of the population has created increased opportunities for health administrators in long-term care. This study consisted of a cross-sectional survey of 68 undergraduate health services administration students to explore factors related to interest in a career in long-term care administration. One third expressed interest working in the…
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Memory in aged mice is rescued by enhanced expression of the GluN2B subunit of the NMDA receptor
Brim, B. L.; Haskell, R.; Awedikian, R.; Ellinwood, N.M.; Jin, L.; Kumar, A.; Foster, T.C.; Magnusson, K.
2012-01-01
The GluN2B subunit of the N-methyl-D-aspartate (NMDA) receptor shows age-related declines in expression across the frontal cortex and hippocampus. This decline is strongly correlated to age-related memory declines. This study was designed to determine if increasing GluN2B subunit expression in the frontal lobe or hippocampus would improve memory in aged mice. Mice were injected bilaterally with either the GluN2B vector, containing cDNA specific for the GluN2B subunit and enhanced Green Fluorescent Protein (eGFP); a control vector or vehicle. Spatial memory, cognitive flexibility, and associative memory were assessed using the Morris water maze. Aged mice, with increased GluN2B subunit expression, exhibited improved long-term spatial memory, comparable to young mice. However, memory was rescued on different days in the Morris water maze; early for hippocampal GluN2B subunit enrichment and later for the frontal lobe. A higher concentration of the GluN2B antagonist, Ro 25-6981, was required to impair long-term spatial memory in aged mice with enhanced GluN2B expression, as compared to aged controls, suggesting there was an increase in the number of GluN2B-containing NMDA receptors. In addition, hippocampal slices from aged mice with increased GluN2B subunit expression exhibited enhanced NMDA receptor-mediated excitatory post-synaptic potentials (EPSP). Treatment with Ro 25-6981 showed that a greater proportion of the NMDA receptor-mediated EPSP was due to the GluN2B subunit in these animals, as compared to aged controls. These results suggest that increasing the production of the GluN2B subunit in aged animals enhances memory and synaptic transmission. Therapies that enhance GluN2B subunit expression within the aged brain may be useful for ameliorating age-related memory declines. PMID:23103326
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Xie, Yi; Liu, Wenhua; Zhang, Xiaohao; Wang, Liumin; Xu, Lili; Xiong, Yunyun; Yang, Lian; Sang, Hongfei; Ye, Ruidong; Liu, Xinfeng
2015-10-01
Subarachnoid hemorrhage results in significant long-lasting neurologic sequelae. Here, we investigated whether human albumin improves long-term outcomes in experimental subarachnoid hemorrhage and whether neurovascular remodeling is involved in the protection of albumin. Laboratory investigation. Hospital research laboratory. Male Sprague-Dawley rats. Rats underwent subarachnoid hemorrhage by endovascular perforation. Albumin of either 0.63 or 1.25 g/kg was injected IV immediately after the surgery. Modified Garcia test, beam-walking test, novel object recognition, and Morris water maze were employed to determine the behavioral deficits. The effects of albumin on early neurovascular dysfunction and chronic synaptic plasticity were also studied. Both doses of albumin significantly improved the sensorimotor scores (F = 31.277; p = 0.001) and cognitive performance (F = 7.982; p = 0.001 in novel object recognition test; and F = 3.431; p = 0.026 in the latency analysis of Morris water maze test) for at least 40 days after subarachnoid hemorrhage. There were remarkable microvasculature hypoperfusion, intracranial pressure rise, early vasoconstriction, neural apoptosis, and degeneration in subarachnoid hemorrhage rats, with albumin significantly attenuating such neurovascular dysfunction. Furthermore, albumin markedly prevented blood-brain barrier disruption, as indicated by less blood-brain barrier leakage, preserved blood-brain barrier-related proteins, and dampened gelatinase activities. The expressions of key synaptic elements were up-regulated with albumin supplementation in both acute and chronic phases. Accordingly, a higher dendritic spine density was observed in the prefrontal and hippocampal areas of albumin-treated subarachnoid hemorrhage animals. Albumin at low-to-moderate doses markedly improves long-term neurobehavioral sequelae after subarachnoid hemorrhage, which may involve an integrated process of neurovascular remodeling.
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Ma, Jie; Sheng, Huachun; Li, Xiuli; Wang, Lijun
2016-07-01
Silicon (Si) can alleviate cadmium (Cd) stress in rice (Oryza sativa) plants, however, the understanding of the molecular mechanisms at the single-cell level remains limited. To address these questions, we investigated suspension cells of rice cultured in the dark environment in the absence and presence of Si with either short- (12 h) or long-term (5 d) Cd treatments using a combination of isobaric tags for relative and absolute quantitation (iTRAQ), fluorescent staining, and inductively coupled plasma mass spectroscopy (ICP-MS). We identified 100 proteins differentially regulated by Si under the short- or long-term Cd stress. 70% of these proteins were down-regulated, suggesting that Si may improve protein use efficiency by maintaining cells in the normal physiological status. Furthermore, we showed two different mechanisms for Si-mediated Cd tolerance. Under the short-term Cd stress, the Si-modified cell walls inhibited the uptake of Cd ions into cells and consequently reduced the expressions of glycosidase, cell surface non-specific lipid-transfer proteins (nsLTPs), and several stress-related proteins. Under the long-term Cd stress, the amount of Cd in the cytoplasm in Si-accumulating (+Si) cells was decreased by compartmentation of Cd into vacuoles, thus leading to a lower expression of glutathione S-transferases (GST). These results provide protein-level insights into the Si-mediated Cd detoxification in rice single cells. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
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Song, Ki-Duk; Dowd, Scott E; Lee, Hak-Kyo; Kim, Sung Woo
2013-03-01
Seventy-two pigs at 34.4 kg body weight (BW) were allotted to two treatments with six replicates/treatment and six pigs/pen: the CON (negative control, no added selenium (Se)) and the OS (0.36 mg/kg added selenium from selenium-enriched yeast). Pigs were fed until 130 kg BW. The CON diet contained 0.18 mg/kg indigenous Se whereas the OS diet contained 0.54 mg/kg Se. Blood samples were collected at 130 kg BW and further processed for microarray analysis, prepared with 885 genes related to immune function of pigs. Among those, 28 genes related to improved immune status and innate immunity were up-regulated (P < 0.05) in leukocytes from Se-fed pigs and those include major histocompatibility class I (> 1.66), arginase I (> 1.27), integrin beta-1-subunit (> 1.20), toll like receptor 2 (> 1.12) and double-stranded RNA-dependent protein kinase. However, 24 genes including tissue factor (< 4.70), serum amyloid A-2 protein (< 3.11) and p27Kip1 (< 1.42) were down-regulated (P < 0.05) in leukocytes from Se-fed pigs. Expression of four selected genes was validated using quantitative PCR (qPCR) showing significant correlation between mircroarray analysis and qPCR analysis. This study indicates that a long- term dietary supplementation (0.3%) of organic Se improves the expression of genes that are related to enhanced immunity of pigs. © 2012 Japanese Society of Animal Science.
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Recombinant AAV-directed gene therapy for type I glycogen storage diseases
Chou, JY; Mansfield, BC
2011-01-01
Introduction Glycogen storage disease (GSD) type Ia and Ib are disorders of impaired glucose homeostasis affecting the liver and kidney. GSD-Ib also affects neutrophils. Current dietary therapies cannot prevent long-term complications. In animal studies, recombinant adeno-associated virus (rAAV) vector-mediated gene therapy can correct or minimize multiple aspects of the disorders, offering hope for human gene therapy. Areas covered A summary of recent progress in rAAV-mediated gene therapy for GSD-I; strategies to improve rAAV-mediated gene delivery, transduction efficiency and immune avoidance; and vector refinements that improve expression. Expert opinion rAAV-mediated gene delivery to the liver can restore glucose homeostasis in preclinical models of GSD-I, but some long-term complications of the liver and kidney remain. Gene therapy for GSD-Ib is less advanced than for GSD-Ia and only transient correction of myeloid dysfunction has been achieved. A question remains whether a single rAAV vector can meet the expression efficiency and tropism required to treat all aspects of GSD-I, or if a multi-prong approach is needed. An understanding of the strengths and weaknesses of rAAV vectors in the context of strategies to achieve efficient transduction of the liver, kidney, and hematopoietic stem cells is required for treating GSD-I. PMID:21504389
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Campos, Carla; Parameswaran, Neeraja; William Langston, J.; Michael McIntosh, J.; Yeluashvili, Michael
2010-01-01
Our previous work had shown that long-term nicotine administration improved dopaminergic markers and nicotinic receptors (nAChRs) in the striatum of monkeys with nigrostriatal damage. The present experiments were done to determine whether nicotine treatment also led to changes in the substantia nigra, the region containing dopaminergic cell bodies. Monkeys were chronically treated with nicotine in the drinking water for 6 months after which they were injected with low dose MPTP for a further 6-month period. Nicotine was administered until the monkeys were euthanized 2 months after the last MPTP injection. Nicotine treatment did not affect the dopamine transporter or the number of tyrosine hydroxylase positive cells in the substantia nigra of lesioned monkeys. However, nicotine administration did lead to a greater increase in α3/α6β2* and α4β2* nAChRs in lesioned monkeys compared to controls. Nicotine also significantly elevated microglia and reduced the number of extracellular neuromelanin deposits in the substantia nigra of MPTP-lesioned monkeys. These findings indicate that long-term nicotine treatment modulates expression of several molecular measures in monkey substantia nigra that may result in an improvement in nigral integrity and/or function. These observations may have therapeutic implications for Parkinson’s disease. PMID:19685015
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ExoMars 2016 Trace Gas Orbiter and Mars Express Coordinated Science Operations Planning
NASA Astrophysics Data System (ADS)
Cardesin Moinelo, Alejandro; Geiger, Bernhard; Costa, Marc; Breitfellner, Michel; Castillo, Manuel; Marin Yaseli de la Parra, Julia; Martin, Patrick; Merritt, Donald R.; Grotheer, Emmanuel; Aberasturi Vega, Miriam; Ashman, Mike; Frew, David; Garcia Beteta, Juan Jose; Metcalfe, Leo; Muñoz, Claudio; Muñoz, Michela; Titov, Dimitri; Svedhem, Hakan
2018-05-01
In this contribution we focus on the science opportunity analysis between the Mars Express and the ExoMars 2016 Trace Gas Orbiter missions and the observations that can be combined to improve the scientific outcome of both missions. In particular we will describe the long term analysis of geometrical conditions that allow for coordinated science observations for solar occultation and nadir pointing. We will provide details on the calculations and results for simultaneous and quasi-simultaneous opportunities, taking into account the observation requirements of the instruments and the operational requirements for feasibility checks.
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Pritchard, Tracy J; Kawase, Yoshiaki; Haghighi, Kobra; Anjak, Ahmad; Cai, Wenfeng; Jiang, Min; Nicolaou, Persoulla; Pylar, George; Karakikes, Ioannis; Rapti, Kleopatra; Rubinstein, Jack; Hajjar, Roger J; Kranias, Evangelia G
2013-01-01
Impaired sarcoplasmic reticulum calcium cycling and depressed contractility are key characteristics in heart failure. Defects in sarcoplasmic reticulum function are characterized by decreased SERCA2a Ca-transport that is partially attributable to dephosphorylation of its regulator phospholamban by increased protein phosphatase 1 activity. Inhibition of protein phosphatase 1 through activation of its endogenous inhibitor-1 has been shown to enhance cardiac Ca-handling and contractility as well as protect from pathological stress remodeling in young mice. In this study, we assessed the long-term effects of inducible expression of constitutively active inhibitor-1 in the adult heart and followed function and remodeling through the aging process, up to 20 months. Mice with inhibitor-1 had normal survival and similar function to WTs. There was no overt remodeling as evidenced by measures of left ventricular end-systolic and diastolic diameters and posterior wall dimensions, heart weight to tibia length ratio, and histology. Higher phosphorylation of phospholamban at both Ser16 and Thr17 was maintained in aged hearts with active inhibitor-1, potentially offsetting the effects of elevated Ser2815-phosphorylation in ryanodine receptor, as there were no increases in arrhythmias under stress conditions in 20-month old mice. Furthermore, long-term expression of active inhibitor-1 via recombinant adeno-associated virus type 9 gene transfer in rats with pressure-overload induced heart failure improved function and prevented remodeling, associated with increased phosphorylation of phospholamban at Ser16 and Thr17. Thus, chronic inhibition of protein phosphatase 1, through increases in active inhibitor-1, does not accelerate age-related cardiomyopathy and gene transfer of this molecule in vivo improves function and halts remodeling in the long term.
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Frémin, Christophe; Bessard, Anne; Ezan, Frédéric; Gailhouste, Luc; Régeard, Morgane; Le Seyec, Jacques; Gilot, David; Pagès, Gilles; Pouysségur, Jacques; Langouët, Sophie; Baffet, Georges
2009-03-01
We investigated the specific role of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 1 (ERK1)/ERK2 pathway in the regulation of multiple cell cycles and long-term survival of normal hepatocytes. An early and sustained epidermal growth factor (EGF)-dependent MAPK activation greatly improved the potential of cell proliferation. In this condition, almost 100% of the hepatocytes proliferated, and targeting ERK1 or ERK2 via RNA interference revealed the specific involvement of ERK2 in this regulation. However, once their first cell cycle was performed, hepatocytes failed to undergo a second round of replication and stayed blocked in G1 phase. We demonstrated that sustained EGF-dependent activation of the MAPK/ERK kinase (MEK)/ERK pathway was involved in this blockage as specific transient inhibition of the cascade repotentiated hepatocytes to perform a new wave of replication and multiple cell cycles. We identified this mechanism by showing that this blockage was in part supported by ERK2-dependent p21 expression. Moreover, continuous MEK inhibition was associated with a lower apoptotic engagement, leading to an improvement of survival up to 3 weeks. Using RNA interference and ERK1 knockout mice, we extended these results by showing that this improved survival was due to the specific inhibition of ERK1 expression/phosphorylation and did not involve ERK2. Our results emphasize that transient MAPK inhibition allows multiple cell cycles in primary cultures of hepatocytes and that ERK2 has a key role in the regulation of S phase entry. Moreover, we revealed a major and distinct role of ERK1 in the regulation of hepatocyte survival. Taken together, our results represent an important advance in understanding long-term survival and cell cycle regulation of hepatocytes.
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Ritz, U; Nusselt, T; Sewing, A; Ziebart, T; Kaufmann, K; Baranowski, A; Rommens, P M; Hofmann, Alexander
2017-01-01
Targeted modifications of the bulk implant surfaces using bioactive agents provide a promising tool for improvement of the long-term bony and soft tissue integration of dental implants. In this study, we assessed the cellular responses of primary human gingival fibroblasts (HGF) to different surface modifications of titanium (Ti) and titanium nitride (TiN) alloys with type I collagen or cyclic-RGDfK-peptide in order to define a modification improving long-term implants in dental medicine. Employing Ti and TiN implants, we compared the performance of simple dip coating and anodic immobilization of type I collagen that provided collagen layers of two different thicknesses. HGF were seeded on the different coated implants, and adhesion, proliferation, and gene expression were analyzed. Although there were no strong differences in initial cell adhesion between the groups at 2 and 4 hours, we found that all surface modifications induced higher proliferation rates as compared to the unmodified controls. Consistently, gene expression levels of cell adhesion markers (focal adhesion kinase (FAK), integrin beta1, and vinculin), cell differentiation markers (FGFR1, TGFb-R1), extracellular protein markers (type I collagen, vimentin), and cytoskeletal protein marker aktinin-1 were consistently higher in all surface modification groups at two different time points of investigation as compared to the unmodified controls. Our results indicate that simple dip coating of Ti and TiN with collagen is sufficient to induce in vitro cellular responses that are comparable to those of more reliable coating methods like anodic adsorption, chemical cross-linking, or RGD coating. TiN alloys do not possess any positive or adverse effects on HGF. Our results demonstrate a simple, yet effective, method for collagen coating on titanium implants to improve the long term integration and stability of dental implants.
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Barrett, Ruth M; Malvaez, Melissa; Kramar, Eniko; Matheos, Dina P; Arrizon, Abraham; Cabrera, Sara M; Lynch, Gary; Greene, Robert W; Wood, Marcelo A
2011-01-01
To identify the role of the histone acetyltransferase (HAT) CREB-binding protein (CBP) in neurons of the CA1 region of the hippocampus during memory formation, we examine the effects of a focal homozygous knockout of CBP on histone modifications, gene expression, synaptic plasticity, and long-term memory. We show that CBP is critical for the in vivo acetylation of lysines on histones H2B, H3, and H4. CBP's homolog p300 was unable to compensate for the loss of CBP. Neurons lacking CBP maintained phosphorylation of the transcription factor CREB, yet failed to activate CREB:CBP-mediated gene expression. Loss of CBP in dorsal CA1 of the hippocampus resulted in selective impairments to long-term potentiation and long-term memory for contextual fear and object recognition. Together, these results suggest a necessary role for specific chromatin modifications, selectively mediated by CBP in the consolidation of memories. PMID:21508930
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Light exposure before learning improves memory consolidation at night
Shan, Li-Li; Guo, Hao; Song, Ning-Ning; Jia, Zheng-Ping; Hu, Xin-Tian; Huang, Jing-Fei; Ding, Yu-Qiang; Richter-Levine, Gal; Zhou, Qi-Xin; Xu, Lin
2015-01-01
Light is recently recognized as a modulator able to activate the hippocampus and modulate memory processing, but little is known about the molecular mechanisms. Here, we report that in mice, a short pulse of white light before learning dramatically improves consolidation of contextual fear memory during the night. The light exposure increases hippocampal active p21-activated kinase 1 (PAK1) and CA1 long-term potentiation (LTP). These light effects are abolished in PAK1 knockout and dominant-negative transgenic mice, but preserved by expression of constitutively active PAK1 in the hippocampus. Our results indicate that light can act as a switch of PAK1 activity that modulate CA1 LTP and thereby memory consolidation without affecting learning and short-term memory. PMID:26493375
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Work Organization and Health Issues in Long-Term Care Centers
Zhang, Yuan; Flum, Marian; Nobrega, Suzanne; Blais, Lara; Qamili, Shpend; Punnett, Laura
2018-01-01
This qualitative study explored common and divergent perceptions of caregivers and managers regarding occupational health and safety, work organization, and psychosocial concerns in long-term care centers. Both common and differing issues were identified. Both groups agreed on the importance of ergonomic concerns, the high prevalence of stress, and receptiveness to participatory health promotion programs. However, numerous work organization issues and physical and psychosocial workplace hazards were identified by certified nursing assistants but were not mentioned by managers. The results suggest that different perceptions naturally arise from people's varying positions in the occupational hierarchy and their consequent exposures to health and safety hazards. Improved systems of communication that allow frontline workers to express their concerns would make it possible to create solutions to these problems. PMID:21261239
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Kosovac, D; Wild, J; Ludwig, C; Meissner, S; Bauer, A P; Wagner, R
2011-02-01
Advanced gene delivery techniques can be combined with rational gene design to further improve the efficiency of plasmid DNA (pDNA)-mediated transgene expression in vivo. Herein, we analyzed the influence of intragenic sequence modifications on transgene expression in vitro and in vivo using murine erythropoietin (mEPO) as a transgene model. A single electro-gene transfer of an RNA- and codon-optimized mEPOopt gene into skeletal muscle resulted in a 3- to 4-fold increase of mEPO production sustained for >1 year and triggered a significant increase in hematocrit and hemoglobin without causing adverse effects. mEPO expression and hematologic levels were significantly lower when using comparable amounts of the wild type (mEPOwt) gene and only marginal effects were induced by mEPOΔCpG lacking intragenic CpG dinucleotides, even at high pDNA amounts. Corresponding with these observations, in vitro analysis of transfected cells revealed a 2- to 3-fold increased (mEPOopt) and 50% decreased (mEPOΔCpG) erythropoietin expression compared with mEPOwt, respectively. RNA analyses demonstrated that the specific design of the transgene sequence influenced expression levels by modulating transcriptional activity and nuclear plus cytoplasmic RNA amounts rather than translation. In sum, whereas CpG depletion negatively interferes with efficient expression in postmitotic tissues, mEPOopt doses <0.5 μg were sufficient to trigger optimal long-term hematologic effects encouraging the use of sequence-optimized transgenes to further reduce effective pDNA amounts.
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Gatto, Federico; Barbieri, Federica; Gatti, Monica; Wurth, Roberto; Schulz, Stefan; Ravetti, Jean-Louis; Zona, Gianluigi; Culler, Michael D; Saveanu, Alexandru; Giusti, Massimo; Minuto, Francesco; Hofland, Leo J; Ferone, Diego; Florio, Tullio
2012-03-01
First-line therapy for thyrotropin-secreting pituitary adenomas (TSHomas) is neurosurgery, while medical treatment rests mainly on somatostatin analogues. Clinically available sst(2) -preferring analogues, octreotide and lanreotide, induce normalization of hormone levels in approximately 90% of patients and tumour shrinkage in 45%. We evaluated somatostatin 1, 2, 3 and 5 and dopamine D2 receptor expression in tumour samples from three TSHomas, and the relationships between receptor expression, in vitro antiproliferative response and clinical data, including octreotide test and three months of therapy with octreotide long-acting repeatable (LAR). TSHoma cell proliferation was tested in vitro using octreotide, cabergoline and two chimeric compounds, BIM-23A760 and BIM-23A387. All patients showed significant TSH lowering to acute octreotide test, but a hormonal response to long-term treatment was observed in only two patients, showing a high sst(5) /sst(2) ratio. Patient 2, characterized by high expression of sst(2) and sst(1) and a relative lower expression of sst(5) , experienced tachyphylaxis after prolonged octreotide treatment. In vitro, the somatostatin/dopamine receptor agonist BIM-23A760 caused the highest antiproliferative effect among those tested. Combined treatment with octreotide and cabergoline displayed an additive effect of magnitude comparable to that of the other chimeric compound (BIM-23A387). Octreotide resistance was confirmed in cells isolated from the nonresponder patient, although it could be overcome by treatment with the chimeric compounds. A high sst(5) /sst(2) ratio might be predictive of a positive outcome to long-term treatment with somatostatin analogues in TSHomas. Moreover, combined somatostatin and D(2) receptor targeting might be considered as a potential tool to improve the response rate in octreotide-resistant tumours. © 2012 Blackwell Publishing Ltd.
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Wu, Minghua; Obara, Yutaro; Ohshima, Shingo; Nagasawa, Yoshinobu; Ishii, Kuniaki
2017-11-04
Diabetes mellitus affects ion channel physiology. We have previously reported that acute application of insulin suppresses the KCNQ1/KCNE1 currents that play an important role in terminating ventricular action potential. In this study, we investigated the effect of long-term insulin treatment on KCNQ1/KCNE1 currents using the Xenopus oocyte expression system. Insulin treatment with a duration longer than 6 h had an opposite effect to acute insulin application, that is, it augmented the KCNQ1/KCNE1 currents. Inhibitors of PI3K, wortmannin and LY294002, and a MEK inhibitor, U0126, abolished the potentiating effect of long-term insulin treatment. The long-term treatment with insulin had no effect on KCNQ1 currents indicating an essential role of KCNE1 in the insulin effect, which is similar to the acute insulin effect. Cycloheximide, an inhibitor of protein synthesis, and brefeldin A, an inhibitor of protein transport from endoplasmic reticulum, suppressed the long-term insulin effect. Western blotting analysis combined with these pharmacological data suggest that long-term insulin treatment augments KCNQ1/KCNE1 currents by increasing KCNE1 protein expression. Copyright © 2017 Elsevier Inc. All rights reserved.
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Berthiaume, Nathalie; Carlson, Christian J; Rondinone, Cristina M; Zinker, Bradley A
2005-11-01
In the present study, we investigated the effects of long-term treatment with the endothelin (ET) antagonist atrasentan, an ET(A)-selective antagonist, on whole body glucose metabolism and insulin signaling in a commonly used model of insulin resistance, the Zucker fatty rat. Zucker lean and fatty rats were maintained for 6 weeks on either control or atrasentan-treated water. Euglycemic-hyperinsulinemic clamps (4 mU/kg per minute) were performed at the end of the 6-week treatment on a subset of rats (n=10/treatment). In another subset (n=5/treatment), an insulin tolerance test was performed; liver and muscle tissues were harvested 10 minutes following the challenge for further analysis. Results of the clamps demonstrated that long-term atrasentan treatment significantly increased whole body glucose metabolism in fatty rats compared with vehicle control subjects. Insulin-induced insulin receptor substrate 1 tyrosine and protein kinase B serine phosphorylation were significantly reduced in the liver and muscle of fatty animals compared with their lean littermates. This reduction was overcome with atrasentan treatment in the liver but not in the muscle. There was no difference between lean and fatty animals, however, in insulin receptor substrate 1 and protein kinase B protein expression in the liver and muscle and no effect by atrasentan. In contrast, expression of the regulatory subunit of PI-3 kinase (p85alpha) was significantly increased in the liver but not in the muscle of fatty animals compared with their lean littermates and this was normalized to levels of lean animals with atrasentan treatment. These findings indicate that long-standing ET antagonism improves whole body glucose metabolism in Zucker fatty rats through improvements in insulin signaling in the liver. These results indicate that therapeutic ET antagonism may assist in correcting the insulin-resistant state.
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Sweet Taste and Nutrient Value Subdivide Rewarding Dopaminergic Neurons in Drosophila
Huetteroth, Wolf; Perisse, Emmanuel; Lin, Suewei; Klappenbach, Martín; Burke, Christopher; Waddell, Scott
2015-01-01
Summary Dopaminergic neurons provide reward learning signals in mammals and insects [1–4]. Recent work in Drosophila has demonstrated that water-reinforcing dopaminergic neurons are different to those for nutritious sugars [5]. Here, we tested whether the sweet taste and nutrient properties of sugar reinforcement further subdivide the fly reward system. We found that dopaminergic neurons expressing the OAMB octopamine receptor [6] specifically convey the short-term reinforcing effects of sweet taste [4]. These dopaminergic neurons project to the β′2 and γ4 regions of the mushroom body lobes. In contrast, nutrient-dependent long-term memory requires different dopaminergic neurons that project to the γ5b regions, and it can be artificially reinforced by those projecting to the β lobe and adjacent α1 region. Surprisingly, whereas artificial implantation and expression of short-term memory occur in satiated flies, formation and expression of artificial long-term memory require flies to be hungry. These studies suggest that short-term and long-term sugar memories have different physiological constraints. They also demonstrate further functional heterogeneity within the rewarding dopaminergic neuron population. PMID:25728694
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The ERM protein Moesin is essential for neuronal morphogenesis and long-term memory in Drosophila.
Freymuth, Patrick S; Fitzsimons, Helen L
2017-08-29
Moesin is a cytoskeletal adaptor protein that plays an important role in modification of the actin cytoskeleton. Rearrangement of the actin cytoskeleton drives both neuronal morphogenesis and the structural changes in neurons that are required for long-term memory formation. Moesin has been identified as a candidate memory gene in Drosophila, however, whether it is required for memory formation has not been evaluated. Here, we investigate the role of Moesin in neuronal morphogenesis and in short- and long-term memory formation in the courtship suppression assay, a model of associative memory. We found that both knockdown and overexpression of Moesin led to defects in axon growth and guidance as well as dendritic arborization. Moreover, reduction of Moesin expression or expression of a constitutively active phosphomimetic in the adult Drosophila brain had no effect on short term memory, but prevented long-term memory formation, an effect that was independent of its role in development. These results indicate a critical role for Moesin in both neuronal morphogenesis and long-term memory formation.
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Astrocyte-neuron lactate transport is required for long-term memory formation.
Suzuki, Akinobu; Stern, Sarah A; Bozdagi, Ozlem; Huntley, George W; Walker, Ruth H; Magistretti, Pierre J; Alberini, Cristina M
2011-03-04
We report that, in the rat hippocampus, learning leads to a significant increase in extracellular lactate levels that derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by L-lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc, and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation. Copyright © 2011 Elsevier Inc. All rights reserved.
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Presynaptic Protein Synthesis Is Required for Long-Term Plasticity of GABA Release.
Younts, Thomas J; Monday, Hannah R; Dudok, Barna; Klein, Matthew E; Jordan, Bryen A; Katona, István; Castillo, Pablo E
2016-10-19
Long-term changes of neurotransmitter release are critical for proper brain function. However, the molecular mechanisms underlying these changes are poorly understood. While protein synthesis is crucial for the consolidation of postsynaptic plasticity, whether and how protein synthesis regulates presynaptic plasticity in the mature mammalian brain remain unclear. Here, using paired whole-cell recordings in rodent hippocampal slices, we report that presynaptic protein synthesis is required for long-term, but not short-term, plasticity of GABA release from type 1 cannabinoid receptor (CB 1 )-expressing axons. This long-term depression of inhibitory transmission (iLTD) involves cap-dependent protein synthesis in presynaptic interneuron axons, but not somata. Translation is required during the induction, but not maintenance, of iLTD. Mechanistically, CB 1 activation enhances protein synthesis via the mTOR pathway. Furthermore, using super-resolution STORM microscopy, we revealed eukaryotic ribosomes in CB 1 -expressing axon terminals. These findings suggest that presynaptic local protein synthesis controls neurotransmitter release during long-term plasticity in the mature mammalian brain. Copyright © 2016 Elsevier Inc. All rights reserved.
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A novel intranuclear RNA vector system for long-term stem cell modification
Ikeda, Yasuhiro; Makino, Akiko; Matchett, William E.; Holditch, Sara J.; Lu, Brian; Dietz, Allan B.; Tomonaga, Keizo
2015-01-01
Genetically modified stem and progenitor cells have emerged as a promising regenerative platform in the treatment of genetic and degenerative disorders, highlighted by their successful therapeutic use in inherent immunodeficiencies. However, biosafety concerns over insertional mutagenesis resulting from integrating recombinant viral vectors have overshadowed the widespread clinical applications of genetically modified stem cells. Here, we report an RNA-based episomal vector system, amenable for long-term transgene expression in stem cells. Specifically, we used a unique intranuclear RNA virus, Borna disease virus (BDV), as the gene transfer vehicle, capable of persistent infections in various cell types. BDV-based vectors allowed for long-term transgene expression in mesenchymal stem cells (MSCs) without affecting cellular morphology, cell surface CD105 expression, or the adipogenicity of MSCs. Similarly, replication-defective BDV vectors achieved long-term transduction of human induced pluripotent stem cells (iPSCs), while maintaining the ability to differentiate into three embryonic germ layers. Thus, the BDV-based vectors offer a genomic modification-free, episomal RNA delivery system for sustained stem cell transduction. PMID:26632671
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Can long-term thiamine treatment improve the clinical outcomes of myotonic dystrophy type 1?
Costantini, Antonio; Trevi, Erika; Pala, Maria Immacolata; Fancellu, Roberto
2016-09-01
Myotonic dystrophy type 1, also known as Steinert's disease, is an autosomal dominant disorder with multisystemic clinical features affecting the skeletal and cardiac muscles, the eyes, and the endocrine system. Thiamine (vitamin B1) is a cofactor of fundamental enzymes involved in the energetic cell metabolism; recent studies described its role in oxidative stress, protein processing, peroxisomal function, and gene expression. Thiamine deficiency is critical mainly in the central and peripheral nervous system, as well as in the muscular cells. Our aim was to investigate the potential therapeutical effects of long-term treatment with thiamine in myotonic dystrophy type 1 in an observational open-label pilot study. We described two patients with myotonic dystrophy type 1 treated with intramuscular thiamine 100 mg twice a week for 12 or 11 months. We evaluated the patients using the grading of muscle strength according to Medical Research Council (MRC), the Muscular Impairment Rating Scale (MIRS), and the Modified Barthel index. High-dose thiamine treatment was well tolerated and effective in improving the motor symptomatology, particularly the muscle strength evaluated with the MRC scale, and the patients' activities of daily living using the Modified Barthel Index. At the end of treatment, the MRC score was 5 in the proximal muscles and 2-4 in the distal muscles (the MRC score before the treatment was 3-4 and 1-3, respectively). The MIRS grade improved by 25% compared to baseline for both patients. In patient #1, the Modified Barthel Index improved by 44%, and in patient #2 by 29%. These findings suggest that clinical outcomes are improved by long-term thiamine treatment.
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Preventing pressure ulcers in long-term care: a cost-effectiveness analysis.
Pham, Ba'; Stern, Anita; Chen, Wendong; Sander, Beate; John-Baptiste, Ava; Thein, Hla-Hla; Gomes, Tara; Wodchis, Walter P; Bayoumi, Ahmed; Machado, Márcio; Carcone, Steven; Krahn, Murray
2011-11-14
Pressure ulcers are common in many care settings, with adverse health outcomes and high treatment costs. We evaluated the cost-effectiveness of evidence-based strategies to improve current prevention practice in long-term care facilities. We used a validated Markov model to compare current prevention practice with the following 4 quality improvement strategies: (1) pressure redistribution mattresses for all residents, (2) oral nutritional supplements for high-risk residents with recent weight loss, (3) skin emollients for high-risk residents with dry skin, and (4) foam cleansing for high-risk residents requiring incontinence care. Primary outcomes included lifetime risk of stage 2 to 4 pressure ulcers, quality-adjusted life-years (QALYs), and lifetime costs, calculated according to a single health care payer's perspective and expressed in 2009 Canadian dollars (Can$1 = US$0.84). Strategies cost on average $11.66 per resident per week. They reduced lifetime risk; the associated number needed to treat was 45 (strategy 1), 63 (strategy 4), 158 (strategy 3), and 333 (strategy 2). Strategy 1 and 4 minimally improved QALYs and reduced the mean lifetime cost by $115 and $179 per resident, respectively. The cost per QALY gained was approximately $78 000 for strategy 3 and $7.8 million for strategy 2. If decision makers are willing to pay up to $50 000 for 1 QALY gained, the probability that improving prevention is cost-effective is 94% (strategy 4), 82% (strategy 1), 43% (strategy 3), and 1% (strategy 2). The clinical and economic evidence supports pressure redistribution mattresses for all long-term care residents. Improving prevention with perineal foam cleansers and dry skin emollients appears to be cost-effective, but firm conclusions are limited by the available clinical evidence.
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Vranckx, Jan Jeroen; Hoeller, Daniela; Velander, Patrik E M; Theopold, Christoph F P; Petrie, Nicola; Takedo, Akira; Eriksson, Elof; Yao, Feng
2007-01-01
The concept of using growth factor therapy to induce wound repair has been endorsed in studies that show reduced growth factors in wound fluid from chronic and aged wounds. In this study, we used cell suspensions of allogenic keratinocytes as gene-delivery vehicles for human epidermal growth factor (hEGF) and analyzed their impact on wound repair in a porcine wound-healing model. Full-thickness wounds were created on the backs of six Yorkshire pigs and covered with a wound chamber to create a wet wound-healing environment. First, 5 x 10(5) allogenic, autogenic, or mixed keratinocytes were transplanted into wounds and healing parameters were analyzed. Second, we measured long-term reepithelialization and contraction rates from day 8 until day 35. In the third experiment, allogenic keratinocytes were transfected with an hEGF-expressing plasmid pCEP-hEGF and transplanted in full-thickness wounds to improve repair. Wounds treated with autogenic, allogenic, or mixed keratinocytes showed a significantly higher rate of reepithelialization relative to saline-treated control wounds. Repetitive biopsies indicated that the use of allogenic keratinocytes did not lead to long-term wound breakdown. Wounds treated with hEGF-expressing allogenic keratinocytes reepithelialized faster than wounds treated with allogenic keratinocytes or control wounds. With a peak hEGF expression of 920.8 pg/mL, hEGF was detectable until day 5 after transplantation compared with minimal hEGF expression in control wounds. This study shows that allogenic keratinocytes can serve as efficient gene transfer vehicles for ex vivo growth factor delivery to full-thickness wounds and overexpression of hEGF further improves reepithelialization rates.
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Jin, Chuan; Fotaki, Grammatiki; Ramachandran, Mohanraj; Nilsson, Berith; Essand, Magnus; Yu, Di
2016-07-01
Chimeric antigen receptor (CAR) T-cell therapy is a new successful treatment for refractory B-cell leukemia. Successful therapeutic outcome depends on long-term expression of CAR transgene in T cells, which is achieved by delivering transgene using integrating gamma retrovirus (RV) or lentivirus (LV). However, uncontrolled RV/LV integration in host cell genomes has the potential risk of causing insertional mutagenesis. Herein, we describe a novel episomal long-term cell engineering method using non-integrating lentiviral (NILV) vector containing a scaffold/matrix attachment region (S/MAR) element, for either expression of transgenes or silencing of target genes. The insertional events of this vector into the genome of host cells are below detection level. CD19 CAR T cells engineered with a NILV-S/MAR vector have similar levels of CAR expression as T cells engineered with an integrating LV vector, even after numerous rounds of cell division. NILV-S/MAR-engineered CD19 CAR T cells exhibited similar cytotoxic capacity upon CD19(+) target cell recognition as LV-engineered T cells and are as effective in controlling tumor growth in vivo We propose that NILV-S/MAR vectors are superior to current options as they enable long-term transgene expression without the risk of insertional mutagenesis and genotoxicity. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.
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Satia, Jessie A; Barlow, Jameta; Armstrong-Brown, Janelle; Watters, Joanne L
2010-01-01
There is a dearth of knowledge regarding factors that may motivate African American adolescents to consume healthier diets. To develop and test cancer prevention messages based on Prospect Theory on motivation to improve dietary intake in African American adolescents and to explore other salient factors that may inform dietary intervention design and implementation in this population. Semistructured in-person qualitative interviews were conducted with 13 African American male and female adolescents, aged 12 to 16 years, in North Carolina. Prospect Theory and message framing were used to guide the design of the 4 sets of diet-related messages related to cancer prevention: short-term, gain-framed; long-term, gain-framed; short-term, loss-framed; and long-term, loss-framed messages. Data were also collected on demographic, behavioral, and psychological factors; usual health behaviors; and preferences for intervention delivery. Most respondents found the gain-framed, short-term messages most salient for both fruits/vegetables (8 [61.5%]) and fat consumption (7 [53.8%]). For fat consumption only, 2 (15.4%) found the loss-framed, short-term messages pertinent; none found the loss-framed, long-term messages relevant for either dietary variable. All indicated interest in participating in a dietary intervention/education program; most preferred the Internet as a channel for intervention delivery. Participants expressed diverse views regarding knowledge, attitudes, and beliefs regarding healthy eating. The gain-framed, short-term messages were most salient for motivating the majority of respondents to consume a healthy diet and most expressed a strong interest in participating in programs about diet and nutrition, with the Internet as the preferred communication channel. Researchers conducting dietary interventions and education initiatives and medical professionals who counsel African American adolescents should consider using Prospect Theory as a theoretical framework, should focus on gain-framed, short-term messages regarding cancer prevention, and should use the Internet for data collection and intervention and information delivery.
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ERIC Educational Resources Information Center
Oliveira, Ana M. M.; Brindle, Paul K.; Abel, Ted; Wood, Marcelo A.; Attner, Michelle A.
2006-01-01
Transcriptional activation is a key process required for long-term memory formation. Recently, the transcriptional coactivator CREB-binding protein (CBP) was shown to be critical for hippocampus-dependent long-term memory and hippocampal synaptic plasticity. As a coactivator with intrinsic histone acetyltransferase activity, CBP interacts with…
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SGK Protein Kinase Facilitates the Expression of Long-Term Potentiation in Hippocampal Neurons
ERIC Educational Resources Information Center
Ma, Yun L.; Tsai, Ming C.; Hsu, Wei L.; Lee, Eminy H.Y.
2006-01-01
Previous studies showed that the serum- and glucocorticoid-inducible kinase ("sgk") gene plays an important role in long-term memory formation. The present study further examined the role of SGK in long-term potentiation (LTP). The dominant-negative mutant of "sgk," SGKS422A, was used to inactivate SGK. Results revealed a time-dependent increase…
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Liu, Long; Fan, Yanfeng; Zhang, Zhenhe; Yang, Chan; Geng, Tuoyu; Gong, Daoqing; Hou, Zhuocheng; Ning, Zhonghua
2017-01-01
The reproductive system of a female bird is responsible for egg production. The genes highly expressed in oviduct are potentially important. From RNA-seq analysis, C2H9orf152 (an orthologous gene of human C9orf152) was identified as highly expressed in chicken uterus. To infer its function, we obtained and characterized its complete cDNA sequence, determined its spatiotemporal expression, and probed its transcription factor(s) through pharmaceutical approach. Data showed that the complete cDNA sequence was 1468bp long with a 789bp of open reading frame. Compared to other tested tissues, this gene was highly expressed in the oviduct and liver tissues, especially uterus. Its expression in uterus was gradually increased during developmental and reproductive periods, which verified its involvement in the growth and maturity of reproductive system. In contrast, its expression was not significant different between active and quiescent uterus, suggesting the role of C2H9orf152 in reproduction is likely due to its long-term effect. Moreover, based on its 5'-flanking sequence, Foxd3 and Hnf4a were predicted as transcription factors of C2H9orf152. Using berberine or retinoic acid (which can regulate the activities of Hnf4a and Foxd3, respectively), we demonstrated suppression of C2H9orf152 by the chemicals in chicken primary hepatocytes. As retinoic acid regulates calcium metabolism, and Hnf4a is a key nuclear factor to liver, these findings suggest that C2H9orf152 is involved in liver function and calcium metabolism of reproductive system. In conclusion, C2H9orf152 may have a long-term effect on chicken reproductive system by regulating calcium metabolism, suggesting this gene has an important implication in the improvement of egg production and eggshell quality. Copyright © 2016 Elsevier B.V. All rights reserved.
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Bonanno, George A; Colak, Deniz M; Keltner, Dacher; Shiota, Michelle N; Papa, Anthony; Noll, Jennie G; Putnam, Frank W; Trickett, Penelope K
2007-11-01
Positive emotions promote adjustment to aversive life events. However, evolutionary theory and empirical research on trauma disclosure suggest that in the context of stigmatized events, expressing positive emotions might incur social costs. To test this thesis, the authors coded genuine (Duchenne) smiling and laughter and also non-Duchenne smiling from videotapes of late-adolescent and young adult women, approximately half with documented histories of childhood sexual abuse (CSA), as they described the most distressing event of their lives. Consistent with previous studies, genuine positive emotional expression was generally associated with better social adjustment two years later. However, as anticipated, CSA survivors who expressed positive emotion in the context of describing a past CSA experience had poorer long-term social adjustment, whereas CSA survivors who expressed positive emotion while describing a nonabuse experience had improved social adjustment. These findings suggest that the benefits of positive emotional expression may often be context specific.
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Kan, Min Hui; Yang, Ting; Fu, Hui Qun; Fan, Long; Wu, Yan; Terrando, Niccolò; Wang, Tian-Long
2016-01-01
Systemic inflammation, for example as a result of infection, often contributes to long-term complications. Neuroinflammation and cognitive decline are key hallmarks of several neurological conditions, including advance age. The contribution of systemic inflammation to the central nervous system (CNS) remains not fully understood. Using a model of peripheral endotoxemia with lipopolysaccharide (LPS) we investigated the role of nuclear factor-κB (NF-κB) activity in mediating long-term neuroinflammation and cognitive dysfunction in aged rats. Herein we describe the anti-inflammatory effects of pyrrolidine dithiocarbamate (PDTC), a selective NF-κB inhibitor, in modulating systemic cytokines including tumor necrosis factor (TNF)-α and interleukin-1β (IL-1β) and CNS markers after LPS exposure in aged rats. In the hippocampus, PDTC not only reduced neuroinflammation by modulating canonical NF-κB activity but also affected IL-1β expression in astrocytes. Parallel effects were observed on behavior and postsynaptic density-95 (PSD95), a marker of synaptic function. Taken together these changes improved acute and long-term cognitive function in aged rats after LPS exposure. PMID:27493629
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Epigenetics and depression: return of the repressed.
Dalton, Victoria S; Kolshus, Erik; McLoughlin, Declan M
2014-02-01
Epigenetics has recently emerged as a potential mechanism by which adverse environmental stimuli can result in persistent changes in gene expression. Epigenetic mechanisms function alongside the DNA sequence to modulate gene expression and ultimately influence protein production. The current review provides an introduction and overview of epigenetics with a particular focus on preclinical and clinical studies relevant to major depressive disorder (MDD). PubMed and Web of Science databases were interrogated from January 1995 up to December 2012 using combinations of search terms, including "epigenetic", "microRNA" and "DNA methylation" cross referenced with "depression", "early life stress" and "antidepressant". There is an association between adverse environmental stimuli, such as early life stress, and epigenetic modification of gene expression. Epigenetic changes have been reported in humans with MDD and may serve as biomarkers to improve diagnosis. Antidepressant treatments appear to reverse or initiate compensatory epigenetic alterations that may be relevant to their mechanism of action. As a narrative review, the current report was interpretive and qualitative in nature. Epigenetic modification of gene expression provides a mechanism for understanding the link between long-term effects of adverse life events and the changes in gene expression that are associated with depression. Although still a developing field, in the future, epigenetic modifications of gene expression may provide novel biomarkers to predict future susceptibility and/or onset of MDD, improve diagnosis, and aid in the development of epigenetics-based therapies for depression. © 2013 Published by Elsevier B.V.
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Yoon, Gwangho; Shah, Shahid Ali; Ali, Tahir; Kim, Myeong Ok
2018-01-15
Alzheimer's disease is a major neurodegenerative disease characterized by memory loss and cognitive deficits. Recently, we reported that osmotin, which is a homolog of adiponectin, improved long-term potentiation and cognitive functions in Alzheimer's disease mice. Several lines of evidence have suggested that Nogo-A and the Nogo-66 receptor 1 (NgR1), which form a complex that inhibits long-term potentiation and cognitive function, might be associated with the adiponectin receptor 1 (AdipoR1), which is a receptor for osmotin. Here, we explore whether osmotin's effects on long-term potentiation and memory function are associated with NgR1 signaling via AdipoR1 in Alzheimer's disease. Osmotin reduced the expression of NgR1 without affecting Nogo-A expression. Furthermore, osmotin inhibited NgR1 signaling by prohibiting the formation of the Nogo-A and NgR1 ligand-receptor complex, resulting in enhanced neurite outgrowth; these effects disappeared in the presence of AdipoR1 interference. In addition, osmotin increased the expression of the pre- and postsynaptic markers synaptophysin and PSD-95, as well as the activation of the memory-associated markers AMPA receptor and CREB; these effects occurred in an AdipoR1- and NgR1-dependent manner. Osmotin was also found to enhance dendritic complexity and spine density in the hippocampal region of Alzheimer's disease mouse brains. These results suggest that osmotin can enhance neurite outgrowth and synaptic complexity through AdipoR1 and NgR1 signaling, implying that osmotin might be an effective therapeutic agent for Alzheimer's disease and that AdipoR1 might be a crucial therapeutic target for neurodegenerative diseases such as Alzheimer's.
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Noordhuizen, J P; Welpelo, H J
1996-12-01
This paper addresses the principles of the Hazard Analysis Critical Control Point (HACCP) concept as applied to animal health management strategy. Characteristics of the concept were analysed and compared with those of current animal health care strategies for disease risk identification and herd health management, insurance, and certification. HACCP is a hybrid strategy of quality control at both production process and product level. Animal health is considered a particular quality feature. We show that process control (expressed in terms of controlling both general and specific disease risk factors) and product control (expressed in terms of testing animals or animal products for specific disease agents) could form the basis for improving animal health. We conclude that HACCP provides ample opportunity for preventive health action and risk management at a relatively low cost in terms of labour, finance and documentation expenditure, at both the farm and sector level. Epidemiological field studies are currently needed to identify critical control points and to design HACCP procedures for livestock producers. In the long run, HACCP based animal health care can be further developed into a quality control systems approach to cover all aspects that are related, either directly or indirectly, to animal health.
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Effects of ibuprofen on cognition and NMDA receptor subunit expression across aging.
Márquez Loza, Alejandra; Elias, Valerie; Wong, Carmen P; Ho, Emily; Bermudez, Michelle; Magnusson, Kathy R
2017-03-06
Age-related declines in long- and short-term memory show relationships to decreases in N-methyl-d-aspartate (NMDA) receptor expression, which may involve inflammation. This study was designed to determine effects of an anti-inflammatory drug, ibuprofen, on cognitive function and NMDA receptor expression across aging. Male C57BL/6 mice (ages 5, 14, 20, and 26months) were fed ibuprofen (375ppm) in NIH31 diet or diet alone for 6weeks prior to testing. Behavioral testing using the Morris water maze showed that older mice performed significantly worse than younger in spatial long-term memory, reversal, and short-term memory tasks. Ibuprofen enhanced overall performance in the short-term memory task, but this appeared to be more related to improved executive function than memory. Ibuprofen induced significant decreases over all ages in the mRNA densities for GluN2B subunit, all GluN1 splice variants, and GluN1-1 splice forms in the frontal cortex and in protein expression of GluN2A, GluN2B and GluN1 C2' cassettes in the hippocampus. GluN1-3 splice form mRNA and C2' cassette protein were significantly increased across ages in frontal lobes of ibuprofen-treated mice. Ibuprofen did not alter expression of pro-inflammatory cytokines IL-1β and TNFα, but did reduce the area of reactive astrocyte immunostaining in frontal cortex of aged mice. Enhancement in executive function showed a relationship to increased GluN1-3 mRNA and decreased gliosis. These findings suggest that inflammation may play a role in executive function declines in aged animals, but other effects of ibuprofen on NMDA receptors appeared to be unrelated to aging or inflammation. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
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Kulterer, Birgit; Friedl, Gerald; Jandrositz, Anita; Sanchez-Cabo, Fatima; Prokesch, Andreas; Paar, Christine; Scheideler, Marcel; Windhager, Reinhard; Preisegger, Karl-Heinz; Trajanoski, Zlatko
2007-03-12
Human mesenchymal stem cells (MSC) with the capacity to differentiate into osteoblasts provide potential for the development of novel treatment strategies, such as improved healing of large bone defects. However, their low frequency in bone marrow necessitate ex vivo expansion for further clinical application. In this study we asked if MSC are developing in an aberrant or unwanted way during ex vivo long-term cultivation and if artificial cultivation conditions exert any influence on their stem cell maintenance. To address this question we first developed human oligonucleotide microarrays with 30.000 elements and then performed large-scale expression profiling of long-term expanded MSC and MSC during differentiation into osteoblasts. The results showed that MSC did not alter their osteogenic differentiation capacity, surface marker profile, and the expression profiles of MSC during expansion. Microarray analysis of MSC during osteogenic differentiation identified three candidate genes for further examination and functional analysis: ID4, CRYAB, and SORT1. Additionally, we were able to reconstruct the three developmental phases during osteoblast differentiation: proliferation, matrix maturation, and mineralization, and illustrate the activation of the SMAD signaling pathways by TGF-beta2 and BMPs. With a variety of assays we could show that MSC represent a cell population which can be expanded for therapeutic applications.
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Pons, Elsa; Peris, Josep E; Peña, Leandro
2012-07-15
The future of genetic transformation as a tool for the improvement of fruit trees depends on the development of proper systems for the assessment of unintended effects in field-grown GM lines. In this study, we used eight transgenic lines of two different citrus types (sweet orange and citrange) transformed with the marker genes β-glucuronidase (uidA) and neomycin phosphotransferase II (nptII) as model systems to study for the first time in citrus the long-term stability of transgene expression and whether transgene-derived pleiotropic effects occur with regard to the morphology, development and fruit quality of orchard-grown GM citrus trees. The stability of the integration and expression of the transgenes was confirmed in 7-year-old, orchard-grown transgenic lines by Southern blot analysis and enzymatic assays (GUS and ELISA NPTII), respectively. Little seasonal variation was detected in the expression levels between plants of the same transgenic line in different organs and over the 3 years of analysis, confirming the absence of rearrangements and/or silencing of the transgenes after transferring the plants to field conditions. Comparisons between the GM citrus lines with their non-GM counterparts across the study years showed that the expression of these transgenes did not cause alterations of the main phenotypic and agronomic plant and fruit characteristics. However, when comparisons were performed between diploid and tetraploid transgenic citrange trees and/or between juvenile and mature transgenic sweet orange trees, significant and consistent differences were detected, indicating that factors other than their transgenic nature induced a much higher phenotypic variability. Our results indicate that transgene expression in GM citrus remains stable during long-term agricultural cultivation, without causing unexpected effects on crop characteristics. This study also shows that the transgenic citrus trees expressing the selectable marker genes that are most commonly used in citrus transformation were substantially equivalent to the non-transformed controls with regard to their overall agronomic performance, as based on the use of robust and powerful assessment techniques. Therefore, future studies of the possible pleiotropic effects induced by the integration and expression of transgenes in field-grown GM citrus may focus on the newly inserted trait(s) of biotechnological interest.
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2012-01-01
Background The future of genetic transformation as a tool for the improvement of fruit trees depends on the development of proper systems for the assessment of unintended effects in field-grown GM lines. In this study, we used eight transgenic lines of two different citrus types (sweet orange and citrange) transformed with the marker genes β-glucuronidase (uidA) and neomycin phosphotransferase II (nptII) as model systems to study for the first time in citrus the long-term stability of transgene expression and whether transgene-derived pleiotropic effects occur with regard to the morphology, development and fruit quality of orchard-grown GM citrus trees. Results The stability of the integration and expression of the transgenes was confirmed in 7-year-old, orchard-grown transgenic lines by Southern blot analysis and enzymatic assays (GUS and ELISA NPTII), respectively. Little seasonal variation was detected in the expression levels between plants of the same transgenic line in different organs and over the 3 years of analysis, confirming the absence of rearrangements and/or silencing of the transgenes after transferring the plants to field conditions. Comparisons between the GM citrus lines with their non-GM counterparts across the study years showed that the expression of these transgenes did not cause alterations of the main phenotypic and agronomic plant and fruit characteristics. However, when comparisons were performed between diploid and tetraploid transgenic citrange trees and/or between juvenile and mature transgenic sweet orange trees, significant and consistent differences were detected, indicating that factors other than their transgenic nature induced a much higher phenotypic variability. Conclusions Our results indicate that transgene expression in GM citrus remains stable during long-term agricultural cultivation, without causing unexpected effects on crop characteristics. This study also shows that the transgenic citrus trees expressing the selectable marker genes that are most commonly used in citrus transformation were substantially equivalent to the non-transformed controls with regard to their overall agronomic performance, as based on the use of robust and powerful assessment techniques. Therefore, future studies of the possible pleiotropic effects induced by the integration and expression of transgenes in field-grown GM citrus may focus on the newly inserted trait(s) of biotechnological interest. PMID:22794278
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Nie, Xingju; Lowe, Danielle W; Rollins, Laura Grace; Bentzley, Jessica; Fraser, Jamie L; Martin, Renee; Singh, Inderjit; Jenkins, Dorothea
2016-07-01
Approximately half of moderate to severely hypoxic-ischemic (HI) newborns do not respond to hypothermia, the only proven neuroprotective treatment. N-acetylcysteine (NAC), an antioxidant and glutathione precursor, shows promise for neuroprotection in combination with hypothermia, mitigating post-HI neuroinflammation due to oxidative stress. As mechanisms of HI injury and cell death differ in males and females, sex differences must be considered in translational research of neuroprotection. We assessed the potential toxicity and efficacy of NAC in combination with hypothermia, in male and female neonatal rats after severe HI injury. NAC 50mg/kg/d administered 1h after initiation of hypothermia significantly decreased iNOS expression and caspase 3 activation in the injured hemisphere versus hypothermia alone. However, only females treated with hypothermia +NAC 50mg/kg showed improvement in short-term infarct volumes compared with saline treated animals. Hypothermia alone had no effect in this severe model. When NAC was continued for 6 weeks, significant improvement in long-term neuromotor outcomes over hypothermia treatment alone was observed, controlling for sex. Antioxidants may provide insufficient neuroprotection after HI for neonatal males in the short term, while long-term therapy may benefit both sexes. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
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Adjuvant-specific regulation of long-term antibody responses by ZBTB20
Wang, Yinan
2014-01-01
The duration of antibody production by long-lived plasma cells varies with the type of immunization, but the basis for these differences is unknown. We demonstrate that plasma cells formed in response to the same immunogen engage distinct survival programs depending on the adjuvant. After alum-adjuvanted immunization, antigen-specific bone marrow plasma cells deficient in the transcription factor ZBTB20 failed to accumulate over time, leading to a progressive loss of antibody production relative to wild-type controls. Fetal liver reconstitution experiments demonstrated that the requirement for ZBTB20 was B cell intrinsic. No defects were observed in germinal center numbers, affinity maturation, or plasma cell formation or proliferation in ZBTB20-deficient chimeras. However, ZBTB20-deficient plasma cells expressed reduced levels of MCL1 relative to wild-type controls, and transgenic expression of BCL2 increased serum antibody titers. These data indicate a role for ZBTB20 in promoting survival in plasma cells. Strikingly, adjuvants that activate TLR2 and TLR4 restored long-term antibody production in ZBTB20-deficient chimeras through the induction of compensatory survival programs in plasma cells. Thus, distinct lifespans are imprinted in plasma cells as they are formed, depending on the primary activation conditions. The durability of vaccines may accordingly be improved through the selection of appropriate adjuvants. PMID:24711582
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Identification of a Functional Connectome for Long-Term Fear Memory in Mice
Wheeler, Anne L.; Teixeira, Cátia M.; Wang, Afra H.; Xiong, Xuejian; Kovacevic, Natasa; Lerch, Jason P.; McIntosh, Anthony R.; Parkinson, John; Frankland, Paul W.
2013-01-01
Long-term memories are thought to depend upon the coordinated activation of a broad network of cortical and subcortical brain regions. However, the distributed nature of this representation has made it challenging to define the neural elements of the memory trace, and lesion and electrophysiological approaches provide only a narrow window into what is appreciated a much more global network. Here we used a global mapping approach to identify networks of brain regions activated following recall of long-term fear memories in mice. Analysis of Fos expression across 84 brain regions allowed us to identify regions that were co-active following memory recall. These analyses revealed that the functional organization of long-term fear memories depends on memory age and is altered in mutant mice that exhibit premature forgetting. Most importantly, these analyses indicate that long-term memory recall engages a network that has a distinct thalamic-hippocampal-cortical signature. This network is concurrently integrated and segregated and therefore has small-world properties, and contains hub-like regions in the prefrontal cortex and thalamus that may play privileged roles in memory expression. PMID:23300432
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Douris, Nicholas; Melman, Tamar; Pecherer, Jordan M; Pissios, Pavlos; Flier, Jeffrey S; Cantley, Lewis C; Locasale, Jason W; Maratos-Flier, Eleftheria
2015-10-01
Ingestion of very low-carbohydrate ketogenic diets (KD) is associated with weight loss, lowering of glucose and insulin levels and improved systemic insulin sensitivity. However, the beneficial effects of long-term feeding have been the subject of debate. We therefore studied the effects of lifelong consumption of this diet in mice. Complete metabolic analyses were performed after 8 and 80weeks on the diet. In addition we performed a serum metabolomic analysis and examined hepatic gene expression. Lifelong consumption of KD had no effect on morbidity or mortality (KD vs. Chow, 676 vs. 630days) despite hepatic steatosis and inflammation in KD mice. The KD fed mice lost weight initially as previously reported (Kennnedy et al., 2007) and remained lighter and had less fat mass; KD consuming mice had higher levels of energy expenditure, improved glucose homeostasis and higher circulating levels of β-hydroxybutyrate and triglycerides than chow-fed controls. Hepatic expression of the critical metabolic regulators including fibroblast growth factor 21 were also higher in KD-fed mice while expression levels of lipogenic enzymes such as stearoyl-CoA desaturase-1 was reduced. Metabolomic analysis revealed compensatory changes in amino acid metabolism, primarily involving down-regulation of catabolic processes, demonstrating that mice eating KD can shift amino acid metabolism to conserve amino acid levels. Long-term KD feeding caused profound and persistent metabolic changes, the majority of which are seen as health promoting, and had no adverse effects on survival in mice. Copyright © 2015. Published by Elsevier B.V.
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Peng, Feng; Lin, Jinxiu; Lin, Liming; Tang, Hong
2012-12-01
The aim of this study was to compare the effectiveness of transient prehypertensive treatment with losartan compared with amlodipine in spontaneously hypertensive rats (SHRs) on long-term blood pressure (BP), cardiac and renal protection. SHRs were prehypertensively treated with losartan, amlodipine or saline. Rats were followed up until 46 weeks of age. The left ventricular (LV) geometry and function were assessed by echocardiography. Angiotensin II (Ang II) and aldosterone (Aldo) were measured by radioimmunoassay. Ang II type 1 (AT1R) and type 2 (AT2R) receptor protein expression was determined by western blotting. The systolic blood pressure (SBP) in losartan-treated SHRs (SHR-Los) was persistently reduced until 46 weeks of age, but returned to untreated SHR levels in amlodipine-treated SHRs (SHR-Aml) from 30 weeks onwards. Compared to untreated SHRs, the albuminuria excretion in SHR-Los at week 46 was markedly decreased, the plasma, myocardium and renal tissue Ang II and Aldo levels in SHR-Los at week 46 were markedly decreased; AT1R and TGF-β1 protein expression was downregulated and AT2R protein was upregulated. Compared to untreated SHRs, the left ventricular mass index (LVMI) and collagen volume fraction (CVF) in SHR-Los were markedly decreased until week 46, and the left ventricular ejection fraction (LVEF) and cardiac brain natriuretic peptide mRNA expression were improved, whereas similar LVMI and elevated CVF were observed in SHR-Aml, and the LVEF decreased significantly below that of untreated SHRs at week 46, with cardiac BNP mRNA expression increasing slightly. Prehypertensive treatment with losartan was more effective than amlodipine on delaying long-term BP increase and ameliorating cardiac, renal structure and function, which may be related to the permanent attenuation of the circulating and local renin-angiotensin systems.
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2006-08-23
Hypothalamic-pituitary-adrenocortical (HPA) Lateral hypothalamus (LH) Long-term depression (LTD) Long-term potentiation (LTP) Medial geniculate ...Aghajanian,GK. Activation of lateral geniculate neurons by norepinephrine: mediation by an alpha-adrenergic receptor. Brain Res. 1980;182: 345- 359...expressed in moderate to high levels, whereas 1B and 1D receptors are expressed at low levels. Conversely, in the lateral nucleus, 1B and 1D receptors are
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Drosophila Neprilysins Are Involved in Middle-Term and Long-Term Memory.
Turrel, Oriane; Lampin-Saint-Amaux, Aurélie; Préat, Thomas; Goguel, Valérie
2016-09-14
Neprilysins are type II metalloproteinases known to degrade and inactivate a number of small peptides. Neprilysins in particular are the major amyloid-β peptide-degrading enzymes. In mouse models of Alzheimer's disease, neprilysin overexpression improves learning and memory deficits, whereas neprilysin deficiency aggravates the behavioral phenotypes. However, whether these enzymes are involved in memory in nonpathological conditions is an open question. Drosophila melanogaster is a well suited model system with which to address this issue. Several memory phases have been characterized in this organism and the neuronal circuits involved are well described. The fly genome contains five neprilysin-encoding genes, four of which are expressed in the adult. Using conditional RNA interference, we show here that all four neprilysins are involved in middle-term and long-term memory. Strikingly, all four are required in a single pair of neurons, the dorsal paired medial (DPM) neurons that broadly innervate the mushroom bodies (MBs), the center of olfactory memory. Neprilysins are also required in the MB, reflecting the functional relationship between the DPM neurons and the MB, a circuit believed to stabilize memories. Together, our data establish a role for neprilysins in two specific memory phases and further show that DPM neurons play a critical role in the proper targeting of neuropeptides involved in these processes. Neprilysins are endopeptidases known to degrade a number of small peptides. Neprilysin research has essentially focused on their role in Alzheimer's disease and heart failure. Here, we use Drosophila melanogaster to study whether neprilysins are involved in memory. Drosophila can form several types of olfactory memory and the neuronal structures involved are well described. Four neprilysin genes are expressed in adult Drosophila Using conditional RNA interference, we show that all four are specifically involved in middle-term memory (MTM) and long-term memory (LTM) and that their expression is required in the mushroom bodies and also in a single pair of closely connected neurons. The data show that these two neurons play a critical role in targeting neuropeptides essential for MTM and LTM. Copyright © 2016 the authors 0270-6474/16/369535-12$15.00/0.
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A review of therapeutic prospects of non-viral gene therapy in the retinal pigment epithelium
Koirala, Adarsha; Conley, Shannon M.; Naash, Muna I.
2013-01-01
Ocular gene therapy has been extensively explored in recent years as a therapeutic avenue to target diseases of the cornea, retina and retinal pigment epithelium (RPE). Adeno-associated virus (AAV)-mediated gene therapy has shown promise in several RPE clinical trials but AAVs have limited payload capacity and potential immunogenicity. Traditionally however, non-viral alternatives have been plagued by low transfection efficiency, short-term expression and low expression levels. Recently, these drawbacks have begun to be overcome by the use of specialty carriers such as polylysine, liposomes, or polyethyleneimines, and by inclusion of suitable DNA elements to enhance gene expression and longevity. Recent advancements in the field have yielded non-viral vectors that have favorable safety profiles, lack immunogenicity, exhibit long-term elevated gene expression, and show efficient transfection in the retina and RPE, making them poised to transition to clinical applications. Here we discuss the advancements in nanotechnology and vector engineering that have improved the prospects for clinical application of non-viral gene therapy in the RPE. PMID:23796578
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Cervical cancer survivorship: Long-term quality of life and social support
Pfaendler, Krista S.; Wenzel, Lari; Mechanic, Mindy B.; Penner, Kristine R.
2015-01-01
Purpose Surgery, radiotherapy and chemotherapy are the mainstays of cervical cancer treatment. Many patients receive multiple treatment modalities, each with its own long-term effects. Given the high 5 year survival rate for cervical cancer patients, evaluation and improvement of long-term quality of life are essential. Methods Pertinent articles were identified through searches of PubMed for literature published from 1993-2014. We summarize quality of life data from long-term follow up studies of cervical cancer patients. We additionally summarize small group interviews of Hispanic and non-Hispanic cervical cancer survivors regarding social support and coping. Findings Data is varied in terms of the long term impact of treatment on quality of life but consistent in suggesting that patients who receive radiotherapy as part of their treatment have the highest risk of increased long term dysfunction of bladder and bowel, as well as sexual dysfunction and psychosocial consequences. Rigorous investigations regarding long-term consequences of treatment modalities are lacking. Implications Continued work to improve treatment outcomes and survival should also include a focus on reducing adverse long-term side effects. Providing supportive care during treatment, and evaluating the effects of supportive care, may reduce the prevalence and magnitude of long-term sequelae of cervical cancer, which will in turn improve quality of life and quality of care. PMID:25592090
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Li, Yuquan; Cheng, Lihong; Qin, Qianhong; Liu, Jian; Lo, Woo-kuen; Brako, Lowrence A; Yang, Qinglin
2009-10-01
Peroxisome proliferator-activated receptor delta (PPARdelta) is an essential determinant of basal myocardial fatty acid oxidation (FAO) and bioenergetics. We wished to determine whether increased lipid loading affects the PPARdelta deficient heart in transcriptional regulation of FAO and in the development of cardiac pathology. Cardiomyocyte-restricted PPARdelta knockout (CR-PPARdelta(-/-)) and control (alpha-MyHC-Cre) mice were subjected to 48 h of fasting and to a long-term maintenance on a (28 weeks) high-fat diet (HFD). The expression of key FAO proteins in heart was examined. Serum lipid profiles, cardiac pathology, and changes of various transduction signaling pathways were also examined. Mice subjected to fasting exhibited upregulated transcript expression of FAO genes in the CR-PPARdelta(-/-) hearts. Moreover, long-term HFD in CR-PPARdelta(-/-) mice induced a strikingly greater transcriptional response. After HFD, genes encoding key FAO enzymes were expressed remarkably more in CR-PPARdelta(-/-) hearts than in those of control mice. Despite the marked rise of FAO gene expression, corresponding protein expression remained low in the CR-PPARdelta(-/-) heart, accompanied by abnormalities in sarcomere structures and mitochondria that were similar to those of CR-PPARdelta(-/-) hearts with regular chow feeding. The CR-PPARdelta(-/-) mice displayed increased expression of PPARgamma co-activator-1alpha (PGC-1alpha) and PPARalpha in the heart with deactivated Akt and p42/44 MAPK signaling in response to HFD. We conclude that PPARdelta is an essential determinant of myocardial FAO. Increased lipid intake activates cardiac expression of FAO genes via PPARalpha/PGC-1alpha pathway, albeit it is not sufficient to improve cardiac pathology due to PPARdelta deficiency.
