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Find video protocols related to scientific articles indexed in Pubmed.
Alcohol impairs skeletal muscle protein synthesis and mTOR signaling in a time-dependent manner following electrically stimulated muscle contraction.
J. Appl. Physiol.
PUBLISHED: 09-25-2014
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Alcohol (EtOH) decreases protein synthesis and mammalian target of rapamycin (mTOR)-mediated signaling and blunts the anabolic response to growth factors in skeletal muscle. The purpose of the current investigation was to determine whether acute EtOH intoxication antagonizes the contraction-induced increase in protein synthesis and mTOR signaling in skeletal muscle. Fasted male mice were injected intraperitoneally with 3 g/kg EtOH or saline (control), and the right hindlimb was electrically stimulated (10 sets of 6 contractions). The gastrocnemius muscle complex was collected 30 min, 4 h, or 12 h after stimulation. EtOH decreased in vivo basal protein synthesis (PS) in the nonstimulated muscle compared with time-matched Controls at 30 min, 4 h, and 12 h. In Control, but not EtOH, PS was decreased 15% after 30 min. In contrast, PS was increased in Control 4 h poststimulation but remained unchanged in EtOH. Last, stimulation increased PS 10% in Control and EtOH at 12 h, even though the absolute rate remained reduced by EtOH. The stimulation-induced increase in the phosphorylation of S6K1 Thr(421)/Ser(424) (20-52%), S6K1 Thr(389) (45-57%), and its substrate rpS6 Ser(240/244) (37-72%) was blunted by EtOH at 30 min, 4 h, and 12 h. Phosphorylation of 4E-BP1 Ser(65) was also attenuated by EtOH (61%) at 4 h. Conversely, phosphorylation of extracellular signal-regulated kinase Thr(202)/Tyr(204) was increased by stimulation in Control and EtOH mice at 30 min but only in Control at 4 h. Our data indicate that acute EtOH intoxication suppresses muscle protein synthesis for at least 12 h and greatly impairs contraction-induced changes in synthesis and mTOR signaling.
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Glucocorticoids attenuate the central sympathoexcitatory actions of insulin.
J. Neurophysiol.
PUBLISHED: 09-03-2014
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Insulin acts within the central nervous system to regulate food intake and sympathetic nerve activity (SNA). Strong evidence indicates that glucocorticoids impair insulin-mediated glucose uptake and food intake. However, few data are available regarding whether glucocorticoids also modulate the sympathoexcitatory response to insulin. Therefore, the present study first confirmed that chronic administration of glucocorticoids attenuated insulin-induced increases in SNA and then investigated whether these effects were attributed to deficits in central insulin-mediated responses. Male Sprague-Dawley rats were given access to water or a drinking solution of the glucocorticoid agonist dexamethasone (0.3 ?g/ml) for 7 days. A hyperinsulinemic-euglycemic clamp significantly increased lumbar SNA in control rats. This response was significantly attenuated in rats given access to dexamethasone for 7, but not 1, days. Similarly, injection of insulin into the lateral ventricle or locally within the arcuate nucleus (ARC) significantly increased lumbar SNA in control rats but this response was absent in rats given access to dexamethasone. The lack of a sympathetic response to insulin cannot be attributed to a generalized depression of sympathetic function or inactivation of ARC neurons as electrical activation of sciatic afferents or ARC injection of gabazine, respectively, produced similar increases in SNA between control and dexamethasone-treated rats. Western blot analysis indicates insulin produced similar activation of Akt Ser(473) and rpS6 Ser(240/244) in the ventral hypothalamus of control and dexamethasone-treated rats. Collectively, these findings suggest that dexamethasone attenuates the sympathoexcitatory actions of insulin through a disruption of ARC neuronal function downstream of Akt or mammalian target of rapamycin (mTOR) signaling.
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Reduced REDD1 expression contributes to activation of mTORC1 following electrically induced muscle contraction.
Am. J. Physiol. Endocrinol. Metab.