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NASA Astrophysics Data System (ADS)
Takagi, R.; Obara, K.; Uchida, N.
2017-12-01
Understanding slow earthquake activity improves our knowledge of slip behavior in brittle-ductile transition zone and subduction process including megathrust earthquakes. In order to understand overall picture of slow slip activity, it is important to make a comprehensive catalog of slow slip events (SSEs). Although short-term SSEs have been detected by GNSS and tilt meter records systematically, analysis of long-term slow slip events relies on individual slip inversions. We develop an algorism to systematically detect long-term SSEs and estimate source parameters of the SSEs using GNSS data. The algorism is similar to GRiD-MT (Tsuruoka et al., 2009), which is grid-based automatic determination of moment tensor solution. Instead of moment tensor fitting to long period seismic records, we estimate parameters of a single rectangle fault to fit GNSS displacement time series. First, we make a two dimensional grid covering possible location of SSE. Second, we estimate best-fit parameters (length, width, slip, and rake) of the rectangle fault at each grid point by an iterative damped least square method. Depth, strike, and dip are fixed on the plate boundary. Ramp function with duration of 300 days is used for expressing time evolution of the fault slip. Third, a grid maximizing variance reduction is selected as a candidate of long-term SSE. We also search onset of ramp function based on the grid search. We applied the method to GNSS data in southwest Japan to detect long-term SSEs in Nankai subduction zone. With current selection criteria, we found 13 events with Mw6.2-6.9 in Hyuga-nada, Bungo channel, and central Shikoku from 1998 to 2015, which include unreported events. Key finding is along strike migrations of long-term SSEs from Hyuga-nada to Bungo channel and from Bungo channel to central Shikoku. In particular, three successive events migrating northward in Hyuga-nada preceded the 2003 Bungo channel SSE, and one event in central Shikoku followed the 2003 SSE in Bungo channel. The space-time dimensions of the possible along-strike migration are about 300km in length and 6 years in time. Systematic detection with assumptions of various durations in the time evolution of SSE may improve the picture of SSE activity and possible interaction with neighboring SSEs.
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Larrosa, Pablo Nicolás Fernández; Ojea, Alejandro; Ojea, Ignacio; Molina, Victor Alejandro; Zorrilla-Zubilete, María Aurelia; Delorenzi, Alejandro
2017-07-01
Acute stress impairs memory retrieval of several types of memories. An increase in glucocorticoids, several minutes after stressful events, is described as essential to the impairing retrieval-effects of stressors. Moreover, memory retrieval under stress can have long-term consequences. Through what process does the reactivated memory under stress, despite the disrupting retrieval effects, modify long-term memories? The reconsolidation hypothesis proposes that a previously consolidated memory reactivated by a reminder enters a vulnerability phase (labilization) during which it is transiently sensitive to modulation, followed by a re-stabilization phase. However, previous studies show that the expression of memories during reminder sessions is not a condition to trigger the reconsolidation process since unexpressed memories can be reactivated and labilized. Here we evaluate whether it is possible to reactivate-labilize a memory under the impairing-effects of a mild stressor. We used a paradigm of human declarative memory whose reminder structure allows us to differentiate between a reactivated-labile memory state and a reactivated but non-labile state. Subjects memorized a list of five cue-syllables associated with their respective response-syllables. Seventy-two hours later, results showed that the retrieval of the paired-associate memory was impaired when tested 20min after a mild stressor (cold pressor stress (CPS)) administration, coincident with cortisol levels increase. Then, we investigated the long-term effects of CPS administration prior to the reminder session. Under conditions where the reminder initiates the reconsolidation process, CPS impaired the long-term memory expression tested 24h later. In contrast, CPS did not show effects when administered before a reminder session that does not trigger reconsolidation. Results showed that memory reactivation-labilization occurs even when retrieval was impaired. Memory reactivation under stress could hinder -via reconsolidation- the probability of the traces to be expressed in the long term. Copyright © 2017 Elsevier Inc. All rights reserved.
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Li, Pei; Zhang, Ruijie; Wang, Liyuan; Gan, Yibo; Xu, Yuan; Song, Lei; Luo, Lei; Zhao, Chen; Zhang, Chengmin; Ouyang, Bin; Tu, Bing; Zhou, Qiang
2017-04-30
Long-term exposure to a mechanical load causes degenerative changes in the disc nucleus pulposus (NP) tissue. A previous study demonstrated that N-cadherin (N-CDH)-mediated signalling can preserve the NP cell phenotype. However, N-CDH expression and the resulting phenotype alteration in NP cells under mechanical compression remain unclear. The present study investigated the effects of the compressive duration on N-CDH expression and on the phenotype of NP cells in an ex vivo disc organ culture. Porcine discs were organ cultured in a self-developed mechanically active bioreactor for 7 days. The discs were subjected to different dynamic compression durations (1 and 8 h at a magnitude of 0.4 MPa and frequency of 1.0 Hz) once per day. Discs that were not compressed were used as controls. The results showed that long-term compression duration (8 h) significantly down-regulated the expression of N-CDH and NP-specific molecule markers (Brachyury, Laminin, Glypican-3 and Keratin 19), attenuated Alcian Blue staining intensity, decreased glycosaminoglycan (GAG) and hydroxyproline (HYP) contents and decreased matrix macromolecule (aggrecan and collagen II) expression compared with the short-term compression duration (1 h). Taken together, these findings demonstrate that long-term load duration can induce N-CDH down-regulation, loss of normal cell phenotype and result in attenuation of NP-related matrix synthesis in NP cells. © 2017 The Author(s).
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Overview of developing desired conditions: Short-term actions, long-term objectives
J. D. Chew; K. O' Hara; J. G. Jones
2001-01-01
A number of modeling tools are required to go from short-term treatments to long-term objectives expressed as desired future conditions. Three models are used in an example that starts with determining desired stand level structure and ends with the implementation of treatments over time at a landscape scale. The Multi-Aged Stocking Assessment Model (MASAM) is used for...
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Transcription Factors in Long-Term Memory and Synaptic Plasticity
Alberini, Cristina M.
2013-01-01
Transcription is a molecular requisite for long-term synaptic plasticity and long-term memory formation. Thus, in the last several years, one main interest of molecular neuroscience has been the identification of families of transcription factors that are involved in both of these processes. Transcription is a highly regulated process that involves the combined interaction and function of chromatin and many other proteins, some of which are essential for the basal process of transcription, while others control the selective activation or repression of specific genes. These regulated interactions ultimately allow a sophisticated response to multiple environmental conditions, as well as control of spatial and temporal differences in gene expression. Evidence based on correlative changes in expression, genetic mutations, and targeted molecular inhibition of gene expression have shed light on the function of transcription in both synaptic plasticity and memory formation. This review provides a brief overview of experimental work showing that several families of transcription factors, including CREB, C/EBP, Egr, AP-1, and Rel have essential functions in both processes. The results of this work suggest that patterns of transcription regulation represent the molecular signatures of long-term synaptic changes and memory formation. PMID:19126756
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Hayashita-Kinoh, Hiromi; Yugeta, Naoko; Okada, Hironori; Nitahara-Kasahara, Yuko; Chiyo, Tomoko; Okada, Takashi; Takeda, Shin'ichi
2015-01-01
Duchenne muscular dystrophy (DMD) is a severe congenital disease due to mutations in the dystrophin gene. Supplementation of dystrophin using recombinant adenoassociated virus vector has promise as a treatment of DMD, although therapeutic benefit of the truncated dystrophin still remains to be elucidated. Besides, host immune responses against the vector as well as transgene products have been denoted in the clinical gene therapy studies. Here, we transduced dystrophic dogs fetuses to investigate the therapeutic effects of an AAV vector expressing microdystrophin under conditions of immune tolerance. rAAV-CMV-microdystrophin and a rAAV-CAG-luciferase were injected into the amniotic fluid surrounding fetuses. We also reinjected rAAV9-CMV-microdystrophin into the jugular vein of an infant dystrophic dog to induce systemic expression of microdystrophin. Gait and cardiac function significantly improved in the rAAV-microdystrophin-injected dystrophic dog, suggesting that an adequate treatment of rAAV-microdystrophin with immune modulation induces successful long-term transgene expression to analyze improved dystrophic phenotype. PMID:25586688
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Lee, Hae In; Lee, Sae-Won; Kim, Nam Gyun; Park, Kyoung-Jun; Choi, Byung Tae; Shin, Yong-Il; Shin, Hwa Kyoung
2017-12-01
We aimed to investigate the effects of low-level light emitting diode therapy (LED-T) on the long-term functional outcomes after cerebral ischemia, and the optimal timing of LED-T initiation for achieving suitable functional recovery. Focal cerebral ischemia was induced in mice via photothrombosis. These mice were assigned to a sham-operated (control), ischemic (vehicle), or LED-T group [initiation immediately (acute), 4 days (subacute) or 10 days (delayed) after ischemia, followed by once-daily treatment for 7 days]. Behavioral outcomes were assessed 21 and 28 days post-ischemia, and histopathological analysis was performed 28 days post-ischemia. The acute and subacute LED-T groups showed a significant improvement in motor function up to 28 days post-ischemia, although no brain atrophy recovery was noted. We observed proliferating cells (BrdU + ) in the ischemic brain, and significant increases in BrdU + /GFAP + , BrdU + /DCX + , BrdU + /NeuN + , and CD31 + cells in the subacute LED-T group. However, the BrdU + /Iba-1 + cell count was reduced in the subacute LED-T group. Furthermore, the brain-derived neurotrophic factor (BDNF) was significantly upregulated in the subacute LED-T group. We concluded that LED-T administered during the subacute stage had a positive impact on the long-term functional outcome, probably via neuron and astrocyte proliferation, blood vessel reconstruction, and increased BDNF expression. Picture: The rotarod test for motor coordination showed that acute and subacute LED-T improves long-term functional recovery after cerebral ischemia. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Aberrant DNA methylation of miR-219 promoter in long-term night shiftworkers.
Shi, Fengqin; Chen, Xinyi; Fu, Alan; Hansen, Johnni; Stevens, Richard; Tjonneland, Anne; Vogel, Ulla B; Zheng, Tongzhang; Zhu, Yong
2013-07-01
The idea that shiftwork may be carcinogenic in humans has gained widespread attention since the pioneering work linking shiftwork to breast cancer over two decades ago. However, the biomolecular consequences of long-term shiftwork exposure have not been fully explored. In this study, we performed a genome-wide CpG island methylation assay of microRNA (miRNA) promoters in long-term night shiftworkers and day workers. This analysis indicated that 50 CpG loci corresponding to 31 miRNAs were differentially methylated in night shiftworkers compared to day workers, including the circadian-relevant miR-219, the expression of which has been implicated in several cancers. A genome-wide expression microarray assay was carried out in a miR-219-overexpressed MCF-7 breast cancer cell line, which identified 319 differentially expressed transcripts. The identified transcriptional targets were analyzed for network and functional interrelatedness using the Ingenuity Pathway Analysis (IPA) software. Overexpression of miR-219 in MCF-7 breast cancer cells resulted in accentuated expression of apoptosis- and proliferation-related anti-viral immunodulators of the Jak-STAT and NF-κβ pathways. These findings suggest that long-term night shiftwork exposure may lead to the methylation-dependent downregulation of miR-219, which may in turn lead to the downregulation of immunomediated antitumor activity and increased breast cancer risk. © 2013 Wiley Periodicals, Inc.
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Romero, Roberto; Tarca, Adi; Chaemsaithong, Piya; Miranda, Jezid; Chaiworapongsa, Tinnakorn; Jia, Hui; Hassan, Sonia S.; Kalita, Cynthia A.; Cai, Juan; Yeo, Lami; Lipovich, Leonard
2014-01-01
Objective The mechanisms responsible for normal and abnormal parturition are poorly understood. Myometrial activation leading to regular uterine contractions is a key component of labor. Dysfunctional labor (arrest of dilatation and/or descent) is a leading indication for cesarean delivery. Compelling evidence suggests that most of these disorders are functional in nature, and not the result of cephalopelvic disproportion. The methodology and the datasets afforded by the post-genomic era provide novel opportunities to understand and target gene functions in these disorders. In 2012, the ENCODE Consortium elucidated the extraordinary abundance and functional complexity of long non-coding RNA genes in the human genome. The purpose of the study was to identify differentially expressed long non-coding RNA genes in human myometrium in women in spontaneous labor at term. Materials and Methods Myometrium was obtained from women undergoing cesarean deliveries who were not in labor (n=19) and women in spontaneous labor at term (n=20). RNA was extracted and profiled using an Illumina® microarray platform. The analysis of the protein coding genes from this study has been previously reported. Here, we have used computational approaches to bound the extent of long non-coding RNA representation on this platform, and to identify co-differentially expressed and correlated pairs of long non-coding RNA genes and protein-coding genes sharing the same genomic loci. Results Upon considering more than 18,498 distinct lncRNA genes compiled nonredundantly from public experimental data sources, and interrogating 2,634 that matched Illumina microarray probes, we identified co-differential expression and correlation at two genomic loci that contain coding-lncRNA gene pairs: SOCS2-AK054607 and LMCD1-NR_024065 in women in spontaneous labor at term. This co-differential expression and correlation was validated by qRT-PCR, an independent experimental method. Intriguingly, one of the two lncRNA genes differentially expressed in term labor had a key genomic structure element, a splice site that lacked evolutionary conservation beyond primates. Conclusions We provide for the first time evidence for coordinated differential expression and correlation of cis-encoded antisense lncRNAs and protein-coding genes with known, as well as novel roles in pregnancy in the myometrium of women in spontaneous labor at term. PMID:24168098
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Boyd, Jamie Kamailani; Kuuleialoha Kamaka, Sharmayne A; Braun, Kathryn L
2012-01-01
Native Hawaiians, representing 25% of Hawai'i's population, suffer socioeconomic and health strains as evidenced by overrepresentation in low-wage jobs without health insurance and a higher prevalence of chronic disease compared with Hawai'i's other ethnic groups. Native Hawaiians are more likely to attend community colleges than 4-year colleges and have high dropout rates. To describe a culturally relevant, community-based action research approach to build a program to keep Hawaiians in college to advance career options and improve long-term health and socioeconomic outcomes. Culturally relevant approaches that depended on participation from a variety of community partners were used to evaluate needs and design interventions. The Pathway Out of Poverty Program uses Hawaiian values and traditions of healthy living to lead students through a nursing pathway from nurse aide (NA) to licensed practical nurse (LPN) to registered nurse (RN), with inherent increases in wage-earning potential. In the first 3.5 years, 150 students enrolled in NA training, and 135 students (90%) graduated and were certified. Of the 135, 77 (57%) transitioned to higher education and 79% transitioned to jobs that offered health insurance (20% were in both groups). Of the 77 entering higher education, 33 (43%) aimed for a degree in nursing. Students expressed growing interest in health promotion for themselves, family members, and others. Community partners were key to developing a successful community college-based Pathway Program to help marginalized and other underrepresented students move from low-wage to living-wage jobs and improve their long-term health outcomes.
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Wattananit, Somsak; Tornero, Daniel; Graubardt, Nadine; Memanishvili, Tamar; Monni, Emanuela; Tatarishvili, Jemal; Miskinyte, Giedre; Ge, Ruimin; Ahlenius, Henrik; Lindvall, Olle; Schwartz, Michal; Kokaia, Zaal
2016-04-13
Stroke is a leading cause of disability and currently lacks effective therapy enabling long-term functional recovery. Ischemic brain injury causes local inflammation, which involves both activated resident microglia and infiltrating immune cells, including monocytes. Monocyte-derived macrophages (MDMs) exhibit a high degree of functional plasticity. Here, we determined the role of MDMs in long-term spontaneous functional recovery after middle cerebral artery occlusion in mice. Analyses by flow cytometry and immunocytochemistry revealed that monocytes home to the stroke-injured hemisphere., and that infiltration peaks 3 d after stroke. At day 7, half of the infiltrating MDMs exhibited a bias toward a proinflammatory phenotype and the other half toward an anti-inflammatory phenotype, but during the subsequent 2 weeks, MDMs with an anti-inflammatory phenotype dominated. Blocking monocyte recruitment using the anti-CCR2 antibody MC-21 during the first week after stroke abolished long-term behavioral recovery, as determined in corridor and staircase tests, and drastically decreased tissue expression of anti-inflammatory genes, including TGFβ, CD163, and Ym1. Our results show that spontaneously recruited monocytes to the injured brain early after the insult contribute to long-term functional recovery after stroke. For decades, any involvement of circulating immune cells in CNS repair was completely denied. Only over the past few years has involvement of monocyte-derived macrophages (MDMs) in CNS repair received appreciation. We show here, for the first time, that MDMs recruited to the injured brain early after ischemic stroke contribute to long-term spontaneous functional recovery through inflammation-resolving activity. Our data raise the possibility that inadequate recruitment of MDMs to the brain after stroke underlies the incomplete functional recovery seen in patients and that boosting homing of MDMs with an anti-inflammatory bias to the injured brain tissue may be a new therapeutic approach to promote long-term improvement after stroke. Copyright © 2016 the authors 0270-6474/16/364182-14$15.00/0.
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Historical and projected climate in the Northern Rockies Region [Chapter 3
Linda A. Joyce; Marian Talbert; Darrin Sharp; Jeffrey Morisette; John Stevenson
2018-01-01
Climate influences the ecosystem services we obtain from forest and rangelands. Climate is described by the long-term characteristics of precipitation, temperature, wind, snowfall, and other measures of weather that occur over a long period in a particular place, and is typically expressed as long-term average conditions. Resource management practices are implemented...
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[Psychosocial issues of long-term cancer survivors].
Weis, J; Faller, H
2012-04-01
Although cancer incidence rates are increasing, recent statistical studies suggest that cancer patients are showing higher cure rates as well as improved overall survival rates for most cancer locations. These advances are explained by improved strategies in early diagnoses as well as improved cancer therapies. Therefore, the number of long-term cancer survivors has also increased, but only few studies, especially within the last years, have focused on psychosocial issues of this subgroup. Some studies show that overall quality of life of long-term cancer survivors is quite high and comparable to that of the normal population. Nevertheless, a substantial percentage of former patients shows reduced quality of life and suffers from various sequelae of cancer and its treatment. This review focuses on the most common psychosocial issue of long-term survivors such as reduced psychological wellbeing, neuropsychological deficits and cancer-related fatigue syndrome. Finally, recommendations for problem-oriented interventions as well as improvement of psychosocial care of long-term survivors are given.
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c-Fos expression predicts long-term social memory retrieval in mice.
Lüscher Dias, Thomaz; Fernandes Golino, Hudson; Moura de Oliveira, Vinícius Elias; Dutra Moraes, Márcio Flávio; Schenatto Pereira, Grace
2016-10-15
The way the rodent brain generally processes socially relevant information is rather well understood. How social information is stored into long-term social memory, however, is still under debate. Here, brain c-Fos expression was measured after adult mice were exposed to familiar or novel juveniles and expression was compared in several memory and socially relevant brain areas. Machine Learning algorithm Random Forest was then used to predict the social interaction category of adult mice based on c-Fos expression in these areas. Interaction with a familiar co-specific altered brain activation in the olfactory bulb, amygdala, hippocampus, lateral septum and medial prefrontal cortex. Remarkably, Random Forest was able to predict interaction with a familiar juvenile with 100% accuracy. Activity in the olfactory bulb, amygdala, hippocampus and the medial prefrontal cortex were crucial to this prediction. From our results, we suggest long-term social memory depends on initial social olfactory processing in the medial amygdala and its output connections synergistically with non-social contextual integration by the hippocampus and medial prefrontal cortex top-down modulation of primary olfactory structures. Copyright © 2016 Elsevier B.V. All rights reserved.
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Rocchetti, Jill; Isingrini, Elsa; Dal Bo, Gregory; Sagheby, Sara; Menegaux, Aurore; Tronche, François; Levesque, Daniel; Moquin, Luc; Gratton, Alain; Wong, Tak Pan; Rubinstein, Marcelo; Giros, Bruno
2015-03-15
Dysfunctional mesocorticolimbic dopamine signaling has been linked to alterations in motor and reward-based functions associated with psychiatric disorders. Converging evidence from patients with psychiatric disorders and use of antipsychotics suggests that imbalance of dopamine signaling deeply alters hippocampal functions. However, given the lack of full characterization of a functional mesohippocampal pathway, the precise role of dopamine transmission in memory deficits associated with these disorders and their dedicated therapies is unknown. In particular, the positive outcome of antipsychotic treatments, commonly antagonizing D2 dopamine receptors (D2Rs), on cognitive deficits and memory impairments remains questionable. Following pharmacologic and genetic manipulation of dopamine transmission, we performed anatomic, neurochemical, electrophysiologic, and behavioral investigations to uncover the role of D2Rs in hippocampal-dependent plasticity and learning. Naïve mice (n = 4-21) were used in the different procedures. Dopamine modulated both long-term potentiation and long-term depression in the temporal hippocampus as well as spatial and recognition learning and memory in mice through D2Rs. Although genetic deletion or pharmacologic blockade of D2Rs led to the loss of long-term potentiation expression, the specific genetic removal of presynaptic D2Rs impaired long-term depression and performances on spatial memory tasks. Presynaptic D2Rs in dopamine fibers of the temporal hippocampus tightly modulate long-term depression expression and play a major role in the regulation of hippocampal learning and memory. This direct role of mesohippocampal dopamine input as uncovered here adds a new dimension to dopamine involvement in the physiology underlying deficits associated with neuropsychiatric disorders. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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Corzett, Christopher H; Goodman, Myron F; Finkel, Steven E
2013-06-01
Escherichia coli DNA polymerases (Pol) II, IV, and V serve dual roles by facilitating efficient translesion DNA synthesis while simultaneously introducing genetic variation that can promote adaptive evolution. Here we show that these alternative polymerases are induced as cells transition from exponential to long-term stationary-phase growth in the absence of induction of the SOS regulon by external agents that damage DNA. By monitoring the relative fitness of isogenic mutant strains expressing only one alternative polymerase over time, spanning hours to weeks, we establish distinct growth phase-dependent hierarchies of polymerase mutant strain competitiveness. Pol II confers a significant physiological advantage by facilitating efficient replication and creating genetic diversity during periods of rapid growth. Pol IV and Pol V make the largest contributions to evolutionary fitness during long-term stationary phase. Consistent with their roles providing both a physiological and an adaptive advantage during stationary phase, the expression patterns of all three SOS polymerases change during the transition from log phase to long-term stationary phase. Compared to the alternative polymerases, Pol III transcription dominates during mid-exponential phase; however, its abundance decreases to <20% during long-term stationary phase. Pol IV transcription dominates as cells transition out of exponential phase into stationary phase and a burst of Pol V transcription is observed as cells transition from death phase to long-term stationary phase. These changes in alternative DNA polymerase transcription occur in the absence of SOS induction by exogenous agents and indicate that cell populations require appropriate expression of all three alternative DNA polymerases during exponential, stationary, and long-term stationary phases to attain optimal fitness and undergo adaptive evolution.
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Near-Term Actions to Address Long-Term Climate Risk
NASA Astrophysics Data System (ADS)
Lempert, R. J.
2014-12-01
Addressing climate change requires effective long-term policy making, which occurs when reflecting on potential events decades or more in the future causes policy makers to choose near-term actions different than those they would otherwise pursue. Contrary to some expectations, policy makers do sometimes make such long-term decisions, but not as commonly and successfully as climate change may require. In recent years however, the new capabilities of analytic decision support tools, combined with improved understanding of cognitive and organizational behaviors, has significantly improved the methods available for organizations to manage longer-term climate risks. In particular, these tools allow decision makers to understand what near-term actions consistently contribute to achieving both short- and long-term societal goals, even in the face of deep uncertainty regarding the long-term future. This talk will describe applications of these approaches for infrastructure, water, and flood risk management planning, as well as studies of how near-term choices about policy architectures can affect long-term greenhouse gas emission reduction pathways.
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Nakatsu, Yusuke; Kotake, Yaichiro; Takishita, Tomoko; Ohta, Shigeru
2009-10-15
Tributyltin (TBT), an endocrine-disrupting chemical, has been used commercially as a heat stabilizer, agricultural pesticide and component of antifouling paints. In this study, we investigated the effect of long-term exposure to endogenous levels of TBT on neuronal glutamate receptors. Cultured rat cortical neurons were exposed to 1-50 nM TBT for 9 days (from day 2 to day 10 in vitro). The number of neurons was reduced by long-term exposure to 50 nM TBT, but not to 1-20 nM TBT. Long-term exposure to 20 nM TBT decreased the mRNA expression of glutamate receptors NR1, NR2A, GluR1 and GluR2, and increased that of NR2B, GluR3 and GluR4. GluR2 protein was also reduced by long-term exposure to TBT. Because AMPA receptor lacking GluR2 exhibits Ca2+ permeability, we investigated whether Ca2+ influx or glutamate toxicity was affected. Indeed, glutamate-induced Ca2+ influx was increased in TBT-treated neurons. Consistent with this, neurons became more susceptible to glutamate toxicity as a result of long-term exposure to TBT and this susceptibility was abolished by an antagonist of GluR2-lacking AMPA receptor. Thus, it is suggested that long-term exposure to endogenous levels of TBT induces a decrease of GluR2 protein, causing neurons become more susceptible to glutamate toxicity.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Eckert, C. A.; Sullivan, R.; Johnson, C.
CO2 and H2 are promising feedstocks for production of valuable biocompounds. Ralstonia eutropha utilizes these feedstocks to generate energy (ATP) and reductant (NAD(P)H) via oxidation of H2 by a membrane-bound (MBH) and a soluble hydrogenase (SH) for CO2 fixation by the Calvin-Benson-Bassham (CBB) cycle. Increased expression of the enzyme that fixes CO2 (RubisCO) resulted in 6-fold activity improvement in vitro, while increased expression of the MBH operon or the SH operon plus MBH operon maturation factors necessary for activity resulted in a 10-fold enhancement. Current research involves genetic manipulation of two endogenous cbb operons for increased expression, analysis of expressionmore » and activity of CBB/MBH/SH, cofactor ratios, and downstream products during autotrophic growth in control versus enhanced strains, and development of strategies for long-term, optimal overexpression. These studies will improve our understanding of autotrophic metabolism and provide a chassis strain for autotrophic production of biodiesel and other valuable carbon biocompounds.« less
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De Rosa, Alfredo; De Francesco, Francesco; Tirino, Virginia; Ferraro, Giuseppe A; Desiderio, Vincenzo; Paino, Francesca; Pirozzi, Giuseppe; D'Andrea, Francesco; Papaccio, Gianpaolo
2009-12-01
Recent studies have shown potential ways for improving stem cell cryopreservation. The major need for autologous stem cell use is a long-term storage: this arises from the humans' hope of future use of their own cells. Therefore, it is important to evaluate the cell potential of vitality and differentiation before and after cryopreservation. Although several studies have shown a long-term preservation of adipose tissue, a few of them focused their attention to stem cells. The aim of this study was to evaluate the fate of cryopreserved stem cells collected from adipose tissue and stored at low a temperature in liquid nitrogen through an optimal cryopreservation solution (using slowly cooling in 6% threalose, 4% dimethyl sulfoxide, and 10% fetal bovine serum) and to develop a novel approach to efficiently preserve adipose-derived stem cells (ASCs) for future clinical applications. Results showed that stem cells, after being thawed, are still capable of differentiation and express all surface antigens detected before storage, confirming the integrity of their biology. In particular, ASCs differentiated into adipocytes, showed diffuse positivity for PPARgamma and adiponectin, and were also able to differentiate into endothelial cells without addition of angiogenic factors. Therefore, ASCs can be long-term cryopreserved, and this, due to their great numbers, is an attractive tool for clinical applications as well as of impact for the derived market.
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Lv, Jing; Pan, Yu; Ju, Huijun; Zhou, Jinxin; Cheng, Dengfeng; Shi, Hongcheng; Zhang, Yifan
2017-01-01
Sleeping Beauty (SB) transposon is an attractive tool in stable transgene integration both in vitro and in vivo; and we introduced SB transposon into recombinant sodium-iodide symporter baculovirus system (Bac-NIS system) to facilitate long-term expression of recombinant sodium-iodide symporter. In our study, two hybrid baculovirus systems (Bac-eGFP-SB-NeoR and Bac-NIS-SB-NeoR) were successfully constructed and used to infect U87 glioma cells. After G418 selection screening, the Bac-eGFP-SB-NeoR-U87 cells remained eGFP positive, at the 18th and 196th day post transfection (96.03 ± 0.21% and 97.43 ± 0.81%), while eGFP positive population declined significantly at 18 days in cells transfected with unmodified baculovirus construct. NIS gene expression by Bac-NIS-SB-NeoR-U87 cells was also maintained for 28 weeks as determined by radioiodine uptake assay, reverse transcription-polymerase chain reaction (RT-PCR) and Western Blot (WB) assay. When transplanted in mice, Bac-NIS-SB-NeoR-U87 cells also expressed NIS gene stably as monitored by SPECT imaging for 43 days until the tumor-bearing mice were sacrificed. Herein, we showed that incorporation of SB in Bac-NIS system (hybrid Bac-NIS-SB-NeoR) can achieve a long-term transgene expression and can improve radionuclide imaging in cell tracking and monitoring in vivo. PMID:28262785
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Benite-Ribeiro, Sandra Aparecida; Putt, David A; Santos, Júlia Matzenbacher
2016-08-01
Over the past decades, life-styles changing have led to exacerbated food and caloric intake and a reduction in energy expenditure. Obesity, main outcome of these changes, increases the risk for developing type 2 diabetes, cardiovascular disease and metabolic syndrome, the leading cause of death in adult and middle age population. Body weight and energy homeostasis are maintained via complex interactions between orexigenic and anorexigenic neuropeptides that take place predominantly in the hypothalamus. Overeating may disrupt the mechanisms of feeding control, by decreasing the expression of proopiomelanocortin (POMC) and α-melanocyte stimulating hormone (α-MSH) and increasing orexigenic neuropeptide Y (NPY) and agouti-related peptide (AgRP), which leads to a disturbance in appetite control and energy balance. Studies have shown that regular physical exercise might decrease body-weight, food intake and improve the metabolic profile, however until the currently there is no consensus about its effects on the expression of orexigenic/anorexigenic neuropeptides expression. Therefore, we propose that the type and length of physical exercise affect POMC/αMSH and NPY/AgRP systems differently and plays an important role in feeding behavior. Moreover, based on the present reports, we hypothesize that increased POMC/αMSH overcome NPY/AgRP expression decreasing food intake in long term physical exercise and that results in amelioration of several conditions related to overweight and obesity. Copyright © 2016 Elsevier Ltd. All rights reserved.
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The expression of long-term potentiation: reconciling the preists and the postivists
MacDougall, Matthew J.; Fine, Alan
2014-01-01
Long-term potentiation (LTP) of excitatory synaptic transmission in the hippocampus has been investigated in great detail over the past 40 years. Where and how LTP is actually expressed, however, remain controversial issues. Considerable evidence has been offered to support both pre- and postsynaptic contributions to LTP expression. Though it is widely held that postsynaptic expression mechanisms are the primary contributors to LTP expression, evidence for that conclusion is amenable to alternative explanations. Here, we briefly review some key contributions to the ‘locus’ debate and describe data that support a dominant role for presynaptic mechanisms. Recognition of the state-dependency of expression mechanisms, and consideration of the consequences of the spatial relationship between postsynaptic glutamate receptors and presynaptic vesicular release sites, lead to a model that may reconcile views from both sides of the synapse. PMID:24298138
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Widmer, Yves F; Bilican, Adem; Bruggmann, Rémy; Sprecher, Simon G
2018-06-20
Memory formation is achieved by genetically tightly controlled molecular pathways that result in a change of synaptic strength and synapse organization. While for short-term memory traces rapidly acting biochemical pathways are in place, the formation of long-lasting memories requires changes in the transcriptional program of a cell. Although many genes involved in learning and memory formation have been identified, little is known about the genetic mechanisms required for changing the transcriptional program during different phases of long-term memory formation. With Drosophila melanogaster as a model system we profiled transcriptomic changes in the mushroom body, a memory center in the fly brain, at distinct time intervals during appetitive olfactory long-term memory formation using the targeted DamID technique. We describe the gene expression profiles during these phases and tested 33 selected candidate genes for deficits in long-term memory formation using RNAi knockdown. We identified 10 genes that enhance or decrease memory when knocked-down in the mushroom body. For vajk-1 and hacd1 , the two strongest hits, we gained further support for their crucial role in appetitive learning and forgetting. These findings show that profiling gene expression changes in specific cell-types harboring memory traces provides a powerful entry point to identify new genes involved in learning and memory. The presented transcriptomic data may further be used as resource to study genes acting at different memory phases. Copyright © 2018, Genetics.
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Decomposition of heterogeneous organic matterand its long-term stabilization in soils
Sierra, Carlos A.; Harmon, Mark E.; Perakis, Steven S.
2011-01-01
Soil organic matter is a complex mixture of material with heterogeneous biological, physical, and chemical properties. Decomposition models represent this heterogeneity either as a set of discrete pools with different residence times or as a continuum of qualities. It is unclear though, whether these two different approaches yield comparable predictions of organic matter dynamics. Here, we compare predictions from these two different approaches and propose an intermediate approach to study organic matter decomposition based on concepts from continuous models implemented numerically. We found that the disagreement between discrete and continuous approaches can be considerable depending on the degree of nonlinearity of the model and simulation time. The two approaches can diverge substantially for predicting long-term processes in soils. Based on our alternative approach, which is a modification of the continuous quality theory, we explored the temporal patterns that emerge by treating substrate heterogeneity explicitly. The analysis suggests that the pattern of carbon mineralization over time is highly dependent on the degree and form of nonlinearity in the model, mostly expressed as differences in microbial growth and efficiency for different substrates. Moreover, short-term stabilization and destabilization mechanisms operating simultaneously result in long-term accumulation of carbon characterized by low decomposition rates, independent of the characteristics of the incoming litter. We show that representation of heterogeneity in the decomposition process can lead to substantial improvements in our understanding of carbon mineralization and its long-term stability in soils.
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Borbon, Ivan; Totenhagen, John; Fiorenza, Maria Teresa; Canterini, Sonia; Ke, Wangjing; Trouard, Theodore; Erickson, Robert P
2012-01-01
Niemann-Pick C1 (NPC) disease, also known as "juvenile Alzheimer's disease", is a disease in which alterations in intracellular cholesterol trafficking occur. The contribution of various CNS cell types to the neurodegeneration has been of much interest. We have previously shown that expression of the normal gene only in fibrillary astrocytes could extend survival of Npc1-/- mice over 3-fold (Zhang et al., 2008 [13]). We have now studied expression only in neurons or in both neurons and fibrillary astrocytes. Neuron-only expression resulted in survivals of over a year (>5-fold) but motor symptoms started at about 6 months. As reflected in weight gain, this especially affected females who weighed less than wild-type starting at about 10 weeks while male differences in weight are delayed. Expression in both cell types led to a nearly normal phenotype with motor symptoms developing at about ten months and increased survival times. Purkinje cell loss was slowed, but severe, in both NSE- and NSE-GFAP-Npc1, transgenic Npc1-/- mice. MRI studies showed that myelination of the long tracts was significantly improved in NSE-Npc1 transgenics, perhaps less than in GFAP-Npc1 transgenics, and not differently than in the double transgenics. Memory was improved in both single and double transgenics. Somatic disease had not been ameliorated and lungs were massively infiltrated with foamy macrophages at 10 months. Our results suggest that neuron-only expression does not completely prevent neurodegeneration and that the addition of astrocyte expression decreases the rate/degree of decline.
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Yin, Xi; Gao, Yuan; Shi, Hai-Shui; Song, Li; Wang, Jie-Chao; Shao, Juan; Geng, Xu-Hong; Xue, Gai; Li, Jian-Li; Hou, Yan-Ning
2016-01-01
Histone modifications have been implicated in learning and memory. Our previous transcriptome data showed that expression of sirtuins 6 (SIRT6), a member of Histone deacetylases (HDACs) family in the hippocampal cornu ammonis 1 (CA1) was decreased after contextual fear conditioning. However, the role of SIRT6 in the formation of memory is still elusive. In the present study, we found that contextual fear conditioning inhibited translational expression of SIRT6 in the CA1. Microinfusion of lentiviral vector-expressing SIRT6 into theCA1 region selectively enhanced the expression of SIRT6 and impaired the formation of long-term contextual fear memory without affecting short-term fear memory. The overexpression of SIRT6 in the CA1 had no effect on anxiety-like behaviors or locomotor activity. Also, we also found that SIRT6 overexpression significantly inhibited the expression of insulin-like factor 2 (IGF2) and amounts of proteins and/or phosphoproteins (e.g. Akt, pAkt, mTOR and p-mTOR) related to the IGF2 signal pathway in the CA1. These results demonstrate that the overexpression of SIRT6 in the CA1 impaired the formation of long-term fear memory, and SIRT6 in the CA1 may negatively modulate the formation of contextual fear memory via inhibiting the IGF signaling pathway. PMID:26732053
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The Molecular and Metabolic Influence of Long Term Agmatine Consumption*
Nissim, Itzhak; Horyn, Oksana; Daikhin, Yevgeny; Chen, Pan; Li, Changhong; Wehrli, Suzanne L.; Nissim, Ilana; Yudkoff, Marc
2014-01-01
Agmatine (AGM), a product of arginine decarboxylation, influences multiple physiologic and metabolic functions. However, the mechanism(s) of action, the impact on whole body gene expression and metabolic pathways, and the potential benefits and risks of long term AGM consumption are still a mystery. Here, we scrutinized the impact of AGM on whole body metabolic profiling and gene expression and assessed a plausible mechanism(s) of AGM action. Studies were performed in rats fed a high fat diet or standard chow. AGM was added to drinking water for 4 or 8 weeks. We used 13C or 15N tracers to assess metabolic reactions and fluxes and real time quantitative PCR to determine gene expression. The results demonstrate that AGM elevated the synthesis and tissue level of cAMP. Subsequently, AGM had a widespread impact on gene expression and metabolic profiling including (a) activation of peroxisomal proliferator-activated receptor-α and its coactivator, PGC1α, and (b) increased expression of peroxisomal proliferator-activated receptor-γ and genes regulating thermogenesis, gluconeogenesis, and carnitine biosynthesis and transport. The changes in gene expression were coupled with improved tissue and systemic levels of carnitine and short chain acylcarnitine, increased β-oxidation but diminished incomplete fatty acid oxidation, decreased fat but increased protein mass, and increased hepatic ureagenesis and gluconeogenesis but decreased glycolysis. These metabolic changes were coupled with reduced weight gain and a curtailment of the hormonal and metabolic derangements associated with high fat diet-induced obesity. The findings suggest that AGM elevated the synthesis and levels of cAMP, thereby mimicking the effects of caloric restriction with respect to metabolic reprogramming. PMID:24523404
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Long-term functional adeno-associated virus-microdystrophin expression in the dystrophic CXMDj dog.
Koo, Taeyoung; Okada, Takashi; Athanasopoulos, Takis; Foster, Helen; Takeda, Shin'ichi; Dickson, George
2011-09-01
Duchenne muscular dystrophy (DMD) is a severe, inherited, muscle-wasting disorder caused by mutations in the dystrophin gene. Preclinical studies of adeno-associated virus gene therapy for DMD have been described in mouse and dog models of this disease. However, low and transient expression of microdystrophin in dystrophic dogs and a lack of long-term microdystrophin expression associated with a CD8(+) T-cell response in DMD patients suggests that the development of improved microdystrophin genes and delivery strategies is essential for successful clinical trials in DMD patients. We have previously shown the efficiency of mRNA sequence optimization of mouse microdystrophin in ameliorating the pathology of dystrophic mdx mice. In the present study, we generated adeno-associated virus (AAV)2/8 vectors expressing an mRNA sequence-optimized canine microdystrophin under the control of a muscle-specific promoter and injected intramuscularly into a single canine X-linked muscular dystrophy (CXMDj) dog. Expression of stable and high levels of microdystrophin was observed along with an association of the dystrophin-associated protein complex in intramuscularly injected muscles of a CXMDj dog for at least 8 weeks without immune responses. Treated muscles were highly protected from dystrophic damage, with reduced levels of myofiber permeability and central nucleation. The data obtained in the present study suggest that the use of canine-specific and mRNA sequence-optimized microdystrophin genes in conjunction with a muscle-specific promoter results in high and stable levels of microdystrophin expression in a canine model of DMD. This approach will potentially allow the reduction of dosage and contribute towards the development of a safe and effective AAV gene therapy clinical trial protocol for DMD. Copyright © 2011 John Wiley & Sons, Ltd.
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NASA Astrophysics Data System (ADS)
Liu, Yaoze; Engel, Bernard A.; Flanagan, Dennis C.; Gitau, Margaret W.; McMillan, Sara K.; Chaubey, Indrajeet; Singh, Shweta
2018-05-01
Best management practices (BMPs) are popular approaches used to improve hydrology and water quality. Uncertainties in BMP effectiveness over time may result in overestimating long-term efficiency in watershed planning strategies. To represent varying long-term BMP effectiveness in hydrologic/water quality models, a high level and forward-looking modeling framework was developed. The components in the framework consist of establishment period efficiency, starting efficiency, efficiency for each storm event, efficiency between maintenance, and efficiency over the life cycle. Combined, they represent long-term efficiency for a specific type of practice and specific environmental concern (runoff/pollutant). An approach for possible implementation of the framework was discussed. The long-term impacts of grass buffer strips (agricultural BMP) and bioretention systems (urban BMP) in reducing total phosphorus were simulated to demonstrate the framework. Data gaps were captured in estimating the long-term performance of the BMPs. A Bayesian method was used to match the simulated distribution of long-term BMP efficiencies with the observed distribution with the assumption that the observed data represented long-term BMP efficiencies. The simulated distribution matched the observed distribution well with only small total predictive uncertainties. With additional data, the same method can be used to further improve the simulation results. The modeling framework and results of this study, which can be adopted in hydrologic/water quality models to better represent long-term BMP effectiveness, can help improve decision support systems for creating long-term stormwater management strategies for watershed management projects.
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Carossino, Mariano; Dini, Pouya; Kalbfleisch, Theodore S; Loynachan, Alan T; Canisso, Igor F; Shuck, Kathleen M; Timoney, Peter J; Cook, R Frank; Balasuriya, Udeni B R
2018-05-01
Equine arteritis virus (EAV) can establish long-term persistent infection in the reproductive tract of stallions and is shed in the semen. Previous studies showed that long-term persistence is associated with a specific allele of the CXCL16 gene ( CXCL16S ) and that persistent infection is maintained despite the presence of a local inflammatory and humoral and mucosal antibody responses. In this study, we demonstrated that equine seminal exosomes (SEs) are enriched in a small subset of microRNAs (miRNAs). Most importantly, we demonstrated that long-term EAV persistence is associated with the downregulation of an SE-associated miRNA (eca-mir-128) and with an enhanced expression of CXCL16 in the reproductive tract, a putative target of eca-mir-128. The findings presented here suggest that SE eca-mir-128 is implicated in the regulation of the CXCL16/CXCR6 axis in the reproductive tract of persistently infected stallions, a chemokine axis strongly implicated in EAV persistence. This is a novel finding and warrants further investigation to identify its specific mechanism in modulating the CXCL16/CXCR6 axis in the reproductive tract of the EAV long-term carrier stallion. IMPORTANCE Equine arteritis virus (EAV) has the ability to establish long-term persistent infection in the stallion reproductive tract and to be shed in semen, which jeopardizes its worldwide control. Currently, the molecular mechanisms of viral persistence are being unraveled, and these are essential for the development of effective therapeutics to eliminate persistent infection. Recently, it has been determined that long-term persistence is associated with a specific allele of the CXCL16 gene ( CXCL16S ) and is maintained despite induction of local inflammatory, humoral, and mucosal antibody responses. This study demonstrated that long-term persistence is associated with the downregulation of seminal exosome miRNA eca-mir-128 and enhanced expression of its putative target, CXCL16, in the reproductive tract. For the first time, this study suggests complex interactions between eca-mir-128 and cellular elements at the site of EAV persistence and implicates this miRNA in the regulation of the CXCL16/CXCR6 axis in the reproductive tract during long-term persistence. Copyright © 2018 American Society for Microbiology.
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Kaiser, Michelle L; Williams, Michele L; Basta, Nicholas; Hand, Michelle; Huber, Sarah
2015-11-01
This study was intended to characterize the perceived risks of urban agriculture by residents of four low-income neighborhoods in which the potential exists for further urban agriculture development and to provide data to support whether any chemical hazards and foodborne pathogens as potential food safety hazards were present. Sixty-seven residents participated in focus groups related to environmental health, food security, and urban gardening. In addition, soils from six locations were tested. Residents expressed interest in the development of urban gardens to improve access to healthy, fresh produce, but they had concerns about soil quality. Soils were contaminated with lead (Pb), zinc, cadmium (Cd), and copper, but not arsenic or chromium. Results from our study suggest paint was the main source of soil contamination. Detectable polyaromatic hydrocarbon (PAH) levels in urban soils were well below levels of concern. These urban soils will require further management to reduce Pb and possibly Cd bioavailability to decrease the potential for uptake into food crops. Although the number of locations in this study is limited, results suggest lower levels of soil contaminants at well-established gardens. Soil tillage associated with long-term gardening could have diluted the soil metal contaminants by mixing the contaminants with clean soil. Also, lower PAH levels in long-term gardening could be due to enhanced microbial activity and PAH degradation, dilution, or both due to mixing, similar to metals. No foodborne pathogen targets were detected by PCR from any of the soils. Residents expressed the need for clearness regarding soil quality and gardening practices in their neighborhoods to consume food grown in these urban areas. Results from this study suggest long-term gardening has the potential to reduce soil contaminants and their potential threat to food quality and human health and to improve access to fresh produce in low-income urban communities.
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Parents' and carers' views about emollients for childhood eczema: qualitative interview study
Muller, I; Yardley, L; Lewis-Jones, S; Ersser, S; Little, P
2016-01-01
Objective Leave-on emollients form the mainstay of eczema treatment, but adherence is poor. We aimed to explore parents’/carers' views on effectiveness and acceptability of leave-on emollients for childhood eczema through secondary analysis of data from 2 qualitative data sets. Setting Study 1 recruited through mail-out from 6 general practices in southern England. Study 2 recruited from a feasibility trial of an intervention to support eczema self-care in 31 practices in the same area. Participants Study 1 included 28 interviews with carers of children aged ≤5 years with eczema. Study 2 included 26 interviews with carers of children aged ≤5 years with eczema. Methods Interviews followed semistructured guides: study 1 explored carers' understandings around eczema treatments in order to develop a web-based self-care support intervention; study 2 explored carers' understandings of eczema and eczema treatments after using the intervention. Interviews were carried out face to face or by telephone, audio-recorded and transcribed. Secondary analysis of data from both studies focused on views and experiences of emollient use. Data were analysed using an inductive thematic approach facilitated by NVivo V.10 software. Results In study 1, most participants felt emollients improved eczema but held mixed views about long-term use to prevent flare-ups. In study 2, where carers had used the web-based intervention, all participants held positive views about long-term emollient use. In both studies, participants expressed a range of preferences about emollient ‘thickness’; some felt that ‘thick’ emollients (ointments) were most effective, while others found these difficult to use. Carers described a process of ‘trial and error’, trying emollients suggested by professionals, friends and family, or bought over-the-counter. Carers expressed a need for understanding differences between products and their effective use. Conclusions Providing a rationale for long-term emollient use and choice of emollients could help improve adherence and help families gain more rapid control of eczema. PMID:27543590
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Kim, Min-Seok; Kim, Bobae; Park, Haryung; Ji, Yosep; Holzapfel, Wilhelm; Kim, Do-Young; Hyun, Chang-Kee
2018-01-08
Recently, Korean traditional fermented soybean paste, called Doenjang, has attracted attention for its protective effect against diet-related chronic diseases such as obesity and type 2 diabetes. Long-term fermented soybean pastes (LFSPs) are made by fermentation with naturally-occurring microorganisms for several months, whereas short-term fermented soybean pastes (SFSPs) are produced by shorter-time fermentation inoculated with a starter culture. Here, we demonstrate that administration of LFSP, but not SFSP, protects high-fat diet (HFD)-fed obese mice against non-alcohol fatty liver disease (NAFLD) and insulin resistance. LFSP suppressed body weight gain in parallel with reduction in fat accumulation in mesenteric adipose tissue (MAT) and the liver via modulation of MAT lipolysis and hepatic lipid uptake. LFSP-treated mice also had improved glucose tolerance and increased adiponectin levels concomitantly with enhanced AMPK activation in skeletal muscle and suppressed expression of pro-inflammatory cytokines in skeletal muscle and the liver. LFSP also attenuated HFD-induced gut permeability and lowered serum lipopolysaccharide level, providing an evidence for its probiotic effects, which was supported by the observation that treatment of a probiotic mixture of LFSP-originated Bacillus strains protected mice against HFD-induced adiposity and glucose intolerance. Our findings suggest that the intake of LFSP, but not SFSP, offers protection against NAFLD and insulin resistance, which is an effect of long-term fermentation resulting in elevated contents of active ingredients (especially flavonoids) and higher diversity and richness of Bacillus probiotic strains compared to SFSP. Copyright © 2017 Elsevier Inc. All rights reserved.
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Suerth, Julia D; Maetzig, Tobias; Brugman, Martijn H; Heinz, Niels; Appelt, Jens-Uwe; Kaufmann, Kerstin B; Schmidt, Manfred; Grez, Manuel; Modlich, Ute; Baum, Christopher; Schambach, Axel
2012-01-01
Comparative integrome analyses have highlighted alpharetroviral vectors with a relatively neutral, and thus favorable, integration spectrum. However, previous studies used alpharetroviral vectors harboring viral coding sequences and intact long-terminal repeats (LTRs). We recently developed self-inactivating (SIN) alpharetroviral vectors with an advanced split-packaging design. In a murine bone marrow (BM) transplantation model we now compared alpharetroviral, gammaretroviral, and lentiviral SIN vectors and showed that all vectors transduced hematopoietic stem cells (HSCs), leading to comparable, sustained multilineage transgene expression in primary and secondary transplanted mice. Alpharetroviral integrations were decreased near transcription start sites, CpG islands, and potential cancer genes compared with gammaretroviral, and decreased in genes compared with lentiviral integrations. Analyzing the transcriptome and intragenic integrations in engrafting cells, we observed stronger correlations between in-gene integration targeting and transcriptional activity for gammaretroviral and lentiviral vectors than for alpharetroviral vectors. Importantly, the relatively “extragenic” alpharetroviral integration pattern still supported long-term transgene expression upon serial transplantation. Furthermore, sensitive genotoxicity studies revealed a decreased immortalization incidence compared with gammaretroviral and lentiviral SIN vectors. We conclude that alpharetroviral SIN vectors have a favorable integration pattern which lowers the risk of insertional mutagenesis while supporting long-term transgene expression in the progeny of transplanted HSCs. PMID:22334016
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Zhang, Jie; Qiu, Hongmei; Huang, Jiajun; Ding, Shumei; Huang, Bo; Wu, Qin; Jiang, Qingsong
2018-07-07
Cardiac hypertrophy is one of the key structural changes in diabetic cardiomyopathy. Naringenin, a dihydroflavonoid extracted from citrus plants with multiple pharmacological activities, yet the underlying effects on diabetic cardiac hypertrophy remain unclear. This study aimed to evaluate the potential effects of naringenin on cardiac hypertrophy in diabetic mice. Long-term high-fat feeding combined with streptozotocin resulted in cardiac hypertrophy after a diabetic model has been established for 4 weeks in mice, which were improved by naringenin supplementation (25 or 75 mg/kg/day, i. g.) for another 4 weeks. The protein and mRNA expressions of PPARs were down-regulated, the protein express of CYP2J3 and level of 14, 15-EET were decreased following diabetic cardiac hypertrophy. Naringenin administration up-regulated PPARs expression, elevated CYP2J3 protein and 14,15-EET content. In conclusion, naringenin can improve cardiac hypertrophy in diabetic mice, which may be related to up-regulate the expression of CYP2J3, elevate the level of EETs, and activate the expression of PPARs. Copyright © 2018 Elsevier Inc. All rights reserved.
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Stringer, Randa L; Laufer, Benjamin I; Kleiber, Morgan L; Singh, Shiva M
2013-08-02
Prenatal alcohol exposure is known to result in fetal alcohol spectrum disorders, a continuum of physiological, behavioural, and cognitive phenotypes that include increased risk for anxiety and learning-associated disorders. Prenatal alcohol exposure results in life-long disorders that may manifest in part through the induction of long-term gene expression changes, potentially maintained through epigenetic mechanisms. Here we report a decrease in the expression of Canabinoid receptor 1 (Cnr1) and an increase in the expression of the regulatory microRNA miR-26b in the brains of adult mice exposed to ethanol during neurodevelopment. Furthermore, we show that miR-26b has significant complementarity to the 3'-UTR of the Cnr1 transcript, giving it the potential to bind and reduce the level of Cnr1 expression. These findings elucidate a mechanism through which some genes show long-term altered expression following prenatal alcohol exposure, leading to persistent alterations to cognitive function and behavioural phenotypes observed in fetal alcohol spectrum disorders.
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Hallett, Penelope J; Cooper, Oliver; Sadi, Damaso; Robertson, Harold; Mendez, Ivar; Isacson, Ole
2014-01-01
Summary To determine the long-term health and function of transplanted dopamine neurons in Parkinson’s disease (PD) patients, the expression of dopamine transporters (DAT) and mitochondrial morphology was examined in human fetal midbrain cellular transplants. DAT was robustly expressed in transplanted dopamine neuron terminals in the reinnervated host putamen and caudate, for at least 14 years after transplantation. The transplanted dopamine neurons showed a healthy and non-atrophied morphology at all time points. Labeling of the mitochondrial outer membrane protein Tom20 and alpha-synuclein showed typical cellular pathology in the patients’ own substantia nigra, which was not observed in transplanted dopamine neurons. These results show that the vast majority of transplanted neurons remain healthy long-term in PD patients, consistent with the clinically maintained function of fetal dopamine neuron transplants for up to 15–18 years in patients. These findings are critically important for the rational development of stem cell-based dopamine neuronal replacement therapies for PD. PMID:24910427
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Shimizu, Takashi; Echizenya, Riku; Miyamoto, Akio
2016-04-01
The aim of this study is to examine the effect of lipopolysaccharide (LPS) on progesterone production during luteinization of granulosa and theca cells isolated from bovine large follicles. Granulosa and theca cells isolated from large follicles of bovine ovaries were exposed to LPS under appropriate hormone conditions in vitro. Progesterone (P4) production in theca cells, but not granulosa cells, was decreased by long-term exposure of LPS. Long-term exposure of LPS suppressed the gene expression of luteinizing hormone receptor in theca cells. Although long-term exposure of LPS did not affect the expression of steroidogenic acute regulatory protein (StAR) and 3β-hydroxy-steroid dehydrogenase (3β-HSD) genes, it did inhibit the protein expression of StAR and 3β-HSD in theca cells. These findings suggest that theca cells, rather than granulosa cells, are susceptible to LPS during luteinization and that LPS inhibits P4 production by decreasing protein levels of StAR during luteinization of theca cells. © 2016 Wiley Periodicals, Inc.
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Identification of repaglinide as a therapeutic drug for glioblastoma multiforme
DOE Office of Scientific and Technical Information (OSTI.GOV)
Xiao, Zui Xuan; Chen, Ruo Qiao; Hu, Dian Xing
Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the genemore » expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients. - Highlights: • Gene expression signarue in long-term survived GBM patients are identified from Gene Expression Omnibus database. • Repaglinide is identified as a survival-related drug for GBM via drug repositioning in CMap. • Repaglinide effectively kills GBM cells, inhibits GBM cell migration and increases survival of mice bearing orthotopic glioma. • Repaglinide reduces Bcl-2, Beclin-1 and PD-L1 in GBM tissues.« less
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Enhanced animal growth via ligand-regulated GHRH myogenic-injectable vectors
NASA Technical Reports Server (NTRS)
Draghia-Akli, Ruxandra; Malone, P. Brandon; Hill, Leigh Anne; Ellis, Kenneth M.; Schwartz, Robert J.; Nordstrom, Jeffrey L.
2002-01-01
Regulated animal growth occurred following a single electroporated injection of a mixture of two plasmids (10 microg of DNA), one expressing the GeneSwitch regulator protein, the other an inducible growth hormone releasing hormone (GHRH) gene, into the tibialis anterior muscles of adult SCID mice. Administration of the ligand mifepristone (MFP) up-regulated GHRH expression, as shown by elevations of IGF-I levels, and when MFP dosing was withdrawn, IGF-I returned to baseline levels. Five cycles of IGF-I induction were observed during a five-month period. Chronic MFP dosing for 25 days increased lean body mass, weight gain, and bone mineral density significantly compared with non-MFP treated controls. In summary, long-term drug-regulated GHRH expression was achieved following plasmid-based gene therapy, and chronic induction of GHRH expression in adult animals led to improvements in weight gain and body composition.
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Enhanced animal growth via ligand-regulated GHRH myogenic-injectable vectors.
Draghia-Akli, Ruxandra; Malone, P Brandon; Hill, Leigh Anne; Ellis, Kenneth M; Schwartz, Robert J; Nordstrom, Jeffrey L
2002-03-01
Regulated animal growth occurred following a single electroporated injection of a mixture of two plasmids (10 microg of DNA), one expressing the GeneSwitch regulator protein, the other an inducible growth hormone releasing hormone (GHRH) gene, into the tibialis anterior muscles of adult SCID mice. Administration of the ligand mifepristone (MFP) up-regulated GHRH expression, as shown by elevations of IGF-I levels, and when MFP dosing was withdrawn, IGF-I returned to baseline levels. Five cycles of IGF-I induction were observed during a five-month period. Chronic MFP dosing for 25 days increased lean body mass, weight gain, and bone mineral density significantly compared with non-MFP treated controls. In summary, long-term drug-regulated GHRH expression was achieved following plasmid-based gene therapy, and chronic induction of GHRH expression in adult animals led to improvements in weight gain and body composition.
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Benner, Ina; Diner, Rachel E; Lefebvre, Stephane C; Li, Dian; Komada, Tomoko; Carpenter, Edward J; Stillman, Jonathon H
2013-01-01
Increased atmospheric pCO2 is expected to render future oceans warmer and more acidic than they are at present. Calcifying organisms such as coccolithophores that fix and export carbon into the deep sea provide feedbacks to increasing atmospheric pCO2. Acclimation experiments suggest negative effects of warming and acidification on coccolithophore calcification, but the ability of these organisms to adapt to future environmental conditions is not well understood. Here, we tested the combined effect of pCO2 and temperature on the coccolithophore Emiliania huxleyi over more than 700 generations. Cells increased inorganic carbon content and calcification rate under warm and acidified conditions compared with ambient conditions, whereas organic carbon content and primary production did not show any change. In contrast to findings from short-term experiments, our results suggest that long-term acclimation or adaptation could change, or even reverse, negative calcification responses in E. huxleyi and its feedback to the global carbon cycle. Genome-wide profiles of gene expression using RNA-seq revealed that genes thought to be essential for calcification are not those that are most strongly differentially expressed under long-term exposure to future ocean conditions. Rather, differentially expressed genes observed here represent new targets to study responses to ocean acidification and warming.
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ERIC Educational Resources Information Center
Hawk, Joshua D.; Florian, Cedrick; Abel, Ted
2011-01-01
Long-term memory formation involves covalent modification of the histone proteins that package DNA. Reducing histone acetylation by mutating histone acetyltransferases impairs long-term memory, and enhancing histone acetylation by inhibiting histone deacetylases (HDACs) improves long-term memory. Previous studies using HDAC inhibitors to enhance…
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Type 1 Adenylyl Cyclase is Essential for Maintenance of Remote Contextual Fear Memory
Shan, Qiang; Chan, Guy C.-K.; Storm, Daniel R.
2008-01-01
Although molecular mechanisms for hippocampus-dependent memory have been extensively studied, much less is known about signaling events important for remote memory. Here we report that mice lacking type 1 adenylyl cyclase (AC1) are able to establish and retrieve remote contextual memory but unable to sustain it as long as wild type mice. Interestingly, mice over-expressing AC1 show superior remote contextual memory even though they exhibit normal hippocampus-dependent contextual memory. These data illustrate that calcium coupling to cAMP contributes to the stability of remote memory and identifies AC1 as a potential drug target site to improve long-term remote memory. PMID:19036980
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Update: Non-Invasive Positive Pressure Ventilation in Chronic Respiratory Failure Due to COPD.
Altintas, Nejat
2016-01-01
Long-term non-invasive positive pressure ventilation (NPPV) has widely been accepted to treat chronic hypercapnic respiratory failure arising from different etiologies. Although the survival benefits provided by long-term NPPV in individuals with restrictive thoracic disorders or stable, slowly-progressing neuromuscular disorders are overwhelming, the benefits provided by long-term NPPV in patients with chronic obstructive pulmonary disease (COPD) remain under question, due to a lack of convincing evidence in the literature. In addition, long-term NPPV reportedly failed in the classic trials to improve important physiological parameters such as arterial blood gases, which might serve as an explanation as to why long-term NPPV has not been shown to substantially impact on survival. However, high intensity NPPV (HI-NPPV) using controlled NPPV with the highest possible inspiratory pressures tolerated by the patient has recently been described as a new and promising approach that is well-tolerated and is also capable of improving important physiological parameters such as arterial blood gases and lung function. This clearly contrasts with the conventional approach of low-intensity NPPV (LI-NPPV) that uses considerably lower inspiratory pressures with assisted forms of NPPV. Importantly, HI-NPPV was very recently shown to be superior to LI-NPPV in terms of improved overnight blood gases, and was also better tolerated than LI-NPPV. Furthermore, HI-NPPV, but not LI-NPPV, improved dyspnea, lung function and disease-specific aspects of health-related quality of life. A recent study showed that long-term treatment with NPPV with increased ventilatory pressures that reduced hypercapnia was associated with significant and sustained improvements in overall mortality. Thus, long-term NPPV seems to offer important benefits in this patient group, but the treatment success might be dependent on effective ventilatory strategies.
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Yi, Bin; Wu, Cong; Shi, Runjie; Han, Kun; Sheng, Haibin; Li, Bei; Mei, Ling; Wang, Xueling; Huang, Zhiwu; Wu, Hao
2018-01-01
Hypothesis: We investigated whether salicylate induces tinnitus through alteration of the expression levels of brain-derived neurotrophic factor (BDNF), proBDNF, tyrosine kinase receptor B (TrkB), cAMP-responsive element-binding protein (CREB), and phosphorylated CREB (p-CREB) in the auditory cortex (AC). Background: Salicylate medication is frequently used for long-term treatment in clinical settings, but it may cause reversible tinnitus. Salicylate-induced tinnitus is associated with changes related to central auditory neuroplasticity. Our previous studies revealed enhanced neural activity and ultrastructural synaptic changes in the central auditory system after long-term salicylate administration. However, the underlying mechanisms remained unclear. Methods: Salicylate-induced tinnitus-like behavior in rats was confirmed using gap prepulse inhibition of acoustic startle and prepulse inhibition testing, followed by comparison of the expression levels of BDNF, proBDNF, TrkB, CREB, and p-CREB. Synaptic ultrastructure was observed under a transmission electron microscope. Results: BDNF and p-CREB were upregulated along with ultrastructural changes at the synapses in the AC of rats treated chronically with salicylate (p < 0.05, compared with control group). These changes returned to normal after 14 days of recovery (p > 0.05). Conclusion: Long-term administration of salicylate increased BDNF expression and CREB activation, upregulated synaptic efficacy, and changed synaptic ultrastructure in the AC. There may be a relationship between these factors and the mechanism of tinnitus. PMID:29342042
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Liu, Rong-Yu; Cleary, Leonard J.; Byrne, John H.
2011-01-01
Accumulating evidence suggests that the transcriptional activator CREB1 is important for serotonin (5-HT)-induced long-term facilitation (LTF) of the sensorimotor synapse in Aplysia. Moreover, creb1 is among the genes activated by CREB1, suggesting a role for this protein beyond the induction phase of LTF. The time course of the requirement for CREB1 synthesis in the consolidation of long-term facilitation was examined using RNA interference (RNAi) techniques in sensorimotor co-cultures. Injection of CREB1 small-interfering RNA (siRNA) immediately or 10 h after 5-HT treatment blocked LTF when measured at 24 h and 48 h after treatment. In contrast, CREB1 siRNA did not block LTF when injected 16 h after 5-HT treatment. These results demonstrate that creb1 expression must be sustained for a relatively long time in order to support the consolidation of LTF. In addition, LTF is also accompanied by a long-term increase in the excitability (LTE) of sensory neurons (SNs). Because LTE was observed in the isolated SN after 5-HT treatment, this long-term change was intrinsic to that element of the circuit. LTE was blocked when CREB1 siRNA was injected into isolated SNs immediately after 5-HT treatment. These data suggest that 5-HT-induced CREB1 synthesis is required for consolidation of both LTF and LTE. PMID:21543617
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NASA Astrophysics Data System (ADS)
Karouia, Fathi; Tirumalai, Madhan R.; Nelman-Gonzalez, Mayra A.; Sams, Clarence F.; Ott, Mark C.; Pierson, Duane L.; Fofanov, Yuriy; Willson, Richard C.; Fox, George E.
Human space travelers experience a unique environment that affects homeostasis and physio-logic adaptation. One of the important regulatory biology interactions affected by space flight is the alteration of the immune response. As such, the impairment of the immune system may lead to higher risk of bacterial and/or viral infection during human space flight missions. Mi-crobiological contaminants have been a source of concern over the years for NASA and there is evidence to suggest that microbes in space do not behave like they do on Earth. Previ-ous studies have examined the physiological response of bacteria when exposed to short-term microgravity either during spaceflight or in a Low Shear Modeled Microgravity (LSMMG) en-vironment. Exposure to these environments has been found to induce increased resistance to stresses and antibiotics, and in one case increase of virulence. As NASA increases the duration of space flight missions and is starting to envision human presence on the lunar surface and Mars, it becomes legitimate to question the long-term effects of microgravity on bacteria. The effect of long-term exposure to LSMMG on microbial gene expression and physiology in Escherichia coli (E. coli) is being examined using functional genomics, and molecular tech-niques. In previous E. coli short term studies, reproducible changes in transcription were seen but no direct responses to changes in the gravity vector were identified. Instead, absence of shear and a randomized gravity vector appeared to cause local extra-cellular environmental changes, which elicited cellular responses. In order to evaluate the long-term effects of micro-gravity on bacteria, E. coli was grown under simulated microgravity for 1000 generations and gene expression patterns and cellular physiology were analyzed in comparison with short-term exposure. The analysis revealed that the long-term response differed significantly from the short-term exposure and 357 genes were expressed significantly differently. Fimbriae encoding genes were significantly up-regulated whereas genes encoding the flagellar motor complex were down-regulated. Additionally, 81 significantly expressed genes have been implicated in and/or associated with biofilm formation. The remaining up-regulated genes seemed to be involved in a response that triggered expression of genes associated with the type II secretion complex. This complex has been involved in virulence factors and members of the multidrug efflux system which confer resistance to a multitude of antimicrobial agents and antibiotics. Biofilm formation and the aggregation of cells were evaluated by scanning electron microscopy (SEM). The analysis revealed that extracellular matrix and complex cellular networking were present among cells that were exposed to the long-term LSMMG environment. In addition the response to a variety of stresses and antibiotics were examined. Significant differences were seen between long-term exposure to LSMMG and the short-term control. Changes in expression may predispose the cells to more efficiently attach to surfaces and/or other cells and thereby confer resistance to antibiotics. Future studies will seek to determine the extent to which the long-term adaptation is influenced by genomic changes. These studies will contribute to the knowledge base needed to develop countermeasures that will decrease the risks associated with astronaut health and mission integrity that are presented by microorganisms.
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Speaking up and Speaking Out? Long-Term Impact of Critical Multicultural Pedagogy
ERIC Educational Resources Information Center
Flynn, Jill Ewing
2017-01-01
This study explores the long-term effects of critical multicultural pedagogy on seven adolescents. Four years later, participants continued to demonstrate awareness of privilege and racism, yet few were actively engaged in antiracist work. Participants also expressed disillusionment and lamented the lack of productive discussions of critical…
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The DOD Humanitarian and Civic Assistance Program Concepts, Trends, Medical Challenges
1997-03-01
program improvements; measuring program performance and effectiveness; and defining military roles relevant to training, long term benefits, and the...support conclusions relevant to trends, benefits, challenges, suggested improvements, and suggested areas for future research. 15. SUBJECT TERMS 16...a Long Term Medical Benefit ................ 28 CONCLUSION
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Lodhi, S A; Lamb, K E; Meier-Kriesche, H U
2011-06-01
Organ survival in the short-term period post-transplant has improved dramatically over the past few decades. Whether this has translated to a long-term survival benefit remains unclear. This study quantifies the progression of nonrenal solid organ transplant outcomes from 1989 to 2009 in liver, lung, heart, intestine and pancreas transplants. Long-term graft survival was analyzed using data on adult solid organ transplant recipients from the UNOS/SRTR database and is reported as organ half-life and yearly attrition rates. Liver, lung, heart, intestine and pancreas half-lives have improved from 5.8 to 8.5, 1.7 to 5.2, 8.8 to 11, 2.1 to 3.6 and 10.5 to 16.7 years, respectively. Long-term attrition rates have not shown the same consistent improvement, with the yearly attrition rate 5-10 years post-transplant for liver, lung, heart and pancreas changing from 4.7 to 4.3, 10.9 to 10.1, 6.4 to 5.1 and 3.3 to 4.2, respectively. Attrition rates for intestine and pancreas transplantation alone display more variability due to smaller sample size but exhibit similar trends of improved first-year attrition and relatively stagnant long-term attrition rates. With first-year survival and attrition rates almost at a pinnacle, further progress in long-term survival will come from targeting endpoints beyond first-year rejection and survival rates. ©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.
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Min, Q; Cheng, S Y; Xi, J F; Ma, J; Xin, T R; Xia, B; Zou, Z W
BACKGROUND: Thitarodes larvae are the host of the caterpillar fungus Ophiocordyceps sinensis. Low temperature is the main environmental limitation for larvae growth. To better understand the cold adaption process in T. pui larvae, the expression patterns of trehalose-6-phosphate synthase (TpTPS), heat shock protein 70 (TpHSP70), and heat shock protein 90 (TpHSP90) were investigated upon short and long-term exposure to 0°C. The 6th instar T. pui larvae were collected in July 2013. TpTPS was firstly sequenced and expression patterns of TpTPS, TpHSP70 and TpHSP90 were investigated using quantitative PCR. Full-length cDNA of TpTPS was 3,012 bp, with an open reading frame of 2,472 bp and an encoding protein of 823 amino acids. TpTPS up-regulation was induced by cold exposure. TpHSP70 expression is altered by cold exposure, but remained low. TpHSP90 expression was obviously up regulated in long-term cold stimulation. All three genes (TpTPS, TpHSP70 and TpHSP90) have likely contributed to cold tolerance in T. pui larvae, TpTPS and TpHSP90 potentially being more important.
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Beetz, Nadine; Rommel, Carolin; Schnick, Tilman; Neumann, Elena; Lother, Achim; Monroy-Ordonez, Elsa Beatriz; Zeeb, Martin; Preissl, Sebastian; Gilsbach, Ralf; Melchior-Becker, Ariane; Rylski, Bartosz; Stoll, Monika; Schaefer, Liliana; Beyersdorf, Friedhelm; Stiller, Brigitte; Hein, Lutz
2016-12-01
Biglycan, a small leucine-rich proteoglycan, has been shown to play an important role in stabilizing fibrotic scars after experimental myocardial infarction. However, the role of biglycan in the development and regression of cardiomyocyte hypertrophy and fibrosis during cardiac pressure overload and unloading remains elusive. Thus, the aim of the present study was to assess the effect of biglycan on cardiac remodeling in a mouse model of left ventricular pressure overload and unloading. Left ventricular pressure overload induced by transverse aortic constriction (TAC) in mice resulted in left ventricular dysfunction, fibrosis and increased biglycan expression. Fluorescence- and magnetic-assisted sorting of cardiac cell types revealed upregulation of biglycan in the fibroblast population, but not in cardiomyocytes, endothelial cells or leukocytes after TAC. Removal of the aortic constriction (rTAC) after short-term pressure overload (3weeks) improved cardiac contractility and reversed ventricular hypertrophy but not fibrosis in wild-type (WT) mice. Biglycan ablation (KO) enhanced functional recovery but did not resolve cardiac fibrosis. After long-term TAC for 9weeks, ablation of biglycan attenuated the development of cardiac hypertrophy and fibrosis. In vitro, biglycan induced hypertrophy of neonatal rat cardiomyocytes and led to activation of a hypertrophic gene program. Putative downstream mediators of biglycan signaling include Rcan1, Abra and Tnfrsf12a. These genes were concordantly induced by TAC in WT but not in biglycan KO mice. Left ventricular pressure overload induces biglycan expression in cardiac fibroblasts. Ablation of biglycan improves cardiac function and attenuates left ventricular hypertrophy and fibrosis after long-term pressure overload. In vitro biglycan induces hypertrophy of cardiomyocytes, suggesting that biglycan may act as a signaling molecule between cell types to modulate cardiac remodeling. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Advances in Patellofemoral Arthroplasty.
Strickland, Sabrina M; Bird, Mackenzie L; Christ, Alexander B
2018-06-01
To describe current indications, implants, economic benefits, comparison to TKA, and functional and patient-reported outcomes of patellofemoral arthroplasty. Modern onlay implants and improved patient selection have allowed for recent improvements in short- and long-term outcomes after patellofemoral joint replacement surgery. Patellofemoral arthroplasty has become an increasingly utilized technique for the successful treatment of isolated patellofemoral arthritis. Advances in patient selection, implant design, and surgical technique have resulted in improved performance and longevity of these implants. Although short- and mid-term data for modern patellofemoral arthroplasties appear promising, further long-term clinical studies are needed to evaluate how new designs and technologies will affect patient outcomes and long-term implant performance.
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Time to look beyond one-year mortality in critically ill hematological patients?
Moors, Ine; Benoit, Dominique D
2014-02-11
The spectacular improvement in long-term prognosis of patients with hematological malignancies since the 1980s, coupled with the subsequent improvement over the past decade in short- and mid-term survival in cases of critical illness, resulted in an increasing referral of such patients to the ICU. A remaining question, however, is how these patients perform in the long term with regard to survival and quality of life. Here we discuss the present multicenter study on survival beyond 1 year in critically ill patients with hematological malignancies. We conclude with suggestions on how we can further improve the long-term outcome of these patients.
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He, De-Hua; Lin, Jin-Xiu; Zhang, Liang-Min; Xu, Chang-Sheng; Xie, Qiang
2017-03-15
Pharmacological treatment of prehypertension may ameliorate hypertension and improve vascular structure and function. This study investigated 1) whether early treatment with either losartan or amlodipine at the onset of prehypertension can prevent hypertension and 2) whether losartan and amlodipine equally improve vascular remodeling and function in a rat model of hypertension. Stroke-prone spontaneously hypertensive (SHRSP) rats were administered losartan, amlodipine or saline for 6 or 16weeks at the onset of prehypertension. Wistar-Kyoto rats were used as a control. All groups were observed for 40weeks. Systolic blood pressure was measured using the tail-cuff method. Vascular structure and function were determined by microscopy and vascular ring contractility assays, respectively. Angiotensin II (Ang II) and aldosterone (Aldo) were measured by radioimmunoassays. Angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) expression was measured by western blot. Losartan effectively reduced progression from prehypertension to hypertension as well as vascular remodeling and improved vascular contractility in SHRSP rats. Long-term losartan (16weeks) had greater benefits than short-term (6weeks) treatment. Losartan increased Ang II and decreased Aldo levels in the serum and vessel walls of resistance vessels in a time-dependent manner. Losartan significantly decreased AT1R and increased AT2R vascular expression. Amlodipine had no effect on vascular AT1R and AT2R expression. Losartan administered at the onset of prehypertension is more effective than amlodipine in ameliorating hypertension and improving vascular remodeling and function, which is likely mediated by the renin-angiotensin-aldosterone system. Copyright © 2017 Elsevier Inc. All rights reserved.
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Olivieri, Ignazio; Cortesi, Paolo A; de Portu, Simona; Salvarani, Carlo; Cauli, Alberto; Lubrano, Ennio; Spadaro, Antonio; Cantini, Fabrizio; Ciampichini, Roberta; Cutro, Maria Stefania; Mathieu, Alessandro; Matucci-Cerinic, Marco; Punzi, Leonardo; Scarpa, Raffaele; Mantovani, Lorenzo G
2016-01-01
Poor information on long-term outcomes and costs on tumour necrosis factor (TNF) inhibitors in psoriatic arthritis (PsA) are available. Our aim was to evaluate long-term costs and benefits of TNF- inhibitors in PsA patients with inadequate response to conventional treatment with traditional disease-modifying anti-rheumatic drugs (tDMARDs). Fifty-five out of 107 enrolled patients included in the study at one year, completed the 5-year follow-up period. These patients were enrolled in 8 of 9 centres included in the study at one year. Patients aged older than 18 years, with different forms of PsA and failure or intolerance to tDMARDs therapy were treated with anti-TNF agents. Information on resource use, health-related quality of life (HRQoL), disease activity, function and laboratory values were collected at baseline and through the 5 years of therapy. Costs (expressed in Euro 2011) and utility (measured by EQ-5D instrument) before TNF inhibitor therapy and after 1 and 5 years were compared. The majority of patients (46 out of 55; 83.6%) had a predominant or exclusive peripheral arthritis and 16.4% had predominant or exclusive axial involvement. There was a statistically significant improvement of the most important clinical variables after 1 year of follow-up. These improvements were maintained also after 5 years. The direct costs increased by approximately €800 per patient-month after 1 year, the indirect costs decreased by €100 and the overall costs increased by more than €700 per patient-month due to the cost of TNF inhibitor therapy. Costs at 5 year were similar to the costs at 1 year. The HRQoL parameters showed the same trends of the clinical variables. EQ-5D VAS, EQ-5D utility and SF-36 PCS score showed a significant improvement after 1 year, maintained at 5 years. SF-36 MCS showed an improvement only at 5 years. The results of our study suggest that TNF blockers have long-term efficacy. The higher cost of TNF inhibitor therapy was balanced by a significant improvement of HRQoL, stable at 5 years of follow-up. Our results need to be confirmed in larger samples of patients.
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A Pilot Study of Expressive Writing Intervention among Chinese Speaking Breast Cancer Survivors
Lu, Qian; Zheng, Dianhan; Young, Lucy; Kagawa-Singer, Marjorie; Loh, Alice
2013-01-01
Objective Little attention has been focused on Asian American breast cancer survivor's psychological needs. No outcome based psychosocial interventions have been reported to target at this population. Expressive writing interventions have been previously shown to improve health outcomes among non-Hispanic white breast cancer populations. This pilot study aimed to test the cultural sensitivity, feasibility, and potential health benefits of an expressive writing intervention among Chinese-speaking breast cancer survivors. Methods Participants (N=19) were asked to write about their deepest thoughts and feelings, their coping efforts, and positive thoughts and feelings regarding their experience with breast cancer each week for three weeks. Health outcomes were assessed at baseline, three, and six months after the intervention. A Community-Based Participatory Research Approach (CBPR) is used. Results Expressive writing was associated with medium and large effect sizes (ηp2= 0.066~0.208) in improving multiple health outcomes (quality of life, fatigue, posttraumatic stress, intrusive thoughts, and positive affect) at follow-ups. Participants perceived the study to be valuable. The study yielded high compliance and completion rates. Conclusion Expressive writing is associated with long-term improvement of health outcomes among Chinese breast cancer survivors and has the potential to be utilized as a support strategy for minority cancer survivors. In addition, CBPR is valuable in improving feasibility and cultural sensitivity of the intervention in understudied populations. Future studies employing randomized controlled trial designs are warranted. PMID:22229930
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Zhong, Yu; Chen, Jing; Li, Li; Qin, Yi; Wei, Yi; Pan, Shining; Jiang, Yage; Chen, Jialin; Xie, Yubo
2018-04-20
Studies have found that propofol can induce widespread neuroapoptosis in developing brains, which leads to cause long-term learning and memory abnormalities. However, the specific cellular and molecular mechanisms underlying propofol-induced neuroapoptosis remain elusive. The aim of the present study was to explore the role of PKA-CREB-BDNF signaling pathway in propofol-induced long-term learning and memory impairment during brain development. Seven-day-old rats were randomly assigned to control, intralipid and three treatment groups (n = 5). Rats in control group received no treatment. Intralipid (10%, 10 mL/kg) for vehicle control and different dosage of propofol for three treatment groups (50, 100 and 200 mg/kg) were administered intraperitoneally. FJB staining, immunohistochemistry analysis for neuronal nuclei antigen and transmission electron microscopy were used to detect neuronal apoptosis and structure changes. MWM test examines the long-term spatial learning and memory impairment. The expression of PKA, pCREB and BDNF was quantified using western blots. Propofol induced significant increase of FJB-positive cells and decrease of PKA, pCREB and BDNF protein levels in the immature brain of P7 rats. Using the MWM test, propofol-treated rats demonstrated long-term spatial learning and memory impairment. Moreover, hippocampal NeuN-positive cell loss, long-lasting ultrastructural abnormalities of the neurons and synapses, and long-term down-regulation of PKA, pCREB and BDNF protein expression in adult hippocampus were also found. Our results indicated that neonatal propofol exposure can significantly result in long-term learning and memory impairment in adulthood. The possible mechanism involved in the propofol-induced neuroapoptosis was related to down-regulation of PKA-CREB-BDNF signaling pathway. Copyright © 2018. Published by Elsevier B.V.
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Suresh, Rahul; Li, Xing; Chiriac, Anca; Goel, Kashish; Terzic, Andre; Perez-Terzic, Carmen; Nelson, Timothy J
2014-09-01
Whole-genome gene expression analysis has been successfully utilized to diagnose, prognosticate, and identify potential therapeutic targets for high-risk cardiovascular diseases. However, the feasibility of this approach to identify outcome-related genes and dysregulated pathways following first-time myocardial infarction (AMI) remains unknown and may offer a novel strategy to detect affected expressome networks that predict long-term outcome. Whole-genome expression microarray on blood samples from normal cardiac function controls (n=21) and first-time AMI patients (n=31) within 48-hours post-MI revealed expected differential gene expression profiles enriched for inflammation and immune-response pathways. To determine molecular signatures at the time of AMI associated with long-term outcomes, transcriptional profiles from sub-groups of AMI patients with (n=5) or without (n=22) any recurrent events over an 18-month follow-up were compared. This analysis identified 559 differentially-expressed genes. Bioinformatic analysis of this differential gene-set for associated pathways revealed 1) increasing disease severity in AMI patients is associated with a decreased expression of genes involved in the developmental epithelial-to-mesenchymal transition pathway, and 2) modulation of cholesterol transport genes that include ABCA1, CETP, APOA1, and LDLR is associated with clinical outcome. Differentially regulated genes and modulated pathways were identified that were associated with recurrent cardiovascular outcomes in first-time AMI patients. This cell-based approach for risk stratification in AMI could represent a novel, non-invasive platform to anticipate modifiable pathways and therapeutic targets to optimize long-term outcome for AMI patients and warrants further study to determine the role of metabolic remodeling and regenerative processes required for optimal outcomes. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Combet, S; Miyata, T; Moulin, P; Pouthier, D; Goffin, E; Devuyst, O
2000-04-01
Long-term peritoneal dialysis (PD) is associated with alterations in peritoneal permeability and loss of ultrafiltration. These changes originate from increased peritoneal surface area, but the morphologic and molecular mechanisms involved remain unknown. The hypothesis that modifications of activity and/or expression of nitric oxide synthase (NOS) isozymes might play a role in these modifications, via enhanced local production of nitric oxide, was tested in this study. NOS activities were measured by the L-citrulline assay in peritoneal biopsies from seven control subjects, eight uremic patients immediately before the onset of PD, and 13 uremic patients on short-term (<18 mo, n = 6) or long-term(>18 mo, n = 7) PD. Peritoneal NOS activity is increased fivefold in long-term PD patients compared with control subjects. In uremic patients, NOS activity is positively correlated with the duration of PD. Increased NOS activity is mediated solely by Ca(2+)-dependent NOS and, as shown by immunoblotting, an upregulation of endothelial NOS. The biologic relevance of increased NOS in long-term PD was demonstrated by enhanced nitrotyrosine immunoreactivity and a significant increase in vascular density and endothelial area in the peritoneum. Immunoblotting and immunostaining studies demonstrated an upregulation of vascular endothelial growth factor (VEGF) mostly along the endothelium lining peritoneal blood vessels in long-term PD patients. In the latter, VEGF colocalized with the advanced glycation end product pentosidine deposits. These data provide a morphologic (angiogenesis and increased endothelial area) and molecular (enhanced NOS activity and endothelial NOS upregulation) basis for explaining the permeability changes observed in long-term PD. They also support the implication of local advanced glycation end product deposits and liberation of VEGF in that process.
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Boyd, Jamie Kamailani; Kuuleialoha Kamaka, Sharmayne A.; Braun, Kathryn L.
2015-01-01
Background Native Hawaiians, representing 25% of Hawai‘i’s population, suffer socioeconomic and health strains as evidenced by overrepresentation in low-wage jobs without health insurance and a higher prevalence of chronic disease compared with Hawai‘i’s other ethnic groups. Native Hawaiians are more likely to attend community colleges than 4-year colleges and have high dropout rates. Objective To describe a culturally relevant, community-based action research approach to build a program to keep Hawaiians in college to advance career options and improve long-term health and socioeconomic outcomes. Methods Culturally relevant approaches that depended on participation from a variety of community partners were used to evaluate needs and design interventions. Results The Pathway Out of Poverty Program uses Hawaiian values and traditions of healthy living to lead students through a nursing pathway from nurse aide (NA) to licensed practical nurse (LPN) to registered nurse (RN), with inherent increases in wage-earning potential. In the first 3.5 years, 150 students enrolled in NA training, and 135 students (90%) graduated and were certified. Of the 135, 77 (57%) transitioned to higher education and 79% transitioned to jobs that offered health insurance (20% were in both groups). Of the 77 entering higher education, 33 (43%) aimed for a degree in nursing. Students expressed growing interest in health promotion for themselves, family members, and others. Conclusion Community partners were key to developing a successful community college-based Pathway Program to help marginalized and other underrepresented students move from low-wage to living-wage jobs and improve their long-term health outcomes. PMID:22643785
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Michalak, Agnieszka; Biala, Grazyna
2017-01-15
Long-term potentiation (LTP) and long-term depression (LTD) depend on specific postsynaptic Ca 2+ /calmodulin concentration. LTP results from Ca 2+ influx through the activated NMDA receptors or voltage-gated calcium channels (VGCCs) and is linked with activation of protein kinases including mitogen-activated protein kinase (MAPK). Weaker synaptic stimulation, as a result of low Ca 2+ influx, leads to activation of Ca 2+ /calmodulin-dependent phosphatase (calcineurin - CaN) and triggers LTD. Interestingly, both memory formation and drug addiction share similar neuroplastic changes. Nicotine, which is one of the most common addictive drugs, manifests its memory effects through nicotinic acetylcholine receptors (nAChRs). Because nAChRs may also gate Ca 2+ , it is suggested that calcium signaling pathways are involved in nicotine-induced memory effects. Within the scope of the study was to evaluate the importance of calcium homeostasis and protein kinase/phosphatase balance in nicotine-induced short- and long-term memory effects. To assess memory function in mice passive avoidance test was used. The presented results confirm that acute nicotine (0.1mg/kg) improves short- and long-term memory. Pretreatment with L-type VGCC blockers (amlodipine, nicardipine verapamil) increased nicotine-induced memory improvement in the context of short- and long-term memory. Pretreatment with FK-506 (a potent CaN inhibitor) enhanced short- but not long-term memory effects of nicotine, while SL-327 (a selective MAPK/ERK kinase inhibitor) attenuated both nicotine-induced short- and long-term memory improvement. Acute nicotine enhances both types of memory via L-type VGCC blockade and via ERK1/2 activation. Only short- but not long-term memory enhancement induced by nicotine is dependent on CaN inhibition. Copyright © 2016 Elsevier B.V. All rights reserved.
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Leroy, G; Baumung, R; Boettcher, P; Scherf, B; Hoffmann, I
2016-02-01
Crossbreeding, considering either terminal or rotational crossing, synthetic breed creation or breed replacement, is often promoted as an efficient strategy to increase farmers' income through the improvement of productivity of local livestock in developing countries. Sustainability of crossbreeding is however frequently challenged by constraints such as poor adaptation to the local environment or lack of logistic support. In this review, we investigate factors that may influence the long-term success or the failure of crossbreeding programs, based on the scientific literature and country reports submitted for The Second Report on the State of the World's Animal Genetic Resources for Food and Agriculture. Crossbreeding activities vary widely across species and countries. Its sustainability is dependent on different prerequisites such as continual access to adequate breeding stock (especially after the end of externally funded crossbreeding projects), the opportunity of improved livestock to express their genetic potential (e.g. through providing proper inputs) and integration within a reliable market chain. As formal crossbreeding programs are often associated with adoption of other technologies, they can be a catalyst for innovation and development for smallholders. Given the increasing global demand for animal products, as well as the potential environmental consequences of climate change, there is a need for practical research to improve the implementation of long-term crossbreeding programs in developing countries.
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Satia, Jessie A.; Barlow, Jameta; Armstrong-Brown, Janelle; Watters, Joanne L.
2010-01-01
Aims To develop and test cancer prevention messages based on Prospect theory on motivation to improve dietary intake in African American adolescents, and to explore other salient factors that may inform dietary intervention design and implementation in this population. Methods Semi-structured in-person qualitative interviews were conducted with 13 African-American male and female adolescents, 12-16 years, in North Carolina. Prospect theory and message framing were used to guide the design of the four sets of diet-related messages related to cancer prevention: short-term gain-, long-term gain-, short-term loss-, and long-term loss-framed messages. Data were also collected on demographic, behavioral, and psychological factors; usual health behaviors; and preferences for intervention delivery. Results The majority of respondents found the gain-framed, short-term messages most salient for both fruits/vegetables (8 (61.5%)), and fat consumption (7 (53.8%)). For fat consumption only, 2 (15.4%) found the loss-framed, short-term messages pertinent; none found the loss-framed, long-term messages relevant for either dietary variable. All indicated interest in participating in a dietary intervention/education program; most preferred the Internet as a channel for intervention delivery. Participants expressed diverse views regarding knowledge, attitudes, and beliefs regarding healthy eating. Conclusions Researchers conducting dietary interventions and education initiatives and medical professionals who counsel African American adolescents should consider using Prospect Theory as a theoretical framework, should focus on gain-framed short-term messages regarding cancer prevention, and should employ the Internet for data collection and intervention and information delivery. PMID:20142738
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Juan, Wei-Sheng; Huang, Sheng-Yang; Chang, Che-Chao; Hung, Yu-Chang; Lin, Yu-Wen; Chen, Tsung-Ying; Lee, Ai-Hua; Lee, Ai-Chiang; Wu, Tian-Shung; Lee, E-Jian
2014-03-01
Recent evidence shows that the NMDAR postsynaptic density-95 (PSD-95), growth-associated protein-43 (GAP-43), and matrix metalloproteinase-9 (MMP-9) protein enhance neuroplasticity at the subacute stage of stroke. Here, we evaluated whether melatonin would modulate the PSD-95, GAP-43, and MMP-9 proteins in cultured neurons exposed to glutamate excitotoxicity and in rats subjected to experimental stroke. Adult male Sprague-Dawley rats were treated with melatonin (5 mg/kg) or vehicle at reperfusion onset after transient occlusion of the right middle cerebral artery (tMCAO) for 90 min. Animals were euthanized for Western immunoblot analyses for the PSD-95 and GAP-43 proteins and gelatin zymography for the MMP-9 activity at 7 days postinsult. Another set of animals was sacrificed for histologic and Golgi-Cox-impregnated sections at 28 days postinsult. In cultured neurons exposed to glutamate excitotoxicity, melatonin significantly upregulated the GAP-43 and PSD-95 expressions and improved dendritic aborizations (P<0.05, respectively). Relative to controls, melatonin-treated stroke animals caused a significant improvement in GAP-43 and PSD-95 expressions as well as the MMP-9 activity in the ischemic brain (P<0.05). Consequently, melatonin also significantly promoted the dendritic spine density and reduced infarction in the ischemic brain, and improved neurobehaviors as well at 28 days postinsult (P<0.05, respectively). Together, melatonin upregulates GAP-43, PSD-95, and MMP-9 proteins, which likely accounts for its actions to improve neuroplasticity in cultured neurons exposed to glutamate excitotoxicity and to enhance long-term neuroprotection, neuroplasticity, and brain remodeling in stroke rats. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Fustiñana, Maria Sol; Ariel, Pablo; Federman, Noel; Freudenthal, Ramiro; Romano, Arturo
2010-09-01
Human β-amyloid, the main component in the neuritic plaques found in patients with Alzheimer's disease, is generated by cleavage of the β-amyloid precursor protein. Beyond the role in pathology, members of this protein family are synaptic proteins and have been associated with synaptogenesis, neuronal plasticity and memory, both in vertebrates and in invertebrates. Consolidation is necessary to convert a short-term labile memory to a long-term and stable form. During consolidation, gene expression and de novo protein synthesis are regulated in order to produce key proteins for the maintenance of plastic changes produced during the acquisition of new information. Here we partially cloned and sequenced the beta-amyloid precursor protein like gene homologue in the crab Chasmagnathus (cappl), showing a 37% of identity with the fruit fly Drosophila melanogaster homologue and 23% with Homo sapiens but with much higher degree of sequence similarity in certain regions. We observed a wide distribution of cappl mRNA in the nervous system as well as in muscle and gills. The protein localized in all tissues analyzed with the exception of muscle. Immunofluorescence revealed localization of cAPPL in associative and sensory brain areas. We studied gene and protein expression during long-term memory consolidation using a well characterized memory model: the context-signal associative memory in this crab species. mRNA levels varied at different time points during long-term memory consolidation and correlated with cAPPL protein levels cAPPL mRNA and protein is widely distributed in the central nervous system of the crab and the time course of expression suggests a role of cAPPL during long-term memory formation.
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Liu, Jun; Wei, Wei; Kuang, Hui; Zhao, Fang; Tsien, Joe Z
2013-01-01
Heart physiology is a highly useful indicator for measuring not only physical states, but also emotional changes in animals. Yet changes of heart rate variability during fear conditioning have not been systematically studied in mice. Here, we investigated changes in heart rate and heart rate variability in both short-term and long-term contextual and cued fear conditioning. We found that while fear conditioning could increase heart rate, the most significant change was the reduction in heart rate variability which could be further divided into two distinct stages: a highly rhythmic phase (stage-I) and a more variable phase (stage-II). We showed that the time duration of the stage-I rhythmic phase were sensitive enough to reflect the transition from short-term to long-term fear memories. Moreover, it could also detect fear extinction effect during the repeated tone recall. These results suggest that heart rate variability is a valuable physiological indicator for sensitively measuring the consolidation and expression of fear memories in mice.
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Anderson, Niall; Ozakinci, Gozde
2018-03-27
Long-term conditions may negatively impact multiple aspects of quality of life including physical functioning and mental wellbeing. The rapid systematic review aimed to examine the effectiveness of psychological interventions to improve quality of life in people with long-term conditions to inform future healthcare provision and research. EBSCOhost and OVID were used to search four databases (PsychInfo, PBSC, Medline and Embase). Relevant papers were systematically extracted by one researcher using the predefined inclusion/exclusion criteria based on titles, abstracts, and full texts. Randomized controlled trial psychological interventions conducted between 2006 and February 2016 to directly target and assess people with long-term conditions in order to improve quality of life were included. Interventions without long-term condition populations, psychological intervention and/or patient-assessed quality of life were excluded. From 2223 citations identified, 6 satisfied the inclusion/exclusion criteria. All 6 studies significantly improved at least one quality of life outcome immediately post-intervention. Significant quality of life improvements were maintained at 12-months follow-up in one out of two studies for each of the short- (0-3 months), medium- (3-12 months), and long-term (≥ 12 months) study duration categories. All 6 psychological intervention studies significantly improved at least one quality of life outcome immediately post-intervention, with three out of six studies maintaining effects up to 12-months post-intervention. Future studies should seek to assess the efficacy of tailored psychological interventions using different formats, durations and facilitators to supplement healthcare provision and practice.
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Neurotrophins play differential roles in short and long-term recognition memory.
Callaghan, Charlotte K; Kelly, Aine M
2013-09-01
The neurotrophin family of proteins are believed to mediate various forms of synaptic plasticity in the adult brain. Here we have assessed the roles of these proteins in object recognition memory in the rat, using icv infusions of function-blocking antibodies or the tyrosine kinase antagonist, tyrphostin AG879, to block Trk receptors. We report that tyrphostin AG879 impairs both short-term and long-term recognition memory, indicating a requirement for Trk receptor activation in both processes. The effect of inhibition of each of the neurotrophins with activity-blocking neutralising antibodies was also tested. Treatment with anti-BDNF, anti-NGF or anti-NT4 had no effect on short-term memory, but blocked long-term recognition memory. Treatment with anti-NT3 had no effect on either process. We also assessed changes in expression of neurotrophins and their respective receptors in the hippocampus, dentate gyrus and perirhinal cortex over a 24 h period following training in the object recognition task. We observed time-dependent changes in expression of the Trk receptors and their ligands in the dentate gyrus and perirhinal cortex. The data are consistent with a pivotal role for neurotrophic factors in the expression of recognition memory. Copyright © 2013 Elsevier Inc. All rights reserved.
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Serghides, Lena; Friedel, Miriam; Cui, Cheryl; Ho, Keith T.; Mount, Howard T. J.; Sled, John G.; Kain, Kevin C.
2014-01-01
Cerebral malaria (CM) is associated with a high mortality rate, and long-term neurocognitive impairment in approximately one third of survivors. Adjunctive therapies that modify the pathophysiological processes involved in CM may improve outcome over anti-malarial therapy alone. PPARγ agonists have been reported to have immunomodulatory effects in a variety of disease models. Here we report that adjunctive therapy with PPARγ agonists improved survival and long-term neurocognitive outcomes in the Plasmodium berghei ANKA experimental model of CM. Compared to anti-malarial therapy alone, PPARγ adjunctive therapy administered to mice at the onset of CM signs, was associated with reduced endothelial activation, and enhanced expression of the anti-oxidant enzymes SOD-1 and catalase and the neurotrophic factors brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brains of infected mice. Two months following infection, mice that were treated with anti-malarials alone demonstrated cognitive dysfunction, while mice that received PPARγ adjunctive therapy were completely protected from neurocognitive impairment and from PbA-infection induced brain atrophy. In humans with P. falciparum malaria, PPARγ therapy was associated with reduced endothelial activation and with induction of neuroprotective pathways, such as BDNF. These findings provide insight into mechanisms conferring improved survival and preventing neurocognitive injury in CM, and support the evaluation of PPARγ agonists in human CM. PMID:24603727
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MicroRNA expression patterns in indeterminate inflammatory bowel disease.
Lin, Jingmei; Cao, Qi; Zhang, Jianjun; Li, Yong; Shen, Bo; Zhao, Zijin; Chinnaiyan, Arul M; Bronner, Mary P
2013-01-01
A diagnosis of idiopathic inflammatory bowel disease requires synthesis of clinical, radiographic, endoscopic, surgical, and histologic data. While most cases of inflammatory bowel disease can be specifically classified as either ulcerative colitis or Crohns disease, 5-10% of patients have equivocal features placing them into the indeterminate colitis category. This study examines whether microRNA biomarkers assist in the classification of classically diagnosed indeterminate inflammatory bowel disease. Fresh frozen colonic mucosa from the distal-most part of the colectomy from 53 patients was used (16 indeterminate colitis, 14 Crohns disease, 12 ulcerative colitis, and 11 diverticular disease controls). Total RNA extraction and quantitative reverse-transcription-PCR was performed using five pairs of microRNA primers (miR-19b, miR-23b, miR-106a, miR-191, and miR-629). Analysis of variance was performed assessing differences among the groups. A significant difference in expressions of miR-19b, miR-106a, and miR-629 was detected between ulcerative colitis and Crohns disease groups (P<0.05). The average expression level of all five microRNAs was statistically different between indeterminate colitis and Crohns disease groups (P<0.05); no significant difference was present between indeterminate and ulcerative colitis groups. Among the 16 indeterminate colitis patients, 15 showed ulcerative colitis-like and one Crohns disease-like microRNA pattern. MicroRNA expression patterns in indeterminate colitis are far more similar to those of ulcerative colitis than Crohns disease. MicroRNA expression patterns of indeterminate colitis provide molecular evidence indicating that most cases are probably ulcerative colitis-similar to the data from long-term clinical follow-up studies. Validation of microRNA results by additional long-term outcome data is needed, but the data presented show promise for improved classification of indeterminate inflammatory bowel disease.
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This document summarizes the presentations and workshops of a conference on improving long-term monitoring (LTM) and remedial systems performance that was held in St. Louis, Missouri between June 8th to 11th, 1999.
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Grundy, Trent; Toben, Catherine; Jaehne, Emily J.; Corrigan, Frances; Baune, Bernhard T.
2014-01-01
Dietary polyunsaturated fatty acid (PUFA) manipulation is being investigated as a potential therapeutic supplement to reduce the risk of developing age-related cognitive decline (ARCD). Animal studies suggest that high omega (Ω)-3 and low Ω-6 dietary content reduces cognitive decline by decreasing central nervous system (CNS) inflammation and modifying neuroimmune activity. However, no previous studies have investigated the long term effects of Ω-3 and Ω-6 dietary levels in healthy aging mice leaving the important question about the preventive effects of Ω-3 and Ω-6 on behavior and underlying molecular pathways unaddressed. We aimed to investigate the efficacy of long-term Ω-3 and Ω-6 PUFA dietary supplementation in mature adult C57BL/6 mice. We measured the effect of low, medium, and high Ω-3:Ω-6 dietary ratio, given from the age of 3–7 months, on anxiety and cognition-like behavior, hippocampal tissue expression of TNF-α, markers of neuronal progenitor proliferation and gliogenesis and serum cytokine concentration. Our results show that a higher Ω-3:Ω-6 PUFA diet ratio increased hippocampal PUFA, increased anxiety, improved hippocampal dependent spatial memory and reduced hippocampal TNF-α levels compared to a low Ω-3:Ω-6 diet. Furthermore, serum TNF-α concentration was reduced in the higher Ω-3:Ω-6 PUFA ratio supplementation group while expression of the neuronal progenitor proliferation markers KI67 and doublecortin (DCX) was increased in the dentate gyrus as opposed to the low Ω-3:Ω-6 group. Conversely, Ω-3:Ω-6 dietary PUFA ratio had no significant effect on astrocyte or microglia number or cell death in the dentate gyrus. These results suggest that supplementation of PUFAs may delay aging effects on cognitive function in unchallenged mature adult C57BL/6 mice. This effect is possibly induced by increasing neuronal progenitor proliferation and reducing TNF-α. PMID:25484856
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McGregor, I S; Callaghan, P D; Hunt, G E
2008-05-01
Addictive drugs can profoundly affect social behaviour both acutely and in the long-term. Effects range from the artificial sociability imbued by various intoxicating agents to the depressed and socially withdrawn state frequently observed in chronic drug users. Understanding such effects is of great potential significance in addiction neurobiology. In this review we focus on the 'social neuropeptide' oxytocin and its possible role in acute and long-term effects of commonly used drugs. Oxytocin regulates social affiliation and social recognition in many species and modulates anxiety, mood and aggression. Recent evidence suggests that popular party drugs such as MDMA and gamma-hydroxybutyrate (GHB) may preferentially activate brain oxytocin systems to produce their characteristic prosocial and prosexual effects. Oxytocin interacts with the mesolimbic dopamine system to facilitate sexual and social behaviour, and this oxytocin-dopamine interaction may also influence the acquisition and expression of drug-seeking behaviour. An increasing body of evidence from animal models suggests that even brief exposure to drugs such as MDMA, cannabinoids, methamphetamine and phencyclidine can cause long lasting deficits in social behaviour. We discuss preliminary evidence that these adverse effects may reflect long-term neuroadaptations in brain oxytocin systems. Laboratory studies and preliminary clinical studies also indicate that raising brain oxytocin levels may ameliorate acute drug withdrawal symptoms. It is concluded that oxytocin may play an important, yet largely unexplored, role in drug addiction. Greater understanding of this role may ultimately lead to novel therapeutics for addiction that can improve mood and facilitate the recovery of persons with drug use disorders.
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Insulin Receptor Signaling in Long-Term Memory Consolidation Following Spatial Learning
ERIC Educational Resources Information Center
Dou, Jing-Tao; Chen, Min; Dufour, Franck; Alkon, Daniel L.; Zhao, Wei-Qin
2005-01-01
Evidence has shown that the insulin and insulin receptor (IR) play a role in cognitive function. However, the detailed mechanisms underlying insulin's action on learning and memory are not yet understood. Here we investigated changes in long-term memory-associated expression of the IR and downstream molecules in the rat hippocampus. After…
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Serotonin- and Training-Induced Dynamic Regulation of CREB2 in "Aplysia"
ERIC Educational Resources Information Center
Liu, Rong-Yu; Shah, Shreyansh; Cleary, Leonard J.; Byrne, John H.
2011-01-01
Long-term memory and plasticity, including long-term synaptic facilitation (LTF) of the "Aplysia" sensorimotor synapse, depend on the activation of transcription factors that regulate genes necessary for synaptic plasticity. In the present study we found that treatment with 5-HT and behavioral training produce biphasic changes in the expression of…
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The health effects of long-term exposure to volatile organic compounds (VOCs) are poorly understood, due primarily to insufficient human exposure data and inconsistent animal models. To develop a rodent model of long-term exposure to VOCs, a sub-chronic inhalation study with mult...
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Penke, Zsuzsa; Morice, Elise; Veyrac, Alexandra; Gros, Alexandra; Chagneau, Carine; LeBlanc, Pascale; Samson, Nathalie; Baumgärtel, Karsten; Mansuy, Isabelle M; Davis, Sabrina; Laroche, Serge
2014-01-05
It is well established that Zif268/Egr1, a member of the Egr family of transcription factors, is critical for the consolidation of several forms of memory; however, it is as yet uncertain whether increasing expression of Zif268 in neurons can facilitate memory formation. Here, we used an inducible transgenic mouse model to specifically induce Zif268 overexpression in forebrain neurons and examined the effect on recognition memory and hippocampal synaptic transmission and plasticity. We found that Zif268 overexpression during the establishment of memory for objects did not change the ability to form a long-term memory of objects, but enhanced the capacity to form a long-term memory of the spatial location of objects. This enhancement was paralleled by increased long-term potentiation in the dentate gyrus of the hippocampus and by increased activity-dependent expression of Zif268 and selected Zif268 target genes. These results provide novel evidence that transcriptional mechanisms engaging Zif268 contribute to determining the strength of newly encoded memories.
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Satb2 determines miRNA expression and long-term memory in the adult central nervous system.
Jaitner, Clemens; Reddy, Chethan; Abentung, Andreas; Whittle, Nigel; Rieder, Dietmar; Delekate, Andrea; Korte, Martin; Jain, Gaurav; Fischer, Andre; Sananbenesi, Farahnaz; Cera, Isabella; Singewald, Nicolas; Dechant, Georg; Apostolova, Galina
2016-11-29
SATB2 is a risk locus for schizophrenia and encodes a DNA-binding protein that regulates higher-order chromatin configuration. In the adult brain Satb2 is almost exclusively expressed in pyramidal neurons of two brain regions important for memory formation, the cerebral cortex and the CA1-hippocampal field. Here we show that Satb2 is required for key hippocampal functions since deletion of Satb2 from the adult mouse forebrain prevents the stabilization of synaptic long-term potentiation and markedly impairs long-term fear and object discrimination memory. At the molecular level, we find that synaptic activity and BDNF up-regulate Satb2, which itself binds to the promoters of coding and non-coding genes. Satb2 controls the hippocampal levels of a large cohort of miRNAs, many of which are implicated in synaptic plasticity and memory formation. Together, our findings demonstrate that Satb2 is critically involved in long-term plasticity processes in the adult forebrain that underlie the consolidation and stabilization of context-linked memory.
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Long-Term Care Ombudsman Program Annual Report: Oct. 1, 1989 through Sept. 30. 1990.
ERIC Educational Resources Information Center
Oklahoma State Dept. of Human Services, Oklahoma City.
This annual report of the Long-Term Care Ombudsmen Program of the Oklahoma Department of Human Services begins by stating the purpose of the program: to improve the quality of life and the quality of care of older residents of long-term care facilities in Oklahoma. It is noted that the Long-Term Care Ombudsman advocates for the rights of long-term…
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The impact of oral health on body image and social interactions among elders in long-term care.
Donnelly, Leeann R; Clarke, Laura Hurd; Phinney, Alison; MacEntee, Michael I
2016-12-01
The objective of this study was to explore how social interactions and body image are influenced by perceived oral health among older people who live in long-term care facilities. Social interactions among frail elders in long-term care (LTC) facilities are limited, but to what extent body image and oral health influence their social relations is poorly understood. A positive body image and the perception of adequate oral health are linked to increased social contacts, as well as improved health and well-being irrespective of age. However, as frailty increases, it is unclear whether appearance and oral health priorities remain stable. Open-ended interviews were conducted with a purposefully selected group of cognitively intact, older men and women who exhibited varying degrees of frailty, social engagement and oral health conditions and lived in one of seven long-term care facilities. The interviews were analysed using a constant comparative technique, and a second interview with participants checked the trustworthiness of the analysis. Three major categories were expressed by the participants: (1) My mouth is fine; (2) It depends; and (3) Not that important. Within each category, there were several contributing and influencing factors. Social interactions among residents in LTC may be negatively impacted by poor oral health, but only if other personal and social issues are less bothersome than conditions with the mouth. © 2015 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd.
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Safety and Efficacy of Rivastigmine in Adolescents with Down Syndrome: Long-Term Follow-Up
Spiridigliozzi, Gail A.; Crissman, Blythe G.; McKillop, Jane Anne; Yamamoto, Haru; Kishnani, Priya S.
2010-01-01
Abstract Following the completion of a 20-week, open-label study of the safety and efficacy of liquid rivastigmine for adolescents with Down syndrome, 5 of the 10 adolescents in the clinical trial continued long-term rivastigmine therapy and 5 did not. After an average period of 38 months, all 10 subjects returned for a follow-up assessment to determine the safety and efficacy of long-term rivastigmine use. Rivastigmine was well tolerated and overall health appeared to be unaffected by long-term rivastigmine use. Performance change on cognitive and language measures administered at the termination of the open-label clinical trial was compared between the two groups. No between-group difference in median performance change across the long-term period was found, suggesting that the long-term use of rivastigmine does not improve cognitive and language performance. However, two subjects demonstrated remarkable improvement in adaptive function over the long-term period. Both subjects had received long-term rivastigmine therapy. The discussion addresses the challenge of assessing cognitive change in clinical trials using adolescents with Down syndrome as subjects and the use of group versus individual data to evaluate the relevance of medication effects. PMID:21186971
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Tricuspid valve replacement with mechanical prostheses: Short and long-term outcomes.
Rossello, Xavier; Muñoz-Guijosa, Christian; Mena, Elisabet; Camprecios, Marta; Mendez, Ana B; Borras, Xavier; Padro, Josep M
2017-09-01
Tricuspid valve replacement has been associated with high mortality and poor long-term outcomes. We report the preoperative risk factors associated with short and long-term outcomes following tricuspid valve replacement with mechanical prostheses. In 62 patients who underwent mechanical tricuspid valve replacement, clinical, laboratory, and echocardiographic findings were analyzed using both univariate and multivariate analyses to describe operative and long-term mortality. In our population (mean age 59 ± 9.7 years, 82.3% female), most common causes of tricuspid valve disease were rheumatic fever (69.4%) and functional regurgitation (19.4%). Operative and long-term mortality were 17.7 and 33.9%, respectively. Age, diabetes mellitus, and coronary artery disease were independently associated with increased long-term mortality. New York Heart Association (NYHA) class and right heart failure symptoms significantly improved during follow-up. In this series of mechanical tricuspid valve replacements in patients with predominately rheumatic heart disease, operative and long-term mortality were increased; however, survivors had significant improvement in their NYHA class and freedom from right heart failure symptoms. Three preoperative factors (age, diabetes mellitus, and coronary artery disease) were independently associated with long-term mortality. © 2017 Wiley Periodicals, Inc.
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Xu, Wen; Cao, Jian; Zhou, Yan; Wang, Lina; Zhu, Guoqi
2018-03-01
Reduced estrogen levels and decreased expression of related receptors are typical cerebral features of aging. The G protein-coupled estrogen receptor 1 (GPER1, also known as GPR30) is considered a novel therapeutic target for neurodegenerative diseases. In this study, we demonstrated that hippocampal GPR30 expression was reduced in middle-aged mice compared with young adult mice. GPR30 agonist G1 improved both fear and spatial memory in both male and female middle-aged mice, but not in young adult mice, which were blocked by the GPR30 antagonist G15. Interestingly, a group I metabotropic glutamate receptor (mGluR) agonist, 3,5-dihydroxyphenylglycine (DHPG)-induced long-term depression (LTD) in mossy fiber-cornu ammonis 3 (MF-CA3) synapses but not Schaffer collateral-CA1 (SC-CA1) synapses was facilitated in brain slices from G1-treated middle-aged mice. Long-term potentiation (LTP) in SC-CA1 synapses was not affected in slices from G1-treated mice. The effects of GPR30 activation on memory and DHPG-LTD in MF-CA3 synapses were further confirmed by viral expression of GPR30 in the CA3. The regulation of hippocampal synaptic plasticity by G1 treatment might be related to brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling, as G15 also blocked G1-induced activation of the BDNF-TrkB pathway. Moreover, we found that DHPG triggered GluA internalization in slices from G1-treated mice but not control mice. Pharmacological experiments showed that G1-mediated facilitation of DHPG-induced LTD in MF-CA3 synapses was dependent on protein kinase B (Akt), mammalian target of rapamycin (mTor), and TrkB signaling. In conclusion, our results indicate that GPR30 activation improves memory in middle-aged mice, likely through facilitating synaptic plasticity in the CA3. This study provides novel evidence that GPR30 activation can improve memory in middle-aged animals. Copyright © 2018 Elsevier Inc. All rights reserved.
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Snabaitis, A K; Chambers, D
1999-11-27
Polarized arrest, induced by tetrodotoxin (TTX) at an optimal concentration of 22 micromol/L, has been shown to reduce ionic imbalance and improve myocardial preservation compared with hyperkalemic (depolarized) arrest. Additional pharmacologic manipulation of ionic changes (involving inhibition of Na+ influx by the Na+/H+ exchanger [HOE694] and Na+/K+/2Cl- cotransporter [furosemide], and calcium desensitization [BDM]) may further improve long-term preservation. In this study, we (i) established optimal concentrations of each drug, (ii) determined additive effects of optimal concentrations of each drug and (iii) compared our optimal preservation solution to an established depolarizing cardioplegia (St Thomas' Hospital solution No 2: STH2) used during long-term hypothermic storage for clinical transplantation. The isolated working rat heart, perfused with Krebs Henseleit (KH) buffer was used; cardiac function was measured after 20 min aerobic working mode perfusion. The hearts (n=6/group) were arrested with a 2 ml infusion (for 30 sec) of the polarizing (control) solution (22 micromol/L TTX in KH) or control+drug and subjected to 5 hr or 8 hr of storage at 7.5 degrees C in the arresting solution. Postischemic function during reperfusion was measured (expressed as percentage of preischemic function). Dose-response studies established optimal concentrations of HOE694 (10 micromol/L), furosemide (1.0 micromol/L) and BDM (30 mmol/L) in the polarizing (control) solution. Sequential addition to the control solution (Group I) of optimal concentrations of HOE694 (Group II), furosemide (Group III), and BDM (Group IV) were compared with STH2 (Group V); postischemic recovery of aortic flow was 29+/-7%, 49+/-6%*, 56+/-2%*, 76+/-3%*, and 25+/-6%, respectively (*P<0.05 vs. I and V). Creatine kinase leakage was lowest, and myocardial ATP content was highest in Group IV. A polarizing preservation solution (KH+TTX) containing HOE694, furosemide, and BDM significantly enhanced long-term preservation compared with an optimized depolarizing solution (STH2) used clinically for long-term donor heart preservation.
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Pancreatic Transduction by Helper-Dependent Adenoviral Vectors via Intraductal Delivery
Morró, Meritxell; Teichenne, Joan; Jimenez, Veronica; Kratzer, Ramona; Marletta, Serena; Maggioni, Luca; Mallol, Cristina; Ruberte, Jesus; Kochanek, Stefan; Bosch, Fatima
2014-01-01
Abstract Pancreatic gene transfer could be useful to treat several diseases, such as diabetes mellitus, cystic fibrosis, chronic pancreatitis, or pancreatic cancer. Helper-dependent adenoviral vectors (HDAds) are promising tools for gene therapy because of their large cloning capacity, high levels of transgene expression, and long-term persistence in immunocompetent animals. Nevertheless, the ability of HDAds to transduce the pancreas in vivo has not been investigated yet. Here, we have generated HDAds carrying pancreas-specific expression cassettes, that is, driven either by the elastase or insulin promoter, using a novel and convenient plasmid family and homologous recombination in bacteria. These HDAds were delivered to the pancreas of immunocompetent mice via intrapancreatic duct injection. HDAds, encoding a CMV-GFP reporter cassette, were able to transduce acinar and islet cells, but transgene expression was lost 15 days postinjection in correlation with severe lymphocytic infiltration. When HDAds encoding GFP under the control of the specific elastase promoter were used, expression was detected in acinar cells, but similarly, the expression almost disappeared 30 days postinjection and lymphocytic infiltration was also observed. In contrast, long-term transgene expression (>8 months) was achieved with HDAds carrying the insulin promoter and the secretable alkaline phosphatase as the reporter gene. Notably, transduction of the liver, the preferred target for adenovirus, was minimal by this route of delivery. These data indicate that HDAds could be used for pancreatic gene therapy but that selection of the expression cassette is of critical importance to achieve long-term expression of the transgene in this tissue. PMID:25046147
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McDonald, S; Togher, L; Tate, R; Randall, R; English, T; Gowland, A
2013-01-01
Many adults with acquired brain injuries, including traumatic brain injuries (TBI) have impaired emotion perception. Impaired perception of emotion in voice can occur independently to facial expression and represents a specific target for remediation. No research to date has addressed this. The current study used a randomised controlled trial to examine the efficacy of a short treatment (three x two-hour sessions) for improving the ability to recognise emotional prosody for people with acquired brain injury, mostly TBI. Ten participants were allocated to treatment and 10 to waitlist. All participants remained involved for the duration of the study in the groups to which they were allocated. There were no significant treatment effects for group, but analyses of individual performances indicated that six of the treated participants made demonstrable improvements on objective measures of prosody recognition. The reasons why some participants showed improvements while others did not, was not obvious. Improvements on objective lab-based measures did not generalise to relative reports of improvements in everyday communicative ability. Nor was there clear evidence of long-term effects. In conclusion, treatment of emotional prosody was effective in the short-term for half of the participants. Further research is required to determine what conditions are required to optimise generalisability and longer-term gains.
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Singh, Rumani; Manchanda, Shaffi; Kaur, Taranjeet; Kumar, Sushil; Lakhanpal, Dinesh; Lakhman, Sukhwinder S; Kaur, Gurcharan
2015-12-01
Intermittent fasting dietary restriction (IF-DR) is recently reported to be an effective intervention to retard age associated disease load and to promote healthy aging. Since sustaining long term caloric restriction regimen is not practically feasible in humans, so use of alternate approach such as late onset short term IF-DR regimen which is reported to trigger similar biological pathways is gaining scientific interest. The current study was designed to investigate the effect of IF-DR regimen implemented for 12 weeks in middle age rats on their motor coordination skills and protein and DNA damage in different brain regions. Further, the effect of IF-DR regimen was also studied on expression of energy regulators, cell survival pathways and synaptic plasticity marker proteins. Our data demonstrate that there was an improvement in motor coordination and learning response with decline in protein oxidative damage and recovery in expression of energy regulating neuropeptides. We further observed significant downregulation in nuclear factor kappa B (NF-κB) and cytochrome c (Cyt c) levels and moderate upregulation of mortalin and synaptophysin expression. The present data may provide an insight on how a modest level of short term IF-DR, imposed in middle age, can slow down or prevent the age-associated impairment of brain functions and promote healthy aging by involving multiple regulatory pathways aimed at maintaining energy homeostasis.
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Cardiovascular Risks Associated with Low Dose Ionizing Particle Radiation
Yan, Xinhua; Sasi, Sharath P.; Gee, Hannah; ...
2014-10-22
Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton ( 1H; 0.5 Gy, 1 GeV) and iron ion ( 56Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiatedmore » mice initially improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in 56Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, 56Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Finally, understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy.« less
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Cardiovascular Risks Associated with Low Dose Ionizing Particle Radiation
DOE Office of Scientific and Technical Information (OSTI.GOV)
Yan, Xinhua; Sasi, Sharath P.; Gee, Hannah
Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton ( 1H; 0.5 Gy, 1 GeV) and iron ion ( 56Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiatedmore » mice initially improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in 56Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, 56Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Finally, understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy.« less
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Benner, Ina; Diner, Rachel E.; Lefebvre, Stephane C.; Li, Dian; Komada, Tomoko; Carpenter, Edward J.; Stillman, Jonathon H.
2013-01-01
Increased atmospheric pCO2 is expected to render future oceans warmer and more acidic than they are at present. Calcifying organisms such as coccolithophores that fix and export carbon into the deep sea provide feedbacks to increasing atmospheric pCO2. Acclimation experiments suggest negative effects of warming and acidification on coccolithophore calcification, but the ability of these organisms to adapt to future environmental conditions is not well understood. Here, we tested the combined effect of pCO2 and temperature on the coccolithophore Emiliania huxleyi over more than 700 generations. Cells increased inorganic carbon content and calcification rate under warm and acidified conditions compared with ambient conditions, whereas organic carbon content and primary production did not show any change. In contrast to findings from short-term experiments, our results suggest that long-term acclimation or adaptation could change, or even reverse, negative calcification responses in E. huxleyi and its feedback to the global carbon cycle. Genome-wide profiles of gene expression using RNA-seq revealed that genes thought to be essential for calcification are not those that are most strongly differentially expressed under long-term exposure to future ocean conditions. Rather, differentially expressed genes observed here represent new targets to study responses to ocean acidification and warming. PMID:23980248
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Young, Eric D; Ingram, Davis; Metcalf-Doetsch, William; Khan, Dilshad; Al Sannaa, Ghadah; Le Loarer, Francois; Lazar, Alexander J F; Slopis, John; Torres, Keila E; Lev, Dina; Pollock, Raphael E; McCutcheon, Ian E
2017-09-08
OBJECTIVE While sporadic peripheral schwannomas (SPSs) are generally well treated with surgery, their biology is not well understood. Consequently, treatment options are limited. The aim of this study was to provide a comprehensive description of SPS. The authors describe clinicopathological features and treatment outcomes of patients harboring these tumors, and they assess expression of biomarkers using a clinically annotated tissue microarray. Together, these data give new insight into the biology and management of SPS. METHODS Patients presenting with a primary SPS between 1993 and 2011 (n = 291) were selected from an institutional registry to construct a clinical database. All patients underwent follow-up, and short- and long-term outcomes were assessed. Expression of relevant biomarkers was assessed using a new tissue microarray (n = 121). RESULTS SPSs were generally large (mean 5.5 cm) and frequently painful at presentation (55%). Most patients were treated with surgery (80%), the majority of whom experienced complete resolution (52%) or improvement (18%) of their symptoms. Tumors that were completely resected (85%) did not recur. Some patients experienced short-term (16%) and long-term (4%) complications postoperatively. Schwannomas expressed higher levels of platelet-derived growth factor receptor-β (2.1) than malignant peripheral nerve sheath tumors (MPNSTs) (1.5, p = 0.004) and neurofibromas (1.33, p = 0.007). Expression of human epidermal growth factor receptor-2 was greater in SPSs (0.91) than in MPNSTs (0.33, p = 0.002) and neurofibromas (0.33, p = 0.026). Epidermal growth factor receptor was expressed in far fewer SPS cells (10%) than in MPNSTs (58%, p < 0.0001) or neurofibromas (37%, p = 0.007). SPSs more frequently expressed cytoplasmic survivin (66% of tumor cells) than normal nerve (46% of cells), but SPS expressed nuclear survivin in fewer tumor cells than in MPNSTs (24% and 50%, respectively; p = 0.018). CONCLUSIONS Complete resection is curative for SPS. Left untreated, however, these tumors can cause significant morbidity, and not all patients are candidates for resection. SPSs express a pattern of biomarkers consistent with the dysregulation of the tumor suppressor merlin observed in neurofibromatosis Type 2-associated schwannomas, suggesting a shared etiology. This SPS pattern is distinct from that of other tumors of the peripheral nerve sheath.
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2013-01-01
Background Prenatal alcohol exposure is known to result in fetal alcohol spectrum disorders, a continuum of physiological, behavioural, and cognitive phenotypes that include increased risk for anxiety and learning-associated disorders. Prenatal alcohol exposure results in life-long disorders that may manifest in part through the induction of long-term gene expression changes, potentially maintained through epigenetic mechanisms. Findings Here we report a decrease in the expression of Canabinoid receptor 1 (Cnr1) and an increase in the expression of the regulatory microRNA miR-26b in the brains of adult mice exposed to ethanol during neurodevelopment. Furthermore, we show that miR-26b has significant complementarity to the 3’-UTR of the Cnr1 transcript, giving it the potential to bind and reduce the level of Cnr1 expression. Conclusions These findings elucidate a mechanism through which some genes show long-term altered expression following prenatal alcohol exposure, leading to persistent alterations to cognitive function and behavioural phenotypes observed in fetal alcohol spectrum disorders. PMID:23915435
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The effects of long-term dopaminergic treatment on locomotor behavior in rats.
Oliveira de Almeida, Welinton Alessandro; Maculano Esteves, Andrea; Leite de Almeida-Júnior, Canuto; Lee, Kil Sun; Kannebley Frank, Miriam; Oliveira Mariano, Melise; Frussa-Filho, Roberto; Tufik, Sergio; Tulio de Mello, Marco
2014-12-01
Long-term treatments with dopaminergic agents are associated with adverse effects, including augmentation. Augmentation consists of an exacerbation of restless legs syndrome (a sleep-related movement disorder) symptoms during treatment compared to those experienced during the period before therapy was initiated. The objective of this study was to examine locomotor activity in rats after long-term dopaminergic treatment and its relationship with expression of the D2 receptor, in addition to demonstrating possible evidence of augmentation. The rats were divided into control (CTRL) and drug (Pramipexole-PPX) groups that received daily saline vehicle and PPX treatments, respectively, for 71 days. The locomotor behavior of the animals was evaluated weekly in the Open Field test for 71 days. The expression of the dopamine D2 receptor was evaluated by Western Blot analysis. The animals that received the PPX demonstrated a significant reduction in locomotor activity from day 1 to day 57 and a significant increase in immobility time from day 1 to day 64 relative to baseline values, but these values had returned to baseline levels at 71 days. No changes in the expression of the D2 receptor were demonstrated after treatment with a dopaminergic agonist. This study suggests changes in locomotor activity in rats after long-term PPX treatment that include an immediate reduction of locomotion and an increase in immobilization, and after 64 days, these values returned to baseline levels without evidence of augmentation. In addition, it was not possible to demonstrate a relationship between locomotor activity and the expression of D2 receptors under these conditions.
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Miklík, Dalibor; Šenigl, Filip; Hejnar, Jiří
2018-01-01
Individual groups of retroviruses and retroviral vectors differ in their integration site preference and interaction with the host genome. Hence, immediately after infection genome-wide distribution of integrated proviruses is non-random. During long-term in vitro or persistent in vivo infection, the genomic position and chromatin environment of the provirus affects its transcriptional activity. Thus, a selection of long-term stably expressed proviruses and elimination of proviruses, which have been gradually silenced by epigenetic mechanisms, helps in the identification of genomic compartments permissive for proviral transcription. We compare here the extent and time course of provirus silencing in single cell clones of the K562 human myeloid lymphoblastoma cell line that have been infected with retroviral reporter vectors derived from avian sarcoma/leukosis virus (ASLV), human immunodeficiency virus type 1 (HIV) and murine leukaemia virus (MLV). While MLV proviruses remain transcriptionally active, ASLV proviruses are prone to rapid silencing. The HIV provirus displays gradual silencing only after an extended time period in culture. The analysis of integration sites of long-term stably expressed proviruses shows a strong bias for some genomic features—especially integration close to the transcription start sites of active transcription units. Furthermore, complex analysis of histone modifications enriched at the site of integration points to the accumulation of proviruses of all three groups in gene regulatory segments, particularly close to the enhancer loci. We conclude that the proximity to active regulatory chromatin segments correlates with stable provirus expression in various retroviral species. PMID:29517993
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The effects of long-term dopaminergic treatment on locomotor behavior in rats
Oliveira de Almeida, Welinton Alessandro; Maculano Esteves, Andrea; Leite de Almeida-Júnior, Canuto; Lee, Kil Sun; Kannebley Frank, Miriam; Oliveira Mariano, Melise; Frussa-Filho, Roberto; Tufik, Sergio; Tulio de Mello, Marco
2014-01-01
Long-term treatments with dopaminergic agents are associated with adverse effects, including augmentation. Augmentation consists of an exacerbation of restless legs syndrome (a sleep-related movement disorder) symptoms during treatment compared to those experienced during the period before therapy was initiated. The objective of this study was to examine locomotor activity in rats after long-term dopaminergic treatment and its relationship with expression of the D2 receptor, in addition to demonstrating possible evidence of augmentation. The rats were divided into control (CTRL) and drug (Pramipexole—PPX) groups that received daily saline vehicle and PPX treatments, respectively, for 71 days. The locomotor behavior of the animals was evaluated weekly in the Open Field test for 71 days. The expression of the dopamine D2 receptor was evaluated by Western Blot analysis. The animals that received the PPX demonstrated a significant reduction in locomotor activity from day 1 to day 57 and a significant increase in immobility time from day 1 to day 64 relative to baseline values, but these values had returned to baseline levels at 71 days. No changes in the expression of the D2 receptor were demonstrated after treatment with a dopaminergic agonist. This study suggests changes in locomotor activity in rats after long-term PPX treatment that include an immediate reduction of locomotion and an increase in immobilization, and after 64 days, these values returned to baseline levels without evidence of augmentation. In addition, it was not possible to demonstrate a relationship between locomotor activity and the expression of D2 receptors under these conditions. PMID:26483930
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Changes in rhizosphere bacterial gene expression following glyphosate treatment.
Newman, Molli M; Lorenz, Nicola; Hoilett, Nigel; Lee, Nathan R; Dick, Richard P; Liles, Mark R; Ramsier, Cliff; Kloepper, Joseph W
2016-05-15
In commercial agriculture, populations and interactions of rhizosphere microflora are potentially affected by the use of specific agrichemicals, possibly by affecting gene expression in these organisms. To investigate this, we examined changes in bacterial gene expression within the rhizosphere of glyphosate-tolerant corn (Zea mays) and soybean (Glycine max) in response to long-term glyphosate (PowerMAX™, Monsanto Company, MO, USA) treatment. A long-term glyphosate application study was carried out using rhizoboxes under greenhouse conditions with soil previously having no history of glyphosate exposure. Rhizosphere soil was collected from the rhizoboxes after four growing periods. Soil microbial community composition was analyzed using microbial phospholipid fatty acid (PLFA) analysis. Total RNA was extracted from rhizosphere soil, and samples were analyzed using RNA-Seq analysis. A total of 20-28 million bacterial sequences were obtained for each sample. Transcript abundance was compared between control and glyphosate-treated samples using edgeR. Overall rhizosphere bacterial metatranscriptomes were dominated by transcripts related to RNA and carbohydrate metabolism. We identified 67 differentially expressed bacterial transcripts from the rhizosphere. Transcripts downregulated following glyphosate treatment involved carbohydrate and amino acid metabolism, and upregulated transcripts involved protein metabolism and respiration. Additionally, bacterial transcripts involving nutrients, including iron, nitrogen, phosphorus, and potassium, were also affected by long-term glyphosate application. Overall, most bacterial and all fungal PLFA biomarkers decreased after glyphosate treatment compared to the control. These results demonstrate that long-term glyphosate use can affect rhizosphere bacterial activities and potentially shift bacterial community composition favoring more glyphosate-tolerant bacteria. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.
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Jurado-Berbel, Patricia; Costa-Miserachs, David; Torras-Garcia, Meritxell; Coll-Andreu, Margalida; Portell-Cortés, Isabel
2010-02-11
The present work examined whether post-training systemic epinephrine (EPI) is able to modulate short-term (3h) and long-term (24 h and 48 h) memory of standard object recognition, as well as long-term (24 h) memory of separate "what" (object identity) and "where" (object location) components of object recognition. Although object recognition training is associated to low arousal levels, all the animals received habituation to the training box in order to further reduce emotional arousal. Post-training EPI improved long-term (24 h and 48 h), but not short-term (3 h), memory in the standard object recognition task, as well as 24 h memory for both object identity and object location. These data indicate that post-training epinephrine: (1) facilitates long-term memory for standard object recognition; (2) exerts separate facilitatory effects on "what" (object identity) and "where" (object location) components of object recognition; and (3) is capable of improving memory for a low arousing task even in highly habituated rats.
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Hermans, Erno J; Kanen, Jonathan W; Tambini, Arielle; Fernández, Guillén; Davachi, Lila; Phelps, Elizabeth A
2017-05-01
After encoding, memories undergo a process of consolidation that determines long-term retention. For conditioned fear, animal models postulate that consolidation involves reactivations of neuronal assemblies supporting fear learning during postlearning "offline" periods. However, no human studies to date have investigated such processes, particularly in relation to long-term expression of fear. We tested 24 participants using functional MRI on 2 consecutive days in a fear conditioning paradigm involving 1 habituation block, 2 acquisition blocks, and 2 extinction blocks on day 1, and 2 re-extinction blocks on day 2. Conditioning blocks were preceded and followed by 4.5-min rest blocks. Strength of spontaneous recovery of fear on day 2 served as a measure of long-term expression of fear. Amygdala connectivity primarily with hippocampus increased progressively during postacquisition and postextinction rest on day 1. Intraregional multi-voxel correlation structures within amygdala and hippocampus sampled during a block of differential fear conditioning furthermore persisted after fear learning. Critically, both these main findings were stronger in participants who exhibited spontaneous recovery 24 h later. Our findings indicate that neural circuits activated during fear conditioning exhibit persistent postlearning activity that may be functionally relevant in promoting consolidation of the fear memory. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Červený, Jan; Sinetova, Maria A; Zavřel, Tomáš; Los, Dmitry A
2015-03-02
Synechocystis sp. PCC 6803 is a widely used model cyanobacterium for studying responses and acclimation to different abiotic stresses. Changes in transcriptome, proteome, lipidome, and photosynthesis in response to short term heat stress are well studied in this organism, and histidine kinase 34 (Hik34) is shown to play an important role in mediating such response. Corresponding data on long term responses, however, are fragmentary and vary depending on parameters of experiments and methods of data collection, and thus are hard to compare. In order to elucidate how the early stress responses help cells to sustain long-term heat stress, as well as the role of Hik34 in prolonged acclimation, we examined the resistance to long-term heat stress of wild-type and ΔHik34 mutant of Synechocystis. In this work, we were able to precisely control the long term experimental conditions by cultivating Synechocystis in automated photobioreactors, measuring selected physiological parameters within a time range of minutes. In addition, morphological and ultrastructural changes in cells were analyzed and western blotting of individual proteins was used to study the heat stress-affected protein expression. We have shown that the majority of wild type cell population was able to recover after 24 h of cultivation at 44 °C. In contrast, while ΔHik34 mutant cells were resistant to heat stress within its first hours, they could not recover after 24 h long high temperature treatment. We demonstrated that the early induction of HspA expression and maintenance of high amount of other HSPs throughout the heat incubation is critical for successful adaptation to long-term stress. In addition, it appears that histidine kinase Hik34 is an essential component for the long term high temperature resistance.