PUBLISHED: 08-26-2014
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Regulated in DNA damage and development 1 (REDD1) is a repressor of mTOR complex 1 (mTORC1) signaling. In humans, REDD1 mRNA expression in skeletal muscle is repressed following resistance exercise in association with activation of mTORC1. However, whether REDD1 protein expression is also reduced after exercise and if so to what extent the loss contributes to exercise-induced activation of mTORC1 is unknown. Thus, the purpose of the present study was to examine the role of REDD1 in governing the response of mTORC1 and protein synthesis to a single bout of muscle contractions. Eccentric contractions of the tibialis anterior were elicited via electrical stimulation of the sciatic nerve in male mice in either the fasted or fed state or in fasted wild-type or REDD1-null mice. Four hours postcontractions, mTORC1 signaling and protein synthesis were elevated in fasted mice in association with repressed REDD1 expression relative to nonstimulated controls. Feeding coupled with contractions further elevated mTORC1 signaling, whereas REDD1 protein expression was repressed compared with either feeding or contractions alone. Basal mTORC1 signaling and protein synthesis were elevated in REDD1-null compared with wild-type mice. The magnitude of the increase in mTORC1 signaling was similar in both wild-type and REDD1-null mice, but, unlike wild-type mice, muscle contractions did not stimulate protein synthesis in mice deficient for REDD1, presumably because basal rates were already elevated. Overall, the data demonstrate that REDD1 expression contributes to the modulation of mTORC1 signaling following feeding- and contraction-induced activation of the pathway.
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Depressive Rumination and Cognitive Processes Associated with Depression in Breast Cancer Patients and Their Spouses.
Fam Syst Health
PUBLISHED: 07-08-2014
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Depression is common among patients with breast cancer (BC) and their spouses. The diagnosis of BC often results in negative cognitive processes, such as appraisals of harm/loss, intrusive thoughts, and depressive rumination, all of which contribute to the occurrence of depression in both the patient and spouse. The present research is a cross-sectional exploration of the mediating role of depressive rumination in the relationships of intrusive thoughts and appraisal of harm/loss with depression, in a sample of 56 BC patients and their partners. We hypothesized that depressive rumination would mediate the relationships between cognitive processes and depression in both BC patient and their partners. Participants completed self-report measures of depressive symptoms, depressive rumination, cognitive appraisals, and intrusive thoughts. Path analyses using hierarchical linear regression were conducted to assess the relationships among variables. Results indicated that for BC patients, harm/loss appraisals and intrusive thoughts had direct effects on depression; only harm/loss appraisals had indirect effects through depressive rumination. For partners, both harm/loss appraisal and intrusive thoughts had direct effects on depression, and both had indirect effects through depressive rumination. Dyadic analysis showed no relation of partner cognitive variables with patient depression or patient cognitive variables with partner depression. Findings show that the perseverative practice of dwelling on these negative thoughts of loss and harm relates to depressive symptoms. Rumination may act as 1 possible mechanism by which intrusive thoughts and harm/loss appraisals lead to depressive symptoms. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
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Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.
Neurobiol. Dis.
PUBLISHED: 06-11-2014
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Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1(+/-) mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1(+/-) mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1(+/-) mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1(+/-) mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1(+/-) nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1(+/-) mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies.
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Dyadic influence of hope and optimism on patient marital satisfaction among couples with advanced breast cancer.
Support Care Cancer
PUBLISHED: 03-09-2014
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An estimated 10-40 % of breast cancer (BC) patients report negative changes to their partnered relationships. Literature suggests that for these patients, marital satisfaction is related to depression and other quality of life factors which are associated with survivorship and treatment response. However, existing literature does not provide a clear explanation of the factors that strengthen vs. create strain in couples facing cancer. Given the benefits of a satisfying relationship to patient quality of life, it is important to better understand factors that put patients at greater risk for marital difficulties. This study examined the differential and combined roles of hope and optimism among BC patients and their partners on patient marital satisfaction.
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Exercise effects on polyp burden and immune markers in the ApcMin/+ mouse model of intestinal tumorigenesis.
Int. J. Oncol.
PUBLISHED: 03-03-2014
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Many observational epidemiologic studies suggest an association between exercise and colon cancer risk. The mechanisms contributing to a preventative effect of exercise on colon cancer are complex and multifaceted. Altered immune system function is one possible mechanism that has been largely unexplored. Therefore, the purpose of this study was to examine the effects of exercise on markers associated with macrophages and select T cell populations in a mouse model of intestinal tumorigenesis and to relate this to polyp characteristics. Male Apc(Min/+) mice were randomly assigned to either sedentary (Sed) or exercise (Ex) treatment (n=6-9/group). The exercise treatment consisted of treadmill running for 1 h/day and 6 days a week at 15 m/min from 4 until 16 weeks of age. Intestinal polyps were counted and categorized by size. Mucosal tissue was analyzed for mRNA expression of overall macrophages (F4/80), for genes associated with M1 (IL-12, IL-23 and Nos2) and M2 (CD206, IL-10, IL-4, CCL17, CCL22 and Arg-1) macrophages and the macrophage chemoattractants MCP-1, fetuin A and CXCL14. Markers for cytotoxic T cells (CTLs) and regulatory T cells were also examined by measuring mRNA expression of CD8 and Foxp3, respectively. While there was no significant difference in overall polyp number between the groups (Sed, 23.3±4.3; and Ex, 16.5±4.3), Ex did have a reduction in the number of large polyps (Sed, 6.1±1.1; and Ex, 3.0±0.6) (P<0.05). This was consistent with a decrease in spleen weight (P<0.05). Similarly, Ex reduced mRNA expression of overall macrophages (F4/80) as well as markers associated with both M1 (IL-12) and M2 (CD206, CCL22 and Arg-1) subtypes (P<0.05) but there was no significant decrease in macrophage chemoattractants. CD8 expression was increased while Foxp3 expression was decreased with Ex (P<0.05). Overall the data provide important new information on immune regulation as a possible mechanism for the documented benefits of exercise training on reducing colon cancer progression.
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Disruption of genes encoding eIF4E binding proteins-1 and -2 does not alter basal or sepsis-induced changes in skeletal muscle protein synthesis in male or female mice.
PLoS ONE
PUBLISHED: 01-01-2014
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Sepsis decreases skeletal muscle protein synthesis in part by impairing mTOR activity and the subsequent phosphorylation of 4E-BP1 and S6K1 thereby controlling translation initiation; however, the relative importance of changes in these two downstream substrates is unknown. The role of 4E-BP1 (and -BP2) in regulating muscle protein synthesis was assessed in wild-type (WT) and 4E-BP1/BP2 double knockout (DKO) male mice under basal conditions and in response to sepsis. At 12 months of age, body weight, lean body mass and energy expenditure did not differ between WT and DKO mice. Moreover, in vivo rates of protein synthesis in gastrocnemius, heart and liver did not differ between DKO and WT mice. Sepsis decreased skeletal muscle protein synthesis and S6K1 phosphorylation in WT and DKO male mice to a similar extent. Sepsis only decreased 4E-BP1 phosphorylation in WT mice as no 4E-BP1/BP2 protein was detected in muscle from DKO mice. Sepsis decreased the binding of eIF4G to eIF4E in WT mice; however, eIF4E•eIF4G binding was not altered in DKO mice under either basal or septic conditions. A comparable sepsis-induced increase in eIF4B phosphorylation was seen in both WT and DKO mice. eEF2 phosphorylation was similarly increased in muscle from WT septic mice and both control and septic DKO mice, compared to WT control values. The sepsis-induced increase in muscle MuRF1 and atrogin-1 (markers of proteolysis) as well as TNF? and IL-6 (inflammatory cytokines) mRNA was greater in DKO than WT mice. The sepsis-induced decrease in myocardial and hepatic protein synthesis did not differ between WT and DKO mice. These data suggest overall basal protein balance and synthesis is maintained in muscle of mice lacking both 4E-BP1/BP2 and that sepsis-induced changes in mTOR signaling may be mediated by a down-stream mechanism independent of 4E-BP1 phosphorylation and eIF4E•eIF4G binding.
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Studying PubMed usages in the field for complex problem solving: Implications for tool design.
J Am Soc Inf Sci Technol
PUBLISHED: 12-31-2013
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Many recent studies on MEDLINE-based information seeking have shed light on scientists behaviors and associated tool innovations that may improve efficiency and effectiveness. Few if any studies, however, examine scientists problem-solving uses of PubMed in actual contexts of work and corresponding needs for better tool support. Addressing this gap, we conducted a field study of novice scientists (14 upper level undergraduate majors in molecular biology) as they engaged in a problem solving activity with PubMed in a laboratory setting. Findings reveal many common stages and patterns of information seeking across users as well as variations, especially variations in cognitive search styles. Based on findings, we suggest tool improvements that both confirm and qualify many results found in other recent studies. Our findings highlight the need to use results from context-rich studies to inform decisions in tool design about when to offer improved features to users.
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Trajectory of change in pain, depression, and physical functioning after physical activity adoption in fibromyalgia.