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Hsueh, Shih-Chang; Lai, Jing-Huei; Wu, Chung-Che; Yu, Yu-Wen; Luo, Yu; Hsieh, Tsung-Hsun; Chiang, Yung-Hsiao
2018-01-01
Background: Parkinson’s disease (PD) is typically characterized by impairment of motor function. Gait disturbances similar to those observed in patients with PD can be observed in animals after injection of neurotoxin 6-hydroxydopamine (6-OHDA) to induce unilateral nigrostriatal dopamine depletion. Exercise has been shown to be a promising non-pharmacological approach to reduce the risk of neurodegenerative disease. Methods: In this study, we investigated the long-term effects of voluntary running wheel exercise on gait phenotypes, depression, cognitive, rotational behaviors as well as histology in a 6-OHDA-lesioned rat model of PD. Results: We observed that, when compared with the non-exercise controls, five-week voluntary exercise alleviated and postponed the 6-OHDA-induced gait deficits, including a significantly improved walking speed, step/stride length, base of support and print length. In addition, we found that the non-motor functions, such as novel object recognition and forced swim test, were also ameliorated by voluntary exercise. However, the rotational behavior of the exercise group did not show significant differences when compared with the non-exercise group. Conclusions: We first analyzed the detailed spatiotemporal changes of gait pattern to investigate the potential benefits after long-term exercise in the rat model of PD, which could be useful for future objective assessment of locomotor function in PD or other neurological animal models. Furthermore, these results suggest that short-term voluntary exercise is sufficient to alleviate cognition deficits and depressive behavior in 6-OHDA lesioned rats and long-term treatment reduces the progression of motor symptoms and elevates tyrosine hydroxylase (TH), Brain-derived neurotrophic factor (BDNF), bone marrow tyrosine kinase in chromosome X (BMX) protein expression level without affecting dopaminergic (DA) neuron loss in this PD rat model. PMID:29419747
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NASA Technical Reports Server (NTRS)
Gallagher, R. R.
1974-01-01
Exercise subroutine modifications are implemented in an exercise-respiratory system model yielding improvement of system response to exercise forcings. A more physiologically desirable respiratory ventilation rate in addition to an improved regulation of arterial gas tensions and cerebral blood flow is observed. A respiratory frequency expression is proposed which would be appropriate as an interfacing element of the respiratory-pulsatile cardiovascular system. Presentation of a circulatory-respiratory system integration scheme along with its computer program listing is given. The integrated system responds to exercise stimulation for both nonstressed and stressed physiological states. Other integration possibilities are discussed with respect to the respiratory, pulsatile cardiovascular, thermoregulatory, and the long-term circulatory systems.
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A two-stage patient enrichment adaptive design in phase II oncology trials.
Song, James X
2014-01-01
Illustrated is the use of a patient enrichment adaptive design in a randomized phase II trial which allows the evaluation of treatment benefits by the biomarker expression level and makes interim adjustment according to the pre-specified rules. The design was applied to an actual phase II metastatic hepatocellular carcinoma (HCC) trial in which progression-free survival (PFS) in two biomarker-defined populations is evaluated at both interim and final analyses. As an extension, a short-term biomarker is used to predict the long-term PFS in a Bayesian model in order to improve the precision of hazard ratio (HR) estimate at the interim analysis. The characteristics of the extended design are examined in a number of scenarios via simulations. The recommended adaptive design is shown to be useful in a phase II setting. When a short-term maker which correlates with the long-term PFS is available, the design can be applied in smaller early phase trials in which PFS requires longer follow-up. In summary, the adaptive design offers flexibility in randomized phase II patient enrichment trials and should be considered in an overall personalized healthcare (PHC) strategy. Copyright © 2013 Elsevier Inc. All rights reserved.
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An, Hui Mei; Tan, Yun Long; Shi, Jing; Wang, Zhiren; Lv, Meng Han; Soares, Jair C; Zhou, Dongfeng; Yang, Fude; Zhang, Xiang Yang
2016-12-01
Tardive dyskinesia (TD) is a serious side effect of long-term administration of typical neuroleptics, such as haloperidol. The pathophysiology of TD remains unclear, but the experimental evidence suggests that free radical-induced neuronal apoptosis in the basal ganglia may play an important role. This study was to investigate changes in Bax and Bcl-2 expression levels in TD-associated brain regions and the effects of the antioxidant EGb761 on Bax and Bcl-2 levels in an animal model of TD. Thirty-two rats were randomly divided into four study groups: saline control (saline), haloperidol-alone (haloperidol), EGb761-haloperidol (EGb), and alpha-tocopherol-haloperidol (vitamin E). Rats were treated with daily intraperitoneal haloperidol injections (2 mg/kg/day) for 5 weeks. EGb761 (50 mg/kg/day) and alpha-tocopherol (20 mg/kg/day) were then administered for another 5 weeks during the withdrawal period. Behavioral assessments were performed, and Bax and Bcl-2 protein expression levels were immunohistochemically analyzed in four brain regions, including the prefrontal cortex, striatum, substantia nigra, and globus pallidum. We found that increased vacuous chewing movements (VCMs) were associated with increased proapoptotic Bax protein expression, decreased antiapoptotic Bcl-2 protein expression, and an increased Bax/Bcl-2 ratio. EGb761 and alpha-tocopherol treatment reversed the increase in VCMs, decreased Bax expression, increased Bcl-2 expression, and decreased the Bax/Bcl-2 ratio. These results demonstrate that long-term haloperidol administration may affect Bcl-2 protein family expression and promote neuronal apoptosis in the basal ganglia. In combination with their antioxidant capacity, EGb761 and alpha-tocopherol's antiapoptotic effects through Bcl-2 might account for the symptom improvement observed in haloperidol-induced TD rats. Copyright © 2016 Elsevier GmbH. All rights reserved.
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Naruse, Tomofumi; Tokuhisa, Mitsuko; Yanamoto, Souichi; Sakamoto, Yuki; Okuyama, Kohei; Tsuchihashi, Hiroki; Umeda, Masahiro
2018-05-01
Long-term cetuximab treatment can lead to acquired resistance, and tumor progression and/or new lesions often occur. The present report describes a case of lower gingival squamous cell carcinoma with brain metastasis during long-term cetuximab treatment in a 60-year-old man, including findings of an immunohistochemical study. The resected primary tumors, biopsy of the lung metastasis before administration of cetuximab, and brain metastasis specimens mediated by cetuximab were immunohistochemically examined. Histologically, the metastatic brain lesion showed hyperkeratinizing tumor cells with deeply stained irregular nuclei with necrotizing tumor cells, and a decrease in cell density was exhibited in part of the tumor nest. Moreover, the brain lesion was less malignant compared with the primary tumor and metastatic lung lesions. Immunohistochemically, the metastatic brain lesions showed low expression of epidermal growth factor receptor (EGFR) and high expression of N-cadherin compared with the primary tumor and metastatic lung lesions. These results suggest that acquired resistance to cetuximab may be associated with low EGFR expression and increased epithelial-to-mesenchymal transition potential.
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A PARP1-ERK2 synergism is required for the induction of LTP
Visochek, L.; Grigoryan, G.; Kalal, A.; Milshtein-Parush, H.; Gazit, N.; Slutsky, I.; Yeheskel, A.; Shainberg, A.; Castiel, A.; Seger, R.; Langelier, M. F.; Dantzer, F.; Pascal, J. M.; Segal, M.; Cohen-Armon, M.
2016-01-01
Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell response to single-strand DNA damage, was also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk synergism, which may underlie this phenomenon. A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk-induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1-bound phosphorylated Erk2. Thus, Erk-induced PARP1 activation mediated IEG expression implicated in long-term memory. PARP1 inhibition, silencing, or genetic deletion abrogated stimulation-induced Erk-recruitment to IEG promoters, gene expression and LTP generation in hippocampal CA3-CA1-connections. Moreover, a predominant binding of PARP1 to single-strand DNA breaks, occluding its Erk binding sites, suppressed IEG expression and prevented the generation of LTP. These findings outline a PARP1-dependent mechanism required for LTP generation, which may be implicated in long-term memory acquisition and in its deterioration in senescence. PMID:27121568
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A PARP1-ERK2 synergism is required for the induction of LTP.
Visochek, L; Grigoryan, G; Kalal, A; Milshtein-Parush, H; Gazit, N; Slutsky, I; Yeheskel, A; Shainberg, A; Castiel, A; Seger, R; Langelier, M F; Dantzer, F; Pascal, J M; Segal, M; Cohen-Armon, M
2016-04-28
Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell response to single-strand DNA damage, was also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk synergism, which may underlie this phenomenon. A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk-induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1-bound phosphorylated Erk2. Thus, Erk-induced PARP1 activation mediated IEG expression implicated in long-term memory. PARP1 inhibition, silencing, or genetic deletion abrogated stimulation-induced Erk-recruitment to IEG promoters, gene expression and LTP generation in hippocampal CA3-CA1-connections. Moreover, a predominant binding of PARP1 to single-strand DNA breaks, occluding its Erk binding sites, suppressed IEG expression and prevented the generation of LTP. These findings outline a PARP1-dependent mechanism required for LTP generation, which may be implicated in long-term memory acquisition and in its deterioration in senescence.
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Postsynaptic Regulation of Long-Term Facilitation in Aplysia
Cai, Diancai; Chen, Shanping; Glanzman, David L.
2009-01-01
Summary Repeated exposure to serotonin (5-HT), an endogenous neurotransmitter that mediates behavioral sensitization in Aplysia [1–3], induces long-term facilitation (LTF) of the Aplysia sensorimotor synapse [4]. LTF, a prominent form of invertebrate synaptic plasticity, is believed to play a major role in long-term learning in Aplysia [5]. Until now, LTF has been thought to be due predominantly to cellular processes activated by 5-HT within the presynaptic sensory neuron [6]. Recent work indicates that LTF depends on the increased expression and release of a sensory neuron-specific neuropeptide, sensorin [7]. Sensorin released during LTF appears to bind to autoreceptors on the sensory neuron, thereby activating critical presynaptic signals, including mitogen-activated protein kinase (MAPK) [8, 9]. Here, we show that LTF depends on elevated postsynaptic Ca2+ and postsynaptic protein synthesis. Furthermore, we find that the increased expression of presynaptic sensorin due to 5-HT stimulation requires elevation of postsynaptic intracellular Ca2+. Our results represent perhaps the strongest evidence to date that the increased expression of a specific presynaptic neuropeptide during LTF is regulated by retrograde signals. PMID:18571411
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Kim, MiJung; Kim, Dong-Ik; Kim, Eun Key; Kim, Chan-Wha
2017-02-16
We investigated the effects of transplantation of CXCR4-overexpressing adipose tissue-derived stem cells (ADSCs) into a mouse diabetic hindlimb ischemia model on homing and engraftment as early as 48 h after transplant. CXCR4-overexpressing ADSCs were intramuscularly or intravenously injected into diabetic mice with hindlimb ischemia. After 48 h, muscle tissues in the femur and tibia were collected, and the CXCR4 expression pattern was analyzed by immunofluorescence staining. The homing and engraftment of transplanted CXCR4-overexpressing ADSCs into the ischemic area were significantly increased, and intravenous (systemic) injection resulted in the more effective delivery of stem cells to the target site 48 h posttransplantation. Furthermore, CXCR4-overexpressing ADSCs more efficiently contributed to long-term engraftment and muscle tissue regeneration than normal ADSCs in a limb ischemia model. In addition, the homing and engraftment of ADSCs were correlated with the CXCR4 transfection efficiency. These results demonstrated that enhanced CXCR4 signaling could significantly improve the early homing and engraftment of ADSCs into ischemic areas as well as the long-term engraftment and ultimate muscle tissue regeneration.
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NASA Astrophysics Data System (ADS)
Griffith, Steven
This thesis is an interpretive analysis of experts' perspectives on the climate implications of New England's reliance on natural gas for electricity generation. Specifically, this research, conducted through interviews and literature review, examines experts' opinions on the desired role of natural gas within the regional electricity sector, alternative energy resources, and state and regional policy opportunities toward the achievement of New England's ambitious long-term greenhouse gas reduction goals. Experts expressed concern about the climate dilemma posed by a dependence on natural gas. However, interviews revealed that short-term reliability and cost considerations are paramount for many experts, and therefore a reliance on natural gas is the existing reality. To incentivize renewable generation technologies for the purposes of long-term climate stabilization, experts advocated for the expanded implementation of renewable portfolio standard, net metering, and feed-in tariff policies. More broadly, interviewees expressed the need for an array of complementary state and regional policies.
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Role of sexual self-disclosure in the sexual satisfaction of long-term heterosexual couples.
MacNeil, Sheila; Byers, E Sandra
2009-01-01
This study examined two proposed pathways between sexual self-disclosure (SSD) and sexual satisfaction in a sample of 104 heterosexual couples in long-term relationships. According to the proposed instrumental pathway, disclosure of sexual preferences increases a partner's understanding of those preferences resulting in a sexual script that is more rewarding and less costly. A more favorable balance of sexual rewards to sexual costs, in turn, results in greater sexual satisfaction for the disclosing individual. According to the proposed expressive pathway, mutual self-disclosure contributes to relationship satisfaction, which in turn leads to greater sexual satisfaction. Support was found for the instrumental pathway for both men and women. Support also was found for an expressive pathway between own SSD and partner nonsexual self-disclosure (NSD) and men's sexual satisfaction, and between own NSD and women's sexual satisfaction. These results are interpreted in terms of mechanisms for establishing and maintaining sexual satisfaction in long-term relationships in men and women.
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Induction of three-dimensional assembly of human liver cells by simulated microgravity
NASA Technical Reports Server (NTRS)
Khaoustov, V. I.; Darlington, G. J.; Soriano, H. E.; Krishnan, B.; Risin, D.; Pellis, N. R.; Yoffe, B.
1999-01-01
The establishment of long-term cultures of functional primary human liver cells (PHLC) is formidable. Developed at NASA, the Rotary Cell Culture System (RCCS) allows the creation of the unique microgravity environment of low shear force, high-mass transfer, and 3-dimensional cell culture of dissimilar cell types. The aim of our study was to establish long-term hepatocyte cultures in simulated microgravity. PHLC were harvested from human livers by collagenase perfusion and were cultured in RCCS. PHLC aggregates were readily formed and increased up to 1 cm long. The expansion of PHLC in bioreactors was further evaluated with microcarriers and biodegradable scaffolds. While microcarriers were not conducive to formation of spheroids, PHLC cultured with biodegradable scaffolds formed aggregates up to 3 cm long. Analyses of PHLC spheroids revealed tissue-like structures composed of hepatocytes, biliary epithelial cells, and/or progenitor liver cells that were arranged as bile duct-like structures along nascent vascular sprouts. Electron microscopy revealed groups of cohesive hepatocytes surrounded by complex stromal structures and reticulin fibers, bile canaliculi with multiple microvilli, and tight cellular junctions. Albumin mRNA was expressed throughout the 60-d culture. A simulated microgravity environment is conducive to maintaining long-term cultures of functional hepatocytes. This model system will assist in developing improved protocols for autologous hepatocyte transplantation, gene therapy, and liver assist devices, and facilitate studies of liver regeneration and cell-to-cell interactions that occur in vivo.
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Bartsch, Lea M; Singmann, Henrik; Oberauer, Klaus
2018-03-19
Refreshing and elaboration are cognitive processes assumed to underlie verbal working-memory maintenance and assumed to support long-term memory formation. Whereas refreshing refers to the attentional focussing on representations, elaboration refers to linking representations in working memory into existing semantic networks. We measured the impact of instructed refreshing and elaboration on working and long-term memory separately, and investigated to what extent both processes are distinct in their contributions to working as well as long-term memory. Compared with a no-processing baseline, immediate memory was improved by repeating the items, but not by refreshing them. There was no credible effect of elaboration on working memory, except when items were repeated at the same time. Long-term memory benefited from elaboration, but not from refreshing the words. The results replicate the long-term memory benefit for elaboration, but do not support its beneficial role for working memory. Further, refreshing preserves immediate memory, but does not improve it beyond the level achieved without any processing.
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Gotway, Michael B; Golden, Jeffrey A; LaBerge, Jeanne M; Webb, W Richard; Reddy, Gautham P; Wilson, Mark W; Kerlan, Robert K; Gordon, Roy L
2002-01-01
To determine the short- and long-term improvement in airflow dynamics in patients undergoing tracheobronchial stent placement for benign airway stenoses. Twenty-two patients underwent 34 tracheal and/or bronchial stent placement procedures for benign airway stenoses and had the results of pulmonary function tests available. Stent placement indications included bronchomalacia after lung transplantation (n = 11), postintubation stenoses (n = 6), relapsing polychondritis (n = 2), and 1 each of tracheomalacia, tracheal compression, and histoplasmosis. Six patients underwent more than one stent placement procedure (range: 2-7 procedures). The mean forced expiratory volume in one second (FEV(1) ), forced expiratory flow rate in the midportion of the forced vital capacity curve (FEF(25-75) ), forced vital capacity, and peak flow (PF) rate obtained before stent placement were compared with those immediately after stent placement and with those measurements most remote from stent placement using the paired two-tailed test. All patients reported improved respiratory function immediately after stent placement. The mean FEV(1), FEF(25-75), and PF rate improved significantly (p < 0.001, p = 0.002, and p = 0.009, respectively) after stent placement. On long-term follow-up averaging 15 months after stent placement, these parameters declined despite patients' subjective sense of improvement. Segregating the population into transplant and nontransplant airway stenosis etiologies, however, FEF(25-75) and PF rate remained significantly improved (p = 0.045, p = 0.027, respectively), over the long term for the latter. FEV increased after subsequent stent placements for patients receiving multiple stents. Stent placement for benign tracheobronchial stenoses provides significant immediate improvement in airflow dynamics. Long-term improvement in airflow obstruction may be expected, and additional stent placements may further improve pulmonary function.
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Andersson, E; Steneby, S; Karlsson, K; Ljótsson, B; Hedman, E; Enander, J; Kaldo, V; Andersson, G; Lindefors, N; Rück, C
2014-10-01
As relapse after completed cognitive behavior therapy (CBT) for obsessive-compulsive disorder (OCD) is common, many treatment protocols include booster programs to improve the long-term effects. However, the effects of booster programs are not well studied. In this study, we investigated the long-term efficacy of Internet-based CBT (ICBT) with therapist support for OCD with or without an Internet-based booster program. A total of 101 participants were included in the long-term follow-up analysis of ICBT. Of these, 93 were randomized to a booster program or no booster program. Outcome assessments were collected at 4, 7, 12 and 24 months after receiving ICBT. The entire sample had sustained long-term effects from pre-treatment to all follow-up assessments, with large within-group effect sizes (Cohen's d = 1.58-2.09). The booster group had a significant mean reduction in OCD symptoms compared to the control condition from booster baseline (4 months) to 7 months, but not at 12 or 24 months. Participants in the booster group improved significantly in terms of general functioning at 7, 12 and 24 months, and had fewer relapses. Kaplan-Meier analysis also indicated a significantly slower relapse rate in the booster group. The results suggest that ICBT has sustained long-term effects and that adding an Internet-based booster program can further improve long-term outcome and prevent relapse for some OCD patients.
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Transcript Profile of the Response of Two Soybean Genotypes to Potassium Deficiency
Hao, QingNan; Sha, AiHua; Shan, ZhiHui; Chen, LiMiao; Zhou, Rong; Zhi, HaiJian; Zhou, XinAn
2012-01-01
The macronutrient potassium (K) is essential to plant growth and development. Crop yield potential is often affected by lack of soluble K. The molecular regulation mechanism of physiological and biochemical responses to K starvation in soybean roots and shoots is not fully understood. In the present study, two soybean varieties were subjected to low-K stress conditions: a low-K-tolerant variety (You06-71) and a low-K-sensitive variety (HengChun04-11). Eight libraries were generated for analysis: 2 genotypes ×2 tissues (roots and shoots) ×2 time periods [short term (0.5 to 12 h) and long term (3 to 12 d)]. RNA derived from the roots and shoots of these two varieties across two periods (short term and long term) were sequenced and the transcriptomes were compared using high-throughput tag-sequencing. To this end, a large number of clean tags (tags used for analysis after removal of dirty tags) corresponding to distinct tags (all types of clean tags) were identified in eight libraries (L1, You06-71-root short term; L2, HengChun04-11-root short term; L3, You06-71-shoot short term; L4, HengChun04-11-shoot short term; L5, You06-71-root long term; L6, HengChun04-11-root long term; L7, You06-71-shoot long term; L8, HengChun04-11-shoot long term). All clean tags were mapped to the available soybean (Glycine max) transcript database (http://www.soybase.org). Many genes showed substantial differences in expression across the libraries. In total, 5,440 transcripts involved in 118 KEGG pathways were either up- or down-regulated. Fifteen genes were randomly selected and their expression levels were confirmed using quantitative RT-PCR. Our results provide preliminary information on the molecular mechanism of potassium absorption and transport under low-K stress conditions in different soybean tissues. PMID:22792192
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Monday, Hannah R; Younts, Thomas J; Castillo, Pablo E
2018-04-25
Long-lasting changes of brain function in response to experience rely on diverse forms of activity-dependent synaptic plasticity. Chief among them are long-term potentiation and long-term depression of neurotransmitter release, which are widely expressed by excitatory and inhibitory synapses throughout the central nervous system and can dynamically regulate information flow in neural circuits. This review article explores recent advances in presynaptic long-term plasticity mechanisms and contributions to circuit function. Growing evidence indicates that presynaptic plasticity may involve structural changes, presynaptic protein synthesis, and transsynaptic signaling. Presynaptic long-term plasticity can alter the short-term dynamics of neurotransmitter release, thereby contributing to circuit computations such as novelty detection, modifications of the excitatory/inhibitory balance, and sensory adaptation. In addition, presynaptic long-term plasticity underlies forms of learning and its dysregulation participates in several neuropsychiatric conditions, including schizophrenia, autism, intellectual disabilities, neurodegenerative diseases, and drug abuse. Expected final online publication date for the Annual Review of Neuroscience Volume 41 is July 8, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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A Comparison of Computer-based and Instructor-led Training for Long-term Care Staff.
ERIC Educational Resources Information Center
Harrington, Susan S.; Walker, Bonnie L.
2002-01-01
Fire safety training was provided to long-term care staff by computer (n=47) or a print-based, instructor-led program (n=47). Compared to 47 controls, both treatment groups significantly increased knowledge. The computer-trained staff were enthusiastic about the learning method and expressed greater interest in additional safety topics. (SK)
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Long-term decline of a winter-resident bird community in Puerto Rico
J. Faaborg; W. J. Arendt; J. D. Toms; K. M. Dugger; W. A. Cox; M. Canals Mora
2013-01-01
Despite concern expressed two decades ago, there has been little recent discussion about continuing declines of migrant bird populations. Monitoring efforts have been focused almost exclusively on the breeding grounds. We describe the long-term decline of a winter-resident bird population in Guanica Commonwealth Forest, Puerto Rico, one of the last remaining tracts of...
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Establishment of rat embryonic stem-like cells from the morula using a combination of feeder layers.
Sano, Chiaki; Matsumoto, Asako; Sato, Eimei; Fukui, Emiko; Yoshizawa, Midori; Matsumoto, Hiromichi
2009-08-01
Embryonic stem (ES) cells are characterized by pluripotency, in particular the ability to form a germline on injection into blastocysts. Despite numerous attempts, ES cell lines derived from rat embryos have not yet been established. The reason for this is unclear, although certain intrinsic biological differences among species and/or strains have been reported. Herein, using Wistar-Imamichi rats, specific characteristics of preimplantation embryos are described. At the blastocyst stage, Oct4 (also called Pou5f1) was expressed in both the inner cell mass (ICM) and the trophectoderm (TE), whereas expression of Cdx2 was localized to the TE. In contrast, at an earlier stage, expression of Oct4 was detected in all the nuclei in the morula. These stages were examined using a combination of feeder layers (rat embryonic fibroblast [REF] for primary outgrowth and SIM mouse embryo-derived thioguanine- and ouabain-resistant [STO] cells for passaging) to establish rat ES-like cell lines. The rat ES-like cell lines obtained from the morula maintained expression of Oct4 over long-term culture, whereas cell lines derived from blastocysts lost pluripotency during early passage. The morula-derived ES-like cell lines showed Oct4 expression in a long-term culture, even after cryogenic preservation, thawing and EGFP transfection. These results indicate that rat ES-like cell lines with long-term Oct4 expression can be established from the morula of Wistar-Imamichi rats using a combination of feeder layers.
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Mera, Paula; Mir, Joan Francesc; Fabriàs, Gemma; Casas, Josefina; Costa, Ana S H; Malandrino, Maria Ida; Fernández-López, José-Antonio; Remesar, Xavier; Gao, Su; Chohnan, Shigeru; Rodríguez-Peña, Maria Sol; Petry, Harald; Asins, Guillermina; Hegardt, Fausto G; Herrero, Laura; Serra, Dolors
2014-01-01
Lipid metabolism in the ventromedial hypothalamus (VMH) has emerged as a crucial pathway in the regulation of feeding and energy homeostasis. Carnitine palmitoyltransferase (CPT) 1A is the rate-limiting enzyme in mitochondrial fatty acid β-oxidation and it has been proposed as a crucial mediator of fasting and ghrelin orexigenic signalling. However, the relationship between changes in CPT1A activity and the intracellular downstream effectors in the VMH that contribute to appetite modulation is not fully understood. To this end, we examined the effect of long-term expression of a permanently activated CPT1A isoform by using an adeno-associated viral vector injected into the VMH of rats. Peripherally, this procedure provoked hyperghrelinemia and hyperphagia, which led to overweight, hyperglycemia and insulin resistance. In the mediobasal hypothalamus (MBH), long-term CPT1AM expression in the VMH did not modify acyl-CoA or malonyl-CoA levels. However, it altered the MBH lipidomic profile since ceramides and sphingolipids increased and phospholipids decreased. Furthermore, we detected increased vesicular γ-aminobutyric acid transporter (VGAT) and reduced vesicular glutamate transporter 2 (VGLUT2) expressions, both transporters involved in this orexigenic signal. Taken together, these observations indicate that CPT1A contributes to the regulation of feeding by modulating the expression of neurotransmitter transporters and lipid components that influence the orexigenic pathways in VMH.
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Fabriàs, Gemma; Casas, Josefina; Costa, Ana S. H.; Malandrino, Maria Ida; Fernández-López, José-Antonio; Remesar, Xavier; Gao, Su; Chohnan, Shigeru; Rodríguez-Peña, Maria Sol; Petry, Harald; Asins, Guillermina; Hegardt, Fausto G.; Herrero, Laura; Serra, Dolors
2014-01-01
Lipid metabolism in the ventromedial hypothalamus (VMH) has emerged as a crucial pathway in the regulation of feeding and energy homeostasis. Carnitine palmitoyltransferase (CPT) 1A is the rate-limiting enzyme in mitochondrial fatty acid β-oxidation and it has been proposed as a crucial mediator of fasting and ghrelin orexigenic signalling. However, the relationship between changes in CPT1A activity and the intracellular downstream effectors in the VMH that contribute to appetite modulation is not fully understood. To this end, we examined the effect of long-term expression of a permanently activated CPT1A isoform by using an adeno-associated viral vector injected into the VMH of rats. Peripherally, this procedure provoked hyperghrelinemia and hyperphagia, which led to overweight, hyperglycemia and insulin resistance. In the mediobasal hypothalamus (MBH), long-term CPT1AM expression in the VMH did not modify acyl-CoA or malonyl-CoA levels. However, it altered the MBH lipidomic profile since ceramides and sphingolipids increased and phospholipids decreased. Furthermore, we detected increased vesicular γ-aminobutyric acid transporter (VGAT) and reduced vesicular glutamate transporter 2 (VGLUT2) expressions, both transporters involved in this orexigenic signal. Taken together, these observations indicate that CPT1A contributes to the regulation of feeding by modulating the expression of neurotransmitter transporters and lipid components that influence the orexigenic pathways in VMH. PMID:24819600
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Joseph, Marie G.; Denninger, John W.; Fricchione, Gregory L.; Benson, Herbert; Libermann, Towia A.
2013-01-01
The relaxation response (RR) is the counterpart of the stress response. Millennia-old practices evoking the RR include meditation, yoga and repetitive prayer. Although RR elicitation is an effective therapeutic intervention that counteracts the adverse clinical effects of stress in disorders including hypertension, anxiety, insomnia and aging, the underlying molecular mechanisms that explain these clinical benefits remain undetermined. To assess rapid time-dependent (temporal) genomic changes during one session of RR practice among healthy practitioners with years of RR practice and also in novices before and after 8 weeks of RR training, we measured the transcriptome in peripheral blood prior to, immediately after, and 15 minutes after listening to an RR-eliciting or a health education CD. Both short-term and long-term practitioners evoked significant temporal gene expression changes with greater significance in the latter as compared to novices. RR practice enhanced expression of genes associated with energy metabolism, mitochondrial function, insulin secretion and telomere maintenance, and reduced expression of genes linked to inflammatory response and stress-related pathways. Interactive network analyses of RR-affected pathways identified mitochondrial ATP synthase and insulin (INS) as top upregulated critical molecules (focus hubs) and NF-κB pathway genes as top downregulated focus hubs. Our results for the first time indicate that RR elicitation, particularly after long-term practice, may evoke its downstream health benefits by improving mitochondrial energy production and utilization and thus promoting mitochondrial resiliency through upregulation of ATPase and insulin function. Mitochondrial resiliency might also be promoted by RR-induced downregulation of NF-κB-associated upstream and downstream targets that mitigates stress. PMID:23650531
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Long-term optical stimulation of channelrhodopsin-expressing neurons to study network plasticity
Lignani, Gabriele; Ferrea, Enrico; Difato, Francesco; Amarù, Jessica; Ferroni, Eleonora; Lugarà, Eleonora; Espinoza, Stefano; Gainetdinov, Raul R.; Baldelli, Pietro; Benfenati, Fabio
2013-01-01
Neuronal plasticity produces changes in excitability, synaptic transmission, and network architecture in response to external stimuli. Network adaptation to environmental conditions takes place in time scales ranging from few seconds to days, and modulates the entire network dynamics. To study the network response to defined long-term experimental protocols, we setup a system that combines optical and electrophysiological tools embedded in a cell incubator. Primary hippocampal neurons transduced with lentiviruses expressing channelrhodopsin-2/H134R were subjected to various photostimulation protocols in a time window in the order of days. To monitor the effects of light-induced gating of network activity, stimulated transduced neurons were simultaneously recorded using multi-electrode arrays (MEAs). The developed experimental model allows discerning short-term, long-lasting, and adaptive plasticity responses of the same neuronal network to distinct stimulation frequencies applied over different temporal windows. PMID:23970852
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Long term effects of neonatal hypoglycaemia on pancreatic function.
Anju, T R; Paulose, C S
2015-02-01
Low blood glucose in neonates predisposes to long term pancreatic damage. We focused on evaluating long term consequences of neonatal hypoglycaemia in pancreatic functions. Pancreatic function was analysed by measuring DNA/protein synthesis, glucose/ATP uptake in vitro. Gene expression of Pdx1, NeuroD1, Pax4, Bax, caspase 3, Beclin1 were done. Muscarinic receptors were analysed by radio receptor assay. Overall pancreatic efficiency was reduced in one-month-old rats exposed to neonatal hypoglycaemia as indicated by decreased DNA/protein synthesis and glucose/ATP uptake in vitro. Both Pdx1 and Neuro D1 expression were significantly down-regulated whereas Pax4 was up-regulated. Up-regulated Bax, caspase 3 and beclin1 along with reduced muscarinic receptors accounts for activation of cell death pathways. The study revealed a drastic reduction in pancreatic functions along with activation of apoptotic factors in one month old rats exposed to neonatal hypoglycaemia.
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Long-term optical stimulation of channelrhodopsin-expressing neurons to study network plasticity.
Lignani, Gabriele; Ferrea, Enrico; Difato, Francesco; Amarù, Jessica; Ferroni, Eleonora; Lugarà, Eleonora; Espinoza, Stefano; Gainetdinov, Raul R; Baldelli, Pietro; Benfenati, Fabio
2013-01-01
Neuronal plasticity produces changes in excitability, synaptic transmission, and network architecture in response to external stimuli. Network adaptation to environmental conditions takes place in time scales ranging from few seconds to days, and modulates the entire network dynamics. To study the network response to defined long-term experimental protocols, we setup a system that combines optical and electrophysiological tools embedded in a cell incubator. Primary hippocampal neurons transduced with lentiviruses expressing channelrhodopsin-2/H134R were subjected to various photostimulation protocols in a time window in the order of days. To monitor the effects of light-induced gating of network activity, stimulated transduced neurons were simultaneously recorded using multi-electrode arrays (MEAs). The developed experimental model allows discerning short-term, long-lasting, and adaptive plasticity responses of the same neuronal network to distinct stimulation frequencies applied over different temporal windows.
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Ha, Chien Van; Watanabe, Yasuko; Tran, Uyen Thi; Le, Dung Tien; Tanaka, Maho; Nguyen, Kien Huu; Seki, Motoaki; Nguyen, Dong Van; Tran, Lam-Son Phan
2015-01-01
The economically important DT2008 and the model Williams 82 (W82) soybean cultivars were reported to have differential drought-tolerant degree to dehydration and drought, which was associated with root trait. Here, we used 66K Affymetrix Soybean Array GeneChip to compare the root transcriptomes of DT2008 and W82 seedlings under normal, as well as mild (2 h treatment) and severe (10 h treatment) dehydration conditions. Out of the 38172 soybean genes annotated with high confidence, 822 (2.15%) and 632 (1.66%) genes showed altered expression by dehydration in W82 and DT2008 roots, respectively, suggesting that a larger machinery is required to be activated in the drought-sensitive W82 cultivar to cope with the stress. We also observed that long-term dehydration period induced expression change of more genes in soybean roots than the short-term one, independently of the genotypes. Furthermore, our data suggest that the higher drought tolerability of DT2008 might be attributed to the higher number of genes induced in DT2008 roots than in W82 roots by early dehydration, and to the expression changes of more genes triggered by short-term dehydration than those by prolonged dehydration in DT2008 roots vs. W82 roots. Differentially expressed genes (DEGs) that could be predicted to have a known function were further analyzed to gain a basic understanding on how soybean plants respond to dehydration for their survival. The higher drought tolerability of DT2008 vs. W82 might be attributed to differential expression in genes encoding osmoprotectant biosynthesis-, detoxification- or cell wall-related proteins, kinases, transcription factors and phosphatase 2C proteins. This research allowed us to identify genetic components that contribute to the improved drought tolerance of DT2008, as well as provide a useful genetic resource for in-depth functional analyses that ultimately leads to development of soybean cultivars with improved tolerance to drought. PMID:26300889
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McAiney, Carrie A.; Hillier, Loretta M.; Ringland, Margaret; Cooper, Nancy
2009-01-01
A collaborative of Ontario-based long-term care associations, researchers, clinicians and educators representing various education initiatives related to dementia care and challenging behaviours used existing research evidence on adult learning principles, knowledge transfer and performance improvement to develop an evidence-based approach to support practice change and improvement in long-term care. The collaborative was led by the two provincial long-term care associations with no external funds to support its activities. This effort illustrates how people with common challenges, visions and goals can work together to share their intellectual and physical resources to address pervasive problems. PMID:21037817
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Gorth, Deborah J; Lothstein, Katherine E; Chiaro, Joseph A; Farrell, Megan J; Dodge, George R; Elliott, Dawn M; Malhotra, Neil R; Mauck, Robert L; Smith, Lachlan J
2015-01-01
Degeneration of the intervertebral discs is strongly implicated as a cause of low back pain. Since current treatments for discogenic low back pain show poor long-term efficacy, a number of new, biological strategies are being pursued. For such therapies to succeed, it is critical that they be validated in conditions that mimic the unique biochemical microenvironment of the nucleus pulposus (NP), which include low oxygen tension. Therefore, the objective of this study was to investigate the effects of oxygen tension on NP cell functional extracellular matrix elaboration in 3D culture. Bovine NP cells were encapsulated in agarose constructs and cultured for 14 or 42 days in either 20% or 2% oxygen in defined media containing transforming growth factor beta-3. At each time point, extracellular matrix composition, biomechanics and mRNA expression of key phenotypic markers were evaluated. Results showed that while bulk mechanics and composition were largely independent of oxygen level, low oxygen promoted improved restoration of the NP phenotype, higher mRNA expression of extracellular matrix and NP specific markers, and more uniform matrix elaboration. These findings indicate that culture under physiological oxygen levels is an important consideration for successful development of cell and growth factor-based regenerative strategies for the disc. PMID:25640328
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Wilhelm, Frank H.; Boger, Sabrina; Georgii, Claudio; Klimesch, Wolfgang; Blechert, Jens
2017-01-01
Abstract Today’s stressors largely arise from social interactions rather than from physical threat. However, the dominant laboratory model of emotional learning relies on physical stimuli (e.g. electric shock) whereas adequate models of social conditioning are missing, possibly due to more subtle and multilayered biobehavioral responses to such stimuli. To fill this gap, we acquired a broad set of measures during conditioning to negative social unconditioned stimuli, also taking into account long-term maintenance of conditioning and inter-individual differences. Fifty-nine healthy participants underwent a classical conditioning task with videos of actors expressing disapproving (US-neg) or neutral (US-neu) statements. Static images of the corresponding actors with a neutral facial expression served as CS+ and CS−, predicting US-neg and US-neu, respectively. Autonomic and facial-muscular measures confirmed differential unconditioned responding whereas experiential CS ratings, event-related potentials, and evoked theta oscillations confirmed differential conditioned responding. Conditioning was maintained at 1 month and 1 year follow-ups on experiential ratings, especially in individuals with elevated anxiety and depressive symptoms, documenting the efficiency of social conditioning and its clinical relevance. This novel, ecologically improved conditioning paradigm uncovered a remarkably efficient multi-layered social learning mechanism that may represent a risk factor for anxiety and depression. PMID:27614767
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Treating acute seizures with benzodiazepines: does seizure duration matter?
Naylor, David E
2014-10-01
Several clinical trials have shown improved seizure control and outcome by early initiation of treatment with benzodiazepines, before arrival in the emergency department and before intravenous access can be established. Here, evidence is provided and reviewed for rapid treatment of acute seizures in order to avoid the development of benzodiazepine pharmacoresistance and the emergence of self-sustaining status epilepticus. Alterations in the physiology, pharmacology, and postsynaptic level of GABA-A receptors can develop within minutes to an hour and hinder the ability of synaptic inhibition to stop seizures while also impairing the efficacy of GABAergic agents, such as benzodiazepines, to boost impaired inhibition. In addition, heightened excitatory transmission further exacerbates the inhibitory/excitatory balance and makes seizure control even more resistant to treatment. The acute increase in the surface expression of NMDA receptors during prolonged seizures also may cause excitotoxic injury, cell death, and other pathological expressions and re-arrangements of receptor subunits that all contribute to long-term sequelae such as cognitive impairment and chronic epilepsy. In conclusion, a short window of opportunity exists when seizures are maximally controlled by first-line benzodiazepine treatment. After that, multiple pathological mechanisms quickly become engaged that make seizures increasingly more difficult to control with high risk for long-term harm.
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Renal Salvage with Renal Artery Stenting Improves Long-term Survival.
Modrall, J Gregory; Trimmer, Clayton; Tsai, Shirling; Kirkwood, Melissa L; Ali, Mujtaba; Rectenwald, John E; Timaran, Carlos H; Rosero, Eric B
2017-11-01
The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) Trial cast doubt on the benefits of renal artery stenting (RAS). However, the outcomes for patients with chronic kidney disease (CKD) were not analyzed separately in the CORAL Trial. We hypothesized that patients who experienced a significant improvement in renal function after RAS would have improved long-term survival, compared with patients whose renal function was not improved by stenting. This single-center retrospective study included 60 patients with stage 3 or worse CKD and renal artery occlusive disease who were treated with RAS for renal salvage. Patients were categorized as "responders" or "nonresponders" based on postoperative changes in estimated glomerular filtration rate (eGFR) after RAS. "Responders" were those patients with an improvement of at least 20% in eGFR over baseline; all others were categorized as "nonresponders." Survival was analyzed using the Kaplan-Meier method. Cox proportional hazards regression was used to identify predictors of long-term survival. The median age of the cohort was 66 years (interquartile range [IQR], 60-73). Median preoperative eGFR was 34 mL/min/1.73 m 2 (IQR, 24-45). At late follow-up (median 35 months, IQR, 22-97 months), 16 of 60 patients (26.7%) were categorized as "responders" with a median increase in postoperative eGFR of 40% (IQR, 21-67). Long-term survival was superior for responders, compared with nonresponders (P = 0.046 by log-rank test). Cox proportional hazards regression identified improved renal function after RAS as the only significant predictor of increased long-term survival (hazard ratio = 0.235, 95% confidence interval = 0.075-0.733; P = 0.0126 for improved versus worsened renal function after RAS). Successful salvage of renal function by RAS is associated with improved long-term survival. These data provide an important counter argument to the prior negative clinical trials that found no benefit to RAS. Published by Elsevier Inc.
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Oxygen Therapy for Patients With COPD
Stoller, James K.; Panos, Ralph J.; Krachman, Samuel; Doherty, Dennis E.
2010-01-01
Long-term use of supplemental oxygen improves survival in patients with COPD and severe resting hypoxemia. However, the role of oxygen in symptomatic patients with COPD and more moderate hypoxemia at rest and desaturation with activity is unclear. The few long-term reports of supplemental oxygen in this group have been of small size and insufficient to demonstrate a survival benefit. Short-term trials have suggested beneficial effects other than survival in patients with COPD and moderate hypoxemia at rest. In addition, supplemental oxygen appeared to improve exercise performance in small short-term investigations of patients with COPD and moderate hypoxemia at rest and desaturation with exercise, but long-term trials evaluating patient-reported outcomes are lacking. This article reviews the evidence for long-term use of supplemental oxygen therapy and provides a rationale for the National Heart, Lung, and Blood Institute Long-term Oxygen Treatment Trial. The trial plans to enroll subjects with COPD with moderate hypoxemia at rest or desaturation with exercise and compare tailored oxygen therapy to no oxygen therapy. PMID:20605816
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Coutinho, Carla P.; dos Santos, Sandra C.; Madeira, Andreia; Mira, Nuno P.; Moreira, Ana S.; Sá-Correia, Isabel
2011-01-01
Long-term respiratory infections with Burkholderia cepacia complex (Bcc) bacteria in cystic fibrosis (CF) patients generally lead to a more rapid decline in lung function and, in some cases, to a fatal necrotizing pneumonia known as the “cepacia syndrome.” Bcc bacteria are ubiquitous in the environment and are recognized as serious opportunistic pathogens that are virtually impossible to eradicate from the CF lung, posing a serious clinical threat. The epidemiological survey of Bcc bacteria involved in respiratory infections at the major Portuguese CF Treatment Center at Santa Maria Hospital, in Lisbon, has been carried out by our research group for the past 16 years, covering over 500 clinical isolates where B. cepacia and B. cenocepacia are the predominant species, with B. stabilis, B. contaminans, B. dolosa, and B. multivorans also represented. The systematic and longitudinal study of this CF population during such an extended period of time represents a unique case–study, comprehending 41 Bcc-infected patients (29 pediatric and 12 adult) of whom around 70% have been persistently colonized between 7 months and 9 years. During chronic infection, the CF airways represent an evolving ecosystem, with multiple phenotypic variants emerging from the clonal population and becoming established in the patients’ airways as the result of genetic adaptation. Understanding the evolutionary mechanisms involved is crucial for an improved therapeutic outcome of chronic infections in CF. This review focuses on our contribution to the understanding of these adaptive mechanisms based on extensive phenotypic, genotypic, and genome-wide expression approaches of selected Bcc clonal variants obtained during long-term colonization of the CF airways. PMID:22919578
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Bell, Catherine C; Dankers, Anita C A; Sison-Young, Rowena; Jenkins, Roz; Rowe, Cliff; Goldring, Chris E; Park, Kevin; Regan, Sophie L; Walker, Tracy; Schofield, Chris; Baze, Audrey; Foster, Alison J; Williams, Dominic P; van de Ven, Amy W M; Jacobs, Frank; van Houdt, Jos; Lähteenmäki, Tuula; Snoeys, Jan; Juhila, Satu; Richert, Lysiane; Ingelman-Sundberg, Magnus
2018-01-01
Abstract Primary human hepatocytes (PHHs) are commonly used for in vitro studies of drug-induced liver injury. However, when cultured as 2D monolayers, PHH lose crucial hepatic functions within hours. This dedifferentiation can be ameliorated when PHHs are cultured in sandwich configuration (2Dsw), particularly when cultures are regularly re-overlaid with extracellular matrix, or as 3D spheroids. In this study, the 6 participating laboratories evaluated the robustness of these 2 model systems made from cryopreserved PHH from the same donors considering both inter-donor and inter-laboratory variability and compared their suitability for use in repeated-dose toxicity studies using 5 different hepatotoxins with different toxicity mechanisms. We found that expression levels of proteins involved in drug absorption, distribution, metabolism, and excretion, as well as catalytic activities of 5 different CYPs, were significantly higher in 3D spheroid cultures, potentially affecting the exposure of the cells to drugs and their metabolites. Furthermore, global proteomic analyses revealed that PHH in 3D spheroid configuration were temporally stable whereas proteomes from the same donors in 2Dsw cultures showed substantial alterations in protein expression patterns over the 14 days in culture. Overall, spheroid cultures were more sensitive to the hepatotoxic compounds investigated, particularly upon long-term exposures, across testing sites with little inter-laboratory or inter-donor variability. The data presented here suggest that repeated-dosing regimens improve the predictivity of in vitro toxicity assays, and that PHH spheroids provide a sensitive and robust system for long-term mechanistic studies of drug-induced hepatotoxicity, whereas the 2Dsw system has a more dedifferentiated phenotype and lower sensitivity to detect hepatotoxicity. PMID:29329425
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Long-term treatment with aldosterone slows the progression of age-related hearing loss.
Halonen, Joshua; Hinton, Ashley S; Frisina, Robert D; Ding, Bo; Zhu, Xiaoxia; Walton, Joseph P
2016-06-01
Age-related hearing loss (ARHL), clinically referred to as presbycusis, is one of the three most prevalent chronic medical conditions of our elderly, with the majority of persons over the age of 60 suffering from some degree of ARHL. The progressive loss of auditory sensitivity and perceptual capability results in significant declines in workplace productivity, quality of life, cognition and abilities to communicate effectively. Aldosterone is a mineralocorticoid hormone produced in the adrenal glands and plays a role in the maintenance of key ion pumps, including the Na-K(+)-Cl co-transporter 1 or NKCC1, which is involved in homeostatic maintenance of the endocochlear potential. Previously we reported that aldosterone (1 μM) increases NKCC1 protein expression in vitro and that this up-regulation of NKCC1 was not dose-dependent (dosing range from 1 nM to 100 μM). In the current study we measured behavioral and electrophysiological hearing function in middle-aged mice following long-term systemic treatment with aldosterone. We also confirmed that blood pressure remained stable during treatment and that NKCC1 protein expression was upregulated. Pre-pulse inhibition of the acoustic startle response was used as a functional measure of hearing, and the auditory brainstem response was used as an objective measure of peripheral sensitivity. Long-term treatment with aldosterone improved both behavioral and physiological measures of hearing (ABR thresholds). These results are the first to demonstrate a protective effect of aldosterone on age-related hearing loss and pave the way for translational drug development, using aldosterone as a key component to prevent or slow down the progression of ARHL. Copyright © 2016 Elsevier B.V. All rights reserved.
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Coutinho, Carla P; Dos Santos, Sandra C; Madeira, Andreia; Mira, Nuno P; Moreira, Ana S; Sá-Correia, Isabel
2011-01-01
Long-term respiratory infections with Burkholderia cepacia complex (Bcc) bacteria in cystic fibrosis (CF) patients generally lead to a more rapid decline in lung function and, in some cases, to a fatal necrotizing pneumonia known as the "cepacia syndrome." Bcc bacteria are ubiquitous in the environment and are recognized as serious opportunistic pathogens that are virtually impossible to eradicate from the CF lung, posing a serious clinical threat. The epidemiological survey of Bcc bacteria involved in respiratory infections at the major Portuguese CF Treatment Center at Santa Maria Hospital, in Lisbon, has been carried out by our research group for the past 16 years, covering over 500 clinical isolates where B. cepacia and B. cenocepacia are the predominant species, with B. stabilis, B. contaminans, B. dolosa, and B. multivorans also represented. The systematic and longitudinal study of this CF population during such an extended period of time represents a unique case-study, comprehending 41 Bcc-infected patients (29 pediatric and 12 adult) of whom around 70% have been persistently colonized between 7 months and 9 years. During chronic infection, the CF airways represent an evolving ecosystem, with multiple phenotypic variants emerging from the clonal population and becoming established in the patients' airways as the result of genetic adaptation. Understanding the evolutionary mechanisms involved is crucial for an improved therapeutic outcome of chronic infections in CF. This review focuses on our contribution to the understanding of these adaptive mechanisms based on extensive phenotypic, genotypic, and genome-wide expression approaches of selected Bcc clonal variants obtained during long-term colonization of the CF airways.
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Human milk for preterm infants: why, what, when and how?
Menon, Gopi; Williams, Thomas C
2013-11-01
A mother's expressed breast milk (MEBM) is overall the best feed for her preterm baby during the neonatal period, and is associated with improved short-term and long-term outcomes. Neonatal services should commit the resources needed to optimise its use. The place of banked donor expressed breast milk (DEBM) is less clear, but it probably has a role in reducing the risk of necrotising enterocolitis and sepsis in preterm infants at particularly high risk. There is considerable variation in the composition of human milk and nutrient fortification is often needed to achieve intrauterine growth rates. Human milk can transmit potentially harmful micro-organisms, and pasteurisation, which denatures some of the bioactive factors, is the only known way of preventing this. This is carried out for DEBM but not MEBM in the UK. Future research on human milk should focus on (a) critical exposure periods, (b) understanding better its bioactive properties, (c) the role of DEBM and (d) nutritional quality assurance.
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A controlled double-duration inducible gene expression system for cartilage tissue engineering.
Ma, Ying; Li, Junxiang; Yao, Yi; Wei, Daixu; Wang, Rui; Wu, Qiong
2016-05-25
Cartilage engineering that combines competent seeding cells and a compatible scaffold is increasingly gaining popularity and is potentially useful for the treatment of various bone and cartilage diseases. Intensive efforts have been made by researchers to improve the viability and functionality of seeding cells of engineered constructs that are implanted into damaged cartilage. Here, we designed an integrative system combining gene engineering and the controlled-release concept to solve the problems of both seeding cell viability and functionality through precisely regulating the anti-apoptotic gene bcl-2 in the short-term and the chondrogenic master regulator Sox9 in the long-term. Both in vitro and in vivo experiments demonstrated that our system enhances the cell viability and chondrogenic effects of the engineered scaffold after introduction of the system while restricting anti-apoptotic gene expression to only the early stage, thereby preventing potential oncogenic and overdose effects. Our system was designed to be modular and can also be readily adapted to other tissue engineering applications with minor modification.
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Wang, Yarong; Du, Dewei; Li, Zhanting; Wei, Junxia; Yang, Angang
2012-01-01
Relative deficiency in production of glycoprotein hormone erythropoietin (Epo) is a major cause of renal anemia. This study planned to investigate whether the hypoxia-regulated system of Epo expression, constructed by fusing Epo gene to the chimeric phosphoglycerate kinase (PGK) hypoxia response elements (HRE) in combination with cytomegalovirus immediate-early (CMV IE) basal gene promoter and delivered by plasmid intramuscular injection, might provide a long-term physiologically regulated Epo secretion expression to correct the anemia in adenine-induced uremic rats. Plasmid vectors (pHRE-Epo) were synthesized by fusing human Epo cDNA to the HRE/CMV promoter. Hypoxia-inducible activity of this promoter was evaluated first in vitro and then in vivo in healthy and uremic rats (n = 30 per group). The vectors (pCMV-Epo) in which Epo expression was directed by a constitutive CMV gene promoter served as control. ANOVA and Student's t-test were used to analyze between-group differences. A high-level expression of Epo was induced by hypoxia in vitro and in vivo. Though both pHRE-Epo and pCMV-Epo corrected anemia, the hematocrit of the pCMV-Epo-treated rats exceeded the normal (P < 0.05), but that of the pHRE-Epo-treated rats didn't. Hypoxia-regulated system of Epo gene expression constructed by fusing Epo to the HRE/CMV promoter and delivered by plasmid intramuscular injection may provide a long-term and stable Epo expression and secretion in vivo to correct the anemia in adenine-induced uremic rats. PMID:22990115
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Trzeciecka, Anna; Paterno, J Jussi; Toropainen, Elisa; Koskela, Ali; Podracka, Lucia; Korhonen, Eveliina; Kauppinen, Anu; Kaarniranta, Kai; Smedowski, Adrian
2016-10-05
Success of the long-term glaucoma therapy and preservation of the visual function strongly depend on patients' compliance which may be affected by the inconvenience of treatment and its side effects. Recently, introduction of preservative-free anti-glaucoma agents has become an important step towards improved glaucoma care by eliminating the negative effects of preservatives on the eye surface. Although, newly developed eye drop formulations do not contain standard preservatives, they still can be harmful to ocular surface due to other excipients. In this study, we compared tolerability of commercial preservative-free (pf) prostaglandin analogues (pf tafluprost, pf latanoprost and pf bimatoprost) in long-term topical application in rabbits in vivo. We found that after eight weeks treatment, pf latanoprost was the worst tolerated among the tested drops. It expressed increased conjunctival redness and blinking frequency. Furthermore, it caused increased LDH release in the aqueous humour, infiltration of macrophages in the eyelids and visible defects in conjunctival goblet cells. However, we did not detect increased levels of inflammatory markers in the tear fluid or in the aqueous humour. Based on our study, we suspect that these negative effects are related to excipients included in pf latanoprost formulation. Copyright © 2016 Elsevier B.V. All rights reserved.
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Lean, Lyn Li; Hong, Ryan Yee Shiun; Ti, Lian Kah
2017-08-01
Communication of feedback during teaching of practical procedures is a fine balance of structure and timing. We investigate if continuous in-task (IT) or end-task feedback (ET) is more effective in teaching spinal anaesthesia to medical students. End-task feedback was hypothesized to improve both short-term and long-term procedural learning retention as experiential learning promotes active learning after encountering errors during practice. Upon exposure to a 5-min instructional video, students randomized to IT or ET feedbacks were trained using a spinal simulator mannequin. A blinded expert tested the students using a spinal anaesthesia checklist in the short term (immediate) and long-term (average 4 months). Sixty-five students completed the training and testing. There were no differences in demographics of age or gender within IT or ET distributions. Both short-term and long-term learning retention of spinal anaesthesia ET feedback proved to be better (P < 0.01) than IT feedback. The time taken for ET students was shorter at long-term testing. End-task feedback improves both short-term and long-term procedural learning retention.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Patel, TN; Park, AHA; Bantat, S
The limited permeability of the E. coli outer membrane can significantly hinder whole-cell biocatalyst performance. In this study, the SARS coronavirus small envelope protein (SCVE) was expressed in E. coli cells previously engineered for periplasmic expression of carbonic anhydrase (CA) activity. This maneuver increased small molecule uptake by the cells, resulting in increased apparent CA activity of the biocatalysts. The enhancements in activity were quantified using methods developed for traditional heterogeneous catalysis. The expression of the SCVE protein was found to significantly reduce the Thiele moduli (phi), as well as increase the effectiveness factors (eta), effective diffusivities (D-e), and permeabilitiesmore » (P) of the biocatalysts. These catalytic improvements translated into superior performance of the biocatalysts for the precipitation of calcium carbonate from solution which is an attractive strategy for long-term sequestration of captured carbon dioxide. Overall, these results demonstrate that synthetic biology approaches can be used to enhance heterogeneous catalysts incorporated into microbial whole-cell scaffolds.« less
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Luo, Lianzhong; Ke, Caihuan; Guo, Xiaoyu; Shi, Bo; Huang, Miaoqin
2014-06-01
Bio-accumulation and bio-transmission of toxic metals and the toxicological responses of organisms exposed to toxic metals have been focused, due to heavy metal contaminations have critically threatened the ecosystem and food security. However, still few investigations focused on the responses of certain organisms exposed to the long term and severe heavy metal contamination in specific environments. In present investigation, the Hong Kong oyster, Crassostrea hongkongensis were obtained from 3 sites which were contaminated by different concentrations of heavy metals (such as zinc, copper, manganese and lead etc.), respectively. Heavy metal concentrations in the sea water samples collected from the 3 sites and the dissected tissues of the oysters with blue visceral mass were determinated to estimate the metal contamination levels in environments and the bio-accumulation ratios of the heavy metals in the different tissues of oysters. Moreover, Proteomic methods were employed to analyze the differentially expressed proteins in the gills of oysters exposed to long-term heavy metal contaminations. Results indicated that the Jiulong River estuary has been severely contaminated by Cu, Zn and slightly with Cr, Ni, Mn, etc, moreover, Zn and Cu were the major metals accumulated by oysters to phenomenally high concentrations (more than 3.0% of Zn and about 2.0% of Cu against what the dry weight of tissues were accumulated), and Cr, Ni, Mn, etc were also significantly accumulated. The differentially expressed proteins in the gills of oysters exposed to heavy metals participate in several cell processes, such as metal binding, transporting and saving, oxidative-reduction balance maintaining, stress response, signal transduction, etc. Significantly up-regulated expression (about 10 folds) of an important metal binding protein, metallothionein (MT) and granular cells was observed in the gills of oysters exposed to long-term and severely heavy-metal-contaminated estuary, it suggested that binding toxic metals with metallothionein-like proteins (MTLP) and storing toxic metals in metal-rich granules (MRG) with insoluble forms were the important strategies of oyster to detoxify the toxic metals and adapt to the high level of metal-contaminated environment. Most of the stress and immunity responsive proteins, such as heat shock proteins (HSP), extracellular superoxide dismutase (ECSOD) and cavortin, and the cellular redox reaction relative proteins such as 20G-Fe (II) oxygenase family oxidoreductase, aldehyde dehydrogenase and retinal dehydrogenase 2, were detected significantly down-regulated in the gills of oysters exposed to long term heavy metal contaminated environments, it indicated that long term exposure different from emergent exposure to heavy metal contamination may significantly suppress the stress and immunity response system of oysters. Moreover, Formin homology 2 domain containing protein (FH2). The only protein domain to directly nucleate actin monomers into unbranched filament polymers, by which will subsequently control gene expression and chromatin remodelling complexes, was also detected greatly up-regulated in the gills of oysters exposed to long-term heavy metal contaminations. It indicated that nuclear activity regulation may also be important for oyster to adapt to the long-term heavy-metal-contaminated environment. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Insulin receptor isoform A ameliorates long-term glucose intolerance in diabetic mice
Diaz-Castroverde, Sabela; Gómez-Hernández, Almudena; Fernández, Silvia; García-Gómez, Gema; Di Scala, Marianna; González-Aseguinolaza, Gloria; Fernández-Millán, Elisa; González-Rodríguez, Águeda; García-Bravo, María; Chambon, Pierre; Álvarez, Carmen; Perdomo, Liliana; Beneit, Nuria; Benito, Manuel
2016-01-01
ABSTRACT Type 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion. Previous in vitro data showed that insulin receptor isoform A, but not B, favours basal glucose uptake through its specific association with endogenous GLUT1/2 in murine hepatocytes and beta cells. With this background, we hypothesized that hepatic expression of insulin receptor isoform A in a mouse model of type 2 diabetes could potentially increase the glucose uptake of these cells, decreasing the hyperglycaemia and therefore ameliorating the diabetic phenotype. To assure this hypothesis, we have developed recombinant adeno-associated viral vectors expressing insulin receptor isoform A (IRA) or isoform B (IRB) under the control of a hepatocyte-specific promoter. Our results demonstrate that in the long term, hepatic expression of IRA in diabetic mice is more efficient than IRB in ameliorating glucose intolerance. Consequently, it impairs the induction of compensatory mechanisms through beta cell hyperplasia and/or hypertrophy that finally lead to beta cell failure, reverting the diabetic phenotype in about 8 weeks. Our data suggest that long-term hepatic expression of IRA could be a promising therapeutic approach for the treatment of type 2 diabetes mellitus. PMID:27562101
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Cognitive effects of pregabalin in the treatment of long-term benzodiazepine-use and dependence.
Oulis, Panagiotis; Kalogerakou, Stamatina; Anyfandi, Eleni; Konstantakopoulos, George; Papakosta, Vassiliki-Maria; Masdrakis, Vasilios; Tsaltas, Eleftheria
2014-05-01
Long-term benzodiazepine (BDZ) use and dependence affect cognitive functioning adversely and partly irreversibly. Emerging evidence suggests that pregabalin (PGB) might be a safe and efficacious treatment of long-term BDZ use. The aim of the present study was to investigate the changes in several core cognitive functions after successful treatment of long-term BDZ use and dependence with PGB. Fourteen patients with long-term BDZ use (mean duration >15 years) underwent neuropsychological assessment with the mini-mental state examination and four tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) battery before the initiation of PGB treatment and at a two months follow-up after the cessation of BDZs. Patients' CANTAB percentile score distributions were compared with normative CANTAB data. Patients improved on cognitive measures of global cognitive functioning, time orientation, psychomotor speed, and visuospatial memory and learning with strong effect sizes. By contrast, they failed to improve on measures of attentional flexibility. Despite their significant improvement, patients' scores on most tests remained still at the lower percentiles of CANTAB normative scores. Although preliminary, our findings suggest that successful treatment of long-term BDZ use with PGB is associated with a substantial, though only partial, recovery of BDZ-compromised neuropsychological functioning, at least at a 2-month follow-up. Copyright © 2014 John Wiley & Sons, Ltd.
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Kuhl, D; Kennedy, T E; Barzilai, A; Kandel, E R
1992-12-01
Long-term memory for sensitization of the gill- and siphon-withdrawal reflexes in Aplysia californica requires RNA and protein synthesis. These long-term behavioral changes are accompanied by long-term facilitation of the synaptic connections between the gill and siphon sensory and motor neurons, which are similarly dependent on transcription and translation. In addition to showing an increase in over-all protein synthesis, long-term facilitation is associated with changes in the expression of specific early, intermediate, and late proteins, and with the growth of new synaptic connections between the sensory and motor neurons of the reflex. We previously focused on early proteins and have identified four proteins as members of the immunoglobulin family of cell adhesion molecules related to NCAM and fasciclin II. We have now cloned the cDNA corresponding to one of the late proteins, and identified it as the Aplysia homolog of BiP, an ER resident protein involved in the folding and assembly of secretory and membrane proteins. Behavioral training increases the steady-state level of BiP mRNA in the sensory neurons. The increase in the synthesis of BiP protein is first detected 3 h after the onset of facilitation, when the increase in overall protein synthesis reaches its peak and the formation of new synaptic terminals becomes apparent. These findings suggest that the chaperon function of BiP might serve to fold proteins and assemble protein complexes necessary for the structural changes characteristic of long-term memory.
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Long-term bed degradation in Maryland streams (phase 2) : Blue Ridge and Western Piedmont provinces.
DOT National Transportation Integrated Search
2012-03-01
Estimation of potential long-term down-cutting of the stream bed is necessary for evaluation and design of bridges for scour and culverts for fish passage. The purpose of this study has been to improve predictions of this potential long-term bed degr...
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NASA Astrophysics Data System (ADS)
Largier, J. L.; Garcia-Reyes, M.; Bjorkstedt, E.; Paduan, J. D.
2016-12-01
More than a decade of HF Radar data off central and northern California provides an unprecedented view of the flow structures and interannual variability in surface circulation in a coastal upwelling area. The interaction of the alongshore shelf jet with shoreline features and mesoscale eddies is well represented in direct analyses of HFR data and also important in improving the performance of data-assimilating models. While invaluable for operational response in the short-term, this long-term record of surface circulation is equally invaluable in ecosystem oceanography. With direct measurement of currents, the different expressions of upwelling can be disaggregated. Wind forcing, transport patterns and water properties can be evaluated independently and indexed independently. In doing this, it becomes clear that wind-current-temperature correlations change from place to place and year to year in any given region and that a single "upwelling index" is a blunt tool to track changes in pelagic and benthic communities in coastal upwelling areas.
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Effects of Long-Term Cranberry Supplementation on Endocrine Pancreas in Aging Rats
Zhu, Min; Hu, Jingping; Perez, Evelyn; Phillips, Dawn; Kim, Wook; Ghaedian, Reza; Napora, Joshua K.
2011-01-01
The effects of long-term cranberry consumption on age-related changes in endocrine pancreas are not fully understood. Here we treated male Fischer 344 rats with either 2% whole cranberry powder supplemented or normal rodent chow from 6 to 22 month old. Both groups displayed an age-related decline in basal plasma insulin concentrations, but this age-related decline was delayed by cranberry. Cranberry supplementation led to increased β-cell glucose responsiveness during the oral glucose tolerance test. Portal insulin concentration was 7.6-fold higher in rats fed cranberry, coupled with improved β-cell function. However, insulin resistance values were similar in both groups. Total β-cell mass and expression of pancreatic and duodenal homeobox 1 and insulin within islets were significantly enhanced in rats fed cranberry relative to controls. Furthermore, cranberry increased insulin release of an insulin-producing β-cell line, revealing its insulinotropic effect. These findings suggest that cranberry is of particular benefit to β-cell function in normal aging rats. PMID:21768504
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Sexuality and physical intimacy in long-term care.
Lichtenberg, Peter A
2014-01-01
Sexuality and sexual needs in older adults remains a neglected area of clinical intervention, particularly so in long-term care settings. Because older adults in medical rehabilitation and long-term care beds present with significant frailties, and often significant neurocognitive disorders, it makes it difficult for occupational therapists and other staff to evaluate the capacity of an older adult resident to participate in sexual relationships. The current paper reviews the current literature on sexuality and aging, examines some of the clinical practices and guidelines regarding sexual expression in long-term care, and presents two case examples. A semistructured interview and decision tree is presented to assist therapists in making careful and informed decisions and thereby balancing the needs for protection with the needs for autonomy.
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Kenny, Nathan J; Dearden, Peter K
2013-12-01
The C termini of N-methyl-D-aspartate (NMDA) receptor NR2 subunits are thought to play a major role in the molecular establishment of memory across the Bilateria, via the phenomenon known as long-term potentiation (LTP). Despite their long history of use as models in the study of memory, the expression and structure of the NR2 subunit in the Lophotrochozoa has remained uncategorized. Here, we report the phylogenic relationships of NR subunits across the Bilateria, and the cloning and in situ analysis of expression of NMDA NR1 and NR2 subunits in the monogont rotifer Brachionus plicatilis. RNA in situ hybridization suggests expression of NMDA receptor subunits in B. plicatilis is neural, consistent with expression observed in other species, and ours is the first report confirming NR2 expression in the lophotrochozoan clade. However, the single NR2 subunit identified in B. plicatilis was found to lack the long C terminal domain found in vertebrates, which is believed to modulate LTP. Further investigation revealed that mollusc and annelid NR2 subunits possess long intracellular C terminal domains. As data from molluscs (and particularly Aplysia californica) are the basis for much of our understanding of LTP, understanding how these diverse lophotrochozoan C termini function in vivo will have many implications for how we consider the evolution of the molecular control of learning and memory across the Metazoa as a whole and interpret the results of experiments into this vital component of cognition.