J Health Psychol
PUBLISHED: 10-30-2013
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Fibromyalgia is associated with widespread pain, depression, and declines in physical functioning. The purpose of this study was to examine the trajectory of these symptoms over time related to physical activity adoption and maintenance via motivational interviewing versus education, to increase physical activity. There were no treatment group differences; we divided the sample (n = 184) based on changes in physical activity. Repeated measures analyses demonstrated differential patterns in depression, pain, and physical functioning at 24 and 36 weeks. Findings suggest increased physical activity may serve as a multiple-target intervention that provides moderate to large, long-lasting benefits for individuals with fibromyalgia.
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Understanding differences in sexting behaviors across gender, relationship status, and sexual identity, and the role of expectancies in sexting.
Cyberpsychol Behav Soc Netw
PUBLISHED: 05-15-2013
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Sexting, or the exchange of sexually explicit material via Internet social-networking site or mobile phone, is an increasingly prevalent behavior. The study sought to (1) identify expectancies regarding sexting behaviors, (2) examine how demographics (i.e., gender, sexual identity, relationship status) might be differentially related to sexting expectancies and behaviors, and (3) examine whether these concurrent relationships are consistent with a theoretical causal model in which sexting expectancies influence sexting behaviors. The sample consisted of 278 undergraduate students (mean age=21.0 years, SD=4.56; 53.8% female; 76.3% caucasian). Factor analyses supported the validity and reliability of the Sextpectancies Measure (?=0.85-0.93 across subscales) and indicated two expectancy domains each for both sending and receiving sexts: positive expectancies (sexual-related and affect-related) and negative expectancies. Males reported stronger positive expectancies (F=4.64, p=0.03) while females reported stronger negative expectancies (F=6.11, p=0.01) about receiving sexts. There were also differences across relationship status regarding negative expectancies (F=2.25, p=0.05 for sending; F=4.24, p=0.002 for receiving). There were also significant effects of positive (F=45.98, p<0.001 for sending, F=22.42, p<0.001 for receiving) and negative expectancies (F=36.65, p=0.02 sending, F=14.41, p<0.001 receiving) on sexting behaviors (?(2) from 0.04-0.13). College students reported both positive and negative sextpectancies, although sextpectancies and sexting varied significantly across gender, race, sexual identity, and relationship status. Concurrent relationships were consistent with the causal model of sextpectancies influencing sexting behaviors, and this study serves as the first test of this model, which could inform future prevention strategies to mitigate sexting risks.
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Combining cognitive-behavioral therapy and milnacipran for fibromyalgia: a feasibility randomized-controlled trial.
Clin J Pain
PUBLISHED: 03-01-2013
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To evaluate the feasibility of a randomized-controlled trial and to obtain estimates of the effects of combined cognitive-behavioral therapy (CBT) and milnacipran for the treatment of fibromyalgia.
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?-Synuclein: the long distance runner.
Brain Pathol.
PUBLISHED: 02-04-2013
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Parkinsons disease is characterized by ?-synuclein pathology in the form of Lewy bodies and Lewy neurites. Braak et?al described the spatial and temporal spread of ?-synuclein pathology in Parkinsons disease. Recent experimental studies have demonstrated that ?-synuclein can transfer from cell to cell. In this review, we highlight the involvement of ?-synuclein in Parkinsons disease and in Braaks staging of Parkinsons disease pathology. We discuss whether a prion-like mechanism of ?-synuclein spread might contribute to Parkinsons disease pathology. We describe recent studies investigating cell-to-cell transfer of ?-synuclein and focus our review on the long-distance axonal transport of ?-synuclein along neurons.
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Ticagrelor: positive, negative and misunderstood properties as a new antiplatelet agent.
Clin. Exp. Pharmacol. Physiol.