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Fuentes, Eduardo N; Safian, Diego; Valdés, Juan Antonio; Molina, Alfredo
2013-08-01
In the present study, different reference genes were isolated, and their stability in the skeletal muscle of fine flounder subjected to different nutritional states was assessed using geNorm and NormFinder. The combinations between 18S and ActB; Fau and 18S; and Fau and Tubb were chosen as the most stable gene combinations in feeding, long-term fasting and refeeding, and short-term refeeding conditions, respectively. In all periods, ActB was identified as the single least stable gene. Subsequently, the expression of the myosin heavy chain (MYH) and the insulin-like growth factor-I receptor (IGF-IR) was assessed. A large variation in MYH and IGF-IR expression was found depending on the reference gene that was chosen for normalizing the expression of both genes. Using the most stable reference genes, mRNA levels of MYH decreased and IGF-IR increased during fasting, with both returning to basal levels during refeeding. However, the drop in mRNA levels for IGF-IR occurred during short-term refeeding, in contrast with the observed events in the expression of MYH, which occurred during long-term refeeding. The present study highlights the vast differences incurred when using unsuitable versus suitable reference genes for normalizing gene expression, pointing out that normalization without proper validation could result in a bias of gene expression.
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New and improved tools and methods for enhanced biosynthesis of natural products in microorganisms.
Wang, Zhiqing; Cirino, Patrick C
2016-12-01
Engineering efficient biosynthesis of natural products in microorganisms requires optimizing gene expression levels to balance metabolite flux distributions and to minimize accumulation of toxic intermediates. Such metabolic optimization is challenged with identifying the right gene targets, and then determining and achieving appropriate gene expression levels. After decades of having a relatively limited set of gene regulation tools available, metabolic engineers are recently enjoying an ever-growing repertoire of more precise and tunable gene expression platforms. Here we review recent applications of natural and designed transcriptional and translational regulatory machinery for engineering biosynthesis of natural products in microorganisms. Customized trans-acting RNAs (sgRNA, asRNA and sRNA), along with appropriate accessory proteins, are allowing for unparalleled tuning of gene expression. Meanwhile metabolite-responsive transcription factors and riboswitches have been implemented in strain screening and evolution, and in dynamic gene regulation. Further refinements and expansions on these platform technologies will circumvent many long-term obstacles in natural products biosynthesis. Copyright © 2016 Elsevier Ltd. All rights reserved.
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López-Granero, Caridad; Cardona, Diana; Giménez, Estela; Lozano, Rafael; Barril, José; Aschner, Michael; Sánchez-Santed, Fernando; Cañadas, Fernando
2014-01-01
Organophosphates (OPs) affect behavior by inhibiting acetylcholinesterase (AChE). While the cognitive short-term effects may be directly attributed to this inhibition, the mechanisms that underlie OP's long-term cognitive effects remain controversial and poorly understood. Accordingly, two experiments were designed to assess the effects of OPs on cognition, and to ascertain whether both the short- and long-term effects of are AChE-dependent. A single subcutaneous dose of 250 mg/kg chlorpyrifos (CPF), 1.5mg/kg diisopropylphosphorofluoridate (DFP) or 15 mg/kg parathion (PTN) was administered to male Wistar rats. Spatial learning was evaluated 72 h or 23 weeks after exposure, and impulsive choice was tested at 10 and 30 weeks following OPs administration (experiment 1 and 2, respectively). Brain soluble and membrane-bound AChE activity, synaptic AChE-S mRNA, read-through AChE-R mRNA and brain acylpeptide hydrolase (APH) activity (as alternative non-cholinergic target) were analyzed upon completion of the behavioral testing (17 and 37 weeks after OPs exposure). Both short- and long-term CPF treatment caused statistically significant effects on spatial learning, while PTN treatment led only to statistically significant short-term effects. Neither CPF, DFP nor PTN affected the long-term impulsivity response. Long-term exposure to CPF and DFP significantly decreased AChE-S and AChE-R mRNA, while in the PTN treated group only AChE-S mRNA levels were decreased. However, after long-term OP exposure, soluble and membrane-bound AChE activity was indistinguishable from controls. Finally, no changes were noted in brain APH activity in response to OP treatment. Taken together, this study demonstrates long-term effects of OPs on AChE-S and AChE-R mRNA in the absence of changes in AChE soluble and membrane-bound activity. Thus, changes in AChE mRNA expression imply non-catalytic properties of the AChE enzyme. Copyright © 2013 Elsevier Inc. All rights reserved.
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De Novo Transcriptional Analysis of Alfalfa in Response to Saline-Alkaline Stress.
An, Yi-Min; Song, Li-Li; Liu, Ying-Rui; Shu, Yong-Jun; Guo, Chang-Hong
2016-01-01
Saline-alkaline stress, caused by high levels of harmful carbonate salts and high soil pH, is a major abiotic stress that affects crop productivity. Alfalfa is a widely cultivated perennial forage legume with some tolerance to biotic and abiotic stresses, especially to saline-alkaline stress. To elucidate the mechanism underlying plant saline-alkaline tolerance, we conducted transcriptome analysis of whole alfalfa seedlings treated with saline-alkaline solutions for 0 day (control), 1 day (short-term treatment), and 7 days (long-term treatment) using ion torrent sequencing technology. A transcriptome database dataset of 53,853 unigenes was generated, and 2,286 and 2,233 genes were differentially expressed in the short-term and long-term treatment, respectively. Gene ontology analysis revealed 14 highly enriched pathways and demonstrated the differential response of metabolic pathways between the short-term and long-term treatment. The expression levels of 109 and 96 transcription factors were significantly altered significantly after 1 day and 7 days of treatment, respectively. Specific responses of peroxidase, flavonoids, and the light pathway component indicated that the antioxidant capacity was one of the central mechanisms of saline-alkaline stress tolerance response in alfalfa. Among the 18 differentially expressed genes examined by real time PCR, the expression levels of eight genes, including inositol transporter, DNA binding protein, raffinose synthase, ferritin, aldo/keto reductase, glutathione S-transferase, xyloglucan endotrans glucosylase, and a NAC transcription factor, exhibited different patterns in response to saline and alkaline stress. The expression levels of the NAC transcription factor and glutathione S-transferase were altered significantly under saline stress and saline-alkaline stress; they were upregulated under saline-alkaline stress and downregulated under salt stress. Physiology assays showed an increased concentration of reactive oxygen species and malondialdehyde and a decreased content of chlorophyll, indicating that anti-oxidation and detoxification play an important role in response to saline-alkaline stress. Overall, the transcriptome analysis provided novel insights into the saline-alkaline stress tolerance response mechanisms in alfalfa.
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De Novo Transcriptional Analysis of Alfalfa in Response to Saline-Alkaline Stress
An, Yi-Min; Song, Li-Li; Liu, Ying-Rui; Shu, Yong-Jun; Guo, Chang-Hong
2016-01-01
Saline-alkaline stress, caused by high levels of harmful carbonate salts and high soil pH, is a major abiotic stress that affects crop productivity. Alfalfa is a widely cultivated perennial forage legume with some tolerance to biotic and abiotic stresses, especially to saline-alkaline stress. To elucidate the mechanism underlying plant saline-alkaline tolerance, we conducted transcriptome analysis of whole alfalfa seedlings treated with saline-alkaline solutions for 0 day (control), 1 day (short-term treatment), and 7 days (long-term treatment) using ion torrent sequencing technology. A transcriptome database dataset of 53,853 unigenes was generated, and 2,286 and 2,233 genes were differentially expressed in the short-term and long-term treatment, respectively. Gene ontology analysis revealed 14 highly enriched pathways and demonstrated the differential response of metabolic pathways between the short-term and long-term treatment. The expression levels of 109 and 96 transcription factors were significantly altered significantly after 1 day and 7 days of treatment, respectively. Specific responses of peroxidase, flavonoids, and the light pathway component indicated that the antioxidant capacity was one of the central mechanisms of saline-alkaline stress tolerance response in alfalfa. Among the 18 differentially expressed genes examined by real time PCR, the expression levels of eight genes, including inositol transporter, DNA binding protein, raffinose synthase, ferritin, aldo/keto reductase, glutathione S-transferase, xyloglucan endotrans glucosylase, and a NAC transcription factor, exhibited different patterns in response to saline and alkaline stress. The expression levels of the NAC transcription factor and glutathione S-transferase were altered significantly under saline stress and saline-alkaline stress; they were upregulated under saline-alkaline stress and downregulated under salt stress. Physiology assays showed an increased concentration of reactive oxygen species and malondialdehyde and a decreased content of chlorophyll, indicating that anti-oxidation and detoxification play an important role in response to saline-alkaline stress. Overall, the transcriptome analysis provided novel insights into the saline-alkaline stress tolerance response mechanisms in alfalfa. PMID:27458463
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Sun, Yue; Zhou, Liping; Fang, Lingdong; Su, Yong; Zhu, Weiyun
2015-01-01
Intake of raw potato starch (RPS) has been associated with various intestinal health benefits, but knowledge of its mechanism in a long-term is limited. The aim of this study was to investigate the effects of long-term intake of RPS on microbial composition, genes expression profiles in the colon of pigs. Thirty-six Duroc × Landrace × Large White growing barrows were randomly allocated to corn starch (CS) and RPS groups with a randomized block design. Each group consisted of six replicates (pens), with three pigs per pen. Pigs in the CS group were offered a corn/soybean-based diet, while pigs in the RPS group were put on a diet in which 230 g/kg (growing period) or 280 g/kg (finishing period) purified CS was replaced with purified RPS during a 100-day trial. Real-time PCR assay showed that RPS significantly decreased the number of total bacteria in the colonic digesta. MiSeq sequencing of the V3-V4 region of the 16S rRNA genes showed that RPS significantly decreased the relative abundance of Clostridium, Treponema, Oscillospira, Phascolarctobacterium, RC9 gut group, and S24-7-related operational taxonomic units (OTUs), and increased the relative abundance of Turicibacter, Blautia, Ruminococcus, Coprococcus, Marvinbryantia, and Ruminococcus bromii-related OTUs in colonic digesta and mucosa. Analysis of the colonic transcriptome profiles revealed that the RPS diet changed the colonic expression profile of the host genes mainly involved in immune response pathways. RPS significantly increased proinflammartory cytokine IL-1β gene expression and suppressed genes involved in lysosome. Our findings suggest that long-term intake of high resistant starch (RS) diet may result in both positive and negative roles in gut health. PMID:26379652
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ERIC Educational Resources Information Center
Brightwell, Jennifer J.; Smith, Clayton A.; Neve, Rachael L.; Colombo, Paul J.
2007-01-01
Extensive research has shown that the hippocampus is necessary for consolidation of long-term spatial memory in rodents. We reported previously that rats using a place strategy to solve a cross maze task showed sustained phosphorylation of hippocampus cyclic AMP response element-binding protein (CREB), a transcription factor implicated in…
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ERIC Educational Resources Information Center
Ahn, Hyung Jin; Hernandez, Caterina M.; Levenson, Jonathan M.; Lubin, Farah D.; Liou, Hsiou-Chi; Sweatt, J. David
2008-01-01
Transcription is a critical component for consolidation of long-term memory. However, relatively few transcriptional mechanisms have been identified for the regulation of gene expression in memory formation. In the current study, we investigated the activity of one specific member of the NF-[kappa]B transcription factor family, c-Rel, during…
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Savings Memory Is Accompanied by Transcriptional Changes That Persist beyond the Decay of Recall
ERIC Educational Resources Information Center
Perez, Leticia; Patel, Ushma; Rivota, Marissa; Calin-Jageman, Irina E.; Calin-Jageman, Robert J.
2018-01-01
Most long-term memories are forgotten. What happens, then, to the changes in neuronal gene expression that were initially required to encode and maintain the memory? Here we show that the decay of recall for long-term sensitization memory in "Aplysia" is accompanied both by a form of savings memory (easier relearning) and by persistent…
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Short- and long-term memory in Drosophila require cAMP signaling in distinct neuron types.
Blum, Allison L; Li, Wanhe; Cressy, Mike; Dubnau, Josh
2009-08-25
A common feature of memory and its underlying synaptic plasticity is that each can be dissected into short-lived forms involving modification or trafficking of existing proteins and long-term forms that require new gene expression. An underlying assumption of this cellular view of memory consolidation is that these different mechanisms occur within a single neuron. At the neuroanatomical level, however, different temporal stages of memory can engage distinct neural circuits, a notion that has not been conceptually integrated with the cellular view. Here, we investigated this issue in the context of aversive Pavlovian olfactory memory in Drosophila. Previous studies have demonstrated a central role for cAMP signaling in the mushroom body (MB). The Ca(2+)-responsive adenylyl cyclase RUTABAGA is believed to be a coincidence detector in gamma neurons, one of the three principle classes of MB Kenyon cells. We were able to separately restore short-term or long-term memory to a rutabaga mutant with expression of rutabaga in different subsets of MB neurons. Our findings suggest a model in which the learning experience initiates two parallel associations: a short-lived trace in MB gamma neurons, and a long-lived trace in alpha/beta neurons.
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ERIC Educational Resources Information Center
Trinh, Mimi A.; Ma, Tao; Kaphzan, Hanoch; Bhattacharya, Aditi; Antion, Marcia D.; Cavener, Douglas R.; Hoeffer, Charles A.; Klann, Eric
2014-01-01
The proper regulation of translation is required for the expression of long-lasting synaptic plasticity. A major site of translational control involves the phosphorylation of eukaryotic initiation factor 2 a (eIF2a) by PKR-like endoplasmic reticulum (ER) kinase (PERK). To determine the role of PERK in hippocampal synaptic plasticity, we used the…
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Open-Porous Hydroxyapatite Scaffolds for Three-Dimensional Culture of Human Adult Liver Cells
Schmelzer, Eva; Over, Patrick; Nettleship, Ian; Gerlach, Joerg C.
2016-01-01
Liver cell culture within three-dimensional structures provides an improved culture system for various applications in basic research, pharmacological screening, and implantable or extracorporeal liver support. Biodegradable calcium-based scaffolds in such systems could enhance liver cell functionality by providing endothelial and hepatic cell support through locally elevated calcium levels, increased surface area for cell attachment, and allowing three-dimensional tissue restructuring. Open-porous hydroxyapatite scaffolds were fabricated and seeded with primary adult human liver cells, which were embedded within or without gels of extracellular matrix protein collagen-1 or hyaluronan. Metabolic functions were assessed after 5, 15, and 28 days. Longer-term cultures exhibited highest cell numbers and liver specific gene expression when cultured on hydroxyapatite scaffolds in collagen-1. Endothelial gene expression was induced in cells cultured on scaffolds without extracellular matrix proteins. Hydroxyapatite induced gene expression for cytokeratin-19 when cells were cultured in collagen-1 gel while culture in hyaluronan increased cytokeratin-19 gene expression independent of the use of scaffold in long-term culture. The implementation of hydroxyapatite composites with extracellular matrices affected liver cell cultures and cell differentiation depending on the type of matrix protein and the presence of a scaffold. The hydroxyapatite scaffolds enable scale-up of hepatic three-dimensional culture models for regenerative medicine applications. PMID:27403430
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Capote, Joana; Martinez, Leonel; Vetrone, Sylvia; Barton, Elisabeth R.; Sweeney, H. Lee; Miceli, M. Carrie
2016-01-01
In the degenerative disease Duchenne muscular dystrophy, inflammatory cells enter muscles in response to repetitive muscle damage. Immune factors are required for muscle regeneration, but chronic inflammation creates a profibrotic milieu that exacerbates disease progression. Osteopontin (OPN) is an immunomodulator highly expressed in dystrophic muscles. Ablation of OPN correlates with reduced fibrosis and improved muscle strength as well as reduced natural killer T (NKT) cell counts. Here, we demonstrate that the improved dystrophic phenotype observed with OPN ablation does not result from reductions in NKT cells. OPN ablation skews macrophage polarization toward a pro-regenerative phenotype by reducing M1 and M2a and increasing M2c subsets. These changes are associated with increased expression of pro-regenerative factors insulin-like growth factor 1, leukemia inhibitory factor, and urokinase-type plasminogen activator. Furthermore, altered macrophage polarization correlated with increases in muscle weight and muscle fiber diameter, resulting in long-term improvements in muscle strength and function in mdx mice. These findings suggest that OPN ablation promotes muscle repair via macrophage secretion of pro-myogenic growth factors. PMID:27091452
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Liu, Xiaolong; Li, Xia; Dai, Chuanchao; Zhou, Jiayu; Yan, Ting; Zhang, Jinfei
2017-11-01
To understand the link between long-term drought tolerance and short-term drought responses in plants, transgenic rice (Oryza sativa L.) plants over-expressing the maize C 4- pepc gene encoding phosphoenolpyruvate carboxylase (PC) and wild-type (WT) rice plants were subjected to PEG 6000 treatments to simulate drought stress. Compared with WT, PC had the higher survival rate and net photosynthetic rate after 16days of drought treatment, and had higher relative water content in leaves after 2h of drought treatment as well, conferring drought tolerance. WT accumulated higher amounts of malondialdehyde, superoxide radicals, and H 2 O 2 than PC under the 2-h PEG 6000 treatment, indicating greater damages in WT. Results from pretreatments with a Ca 2+ chelator and/or antagonist showed that the regulation of the early drought response in PC was Ca 2+ -dependent. The NO and H 2 O 2 levels in PC lines were also up-regulated via Ca 2+ signals, indicating that Ca 2+ in PC lines also reacted upstream of NO and H 2 O 2 . 2-h drought treatment increased the transcripts of CPK9 and CPK4 in PC via positive up-regulation of Ca 2+ . The transcripts of NAC6 [NACs (NAM, ATAF1, ATAF2, and CUC2)] and bZIP60 (basic leucine zipper, bZIP) were up-regulated, but those of DREB2B (dehydration-responsive element-binding protein, DREB) were down-regulated, both via Ca 2+ signals in PC. PEPC activity, expressions of C 4 -pepc, and the antioxidant enzyme activities in PC lines were up-regulated via Ca 2+ . These results indicated that Ca 2+ signals in PC lines can up-regulate the NAC6 and bZIP60 and the downstream targets for early drought responses, conferring drought tolerance for the long term. Copyright © 2017 Elsevier GmbH. All rights reserved.
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The Mediating Role of Insight for Long-Term Improvements in Psychodynamic Therapy
ERIC Educational Resources Information Center
Johansson, Paul; Hoglend, Per; Ulberg, Randi; Amlo, Svein; Marble, Alice; Bogwald, Kjell-Petter; Sorbye, Oystein; Sjaastad, Mary Cosgrove; Heyerdahl, Oscar
2010-01-01
Objective: According to psychoanalytic theory, interpretation of transference leads to increased insight that again leads to improved interpersonal functioning over time. In this study, we performed a full mediational analysis to test whether insight gained during treatment mediates the long-term effects of transference interpretation in dynamic…
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Rocha, Filipa; Dias, Jorge; Engrola, Sofia; Gavaia, Paulo; Geurden, Inge; Dinis, Maria Teresa; Panserat, Stephane
2015-02-14
Knowledge on the role of early nutritional stimuli as triggers of metabolic pathways in fish is extremely scarce. The objective of the present study was to assess the long-term effects of glucose injection in the yolk (early stimulus) on carbohydrate metabolism and gene regulation in zebrafish juveniles challenged with a high-carbohydrate low-protein (HC) diet. Eggs were microinjected at 1 d post-fertilisation (dpf) with either glucose (2 M) or saline solutions. Up to 25 dpf, fish were fed a low-carbohydrate high-protein (LC) control diet, which was followed by a challenge with the HC diet. Survival and growth of 35 dpf juveniles were not affected by injection or the HC diet. Glucose stimulus induced some long-term metabolic changes in the juveniles, as shown by the altered expression of genes involved in glucose metabolism. On glycolysis, the expression levels of hexokinase 1 (HK1) and phosphofructokinase-6 (6PFK) were up-regulated in the visceral and muscle tissues, respectively, of juveniles exposed to the glucose stimulus, indicating a possible improvement in glucose oxidation. On gluconeogenesis, the inhibition of the expression levels of PEPCK in fish injected with glucose suggested lower production of hepatic glucose. Unexpectedly, fructose-1,6-bisphosphatase (FBP) expression was induced and 6PFK expression reduced by glucose stimulus, leaving the possibility of a specific regulation of the FBP-6PFK metabolic cycle. Glucose metabolism in juveniles was estimated using a [¹⁴C]glucose tracer; fish previously exposed to the stimulus showed lower retention of [¹⁴C]glucose in visceral tissue (but not in muscle tissue) and, accordingly, higher glucose catabolism, in comparison with the saline group. Globally, our data suggest that glucose stimulus at embryo stage has the potential to alter particular steps of glucose metabolism in zebrafish juveniles.
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Tasnim, Farah; Toh, Yi-Chin; Qu, Yinghua; Li, Huan; Phan, Derek; Narmada, Balakrishnan C; Ananthanarayanan, Abhishek; Mittal, Nikhil; Meng, Ryan Q; Yu, Hanry
2016-06-06
Pluripotent stem cell derived hepatocyte-like cells (hPSC-HLCs) are an attractive alternative to primary human hepatocytes (PHHs) used in applications ranging from therapeutics to drug safety testing studies. It would be critical to improve and maintain mature hepatocyte functions of the hPSC-HLCs, especially for long-term studies. If 3D culture systems were to be used for such purposes, it would be important that the system can support formation and maintenance of optimal-sized spheroids for long periods of time, and can also be directly deployed in liver drug testing assays. We report the use of 3-dimensional (3D) cellulosic scaffold system for the culture of hPSC-HLCs. The scaffold has a macroporous network which helps to control the formation and maintenance of the spheroids for weeks. Our results show that culturing hPSC-HLCs in 3D cellulosic scaffolds increases functionality, as demonstrated by improved urea production and hepatic marker expression. In addition, hPSC-HLCs in the scaffolds exhibit a more mature phenotype, as shown by enhanced cytochrome P450 activity and induction. This enables the system to show a higher sensitivity to hepatotoxicants and a higher degree of similarity to PHHs when compared to conventional 2D systems. These results suggest that 3D cellulosic scaffolds are ideal for the long-term cultures needed to mature hPSC-HLCs. The mature hPSC-HLCs with improved cellular function can be continually maintained in the scaffolds and directly used for hepatotoxicity assays, making this system highly attractive for drug testing applications.
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Mishima, Kazuo; Fujiki, Nobuhiro; Yoshida, Yasushi; Sakurai, Takeshi; Honda, Makoto; Mignot, Emmanuel; Nishino, Seiji
2008-01-01
Study Objective: To determine whether hypocretin receptor gene (hcrtR1 and hcrtR2) expression is affected after long-term hypocretin ligand loss in humans and animal models of narcolepsy. Design: Animal and human study. We measured hcrtR1 and hcrtR2 expression in the frontal cortex and pons using the RT-PCR method in murine models (8-week-old and 27-week-old orexin/ataxin-3 transgenic (TG) hypocretin cell ablated mice and wild-type mice from the same litter, 10 mice for each group), in canine models (8 genetically narcoleptic Dobermans with null mutations in the hcrtR2, 9 control Dobermans, 3 sporadic ligand-deficient narcoleptics, and 4 small breed controls), and in humans (5 narcolepsy-cataplexy patients with hypocretin deficiency (average age 77.0 years) and 5 control subjects (72.6 years). Measurement and Results: 27-week-old (but not 8-week-old) TG mice showed significant decreases in hcrtR1 expression, suggesting the influence of the long-term ligand loss on the receptor expression. Both sporadic narcoleptic dogs and human narcolepsy-cataplexy subjects showed a significant decrease in hcrtR1 expression, while declines in hcrtR2 expression were not significant in these cases. HcrtR2-mutated narcoleptic Dobermans (with normal ligand production) showed no alteration in hcrtR1 expression. Conclusions: Moderate declines in hcrtR expressions, possibly due to long-term postnatal loss of ligand production, were observed in hypocretin-ligand deficient narcoleptic subjects. These declines are not likely to be progressive and complete. The relative preservation of hcrtR2 expression also suggests that hypocretin based therapies are likely to be a viable therapeutic options in human narcolepsy-cataplexy. Citation: Mishima K; Fujiki N; Yoshida Y; Sakurai T; Honda M; Mignot E; Nishino S. Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy. SLEEP 2008;31(8):1119-1126. PMID:18714784
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Busscher, Bert; Spinhoven, Philip
2017-09-01
To examine the predictive value of cognitive coping strategies at pretreatment and the value of changes in these strategies during cognitive-behavioral treatment for aviophobia for long-term therapy results. Data from baseline, after therapy at 2 months, short-term follow-up at 5 months, and long-term follow-up at 41 months were analyzed (N = 59). Participants were in a long-term process of change, which continued positively after therapy for maladaptive cognitive coping strategies. The use of cognitive coping strategies at baseline was not predictive of long-term outcome. However, a greater increase in the use of adaptive coping strategies, and more importantly, a greater decrease in the use of maladaptive coping strategies were predictive of improvements indicated in self-report of flight anxiety and actual flight behavior at long-term follow-up. Improvement of maladaptive cognitive coping strategies is possibly a key mechanism of change in cognitive-behavioral therapy for aviophobia. © 2016 Wiley Periodicals, Inc.
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Roach, Kathryn E; Tappen, Ruth M; Kirk-Sanchez, Neva; Williams, Christine L; Loewenstein, David
2011-01-01
To determine whether an activity specific exercise program could improve ability to perform basic mobility activities in long-term care residents with Alzheimer disease (AD). Randomized, controlled, single-blinded clinical trial. Residents of 7 long-term care facilities. Eighty-two long-term care residents with mild to severe AD. An activity specific exercise program was compared to a walking program and to an attention control. Ability to perform bed mobility and transfers was assessed using the subscales of the Acute Care Index of Function; functional mobility was measured using the 6-Minute Walk test. Subjects receiving the activity specific exercise program improved in ability to perform transfers, whereas subjects in the other 2 groups declined.
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Pathway Analysis Hints Towards Beneficial Effects of Long-Term Vibration on Human Chondrocytes.
Lützenberg, Ronald; Solano, Kendrick; Buken, Christoph; Sahana, Jayashree; Riwaldt, Stefan; Kopp, Sascha; Krüger, Marcus; Schulz, Herbert; Saar, Kathrin; Huebner, Norbert; Hemmersbach, Ruth; Bauer, Johann; Infanger, Manfred; Grimm, Daniela; Wehland, Markus
2018-06-27
Spaceflight negatively influences the function of cartilage tissue in vivo. In vitro human chondrocytes exhibit an altered gene expression of inflammation markers after a two-hour exposure to vibration. Little is known about the impact of long-term vibration on chondrocytes. Human cartilage cells were exposed for up to 24 h (VIB) on a specialised vibration platform (Vibraplex) simulating the vibration profile which occurs during parabolic flights and compared to static control conditions (CON). Afterwards, they were investigated by phase-contrast microscopy, rhodamine phalloidin staining, microarray analysis, qPCR and western blot analysis. Morphological investigations revealed no changes between CON and VIB chondrocytes. F-Actin staining showed no alterations of the cytoskeleton in VIB compared with CON cells. DAPI and TUNEL staining did not identify apoptotic cells. ICAM-1 was elevated and vimentin, beta-tubulin and osteopontin proteins were significantly reduced in VIB compared to CON cells. qPCR of cytoskeletal genes, ITGB1, SOX3, SOX5, SOX9 did not reveal differential regulations. Microarray analysis detected 13 differentially expressed genes, mostly indicating unspecific stimulations. Pathway analyses demonstrated interactions of PSMD4 and CNOT7 with ICAM. Long-term vibration did not damage human chondrocytes in vitro. The reduction of osteopontin protein and the down-regulation of PSMD4 and TBX15 gene expression suggest that in vitro long-term vibration might even positively influence cultured chondrocytes. © 2018 The Author(s). Published by S. Karger AG, Basel.
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Loyau, T; Collin, A; Yenisey, C; Crochet, S; Siegel, P B; Akşit, M; Yalçin, S
2014-08-01
Cyclically cold incubation temperatures have been suggested as a means to improve resistance of broiler chickens to ascites; however, the underlying mechanisms are not known. Nine hundred eggs obtained from 48 wk Ross broiler breeders were randomly assigned to 2 incubation treatments: control I eggs were incubated at 37.6°C throughout, whereas for cold I eggs the incubation temperature was reduced by 1°C for 6 h daily from 10 to 18 d of incubation. Thereafter, chickens were reared at standard temperatures or under cold exposure that was associated or not with a postnatal cold acclimation at d 5 posthatch. At hatch, hepatic catalase activity and malondialdehyde content were measured. Serum thyroid hormone and triglyceride concentrations, and muscle expression of several genes involved in the regulation of energy metabolism and oxidative stress were also measured at hatch and 5 and 25 d posthatch. Cold incubation induced modifications in antioxidant pathways with higher catalase activity, but lower expression of avian uncoupling protein 3 at hatch. However, long-term enhancement in the expression of avian uncoupling protein 3 was observed, probably caused by an increase in the expression of the transcription factor peroxisome proliferator activated receptor-γ coactivator-1α. These effects were not systematically associated with an increase in serum triiodothyronine concentrations that were observed only in chickens exposed to both cold incubation and later acclimation at 5 d with cold rearing. Our results suggest that these conditions of cyclically cold incubation resulted in the long-term in changes in antioxidant pathways and energy metabolism, which could enhance the health of chickens reared under cold conditions. © Poultry Science Association Inc.
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Liu, Jing; Xiao, Zhijie; Wong, Sunny Kit-Man; Tin, Vicky Pui-Chi; Ho, Ka-Yan; Wang, Junwen; Sham, Mai-Har; Wong, Maria Pik
2013-10-01
Limited improvement in long term survival of lung cancer patients has been achieved by conventional chemotherapy or targeted therapy. To explore the potentials of tumor initiating cells (TIC)-directed therapy, it is essential to identify the cell targets and understand their maintenance mechanisms. We have analyzed the performance of ALDH/CD44 co-expression as TIC markers and treatment targets of lung cancer using well-validated in vitro and in vivo analyses in multiple established and patient-derived lung cancer cells. The ALDH(hi)CD44(hi) subset showed the highest enhancement of stem cell phenotypic properties compared to ALDH(hi)CD44(lo), ALDH(lo)CD44(hi), ALDH(lo)CD44(lo) cells and unsorted controls. They showed higher invasion capacities, pluripotency genes and epithelial-mesenchymal transition transcription factors expression, lower intercellular adhesion protein expression and higher G2/M phase cell cycle fraction. In immunosuppressed mice, the ALDH(hi)CD44(hi)xenografts showed the highest tumor induction frequency, serial transplantability, shortest latency, largest volume and highest growth rates. Inhibition of sonic Hedgehog and Notch developmental pathways reduced ALDH+CD44+ compartment. Chemotherapy and targeted therapy resulted in higher AALDH(hi)CD44(hi) subset viability and ALDH(lo)CD44(lo) subset apoptosis fraction. ALDH inhibition and CD44 knockdown led to reduced stemness gene expression and sensitization to drug treatment. In accordance, clinical lung cancers containing a higher abundance of ALDH and CD44-coexpressing cells was associated with lower recurrence-free survival. Together, results suggested theALDH(hi)CD44(hi)compartment was the cellular mediator of tumorigenicity and drug resistance. Further investigation of the regulatory mechanisms underlying ALDH(hi)CD44(hi)TIC maintenance would be beneficial for the development of long term lung cancer control.
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Parents' and carers' views about emollients for childhood eczema: qualitative interview study.
Santer, M; Muller, I; Yardley, L; Lewis-Jones, S; Ersser, S; Little, P
2016-08-19
Leave-on emollients form the mainstay of eczema treatment, but adherence is poor. We aimed to explore parents'/carers' views on effectiveness and acceptability of leave-on emollients for childhood eczema through secondary analysis of data from 2 qualitative data sets. Study 1 recruited through mail-out from 6 general practices in southern England. Study 2 recruited from a feasibility trial of an intervention to support eczema self-care in 31 practices in the same area. Study 1 included 28 interviews with carers of children aged ≤5 years with eczema. Study 2 included 26 interviews with carers of children aged ≤5 years with eczema. Interviews followed semistructured guides: study 1 explored carers' understandings around eczema treatments in order to develop a web-based self-care support intervention; study 2 explored carers' understandings of eczema and eczema treatments after using the intervention. Interviews were carried out face to face or by telephone, audio-recorded and transcribed. Secondary analysis of data from both studies focused on views and experiences of emollient use. Data were analysed using an inductive thematic approach facilitated by NVivo V.10 software. In study 1, most participants felt emollients improved eczema but held mixed views about long-term use to prevent flare-ups. In study 2, where carers had used the web-based intervention, all participants held positive views about long-term emollient use. In both studies, participants expressed a range of preferences about emollient 'thickness'; some felt that 'thick' emollients (ointments) were most effective, while others found these difficult to use. Carers described a process of 'trial and error', trying emollients suggested by professionals, friends and family, or bought over-the-counter. Carers expressed a need for understanding differences between products and their effective use. Providing a rationale for long-term emollient use and choice of emollients could help improve adherence and help families gain more rapid control of eczema. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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Erythropoietin Improves the Survival of Fat Tissue after Its Transplantation in Nude Mice
Hamed, Saher; Egozi, Dana; Kruchevsky, Danny; Teot, Luc; Gilhar, Amos; Ullmann, Yehuda
2010-01-01
Background Autologous transplanted fat has a high resorption rate, providing a clinical challenge for the means to reduce it. Erythropoietin (EPO) has non-hematopoietic targets, and we hypothesized that EPO may improve long-term fat graft survival because it has both pro-angiogenic and anti-apoptotic properties. We aimed to determine the effect of EPO on the survival of human fat tissue after its transplantation in nude mice. Methodology/Principal Findings Human fat tissue was injected subcutaneously into immunologically-compromised nude mice, and the grafts were then treated with either 20 IU or 100 IU EPO. At the end of the 15-week study period, the extent of angiogenesis, apoptosis, and histology were assessed in the fat grafts. The results were compared to vascular endothelial growth factor (VEGF)-treated and phosphate-buffered saline (PBS)-treated fat grafts. The weight and volume of the EPO-treated grafts were higher than those of the PBS-treated grafts, whose weights and volumes were not different from those of the VEGF-treated grafts. EPO treatment also increased the expression of angiogenic factors and microvascular density, and reduced inflammation and apoptosis in a dose-dependent manner in the fat grafts. Conclusions/Significance Our data suggest that stimulation of angiogenesis by a cluster of angiogenic factors and decreased fat cell apoptosis account for potential mechanisms that underlie the improved long-term survival of fat transplants following EPO treatment. PMID:21085572
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Erythropoietin improves the survival of fat tissue after its transplantation in nude mice.
Hamed, Saher; Egozi, Dana; Kruchevsky, Danny; Teot, Luc; Gilhar, Amos; Ullmann, Yehuda
2010-11-15
Autologous transplanted fat has a high resorption rate, providing a clinical challenge for the means to reduce it. Erythropoietin (EPO) has non-hematopoietic targets, and we hypothesized that EPO may improve long-term fat graft survival because it has both pro-angiogenic and anti-apoptotic properties. We aimed to determine the effect of EPO on the survival of human fat tissue after its transplantation in nude mice. Human fat tissue was injected subcutaneously into immunologically-compromised nude mice, and the grafts were then treated with either 20 IU or 100 IU EPO. At the end of the 15-week study period, the extent of angiogenesis, apoptosis, and histology were assessed in the fat grafts. The results were compared to vascular endothelial growth factor (VEGF)-treated and phosphate-buffered saline (PBS)-treated fat grafts. The weight and volume of the EPO-treated grafts were higher than those of the PBS-treated grafts, whose weights and volumes were not different from those of the VEGF-treated grafts. EPO treatment also increased the expression of angiogenic factors and microvascular density, and reduced inflammation and apoptosis in a dose-dependent manner in the fat grafts. Our data suggest that stimulation of angiogenesis by a cluster of angiogenic factors and decreased fat cell apoptosis account for potential mechanisms that underlie the improved long-term survival of fat transplants following EPO treatment.
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Puyal, Julien; Grassi, Silvarosa; Dieni, Cristina; Frondaroli, Adele; Demêmes, Danielle; Raymond, Jaqueline; Pettorossi, Vito Enrico
2003-12-01
The effects of high frequency stimulation (HFS) of the primary vestibular afferents on synaptic transmission in the ventral part of the medial vestibular nuclei (vMVN) were studied during postnatal development and compared with the changes in the expression of the group I metabotropic glutamate receptor (mGluR) subtypes, mGluR1 and mGluR5. During the first stages of development, HFS always induced a mGluR5- and GABAA-dependent long-term depression (LTD) which did not require NMDA receptor and mGluR1 activation. The probability of inducing LTD decreased progressively throughout the development and it was zero at about the end of the second postnatal week. Conversely, long-term potentiation (LTP) appeared at the beginning of the second week and its occurrence increased to reach the adult value at the end of the third week. Of interest, the sudden change in the LTP frequency occurred at the time of eye opening, about the end of the second postnatal week. LTP depended on NMDA receptor and mGluR1 activation. In parallel with the modifications in synaptic plasticity, we observed that the expression patterns and localizations of mGluR5 and mGluR1 in the medial vestibular nuclei (MVN) changed during postnatal development. At the earlier stages the mGluR1 expression was minimal, then increased progressively. In contrast, mGluR5 expression was initially high, then decreased. While mGluR1 was exclusively localized in neuronal compartments and concentrated at the postsynaptic sites at all stages observed, mGluR5 was found mainly in neuronal compartments at immature stages, then preferentially in glial compartments at mature stages. These results provide the first evidence for a progressive change from LTD to LTP accompanied by a distinct maturation expression of mGluR1 and mGluR5 during the development of the MVN.
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DOT National Transportation Integrated Search
2014-05-01
Estimation of potential long-term down-cutting of the stream bed is necessary for evaluation and design of bridges for scour and culverts for fish passage. The purpose of this study has been to improve predictions of this potential long-term bed degr...
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Improving the Navys Passive Underwater Acoustic Monitoring of Marine Mammal Populations
2015-09-30
DISTRIBUTION STATEMENT A: Distribution approved for public release; distribution is unlimited. Improving the Navy’s Passive Underwater Acoustic...mpl.ucsd.edu LONG-TERM GOALS The long-term goals of this research effort are to improve the Navy’s passive underwater acoustic monitoring of marine...research of a graduate student in marine bioacoustics and ocean acoustics at the Scripps Institution of Oceanography. OBJECTIVES The
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Cho, Min Chul; Song, Won Hoon; Park, Juhyun; Cho, Sung Yong; Jeong, Hyeon; Oh, Seung-June; Paick, Jae-Seung; Son, Hwancheol
2018-06-01
We compared long-term storage symptom outcomes between photoselective laser vaporization of the prostate with a 120 W high performance system and holmium laser enucleation of the prostate. We also determined factors influencing postoperative improvement of storage symptoms in the long term. Included in our study were 266 men, including 165 treated with prostate photoselective laser vaporization using a 120 W high performance system and 101 treated with holmium laser enucleation of the prostate, on whom 60-month followup data were available. Outcomes were assessed serially 6, 12, 24, 36, 48 and 60 months postoperatively using the International Prostate Symptom Score, uroflowmetry and the serum prostate specific antigen level. Postoperative improvement in storage symptoms was defined as a 50% or greater reduction in the subtotal storage symptom score at each followup visit after surgery compared to baseline. Improvements in frequency, urgency, nocturia, subtotal storage symptom scores and the quality of life index were maintained up to 60 months after photoselective laser vaporization or holmium laser enucleation of the prostate. There was no difference in the degree of improvement in storage symptoms or the percent of patients with postoperative improvement in storage symptoms between the 2 groups throughout the long-term followup. However, the holmium laser group showed greater improvement in voiding symptoms and quality of life than the laser vaporization group. On logistic regression analysis a higher baseline subtotal storage symptom score and a higher BOOI (Bladder Outlet Obstruction Index) were the factors influencing the improvement in storage symptoms 5 years after prostate photoselective laser vaporization or holmium laser enucleation. Our serial followup data suggest that storage symptom improvement was maintained throughout the long-term postoperative period for prostate photoselective laser vaporization with a 120 W high performance system and holmium laser enucleation without any difference between the 2 surgeries. Also, more severe storage symptoms at baseline and a more severe BOOI predicted improved storage symptoms in the long term after each surgery. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
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Tucci, Sara; Herebian, Diran; Sturm, Marga; Seibt, Annette; Spiekerkoetter, Ute
2012-01-01
Very long-chain acyl-CoA dehydrogenase (VLCAD)-deficiency is the most common long-chain fatty acid oxidation disorder presenting with heterogeneous phenotypes. Similar to many patients with VLCADD, VLCAD-deficient mice (VLCAD(-/-)) remain asymptomatic over a long period of time. In order to identify the involved compensatory mechanisms, wild-type and VLCAD(-/-) mice were fed one year either with a normal diet or with a diet in which medium-chain triglycerides (MCT) replaced long-chain triglycerides, as approved intervention in VLCADD. The expression of the mitochondrial long-chain acyl-CoA dehydrogenase (LCAD) and medium-chain acyl-CoA dehydrogenase (MCAD) was quantified at mRNA and protein level in heart, liver and skeletal muscle. The oxidation capacity of the different tissues was measured by LC-MS/MS using acyl-CoA substrates with a chain length of 8 to 20 carbons. Moreover, in white skeletal muscle the role of glycolysis and concomitant muscle fibre adaptation was investigated. In one year old VLCAD(-/-) mice MCAD and LCAD play an important role in order to compensate deficiency of VLCAD especially in the heart and in the liver. However, the white gastrocnemius muscle develops alternative compensatory mechanism based on a different substrate selection and increased glucose oxidation. Finally, the application of an MCT diet over one year has no effects on LCAD or MCAD expression. MCT results in the VLCAD(-/-) mice only in a very modest improvement of medium-chain acyl-CoA oxidation capacity restricted to cardiac tissue. In conclusion, VLCAD(-/-) mice develop tissue-specific strategies to compensate deficiency of VLCAD either by induction of other mitochondrial acyl-CoA dehydrogenases or by enhancement of glucose oxidation. In the muscle, there is evidence of a muscle fibre type adaptation with a predominance of glycolytic muscle fibres. Dietary modification as represented by an MCT-diet does not improve these strategies long-term.
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Sela, M; Tirza, G; Ravid, O; Volovitz, I; Solodeev, I; Friedman, O; Zipori, D; Gur, E; Krelin, Y; Shani, N
2015-01-01
Mesenchymal stromal cells (MSCs) are multipotent and can be derived from different adult tissues including fat. Our repeated attempts to produce long-term proliferative cultures of rat abdominal adipose stem cells (aASCs) under normal oxygen concentration (21%) were unsuccessful. We set to examine the events controlling this cytostasis of aASCs and found that it resulted from overproduction of reactive oxygen species (ROS) that led to apoptosis. ROS overproduction in aASCs was accompanied by increased expression of NOX1 but not of NOX2 or NOX4. NOX family members are an important source of intracellular ROS pointing to NOX1 involvement in ROS accumulation. This was verified when aASCs that were grown under 3% oxygen conditions expanded long term, displaying reduced NOX1 expression and decreased ROS accumulation. NOX1 involvement in aASC cytostasis was reaffirmed when cells that were expanded under normoxic conditions in the presence of a specific NOX1 inhibitor, ML171, demonstrated reduced ROS accumulation, reduced apoptosis and long-term expansion. aASC expansion arrest was accompanied also by a weak fat differentiation and migratory potential, which was enhanced by NOX1 inhibition. This suggests an inhibitory role for NOX1-induced ROS overproduction on aASCs, their fat differentiation and migratory potential. In contrast to aASCs, similar cells produced from subcutaneous fat were easily expanded in normoxic cultures, exhibiting low ROS concentrations, a low number of apoptotic cells and improved fat differentiation and migration. Taken together, our results show, for the first time, that NOX1-induced ROS accumulation halts ASC expansion and reduces their differentiation and migratory potential under normoxic conditions. Importantly, this phenotype comprises a tissue-specific signature as it was evident in aASCs but not in subcutaneous ASCs. NOX-induced ROS accumulation and cytokine production by fat are part of the metabolic syndrome. The similarity of this phenomenon to aASC phenotype may indicate that they arise from similar molecular mechanisms. PMID:25880095
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Identification of repaglinide as a therapeutic drug for glioblastoma multiforme.
Xiao, Zui Xuan; Chen, Ruo Qiao; Hu, Dian Xing; Xie, Xiao Qiang; Yu, Shang Bin; Chen, Xiao Qian
2017-06-17
Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the gene expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients. Copyright © 2017. Published by Elsevier Inc.
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Pavelitz, Thomas; Renfro, Lindsay; Foster, Nathan R; Caracol, Amber; Welsch, Piri; Lao, Victoria Valinluck; Grady, William B; Niedzwiecki, Donna; Saltz, Leonard B; Bertagnolli, Monica M; Goldberg, Richard M; Rabinovitch, Peter S; Emond, Mary; Monnat, Raymond J; Maizels, Nancy
2014-01-01
Colon cancers deficient in mismatch repair (MMR) may exhibit diminished expression of the DNA repair gene, MRE11, as a consequence of contraction of a T11 mononucleotide tract. This study investigated MRE11 status and its association with prognosis, survival and drug response in patients with stage III colon cancer. Cancer and Leukemia Group B 89803 (Alliance) randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly adjuvant bolus 5-fluorouracil/leucovorin (FU/LV) or irinotecan+FU/LV (IFL), with 8 year follow-up. Tumors from these patients were analyzed to determine stability of a T11 tract in the MRE11 gene. The primary endpoint was overall survival (OS), and a secondary endpoint was disease-free survival (DFS). Non-proportional hazards were addressed using time-dependent covariates in Cox analyses. Of 625 tumor cases examined, 70 (11.2%) exhibited contraction at the T11 tract in one or both MRE11 alleles and were thus predicted to be deficient in MRE11 (dMRE11). In pooled treatment analyses, dMRE11 patients showed initially reduced DFS and OS but improved long-term DFS and OS compared with patients with an intact MRE11 T11 tract. In the subgroup of dMRE11 patients treated with IFL, an unexplained early increase in mortality but better long-term DFS than IFL-treated pMRE11 patients was observed. Analysis of this relatively small number of patients and events showed that the dMRE11 marker predicts better prognosis independent of treatment in the long-term. In subgroup analyses, dMRE11 patients treated with irinotecan exhibited unexplained short-term mortality. MRE11 status is readily assayed and may therefore prove to be a useful prognostic marker, provided that the results reported here for a relatively small number of patients can be generalized in independent analyses of larger numbers of samples. ClinicalTrials.gov NCT00003835.
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Pavelitz, Thomas; Renfro, Lindsay; Foster, Nathan R.; Caracol, Amber; Welsch, Piri; Lao, Victoria Valinluck; Grady, William B.; Niedzwiecki, Donna; Saltz, Leonard B.; Bertagnolli, Monica M.; Goldberg, Richard M.; Rabinovitch, Peter S.; Emond, Mary; Monnat, Raymond J.; Maizels, Nancy
2014-01-01
Purpose Colon cancers deficient in mismatch repair (MMR) may exhibit diminished expression of the DNA repair gene, MRE11, as a consequence of contraction of a T11 mononucleotide tract. This study investigated MRE11 status and its association with prognosis, survival and drug response in patients with stage III colon cancer. Patients and Methods Cancer and Leukemia Group B 89803 (Alliance) randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly adjuvant bolus 5-fluorouracil/leucovorin (FU/LV) or irinotecan+FU/LV (IFL), with 8 year follow-up. Tumors from these patients were analyzed to determine stability of a T11 tract in the MRE11 gene. The primary endpoint was overall survival (OS), and a secondary endpoint was disease-free survival (DFS). Non-proportional hazards were addressed using time-dependent covariates in Cox analyses. Results Of 625 tumor cases examined, 70 (11.2%) exhibited contraction at the T11 tract in one or both MRE11 alleles and were thus predicted to be deficient in MRE11 (dMRE11). In pooled treatment analyses, dMRE11 patients showed initially reduced DFS and OS but improved long-term DFS and OS compared with patients with an intact MRE11 T11 tract. In the subgroup of dMRE11 patients treated with IFL, an unexplained early increase in mortality but better long-term DFS than IFL-treated pMRE11 patients was observed. Conclusions Analysis of this relatively small number of patients and events showed that the dMRE11 marker predicts better prognosis independent of treatment in the long-term. In subgroup analyses, dMRE11 patients treated with irinotecan exhibited unexplained short-term mortality. MRE11 status is readily assayed and may therefore prove to be a useful prognostic marker, provided that the results reported here for a relatively small number of patients can be generalized in independent analyses of larger numbers of samples. Trial Registration ClinicalTrials.gov NCT00003835 PMID:25310185
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Cancer survival classification using integrated data sets and intermediate information.
Kim, Shinuk; Park, Taesung; Kon, Mark
2014-09-01
Although numerous studies related to cancer survival have been published, increasing the prediction accuracy of survival classes still remains a challenge. Integration of different data sets, such as microRNA (miRNA) and mRNA, might increase the accuracy of survival class prediction. Therefore, we suggested a machine learning (ML) approach to integrate different data sets, and developed a novel method based on feature selection with Cox proportional hazard regression model (FSCOX) to improve the prediction of cancer survival time. FSCOX provides us with intermediate survival information, which is usually discarded when separating survival into 2 groups (short- and long-term), and allows us to perform survival analysis. We used an ML-based protocol for feature selection, integrating information from miRNA and mRNA expression profiles at the feature level. To predict survival phenotypes, we used the following classifiers, first, existing ML methods, support vector machine (SVM) and random forest (RF), second, a new median-based classifier using FSCOX (FSCOX_median), and third, an SVM classifier using FSCOX (FSCOX_SVM). We compared these methods using 3 types of cancer tissue data sets: (i) miRNA expression, (ii) mRNA expression, and (iii) combined miRNA and mRNA expression. The latter data set included features selected either from the combined miRNA/mRNA profile or independently from miRNAs and mRNAs profiles (IFS). In the ovarian data set, the accuracy of survival classification using the combined miRNA/mRNA profiles with IFS was 75% using RF, 86.36% using SVM, 84.09% using FSCOX_median, and 88.64% using FSCOX_SVM with a balanced 22 short-term and 22 long-term survivor data set. These accuracies are higher than those using miRNA alone (70.45%, RF; 75%, SVM; 75%, FSCOX_median; and 75%, FSCOX_SVM) or mRNA alone (65.91%, RF; 63.64%, SVM; 72.73%, FSCOX_median; and 70.45%, FSCOX_SVM). Similarly in the glioblastoma multiforme data, the accuracy of miRNA/mRNA using IFS was 75.51% (RF), 87.76% (SVM) 85.71% (FSCOX_median), 85.71% (FSCOX_SVM). These results are higher than the results of using miRNA expression and mRNA expression alone. In addition we predict 16 hsa-miR-23b and hsa-miR-27b target genes in ovarian cancer data sets, obtained by SVM-based feature selection through integration of sequence information and gene expression profiles. Among the approaches used, the integrated miRNA and mRNA data set yielded better results than the individual data sets. The best performance was achieved using the FSCOX_SVM method with independent feature selection, which uses intermediate survival information between short-term and long-term survival time and the combination of the 2 different data sets. The results obtained using the combined data set suggest that there are some strong interactions between miRNA and mRNA features that are not detectable in the individual analyses. Copyright © 2014 Elsevier B.V. All rights reserved.
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Kinetin improves IKBKAP mRNA splicing in patients with familial dysautonomia
Axelrod, Felicia B.; Liebes, Leonard; Gold-von Simson, Gabrielle; Mendoza, Sandra; Mull, James; Leyne, Maire; Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio; Slaugenhaupt, Susan A.
2011-01-01
Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-κ-B kinase complex associated protein/ elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase wild-type IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine if oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/day for 28 days. An increase in wild-type IKBKAP mRNA expression in leukocytes was noted after eight days in six of eight individuals; after 28 days the mean increase as compared to baseline was significant (p=0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients, but also that effect appears to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine if kinetin will prove therapeutic in FD patients. PMID:21775922
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Adverse event reporting in Czech long-term care facilities.
Hěib, Zdenřk; Vychytil, Pavel; Marx, David
2013-04-01
To describe adverse event reporting processes in long-term care facilities in the Czech Republic. Prospective cohort study involving a written questionnaire followed by in-person structured interviews with selected respondents. Long-term care facilities located in the Czech Republic. Staff of 111 long-term care facilities (87% of long-term care facilities in the Czech Republic). None. Sixty-three percent of long-term health-care facilities in the Czech Republic have adverse event-reporting processes already established, but these were frequently very immature programs sometimes consisting only of paper recording of incidents. Compared to questionnaire responses, in-person interview responses only partially tended to confirm the results of the written survey. Twenty-one facilities (33%) had at most 1 unconfirmed response, 31 facilities (49%) had 2 or 3 unconfirmed responses and the remaining 11 facilities (17%) had 4 or more unconfirmed responses. In-person interviews suggest that use of a written questionnaire to assess the adverse event-reporting process may have limited validity. Staff of the facilities we studied expressed an understanding of the importance of adverse event reporting and prevention, but interviews also suggested a lack of knowledge necessary for establishing a good institutional reporting system in long-term care.
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Expression of human PQBP-1 in Drosophila impairs long-term memory and induces abnormal courtship.
Yoshimura, Natsue; Horiuchi, Daisuke; Shibata, Masao; Saitoe, Minoru; Qi, Mei-Ling; Okazawa, Hitoshi
2006-04-17
Frame shift mutations of the polyglutamine binding protein-1 (PQBP1) gene lead to total or partial truncation of the C-terminal domain (CTD) and cause mental retardation in human patients. Interestingly, normal Drosophila homologue of PQBP-1 lacks CTD. As a model to analyze the molecular network of PQBP-1 affecting intelligence, we generated transgenic flies expressing human PQBP-1 with CTD. Pavlovian olfactory conditioning revealed that the transgenic flies showed disturbance of long-term memory. In addition, they showed abnormal courtship that male flies follow male flies. Abnormal functions of PQBP-1 or its binding partner might be linked to these symptoms.
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Lee, Jungnam; Roberts, JoAnn S.; Atanasova, Kalina R.; Chowdhury, Nityananda; Han, Kyudong; Yilmaz, Özlem
2017-01-01
Porphyromonas gingivalis is a host-adapted oral pathogen associated with chronic periodontitis that successfully survives and persists in the oral epithelium. Recent studies have positively correlated periodontitis with increased risk and severity of oral squamous cell carcinoma (OSCC). Intriguingly, the presence of P. gingivalis enhances tumorigenic properties independently of periodontitis and has therefore been proposed as a potential etiological agent for OSCC. However, the initial host molecular changes induced by P. gingivalis infection which promote predisposition to cancerous transformation through EMT (epithelial-mesenchymal-transition), has never been studied in human primary cells which more closely mimic the physiological state of cells in vivo. In this study, we examine for the first time in primary oral epithelial cells (OECs) the expression and activation of key EMT mediators during long-term P. gingivalis infection in vitro. We examined the inactive phosphorylated state of glycogen synthase kinase-3 beta (p-GSK3β) over 120 h P. gingivalis infection and found p-GSK3β, an important EMT regulator, significantly increases over the course of infection (p < 0.01). Furthermore, we examined the expression of EMT-associated transcription factors, Slug, Snail, and Zeb1 and found significant increases (p < 0.01) over long-term P. gingivalis infection in protein and mRNA expression. Additionally, the protein expression of mesenchymal intermediate filament, Vimentin, was substantially increased over 120 h of P. gingivalis infection. Analysis of adhesion molecule E-cadherin showed a significant decrease (p < 0.05) in expression and a loss of membrane localization along with β-catenin in OECs. Matrix metalloproteinases (MMPs) 2, 7, and 9 are all markedly increased with long-term P. gingivalis infection. Finally, migration of P. gingivalis infected cells was evaluated using scratch assay in which primary OEC monolayers were wounded and treated with proliferation inhibitor, Mitomycin C. The cellular movement was determined by microscopy. Results displayed P. gingivalis infection promoted cell migration which was slightly enhanced by co-infection with Fusobacterium nucleatum, another oral opportunistic pathogen. Therefore, this study demonstrates human primary OECs acquire initial molecular/cellular changes that are consistent with EMT induction during long-term infection by P. gingivalis and provides a critically novel framework for future mechanistic studies. PMID:29250491
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McClintick, Jeanette N; McBride, William J; Bell, Richard L; Ding, Zheng-Ming; Liu, Yunlong; Xuei, Xiaoling; Edenberg, Howard J
2018-05-01
Binge drinking of alcohol during adolescence is a serious public health concern with long-term consequences, including decreased hippocampal and prefrontal cortex volume and deficits in memory. We used RNA sequencing to assess the effects of adolescent binge drinking on gene expression in these regions. Male adolescent alcohol-preferring (P) rats were exposed to repeated binge drinking (three 1-h sessions/day during the dark/cycle, 5 days/week for 3 weeks starting at 28 days of age; ethanol intakes of 2.5-3 g/kg/session). Ethanol significantly altered the expression of 416 of 11,727 genes expressed in the ventral hippocampus. Genes and pathways involved in neurogenesis, long-term potentiation, and axonal guidance were decreased, which could relate to the impaired memory function found in subjects with adolescent alcohol binge-like exposure. The decreased expression of myelin and cholesterol genes and apparent decrease in oligodendrocytes in P rats could result in decreased myelination. In the medial prefrontal cortex, 638 of 11,579 genes were altered; genes in cellular stress and inflammatory pathways were increased, as were genes involved in oxidative phosphorylation. Overall, the results of this study suggest that adolescent binge-like alcohol drinking may alter the development of the ventral hippocampus and medial prefrontal cortex and produce long-term consequences on learning and memory, and on control of impulsive behaviors. Copyright © 2017 Elsevier Inc. All rights reserved.
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Fish passage through retrofitted culverts : final report.
DOT National Transportation Integrated Search
2004-11-01
Long term and short term studies of fish movement were conducted at several retrofitted culverts within Oregon. This was done to assess the effectiveness of retrofitting culverts with baffles to improve fish passage. The long term results showed that...
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Gilbert, Rebecca S; Nunez, Brandy; Sakurai, Kumi; Fielder, Thomas; Ni, Hsiao-Tzu
2016-03-24
Growing concerns about safety of ART on human gametes, embryos, clinical outcomes and long-term health of offspring require improved methods of risk assessment to provide functionally relevant assays for quality control testing and pre-clinical studies prior to clinical implementation. The one-cell mouse embryo assay (MEA) is the most widely used for development and quality testing of human ART products; however, concerns exist due to the insensitivity/variability of this bioassay which lacks standardization and involves subjective analysis by morphology alone rather than functional analysis of the developing embryos. We hypothesized that improvements to MEA by the use of functional molecular biomarkers could enhance sensitivity and improve detection of suboptimal materials/conditions. Fresh one-cell transgenic mouse embryos with green fluorescent protein (GFP) expression driven by Pou6f1 or Cdx2 control elements were harvested and cultured to blastocysts in varied test and control conditions to compare assessment by standard morphology alone versus the added dynamic expression of GFP for screening and selection of critical raw materials and detection of suboptimal culture conditions. Transgenic mouse embryos expressing functionally relevant biomarkers of normal early embryo development can be used to monitor the developmental impact of culture conditions. This novel approach provides a superior MEA that is more meaningful and sensitive for detection of embryotoxicity than morphological assessment alone.
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Andersen, Lars L; Clausen, Thomas; Persson, Roger; Holtermann, Andreas
2012-12-19
The prevalence of musculoskeletal pain is high among healthcare workers. Knowledge about risk factors at work is needed to efficiently target preventive strategies. This study estimates the prognosis for recovery from long-term musculoskeletal pain in different body regions among healthcare workers with different levels of perceived physical exertion during healthcare work. Prospective cohort study among 4,977 Danish female healthcare workers responding to a baseline and follow-up questionnaire in 2005 and 2006, respectively. We defined long-term pain, short-term pain and pain-free as > 30, 1-30 and 0 days with pain during the last year, and included in the analyses only those with long-term pain at baseline in the low back (N=1,089), neck/shoulder (N=1,400) and knees (N = 579), respectively. Using cumulative logistic regression analysis, the prognosis for recovering from long-term pain at baseline to short-term pain or pain-free at follow-up in the respective body regions when experiencing moderate or light (reference: strenuous) physical exertion during healthcare work was modeled. Among those with long-term pain at baseline 34% (low back), 29% (neck/shoulders), and 29% (knees) recovered to short-term pain at follow-up and 7% (low back), 8% (neck/shoulders), and 17% (knees) recovered to being pain-free. After adjusting for potential confounders (age, BMI, tenure, smoking status, leisure physical activity and psychosocial work conditions), light perceived physical exertion during healthcare work was associated with improved prognosis for recovery from long-term pain in the low back (OR 1.42, 95% CI 1.01 - 1.99) and neck/shoulders (OR 1.89, 95% CI 1.43 - 2.50), but not in the knees. Moderate physical exertion was not associated with improved prognosis for recovery from long-term pain for any of the body regions. In the present study, healthcare workers with light perceived physical exertion during healthcare work had the best prognosis for recovery from long-term pain in the low back and neck/shoulders. This suggests that efforts to reduce perceived exertion during work may improve recovery from chronic pain.
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Rebouças, Elce C C; Leal, Sandra; Silva, Susana M; Sá, Susana I
2016-11-01
Ethanol is a macronutrient whose intake is a form of ingestive behavior, sharing physiological mechanisms with food intake. Chronic ethanol consumption is detrimental to the brain, inducing gender-dependent neuronal damage. The hypothalamic arcuate nucleus (ARN) is a modulator of food intake that expresses feeding-regulatory neuropeptides, such as alpha melanocyte-stimulating hormone (α-MSH) and neuropeptide Y (NPY). Despite its involvement in pathways associated with eating disorders and ethanol abuse, the impact of ethanol consumption and withdrawal in the ARN structure and neurochemistry in females is unknown. We used female rat models of 20% ethanol consumption for six months and of subsequent ethanol withdrawal for two months. Food intake and body weights were measured. ARN morphology was stereologically analyzed to estimate its volume, total number of neurons and total number of neurons expressing NPY, α-MSH, tyrosine hydroxylase (TH) and estrogen receptor alpha (ERα). Ethanol decreased energy intake and body weights. However, it did not change the ARN morphology or the expression of NPY, α-MSH and TH, while increasing ERα expression. Withdrawal induced a significant volume and neuron loss that was accompanied by an increase in NPY expression without affecting α-MSH and TH expression. These findings indicate that the female ARN is more vulnerable to withdrawal than to excess alcohol. The data also support the hypothesis that the same pathways that regulate the expression of NPY and α-MSH in long-term ethanol intake may regulate food intake. The present model of long-term ethanol intake and withdrawal induces new physiological conditions with adaptive responses. Copyright © 2016 Elsevier B.V. All rights reserved.
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ERIC Educational Resources Information Center
McNulty, Susan E.; Barrett, Ruth M.; Vogel-Ciernia, Annie; Malvaez, Melissa; Hernandez, Nicole; Davatolhagh, M. Felicia; Matheos, Dina P.; Schiffman, Aaron; Wood, Marcelo A.
2012-01-01
"Nr4a1" and "Nr4a2" are transcription factors and immediate early genes belonging to the nuclear receptor Nr4a family. In this study, we examine their role in long-term memory formation for object location and object recognition. Using siRNA to block expression of either "Nr4a1" or "Nr4a2", we found that "Nr4a2" is necessary for both long-term…
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Calvo-Rodríguez, María; de la Fuente, Carmen; García-Durillo, Mónica; García-Rodríguez, Carmen; Villalobos, Carlos; Núñez, Lucía
2017-01-31
Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors of the innate immune system recognizing diverse pathogen-derived and tissue damage-related ligands. It has been suggested that TLR signaling contributes to the pathogenesis of age-related, neurodegenerative diseases, including Alzheimer's disease (AD). AD is associated to oligomers of the amyloid β peptide (Aβo) that cause intracellular Ca 2+ dishomeostasis and neuron cell death in rat hippocampal neurons. Here we assessed the interplay between inflammation and Aβo in long-term cultures of rat hippocampal neurons, an in vitro model of neuron aging and/or senescence. Ca 2+ imaging and immunofluorescence against annexin V and TLR4 were applied in short- and long-term cultures of rat hippocampal neurons to test the effects of TLR4-agonist LPS and Aβo on cytosolic [Ca 2+ ] and on apoptosis as well as on expression of TLR4. LPS increases cytosolic [Ca 2+ ] and promotes apoptosis in rat hippocampal neurons in long-term culture considered aged and/or senescent neurons, but not in short-term cultured neurons considered young neurons. TLR4 antagonist CAY10614 prevents both effects. TLR4 expression in rat hippocampal neurons is significantly larger in aged hippocampal cultures. Treatment of aged hippocampal cultures with Aβo increases TLR4 expression and enhances LPS-induced Ca 2+ responses and neuron cell death. Aging and amyloid β oligomers, the neurotoxin involved in Alzheimer's disease, enhance TLR4 expression as well as LPS-induced Ca 2+ responses and neuron cell death in rat hippocampal neurons aged in vitro.
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Trojan, Karina; Unterrainer, Christian; Aly, Mostafa; Zhu, Li; Weimer, Rolf; Bulut, Nuray; Morath, Christian; Opelz, Gerhard; Daniel, Volker
2016-10-29
Treg are a heterogenous cell population. In the present study we attempted to identify Treg subsets that might contribute to stable and good long-term graft function. Lymphocyte and Treg subsets were studied in 136 kidney transplant recipients with good long-term graft function and in 52 healthy control individuals using eight-color-fluorescence flow cytometry. Foxp3 TSDR methylation status was investigated in enriched IFNy+ and IFNy- Treg preparations using high resolution melt analysis. Compared with healthy controls, patients showed strong associations of IFNy secreting Helios+ and Helios- Treg with Treg that co-expressed perforin and/or CTLA4 (CD152; p<0.01). Moreover they showed associations of IFNy-Helios+ Treg with Treg that produced TGFβ and/or perforin and of IFNy-Helios- Treg with TGFβ production (all p<0.01). Only in patients, but not in healthy controls, were IFNy- Helios+ and Helios- Treg associated with higher CD45+, CD3+, (CD4+), CD19+ lymphocyte counts (p<0.001). In addition IFNy-Helios+ Treg were associated with CD16+56+ lymphocytes (p<0.001). Enriched IFNy- Treg from female but not male patients showed an association of Foxp3 methylation with higher total Treg and higher Helios+IFNy-, CXCR3+Lselectin+ (CD183+CD62L+), CXCR3-Lselectin+ and CD28+HLADR+ Treg subsets (p<0.01). Enriched IFNy+ Treg from male patients showed an association of demethylated Foxp3 with total Treg and IL10-TFGβ+ Treg counts, and in enriched IFNy- Treg an association of methylated Foxp3 with APO1/FasR+FasL+ (CD95+CD178+) Treg (p<0.01). Kidney recipients with good long-term graft function possess IFNy+ and IFNy- Treg with stable and unstable Foxp3 expression in the blood. They co-express CD28, HLADR, CTLA4, CXCR3, Lselectin, TGFβ, perforin and FasL and might contribute to the establishment and maintenance of good long-term graft function. Copyright © 2016. Published by Elsevier B.V.