PUBLISHED: 01-19-2013
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Dual antiplatelet therapy is essential for the management of acute coronary syndrome. In particular, combination therapy using aspirin with a platelet ADP (i.e. P2Y12 ) receptor inhibitor, such as clopidogrel, prasugrel or, more recently, ticagrelor, has been recommended for patients with acute coronary syndrome. Pharmacological agents that reversibly inhibit platelet aggregation without metabolic activation in the liver are believed to reduce cardiovascular mortality compared with the current drug of choice for antiplatelet therapy, namely clopidogrel. These findings are based on a multicentre, double-blind, double-dummy, randomized controlled trial. Numerous factors are postulated to contribute to the improved survival of patients who take ticagrelor compared with those taking clopidogrel, including the risk of myocardial infarction, heart failure, arrhythmia and bleeding. In addition, clopidogrel may lead to a much higher incidence of infection. Although ticagrelor has recently been approved for use in the US and exhibits superiority over other antiplatelet agents, certain concerns remain regarding its use, including lung injury and dyspnoea, thus raising the issue of its true superiority over clopidogrel or prasugrel. Recent studies into ticagrelor report conflicting data, with certain aspects of its mechanisms of action still not fully understood. Ticagrelor has beneficial effects following its clinical application, such as achieving overall higher reductions in mortality compared with the use of clopidogrel and prasugrel. Harmful effects associated with the use of ticagrelor include a higher incidence of dyspnoea and major bleeding compared with clopidogrel.
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Can Parkinsons disease pathology be propagated from one neuron to another?
Prog. Neurobiol.
PUBLISHED: 08-16-2011
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Parkinsons disease is the second most prevalent neurodegenerative disease, yet despite this, very little is known about the underlying cellular mechanisms. Initially it was thought to be a disease primarily involving loss of dopaminergic neurons in the substantia nigra pars compacta. Recent studies, however, have focused on observations that aggregated ?-synuclein protein, the major component of Lewy bodies, is found throughout the nervous system. It is speculated that misfolded ?-synuclein transfers between cells in a prion-like manner, thereby mediating the spread of the neuropathology. In this review, we discuss the staging (according to Braak) of Parkinson pathology and the concept describing the disease progression from one region of the brain to the other. We highlight how ?-synuclein might be responsible for the spread of the disease. We compare the idea of a prion-like mechanism contributing to Parkinsons disease to emerging concepts that other proteins participate in similar processes in other neurodegenerative diseases. We then examine the future implications of a critical role in disease pathogenesis of ?-synuclein for the classification, diagnosis and treatment of Parkinsons disease in the future.
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Exercise training increases mitochondrial biogenesis in the brain.
J. Appl. Physiol.
PUBLISHED: 08-04-2011
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Increased muscle mitochondria are largely responsible for the increased resistance to fatigue and health benefits ascribed to exercise training. However, very little attention has been given to the likely benefits of increased brain mitochondria in this regard. We examined the effects of exercise training on markers of both brain and muscle mitochondrial biogenesis in relation to endurance capacity assessed by a treadmill run to fatigue (RTF) in mice. Male ICR mice were assigned to exercise (EX) or sedentary (SED) conditions (n = 16-19/group). EX mice performed 8 wk of treadmill running for 1 h/day, 6 days/wk at 25 m/min and a 5% incline. Twenty-four hours after the last training bout a subgroup of mice (n = 9-11/group) were euthanized, and brain (brain stem, cerebellum, cortex, frontal lobe, hippocampus, hypothalamus, and midbrain) and muscle (soleus) tissues were isolated for analysis of mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1?), Silent Information Regulator T1 (SIRT1), citrate synthase (CS), and mitochondrial DNA (mtDNA) using RT-PCR. A different subgroup of EX and SED mice (n = 7-8/group) performed a treadmill RTF test. Exercise training increased PGC-1?, SIRT1, and CS mRNA and mtDNA in most brain regions in addition to the soleus (P < 0.05). Mean treadmill RTF increased from 74.0 ± 9.6 min to 126.5 ± 16.1 min following training (P < 0.05). These findings suggest that exercise training increases brain mitochondrial biogenesis, which may have important implications, not only with regard to fatigue, but also with respect to various central nervous system diseases and age-related dementia that are often characterized by mitochondrial dysfunction.
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Breast cancer in a wife: how husbands cope and how well it works.
Cancer Nurs
PUBLISHED: 04-28-2011
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Husbands of patients with breast cancer (HBCs) experience as much as or even more distress than patients. Husbands coping strategies may predict their level of distress.
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Intestinal inflammatory cytokine response in relation to tumorigenesis in the Apc(Min/+) mouse.