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Arnold, L. Eugene; Hodgkins, Paul; Caci, Hervé; Kahle, Jennifer; Young, Susan
2015-01-01
Background Evaluation of treatments for attention-deficit/hyperactivity disorder (ADHD) previously focused on symptom control, but attention has shifted to functional outcomes. The effect of different ADHD treatment periods and modalities (pharmacological, non-pharmacological, and combination) on long-term outcomes needs to be more comprehensively understood. Methods A systematic search of 12 literature databases using Cochrane’s guidelines yielded 403 English-language peer-reviewed, primary studies reporting long-term outcomes (≥2 years). We evaluated relative effects of treatment modalities and durations and effect sizes of outcomes reported as statistically significantly improved with treatment. Results The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes. A majority of outcomes improved regardless of age of treatment initiation (60%–75%) or treatment duration (62%–72%). Studies with short treatment duration had shorter follow-up times (mean 3.2 years total study length) than those with longer treatment durations (mean 7.1 years total study length). Studies with follow-up times <3 years reported benefit with treatment for 93% of outcomes, whereas those with follow-up times ≥3 years reported treatment benefit for 57% of outcomes. Post-hoc analysis indicated that this result was related to the measurement of outcomes at longer periods (3.2 versus 0.4 years) after treatment cessation in studies with longer total study length. Conclusions While the majority of long-term outcomes of ADHD improve with all treatment modalities, the combination of pharmacological and non-pharmacological treatment was most consistently associated with improved long-term outcomes and large effect sizes. Older treatment initiation age or longer durations did not markedly affect proportion of improved outcomes reported, but measurement of outcomes long periods after treatment cessation may attenuate results. PMID:25714373
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Chen, Ying-Hua; Yuan, Li; Chen, Yuan-Yuan; Qi, Cui-Juan
2008-03-01
To observe the relationship between liver steatosis in rats with long-term high-caloric and high-fat diet and the expression of angiotensinogen (AGT), uncoupling protein 2 (UCP-2) and transforming growth factor beta1 (TGFbeta1). Then angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) drugs were given to investigate whether rennin-angiotensin system (RAS) blockade can mitigate the liver steatosis and to probe its mechanisms. Forty male Wistar rats were divided into normal control group (NC group, n = 10), high-calorie and high-fat fed group (HF group, n = 10), ARB treated group (AR group, n = 10) and ACEI treated group (AE group, n = 10). Rats were fed with high-calorie and high-fat diet and given RAS inhibitor drugs (valsartan 40 mg/kg to the AR group and perindopril 4 mg/kg to the AE group) for eight weeks. Serum TG, free fatty acids (FFAs) lever and the fat content in liver were then measured with biochemical tests; insulin resistance was evaluated with euglycemic hyperinsulinemia clamp technique, the expression of UCP-2 and TGFbeta1 in liver tissue were examined with immunohistochemical staining and AGT mRNA, UCP-2 mRNA and TGFbeta1 mRNA were tested with RT-PCR. With the administration of RAS inhibitor drugs, following changes were observed. The levels of TG and FFAs and the fat content in liver decreased (P < 0.01 or P < 0.05), insulin resistance in high-fat fed rats was improved (P < 0.05), liver steatosis, inflammation and fibrosis were mitigated. The levels of UCP-2 decreased by 36.5% (P < 0.05) in AE group and 42.5% (P < 0.05) in AR group and TGFbeta1 decreased by 37% (P < 0.05) in AE group and 41.6% (P < 0.05) in AR group as compared with the HF group with immunohistochemical staining. The expression of AGTmRNA decreased by 14.9% (P < 0.05) in AE group and 21% (P < 0 .05) in AR group, UCP-2 mRNA decreased by 9% (P < 0.05) in AE group and 11% (P < 0.05) in AR group and TGFbeta1 mRNA decreased by 17% (P < 0.05) in AE group and 19% (P < 0.05) in AR group as compared with the HF group with RT-PCR. RAS blockade could improve insulin resistance, mitigate the liver injury of long term high-fat fed rats and have a protective effect on liver. The mechanism may be associated with the effects of improved insulin resistance, the interaction within RAS and the down-regulation of UCP-2 and TGFbeta1 in liver tissue.
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Musekamp, Gunda; Schuler, Michael; Seekatz, Bettina; Bengel, Jürgen; Faller, Hermann; Meng, Karin
2017-02-15
Heart failure (HF) patient education aims to foster patients' self-management skills. These are assumed to bring about, in turn, improvements in distal outcomes such as quality of life. The purpose of this study was to test the hypothesis that change in self-reported self-management skills observed after participation in self-management education predicts changes in physical and mental quality of life and depressive symptoms up to one year thereafter. The sample comprised 342 patients with chronic heart failure, treated in inpatient rehabilitation clinics, who received a heart failure self-management education program. Latent change modelling was used to analyze relationships between both short-term (during inpatient rehabilitation) and intermediate-term (after six months) changes in self-reported self-management skills and both intermediate-term and long-term (after twelve months) changes in physical and mental quality of life and depressive symptoms. Short-term changes in self-reported self-management skills predicted intermediate-term changes in mental quality of life and long-term changes in physical quality of life. Intermediate-term changes in self-reported self-management skills predicted long-term changes in all outcomes. These findings support the assumption that improvements in self-management skills may foster improvements in distal outcomes.
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ERIC Educational Resources Information Center
Gelinas, Jennifer N.; Tenorio, Gustavo; Lemon, Neal; Abel, Ted; Nguyen, Peter V.
2008-01-01
Activation of Beta-adrenergic receptors (Beta-ARs) enhances hippocampal memory consolidation and long-term potentiation (LTP), a likely mechanism for memory storage. One signaling pathway linked to Beta-AR activation is the cAMP-PKA pathway. PKA is critical for the consolidation of hippocampal long-term memory and for the expression of some forms…
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ERIC Educational Resources Information Center
Wang, Yan; Zhang, Ming; Moon, Changjong; Hu, Qubai; Wang, Baiping; Martin, George; Sun, Zhongsheng; Wang, Hongbing
2009-01-01
FE65 is expressed predominantly in the brain and interacts with the C-terminal domain of [beta]-amyloid precursor protein (APP). We examined hippocampus-dependent memory and in vivo long-term potentiation (LTP) at the CA1 synapses with isoform-specific FE65 knockout (p97FE65[superscript -/-]) mice. When examined using the Morris water maze,…
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ERIC Educational Resources Information Center
Bhattacharya, Sriya; Mukherjee, Bandhan; Doré, Jules J. E.; Yuan, Qi; Harley, Carolyn W.; McLean, John H.
2017-01-01
Histone deacetylase (HDAC) plays a role in synaptic plasticity and long-term memory formation. We hypothesized that trichostatin-A (TSA), an HDAC inhibitor, would promote long-term odor preference memory and maintain enhanced GluA1 receptor levels that have been hypothesized to support memory. We used an early odor preference learning model in…
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NASA Astrophysics Data System (ADS)
Pan, Zhiyuan; Liu, Li
2018-02-01
In this paper, we extend the GARCH-MIDAS model proposed by Engle et al. (2013) to account for the leverage effect in short-term and long-term volatility components. Our in-sample evidence suggests that both short-term and long-term negative returns can cause higher future volatility than positive returns. Out-of-sample results show that the predictive ability of GARCH-MIDAS is significantly improved after taking the leverage effect into account. The leverage effect for short-term volatility component plays more important role than the leverage effect for long-term volatility component in affecting out-of-sample forecasting performance.
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Hou, Jue; Zhang, Qicheng; Liu, Zheng; Wang, Shuhui; Li, Dan; Liu, Chang; Liu, Ying; Shao, Yiming
2016-01-01
Previous research has shown that host Cyclophilin A (CyPA) can promote dendritic cell maturation and the subsequent innate immune response when incorporated into an HIV-1 Gag protein to circumvent the resistance of dendritic cells to HIV-1 infection. This led us to hypothesize that CyPA may improve HIV-1 Gag-specific vaccine immunogenicity via binding with Gag antigen. The adjuvant effect of CyPA was evaluated using a DNA vaccine with single or dual expression cassettes. Mouse studies indicated that CyPA specifically and markedly promoted HIV-1 Gag-specific cellular immunity but not an HIV-1 Env-specific cellular response. The Gag/CyPA dual expression cassettes stimulated a greater Gag-specific cellular immune response, than Gag immunization alone. Furthermore, CyPA induced a broad Gag-specific T cell response and strong cellular immunity that lasted up to 5 months. In addition, CyPA skewed to cellular rather than humoral immunity. To investigate the mechanisms of the adjuvant effect, site-directed mutagenesis in CyPA, including active site residues H54Q and F60A resulted in mutants that were co-expressed with Gag in dual cassettes. The immune response to this vaccine was analyzed in vivo. Interestingly, the wild type CyPA markedly increased Gag cellular immunity, but the H54Q and F60A mutants drastically reduced CyPA adjuvant activation. Therefore, we suggest that the adjuvant effect of CyPA was based on Gag-CyPA-specific interactions. Herein, we report that Cyclophilin A can augment HIV-1 Gag-specific cellular immunity as a genetic adjuvant in multiplex DNA immunization strategies, and that activity of this adjuvant is specific, broad, long-term, and based on Gag-CyPA interaction.
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Croffie, Joseph M; Ammar, M Samer; Pfefferkorn, Marian D; Horn, Debra; Klipsch, Ann; Fitzgerald, Joseph F; Gupta, Sandeep K; Molleston, Jean P; Corkins, Mark R
2005-01-01
The purpose of this study was to determine whether biofeedback benefits children with dyssynergic defecation and constipation/encopresis, and whether home biofeedback improves long-term outcomes. Thirty-six patients with chronic constipation who had failed at least 6 months of conventional treatment and demonstrated dyssynergic defecation at anorectal manometry were randomized to biofeedback in the laboratory alone (group 1, n=24) or in the laboratory and at home (group 2, n=12) and followed up at 2, 4, and a mean of 44 months. Thirty patients were available for long-term follow-up. Bowel movements increased in all from a mean of 1.4/week to 5.1, 5.8, and 5.1 per week at 2 months, 4 months, and long-term, respectively (p < or = 0.001). Soiling decreased in all from a mean of 5.5/week to 0.6, 0.1, and 1 per week at 2 months, 4 months, and long-term, respectively (p < or = 0.001). Laxative use decreased from a mean of 4.1 days/week to 0.6, 0.3, and 0.7 per week at 2 months, 4 months, and long-term, respectively (p < or = 0.001). Twenty-seven of 30 parents ranked their satisfaction a mean of 2.2 (range 1-excellent to 3-good). There were no significant differences in outcomes between the laboratory alone group and the laboratory plus home group. Biofeedback is beneficial for some children with chronic constipation and dyssynergic defecation. Supplemental home biofeedback does not improve long-term outcomes.
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The Lyman-α power spectrum—CMB lensing convergence cross-correlation
Chiang, Chi-Ting; Slosar, Anže
2018-01-11
We investigate the three-point correlation between the Lyman-α forest and the CMB weak lensing (δ Fδ FΚ) expressed as the cross-correlation between the CMB weak lensing field and local variations in the forest power spectrum. In addition to the standard gravitational bispectrum term, we note the existence of a non-standard systematic term coming from mis-estimation of the mean flux over the finite length of Lyman-α skewers. We numerically calculate the angular cross-power spectrum and discuss its features. We integrate it into zero-lag correlation function and compare our predictions with recent results by Doux et al.. We nd that our predictionsmore » are statistically consistent with the measurement, and including the systematic term improves the agreement with the measurement. We comment on the implication of the response of the Lyman-α forest power spectrum to the long-wavelength density perturbations.« less
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The Lyman-α power spectrum—CMB lensing convergence cross-correlation
DOE Office of Scientific and Technical Information (OSTI.GOV)
Chiang, Chi-Ting; Slosar, Anže
We investigate the three-point correlation between the Lyman-α forest and the CMB weak lensing (δ Fδ FΚ) expressed as the cross-correlation between the CMB weak lensing field and local variations in the forest power spectrum. In addition to the standard gravitational bispectrum term, we note the existence of a non-standard systematic term coming from mis-estimation of the mean flux over the finite length of Lyman-α skewers. We numerically calculate the angular cross-power spectrum and discuss its features. We integrate it into zero-lag correlation function and compare our predictions with recent results by Doux et al.. We nd that our predictionsmore » are statistically consistent with the measurement, and including the systematic term improves the agreement with the measurement. We comment on the implication of the response of the Lyman-α forest power spectrum to the long-wavelength density perturbations.« less
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Schranz, Christian; Kruse, Annika; Kraus, Tanja; Steinwender, Gerhardt; Svehlik, Martin
2017-02-01
Single event multilevel surgery (SEMLS) has become a standard intervention for children with cerebral palsy (CP). SEMLS proved to improve the gait in bilateral spastic cerebral palsy and those improvements can be maintained in the long term. However there is no evidence on the long-term outcome of unilateral SEMLS in children with unilateral spastic cerebral palsy. The gait analyses and clinical data of 14 children (9 male/5 female, mean age 12.1) with unilateral CP (6 children Gross Motor Function Classification System Scale level I and 8 children level II) were retrospectively reviewed at four time-points: preoperatively, 1year, 3-5 years and approximately 10 years after unilateral SEMLS. The Gait Profile Score (GPS) of the affected leg was used as a main and the number of fine tuning procedures as well as complications rate (Clavien-Dindo classification) as secondary outcome measures. The gait improved postoperatively and the GPS of the affected leg significantly declined by 3.73° which is well above the minimal clinical important difference of 1.6°. No deterioration of GPS occurred throughout the follow-up period. Therefore the postoperative improvement was maintained long-term. However, additional fine-tuning procedures had to be performed during the follow-up in 5 children and three complications occurred (one level II and two level III). The results indicate that children with unilateral cerebral palsy benefit from unilateral SEMLS and maintain gait improvements long-term. Copyright © 2016 Elsevier B.V. All rights reserved.
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Kim, Jiyeon; Seandel, Marco; Falciatori, Ilaria; Wen, Duancheng; Rafii, Shahin
2010-01-01
Stem cells reside in specialized microenvironments created by supporting stromal cells that orchestrate self-renewal and lineage-specific differentiation. However, the precise identity of the cellular and molecular pathways that support self-renewal of stem cells is not known. For example, long-term culture of prototypical stem cells, such as adult spermatogonial stem and progenitor cells (SPCs), in vitro has been impeded by the lack of an optimal stromal cell line that initiates and sustains proliferation of these cells. Indeed, current methods, including the use of mouse embryonic fibroblasts (MEFs), have not been efficient and have generally led to inconsistent results. Here, we report the establishment of a novel CD34-positive cell line, referred to as JK1, derived from mouse testicular stromal cells that not only facilitated long-term SPC culture but also allowed faithful generation of SPCs and multipotent stem cells. SPCs generated on JK1 maintained key features of germ line stem cells, including expression of PLZF, DAZL, and GCNA. Furthermore, these feeders also promoted the long-term cultivation of other types of primitive cells including multi-potent adult spermatogonial-derived stem cells, pluripotent murine embryonic stem cells, and embryonic germ cells derived from primordial germ cells. Stem cells could be passaged serially and still maintained expression of characteristic markers such as OCT4 and NANOG in vitro, as well as the ability to generate all three germ layers in vivo. These results indicate that the JK1 cell line is capable of promoting long-term culture of primitive cells. As such, this cell line allows for identification of stromal-derived factors that support long-term proliferation of various types of stem cells and constitutes a convenient alternative to other types of feeder layers. PMID:18669907
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Bruining, Hilgo; Matsui, Asuka; Oguro-Ando, Asami; Kahn, René S; Van't Spijker, Heleen M; Akkermans, Guus; Stiedl, Oliver; van Engeland, Herman; Koopmans, Bastijn; van Lith, Hein A; Oppelaar, Hugo; Tieland, Liselotte; Nonkes, Lourens J; Yagi, Takeshi; Kaneko, Ryosuke; Burbach, J Peter H; Yamamoto, Nobuhiko; Kas, Martien J
2015-10-01
Quantitative genetic analysis of basic mouse behaviors is a powerful tool to identify novel genetic phenotypes contributing to neurobehavioral disorders. Here, we analyzed genetic contributions to single-trial, long-term social and nonsocial recognition and subsequently studied the functional impact of an identified candidate gene on behavioral development. Genetic mapping of single-trial social recognition was performed in chromosome substitution strains, a sophisticated tool for detecting quantitative trait loci (QTL) of complex traits. Follow-up occurred by generating and testing knockout (KO) mice of a selected QTL candidate gene. Functional characterization of these mice was performed through behavioral and neurological assessments across developmental stages and analyses of gene expression and brain morphology. Chromosome substitution strain 14 mapping studies revealed an overlapping QTL related to long-term social and object recognition harboring Pcdh9, a cell-adhesion gene previously associated with autism spectrum disorder. Specific long-term social and object recognition deficits were confirmed in homozygous (KO) Pcdh9-deficient mice, while heterozygous mice only showed long-term social recognition impairment. The recognition deficits in KO mice were not associated with alterations in perception, multi-trial discrimination learning, sociability, behavioral flexibility, or fear memory. Rather, KO mice showed additional impairments in sensorimotor development reflected by early touch-evoked biting, rotarod performance, and sensory gating deficits. This profile emerged with structural changes in deep layers of sensory cortices, where Pcdh9 is selectively expressed. This behavior-to-gene study implicates Pcdh9 in cognitive functions required for long-term social and nonsocial recognition. This role is supported by the involvement of Pcdh9 in sensory cortex development and sensorimotor phenotypes. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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Faleiros, Rogério O; Garçon, Daniela P; Lucena, Malson N; McNamara, John C; Leone, Francisco A
2018-06-19
The evolutionary history of the Crustacea reveals ample adaptive radiation and the subsequent occupation of many osmotic niches resulting from physiological plasticity in their osmoregulatory mechanisms. We evaluate osmoregulatory ability in the intertidal, thinstripe hermit crab Clibanarius symmetricus after short-term exposure (6 h) or long-term acclimation (10 days) to a wide salinity range, also analyzing kinetic behavior and α-subunit mRNA expression of the gill (Na + , K + )-ATPase. The crab strongly hyper-regulates its hemolymph at 5 and 15‰S (Salinity, g L -1 ) but weakly hyper-regulates up to ≈27‰S. After 6 h exposure to 35‰S and 45‰S, C. symmetricus slightly hypo-regulates its hemolymph, becoming isosmotic after 10 days acclimation to these salinities. (Na + , K + )-ATPase specific activity decreases with increasing salinity for both exposure periods, reflecting physiological adjustment to isosmoticity. At low salinities, the gill enzyme exhibits a single, low affinity ATP binding site. However, at elevated salinities, a second, high affinity, ATP binding site appears, independently of exposure time. (Na + , K + )-ATPase α-subunit mRNA expression increases only after 10 days acclimation to 5‰S. Our findings suggest that hemolymph hyper-regulation is effected by alterations in enzyme activity during short-term exposure, but is sustained by increased mRNA expression during long-term acclimation. The decrease in gill (Na + , K + )-ATPase activity seen as a consequence of increasing salinity appears to underlie biochemical adjustments to hemolymph isosmoticity as hypo-regulatory ability diminishes. Copyright © 2018. Published by Elsevier Inc.
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DOT National Transportation Integrated Search
2017-02-01
Estimation of potential long-term down-cutting of the stream bed is necessary for evaluation and design of bridges for scour and culverts for fish passage. The purpose of this study has been to improve predictions of this potential long-term bed degr...
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A new image for long-term care.
Wager, Richard; Creelman, William
2004-04-01
To counter widely held negative images of long-term care, managers in the industry should implement quality-improvement initiatives that include six key strategies: Manage the expectations of residents and their families. Address customers' concerns early. Build long-term customer satisfaction. Allocate resources to achieve exceptional outcomes in key areas. Respond to adverse events with compassion. Reinforce the facility's credibility.
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Living biointerfaces based on non-pathogenic bacteria support stem cell differentiation
NASA Astrophysics Data System (ADS)
Hay, Jake J.; Rodrigo-Navarro, Aleixandre; Hassi, Karoliina; Moulisova, Vladimira; Dalby, Matthew J.; Salmeron-Sanchez, Manuel
2016-02-01
Lactococcus lactis, a non-pathogenic bacteria, has been genetically engineered to express the III7-10 fragment of human fibronectin as a membrane protein. The engineered L. lactis is able to develop biofilms on different surfaces (such as glass and synthetic polymers) and serves as a long-term substrate for mammalian cell culture, specifically human mesenchymal stem cells (hMSC). This system constitutes a living interface between biomaterials and stem cells. The engineered biofilms remain stable and viable for up to 28 days while the expressed fibronectin fragment induces hMSC adhesion. We have optimised conditions to allow long-term mammalian cell culture, and found that the biofilm is functionally equivalent to a fibronectin-coated surface in terms of osteoblastic differentiation using bone morphogenetic protein 2 (BMP-2) added to the medium. This living bacteria interface holds promise as a dynamic substrate for stem cell differentiation that can be further engineered to express other biochemical cues to control hMSC differentiation.
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Grassi, S; Pettorossi, V E
2001-08-01
The analysis of cellular-molecular events mediating synaptic plasticity within vestibular nuclei is an attempt to explain the mechanisms underlying vestibular plasticity phenomena. The present review is meant to illustrate the main results, obtained in vitro, on the mechanisms underlying long-term changes in synaptic strength within the medial vestibular nuclei. The synaptic plasticity phenomena taking place at the level of vestibular nuclei could be useful for adapting and consolidating the efficacy of vestibular neuron responsiveness to environmental requirements, as during visuo-vestibular recalibration and vestibular compensation. Following a general introduction on the most salient features of vestibular compensation and visuo-vestibular adaptation, which are two plastic events involving neuronal circuitry within the medial vestibular nuclei, the second and third sections describe the results from rat brainstem slice studies, demonstrating the possibility to induce long-term potentiation and depression in the medial vestibular nuclei, following high frequency stimulation of the primary vestibular afferents. In particular the mechanisms sustaining the induction and expression of vestibular long-term potentiation and depression, such as the role of various glutamate receptors and retrograde messengers have been described. The relevant role of the interaction between the platelet-activating factor, acting as a retrograde messenger, and the presynaptic metabotropic glutamate receptors, in determining the full expression of vestibular long-term potentiation is also underlined. In addition, the mechanisms involved in vestibular long-term potentiation have been compared with those leading to long-term potentiation in the hippocampus to emphasize the most significant differences emerging from vestibular studies. The fourth part, describes recent results demonstrating the essential role of nitric oxide, another retrograde messenger, in the induction of vestibular potentiation. Finally the fifth part suggests the possible functional significance of different action times of the two retrograde messengers and metabotropic glutamate receptors, which are involved in mediating the presynaptic mechanism sustaining vestibular long-term potentiation.
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USDA-ARS?s Scientific Manuscript database
The utility of transgenic plants for both experimental and practical agronomic purposes is highly dependent on stable, predictable, and heritable expression of the introduced genes. This requirement is frequently unfulfilled, and transgenes are frequently subject to silencing. Studies of the charact...
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USDA-ARS?s Scientific Manuscript database
Jasmonic acid is a natural plant hormone that induces native defense responses in plants. Sugarbeet (Beta vulgaris L.) root unigenes that were differentially expressed 2 and 60 days after a postharvest jasmonic acid treatment are presented. Data include changes in unigene expression relative to wate...
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Uncoupling proteins and sleep deprivation.
Cirelli, C; Tononi, G
2004-07-01
In both humans and animals sleep deprivation (SD) produces an increase in food intake and in energy expenditure (EE). The increase in EE is a core element of the SD syndrome and, in rats, is negatively correlated with survival rate. However, the mechanisms involved are not understood. A large component of resting EE is accounted for by the mitochondrial proton leak, which is mediated by uncoupling proteins (UCPs). We measured UCP2, UCP3, and UCP5 mRNA levels in rats during the spontaneous sleep/waking cycle and after short (8 hours) and long (7 days) SD. During spontaneous sleep and waking there was no change in the level of mitochondrial uncoupling as measured by UCPs expression, either in the brain or in peripheral tissues. During SD, by contrast, UCP3 expression in skeletal muscle was elevated, but the increase was similar, compared to sleep, after both short-term and long-term SD. UCP2 expression, on the other hand, was strongly increased in the liver and skeletal muscle of long-term sleep deprived animals and much less so, or not at all, in yoked controls or in rats that lost only 8 hours of sleep. Since the skeletal muscle is the largest tissue in the body, an elevated muscular expression of UCP2 is likely to affect the overall resting EE and may thus contribute to its increase after SD.
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A time-course study of long term over-expression of ARR19 in mice
Qamar, Imteyaz; Ahmad, Mohammad Faiz; Narayanasamy, Arul
2015-01-01
A leucine-rich protein, ARR19 (androgen receptor corepressor-19 kDa), is highly expressed in male reproductive organs and moderately in others. Previously, we have reported that ARR19 is differentially expressed in adult Leydig cells during the testis development and inhibits steroidogenesis by reducing the expression of steroidogenic enzymes. Whereas in prostate, ARR19 represses the transcriptional activity of AR (androgen receptor), it is important for male sexual differentiation and maturation in prostate and epididymis, through the recruitment of HDAC4. In this study we show that long term adenovirus mediated overexpression of ARR19 in mice testis has the potential of inhibiting the differentiation of testicular and prostatic cells by reducing the size of testis and prostate but has no effect on the growth of seminal vesicles. Further, it reduces the level of progesterone and testosterone by reducing the steroidogenic enzymes such as 3HSD, P450c17 and StAR. This is the first study reporting a time-course analysis of the implications of long term overexpression of ARR19 in mice testis and its effect on other organs such as prostate and seminal vesicles. Taken together, these results suggest that ARR19 may play an important role in the differentiation of male reproductive organs such as testis and prostate. PMID:26260329
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Zhang, Ming; Wang, Ximin; Xie, Xinxing; Wang, Zhongsu; Liu, Xiaoyan; Guan, Juan; Wang, Weizong; Li, Zhan; Wang, Jiangrong; Gao, Mei; Hou, Yinglong
2015-10-01
Long-term effects of ganglionated plexi (GP) ablation on sinoatrial node (SAN) and atrioventricular node (AVN) remain unclear. This study is to investigate the long-term effects of ablation of cardiac anterior right GP (ARGP) and inferior right GP (IRGP) on function and structure of SAN and AVN in canine. Thirty-two dogs were randomly divided into an operated group (n = 24) and sham-operated group (n = 8). ARGP and IRGP were ablated in operated group which was randomly divided into three subgroups according to the period of evaluation after operation (1 month, 6 months, 12 months). The functional and histological characteristics of SAN and AVN, as well as the expression of connexin (Cx) 43 and Cx 45 in SAN and AVN, were evaluated before and after ablation. Resting heart rate was increased and AVN effective refractory period was prolonged and sinus node recovery time (SNRT) and corrected SNRT were shortened immediately after ablation. These changes were reverted to preablation level after 1 month. At 1 month, ventricular rate during atrial fibrillation was slowed, atria-His intervals were prolonged, and Cx43 and Cx45 expression in SAN and AVN were downregulated. At 6 months, all changes were reverted to preablation level. The histological characteristics of SAN and AVN did not change. Ablation of ARGP and IRGP has short-term effects on function and structure of SAN and AVN rather than long-term effects, which suggests that ablation of ARGP and IRGP is safe. Atrioventricular conduction dysfunction after ablation may be related to downregulated Cx43 and Cx45 expression in AVN. © 2015 Wiley Periodicals, Inc.
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Chen, David; Chang, Richard; Umakanthan, Branavan; Stoletniy, Liset N; Heywood, J Thomas
2007-09-01
In certain patients with left ventricular (LV) systolic dysfunction, improvements in cardiac function are seen after initiation of medical therapy; however, the long-term stability of ventricular function in such patients is not well described. We retrospectively analyzed 171 patients who had a baseline ejection fraction of 45% or less, a follow-up echocardiogram at 2 to 12 months after initiation of medical therapy, and a final echocardiogram. We found that 48.5% of the patients demonstrated initial improvements in LV function after initiation of medical therapy, and the improvements appear to be sustained (88% of patients) at 44 +/- 21 months follow-up. A nonischemic etiology and younger age were the only independent predictors of change of LV ejection fraction of 10 or more at a mean 8.4 +/- 3.4 months after optimal medical therapy. Our study revealed a trend toward improved long-term survival in individuals with an early improvement in LV ejection fraction with medical therapy, especially in those with sustained improvement.
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Pandey, Pallavi; Kaur, Ranjeet; Singh, Sailendra; Chattopadhyay, Sunil Kumar; Srivastava, Santosh Kumar; Banerjee, Suchitra
2014-07-01
The effect of 6 years of cultivation and use of table-sugar (TS) on the biomass/terpene alkaloid productivities and rol gene expression were studied in a hairy root (HR) clone of Rauvolfia serpentina. The media cost could be reduced >94 % by replacing sucrose (SUC) with TS—an unexplored avenue for HR cultivation. The overall productivities increased over long-term cultivation with sugar proving superior to SUC for biomass (24.4 ± 2.11 g/l DW after 40 days to 17.31 % higher) and reserpine (0.094 ± 0.008 % DW after 60 days to 193.8 % more) production. The latter however revealed comparatively better yields concerning ajmaline (0.507 ± 0.048 % DW after 60 days to 61.98 % higher) and yohimbine (0.628 ± 0.062 % DW after 60 days to 38.32 % higher), respectively. PCR amplification of rol genes confirmed long-term expression stability.
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Effects of long term ethanol consumption mediated oxidative stress on neovessel generation in liver.
Das, Subir Kumar; Mukherjee, Sukhes; Vasudevan, D M
2012-06-01
Angiogenesis, the growth of new blood vessels, is essential during tissue repair. Though most molecular mechanisms of angiogenesis are common to the liver and other organs, there was no report available whether alcoholic liver disease also causes angiogenesis. In this study, we examined the effects of long term ethanol (1.6 g/kg body weight/day) consumption on angiogenic responses in the liver of male Wistar strain albino rats (16-18 weeks old, weighing 200-220 g) up to 36 weeks. Chronic ethanol consumption was associated with not only elevated oxidative stress, and altered cytokines expression, but also developed large von Willebrand factor, fibrosis and activation of matrix metalloproteinases. Moreover, vascular endothelial growth factor-receptor 2 (VEGF-R2, fetal liver kinase 1: Flk-1/KDR) expression and neovessel generation in the rat liver were noted after 36 weeks of ethanol consumption. Thus our study provides novel evidence that long-term ethanol consumption is associated with angiogenesis through delicate and coordinated action of a variety of mediators.
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Lakhina, Vanisha; Arey, Rachel N.; Kaletsky, Rachel; Kauffman, Amanda; Stein, Geneva; Keyes, William; Xu, Daniel; Murphy, Coleen T.
2014-01-01
SUMMARY Induced CREB activity is a hallmark of long-term memory, but the full repertoire of CREB transcriptional targets required specifically for memory is not known in any system. To obtain a more complete picture of the mechanisms involved in memory, we combined memory training with genome-wide transcriptional analysis of C. elegans CREB mutants. This approach identified 757 significant CREB/memory-induced targets and confirmed the involvement of known memory genes from other organisms, but also suggested new mechanisms and novel components that may be conserved through mammals. CREB mediates distinct basal and memory transcriptional programs at least partially through spatial restriction of CREB activity: basal targets are regulated primarily in nonneuronal tissues, while memory targets are enriched for neuronal expression, emanating from CREB activity in AIM neurons. This suite of novel memory-associated genes will provide a platform for the discovery of orthologous mammalian long-term memory components. PMID:25611510
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Long-term health of dopaminergic neuron transplants in Parkinson's disease patients.
Hallett, Penelope J; Cooper, Oliver; Sadi, Damaso; Robertson, Harold; Mendez, Ivar; Isacson, Ole
2014-06-26
To determine the long-term health and function of transplanted dopamine neurons in Parkinson's disease (PD) patients, the expression of dopamine transporters (DATs) and mitochondrial morphology were examined in human fetal midbrain cellular transplants. DAT was robustly expressed in transplanted dopamine neuron terminals in the reinnervated host putamen and caudate for at least 14 years after transplantation. The transplanted dopamine neurons showed a healthy and nonatrophied morphology at all time points. Labeling of the mitochondrial outer membrane protein Tom20 and α-synuclein showed a typical cellular pathology in the patients' own substantia nigra, which was not observed in transplanted dopamine neurons. These results show that the vast majority of transplanted neurons remain healthy for the long term in PD patients, consistent with clinical findings that fetal dopamine neuron transplants maintain function for up to 15-18 years in patients. These findings are critically important for the rational development of stem-cell-based dopamine neuronal replacement therapies for PD. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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Rational and combinatorial approaches to engineering styrene production by Saccharomyces cerevisiae.
McKenna, Rebekah; Thompson, Brian; Pugh, Shawn; Nielsen, David R
2014-08-21
Styrene is an important building-block petrochemical and monomer used to produce numerous plastics. Whereas styrene bioproduction by Escherichia coli was previously reported, the long-term potential of this approach will ultimately rely on the use of hosts with improved industrial phenotypes, such as the yeast Saccharomyces cerevisiae. Classical metabolic evolution was first applied to isolate a mutant capable of phenylalanine over-production to 357 mg/L. Transcription analysis revealed up-regulation of several phenylalanine biosynthesis pathway genes including ARO3, encoding the bottleneck enzyme DAHP synthase. To catalyze the first pathway step, phenylalanine ammonia lyase encoded by PAL2 from A. thaliana was constitutively expressed from a high copy plasmid. The final pathway step, phenylacrylate decarboxylase, was catalyzed by the native FDC1. Expression of FDC1 was naturally induced by trans-cinnamate, the pathway intermediate and its substrate, at levels sufficient for ensuring flux through the pathway. Deletion of ARO10 to eliminate the competing Ehrlich pathway and expression of a feedback-resistant DAHP synthase encoded by ARO4K229L preserved and promoted the endogenous availability precursor phenylalanine, leading to improved pathway flux and styrene production. These systematic improvements allowed styrene titers to ultimately reach 29 mg/L at a glucose yield of 1.44 mg/g, a 60% improvement over the initial strain. The potential of S. cerevisiae as a host for renewable styrene production has been demonstrated. Significant strain improvements, however, will ultimately be needed to achieve economical production levels.
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Semple, Bridgette D; Trivedi, Alpa; Gimlin, Kayleen; Noble-Haeusslein, Linda J
2015-02-01
While neutrophil elastase (NE), released by activated neutrophils, is a key mediator of secondary pathogenesis in adult models of brain ischemia and spinal cord injury, no studies to date have examined this protease in the context of the injured immature brain, where there is notable vulnerability resulting from inadequate antioxidant reserves and prolonged exposure to infiltrating neutrophils. We thus reasoned that NE may be a key determinant of secondary pathogenesis, and as such, adversely influence long-term neurological recovery. To address this hypothesis, wild-type (WT) and NE knockout (KO) mice were subjected to a controlled cortical impact at post-natal day 21, approximating a toddler-aged child. To determine if NE is required for neutrophil infiltration into the injured brain, and whether this protease contributes to vasogenic edema, we quantified neutrophil numbers and measured water content in the brains of each of these genotypes. While leukocyte trafficking was indistinguishable between genotypes, vasogenic edema was markedly attenuated in the NE KO. To determine if early pathogenesis is dependent on NE, indices of cell death (TUNEL and activated caspase-3) were quantified across genotypes. NE KO mice showed a reduction in these markers of cell death in the injured hippocampus, which corresponded to greater preservation of neuronal integrity as well as reduced expression of heme oxygenase-1, a marker of oxidative stress. WT mice, treated with a competitive inhibitor of NE at 2, 6 and 12h post-injury, likewise showed a reduction in cell death and oxidative stress compared to vehicle-treated controls. We next examined the long-term behavioral and structural consequences of NE deficiency. NE KO mice showed an improvement in long-term spatial memory retention and amelioration of injury-induced hyperactivity. However, volumetric and stereological analyses found comparable tissue loss in the injured cortex and hippocampus independent of genotype. Further, WT mice treated acutely with the NE inhibitor showed no long-term behavioral or structural improvements. Together, these findings validate the central role of NE in both acute pathogenesis and chronic functional recovery, and support future exploration of the therapeutic window, taking into account the prolonged period of neutrophil trafficking into the injured immature brain. Copyright © 2014 Elsevier Inc. All rights reserved.
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Semple, Bridgette D; Trivedi, Alpa; Gimlin, Kayleen; Noble-Haeusslein, Linda J
2014-01-01
While neutrophil elastase (NE), released by activated neutrophils, is a key mediator of secondary pathogenesis in adult models of brain ischemia and spinal cord injury, no studies to date have examined this protease in the context of the injured immature brain, where there is notable vulnerability resulting from inadequate antioxidant reserves and prolonged exposure to infiltrating neutrophils. We thus reasoned that NE may be a key determinant of secondary pathogenesis, and as such, adversely influence long-term neurological recovery. To address this hypothesis, wild-type (WT) and NE knockout (KO) mice were subjected to a controlled cortical impact at post-natal day 21, approximating a toddler-aged child. To determine if NE is required for neutrophil infiltration into the injured brain, and whether this protease contributes to vasogenic edema, we quantified neutrophil numbers and measured water content in the brains of each of these genotypes. While leukocyte trafficking was indistinguishable between genotypes, vasogenic edema was markedly attenuated in the NE KO. To determine if early pathogenesis is dependent on NE, indices of cell death (TUNEL and activated caspase-3) were quantified across genotypes. NE KO mice showed a reduction in these markers of cell death in the injured hippocampus, which corresponded to greater preservation of neuronal integrity as well as reduced expression of heme oxygenase-1, a marker of oxidative stress. WT mice, treated with a competitive inhibitor of NE at 2, 6 and 12 h post-injury, likewise showed a reduction in cell death and oxidative stress compared to vehicle-treated controls. We next examined the long-term behavioral and structural consequences of NE deficiency. NE KO mice showed an improvement in long-term spatial memory retention and amelioration of injury-induced hyperactivity. However, volumetric and stereological analyses found comparable tissue loss in the injured cortex and hippocampus independent of genotype. Further, WT mice treated acutely with the NE inhibitor showed no long-term behavioral or structural improvements. Together, these findings validate the central role of NE in both acute pathogenesis and chronic functional recovery, and support future exploration of the therapeutic window, taking into account the prolonged period of neutrophil trafficking into the injured immature brain. PMID:25497734
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Davila, G. Willy
2011-01-01
Objective. To evaluate long-term effectiveness and safety of conservative and minimally invasive outpatient treatments for female stress urinary incontinence (SUI) through a review of the literature. Methods. PubMed was searched for reports on prospective clinical trials with at least 12-month follow-up of minimally invasive treatments, pelvic floor rehabilitation, or pharmacotherapy in women with SUI. Each report was examined for long-term rates of effectiveness and safety. Results. Thirty-two clinical trial reports were included. Prospective long-term studies of pelvic floor rehabilitation were limited but indicated significant improvements with treatment adherence for at least 12 months. Poor initial tolerability with duloxetine resulted in substantial discontinuation. Most patients receiving transurethral radiofrequency collagen denaturation or urethral bulking agents reported significant long-term improvements, generally good tolerability, and safety. Conclusions. Conservative therapy is an appropriate initial approach for female SUI, but if therapy fails, radiofrequency collagen denaturation or bulking agents may be an attractive intermediate management step or alternative to surgery. PMID:21738529
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The affordable care act and long-term care: comprehensive reform or just tinkering around the edges?
Miller, Edward Alan
2012-01-01
The Patient Protection and Affordable Care Act (ACA) includes several provisions that aim to improve prevailing deficiencies in the nation's long-term care system. But just how effective is the ACA likely to be in addressing these challenges? Will it result in meaningful or marginal reform? This special issue of Journal of Aging & Social Policy seeks to answer these questions. The most prominent long-term care provision is the now-suspended Community Living Assistance Services and Supports Act. Others include incentives and options for expanding home- and community-based care, a number of research and demonstration projects in the areas of chronic care coordination and the dually eligible, and nursing home quality reforms. There are also elements that seek to improve workforce recruitment and retention, in addition to benefit improvements and spending reductions under Medicare. This article reviews the basic problems plaguing the long-term care sector and the provisions within the ACA meant to address them. It also includes a brief overview of issue content.
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Short-term memory and long-term memory are still different.
Norris, Dennis
2017-09-01
A commonly expressed view is that short-term memory (STM) is nothing more than activated long-term memory. If true, this would overturn a central tenet of cognitive psychology-the idea that there are functionally and neurobiologically distinct short- and long-term stores. Here I present an updated case for a separation between short- and long-term stores, focusing on the computational demands placed on any STM system. STM must support memory for previously unencountered information, the storage of multiple tokens of the same type, and variable binding. None of these can be achieved simply by activating long-term memory. For example, even a simple sequence of digits such as "1, 3, 1" where there are 2 tokens of the digit "1" cannot be stored in the correct order simply by activating the representations of the digits "1" and "3" in LTM. I also review recent neuroimaging data that has been presented as evidence that STM is activated LTM and show that these data are exactly what one would expect to see based on a conventional 2-store view. (PsycINFO Database Record (c) 2017 APA, all rights reserved).
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Short-Term Memory and Long-Term Memory are Still Different
2017-01-01
A commonly expressed view is that short-term memory (STM) is nothing more than activated long-term memory. If true, this would overturn a central tenet of cognitive psychology—the idea that there are functionally and neurobiologically distinct short- and long-term stores. Here I present an updated case for a separation between short- and long-term stores, focusing on the computational demands placed on any STM system. STM must support memory for previously unencountered information, the storage of multiple tokens of the same type, and variable binding. None of these can be achieved simply by activating long-term memory. For example, even a simple sequence of digits such as “1, 3, 1” where there are 2 tokens of the digit “1” cannot be stored in the correct order simply by activating the representations of the digits “1” and “3” in LTM. I also review recent neuroimaging data that has been presented as evidence that STM is activated LTM and show that these data are exactly what one would expect to see based on a conventional 2-store view. PMID:28530428
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Jessen, Niels; Pold, Rasmus; Buhl, Esben S; Jensen, Lasse S; Schmitz, Ole; Lund, Sten
2003-04-01
Physical activity is known to increase insulin action in skeletal muscle, and data have indicated that 5'-AMP-activated protein kinase (AMPK) is involved in the molecular mechanisms behind this beneficial effect. 5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) can be used as a pharmacological tool to repetitively activate AMPK, and the objective of this study was to explore whether the increase in insulin-stimulated glucose uptake after either long-term exercise or chronic AICAR administration was followed by fiber-type-specific changes in insulin signaling and/or changes in GLUT-4 expression. Wistar rats were allocated into three groups: an exercise group trained on treadmill for 5 days, an AICAR group exposed to daily subcutaneous injections of AICAR, and a sedentary control group. AMPK activity, insulin-stimulated glucose transport, insulin signaling, and GLUT-4 expression were determined in muscles characterized by different fiber type compositions. Both exercised and AICAR-injected animals displayed a fiber-type-specific increase in glucose transport with the most marked increase in muscles with a high content of type IIb fibers. This increase was accompanied by a concomitant increase in GLUT-4 expression. Insulin signaling as assessed by phosphatidylinositol 3-kinase and PKB/Akt activity was enhanced only after AICAR administration and in a non-fiber-type-specific manner. In conclusion, chronic AICAR administration and long-term exercise both improve insulin-stimulated glucose transport in skeletal muscle in a fiber-type-specific way, and this is associated with an increase in GLUT-4 content.
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Gong, Bing; Vitolo, Ottavio V.; Trinchese, Fabrizio; Liu, Shumin; Shelanski, Michael; Arancio, Ottavio
2004-01-01
Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid β-peptide 1–42 (Aβ42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for amyloid precursor protein (AA substitution K670N,M671L) and presenilin-1 (AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element–binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Aβ. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Aβ42 levels. PMID:15578094
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Gabbita, S. Prasad; Johnson, Ming F.; Kobritz, Naomi; Eslami, Pirooz; Poteshkina, Aleksandra; Varadarajan, Sridhar; Turman, John; Zemlan, Frank; Harris-White, Marni E.
2015-01-01
Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer’s Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression. In this study, 3xTgAD mice, age 6 months, were treated orally with 3 doses of the TNFα modulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFα modulating compound both in vitro and in vivo. Following long-term IDT administration, mice were assessed for learning & memory and tissue and serum were collected for analysis. Results demonstrate that IDT is safe for long-term treatment and significantly improves learning and memory in the 3xTgAD mouse model. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation. Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT is a safe and effective TNFα and innate immune system modulator. Thus small molecule, orally bioavailable modulators are promising therapeutics for Alzheimer’s disease. PMID:26436670
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Valsesia, Armand; Saris, Wim Hm; Astrup, Arne; Hager, Jörg; Masoodi, Mojgan
2016-09-01
An aim of weight loss is to reduce the risk of type 2 diabetes (T2D) in obese subjects. However, the relation with long-term glycemic improvement remains unknown. We evaluated the changes in lipid composition during weight loss and their association with long-term glycemic improvement. We investigated the plasma lipidome of 383 obese, nondiabetic patients within a randomized, controlled dietary intervention in 8 European countries at baseline, after an 8-wk low-caloric diet (LCD) (800-1000 kcal/d), and after 6 mo of weight maintenance. After weight loss, a lipid signature identified 2 groups of patients who were comparable at baseline but who differed in their capacities to lose weight and improve glycemic control. Six months after the LCD, one group had significant glycemic improvement [homeostasis model assessment of insulin resistance (HOMA-IR) mean change: -0.92; 95% CI: -1.17, -0.67)]. The other group showed no improvement in glycemic control (HOMA-IR mean change: -0.26; 95% CI: -0.64, 0.13). These differences were sustained for ≥1 y after the LCD. The same conclusions were obtained with other endpoints (Matsuda index and fasting insulin and glucose concentrations). Significant differences between the 2 groups were shown in leptin gene expression in adipose tissue biopsies. Significant differences were also observed in weight-related endpoints (body mass index, weight, and fat mass). The lipid signature allowed prediction of which subjects would be considered to be insulin resistant after 6 mo of weight maintenance [validation's receiver operating characteristic (ROC) area under the curve (AUC): 71%; 95% CI: 62%, 81%]. This model outperformed a clinical data-only model (validation's ROC AUC: 61%; 95% CI: 50%, 71%; P = 0.01). In this study, we report a lipid signature of LCD success (for weight and glycemic outcome) in obese, nondiabetic patients. Lipid changes during an 8-wk LCD allowed us to predict insulin-resistant patients after 6 mo of weight maintenance. The determination of the lipid composition during an LCD enables the identification of nonresponders and may help clinicians manage metabolic outcomes with further intervention, thereby improving the long-term outcome and preventing T2D. This trial was registered at clinicaltrials.gov as NCT00390637. © 2016 American Society for Nutrition.
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Got (the Right) Milk? How a Blended Quality Improvement Approach Catalyzed Change.
Luton, Alexandra; Bondurant, Patricia G; Campbell, Amy; Conkin, Claudia; Hernandez, Jae; Hurst, Nancy
2015-10-01
The expression, storage, preparation, fortification, and feeding of breast milk are common ongoing activities in many neonatal intensive care units (NICUs) today. Errors in breast milk administration are a serious issue that should be prevented to preserve the health and well-being of NICU babies and their families. This paper describes how a program to improve processes surrounding infant feeding was developed, implemented, and evaluated. The project team used a blended quality improvement approach that included the Model for Improvement, Lean and Six Sigma methodologies, and principles of High Reliability Organizations to identify and drive short-term, medium-term, and long-term improvement strategies. Through its blended quality improvement approach, the team strengthened the entire dispensation system for both human milk and formula and outlined a clear vision and plan for further improvements as well. The NICU reduced feeding errors by 83%. Be systematic in the quality improvement approach, and apply proven methods to improving processes surrounding infant feeding. Involve expert project managers with nonclinical perspective to guide work in a systematic way and provide unbiased feedback. Create multidisciplinary, cross-departmental teams that include a vast array of stakeholders in NICU feeding processes to ensure comprehensive examination of current state, identification of potential risks, and "outside the box" potential solutions. As in the realm of pharmacy, the processes involved in preparing feedings for critically ill infants should be carried out via predictable, reliable means including robust automated verification that integrates seamlessly into existing processes. The use of systems employed in pharmacy for medication preparation should be considered in the human milk and formula preparation setting.
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González, Germán E; Seropian, Ignacio M; Krieger, Maria Laura; Palleiro, Jimena; Lopez Verrilli, Maria A; Gironacci, Mariela M; Cavallero, Susana; Wilensky, Luciana; Tomasi, Victor H; Gelpi, Ricardo J; Morales, Celina
2009-07-01
To characterize the temporal activation of the renin-angiotensin system after myocardial infarction (MI) in rabbits, we examined cardiac ANG II type 1 receptor (AT(1)R) expression and ANG II levels from 3 h to 35 days. The effects of losartan (12.5 mg.kg(-1).day(-1)) on functional and histomorphometric parameters when treatment was initiated early (3 h) and late (day 15) post-MI and maintained for different periods of time [short term (4 days), midterm (20 days), and long term (35 days)] were also studied. AT(1)R expression increased in the MI zone at 15 and 35 days (P < 0.05). ANG II levels increased (P < 0.05) in the non-MI zone at 24 h and in the MI zone as well as in plasma at 4 days and then progressively decreased until 35 days. The survival rate was significantly lower in untreated MI and early long-term-treated animals. Diastolic pressure-volume curves in MI at 35 and 56 days shifted to the right (P < 0.05). This shift was even more pronounced in long-term-treated groups (P < 0.05). Contractility decreased (P < 0.05 vs. sham) in the untreated and long-term-treated groups and was attenuated in the midterm-treated group. The early administration of losartan reduced RAM 11-positive macrophages from 4.15 +/- 0.05 to 3.05 +/- 0.02 cells/high-power field (HPF; P < 0.05) and CD45 RO-positive lymphocytes from 2.23 +/- 0.05 to 1.48 +/- 0.01 cells/HPF (P < 0.05) in the MI zone at 4 days. Long-term treatment reduced the scar collagen (MI: 70.50 +/- 2.35% and MI + losartan: 57.50 +/- 2.48, P < 0.05), determined the persistency of RAM 11-positive macrophages (3.02 +/- 0.13 cells/HPF) and CD45 RO-positive lymphocytes (2.77 +/- 0.58 cells/HPF, P < 0.05 vs. MI), and reduced the scar thinning ratio at 35 days (P < 0.05). Consequently, the temporal expressions of cardiac AT(1)R and ANG II post-MI in rabbits are different from those described in other species. Long-term treatment unfavorably modified post-MI remodeling, whereas midterm treatment attenuated this harmful effect. The delay in wound healing (early reduction and late persistency of inflammatory infiltrate) and adverse remodeling observed in long-term-treated animals might explain the unfavorable effect observed in rabbits.
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Tanshinol suppresses cardiac allograft rejection in a murine model.
Lu, Chuanjian; Zeng, Yu-Qun; Liu, Huazhen; Xie, Qingfeng; Xu, Shengmei; Tu, Kangsheng; Dou, Changwei; Dai, Zhenhua
2017-02-01
Achieving long-term cardiac allograft survival without continuous immunosuppression is highly desired in organ transplantation. Studies have shown that Salvia miltiorrhiza, an herb also known as danshen, improves microcirculation and is highly effective in treating coronary heart disease. Our objective is to determine whether tanshinol, an ingredient of danshen, improves cardiac allograft survival. Fully vascularized heterotopic heart transplantation was performed using BALB/c mice as donors and C57BL/6 mice as recipients, which were then treated with tanshinol and rapamycin. CD4 + FoxP3 + regulatory T cells (Tregs) were quantified by flow analyses, whereas CCL22 was measured by real-time polymerase chain reaction and Western blotting. We found that tanshinol significantly delayed cardiac allograft rejection. It promoted long-term allograft survival induced by rapamycin, a mammalian target-of-rapamycin (mTOR) inhibitor. Tanshinol increased CD4 + FoxP3 + Treg numbers in cardiac allografts, but not spleens and lymph nodes, of recipient mice by enhancing chemokine CCL22 expression in cardiac allografts, especially cardiac dendritic cells. In contrast, rapamycin increased Treg numbers in both lymphoid organs and allografts, suggesting that it generally expands Tregs. Moreover, Tregs induced by rapamycin plus tanshinol were more potent in suppressing T-cell proliferation in vitro than those from untreated recipients. Neutralizing CCL22 hindered CD4 + FoxP3 + Treg migration to cardiac allografts and reversed long-term allograft survival induced by tanshinol plus rapamycin. Tanshinol suppresses cardiac allograft rejection by recruiting CD4 + FoxP3 + Tregs to the graft, whereas rapamycin does so via expanding the Tregs. Thus, tanshinol cooperates with rapamycin to further extend cardiac allograft survival. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
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Perez-Basterrechea, Marcos; Esteban, Manuel Martinez; Alvarez-Viejo, Maria; Fontanil, Tania; Cal, Santiago; Sanchez Pitiot, Marta; Otero, Jesus; Obaya, Alvaro Jesus
2017-01-01
Pancreatic islet transplantation has been considered for many years a promising therapy for beta-cell replacement in patients with type-1 diabetes despite that long-term clinical results are not as satisfactory. This fact points to the necessity of designing strategies to improve and accelerate islets engraftment, paying special attention to events assuring their revascularization. Fibroblasts constitute a cell population that collaborates on tissue homeostasis, keeping the equilibrium between production and degradation of structural components as well as maintaining the required amount of survival factors. Our group has developed a model for subcutaneous islet transplantation using a plasma-based scaffold containing fibroblasts as accessory cells that allowed achieving glycemic control in diabetic mice. Transplanted tissue engraftment is critical during the first days after transplantation, thus we have gone in depth into the graft-supporting role of fibroblasts during the first ten days after islet transplantation. All mice transplanted with islets embedded in the plasma-based scaffold reversed hyperglycemia, although long-term glycemic control was maintained only in the group transplanted with the fibroblasts-containing scaffold. By gene expression analysis and histology examination during the first days we could conclude that these differences might be explained by overexpression of genes involved in vessel development as well as in β-cell regeneration that were detected when fibroblasts were present in the graft. Furthermore, fibroblasts presence correlated with a faster graft re-vascularization, a higher insulin-positive area and a lower cell death. Therefore, this work underlines the importance of fibroblasts as accessory cells in islet transplantation, and suggests its possible use in other graft-supporting strategies.
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Alvarez-Viejo, Maria; Fontanil, Tania; Cal, Santiago; Sanchez Pitiot, Marta; Otero, Jesus; Obaya, Alvaro Jesus
2017-01-01
Pancreatic islet transplantation has been considered for many years a promising therapy for beta-cell replacement in patients with type-1 diabetes despite that long-term clinical results are not as satisfactory. This fact points to the necessity of designing strategies to improve and accelerate islets engraftment, paying special attention to events assuring their revascularization. Fibroblasts constitute a cell population that collaborates on tissue homeostasis, keeping the equilibrium between production and degradation of structural components as well as maintaining the required amount of survival factors. Our group has developed a model for subcutaneous islet transplantation using a plasma-based scaffold containing fibroblasts as accessory cells that allowed achieving glycemic control in diabetic mice. Transplanted tissue engraftment is critical during the first days after transplantation, thus we have gone in depth into the graft-supporting role of fibroblasts during the first ten days after islet transplantation. All mice transplanted with islets embedded in the plasma-based scaffold reversed hyperglycemia, although long-term glycemic control was maintained only in the group transplanted with the fibroblasts-containing scaffold. By gene expression analysis and histology examination during the first days we could conclude that these differences might be explained by overexpression of genes involved in vessel development as well as in β-cell regeneration that were detected when fibroblasts were present in the graft. Furthermore, fibroblasts presence correlated with a faster graft re-vascularization, a higher insulin-positive area and a lower cell death. Therefore, this work underlines the importance of fibroblasts as accessory cells in islet transplantation, and suggests its possible use in other graft-supporting strategies. PMID:28672010
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Miao, Weimin; XuFeng, Richard; Park, Moo-Rim; Gu, Haihui; Hu, Linping; Kang, Jin Wook; Ma, Shihui; Liang, Paulina H; Li, Yanxin; Cheng, Haizi; Yu, Hui; Epperly, Michael; Greenberger, Joel; Cheng, Tao
2013-01-01
High levels of reactive oxygen species (ROS) can exhaust hematopoietic stem cells (HSCs). Thus, maintaining a low state of redox in HSCs by modulating ROS-detoxifying enzymes may augment the regeneration potential of HSCs. Our results show that basal expression of manganese superoxide dismutase (MnSOD) and catalase were at low levels in long-term and short-term repopulating HSCs, and administration of a MnSOD plasmid and lipofectin complex (MnSOD-PL) conferred radiation protection on irradiated recipient mice. To assess the intrinsic role of elevated MnSOD or catalase in HSCs and hematopoietic progenitor cells, the MnSOD or catalase gene was overexpressed in mouse hematopoietic cells via retroviral transduction. The impact of MnSOD and catalase on hematopoietic progenitor cells was mild, as measured by colony-forming units (CFUs). However, overexpressed catalase had a significant beneficial effect on long-term engraftment of transplanted HSCs, and this effect was further enhanced after an insult of low-dose γ-irradiation in the transplant mice. In contrast, overexpressed MnSOD exhibited an insignificant effect on long-term engraftment of transplanted HSCs, but had a significant beneficial effect after an insult of sublethal irradiation. Taken together, these results demonstrate that HSC function can be enhanced by ectopic expression of ROS-detoxifying enzymes, especially after radiation exposure in vivo. PMID:23295952
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The 2020 statewide transportation plan : investing in Colorado's future
DOT National Transportation Integrated Search
2000-11-01
The 2015 plan was Colorado's first long-range, statewide, multi-modal transportation plan. Its strongest asset was the consensus among local, regional, and state participants about the long-term needs expressed in the plan. The lack of a comprehensiv...
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Development of a Long-Life-Cycle, Highly Water-Resistant Solar Reflective Retrofit Roof Coating
DOE Office of Scientific and Technical Information (OSTI.GOV)
Polyzos, Georgios; Hunter, Scott; Sharma, Jaswinder
2016-03-04
Highly water-resistant and solar-reflective coatings for low-slope roofs are potentially among the most economical retrofit approaches to thermal management of the building envelope. Therefore, they represent a key building technology research program within the Department of Energy. Research efforts in industry and the Department of Energy are currently under way to increase long-term solar reflectance on a number of fronts. These include new polymer coatings technologies to provide longer-lasting solar reflectivity and improved test methodologies to predict long-term soiling and microbial performance. The focus on long-term improvements in soiling and microbial resistance for maximum reflectance does not address the singlemore » most important factor impacting the long-term sustainability of low-slope roof coatings: excellent water resistance. The hydrophobic character of asphaltic roof products makes them uniquely suitable for water resistance, but their low albedo and poor exterior durability are disadvantages. A reflective coating that maintains very high water resistance with increased long-term resistance to soiling and microbial activity would provide additional energy savings and extend roof service life.« less
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Furuhashi, Masato; Hiramitsu, Shinya; Mita, Tomohiro; Fuseya, Takahiro; Ishimura, Shutaro; Omori, Akina; Matsumoto, Megumi; Watanabe, Yuki; Hoshina, Kyoko; Tanaka, Marenao; Moniwa, Norihito; Yoshida, Hideaki; Ishii, Junnichi; Miura, Tetsuji
2015-01-01
Fatty acid binding protein 4 (FABP4), also known as adipocyte FABP or aP2, is secreted from adipocytes in association with lipolysis as a novel adipokine, and elevated serum FABP4 level is associated with obesity, insulin resistance, and atherosclerosis. However, little is known about the modulation of serum FABP4 level by therapeutic drugs. Sitagliptin (50 mg/day), a dipeptidyl peptidase 4 (DPP-4) inhibitor that increases glucagon-like peptide 1 (GLP-1), was administered to patients with type 2 diabetes (n = 24) for 12 weeks. Treatment with sitagliptin decreased serum FABP4 concentration by 19.7% (17.8 ± 1.8 vs. 14.3 ± 1.5 ng/ml, P < 0.001) and hemoglobin A1c without significant changes in adiposity or lipid variables. In 3T3-L1 adipocytes, sitagliptin or exendin-4, a GLP-1 receptor agonist, had no effect on short-term (2 h) secretion of FABP4. However, gene expression and long-term (24 h) secretion of FABP4 were significantly reduced by sitagliptin, which was not mimicked by exendin-4. Treatment with recombinant DPP-4 increased gene expression and long-term secretion of FABP4, and the effects were cancelled by sitagliptin. Furthermore, knockdown of DPP-4 in 3T3-L1 adipocytes decreased gene expression and long-term secretion of FABP4. In conclusion, sitagliptin decreases serum FABP4 level, at least in part, via reduction in the expression and consecutive secretion of FABP4 in adipocytes by direct inhibition of DPP-4. PMID:26467280
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ERIC Educational Resources Information Center
Wilson, Suzanne M.; Darling-Hammond, Linda; Berry, Barnett
In this monograph, the authors describe Connecticut's long-term efforts to implement a comprehensive set of teaching quality policies to support improved student learning. The authors begin by describing the 15-year evolution of policies designed to recruit, prepare, and support teachers, while also creating greater accountability for the…
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Profile extrusion and mechanical properties of crosslinked wood–thermoplastic composites
Magnus Bengtsson; Kristiina Oksman; Stark Nicole M.
2006-01-01
Challenges for wood-thermoplastic composites to be utilized in structural applications are to lower product weight and to improve the long-term load performance. Silane crosslinking of the composites is one way to reduce the creep during long-term loading and to improve the mechanical properties. In this study, silane crosslinked wood-polyethylene composites were...
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Yoon, Ju Young; Lee, Ji Yun; Bowers, Barbara J; Zimmerman, David R
2012-12-01
With the rapid increase in the number of long-term care hospitals in Korea, care quality has become an important issue. Urinary incontinence is an important condition affecting many residents' quality of life. Thus, it is important that urinary incontinence be amenable to improving conditions with appropriate interventions, since a change in urinary incontinence status can reflect care quality in long-term care facilities if patient level factors are adjusted. We aim to examine the impact of organizational factors on urinary incontinence care quality defined as the improvement of urinary incontinence status or maintenance of continent status post-admission to Korean long-term care hospitals. DESIGN AND DATA: This is a longitudinal correlation study. Data came from two sources: monthly patient assessment reports using the Patient Assessment Instrument and the hospital information system from the Health Insurance Review and Assessment Services. The final analysis includes 5271 elderly adults without indwelling urinary catheter or urostomy who were admitted to 534 Korean long-term care hospitals in April 2008. Multi-level logistic analysis was used to explore the organizational factors that influence urinary incontinence care quality controlling for patient level factors. With respect to the organizational factors, the findings showed that location and RN/total nursing staff ratio variables were statistically significant, controlling for risk factors at the patient level. The odds of urinary incontinence improvement from admission in urban long-term care hospitals were 1.28 times higher than rural long-term care hospitals. In addition, when a long-term care hospital increased one standard deviation (0.19) in the RN ratio, the odds of urinary incontinence status improvement or maintenance of continence status from admission increased about 1.8 times. The most significant finding was that a higher RN to patient ratio and urban location were associated with better resident outcomes of urinary incontinence among organizational factors. For a better understanding of how these significant organizational factors influence positive care outcomes and provide more practical implications, studies should examine concrete care process measures as well as structure and outcome measures based on systematic conceptual models. Copyright © 2012 Elsevier Ltd. All rights reserved.
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The topical treatment of psoriasis.
van de Kerkhof, P C M; Vissers, W H P M
2003-01-01
According to the patients, improvement of efficacy, long-term safety and improvement of compliance are needed. The topical treatment has been innovated during the last decade. Most important are the introduction of two new classes of treatments: topical vitamin D(3) analogues and the retinoid tazarotene. To what extent, however, have we achieved developments which are in line with the needs as expressed by the patients? Improved efficacy has been realized by successful combinations of topical treatments. In particular, the combinations of dithranol, vitamin D(3) and tazarotene with a topical corticosteroid proved to be very effective with a reduced profile of side-effects. The efficacy of vitamin D(3) analogues and tazarotene is such that the efficacy of a potent corticosteroid (betamethasone-17-valerate) is approached; calcipotriol even showed an efficacy which is at least as good as this corticosteroid. The long-term safety of new compounds has been evaluated for at least 12 months in large studies. Remarkably for corticosteroids such information is available for only 12 weeks. However, intermittent applications of a topical corticosteroid in combination with another topical treatment provide an effective and safe long-term control of psoriasis. Compliance is a conditio sine qua non for an effective topical treatment. Important progress has been made to increase compliance. Short-contact dithranol has been popularized as an ambulatory treatment which is a highly effective approach as a care instruction programme. Formulations which are better from a cosmetical point of view have been developed for various topical treatments. Reduction of the frequency of applications proved to be possible for most treatments. Once daily applications for corticosteroids, vitamin D(3) analogues and retinoids have been developed, and intermittent applications, a few times per week, are possible for corticosteroids, which proved to be very effective with a reduced profile of side-effects, and are also developed for dithranol. Copyright 2003 S. Karger AG, Basel
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van den Berg, M; Verbaarschot, P; Hontelez, S; Vet, L E M; Dicke, M; Smid, H M
2010-06-01
The cAMP/PKA signalling pathway and transcription factor cAMP response element-binding protein (CREB) play key roles in long-term memory (LTM) formation. We used two closely related parasitic wasp species, Cotesia glomerata and Cotesia rubecula, which were previously shown to be different in LTM formation, and sequenced at least nine different CREB transcripts in both wasp species. The splicing patterns, functional domains and amino acid sequences were similar to those found in the CREB genes of other organisms. The predicted amino acid sequences of the CREB isoforms were identical in both wasp species. Using real-time quantitative PCR we found that two low abundant CREB transcripts are differentially expressed in the two wasps, whereas the expression levels of high abundant transcripts are similar.
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EPO improved neurologic outcome in rat pups late after traumatic brain injury.
Schober, Michelle E; Requena, Daniela F; Rodesch, Christopher K
2018-05-01
In adult rats, erythropoietin improved outcomes early and late after traumatic brain injury, associated with increased levels of Brain Derived Neurotrophic Factor. Using our model of pediatric traumatic brain injury, controlled cortical impact in 17-day old rats, we previously showed that erythropoietin increased hippocampal neuronal fraction in the first two days after injury. Erythropoietin also decreased activation of caspase3, an apoptotic enzyme modulated by Brain Derived Neurotrophic Factor, and improved Novel Object Recognition testing 14 days after injury. Data on long-term effects of erythropoietin on Brain Derived Neurotrophic Factor expression, histology and cognitive function after developmental traumatic brain injury are lacking. We hypothesized that erythropoietin would increase Brain Derived Neurotrophic Factor and improve long-term object recognition in rat pups after controlled cortical impact, associated with increased neuronal fraction in the hippocampus. Rats pups received erythropoietin or vehicle at 1, 24, and 48 h and 7 days after injury or sham surgery followed by histology at 35 days, Novel Object Recognition testing at adulthood, and Brain Derived Neurotrophic Factor measurements early and late after injury. Erythropoietin improved Novel Object Recognition performance and preserved hippocampal volume, but not neuronal fraction, late after injury. Improved object recognition in erythropoietin treated rats was associated with preserved hippocampal volume late after traumatic brain injury. Erythropoietin is approved to treat various pediatric conditions. Coupled with exciting experimental and clinical studies suggesting it is beneficial after neonatal hypoxic ischemic brain injury, our preliminary findings support further study of erythropoietin use after developmental traumatic brain injury. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
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Faehling, Martin; Wienhausen-Wilke, Vera; Fallscheer, Sabine; Trinajstic-Schulz, B; Weber, J; Leschke, Matthias
2015-09-14
We present a patient with lymphangioleiomyomatosis (LAM) on long-term sirolimus (now 79 months) who has had a second successful pregnancy. The second pregnancy on uninterrupted low-dose sirolimus (plasma levels 3-5 mg/L) was uncomplicated both with respect to mother and child suggesting that low-dose sirolimus might be safe in selected pregnant patients with stable LAM. The long-term time course in this patient is in agreement with recent reports of a long-term beneficial effect of sirolimus in LAM. In this patient, the pregnancies did not seem to impair the long-term improvement of lung-function on sirolimus.
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Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B
Nathwani, A.C.; Reiss, U.M.; Tuddenham, E.G.D.; Rosales, C.; Chowdary, P.; McIntosh, J.; Della Peruta, M.; Lheriteau, E.; Patel, N.; Raj, D.; Riddell, A.; Pie, J.; Rangarajan, S.; Bevan, D.; Recht, M.; Shen, Y.-M.; Halka, K.G.; Basner-Tschakarjan, E.; Mingozzi, F.; High, K.A.; Allay, J.; Kay, M.A.; Ng, C.Y.C.; Zhou, J.; Cancio, M.; Morton, C.L.; Gray, J.T.; Srivastava, D.; Nienhuis, A.W.; Davidoff, A.M.
2014-01-01
BACKGROUND In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose–response relationship, and the level of persistent or late toxicity. METHODS We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×1012 vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.) PMID:25409372
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Kim, Yeon-Ju; Ji, Seung Taek; Kim, Da Yeon; Jung, Seok Yun; Kang, Songhwa; Park, Ji Hye; Jang, Woong Bi; Yun, Jisoo; Ha, Jongseong; Lee, Dong Hyung; Kwon, Sang-Mo
2018-06-12
Endothelial progenitor cells (EPCs) and outgrowth endothelial cells (OECs) play a pivotal role in vascular regeneration in ischemic tissues; however, their therapeutic application in clinical settings is limited due to the low quality and quantity of patient-derived circulating EPCs. To solve this problem, we evaluated whether three priming small molecules (tauroursodeoxycholic acid, fucoidan, oleuropein) could enhance the angiogenic potential of EPCs. Such enhancement would promote the cellular bioactivities and help to develop functionally improved EPC therapeutics for ischemic diseases by accelerating the priming effect of the defined physiological molecules. We found that preconditioning of each of the three small molecules significantly induced the differentiation potential of CD34+ stem cells into EPC lineage cells. Notably, long-term priming of OECs with the three chemical cocktail (OEC-3C) increased the proliferation potential of EPCs via ERK activation. The migration, invasion, and tube-forming capacities were also significantly enhanced in OEC-3Cs compared with unprimed OECs. Further, the cell survival ratio was dramatically increased in OEC-3Cs against H2O2-induced oxidative stress via the augmented expression of Bcl-2, a prosurvival protein. In conclusion, we identified three small molecules for enhancing the bioactivities of ex vivo-expanded OECs for vascular repair. Long-term 3C priming might be a promising methodology for EPC-based therapy against ischemic diseases.
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Treatment of anorexia nervosa with long-term risperidone in an outpatient setting: case study.
Kracke, Elsa J; Tosh, Aneesh K
2014-01-01
There are currently few studies focusing on the efficacy of long-term atypical antipsychotics to treat anorexia nervosa in the pediatric population. This case report follows the treatment of a 17 year-old female with anorexia nervosa over her four-year undergraduate career. After two years of multidisciplinary treatment, low-dose risperidone was initiated due to persistence of her disease. She expressed decreased rigidity around meal times, her weight improved and she had resumption of menses. She was compliant with treatment through graduation and maintained her weight gain. Atypical antipsychotics are a treatment option in the management of anorexia nervosa. Risperidone has not been studied as frequently as olanzapine for eating disorders. Risperidone was chosen for its more favorable side effect profile and decreased cost to the patient. Previous studies on anorexia nervosa treatment have occurred during inpatient treatment and have limited follow-up due to patients' refusal to initiate or maintain medication compliance. This case presents 17 months of outpatient data. The efficacy of risperidone therapy was evaluated with frequent weight checks, subjective decrease in rigidity, serial complete metabolic panels, and restoration of menses. In this case report, an adolescent female treated with low-dose risperidone had decreased rigid thinking, weight gain and resolution of secondary amenorrhea without medication side effects. Therefore, the atypical antipsychotic risperidone may be an effective long-term outpatient treatment option for patients with anorexia nervosa.
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Ten-Year Recovery Outcomes for Clients With Co-Occurring Schizophrenia and Substance Use Disorders
Drake, Robert E.; McHugo, Gregory J.; Xie, Haiyi; Fox, Melinda; Packard, Joan; Helmstetter, Barbara
2006-01-01
The long-term courses of people with schizophrenia and of those with substance use disorder have been studied separately and extensively. The long-term course of clients with co-occurring schizophrenic and substance use disorders has, however, not been examined. This article reports 10-year outcomes for 130 clients with co-occurring schizophrenic and substance use disorders in the New Hampshire Dual Diagnosis Study. In addition, we report on 6 “recovery outcomes,” identified by dual diagnosis clients, as examples of positive coping behaviors. Longitudinal data were modeled using generalized estimating equation (GEE) methods. Participants improved steadily over 10 years in the outcome domains of symptoms, substance abuse, institutionalization, functional status, and quality of life. Further, at the 10-year follow-up, substantial proportions were above cutoffs selected by dual diagnosis clients as indicators of recovery: 62.7% were controlling symptoms of schizophrenia; 62.5% were actively attaining remissions from substance abuse; 56.8% were in independent living situations; 41.4% were competitively employed; 48.9% had regular social contacts with non–substance abusers; and 58.3% expressed overall life satisfaction. These 6 outcomes were only weakly interrelated over time, suggesting that recovery, as defined by clients, is a multidimensional concept. Overall, the 10-year findings on recovery outcomes provide a hopeful long-term perspective for dual diagnosis clients. PMID:16525088
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Ten-year recovery outcomes for clients with co-occurring schizophrenia and substance use disorders.
Drake, Robert E; McHugo, Gregory J; Xie, Haiyi; Fox, Melinda; Packard, Joan; Helmstetter, Barbara
2006-07-01
The long-term courses of people with schizophrenia and of those with substance use disorder have been studied separately and extensively. The long-term course of clients with co-occurring schizophrenic and substance use disorders has, however, not been examined. This article reports 10-year outcomes for 130 clients with co-occurring schizophrenic and substance use disorders in the New Hampshire Dual Diagnosis Study. In addition, we report on 6 "recovery outcomes," identified by dual diagnosis clients, as examples of positive coping behaviors. Longitudinal data were modeled using generalized estimating equation (GEE) methods. Participants improved steadily over 10 years in the outcome domains of symptoms, substance abuse, institutionalization, functional status, and quality of life. Further, at the 10-year follow-up, substantial proportions were above cutoffs selected by dual diagnosis clients as indicators of recovery: 62.7% were controlling symptoms of schizophrenia; 62.5% were actively attaining remissions from substance abuse; 56.8% were in independent living situations; 41.4% were competitively employed; 48.9% had regular social contacts with non-substance abusers; and 58.3% expressed overall life satisfaction. These 6 outcomes were only weakly interrelated over time, suggesting that recovery, as defined by clients, is a multidimensional concept. Overall, the 10-year findings on recovery outcomes provide a hopeful long-term perspective for dual diagnosis clients.
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Zou, Zhilu; Chen, Yin; Shen, Qinqin; Guo, Xiaoyan; Zhang, Yuxuan
2017-01-01
Yueju pill is a traditional Chinese medicine formulated to treat syndromes of mood disorders. Here, we investigated the therapeutic effect of repeated low dose of Yueju in the animal model mimicking clinical long-term depression condition and the role of neural plasticity associated with PKA- (protein kinase A-) CREB (cAMP response element binding protein) and NMDA (N-methyl-D-aspartate) signaling. We showed that a single low dose of Yueju demonstrated antidepressant effects in tests of tail suspension, forced swim, and novelty-suppressed feeding. A chronic learned helplessness (LH) protocol resulted in a long-term depressive-like condition. Repeated administration of Yueju following chronic LH remarkably alleviated all of depressive-like symptoms measured, whereas conventional antidepressant fluoxetine only showed a minor improvement. In the hippocampus, Yueju and fluoxetine both normalized brain-derived neurotrophic factor (BDNF) and PKA level. Only Yueju, not fluoxetine, rescued the deficits in CREB signaling. The chronic LH upregulated the expression of NMDA receptor subunits NR1, NR2A, and NR2B, which were all attenuated by Yueju. Furthermore, intracerebraventricular administration of NMDA blunted the antidepressant effect of Yueju. These findings supported the antidepressant efficacy of repeated routine low dose of Yueju in a long-term depression model and the critical role of CREB and NMDA signaling. PMID:29075536
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Zou, Zhilu; Chen, Yin; Shen, Qinqin; Guo, Xiaoyan; Zhang, Yuxuan; Chen, Gang
2017-01-01
Yueju pill is a traditional Chinese medicine formulated to treat syndromes of mood disorders. Here, we investigated the therapeutic effect of repeated low dose of Yueju in the animal model mimicking clinical long-term depression condition and the role of neural plasticity associated with PKA- (protein kinase A-) CREB (cAMP response element binding protein) and NMDA (N-methyl-D-aspartate) signaling. We showed that a single low dose of Yueju demonstrated antidepressant effects in tests of tail suspension, forced swim, and novelty-suppressed feeding. A chronic learned helplessness (LH) protocol resulted in a long-term depressive-like condition. Repeated administration of Yueju following chronic LH remarkably alleviated all of depressive-like symptoms measured, whereas conventional antidepressant fluoxetine only showed a minor improvement. In the hippocampus, Yueju and fluoxetine both normalized brain-derived neurotrophic factor (BDNF) and PKA level. Only Yueju, not fluoxetine, rescued the deficits in CREB signaling. The chronic LH upregulated the expression of NMDA receptor subunits NR1, NR2A, and NR2B, which were all attenuated by Yueju. Furthermore, intracerebraventricular administration of NMDA blunted the antidepressant effect of Yueju. These findings supported the antidepressant efficacy of repeated routine low dose of Yueju in a long-term depression model and the critical role of CREB and NMDA signaling.
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Zheng, Min; Mitra, Rajendra N; Filonov, Nazar A; Han, Zongchao
2016-03-01
Previously, we compared the efficacy of nanoparticle (NP)-mediated intron-containing rhodopsin (sgRho) vs. intronless cDNA in ameliorating retinal disease phenotypes in a rhodopsin knockout (RKO) mouse model of retinitis pigmentosa. We showed that NP-mediated sgRho delivery achieved long-term expression and phenotypic improvement in RKO mice, but not NP housing cDNA. However, the protein level of the NP-sgRho construct was only 5-10% of wild-type at 8 mo postinjection. To have a better understanding of the reduced levels of long-term expression of the vectors, in the present study, we evaluated the epigenetic changes of subretinal delivering NP-cDNA vs. NP-sgRho in the RKO mouse eyes. Following the administration, DNA methylation and histone status of specific regions (bacteria plasmid backbone, promoter, rhodopsin gene, and scaffold/matrix attachment region) of the vectors were evaluated at various time points. We documented that epigenetic transgene silencing occurred in vector-mediated gene transfer, which were caused by the plasmid backbone and the cDNA of the transgene, but not the intron-containing transgene. No toxicity or inflammation was found in the treated eyes. Our results suggest that cDNA of the rhodopsin transgene and bacteria backbone interfered with the host defense mechanism of DNA methylation-mediated transgene silencing through heterochromatin-associated modifications. © FASEB.
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ERIC Educational Resources Information Center
Fraize, Nicolas; Hamieh, Al Mahdy; Joseph, Mickael Antoine; Touret, Monique; Parmentier, Regis; Salin, Paul Antoine; Malleret, Gael
2017-01-01
Phosphorylation of CaMKII and AMPA receptor GluA1 subunit has been shown to play a major role in hippocampal-dependent long-term/reference memory (RM) and in the expression of long-term synaptic potentiation (LTP). In contrast, it has been proposed that dephosphorylation of these proteins could be involved in the opposite phenomenon of hippocampal…
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Enhancement of Immune Memory Responses to Respiratory Infection
2017-08-01
Unlimited Distribution 13. SUPPLEMENTARY NOTES 14. ABSTRACT Maintenance of long - term immunological memory against pathogens is crucial for the rapid...highly expressed in memory B cells in mice, and Atg7 is required for maintenance of long - term memory B cells needed to protect against influenza...AWARD NUMBER: W81XWH-16-1-0360 TITLE: Enhancement of Immune Memory Responses to Respiratory Infection PRINCIPAL INVESTIGATORs: Dr Min Chen PhD
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ERIC Educational Resources Information Center
Johnstone, Victoria P. A.; Raymond, Clarke R.
2011-01-01
Long-term potentiation (LTP) is an important process underlying learning and memory in the brain. At CA3-CA1 synapses in the hippocampus, three discrete forms of LTP (LTP1, 2, and 3) can be differentiated on the basis of maintenance and induction mechanisms. However, the relative roles of pre- and post-synaptic expression mechanisms in LTP1, 2,…
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Long-Term Durability of Pressure-Treated Wood in a Severe Test Site
Stan Lebow; Bessie Woodward; Grant Kirker; Patricia Lebow
2013-01-01
Improved estimates of the long-term durability of treated wood products are needed to guide choices about construction materials and allow estimates of design life. This report summarizes the long-term decay and insect resistance of treated wood post and lumber specimens placed in ground contact at a test site of the U.S. Department of Agriculture, Forest Service,...
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USDA-ARS?s Scientific Manuscript database
Best management practices (BMPs) are popular approaches used to improve hydrology and water quality. Uncertainties in BMP effectiveness over time may result in overestimating long-term efficiency in watershed planning strategies. To represent varying long-term BMP effectiveness in hydrologic/water q...
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Progress toward a non-viral gene therapy protocol for the treatment of anemia
Sebestyén, Magdolna G.; Hegge, Julia O.; Noble, Mark A.; Lewis, David L.; Herweijer, Hans; Wolff, Jon A.
2008-01-01
Anemia frequently accompanies chronic diseases such as progressive renal failure, AIDS and cancer. Patients are currently treated with erythropoietin (EPO) replacement therapy using various recombinant human EPO protein formulations. Although this treatment is effective, gene therapy could be more economical and more convenient for the long-term management of the disease. The objective of this study was to develop a naked DNA-based gene therapy protocol that could fill this need. The hydrodynamic limb vein technology has been shown to be an effective and safe procedure for delivering naked plasmid DNA (pDNA) into the skeletal muscles of the limb. Using this method, we addressed the major challenge of an EPO-based gene therapy of anemia: maintaining stable, long-term expression at a level that sufficiently promotes erythropoiesis without leading to polycythemia. The results of our study using a rat anemia model provide proof of principle that repeated delivery of small pDNA doses has an additive effect and can gradually lead to the correction of anemia without triggering excessive hemopoiesis. This simple method provides an alternative approach for regulating EPO expression. EPO expression was also proportional to the injected pDNA dose in non-human primates. In addition, long-term (over 450 days) expression was obtained after delivering rhesus EPO cDNA under the transcriptional control of the muscle-specific MCK promoter. In conclusion, these data suggest that the repeated delivery of small doses of EPO expressing pDNA into skeletal muscle is a promising, clinically viable approach to alleviate the symptoms of anemia. Overview summary We delivered various EPO-expressing naked pDNA constructs into the skeletal muscles of the limb by the minimally invasive, hydrodynamic limb vein (HLV) procedure. Serum EPO concentrations and the physiological response were pDNA dose-dependent both in rats and rhesus monkeys. The kinetics and longevity of expression were promoter-dependent. The mouse MCK promoter provided stable expression for well over a year, while the effect of the CMV promoter construct lasted only for 5–7 months. By using repeated, small-dose pDNA injections in a rat anemia model, EPO expression was controlled at the most fundamental level of the delivered gene dose. Our results suggest that this non-viral gene therapy approach provides safe and long-term solution for the treatment of chronic anemia and that it can be tailored to the individual needs of the patient. PMID:17376007
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Du, Fang; Ding, Ye; Zou, Jun; Li, Zhili; Tian, Jijing; She, Ruiping; Wang, Desheng; Wang, Huijuan; Lv, Dongqiang; Chang, Lingling
2015-01-01
This study investigated the effects of long-term simulated weightlessness on liver morphology, enzymes, glycogen, and apoptosis related proteins by using two-month rat-tail suspension model (TS), and liver injury improvement by rat-tail suspension with resistance training model (TS&RT). Microscopically the livers of TS rats showed massive granular degeneration, chronic inflammation, and portal fibrosis. Mitochondrial and endoplasmic reticulum swelling and loss of membrane integrity were observed by transmission electron microscopy (TEM). The similar, but milder, morphological changes were observed in the livers of TS&RT rats. Serum biochemistry analysis revealed that the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly higher (p<0.05) in TS rats than in controls. The levels of ALT and AST in TS&RT rats were slightly lower than in RT rats, but they were insignificantly higher than in controls. However, both TS and TS&RT rats had significantly lower levels (p<0.05) of serum glucose and hepatic glycogen than in controls. Immunohistochemistry demonstrated that the expressions of Bax, Bcl-2, and active caspase-3 were higher in TS rats than in TS&RT and control rats. Real-time polymerase chain reaction (real-time PCR) showed that TS rats had higher mRNA levels (P < 0.05) of glucose-regulated protein 78 (GRP78) and caspase-12 transcription than in control rats; whereas mRNA expressions of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) were slightly higher in TS rats. TS&RT rats showed no significant differences of above 4 mRNAs compared with the control group. Our results demonstrated that long-term weightlessness caused hepatic injury, and may trigger hepatic apoptosis. Resistance training slightly improved hepatic damage.
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Zou, Jun; Li, Zhili; Tian, Jijing; She, Ruiping; Wang, Desheng; Wang, Huijuan; Lv, Dongqiang; Chang, Lingling
2015-01-01
This study investigated the effects of long-term simulated weightlessness on liver morphology, enzymes, glycogen, and apoptosis related proteins by using two-month rat-tail suspension model (TS), and liver injury improvement by rat-tail suspension with resistance training model (TS&RT). Microscopically the livers of TS rats showed massive granular degeneration, chronic inflammation, and portal fibrosis. Mitochondrial and endoplasmic reticulum swelling and loss of membrane integrity were observed by transmission electron microscopy (TEM). The similar, but milder, morphological changes were observed in the livers of TS&RT rats. Serum biochemistry analysis revealed that the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly higher (p<0.05) in TS rats than in controls. The levels of ALT and AST in TS&RT rats were slightly lower than in RT rats, but they were insignificantly higher than in controls. However, both TS and TS&RT rats had significantly lower levels (p<0.05) of serum glucose and hepatic glycogen than in controls. Immunohistochemistry demonstrated that the expressions of Bax, Bcl-2, and active caspase-3 were higher in TS rats than in TS&RT and control rats. Real-time polymerase chain reaction (real-time PCR) showed that TS rats had higher mRNA levels (P < 0.05) of glucose-regulated protein 78 (GRP78) and caspase-12 transcription than in control rats; whereas mRNA expressions of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) were slightly higher in TS rats. TS&RT rats showed no significant differences of above 4 mRNAs compared with the control group. Our results demonstrated that long-term weightlessness caused hepatic injury, and may trigger hepatic apoptosis. Resistance training slightly improved hepatic damage. PMID:26000905
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Merema, Matt R; Speelman, Craig P
2015-01-01
It has been suggested that unmasked repetition priming is composed of distinct long-and short-term priming components. The current study sought to clarify the relationship between these components by examining the relationship between them. A total of 60 people (45 females, 15 males) participated in a computer-based lexical decision task designed to measure levels of short-term priming across different levels of long-term priming. The results revealed an interdependent relationship between the two components, whereby an increase in long-term priming prompted a decrease in short-term priming. Both long-term and short-term priming were accurately captured by a single power function over seven minutes post repetition, suggesting the two components may draw on the same resources. This interdependence between long- and short-term priming may serve to improve fluency in reading.
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Long-term follow-up of disease-specific quality of life after bariatric surgery.
Biron, Simon; Biertho, Laurent; Marceau, Simon; Lacasse, Yves
2018-05-01
Substantial improvements in health-related quality of life measured by generic questionnaires (most often the Short Form-36) have been noted over the long term in patients with morbid obesity who had undergone bariatric surgery. To obtain long-term follow-up data on disease-specific quality of life in patients who underwent bariatric surgery (biliopancreatic diversion with duodenal switch) in 2007 to 2008. Québec Heart and Lung Institute, Québec, Canada. This study is a follow-up of the validation study, the Laval Questionnaire, an obesity-specific measure of health-related quality of life developed to be used in clinical trials. Patients who contributed to the validation study in 2007 to 2008 were administered the Laval Questionnaire again at long-term follow-up. Of 112 patients who contributed to the validation study, 90 were available for this long-term follow-up study (retention rate: 80%). Median follow-up was 8.8 years. For all 6 domains of the Laval Questionnaire, the improvements in quality-of-life scores were much larger than our best estimate of the minimal clinically important difference. In others, we observed some decline in quality-of-life scores over time after initial changes that occurred 1 to 2 years after surgery, during the so-called "honeymoon period." Improvements in quality of life were clearly related to surgery. This study confirms that bariatric surgery using biliopancreatic diversion with duodenal switch improves disease-specific quality of life in the short and long term. It also demonstrates that the Laval Questionnaire is responsive to treatment-induced changes. Copyright © 2018 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.
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NASA Astrophysics Data System (ADS)
Popova, Nina; Shenkman, Boris; Naumenko, Vladimir; Kulikov, Alexander; Kondaurova, Elena; Tsybko, Anton; Kulikova, Elisabeth; Krasnov, I. B.; Bazhenova, Ekaterina; Sinyakova, Nadezhda
The effect of long-term spaceflight on the central nervous system represents important but yet undeveloped problem. The aim of our work was to study the effect of 30-days spaceflight of mice on Russian biosatellite BION-M1 on the expression in the brain regions of key genes of a) serotonin (5-HT) system (main enzymes in 5-HT metabolism - tryptophan hydroxylase-2 (TPH-2), monoamine oxydase A (MAO A), 5-HT1A, 5-HT2A and 5-HT3 receptors); b) pivotal enzymes in DA metabolism (tyrosine hydroxylase, COMT, MAO A, MAO B) and D1, D2 receptors. Decreased expression of genes encoding the 5-HT catabolism (MAO A) and 5-HT2A receptor in some brain regions was shown. There were no differences between “spaceflight” and control mice in the expression of TPH-2 and 5-HT1A, 5-HT3 receptor genes. Significant changes were found in genetic control of DA system. Long-term spaceflight decreased the expression of genes encoding the enzyme in DA synthesis (tyrosine hydroxylase in s.nigra), DA metabolism (MAO B in the midbrain and COMT in the striatum), and D1 receptor in hypothalamus. These data suggested that 1) microgravity affected genetic control of 5-HT and especially the nigrostriatal DA system implicated in the central regulation of muscular tonus and movement, 2) the decrease in the expression of genes encoding key enzyme in DA synthesis, DA degradation and D1 receptor contributes to the movement impairment and dyskinesia produced by the spaceflight. The study was supported by Russian Foundation for Basic Research grant No. 14-04-00173.
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Takahagi, Kotaro; Inoue, Komaki; Shimizu, Minami; Uehara-Yamaguchi, Yukiko; Onda, Yoshihiko; Mochida, Keiichi
2018-04-01
Allopolyploid plants often show wider environmental tolerances than their ancestors; this is expected to be due to the merger of multiple distinct genomes with a fixed heterozygosity. The complex homoeologous gene expression could have been evolutionarily advantageous for the adaptation of allopolyploid plants. Despite multiple previous studies reporting homoeolog-specific gene expression in allopolyploid species, there are no clear examples of homoeolog-specific function in acclimation to a long-term stress condition. We found that the allopolyploid grass Brachypodium hybridum and its ancestor Brachypodium stacei show long-term heat stress tolerance, unlike its other ancestor, Brachypodium distachyon. To understand the physiological traits of B. hybridum, we compared the transcriptome of the 3 Brachypodium species grown under normal and heat stress conditions. We found that the expression patterns of approximately 26% and approximately 38% of the homoeolog groups in B. hybridum changed toward nonadditive expression and nonancestral expression, respectively, under normal condition. Moreover, we found that B. distachyon showed similar expression patterns between normal and heat stress conditions, whereas B. hybridum and B. stacei significantly altered their transcriptome in response to heat after 3 days of stress exposure, and homoeologs that were inherited from B. stacei may have contributed to the transcriptional stress response to heat in B. hybridum. After 15 days of heat exposure, B. hybridum and B. stacei maintained transcriptional states similar to those under normal conditions. These results suggest that an earlier response to heat that was specific to homoeologs originating from B. stacei contributed to cellular homeostasis under long-term heat stress in B. hybridum. Our results provide insights into different regulatory events of the homoeo-transcriptome that are associated with stress acclimation in allopolyploid plants.
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Li, Wennan; Chen, Xingjuan; Riley, Ashley M; Hiett, S Christopher; Temm, Constance J; Beli, Eleni; Long, Xin; Chakraborty, Saikat; Alloosh, Mouhamad; White, Fletcher A; Grant, Maria B; Sturek, Michael; Obukhov, Alexander G
2017-09-01
Coronary transient receptor potential canonical (TRPC) channel expression is elevated in metabolic syndrome (MetS). However, differential contribution of TRPCs to coronary pathology in MetS is not fully elucidated. We investigated the roles of TRPC1 and TRPC6 isoforms in coronary arteries of MetS pigs and determined whether long-term treatment with a mineralocorticoid receptor inhibitor, spironolactone, attenuates coronary TRPC expression and associated dysfunctions. MetS coronary arteries exhibited significant atherosclerosis, endothelial dysfunction, and increased histamine-induced contractions. Immunohistochemical studies revealed that TRPC6 immunostaining was significantly greater in the medial layer of MetS pig coronary arteries compared to that in Lean pigs, whereas little TRPC6 immunostaining was found in atheromas. Conversely, TRPC1 immunostaining was weak in the medial layer but strong in MetS atheromas, where it was predominantly localized to macrophages. Spironolactone treatment significantly decreased coronary TRPC expression and dysfunctions in MetS pigs. In vivo targeted delivery of the dominant-negative (DN)-TRPC6 cDNA to the coronary wall reduced histamine-induced calcium transients in the MetS coronary artery medial layer, implying a role for TRPC6 in mediating calcium influx in MetS coronary smooth muscles. Monocyte adhesion was increased in Lean pig coronary arteries cultured in the presence of aldosterone; and spironolactone antagonized this effect, suggesting that coronary mineralocorticoid receptor activation may regulate macrophage infiltration. TRPC1 expression in atheroma macrophages was associated with advanced atherosclerosis, whereas medial TRPC6 upregulation correlated with increased histamine-induced calcium transients and coronary contractility. We propose that long-term spironolactone treatment may be a therapeutic strategy to decrease TRPC expression and coronary pathology associated with MetS.
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Roach, Kathryn E.; Tappen, Ruth M.; Kirk-Sanchez, Neva; Williams, Christine L.; Loewenstein, David
2011-01-01
Objective To determine whether an activity specific exercise program could improve ability to perform basic mobility activities in long-term care residents with Alzheimer disease (AD). Design Randomized, controlled, single-blinded clinical trial. Setting Residents of 7 long-term care facilities. Participants Eighty-two long-term care residents with mild to severe AD. Intervention An activity specific exercise program was compared to a walking program and to an attention control. Measurements Ability to perform bed mobility and transfers were assessed using the subscales of the Acute Care Index of Function; functional mobility was measured using the 6-Minute Walk test. Results Subjects receiving the activity specific exercise program improved in ability to perform transfers, whereas subjects in the other 2 groups declined. PMID:21937893
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Evaluating and improving pressure ulcer care: the VA experience with administrative data.
Berlowitz, D R; Halpern, J
1997-08-01
A number of state initiatives are using databases originally developed for nursing home reimbursements to assess the quality of care. Since 1991 the Department of Veterans Affairs (VA; Washington, DC) has been using a long term care administrative database to calculate facility-specific rates of pressure ulcer development. This information is disseminated to all 140 long term care facilities as part of a quality assessment and improvement program. Assessments are performed on all long term care residents on April 1 and October 1, as well as at the time of admission or transfer to a long term care unit. Approximately 18,000 long term care residents are evaluated in each six-month period; the VA rate of pressure ulcer development is approximately 3.5%. Reports of the rates of pressure ulcer development are then disseminated to all facilities, generally within two months of the assessment date. The VA's more than five years' experience in using administrative data to assess outcomes for long term care highlights several important issues that should be considered when using outcome measures based on administrative data. These include the importance of carefully selecting the outcome measure, the need to consider the structure of the database, the role of case-mix adjustment, strategies for reporting rates to small facilities, and methods for information dissemination. Attention to these issues will help ensure that results from administrative databases lead to improvements in the quality of care.
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Catic, Angela G; Mattison, Melissa L P; Bakaev, Innokentiy; Morgan, Marisa; Monti, Sara M; Lipsitz, Lewis
2014-12-01
To design, implement, and assess the pilot phase of an innovative, remote case-based video-consultation program called ECHO-AGE that links experts in the management of behavior disorders in patients with dementia to nursing home care providers. Pilot study involving surveying of participating long-term care sites regarding utility of recommendations and resident outcomes. Eleven long-term care sites in Massachusetts and Maine. An interprofessional specialty team at a tertiary care center and staff from 11 long-term care sites. Long-term care sites presented challenging cases regarding residents with dementia and/or delirium related behavioral issues to specialists via video-conferencing. Baseline resident characteristics and follow-up data regarding compliance with ECHO-AGE recommendations, resident improvement, hospitalization, and mortality were collected from the long-term care sites. Forty-seven residents, with a mean age of 82 years, were presented during the ECHO-AGE pilot period. Eighty-three percent of residents had a history of dementia and 44% were taking antipsychotic medications. The most common reasons for presentation were agitation, intrusiveness, and paranoia. Behavioral plans were recommended in 72.3% of patients. Suggestions for medication adjustments were also frequent. ECHO-AGE recommendations were completely or partially followed in 88.6% of residents. When recommendations were followed, sites were much more likely to report clinical improvement (74% vs 20%, P < .03). Hospitalization was also less common among residents for whom recommendations were followed. The results suggest that a case-based video-consultation program can be successful in improving the care of elders with dementia and/or delirium related behavioral issues by linking specialists with long-term care providers. Published by Elsevier Inc.
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Royo, Jose Luis; Moreno-Ruiz, Emilia; Cebolla, Angel; Santero, Eduardo
2005-03-16
In our laboratory we have analyzed different factors to maximize the yield in heterologous protein expression for long-term cultivation, by combination of an efficient cascade expression system and stable integration in the bacterial chromosome. In this work, we have explored this system for the production of indigo dye as a model for biotechnological production, by expressing in Escherichia coli the thnA1A2A3A4 genes from Sphingomonas macrogolitabida strain TFA, which encode the components of a tetralin dioxygenase activity. We compared Ptac, and the Pm-based cascade expression circuit in a multicopy plasmid and stably integrated into the bacterial chromosome. Plasmid-based expression systems resulted in instability of indigo production when serially diluted batch experiments were performed without a selective pressure. This problem was solved by integrating the expression module in the chromosome. Despite the gene dosage reduction, the synergic effect of the cascade expression system produced comparable expression to the dioxygenase activity in the plasmid configuration but could be stably maintained for at least 5 days. Here, we show that the cascade amplification circuit integrated in the chromosome could be an excellent system for tight control and stable production of recombinant products.
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Long-term exercise-specific neuroprotection in spinal muscular atrophy-like mice.
Chali, Farah; Desseille, Céline; Houdebine, Léo; Benoit, Evelyne; Rouquet, Thaïs; Bariohay, Bruno; Lopes, Philippe; Branchu, Julien; Della Gaspera, Bruno; Pariset, Claude; Chanoine, Christophe; Charbonnier, Frédéric; Biondi, Olivier
2016-04-01
The real impact of physical exercise parameters, i.e. intensity, type of contraction and solicited energetic metabolism, on neuroprotection in the specific context of neurodegeneration remains poorly explored. In this study behavioural, biochemical and cellular analyses were conducted to compare the effects of two different long-term exercise protocols, high intensity swimming and low intensity running, on motor units of a type 3 spinal muscular atrophy (SMA)-like mouse model. Our data revealed a preferential SMA-induced death of intermediate and fast motor neurons which was limited by the swimming protocol only, suggesting a close relationship between neuron-specific protection and their activation levels by specific exercise. The exercise-induced neuroprotection was independent of SMN protein expression and associated with specific metabolic and behavioural adaptations with notably a swimming-induced reduction of muscle fatigability. Our results provide new insight into the motor units' adaptations to different physical exercise parameters and will contribute to the design of new active physiotherapy protocols for patient care. Spinal muscular atrophy (SMA) is a group of autosomal recessive neurodegenerative diseases differing in their clinical outcome, characterized by the specific loss of spinal motor neurons, caused by insufficient level of expression of the protein survival of motor neuron (SMN). No cure is at present available for SMA. While physical exercise might represent a promising approach for alleviating SMA symptoms, the lack of data dealing with the effects of different exercise types on diseased motor units still precludes the use of active physiotherapy in SMA patients. In the present study, we have evaluated the efficiency of two long-term physical exercise paradigms, based on either high intensity swimming or low intensity running, in alleviating SMA symptoms in a mild type 3 SMA-like mouse model. We found that 10 months' physical training induced significant benefits in terms of resistance to muscle damage, energetic metabolism, muscle fatigue and motor behaviour. Both exercise types significantly enhanced motor neuron survival, independently of SMN expression, leading to the maintenance of neuromuscular junctions and skeletal muscle phenotypes, particularly in the soleus, plantaris and tibialis of trained mice. Most importantly, both exercises significantly improved neuromuscular excitability properties. Further, all these training-induced benefits were quantitatively and qualitatively related to the specific characteristics of each exercise, suggesting that the related neuroprotection is strongly dependent on the specific activation of some motor neuron subpopulations. Taken together, the present data show significant long-term exercise benefits in type 3 SMA-like mice providing important clues for designing rehabilitation programmes in patients. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.
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Knekt, Paul; Lindfors, Olavi; Keinänen, Matti; Heinonen, Erkki; Virtala, Esa; Härkänen, Tommi
2017-09-01
How level of personality organization (LPO) predicts psychiatric symptoms and work ability in short- versus long-term psychotherapies is poorly known. We investigated the importance of the LPO on the benefits of short-term versus long-term psychotherapies. A cohort study based on 326 outpatients with mood or anxiety disorder was allocated to long-term (LPP) and short-term (SPP) psychodynamic psychotherapy, and solution-focused therapy (SFT). The LPO was assessed by interview at baseline and categorized into neuroses and higher level borderline. Outcome was assessed at baseline and 4-9 times during a 5-year follow-up, using self-report and interview-based measures of symptoms and work ability. For patients receiving SPP, improvement in work ability, symptom reduction, and the remission rate were more considerable in patients with neuroses than in higher level borderline patients, whereas LPP or SFT showed no notable differences in effectiveness in the two LPO groups. In patients with neuroses, improvement was more considerable in the short-term therapy groups during the first year of follow-up, and in higher level borderline patients LPP was more effective after 3 years of follow-up. The remission rate, defined as both symptom reduction and lack of auxiliary treatment, was higher in LPP than in SPP for both the LPO groups considered. In neuroses, short-term psychotherapy was associated with a more rapid reduction of symptoms and increase in work ability, whereas LPP was more effective for longer follow-ups in both LPO groups. Further large-scale studies are needed. Level of personality organization is relevant for selection between short- and long-term psychotherapies. Short-term therapy gives faster benefits for neurotic patients but not for patients with higher level borderline personality organization. Sustained remission from symptoms is more probable after long-term than short-term therapy. © 2016 The British Psychological Society.
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Sharma, Nynne; Hollensen, Anne Kruse; Bak, Rasmus O; Staunstrup, Nicklas Heine; Schrøder, Lisbeth Dahl; Mikkelsen, Jacob Giehm
2012-01-01
DNA transposons have become important vectors for efficient non-viral integration of transgenes into genomic DNA. The Sleeping Beauty (SB), piggyBac (PB), and Tol2 transposable elements have distinct biological properties and currently represent the most promising transposon systems for animal transgenesis and gene therapy. A potential obstacle, however, for persistent function of integrating vectors is transcriptional repression of the element and its genetic cargo. In this study we analyze the insulating effect of the 1.2-kb 5'-HS4 chicken β-globin (cHS4) insulator element in the context of SB, PB, and Tol2 transposon vectors. By examining transgene expression from genomically inserted transposon vectors encoding a marker gene driven by a silencing-prone promoter, we detect variable levels of transcriptional silencing for the three transposon systems in retinal pigment epithelium cells. Notably, the PB system seems less vulnerable to silencing. Incorporation of cHS4 insulator sequences into the transposon vectors results in 2.2-fold and 1.5-fold increased transgene expression levels for insulated SB and PB vectors, respectively, but an improved persistency of expression was not obtained for insulated transgenes. Colony formation assays and quantitative excision assays unveil enhanced SB transposition efficiencies by the inclusion of the cHS4 element, resulting in a significant increase in the stable transfection rate for insulated SB transposon vectors in human cell lines. Our findings reveal a positive impact of cHS4 insulator inclusion for SB and PB vectors in terms of increased transgene expression levels and improved SB stable transfection rates, but also the lack of a long-term protective effect of the cHS4 insulator against progressive transgene silencing in retinal pigment epithelium cells.
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Sharma, Nynne; Hollensen, Anne Kruse; Bak, Rasmus O.; Staunstrup, Nicklas Heine; Schrøder, Lisbeth Dahl; Mikkelsen, Jacob Giehm
2012-01-01
DNA transposons have become important vectors for efficient non-viral integration of transgenes into genomic DNA. The Sleeping Beauty (SB), piggyBac (PB), and Tol2 transposable elements have distinct biological properties and currently represent the most promising transposon systems for animal transgenesis and gene therapy. A potential obstacle, however, for persistent function of integrating vectors is transcriptional repression of the element and its genetic cargo. In this study we analyze the insulating effect of the 1.2-kb 5′-HS4 chicken β-globin (cHS4) insulator element in the context of SB, PB, and Tol2 transposon vectors. By examining transgene expression from genomically inserted transposon vectors encoding a marker gene driven by a silencing-prone promoter, we detect variable levels of transcriptional silencing for the three transposon systems in retinal pigment epithelium cells. Notably, the PB system seems less vulnerable to silencing. Incorporation of cHS4 insulator sequences into the transposon vectors results in 2.2-fold and 1.5-fold increased transgene expression levels for insulated SB and PB vectors, respectively, but an improved persistency of expression was not obtained for insulated transgenes. Colony formation assays and quantitative excision assays unveil enhanced SB transposition efficiencies by the inclusion of the cHS4 element, resulting in a significant increase in the stable transfection rate for insulated SB transposon vectors in human cell lines. Our findings reveal a positive impact of cHS4 insulator inclusion for SB and PB vectors in terms of increased transgene expression levels and improved SB stable transfection rates, but also the lack of a long-term protective effect of the cHS4 insulator against progressive transgene silencing in retinal pigment epithelium cells. PMID:23110238
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Kulikova, E A; Kulikov, V A; Sinyakova, N A; Kulikov, A V; Popova, N K
2017-02-15
The study of spaceflight effects on the brain is technically complex concern; complicated by the problem of applying an adequate ground model. The most-widely used experimental model to study the effect of microgravity is the tail-suspension hindlimb unloading model; however, its compliance with the effect of actual spaceflight on the brain is still unclear. We evaluated the effect of one month hindlimb unloading on the expression of genes related to the brain neuroplasticity-brain neutotrophic factors (Gdnf, Cdnf), apoptotic factors (Bcl-xl, Bax), serotonin- and dopaminergic systems (5-HT 2A , Maoa, Maob, Th, D1r, Comt), and compared the results with the data obtained on mice that spent one month in spaceflight on Russian biosatellite Bion-M1. No effect of hindlimb unloading was observed on the expression of most genes, which were considered as risk neurogenes for long-term actual spaceflight. The opposite effect of hindlimb unloading and spaceflight was found on the level of mRNA of D1 dopamine receptor and catechol-O-methyltransferase in the striatum. At the same time, the expression of Maob in the midbrain decreased, and the expression of Bcl-xl genes increased in the hippocampus, which corresponds to the effect of spaceflight. However, the hindlimb unloading model failed to reproduce the majority of effects of long-term spaceflight on serotonin-, dopaminergic systems and some apoptotic factors. Copyright © 2017 Elsevier B.V. All rights reserved.
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Zhang, Guicheng; Wang, Kui; Schultz, Ennee; Khoo, Siew-Kim; Zhang, Xiaopeng; Annamalay, Alicia; Laing, Ingrid A; Hales, Belinda J; Goldblatt, Jack; Le Souëf, Peter N
2016-01-01
Several human diseases and conditions are disproportionally distributed in the world with a significant "Western-developed" vs. "Eastern-developing" gradient. We compared genome-wide DNA methylation of peripheral blood mononuclear cells in 25 newly arrived Chinese immigrants living in a Western environment for less than 6 months ("Newly arrived") with 23 Chinese immigrants living in the Western environment for more than two years ("Long-term") with a mean of 8.7 years, using the Infinium HumanMethylation450 BeadChip. In a sub-group of both subject groups (n = 12 each) we also investigated genome-wide gene expression using a Human HT-12 v4 expression beadChip. There were 62.5% probes among the total number of 382,250 valid CpG sites with greater mean Beta (β) in "Long-term" than in "Newly arrived". In the regions of CpG islands and gene promoters, compared with the CpG sites in all other regions, lower percentages of CpG sites with mean methylation levels in "Long-term" greater than "Newly arrived" were observed, but still >50%. The increase of methylation was associated with a general decrease of gene expression in Chinese immigrants living in the Western environment for a longer period of time. After adjusting for age, gender and other confounding factors the findings remained. Chinese immigrants living in Australia for a longer period of time have increased overall genome methylation and decreased overall gene expression compared with newly arrived immigrants. © 2015 Wiley Periodicals, Inc.
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Ramírez, M Á; Pericuesta, E; Yáñez-Mó, M; Palasz, A; Gutiérrez-Adán, A
2011-02-01
Maintaining undifferentiated stem cells in defined conditions is of critical importance to improve their in vitro culture. We have evaluated the effects of culturing mouse stem (mES) cells under physiological oxygen concentration as well as by replacing fibroblast feeder layer (mEF) with gelatin or glycosaminoglycan hyaluronan (HA), on cell proliferation and differentiation. After 3 days culture or after long-term cell culture under different conditions, levels of apoptotic cell death were determined by cell cycle and TUNEL (TdT-mediated dUTP nick end labelling) assays and levels of cell proliferation by CFSE (5-(and-6)-carboxyfluorescein diacetate succinimidyl ester) labelling. We assessed spontaneous differentiation into cardiomyocytes and mRNA expression of pluripotency and differentiation biomarkers. After 3 days culture under hypoxic conditions, levels of proliferation and apoptosis of mES cells were higher, in correlation with increase in intracellular reactive oxygen species. However, when cells were continuously grown for 1 month under those conditions, the level of apoptosis was, in all cases, under 4%. Hypoxia reduced spontaneous differentiation of mES into cardiomyocytes. Long-term culture on HA was more effective in maintaining the pluripotent state of the mES cells when compared to that on gelatin. Level of terminal differentiation was highest on mEF, intermediate on HA and lowest on gelatin. Our data suggest that hypoxia is not necessary for maintaining pluripotency of mES cells and appeared to be detrimental during ES differentiation. Moreover, HA may offer a valuable alternative for long-term culture of mES cells in vitro. © 2010 Blackwell Publishing Ltd.
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Rabbitts, Jennifer A; Aaron, Rachel V; Fisher, Emma; Lang, Emily A; Bridgwater, Caroline; Tai, Gabrielle Ghafari; Palermo, Tonya M
2017-07-01
Research developing targeted treatment focused on coping with children's long-term pain after surgery is needed because of the high prevalence of chronic pain after surgery. This qualitative study aimed to: 1) understand the child's and family's experiences of pain over the course of their surgical experience, and 2) gather stakeholder input regarding potential barriers and facilitators of perioperative intervention delivery. Fifteen children ages 10 to 18 years who underwent recent major surgery, their primary caregivers, and 17 perioperative health care providers were interviewed. Interviews were coded using semantic thematic analysis. The perioperative period presented emotional challenges for families. Families felt unprepared for surgery and pain. Recovery and regaining physical functioning at home was challenging. Families struggled to return to valued activities. Families reported interest in a perioperative psychosocial intervention. Providers endorsed that families would benefit from enhanced coping skills. They emphasized that families would benefit from more detailed preparatory information. Providers suggested that flexible intervention delivery at home would be ideal. Research developing interventions addressing pain and anxiety in children undergoing major surgery is critically needed. The findings of the present study can inform intervention development with the aim of improving short- as well as long-term recovery in children undergoing major surgery. This qualitative study examined children and their parents' experience of long-term pain and recovery after major surgery, identifying barriers and facilitators of perioperative intervention delivery. Families experienced surgery as stressful, and felt underprepared for pain and recovery. Families and health care providers expressed interest in a preoperative intervention teaching coping skills. Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.
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Mihaljevic, Susan E; Howard, Valerie M
2016-01-01
Improving resident safety and quality of care by maximizing interdisciplinary communication among long-term care providers is essential in meeting the goals of the United States' Federal Health care reform. The new Triple Aim goals focus on improved patient outcomes, increasing patient satisfaction, and decreased health care costs, thus providing consumers with quality, efficient patient-focused care. Within the United States, sepsis is the 10th leading cause of death with a 28.6% mortality rate in the elderly, increasing to 40% to 60% in septic shock. As a result of the Affordable Care Act, the Centers for Medicare & Medicaid services supported the Interventions to Reduce Acute Care Transfers 3.0 program to improve health care quality and prevent avoidable rehospitalization by improving assessment, documentation, and communication among health care providers. The Interventions to Reduce Acute Care Transfers 3.0 tools were incorporated in interprofessional sepsis simulations throughout 19 long-term care facilities to encourage the early recognition of sepsis symptoms and prompt communication of sepsis symptoms among interdisciplinary teams. As a result of this simulation training, many long-term care organizations have adopted the STOP and WATCH and SBAR tools as a venue to communicate resident condition changes.
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Fleiszer, Andrea R; Semenic, Sonia E; Ritchie, Judith A; Richer, Marie-Claire; Denis, Jean-Louis
2016-04-01
To describe how actions of nursing unit leaders influenced the long-term sustainability of a best practice guidelines (BPG) program on inpatient units. Several factors influence the initial implementation of evidence-based practice improvements in nursing, with leadership recognized as essential. However, there is limited knowledge about enduring change, including how frontline nursing leaders influence the sustainability of practice improvements over the long term. A qualitative descriptive case study included 39 in-depth interviews, observations, and document reviews. Four embedded nursing unit subcases had differing levels of program sustainability at 7 years (average) following implementation. Higher levels of BPG sustainability occurred on units where formal leadership teams used an integrated set of strategies and activities. Two key strategies were maintaining priorities and reinforcing expectations. The coordinated use of six activities (e.g., discussing, evaluating, integrating) promoted the continuation of BPG practices among staff. These leadership processes, fostering exchange and learning, contributed to sustainability-promoting environments characterized by teamwork and accountability. Unit leaders are required to strategically orchestrate several overlapping and synergistic efforts to achieve long-term sustainability of BPG-based practice improvements. As part of managing overall unit performance, unit leaders may influence practice improvement sustainability by aligning vision, strategies, and activities. © 2015 John Wiley & Sons Ltd.
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Postnikova, T Y; Zubareva, O E; Kovalenko, A A; Kim, K K; Magazanik, L G; Zaitsev, A V
2017-03-01
Cognitive deficits and memory loss are frequent in patients with temporal lobe epilepsy. Persistent changes in synaptic efficacy are considered as a cellular substrate underlying memory processes. Electrophysiological studies have shown that the properties of short-term and long-term synaptic plasticity in the cortex and hippocampus may undergo substantial changes after seizures. However, the neural mechanisms responsible for these changes are not clear. In this study, we investigated the properties of short-term and long-term synaptic plasticity in rat hippocampal slices 24 h after pentylenetetrazole (PTZ)-induced status epilepticus. We found that the induction of long-term potentiation (LTP) in CA1 pyramidal cells is reduced compared to the control, while short-term facilitation is increased. The experimental results do not support the hypothesis that status epilepticus leads to background potentiation of hippocampal synapses and further LTP induction becomes weaker due to occlusion, as the dependence of synaptic responses on the strength of input stimulation was not different in the control and experimental animals. The decrease in LTP can be caused by impairment of molecular mechanisms of neuronal plasticity, including those associated with NMDA receptors and/or changes in their subunit composition. Real-time PCR demonstrated significant increases in the expression of GluN1 and GluN2A subunits 3 h after PTZ-induced status epilepticus. The overexpression of obligate GluN1 subunit suggests an increase in the total number of NMDA receptors in the hippocampus. A 3-fold increase in the expression of the GluN2B subunit observed 24 h after PTZ-induced status epilepticus might be indicative of an increase in the proportion of GluN2B-containing NMDA receptors. Increased expression of the GluN2B subunit may be a cause for reducing the magnitude of LTP at hippocampal synapses after status epilepticus.
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Lofrano-Prado, Mara Cristina; Antunes, Hanna Karen Moreira; Prado, Wagner Luiz do; de Piano, Aline; Caranti, Danielle Arisa; Tock, Lian; Carnier, June; Tufik, Sergio; de Mello, Marco Túlio; Dâmaso, Ana R
2009-01-01
Background Obesity has adverse physical, social, and economic consequences that can negatively affect quality of life (QOL). Thus the aim of this study was to verify the effects of a long-term multidisciplinary lifestyle intervention on QOL, body image, anxiety, depression and binge eating in obese adolescents. Methods Sixty-six obese adolescents (41 girls and 25 boys; BMI: 35.62 ± 4.18 kg/m2) were recruited from the Multidisciplinary Obesity Intervention Program outpatient clinic, and were submitted to a multidisciplinary lifestyle therapy (short-term = 12 weeks and long-term = 24 weeks), composed of medical, dietary, exercise and psychological programs. Validated self-report questionnaires were used to assess symptoms of anxiety Trait/State (STAI); depression (BDI); binge eating (BES), body image dissatisfaction (BSQ) and QOL (SF-36). Data were analyzed by means of scores; comparisons were made by ANOVA for repeated measures, and Tukey's test as post-hoc and Students T test. Results Long-term therapy decreased depression and binge eating symptoms, body image dissatisfaction, and improved QOL in girls, whereas, for boys, 24 weeks, were effective to reduce anxiety trait/state and symptoms of binge eating, and to improve means of dimensions of QOL (p < .05). Conclusion A long-term multidisciplinary lifestyle therapy is effective to control psychological aspects and to improve QOL in obese adolescents. PMID:19575801
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Promoting Healthy Weight with "Stability Skills First": A Randomized Trial
ERIC Educational Resources Information Center
Kiernan, Michaela; Brown, Susan D.; Schoffman, Danielle E.; Lee, Katherine; King, Abby C.; Taylor, C. Barr; Schleicher, Nina C.; Perri, Michael G.
2013-01-01
Objective: Although behavioral weight-loss interventions produce short-term weight loss, long-term maintenance remains elusive. This randomized trial examined whether learning a novel set of "stability skills" before losing weight improved long-term weight management. Stability skills were designed to optimize individuals' current…
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Enabling the Future: Linking Science and Technology to Societal Goals. A Report.
ERIC Educational Resources Information Center
Carnegie Commission on Science, Technology, and Government, New York, NY.
This report seeks ways to improve the knowledge, understanding, and information available to the federal government on the long-term nature of the science and technology (S&T) enterprise as it relates to societal goals. The recommendations focus on a few key issues: improving the national capacity to define and revise long-term S&T goals; linking…
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ERIC Educational Resources Information Center
Hamilton, Gayle; Michalopoulos, Charles
2016-01-01
There is a longstanding debate about whether helping welfare recipients quickly find work or helping them to first obtain some basic education and training better improves their economic well-being. This brief contributes to the debate by presenting long-term findings from three sites in the seven-site National Evaluation of Welfare-to-Work…
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As part of an ongoing effort to understand and address the short and long-term consequences of increasing levels of environmental contaminants, we used suppressive subtractive hydridization (SSH) to develop gene expression profiles from Japanese medaka (Oryzias latipes) exposed ...
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An Online Course Improves Nurses’ Awareness of their Role as Antimicrobial Stewards in Nursing Homes
Wilson, Brigid M.; Shick, Sue; Carter, Rebecca R.; Heath, Barbara; Higgins, Patricia A.; Sychla, Basia; Olds, Danielle M; Jump, Robin L. P.
2017-01-01
Background To support the role of nurses as active proponents of antimicrobial stewardship in long-term care facilities, we developed an educational intervention consisting of a free online course comprised of 6 interactive modules. Here, we report the effect of the course on the knowledge, beliefs and attitudes towards antimicrobial stewardship of nurses working in long-term care facilities. Measurements We used a paired pre- and post-course survey instrument to assess nurses’ knowledge regarding the care of long-term care facility residents with infections as well as attitudes and beliefs regarding antimicrobial stewardship. Results 103 respondents, RNs or LPNs, completed the pre and post-surveys. Their mean knowledge scores improved, from 75% (pre-course) to 86% (post-course, P < 0.001). Following the course, nurses’ agreement that their role influences whether or not residents receive antimicrobials increased significantly (P < 0.001). Discussion The online course improves nurses’ knowledge regarding the care of long-term care facility residents with infections and improves their confidence to engage in antimicrobial stewardship activities. Conclusion Empowering nurses to be antimicrobial stewards may help reduce unnecessary antibiotic use among institutionalized older adults. PMID:28189411
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Genetic lineage tracing identifies in situ Kit-expressing cardiomyocytes
Liu, Qiaozhen; Yang, Rui; Huang, Xiuzhen; Zhang, Hui; He, Lingjuan; Zhang, Libo; Tian, Xueying; Nie, Yu; Hu, Shengshou; Yan, Yan; Zhang, Li; Qiao, Zengyong; Wang, Qing-Dong; Lui, Kathy O; Zhou, Bin
2016-01-01
Cardiac cells marked by c-Kit or Kit, dubbed cardiac stem cells (CSCs), are in clinical trials to investigate their ability to stimulate cardiac regeneration and repair. These studies were initially motivated by the purported cardiogenic activity of these cells. Recent lineage tracing studies using Kit promoter to drive expression of the inducible Cre recombinase showed that these CSCs had highly limited cardiogenic activity, inadequate to support efficient cardiac repair. Here we reassess the lineage tracing data by investigating the identity of cells immediately after Cre labeling. Our instant lineage tracing approach identifies Kit-expressing cardiomyocytes, which are labeled immediately after tamoxifen induction. In combination with long-term lineage tracing experiments, these data reveal that the large majority of long-term labeled cardiomyocytes are pre-existing Kit-expressing cardiomyocytes rather than cardiomyocytes formed de novo from CSCs. This study presents a new interpretation for the contribution of Kit+ cells to cardiomyocytes and shows that Kit genetic lineage tracing over-estimates the cardiogenic activity of Kit+ CSCs. PMID:26634606
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Tian, C; Bagley, J; Iacomini, J
2006-09-01
Genetic modification of hematopoietic stem cells (HSCs) resulting in a state of molecular chimerism can be used to induce donor-specific tolerance to allografts. However, the requirements for maintaining tolerance in molecular chimeras remain unknown. Here, we examined whether long-term expression of a retrovirally encoded alloantigen in hematopoietic cells is required to maintain donor-specific tolerance in molecular chimeras. To this end, mice were reconstituted with syngeneic bone marrow transduced with retroviruses carrying the gene encoding the allogeneic MHC class I molecule Kb. Following induction of molecular chimerism, mice were depleted of cells expressing Kb by administration of the anti-Kb monoclonal antibody Y-3. Mice that were effectively depleted of cells expressing the retrovirally encoded MHC class I antigen rejected Kb disparate skin allografts. In contrast, control molecular chimeras accepted Kb disparate skin allografts indefinitely. These data suggest maintenance of tolerance in molecular chimeras requires long-term expression of retrovirally transduced alloantigen on the progeny of retrovirally transduced HSCs.
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Use of culture care theory with Anglo- and African American elders in a long-term care setting.
McFarland, M R
1997-01-01
The purpose of this study was to discover the care expressions, practices, and patterns of elderly Anglo- and African American elders. The domain of inquiry was the cultural care of elderly residents within the environmental context of a long-term care institution. The ethnonursing qualitative research method was used to conduct the study which was conceptualized within Leininger's theory of culture care diversity and universality. Four major themes were discovered: (a) Residents expressed and lived generic care to maintain their preadmission lifeways; (b) The nursing staff provided aspects of professional care to support satisfying lifeways for residents; (c) Institutional care patterns and expressions were viewed as a continuing life experience but with major differences between the apartment section and nursing home units; and (d) An institutional culture of the retirement home was discovered which reflected unique lifeways and shared care and health expressions and practices. These themes substantiated the culture care theory and revealed new modes of care for the elderly in an institutional setting.
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Oxygenated thawing and rewarming alleviate rewarming injury of cryopreserved pancreatic islets.
Komatsu, Hirotake; Barriga, Alyssa; Medrano, Leonard; Omori, Keiko; Kandeel, Fouad; Mullen, Yoko
2017-05-06
Pancreatic islet transplantation is an effective treatment for Type 1 diabetic patients to eliminate insulin injections; however, a shortage of donor organs hinders the widespread use. Although long-term islet storage, such as cryopreservation, is considered one of the key solutions, transplantation of cryopreserved islets is still not practical due to the extensive loss during the cryopreservation-rewarming process. We have previously reported that culturing islets in a hyperoxic environment is an effective treatment to prevent islet death from the hypoxic injury during culture. In this study, we explored the effectiveness of thawing and rewarming cryopreserved islets in a hyperoxic environment. Following cryopreservation of isolated human islets, the thawing solution and culture media were prepared with or without pre-equilibration to 50% oxygen. Thawing/rewarming and the pursuant two-day culture were performed with or without oxygenation. Short-term recovery rate, defined as the volume change during cryopreservation and thawing/rewarming, was assessed. Ischemia-associated and inflammation-associated gene expressions were examined using qPCR after the initial rewarming period. Long-term recovery rate, defined as the volume change during the two-day culture after the thawing/rewarming, was also examined. Islet metabolism and function were assessed by basal oxygen consumption rate and glucose stimulated insulin secretion after long-term recovery. Oxygenated thawing/rewarming did not alter the short-term recovery rate. Inflammation-associated gene expressions were elevated by the conventional thawing/rewarming method and suppressed by the oxygenated thawing/rewarming, whereas ischemia-associated gene expressions did not change between the thawing/rewarming methods. Long-term recovery rate experiments revealed that only the combination therapy of oxygenated thawing/rewarming and oxygenated culture alleviated islet volume loss. These islets showed higher metabolism and better function among the conditions examined. Oxygenated thawing/rewarming alleviated islet volume loss, with the help of oxygenated culture. Copyright © 2017. Published by Elsevier Inc.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Hatch, Douglas R.; Branstetter, Ryan; Whiteaker, John
Iteroparity, the ability to repeat spawn, is a life history strategy that is expressed by some species from the family Salmonidae. Rates of repeat spawning for post-development Columbia River steelhead Oncorhynchus mykiss populations range from 1.6 to 17%. It is expected that currently observed iteroparity rates for wild steelhead in the Basin are severely depressed due to development and operation of the hydropower system and various additional anthropogenic factors. Increasing the expression of historical repeat spawning rates using fish culturing methods could be a viable technique to assist the recovery of depressed steelhead populations, and could help reestablish this naturallymore » occurring life history trait. Reconditioning is the process of culturing post-spawned fish (kelts) in a captive environment until they are able to reinitiate feeding, growth, and redevelop mature gonads. Kelt reconditioning techniques were initially developed for Atlantic salmon Salmo salar and sea-trout S. trutta. The recent Endangered Species Act listing of many Columbia River Basin steelhead populations has prompted interest in developing reconditioning methods for wild steelhead populations within the Basin. To test kelt steelhead reconditioning as a potential recovery tool, wild emigrating steelhead kelts were placed into one of three study groups (direct capture and transport, short-term reconditioning, or long-term reconditioning). Steelhead kelts from the Yakima River were collected at the Chandler Juvenile Monitoring Facility (CJMF, located on the Yakima River at river kilometer 75.6) from 15 March to 21 June 2004. In total, 842 kelts were collected for reconditioning at Prosser Hatchery. Captive specimens represented 30.5% (842 of 2,755) of the entire 2003-2004 Yakima River wild steelhead population, based on fish ladder counts at Prosser Dam. All steelhead kelts were reconditioned in 20-foot circular tanks, and fed freeze-dried krill initially or for the duration of the experiment. All steelhead kelts received hw-wiegandt multi vit dietary supplement as a means to improve initial nutrition. Long-term steelhead kelts received Moore-Clark pellets to provide essential minerals and nutrients necessary for gonadal redevelopment. Oxytetracycline was administered to all reconditioned fish to boost immune system response following the stress of initial capture. To control parasitic infestations two methods were used, first, after initial capture an intubation of Ivermectin{trademark} was administered to control internal parasites (e.g., Salmincola spp.). Next, a Formalin drip was used for the duration of reconditioning to prevent fungal outbreaks. Captured kelts were separated into three experimental groups: short-term reconditioning, long-term reconditioning, and direct transport and release. Success indicators for the short-term experiment include the proportion of fish that survived the reconditioning process and the proportion of fish that initiated a feeding response. Short-term kelts were reconditioned for 3 to 5 weeks. Surviving specimens were released for natural spawning on May 11, 2004. Survival-to-release was good for the short-term experiment, with a rate of 79.0%. Long-term steelhead kelts are currently being held for a 6-9 month period with a scheduled release in December 2004. Long-term success indicators include the proportion of fish that survived the reconditioning process and the proportion of surviving fish that successfully remature. Survival and rematuration for long-term kelts has not been determined and will be presented in the 2005 annual report. Direct transport and release kelts and short-term reconditioned kelts were radio or acoustic tagged to assess their travel time and migratory behaviors below Bonneville Dam. A total of 29 direct-transport and release kelts and 29 short-term reconditioned kelts received surgically implanted radio tags, and a total of 28 direct-transport/release and 26 short-term reconditioned fish received surgically implanted hydro acoustic tags. These tags will allow us to determine outmigration timing for adults as well as determine if reconditioning has any deleterious effects on migration behavior. Long-term reconditioned fish will have radio tags inserted gastrically to monitor migration to spawning grounds. As in previous years, the kelts reconditioned during this project should substantially bolster the number of repeat spawners in the Yakima River. Valuable knowledge regarding kelt husbandry, condition, and rearing environments were obtained during this research endeavor. The authors were very pleased with the high survival rates. Information collected during this feasibility study will be incorporated into the experimental design for next year's research, and is expected to continue to increase survival of long-term reconditioned fish and the successful expression of iteroparity.« less
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2012-01-01
Background In childhood, attention deficit/hyperactivity disorder (ADHD) is characterized by age-inappropriate levels of inattentiveness/disorganization, hyperactivity/impulsiveness, or a combination thereof. Although the criteria for ADHD are well defined, the long-term consequences in adults and children need to be more comprehensively understood and quantified. We conducted a systematic review evaluating the long-term outcomes (defined as 2 years or more) of ADHD with the goal of identifying long-term outcomes and the impact that any treatment (pharmacological, non-pharmacological, or multimodal) has on ADHD long-term outcomes. Methods Studies were identified using predefined search criteria and 12 databases. Studies included were peer-reviewed, primary studies of ADHD long-term outcomes published between January 1980 to December 2010. Inclusion was agreed on by two independent researchers on review of abstracts or full text. Published statistical comparison of outcome results were summarized as poorer than, similar to, or improved versus comparators, and quantified as percentage comparisons of these categories. Results Outcomes from 351 studies were grouped into 9 major categories: academic, antisocial behavior, driving, non-medicinal drug use/addictive behavior, obesity, occupation, services use, self-esteem, and social function outcomes. The following broad trends emerged: (1) without treatment, people with ADHD had poorer long-term outcomes in all categories compared with people without ADHD, and (2) treatment for ADHD improved long-term outcomes compared with untreated ADHD, although not usually to normal levels. Only English-language papers were searched and databases may have omitted relevant studies. Conclusions This systematic review provides a synthesis of studies of ADHD long-term outcomes. Current treatments may reduce the negative impact that untreated ADHD has on life functioning, but does not usually 'normalize' the recipients. PMID:22947230
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Temporal information processing in short- and long-term memory of patients with schizophrenia.
Landgraf, Steffen; Steingen, Joerg; Eppert, Yvonne; Niedermeyer, Ulrich; van der Meer, Elke; Krueger, Frank
2011-01-01
Cognitive deficits of patients with schizophrenia have been largely recognized as core symptoms of the disorder. One neglected factor that contributes to these deficits is the comprehension of time. In the present study, we assessed temporal information processing and manipulation from short- and long-term memory in 34 patients with chronic schizophrenia and 34 matched healthy controls. On the short-term memory temporal-order reconstruction task, an incidental or intentional learning strategy was deployed. Patients showed worse overall performance than healthy controls. The intentional learning strategy led to dissociable performance improvement in both groups. Whereas healthy controls improved on a performance measure (serial organization), patients improved on an error measure (inappropriate semantic clustering) when using the intentional instead of the incidental learning strategy. On the long-term memory script-generation task, routine and non-routine events of everyday activities (e.g., buying groceries) had to be generated in either chronological or inverted temporal order. Patients were slower than controls at generating events in the chronological routine condition only. They also committed more sequencing and boundary errors in the inverted conditions. The number of irrelevant events was higher in patients in the chronological, non-routine condition. These results suggest that patients with schizophrenia imprecisely access temporal information from short- and long-term memory. In short-term memory, processing of temporal information led to a reduction in errors rather than, as was the case in healthy controls, to an improvement in temporal-order recall. When accessing temporal information from long-term memory, patients were slower and committed more sequencing, boundary, and intrusion errors. Together, these results suggest that time information can be accessed and processed only imprecisely by patients who provide evidence for impaired time comprehension. This could contribute to symptomatic cognitive deficits and strategic inefficiency in schizophrenia.
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Rodriguez-Cuenca, Sergio; Cochemé, Helena M; Logan, Angela; Abakumova, Irina; Prime, Tracy A; Rose, Claudia; Vidal-Puig, Antonio; Smith, Anthony C; Rubinsztein, David C; Fearnley, Ian M; Jones, Bruce A; Pope, Simon; Heales, Simon J R; Lam, Brian Y H; Neogi, Sudeshna Guha; McFarlane, Ian; James, Andrew M; Smith, Robin A J; Murphy, Michael P
2010-01-01
The mitochondria-targeted quinone MitoQ protects mitochondria in animal studies of pathologies in vivo and is being developed as a therapy for humans. However, it is unclear whether the protective action of MitoQ is entirely due to its antioxidant properties, because long-term MitoQ administration may alter whole-body metabolism and gene expression. To address this point, we administered high levels of MitoQ orally to wild-type C57BL/6 mice for up to 28 weeks and investigated the effects on whole-body physiology, metabolism, and gene expression, finding no measurable deleterious effects. In addition, because antioxidants can act as pro-oxidants under certain conditions in vitro, we examined the effects of MitoQ administration on markers of oxidative damage. There were no changes in the expression of mitochondrial or antioxidant genes as assessed by DNA microarray analysis. There were also no increases in oxidative damage to mitochondrial protein, DNA, or cardiolipin, and the activities of mitochondrial enzymes were unchanged. Therefore, MitoQ does not act as a pro-oxidant in vivo. These findings indicate that mitochondria-targeted antioxidants can be safely administered long-term to wild-type mice. Copyright 2009 Elsevier Inc. All rights reserved.
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Zhou, Xiaoou; Di Stasi, Antonio; Tey, Siok-Keen; Krance, Robert A.; Martinez, Caridad; Leung, Kathryn S.; Durett, April G.; Wu, Meng-Fen; Liu, Hao; Leen, Ann M.; Savoldo, Barbara; Lin, Yu-Feng; Grilley, Bambi J.; Gee, Adrian P.; Spencer, David M.; Rooney, Cliona M.; Heslop, Helen E.; Brenner, Malcolm K.
2014-01-01
Adoptive transfer of donor-derived T lymphocytes expressing a safety switch may promote immune reconstitution in patients undergoing haploidentical hematopoietic stem cell transplant (haplo-HSCT) without the risk for uncontrolled graft versus host disease (GvHD). Thus, patients who develop GvHD after infusion of allodepleted donor-derived T cells expressing an inducible human caspase 9 (iC9) had their disease effectively controlled by a single administration of a small-molecule drug (AP1903) that dimerizes and activates the iC9 transgene. We now report the long-term follow-up of 10 patients infused with such safety switch-modified T cells. We find long-term persistence of iC9-modified (iC9-T) T cells in vivo in the absence of emerging oligoclonality and a robust immunologic benefit, mediated initially by the infused cells themselves and subsequently by an apparently accelerated reconstitution of endogenous naive T lymphocytes. As a consequence, these patients have immediate and sustained protection from major pathogens, including cytomegalovirus, adenovirus, BK virus, and Epstein-Barr virus in the absence of acute or chronic GvHD, supporting the beneficial effects of this approach to immune reconstitution after haplo-HSCT. This study was registered at www.clinicaltrials.gov as #NCT00710892. PMID:24753538
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Lead and Copper Rule Long-Term Revisions
The goal for the Lead and Copper Rule (LCR) Long-Term Revisions is to improve public health protection provided by the by making substantive changes based on topics that were identified in the 2004 National Review.
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Li, Yuting; Liu, Xing; Liu, Chang; Kang, Jiuhong; Yang, Jingyu; Pei, Gang; Wu, Chunfu
2009-01-01
Morphine is a well-known μ-opioid receptor (MOR) agonist and an efficient analgesic, but its long-term use inevitably leads to drug addiction and tolerance. Here, we show that specific inhibition of β-arrestin2 with its siRNA lentivirus microinjected in mice periaqueductal gray matter (PAG) significantly improved both acute and chronic morphine analgesia and delayed the tolerance in the hotplate test. The specific effect of β-arrestin2 was proven by overexpression or knockdown of its homology β-arrestin1 in PAG, which showed no significant effects on morphine analgesia. These findings suggest that specific siRNA targeting β-arrestin2 may constitute a new approach to morphine therapy and other MOR agonist-mediated analgesia and tolerance. PMID:19399231
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NASA Astrophysics Data System (ADS)
Wang, Ji; Li, Ye; Dai, Juan; Su, Xiurong; Li, Chenghua; Shen, Lingling
2016-05-01
Di-octyl phthalate (DOP) is widely used as a plasticizer in the plastics industry. As a result, DOP is often found in marine water ecosystems where many species are exposed to it. Our objective was to evaluate the effect of long-term (14 d) DOP exposure (2.6, 7.8, or 31.2 mg/L) on the expression of immunerelated genes in Tegillarca granosa. The expression of small heat shock protein (sHSPs) and tissue inhibitor of metalloproteinase (TIMP) were highest in clams exposed to 31.2 mg/L DOP on days 7 and 14. The relative expression of Tg-ferritin, superoxide dismutase (SOD), and metallothionein (MT) increased initially then decreased as the concentration of DOP increased. The hemoglobin of T. granosa (Tg-HbI) exhibited two distinct expression patterns at two time points. Our results suggest that the immune response of T. granosa against DOP pollution varies depending on the dose. Additionally, we identified some immune-related genes that are promising candidates for biomarkers of DOP.
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Strategic implementation and accountability: the case of the long-term care alliance.
Seaman, Al; Elias, Maria; O'Neill, Bill; Yatabe, Karen
2010-01-01
A group of chief executives of long-term care homes formed an alliance in order to tap the resources residing within their management teams. Adopting a strategic implementation project based on a framework of accountability, the executives were able to better understand the uncertainties of the environment and potentially structure their strategic implementation to best use scarce resources. The framework of accountability allowed the homes to recognize the need for a strong business approach to long-term care. Communication improved throughout the organizations while systems and resources showed improved utilization. Quality became the driving force for all actions taken to move the organizations toward achieving their visions.
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Long-term Recovery in Stroke Accompanied by Aphasia: A Reconsideration.
Holland, Audrey; Fromm, Davida; Forbes, Margaret; MacWhinney, Brian
2017-01-01
This work focuses on the twenty-six individuals who provided data to AphasiaBank on at least two occasions, with initial testing between 6 months and 5.8 years post-onset of aphasia. The data are archival in nature and were collected from the extensive database of aphasic discourse in AphasiaBank. The aim is to furnish data on the nature of long-term changes in both the impairment of aphasia as measured by the Western Aphasia Battery-Revised (WAB-R) and its expression in spoken discourse. AphasiaBank's demographic database was searched to discover all individuals who were tested twice at an interval of at least a year with either: 1) the AphasiaBank protocol; or 2) the AphasiaBank protocol at first testing, and the Famous People Protocol (FPP) at second testing. The Famous People Protocol is a measure developed to assess the communication strategies of individuals whose spoken language limitations preclude full participation in the AphasiaBank protocol. The 26 people with aphasia (PWA) who were identified had completed formal speech therapy before being seen for AphasiaBank. However, all were participants in aphasia centers where at least three hours of planned activities were available, in most cases, twice weekly. WAB-R Aphasia Quotient scores (AQ) were examined, and in those cases where AQ scores improved, changes were assessed on a number of measures from the AphasiaBank discourse protocol. Sixteen individuals demonstrated improved WAB-R AQ scores, defined as positive AQ change scores greater than the WAB-R AQ standard error of the mean (WAB-SEM); seven maintained their original WAB quotients, defined as AQ change scores that were not greater than the WAB-SEM; and the final three showed negative WAB-R change scores, defined as a negative WAB-R AQ change score greater than the WAB-SEM. Concurrent changes on several AphasiaBank tasks were also found, suggesting that the WAB-R improvements were noted in more natural discourse as well. These data are surprising, since conventional wisdom suggests that spontaneous improvement in language is unlikely to occur beyond one year. Long-term improvement or maintenance of early test scores, such as that shown here, has seldom been demonstrated in the absence of formal treatment. Speculations about why these PWA improved, maintained or declined in their scores are considered.
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Research for new UAV capabilities
DOE Office of Scientific and Technical Information (OSTI.GOV)
Canavan, G.H.; Leadabrand, R.
1996-07-01
This paper discusses research for new Unmanned Aerial Vehicles (UAV) capabilities. Findings indicate that UAV performance could be greatly enhanced by modest research. Improved sensors and communications enhance near term cost effectiveness. Improved engines, platforms, and stealth improve long term effectiveness.
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In vivo over-expression of KGF mimic human middle ear cholesteatoma.
Yamamoto-Fukuda, Tomomi; Akiyama, Naotaro; Shibata, Yasuaki; Takahashi, Haruo; Ikeda, Tohru; Koji, Takehiko
2015-10-01
We reported previously that keratinocyte growth factor (KGF), a mesenchymal cell-derived paracrine growth factor, plays an important role in middle ear cholesteatoma formation, which is characterized by marked proliferation of epithelial cells. Here, we investigated whether KGF, the main factor that induces cholesteatoma, overexpression in vivo results in the formation of cholesteatoma. Flag-hKGF cDNA driven by CMV14 promoter was transfected through electroporation into the external auditory canal (EAC) of rats once (short-term model) or five times on every fourth day (long-term model). Ears transfected with empty vector were used as controls. Successful transfection of plasmids into epithelial and stromal cells was confirmed by Flag immunohistochemistry. In the short-term model, the intensity of KGF protein was the strongest in hKGF transfected ear at day 4. KGF expression induced epithelial cell proliferation, reaching a peak level at day 4 and then decreased later, while in the long-term model, KGF expression in the EAC led to middle ear cholesteatoma formation. In conclusion, we described here a new experimental model of human middle ear cholesteatoma, and demonstrated that KGF and KGF receptor paracrine action play an essential role in middle ear cholesteatoma formation in an in vivo model.
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Hagstrom, J N; Couto, L B; Scallan, C; Burton, M; McCleland, M L; Fields, P A; Arruda, V R; Herzog, R W; High, K A
2000-04-15
Hemophilia B is caused by the absence of functional coagulation factor IX (F.IX) and represents an important model for treatment of genetic diseases by gene therapy. Recent studies have shown that intramuscular injection of an adeno-associated viral (AAV) vector into mice and hemophilia B dogs results in vector dose-dependent, long-term expression of biologically active F.IX at therapeutic levels. In this study, we demonstrate that levels of expression of approximately 300 ng/mL (6% of normal human F.IX levels) can be reached by intramuscular injection of mice using a 2- to 4-fold lower vector dose (1 x 10(11) vector genomes/mouse, injected into 4 intramuscular sites) than previously described. This was accomplished through the use of an improved expression cassette that uses the cytomegalovirus (CMV) immediate early enhancer/promoter in combination with a 1.2-kilobase portion of human skeletal actin promoter. These results correlated with enhanced levels of F.IX transcript and secreted F.IX protein in transduced murine C2C12 myotubes. Systemic F.IX expression from constructs containing the CMV enhancer/promoter alone was 120 to 200 ng/mL in mice injected with 1 x 10(11) vector genomes. Muscle-specific promoters performed poorly for F.IX transgene expression in vitro and in vivo. However, the incorporation of a sequence from the alpha-skeletal actin promoter containing at least 1 muscle-specific enhancer and 1 enhancer-like element further improved muscle-derived expression of F.IX from a CMV enhancer/promoter-driven expression cassette over previously published results. These findings will allow the design of a clinical protocol for therapeutic levels of F.IX expression with lower vector doses, thus enhancing efficacy and safety of the protocol. (Blood. 2000;95:2536-2542)
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Tomada, I; Negrão, R; Almeida, H; Neves, D
2014-04-01
Long-term consumption of high-fat diets negatively interferes with metabolic status and promotes endothelial dysfunction and inflammation. In the cavernous tissue, these outcomes become conspicuous in the elderly and strongly affect penile erection, a vascular process highly dependent on local nitric oxide bioavailability. Although epidemiological data links erectile dysfunction to nutritional patterns, the underlying molecular mechanisms remain unclear. Therefore, we investigated the effects of long-term high-fat diet on endothelial nitric oxide synthase (eNOS)-Sirtuin-1 axis and Akt/eNOS phosphorylation in the cavernous tissue of Sprague-Dawley rats, and compared with energy-restricted animals. We demonstrated that high-fat diet intake led to a noteworthy decrease in eNOS phosphorylation at Ser1177 residue through the Akt pathway, which seems to be compensated by upregulation of phosphorylation at Ser615, but without an increment in nitric oxide production. These results are accompanied by an increase of systemic inflammatory markers and upregulation of the inducible NOS and of the deacetylase Sirtuin-1 in the cavernous tissue to levels apparently detrimental to cells and to metabolic homeostasis. Conversely, in long-term energy-restricted animals, the rate of phosphorylation of eNOS at Ser1177 diminished, but the activation of the enzyme increased through phosphorylation of eNOS at Ser615, resulting in an enhancement in nitric oxide bioavailability. Taken together, our results demonstrate that long-term nutritional conditions override the influence of age on the eNOS expression and activation in rat cavernous tissue.
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Seugnet, Laurent; Galvin, James E.; Suzuki, Yasuko; Gottschalk, Laura; Shaw, Paul J.
2009-01-01
Study Objectives: Parkinson disease (PD) is the second most common neurodegenerative disorder in the United States. It is associated with motor deficits, sleep disturbances, and cognitive impairment. The pathology associated with PD and the effects of sleep deprivation impinge, in part, upon common molecular pathways suggesting that sleep loss may be particularly deleterious to the degenerating brain. Thus we investigated the long-term consequences of sleep deprivation on short-term memory using a Drosophila model of Parkinson disease. Participants: Transgenic strains of Drosophila melanogaster. Design: Using the GAL4-UAS system, human α-synuclein was expressed throughout the nervous system of adult flies. α-Synuclein expressing flies (αS flies) and the corresponding genetic background controls were sleep deprived for 12 h at age 16 days and allowed to recover undisturbed for at least 3 days. Short-term memory was evaluated using aversive phototaxis suppression. Dopaminergic systems were assessed using mRNA profiling and immunohistochemistry. Measurments and Results: When sleep deprived at an intermediate stage of the pathology, αS flies showed persistent short-term memory deficits that lasted ≥ 3 days. Cognitive deficits were not observed in younger αS flies nor in genetic background controls. Long-term impairments were not associated with accelerated loss of dopaminergic neurons. However mRNA expression of the dopamine receptors dDA1 and DAMB were significantly increased in sleep deprived αS flies. Blocking D1-like receptors during sleep deprivation prevented persistent short-term memory deficits. Importantly, feeding flies the polyphenolic compound curcumin blocked long-term learning deficits. Conclusions: These data emphasize the importance of sleep in a degenerating/reorganizing brain and shows that pathological processes induced by sleep deprivation can be dissected at the molecular and cellular level using Drosophila genetics. Citation: Seugnet L; Galvin JE; Suzuki Y; Gottschalk L; Shaw PJ. Persistent short-term memory defects following sleep deprivation in a drosophila model of parkinson disease. SLEEP 2009;32(8):984-992. PMID:19725249
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Establishment and characterization of the reversibly immortalized mouse fetal heart progenitors.
Li, Mi; Chen, Yuan; Bi, Yang; Jiang, Wei; Luo, Qing; He, Yun; Su, Yuxi; Liu, Xing; Cui, Jing; Zhang, Wenwen; Li, Ruidong; Kong, Yuhan; Zhang, Jiye; Wang, Jinhua; Zhang, Hongyu; Shui, Wei; Wu, Ningning; Zhu, Jing; Tian, Jie; Yi, Qi-Jian; Luu, Hue H; Haydon, Rex C; He, Tong-Chuan; Zhu, Gao-Hui
2013-01-01
Progenitor cell-based cardiomyocyte regeneration holds great promise of repairing an injured heart. Although cardiomyogenic differentiation has been reported for a variety of progenitor cell types, the biological factors that regulate effective cardiomyogenesis remain largely undefined. Primary cardiomyogenic progenitors (CPs) have a limited life span in culture, hampering the CPs' in vitro and in vivo studies. The objective of this study is to investigate if primary CPs isolated from fetal mouse heart can be reversibly immortalized with SV40 large T and maintain long-term cell proliferation without compromising cardiomyogenic differentiation potential. Primary cardiomyocytes were isolated from mouse E15.5 fetal heart, and immortalized retrovirally with the expression of SV40 large T antigen flanked with loxP sites. Expression of cardiomyogenic markers were determined by quantitative RT-PCR and immunofluorescence staining. The immortalization phenotype was reversed by using an adenovirus-mediated expression of the Cre reconbinase. Cardiomyogenic differentiation induced by retinoids or dexamethasone was assessed by an α-myosin heavy chain (MyHC) promoter-driven reporter. We demonstrate that the CPs derived from mouse E15.5 fetal heart can be efficiently immortalized by SV40 T antigen. The conditionally immortalized CPs (iCP15 clones) exhibit an increased proliferative activity and are able to maintain long-term proliferation, which can be reversed by Cre recombinase. The iCP15 cells express cardiomyogenic markers and retain differentiation potential as they can undergo terminal differentiate into cardiomyctes under appropriate differentiation conditions although the iCP15 clones represent a large repertoire of CPs at various differentiation stages. The removal of SV40 large T increases the iCPs' differentiation potential. Thus, the iCPs not only maintain long-term cell proliferative activity but also retain cardiomyogenic differentiation potential. Our results suggest that the reported reversible SV40 T antigen-mediated immortalization represents an efficient approach for establishing long-term culture of primary cardiomyogenic progenitors for basic and translational research.
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NASA Astrophysics Data System (ADS)
Predina, Jarrod D.; Newton, Andrew; Deshpande, Charuhas; Low, Philip; Singhal, Sunil
2018-01-01
Pulmonary metastasectomy for osteosarcoma provides a select group of patients an opportunity for long-term survival and possible cure. Unfortunately, a complete metastasectomy is challenging due an inability to accurately identify lesions that lay below the threshold of preoperative imaging or intraoperative visual and tactile inspection. Growing evidence suggests that osteosarcomas express a number of unique molecular markers, including the folate receptor alpha. In this case report, we describe the application of a folate receptor-targeted, near-infrared optical contrast agent (OTL38) to improve osteosarcoma localization during minimally invasive pulmonary resection. In addition to localizing preoperatively identified lesions, this technology helped identify additional disease that was undetected on preoperative imaging or with traditional intraoperative techniques. This report marks the first successful utilization of a molecular imaging probe useful for osteosarcomas. This technology may provide a unique approach to improve pulmonary metastasectomy of osteosarcomas.
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Motivation and placebos: do different mechanisms occur in different contexts?
Hyland, Michael E
2011-06-27
This paper challenges the common assumption that the mechanisms underlying short-term placebo paradigms (where there is no motivation for health improvement) and long-term placebo paradigms (where patients value improvement in their health) are the same. Three types of motivational theory are reviewed: (i) classical placebo motivation theory that the placebo response results from the desire for therapeutic improvement; (ii) goal activation model that expectancy-driven placebo responses are enhanced when the placebo response satisfies an activated goal; and (iii) motivational concordance model that the placebo response is the consequence of concordance between the placebo ritual and significant intrinsic motives. It is suggested that current data are consistent with the following theory: response expectancy, conditioning and goal activation are responsible for short-term placebo effects but long-term therapeutic change is achieved through the effects of goal satisfaction and affect on the inflammatory response system and hypothalamic-pituitary-adrenal axis. Empirical predictions of this new theory are outlined, including ways in which placebo effects can be combined with other psychologically mediated effects on short-term and long-term psychological and physiological state.
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Motivation and placebos: do different mechanisms occur in different contexts?
Hyland, Michael E.
2011-01-01
This paper challenges the common assumption that the mechanisms underlying short-term placebo paradigms (where there is no motivation for health improvement) and long-term placebo paradigms (where patients value improvement in their health) are the same. Three types of motivational theory are reviewed: (i) classical placebo motivation theory that the placebo response results from the desire for therapeutic improvement; (ii) goal activation model that expectancy-driven placebo responses are enhanced when the placebo response satisfies an activated goal; and (iii) motivational concordance model that the placebo response is the consequence of concordance between the placebo ritual and significant intrinsic motives. It is suggested that current data are consistent with the following theory: response expectancy, conditioning and goal activation are responsible for short-term placebo effects but long-term therapeutic change is achieved through the effects of goal satisfaction and affect on the inflammatory response system and hypothalamic–pituitary–adrenal axis. Empirical predictions of this new theory are outlined, including ways in which placebo effects can be combined with other psychologically mediated effects on short-term and long-term psychological and physiological state. PMID:21576140
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Regulation of leptin production in humans.
Fried, S K; Ricci, M R; Russell, C D; Laferrère, B
2000-12-01
Serum levels of the adipocyte hormone leptin are increased in proportion to body fat stores as a result of increased production in enlarged fat cells from obese subjects. In vitro studies indicate that insulin and glucocorticoids work directly on adipose tissue to upregulate in a synergistic manner leptin mRNA levels and rates of leptin secretion in human adipose tissue over the long term. Thus, the increased leptin expression observed in obesity could result from the chronic hyperinsulinemia and increased cortisol turnover. Superimposed upon the long-term regulation, nutritional status can influence serum leptin over the short term, independent of adiposity. Fasting leads to a gradual decline in serum leptin that is probably attributable to the decline in insulin and the ability of catecholamines to decrease leptin expression, as observed in both in vivo and in vitro studies. In addition, increases in serum leptin occur approximately 4-7 h after meals. Increasing evidence indicates that insulin, in concert with permissive effects of cortisol, can increase serum leptin over this time frame and likely contributes to meal-induced increases in serum leptin. Further research is required to elucidate the cellular and molecular mechanisms underlying short- and long-term nutritional and hormonal regulation of leptin production and secretion.
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Latorre, Eva; Layunta, Elena; Grasa, Laura; Castro, Marta; Pardo, Julián; Gomollón, Fernando; Alcalde, Ana I; Mesonero, José E
2016-01-01
TLR2 is a microbiota recognition receptor that has been described to contribute to intestinal homeostasis and to ameliorate inflammatory intestinal injury. In this context, serotonin (5-HT) has shown to be an essential intestinal physiological neuromodulator that is also involved in intestinal inflammatory diseases. Since the interaction between TLR2 activation and the intestinal serotoninergic system remains non-investigated, our main aim was to analyze the effect of TLR2 on intestinal serotonin transporter (SERT) activity and expression and the intracellular pathways involved. Caco-2/TC7 cells were used to analyze SERT and TLR2 molecular expression and SERT activity by measuring 5-HT uptake. The results showed that apical TLR2 activation inhibits SERT activity in Caco-2/TC7 cells mainly by reducing SERT protein level either in the plasma membrane, after short-term TLR2 activation or in both the plasma membrane and cell lysate, after long-term activation. cAMP/PKA pathway appears to mediate short-term inhibitory effect of TLR2 on SERT; however, p38 MAPK pathway has been shown to be involved in both short- and long-term TLR2 effect. Reciprocally, 5-HT long-term treatment yielded TLR2 down regulation in Caco-2/TC7 cells. Finally, results from in vivo showed an augmented intestinal SERT expression in mice Tlr2-/-, thus confirming our inhibitory effect of TLR2 on intestinal SERT in vitro. The present work infers that TLR2 may act in intestinal pathophysiology, not only by its inherent innate immune role, but also by regulating the intestinal serotoninergic system.
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Layunta, Elena; Grasa, Laura; Castro, Marta; Pardo, Julián; Gomollón, Fernando; Mesonero, José E.
2016-01-01
TLR2 is a microbiota recognition receptor that has been described to contribute to intestinal homeostasis and to ameliorate inflammatory intestinal injury. In this context, serotonin (5-HT) has shown to be an essential intestinal physiological neuromodulator that is also involved in intestinal inflammatory diseases. Since the interaction between TLR2 activation and the intestinal serotoninergic system remains non-investigated, our main aim was to analyze the effect of TLR2 on intestinal serotonin transporter (SERT) activity and expression and the intracellular pathways involved. Caco-2/TC7 cells were used to analyze SERT and TLR2 molecular expression and SERT activity by measuring 5-HT uptake. The results showed that apical TLR2 activation inhibits SERT activity in Caco-2/TC7 cells mainly by reducing SERT protein level either in the plasma membrane, after short-term TLR2 activation or in both the plasma membrane and cell lysate, after long-term activation. cAMP/PKA pathway appears to mediate short-term inhibitory effect of TLR2 on SERT; however, p38 MAPK pathway has been shown to be involved in both short- and long-term TLR2 effect. Reciprocally, 5-HT long-term treatment yielded TLR2 down regulation in Caco-2/TC7 cells. Finally, results from in vivo showed an augmented intestinal SERT expression in mice Tlr2-/-, thus confirming our inhibitory effect of TLR2 on intestinal SERT in vitro. The present work infers that TLR2 may act in intestinal pathophysiology, not only by its inherent innate immune role, but also by regulating the intestinal serotoninergic system. PMID:28033388
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The norepinephrine transporter and its regulation.
Mandela, Prashant; Ordway, Gregory A
2006-04-01
For many years, the norepinephrine transporter (NET) was considered a 'static' protein that contributed to the termination of the action of norepinephrine in the synapse of noradrenergic neurons. The concept that the NET is dynamically regulated, adjusting noradrenergic transmission by changing its function and/or expression, was considered initially in the mid 1980s. Since that time, a plethora of studies demonstrate that the NET is regulated by several intracellular and extracellular signaling molecules, and that phosphorylation of the NET is a major pathway regulating its cell surface expression and thereby its function. The NET is a target of action of a number of drugs that are used long-term therapeutically or abused chronically. This has driven numerous investigations of how the NET and its function are regulated by long-term exposure to drugs. While repeated exposure to many drugs has been shown to affect NET function and expression, the intracellular mechanisms for these effects remains elusive.
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Pitman, Kimberley A; Borgland, Stephanie L
2015-10-01
The incidence of obesity in both adults and children is rising. In order to develop effective treatments for obesity, it is important to understand how diet can induce changes in the brain that could promote excessive intake of high-calorie foods and alter the efficacy of therapeutic targets. The mu-opioid receptor is involved in regulating the motivation for and hedonic reaction to food. Here, we review the literature examining changes in the expression and function of mu-opioid receptors in the mesolimbic system of rodents after extended access to a high-fat diet. We also review how maternal diet can induce long-term changes in the expression or function of mu-opioid receptors in the mesolimbic system of offspring. Understanding the behavioural and therapeutic implications of these changes requires further study. Copyright © 2015 Elsevier Inc. All rights reserved.
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Hirane, Miku; Ishii, Shuhei; Tomimatsu, Ayaka; Fukushima, Kaori; Takahashi, Kaede; Fukushima, Nobuyuki; Honoki, Kanya; Tsujiuchi, Toshifumi
2016-11-01
Lysophosphatidic acid (LPA) signaling via LPA receptors (LPA 1 to LPA 6 ) mediates a variety of cellular functions, including cell motility. In the present study, we investigated the effects of LPA receptors on cell motile activity during multi-stage hepatocarcinogenesis in rat liver epithelial WB-F344 cells treated with chemical liver carcinogens. Cells were treated with a initiator (N-nitrosodiethylamine (DEN)) and three promoters (phenobarbital (PB), okadaic acid (OA) and clofibrate) every 24 h for 2 days. Cell motile activity was elevated by DEN, correlating with Lpar3 expression. PB, OA, and clofibrate elevated Lpar1 expression and inhibited cell motile activity. To evaluate the effects of long-term treatment on cell motility, cells were treated with DEN and/or PB for at least 6 months. Lpar3 expression and cell motile activity were significantly elevated by the long-term DEN treatment with or without further PB treatment. In contrast, long-term PB treatment with or without further DEN elevated Lpar1 expression and inhibited cell motility. When the synthesis of extracellular LPA was blocked by a potent ATX inhibitor S32826 before cell motility assay, the cell motility induced by DEN and PB was markedly suppressed. These results suggest that activation of the different LPA receptors may regulate the biological functions of cells treated with chemical carcinogens. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
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Lopes, Marta S; Araus, José L
2008-09-01
Long-term differences in photosynthesis, respiration and growth of plants receiving distinct nitrogen (N) sources imply that N metabolism generates signals that regulate metabolism and development. The molecular basis of these signals remains unclear. Here we studied the gene expression profiles of barley (Hordeum vulgare L. cv. Graphic) seedlings fertilized either with ammonium (NH4+), with ammonium and nitrate (NH4+:NO3-), or with nitrate (NO3-) only. Our transcriptome analysis after 48 h of growth in these N sources showed major changes in the expression of genes involved in N metabolism (nitrate reductase), signalling (protein kinases and protein phosphatases), photosynthesis (chlorophyll a/b-binding protein and a PsbQ domain), where increases in NO3- as compared with NH4+ were observed. Moreover, NH4+ assimilation induced genes participating in C and sugars metabolism (phosphoglycerate kinase, glucosyltranferase and galactokinase), respiration (cytochrome c oxidase), protein fate (heat shock proteins) and development (MTN3-like protein). These changes in gene expression could well explain the long-term growth depression observed in NH4+ plants. Even if a few genes participating in protein fate (proteases) and development (OsNAC5) were upregulated in NH4+ as compared with NH4+:NO3-, the general pattern of expression was quite similar between these two N sources. Taken together, these results indicated that other downstream mechanisms should be involved in the synergetic long-term response of NH4+:NO3-.
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Blaker, Carina; Clarke, Elizabeth; Jeffcott, Leo; Little, Christopher
2017-01-01
Flexor tendinopathy is a common problem affecting humans and animals. Tendon healing is poorly understood and the outcomes of conservative and surgical management are often suboptimal. While often considered a localized injury, recent evidence indicates that in the short term, tendinopathic changes are distributed widely throughout the tendon, remote from the lesion itself. Whether these changes persist throughout healing is unknown. The aim of this study was to document gene expression, histopathological and biomechanical changes that occur throughout the superficial digital flexor tendon (SDFT) up to 16 weeks post-injury, using an ovine surgical model of tendinopathy. Partial tendon transection was associated with decreased gene expression for aggrecan, decorin, fibromodulin, tissue inhibitors of metalloproteinases (TIMPS 1, 2 and 3), collagen I and collagen II. Gene expression for collagen III, lumican and matrix metalloproteinase 13 (MMP13) increased locally around the lesion site. Expression of collagen III and MMP13 decreased with time, but compared to controls, collagen III, MMP13 and lumican expression remained regionally high throughout the study. An increase in TIMP3 was observed over time. Histologically, operated tendons had higher pathology scores than controls, especially around the injured region. A chondroid phenotype was observed with increased cellular rounding and marked proteoglycan accumulation which only partially improved with time. Biomechanically, partial tendon transection resulted in a localized decrease in elastic modulus (in compression) but only at 8 weeks postoperatively. This study improves our understanding of tendon healing, demonstrating an early ‘peak’ in pathology characterized by altered gene expression and notable histopathological changes. Many of these pathological changes become more localized to the region of injury during healing. Collagen III and MMP13 expression levels remained high close to the lesion throughout the study and may reflect the production of tendon tissue with suboptimal biomechanical properties. Further studies evaluating the long-term response of tendon to injury (6–12 months) are warranted to provide additional information on tendon healing and provide further understanding of the mechanisms underlying the pathology observed in this study. PMID:29023489
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Seugnet, Laurent; Galvin, James E; Suzuki, Yasuko; Gottschalk, Laura; Shaw, Paul J
2009-08-01
Parkinson disease (PD) is the second most common neurodegenerative disorder in the United States. It is associated with motor deficits, sleep disturbances, and cognitive impairment. The pathology associated with PD and the effects of sleep deprivation impinge, in part, upon common molecular pathways suggesting that sleep loss may be particularly deleterious to the degenerating brain. Thus we investigated the long-term consequences of sleep deprivation on shortterm memory using a Drosophila model of Parkinson disease. Transgenic strains of Drosophila melanogaster. Using the GAL4-UAS system, human alpha-synuclein was expressed throughout the nervous system of adult flies. Alpha-synuclein expressing flies (alpha S flies) and the corresponding genetic background controls were sleep deprived for 12 h at age 16 days and allowed to recover undisturbed for at least 3 days. Short-term memory was evaluated using aversive phototaxis suppression. Dopaminergic systems were assessed using mRNA profiling and immunohistochemistry. MEASURMENTS AND RESULTS: When sleep deprived at an intermediate stage of the pathology, alpha S flies showed persistent short-term memory deficits that lasted > or = 3 days. Cognitive deficits were not observed in younger alpha S flies nor in genetic background controls. Long-term impairments were not associated with accelerated loss of dopaminergic neurons. However mRNA expression of the dopamine receptors dDA1 and DAMB were significantly increased in sleep deprived alpha S flies. Blocking D1-like receptors during sleep deprivation prevented persistent shortterm memory deficits. Importantly, feeding flies the polyphenolic compound curcumin blocked long-term learning deficits. These data emphasize the importance of sleep in a degenerating/reorganizing brain and shows that pathological processes induced by sleep deprivation can be dissected at the molecular and cellular level using Drosophila genetics.
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Wound signaling: The missing link in plant regeneration.
Chen, Lyuqin; Sun, Beibei; Xu, Lin; Liu, Wu
2016-10-02
Wounding is the first event that occurs in plant regeneration. However, wound signaling in plant regeneration is barely understood. Using a simple system of de novo root organogenesis from Arabidopsis thaliana leaf explants, we analyzed the genes downstream of wound signaling. Leaf explants may produce at least two kinds of wound signals to trigger short-term and long-term wound signaling. Short-term wound signaling is primarily involved in controlling auxin behavior and the fate transition of regeneration-competent cells, while long-term wound signaling mainly modulates the cellular environment at the wound site and maintains the auxin level in regeneration-competent cells. YUCCA (YUC) genes, which are involved in auxin biogenesis, are targets of short-term wound signaling in mesophyll cells and of long-term wound signaling in regeneration-competent cells. The expression patterns of YUCs provide important information about the molecular basis of wound signaling in plant regeneration.
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Puyal, Julien; Grassi, Silvarosa; Dieni, Cristina; Frondaroli, Adele; Demêmes, Danielle; Raymond, Jaqueline; Pettorossi, Vito Enrico
2003-01-01
The effects of high frequency stimulation (HFS) of the primary vestibular afferents on synaptic transmission in the ventral part of the medial vestibular nuclei (vMVN) were studied during postnatal development and compared with the changes in the expression of the group I metabotropic glutamate receptor (mGluR) subtypes, mGluR1 and mGluR5. During the first stages of development, HFS always induced a mGluR5- and GABAA-dependent long-term depression (LTD) which did not require NMDA receptor and mGluR1 activation. The probability of inducing LTD decreased progressively throughout the development and it was zero at about the end of the second postnatal week. Conversely, long-term potentiation (LTP) appeared at the beginning of the second week and its occurrence increased to reach the adult value at the end of the third week. Of interest, the sudden change in the LTP frequency occurred at the time of eye opening, about the end of the second postnatal week. LTP depended on NMDA receptor and mGluR1 activation. In parallel with the modifications in synaptic plasticity, we observed that the expression patterns and localizations of mGluR5 and mGluR1 in the medial vestibular nuclei (MVN) changed during postnatal development. At the earlier stages the mGluR1 expression was minimal, then increased progressively. In contrast, mGluR5 expression was initially high, then decreased. While mGluR1 was exclusively localized in neuronal compartments and concentrated at the postsynaptic sites at all stages observed, mGluR5 was found mainly in neuronal compartments at immature stages, then preferentially in glial compartments at mature stages. These results provide the first evidence for a progressive change from LTD to LTP accompanied by a distinct maturation expression of mGluR1 and mGluR5 during the development of the MVN. PMID:12972627
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Nagayasu, Yuko; Morita, Shin-Ya; Hayashi, Hideki; Miura, Yutaka; Yokoyama, Kazuki; Michikawa, Makoto; Ito, Jin-Ichi
2014-05-14
We found in a previous study that both mRNA expression and release of fibroblast growth factor 1 (FGF-1) are greater in rat astrocytes that are long term-cultured for one month (W/M cells) than in the cells cultured for one week (W/W cells). However, FGF-1 does not enhance phosphorylation of Akt, MEK, and ERK in W/M cells, while it does in W/W cells. In this work we studied the mechanism to cause these differences between W/W and W/M cells in culture. As it is known that long term culture generates oxidative stress, we characterized the stresses which W/M cells undergo in comparison with W/W cells. The levels of superoxide dismutase 1 (SOD1) and mitochondrial Bax were higher in W/M cells than in W/W cells. W/M cells recovered their ability to respond to FGF-1 to enhance phosphorylation of Akt, MEK, and ERK in the presence of antioxidants. Oxidative stress induced by hydrogen peroxide (H2O2) had no effect on mRNA expression of FGF-1 in W/W cells, although H2O2 enhances release of FGF-1 from W/W cells without inducing apoptosis. The influence of cell density was studied on mRNA expression of FGF-1 and cellular response to FGF-1, as an increasing cell density is observed in W/M cells. The increasing cell density enhanced mRNA expression of FGF-1 in W/W cells without suppression of responses to FGF-1. The decrease in cell density lowered the FGF-1 mRNA expression in W/M cells without recovery of the response to FGF-1 to enhance phosphorylation of Akt, MEK, and ERK. These findings suggest that oxidative stress attenuate sensitivity to FGF-1 and higher cell density may enhance FGF-1 expression in W/M cells. In addition, we found that the cellular level of phosphatidic acid (PA) increased in H2O2-treated W/W and W/M cells and decreased by the treatment with antioxidants, and that PA enhances the mRNA expression of FGF-1 in the W/W cells. These findings suggest that the increasing PA production may enhance FGF-1 expression to protect astrocytes against oxidative stress induced by long-term culture. Copyright © 2014 Elsevier B.V. All rights reserved.
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O'Connor, W T; Lindefors, N; Brené, S; Herrera-Marschitz, M; Persson, H; Ungerstedt, U
1991-07-08
In vivo microdialysis and in situ hybridization were combined to study dopaminergic regulation of gamma-amino butyric acid (GABA) neurons in rat caudate-putamen (CPu). Potassium-stimulated GABA release in CPu was elevated following a dopamine deafferentation. Local perfusion with exogenous dopamine (50 microM) for 3 h via the microdialysis probe attenuated the potassium-stimulated increase in extracellular GABA in CPu. Expression of glutamic acid decarboxylase (GAD) mRNA was also increased in the dopamine deafferented CPu. However, local perfusion with dopamine had no significant attenuating effect on the increased GAD mRNA expression. These findings indicate that dopaminergic regulation of GABA neurons in the dopamine deafferented CPu includes both a short-term effect at the level of GABA release independent of changes in GAD mRNA expression and a long-term modulation at the level of GAD gene expression.
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Ramon-Krauel, Marta; Pentinat, Thais; Bloks, Vincent W; Cebrià, Judith; Ribo, Silvia; Pérez-Wienese, Ricky; Vilà, Maria; Palacios-Marin, Ivonne; Fernández-Pérez, Antonio; Vallejo, Mario; Téllez, Noèlia; Rodríguez, Miguel Àngel; Yanes, Oscar; Lerin, Carles; Díaz, Rubén; Plosch, Torsten; Tietge, Uwe J F; Jimenez-Chillaron, Josep C
2018-05-29
Postnatal overfeeding increases the risk of chronic diseases later in life, including obesity, insulin resistance, hepatic steatosis, and type 2 diabetes. Epigenetic mechanisms might underlie the long-lasting effects associated with early nutrition. Here we aimed to explore the molecular pathways involved in early development of insulin resistance and hepatic steatosis, and we examined the potential contribution of DNA methylation and histone modifications to long-term programming of metabolic disease. We used a well-characterized mouse model of neonatal overfeeding and early adiposity by litter size reduction. Neonatal overfeeding led to hepatic insulin resistance very early in life that persisted throughout adulthood despite normalizing food intake. Up-regulation of monoacylglycerol O-acyltransferase ( Mogat) 1 conceivably mediates hepatic steatosis and insulin resistance through increasing intracellular diacylglycerol content. Early and sustained deregulation of Mogat1 was associated with a combination of histone modifications that might favor Mogat1 expression. In sum, postnatal overfeeding causes extremely rapid derangements of hepatic insulin sensitivity that remain relatively stable until adulthood. Epigenetic mechanisms, particularly histone modifications, could contribute to such long-lasting effects. Our data suggest that targeting hepatic monoacylglycerol acyltransferase activity during early life might provide a novel strategy to improve hepatic insulin sensitivity and prevent late-onset insulin resistance and fatty liver disease.-Ramon-Krauel, M., Pentinat, T., Bloks, V. W., Cebrià, J., Ribo, S., Pérez-Wienese, R., Vilà, M., Palacios-Marin, I., Fernández-Pérez, A., Vallejo, M., Téllez, N., Rodríguez, M. À., Yanes, O., Lerin, C., Díaz, R., Plosch, T., Tietge, U. J. F., Jimenez-Chillaron, J. C. Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long-term hepatic steatosis and insulin resistance.
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Cross talk between primary human renal tubular cells and endothelial cells in cocultures.
Tasnim, Farah; Zink, Daniele
2012-04-15
Interactions between renal tubular epithelial cells and adjacent endothelial cells are essential for normal renal functions but also play important roles in renal disease and repair. Here, we investigated cocultures of human primary renal proximal tubular cells (HPTC) and human primary endothelial cells to address the cross talk between these cell types. HPTC showed improved proliferation, marker gene expression, and enzyme activity in cocultures. Also, the long-term maintenance of epithelia formed by HPTC was improved, which was due to the secretion of transforming growth factor-β1 and its antagonist α2-macroglobulin. HPTC induced endothelial cells to secrete increased amounts of these factors, which balanced each other functionally and only displayed in combination the observed positive effects. In addition, in the presence of HPTC endothelial cells expressed increased amounts of hepatocyte growth factor and vascular endothelial growth factor, which have well-characterized effects on renal tubular epithelial cells as well as on endothelial cells. Together, the results showed that HPTC stimulated endothelial cells to express a functionally balanced combination of various factors, which in turn improved the performance of HPTC. The results give new insights into the cross talk between renal epithelial and endothelial cells and suggest that cocultures could be also useful models for the analysis of cellular communication in renal disease and repair. Furthermore, the characterization of defined microenvironments, which positively affect HPTC, will be helpful for improving the performance of this cell type in in vitro applications including in vitro toxicology and kidney tissue engineering.
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Haker, Björn; Fuchs, Sigrid; Dierlamm, Judith; Brümmendorf, Tim H; Wege, Henning
2007-10-18
As a culture model to study hepatocarcinogenesis, telomerase-immortalized human fetal hepatocytes were monitored for karyotype changes evolving in long-term culture and development of functional defects in DNA damage response. G-banding revealed acquisition of characteristic karyotype abnormalities, e.g., trisomy 7 and monosomy X, in two independently immortalized and cultured populations after 80-100 population doublings. Interestingly, the detected aneuploidies resemble some of the genetic events observed in hepatocellular cancer. However, these genetic changes were not sufficient to induce oncogenic transformation reflected by absence of anchorage-independent growth. Furthermore, long-term cultured telomerase-immortalized cells preserved p53 expression levels and effective p53-mediated damage response.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Curtis, Peter; Bohrer, Gil; Gough, Christopher
2015-03-12
At the University of Michigan Biological Station (UMBS) AmeriFlux sites (US-UMB and US-UMd), long-term C cycling measurements and a novel ecosystem-scale experiment are revealing physical, biological, and ecological mechanisms driving long-term trajectories of C cycling, providing new data for improving modeling forecasts of C storage in eastern forests. Our findings provide support for previously untested hypotheses that stand-level structural and biological properties constrain long-term trajectories of C storage, and that remotely sensed canopy structural parameters can substantially improve model forecasts of forest C storage. Through the Forest Accelerated Succession ExperimenT (FASET), we are directly testing the hypothesis that forest Cmore » storage will increase due to increasing structural and biological complexity of the emerging tree communities. Support from this project, 2011-2014, enabled us to incorporate novel physical and ecological mechanisms into ecological, meteorological, and hydrological models to improve forecasts of future forest C storage in response to disturbance, succession, and current and long-term climate variation« less
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Long-term hepatotoxicity of polyethylene-glycol functionalized multi-walled carbon nanotubes in mice
NASA Astrophysics Data System (ADS)
Zhang, Danying; Deng, Xiaoyong; Ji, Zongfei; Shen, Xizhong; Dong, Ling; Wu, Minghong; Gu, Taoying; Liu, Yuanfang
2010-04-01
The toxicity of polyethylene-glycol functionalized (PEGylated) multi-walled carbon nanotubes (MWCNTs) and non-PEGylated MWCNTs in vivo was evaluated and compared. Mice were exposed to MWCNTs by intravenous injection. The activity level of glutathione, superoxide dismutase and gene expression in liver, as well as some biochemical parameters and the tumor necrosis factor alpha level in blood were measured over 2 months. The pathological and electron micrographic observations of liver evidently indicate that the damage caused by non-PEGylated MWCNTs is slightly more severe than that of PEGylated MWCNTs, which means that PEGylation can partly, but not substantially, improve the in vivo biocompatibility of MWCNTs.
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Rhes suppression enhances disease phenotypes in Huntington's disease mice.
Lee, John H; Sowada, Matthew J; Boudreau, Ryan L; Aerts, Andrea M; Thedens, Daniel R; Nopoulos, Peg; Davidson, Beverly L
2014-01-01
In Huntington's disease (HD) mutant HTT is ubiquitously expressed yet the striatum undergoes profound early degeneration. Cell culture studies suggest that a striatal-enriched protein, Rhes, may account for this vulnerability. We investigated the therapeutic potential of silencing Rhes in vivo using inhibitory RNAs (miRhes). While Rhes suppression was tolerated in wildtype mice, it failed to improve rotarod function in two distinct HD mouse models. Additionally, miRhes treated HD mice had increased anxiety-like behaviors and enhanced striatal atrophy as measured by longitudinal MRI when compared to control treated mice. These findings raise caution regarding the long-term implementation of inhibiting Rhes as a therapy for HD.
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Time-course of 5-HT(6) receptor mRNA expression during memory consolidation and amnesia.
Huerta-Rivas, A; Pérez-García, G; González-Espinosa, C; Meneses, A
2010-01-01
Growing evidence indicates that antagonists of the 5-hydroxytryptamine (serotonin) receptor(6) (5-HT(6)) improve memory and reverse amnesia although the mechanisms involved are poorly understood. Hence, in this paper RT-PCR was used to evaluate changes in mRNA expression of 5-HT(6) receptor in trained and untrained rats treated with the 5-HT(6) receptor antagonist SB-399885 and amnesic drugs scopolamine or dizocilpine. Changes in mRNA expression of 5-HT(6) receptor were investigated at different times in prefrontal cortex, hippocampus and striatum. Data indicated that memory in the Pavlovian/instrumental autoshaping task was a progressive process associated to reduced mRNA expression of 5-HT(6) receptor in the three structures examined. SB-399885 improved long-term memory at 48h, while the muscarinic receptor antagonist scopolamine or the non-competitive NMDA receptor antagonist dizocilpine impaired it at 24h. Autoshaping training and treatment with SB-399885 increased 5-HT(6) receptor mRNA expression in (maximum increase) prefrontal cortex and striatum, 24 or 48h. The scopolamine-induced amnesia suppressed 5-HT(6) receptor mRNA expression while the dizocilpine-induced amnesia did not modify 5-HT(6) receptor mRNA expression. SB-399885 and scopolamine or dizocilpine were able to reestablish memory and 5-HT(6) receptor mRNA expression. These data confirmed previous memory evidence and of more interest is the observation that training, SB-399885 and amnesic drugs modulated 5-HT(6) receptor mRNA expression in prefrontal cortex, hippocampus and striatum. Further investigation in different memory tasks, times and amnesia models together with more complex control groups might provide further clues. Copyright 2009 Elsevier Inc. All rights reserved.
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Xiong, Kun; Long, Lingling; Zhang, Xudong; Qu, Hongke; Deng, Haixiao; Ding, Yanjun; Cai, Jifeng; Wang, Shuchao; Wang, Mi; Liao, Lvshuang; Huang, Jufang; Yi, Chun-Xia; Yan, Jie
2017-10-01
Long non-coding RNAs (lncRNAs) display multiple functions including regulation of neuronal injury. However, their impact in methamphetamine (METH)-induced neurotoxicity has rarely been reported. Here, using microarray analysis, we investigated the expression profiling of lncRNAs and mRNAs in primary cultured prefrontal cortical neurons after METH treatment. We observed a difference in lncRNA and mRNA expression between the experimental and sham control groups. Using bioinformatics, we analyzed the highest enriched gene ontology (GO) terms of biological process, cellular component, and molecular function, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and pathway network analysis. Furthermore, an lncRNA-mRNA co-expression sub-network for aberrantly expressed terms revealed possible interactions of lncRNA NR_110713 and NR_027943 with their related genes. Afterwards, three lncRNAs (NR_110713, NR_027943, GAS5) and two mRNAs (Ddit3, Casp12) were targeted to validate the microarray data by qRT-PCR. This presented an overview of lncRNA and mRNA expression profiling and indicated that lncRNA might participate in METH-induced neuronal apoptosis by regulating the coding genes of neurons. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Furuhashi, Masato; Hiramitsu, Shinya; Mita, Tomohiro; Fuseya, Takahiro; Ishimura, Shutaro; Omori, Akina; Matsumoto, Megumi; Watanabe, Yuki; Hoshina, Kyoko; Tanaka, Marenao; Moniwa, Norihito; Yoshida, Hideaki; Ishii, Junnichi; Miura, Tetsuji
2015-12-01
Fatty acid binding protein 4 (FABP4), also known as adipocyte FABP or aP2, is secreted from adipocytes in association with lipolysis as a novel adipokine, and elevated serum FABP4 level is associated with obesity, insulin resistance, and atherosclerosis. However, little is known about the modulation of serum FABP4 level by therapeutic drugs. Sitagliptin (50 mg/day), a dipeptidyl peptidase 4 (DPP-4) inhibitor that increases glucagon-like peptide 1 (GLP-1), was administered to patients with type 2 diabetes (n = 24) for 12 weeks. Treatment with sitagliptin decreased serum FABP4 concentration by 19.7% (17.8 ± 1.8 vs. 14.3 ± 1.5 ng/ml, P < 0.001) and hemoglobin A1c without significant changes in adiposity or lipid variables. In 3T3-L1 adipocytes, sitagliptin or exendin-4, a GLP-1 receptor agonist, had no effect on short-term (2 h) secretion of FABP4. However, gene expression and long-term (24 h) secretion of FABP4 were significantly reduced by sitagliptin, which was not mimicked by exendin-4. Treatment with recombinant DPP-4 increased gene expression and long-term secretion of FABP4, and the effects were cancelled by sitagliptin. Furthermore, knockdown of DPP-4 in 3T3-L1 adipocytes decreased gene expression and long-term secretion of FABP4. In conclusion, sitagliptin decreases serum FABP4 level, at least in part, via reduction in the expression and consecutive secretion of FABP4 in adipocytes by direct inhibition of DPP-4. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.
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ERIC Educational Resources Information Center
Wood, Stacey; Cummings, Jeffrey L.; Schnelle, Betha; Stephens, Mary
2002-01-01
Purpose: This article reviews the effectiveness of a new training program for improving nursing staffs' detection of depression within long-term care facilities. The course was designed to increase recognition of the Minimal Data Set (MDS) Mood Trigger items, to be brief, and to rely on images rather than didactics. Design and Methods: This study…
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Thomas E. Ingersoll; Brent J. Sewall; Sybill K. Amelon
2013-01-01
Bats are diverse and ecologically important, but are also subject to a suite of severe threats. Evidence for localized bat mortality from these threats is well-documented in some cases, but long-term changes in regional populations of bats remain poorly understood. Bat hibernation surveys provide an opportunity to improve understanding, but analysis is complicated by...
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Gray, Steven J; Foti, Stacey B; Schwartz, Joel W; Bachaboina, Lavanya; Taylor-Blake, Bonnie; Coleman, Jennifer; Ehlers, Michael D; Zylka, Mark J; McCown, Thomas J; Samulski, R Jude
2011-09-01
With the increased use of small self-complementary adeno-associated viral (AAV) vectors, the design of compact promoters becomes critical for packaging and expressing larger transgenes under ubiquitous or cell-specific control. In a comparative study of commonly used 800-bp cytomegalovirus (CMV) and chicken β-actin (CBA) promoters, we report significant differences in the patterns of cell-specific gene expression in the central and peripheral nervous systems. The CMV promoter provides high initial neural expression that diminishes over time. The CBA promoter displayed mostly ubiquitous and high neural expression, but substantially lower expression in motor neurons (MNs). We report the creation of a novel hybrid form of the CBA promoter (CBh) that provides robust long-term expression in all cells observed with CMV or CBA, including MNs. To develop a short neuronal promoter to package larger transgenes into AAV vectors, we also found that a 229-bp fragment of the mouse methyl-CpG-binding protein-2 (MeCP2) promoter was able to drive neuron-specific expression within the CNS. Thus the 800-bp CBh promoter provides strong, long-term, and ubiquitous CNS expression whereas the MeCP2 promoter allows an extra 570-bp packaging capacity, with low and mostly neuronal expression within the CNS, similar to the MeCP2 transcription factor.
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Data Base Analysis for Perceptions of Emergency Programs.
1984-02-01
greater anxiety re the nuclear issue is possible long term. Concern About Nuclear War The possibility of nuclear war is a salient issue for the general...role for nuclear plants more long term (into the next century). Apparently, the public hopes for improvements in technology to mitigate nuclear hazards...ticular. More than half (54%) of government officials currently believe that management of decommissioned plants is the most important long -term
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Tucci, Sara; Primassin, Sonja; Ter Veld, Frank; Spiekerkoetter, Ute
2010-09-01
A medium-chain-triglyceride (MCT)-based diet is mainstay of treatment in very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), a long-chain fatty acid beta-oxidation defect. Beneficial effects have been reported with an MCT-bolus prior to exercise. Little is known about the impact of a long-term MCT diet on hepatic lipid metabolism. Here we investigate the effects of MCT-supplementation on liver and blood lipids in the murine model of VLCADD. Wild-type (WT) and VLCAD-knock-out (KO) mice were fed (1) a long-chain triglyceride (LCT)-diet over 5weeks, (2) an MCT diet over 5 weeks and (3) an LCT diet plus MCT-bolus. Blood and liver lipid content were determined. Expression of genes regulating lipogenesis was analyzed by RT-PCR. Under the LCT diet, VLCAD-KO mice accumulated significantly higher blood cholesterol concentrations compared to WT mice. The MCT-diet induced severe hepatic steatosis, significantly higher serum free fatty acids and impaired hepatic lipid mobilization in VLCAD-KO mice. Expression at mRNA level of hepatic lipogenic genes was up-regulated. The long-term MCT diet stimulates lipogenesis and impairs hepatic lipid metabolism in VLCAD-KO mice. These results suggest a critical reconsideration of a long-term MCT-modified diet in human VLCADD. In contrast, MCT in situations of increased energy demand appears to be a safer treatment alternative.
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Stenfert Kroese, Biza; Jahoda, Andrew; Pert, Carol; Trower, Peter; Dagnan, Dave; Selkirk, Mhairi
2014-03-01
The role of support workers and other professionals in the psychotherapeutic process has been commented upon but not as yet been systematically investigated. To explore their views and expectations of cognitive behaviour therapy (CBT) for adults with intellectual disabilities, eleven paid support workers and professionals were recruited and interviewed before the CBT sessions commenced for their service users and nine took part in the second interview that took place after nine sessions. Thematic Analysis of the interview transcripts indicates that staff members do not perceive CBT as a long-term solution for psychological problems have little knowledge of CBT and do not feel included in the process. Nevertheless, after nine sessions, most participants reported improved psychological well-being for their service users and expressed a wish for longer-term involvement of the therapist. The results suggest that for CBT to be effective in the longer term, the therapist is required to consider a wider systemic approach including staff training and supervision, staff and management consultancy and creating a delicate balance between confidentiality and sharing the psychological formulation with 'significant others' to ensure maintenance and generalisation of improved psychological well-being. © 2013 John Wiley & Sons Ltd.
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Metabolic Profiles in Ovine Carotid Arteries with Developmental Maturation and Long-Term Hypoxia
Goyal, Ravi; Longo, Lawrence D.
2015-01-01
Background Long-term hypoxia (LTH) is an important stressor related to health and disease during development. At different time points from fetus to adult, we are exposed to hypoxic stress because of placental insufficiency, high-altitude residence, smoking, chronic anemia, pulmonary, and heart disorders, as well as cancers. Intrauterine hypoxia can lead to fetal growth restriction and long-term sequelae such as cognitive impairments, hypertension, cardiovascular disorders, diabetes, and schizophrenia. Similarly, prolonged hypoxic exposure during adult life can lead to acute mountain sickness, chronic fatigue, chronic headache, cognitive impairment, acute cerebral and/or pulmonary edema, and death. Aim LTH also can lead to alteration in metabolites such as fumarate, 2-oxoglutarate, malate, and lactate, which are linked to epigenetic regulation of gene expression. Importantly, during the intrauterine life, a fetus is under a relative hypoxic environment, as compared to newborn or adult. Thus, the changes in gene expression with development from fetus to newborn to adult may be as a consequence of underlying changes in the metabolic profile because of the hypoxic environment along with developmental maturation. To examine this possibility, we examined the metabolic profile in carotid arteries from near-term fetus, newborn, and adult sheep in both normoxic and long-term hypoxic acclimatized groups. Results Our results demonstrate that LTH differentially regulated glucose metabolism, mitochondrial metabolism, nicotinamide cofactor metabolism, oxidative stress and antioxidants, membrane lipid hydrolysis, and free fatty acid metabolism, each of which may play a role in genetic-epigenetic regulation. PMID:26110419
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Cruz, Catarina; Meireles, Manuela; Silva, Susana M
2017-05-01
Neuroinflammation has been implicated in the pathogenesis of several disorders. Activation of microglia leads to the release of pro-inflammatory mediators and microglial-mediated neuroinflammation has been proposed as one of the alcohol-induced neuropathological mechanisms. The present study aimed to examine the effect of chronic ethanol exposure and long-term withdrawal on microglial activation and neuroinflammation in the hippocampal formation. Male rats were submitted to 6 months of ethanol treatment followed by a 2-month withdrawal period. Stereological methods were applied to estimate the total number of microglia and activated microglia detected by CD11b immunohistochemistry in the hippocampal formation. The expression levels of the pro-inflammatory cytokines TNF-α, COX-2 and IL-15 were measured by qRT-PCR. Alcohol consumption was associated with an increase in the total number of activated microglia but morphological assessment indicated that microglia did not exhibit a full activation phenotype. These data were supported by functional evidence since chronic alcohol consumption produced no changes in the expression of TNF-α or COX-2. The levels of IL-15 a cytokine whose expression is increased upon activation of both astrocytes and microglia, was induced by chronic alcohol treatment. Importantly, the partial activation of microglia induced by ethanol was not reversed by long-term withdrawal. This study suggests that chronic alcohol exposure induces a microglial phenotype consistent with partial activation without significant increase in classical cytokine markers of neuroinflammation in the hippocampal formation. Furthermore, long-term cessation of alcohol intake is not sufficient to alter the microglial partial activation phenotype induced by ethanol. Copyright © 2017 Elsevier B.V. All rights reserved.
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Freytag, Virginie; Probst, Sabine; Hadziselimovic, Nils; Boglari, Csaba; Hauser, Yannick; Peter, Fabian; Gabor Fenyves, Bank; Milnik, Annette; Demougin, Philippe; Vukojevic, Vanja; de Quervain, Dominique J-F; Papassotiropoulos, Andreas; Stetak, Attila
2017-07-12
The identification of genes related to encoding, storage, and retrieval of memories is a major interest in neuroscience. In the current study, we analyzed the temporal gene expression changes in a neuronal mRNA pool during an olfactory long-term associative memory (LTAM) in Caenorhabditis elegans hermaphrodites. Here, we identified a core set of 712 (538 upregulated and 174 downregulated) genes that follows three distinct temporal peaks demonstrating multiple gene regulation waves in LTAM. Compared with the previously published positive LTAM gene set (Lakhina et al., 2015), 50% of the identified upregulated genes here overlap with the previous dataset, possibly representing stimulus-independent memory-related genes. On the other hand, the remaining genes were not previously identified in positive associative memory and may specifically regulate aversive LTAM. Our results suggest a multistep gene activation process during the formation and retrieval of long-term memory and define general memory-implicated genes as well as conditioning-type-dependent gene sets. SIGNIFICANCE STATEMENT The identification of genes regulating different steps of memory is of major interest in neuroscience. Identification of common memory genes across different learning paradigms and the temporal activation of the genes are poorly studied. Here, we investigated the temporal aspects of Caenorhabditis elegans gene expression changes using aversive olfactory associative long-term memory (LTAM) and identified three major gene activation waves. Like in previous studies, aversive LTAM is also CREB dependent, and CREB activity is necessary immediately after training. Finally, we define a list of memory paradigm-independent core gene sets as well as conditioning-dependent genes. Copyright © 2017 the authors 0270-6474/17/376661-12$15.00/0.
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Templin, Christian; Zweigerdt, Robert; Schwanke, Kristin; Olmer, Ruth; Ghadri, Jelena-Rima; Emmert, Maximilian Y; Müller, Ennio; Küest, Silke M; Cohrs, Susan; Schibli, Roger; Kronen, Peter; Hilbe, Monika; Reinisch, Andreas; Strunk, Dirk; Haverich, Axel; Hoerstrup, Simon; Lüscher, Thomas F; Kaufmann, Philipp A; Landmesser, Ulf; Martin, Ulrich
2012-07-24
Evaluation of novel cellular therapies in large-animal models and patients is currently hampered by the lack of imaging approaches that allow for long-term monitoring of viable transplanted cells. In this study, sodium iodide symporter (NIS) transgene imaging was evaluated as an approach to follow in vivo survival, engraftment, and distribution of human-induced pluripotent stem cell (hiPSC) derivatives in a pig model of myocardial infarction. Transgenic hiPSC lines stably expressing a fluorescent reporter and NIS (NIS(pos)-hiPSCs) were established. Iodide uptake, efflux, and viability of NIS(pos)-hiPSCs were assessed in vitro. Ten (±2) days after induction of myocardial infarction by transient occlusion of the left anterior descending artery, catheter-based intramyocardial injection of NIS(pos)-hiPSCs guided by 3-dimensional NOGA mapping was performed. Dual-isotope single photon emission computed tomographic/computed tomographic imaging was applied with the use of (123)I to follow donor cell survival and distribution and with the use of (99m)TC-tetrofosmin for perfusion imaging. In vitro, iodide uptake in NIS(pos)-hiPSCs was increased 100-fold above that of nontransgenic controls. In vivo, viable NIS(pos)-hiPSCs could be visualized for up to 15 weeks. Immunohistochemistry demonstrated that hiPSC-derived endothelial cells contributed to vascularization. Up to 12 to 15 weeks after transplantation, no teratomas were detected. This study describes for the first time the feasibility of repeated long-term in vivo imaging of viability and tissue distribution of cellular grafts in large animals. Moreover, this is the first report demonstrating vascular differentiation and long-term engraftment of hiPSCs in a large-animal model of myocardial infarction. NIS(pos)-hiPSCs represent a valuable tool to monitor and improve current cellular treatment strategies in clinically relevant animal models.
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Rosati, Alessandra; Bersani, Samantha; Tavano, Francesca; Dalla Pozza, Elisa; De Marco, Margot; Palmieri, Marta; De Laurenzi, Vincenzo; Franco, Renato; Scognamiglio, Giosuè; Palaia, Raffaele; Fontana, Andrea; di Sebastiano, Pierluigi; Donadelli, Massimo; Dando, Ilaria; Medema, Jan Paul; Dijk, Frederike; Welling, Lieke; di Mola, Fabio Francesco; Pezzilli, Raffaele; Turco, Maria Caterina; Scarpa, Aldo
2012-11-01
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers, being the fourth leading cause of cancer-related deaths. Long-term survival reaching 15% is achieved in less than 5% of patients who undergo surgery, and median survival is only 6 months in those with inoperable lesions. A deeper understanding of PDAC biologic characteristics as well as novel prognostic markers are therefore required to improve outcomes. Herein we report that BAG3, a protein with recognized anti-apoptotic activity, was expressed in 346 PDACs analyzed, but was not expressed in the surrounding nonneoplastic tissue. In a cohort of 66 patients who underwent radical resection (R0), survival was significantly shorter in patients with high BAG3 expression (median, 12 months) than in those with low BAG3 expression (median, 23 months) (P = 0.001). Furthermore, we report that BAG3 expression in PDAC-derived cell lines protects from apoptosis and confers resistance to gemcitabine, offering a partial explanation for the survival data. Our results indicate that BAG3 has a relevant role in PDAC biology, and suggest that BAG3 expression level might be a potential marker for prediction of patient outcome. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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The Regulation of Transcription in Memory Consolidation
Alberini, Cristina M.; Kandel, Eric R.
2015-01-01
De novo transcription of DNA is a fundamental requirement for the formation of long-term memory. It is required during both consolidation and reconsolidation, the posttraining and postreactivation phases that change the state of the memory from a fragile into a stable and long-lasting form. Transcription generates both mRNAs that are translated into proteins, which are necessary for the growth of new synaptic connections, as well as noncoding RNA transcripts that have regulatory or effector roles in gene expression. The result is a cascade of events that ultimately leads to structural changes in the neurons that mediate long-term memory storage. The de novo transcription, critical for synaptic plasticity and memory formation, is orchestrated by chromatin and epigenetic modifications. The complexity of transcription regulation, its temporal progression, and the effectors produced all contribute to the flexibility and persistence of long-term memory formation. In this article, we provide an overview of the mechanisms contributing to this transcriptional regulation underlying long-term memory formation. PMID:25475090
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Effect of Aerobic Exercise Training on Mood in People With Traumatic Brain Injury: A Pilot Study.
Weinstein, Ali A; Chin, Lisa M K; Collins, John; Goel, Divya; Keyser, Randall E; Chan, Leighton
Exercise training is associated with elevations in mood in patients with various chronic illnesses and disabilities. However, little is known regarding the effect of exercise training on short and long-term mood changes in those with traumatic brain injury (TBI). The purpose of this study was to examine the time course of mood alterations in response to a vigorous, 12-week aerobic exercise training regimen in ambulatory individuals with chronic TBI (>6 months postinjury). Short and long-term mood changes were measured using the Profile of Mood States-Short Form, before and after specific aerobic exercise bouts performed during the 12-week training regimen. Ten subjects with nonpenetrating TBI (6.6 ± 6.8 years after injury) completed the training regimen. A significant improvement in overall mood was observed following 12 weeks of aerobic exercise training (P = .04), with moderate to large effect sizes observed for short-term mood improvements following individual bouts of exercise. Specific improvements in long-term mood state and short-term mood responses following individual exercise sessions were observed in these individuals with TBI. The largest improvement in overall mood was observed at 12 weeks of exercise training, with improvements emerging as early as 4 weeks into the training regimen.
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Vadnais, Mary A.; Dodge, Laura E.; Awtrey, Christopher S.; Ricciotti, Hope A.; Golen, Toni H.; Hacker, Michele R.
2013-01-01
Objective The objectives were to determine (i) whether simulation training results in short-term and long-term improvement in the management of uncommon but critical obstetrical events and (ii) to determine whether there was additional benefit from annual exposure to the workshop. Methods Physicians completed a pretest to measure knowledge and confidence in the management of eclampsia, shoulder dystocia, postpartum hemorrhage and vacuum-assisted vaginal delivery. They then attended a simulation workshop and immediately completed a posttest. Residents completed the same posttests 4 and 12 months later, and attending physicians completed the posttest at 12 months. Physicians participated in the same simulation workshop 1 year later and then completed a final posttest. Scores were compared using paired t-tests. Results Physicians demonstrated improved knowledge and comfort immediately after simulation. Residents maintained this improvement at 1 year. Attending physicians remained more comfortable managing these scenarios up to 1 year later; however, knowledge retention diminished with time. Repeating the simulation after 1 year brought additional improvement to physicians. Conclusion Simulation training can result in short-term and contribute to long-term improvement in objective measures of knowledge and comfort level in managing uncommon but critical obstetrical events. Repeat exposure to simulation training after 1 year can yield additional benefits. PMID:22191668
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Long-term effects of transference interpretation in dynamic psychotherapy of personality disorders.
Høglend, P; Dahl, H-S; Hersoug, A G; Lorentzen, S; Perry, J C
2011-10-01
Only a few treatment studies of personality disorders (PD) patients are on longer-term psychotherapy, general outcome measures are used, and follow-up periods are usually short. More studies of long-term therapies, using outcome measures of core psychopathology, are needed. This study is a dismantling randomized controlled clinical trial, specifically designed to study long-term effects of transference interpretation. Forty-six patients with mainly cluster C personality disorders were randomly assigned to 1 year of dynamic psychotherapy with or without transference interpretations. The outcome measures were remission from PD, improvement in interpersonal functioning, and use of mental health resources in the 3-year period after treatment termination. After therapy with transference interpretation PD-patients improved significantly more in core psychopathology and interpersonal functioning, the drop-out rate was reduced to zero, and use of health services was reduced to 50%, compared to therapy without this ingredient. Three years after treatment termination, 73% no longer met diagnostic criteria for any PD in the transference group, compared to 44% in the comparison group. PD-patients with co-morbid disorders improved in both treatment arms in this study. However, transference interpretation improved outcome substantially more. Long-term psychotherapy that includes transference interpretation is an effective treatment for cluster C personality disorders and milder cluster B personality disorders. Copyright © 2010 Elsevier Masson SAS. All rights reserved.
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Ang, Kexin; Maddocks, Matthew; Xu, Huiying; Higginson, Irene J
2017-03-01
Many long-term neurological conditions adversely affect respiratory function. Singing and playing wind instruments are relatively inexpensive interventions with potential for improving respiratory function; however, synthesis of current evidence is needed to inform research and clinical use of music in respiratory care. To critically appraise, analyze, and synthesize published evidence on the effectiveness of singing or playing a wind instrument to improve respiratory function in people with long-term neurological conditions. Systematic review of published randomized controlled trials and observational studies examining singing or playing wind instruments to improve respiratory function in individuals with long-term neurological conditions. Articles meeting specified inclusion criteria were identified through a search of the Medline, Embase, PsycINFO, Cochrane Library, CINAHL, Web of Science, CAIRSS for Music, WHO International Clinical Trials Registry Platform Search Portal, and AMED databases as early as 1806 through March 2015. Information on study design, clinical populations, interventions, and outcome measures was extracted and summarized using an electronic standardized coding form. Methodological quality was assessed and summarized across studies descriptively. From screening 584 references, 68 full texts were reviewed and five studies included. These concerned 109 participants. The studies were deemed of low quality, due to evidence of bias, in part due to intervention complexity. No adverse effects were reported. Overall, there was a trend toward improved respiratory function, but only one study on Parkinson's disease had significant between-group differences. The positive trend in respiratory function in people with long-term neurological conditions following singing or wind instrument therapy is of interest, and warrants further investigation. © the American Music Therapy Association 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
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Manno, Catherine S; Pierce, Glenn F; Arruda, Valder R; Glader, Bertil; Ragni, Margaret; Rasko, John J; Rasko, John; Ozelo, Margareth C; Hoots, Keith; Blatt, Philip; Konkle, Barbara; Dake, Michael; Kaye, Robin; Razavi, Mahmood; Zajko, Albert; Zehnder, James; Rustagi, Pradip K; Nakai, Hiroyuki; Chew, Amy; Leonard, Debra; Wright, J Fraser; Lessard, Ruth R; Sommer, Jürg M; Tigges, Michael; Sabatino, Denise; Luk, Alvin; Jiang, Haiyan; Mingozzi, Federico; Couto, Linda; Ertl, Hildegund C; High, Katherine A; Kay, Mark A
2006-03-01
We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.