Cytokine
PUBLISHED: 04-18-2011
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The etiology of colon cancer is a complex phenomenon that involves both genetic and environmental factors. However, only about 20% have a familial basis with the largest fraction being attributed to environmental causes that can lead to chronic inflammation. While the link between inflammation and colon cancer is well established, the temporal sequence of the inflammatory response in relation to tumorigenesis has not been characterized. We examined the timing and magnitude of the intestinal inflammatory cytokine response in relation to tumorigenesis in the Apc(Min/+) mouse. Apc(Min/+) mice and wildtype mice were sacrificed at one of 4 time-points: 8, 12, 16, and 20 weeks of age. Intestinal tissue was analyzed for polyp burden (sections 1, 4 and 5) and mRNA expression and protein concentration of MCP-1, IL-1?, IL-6 and TNF-? (sections 2 and 3). The results show that polyp burden was increased at 12, 16 and 20 weeks compared to 8 weeks (P<0.05). Gene expression (mRNA) of MCP-1, IL-1?, IL-6 and TNF-? was increased in sections 2 and 3 starting at week 12 (P<0.05), with further increases in MCP-1, IL-1? and IL-6 at 16 weeks (P<0.05). Protein concentration for these cytokines followed a similar pattern in section 3. Similarly, circulating MCP-1 was increased at 12 weeks (P<0.05) and then again at 20 weeks (P<0.05). In general, overall polyp number and abundance of large polyps were significantly correlated with the inflammatory cytokine response providing further support for a relationship between polyp progression and these markers. These data confirm the association between intestinal cytokines and tumorigenesis in the Apc(Min/+) mouse and provide new information on the timing and magnitude of this response in relation to polyp development. These findings may lead to the development of inflammatory mediators as important biomarkers for colon cancer progression. Further, these data may be relevant in the design of future investigations of therapeutic interventions to effectively target inflammatory processes in rodent models.
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?-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells.
J. Clin. Invest.
PUBLISHED: 01-18-2011
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Post-mortem analyses of brains from patients with Parkinson disease who received fetal mesencephalic transplants show that ?-synuclein-containing (?-syn-containing) Lewy bodies gradually appear in grafted neurons. Here, we explored whether intercellular transfer of ?-syn from host to graft, followed by seeding of ?-syn aggregation in recipient neurons, can contribute to this phenomenon. We assessed ?-syn cell-to-cell transfer using microscopy, flow cytometry, and high-content screening in several coculture model systems. Coculturing cells engineered to express either GFP- or DsRed-tagged ?-syn resulted in a gradual increase in double-labeled cells. Importantly, ?-syn-GFP derived from 1 neuroblastoma cell line localized to red fluorescent aggregates in other cells expressing DsRed-?-syn, suggesting a seeding effect of transmitted ?-syn. Extracellular ?-syn was taken up by cells through endocytosis and interacted with intracellular ?-syn. Next, following intracortical injection of recombinant ?-syn in rats, we found neuronal uptake was attenuated by coinjection of an endocytosis inhibitor. Finally, we demonstrated in vivo transfer of ?-syn between host cells and grafted dopaminergic neurons in mice overexpressing human ?-syn. In summary, intercellularly transferred ?-syn interacts with cytoplasmic ?-syn and can propagate ?-syn pathology. These results suggest that ?-syn propagation is a key element in the progression of Parkinson disease pathology.
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Matched and mismatched cognitive appraisals in patients with breast cancer and their partners: implications for psychological distress.
Psychooncology
PUBLISHED: 01-12-2011
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The present study sought to identify couples cognitive appraisals of breast cancer and the extent to which matched or mismatched appraisals within a couple contribute to distress.
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Social support mediates the relations between role strains and marital satisfaction in husbands of patients with fibromyalgia syndrome.
Fam Syst Health
PUBLISHED: 10-14-2010
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Husbands of patients with fibromyalgia syndrome (HFMS) report poorer physical and mental health than husbands of women without illness, as well as role strains because of their wives condition. There are no published reports regarding the impact of fibromyalgia on their marital relationship. In the present study, we used Lazarus and Folkmans (1984) model of stress and coping as a framework to examine marital satisfaction among HFMS. We hypothesized that role strains would be related to marital satisfaction, mediated or moderated by social support and problem and emotion focused coping. HFMS (n=135) and husbands of healthy women (n=153) completed the Locke Wallace Marital Adjustment Test, the Interpersonal Support Evaluation List, and the Ways of Coping Questionnaire. Only HFMS completed the Psychological Adjustment to Illness Scale-Spouse Version. HFMS reported lower marital satisfaction than comparison husbands. Among HFMS, sexual and domestic roles strains and social support were related to marital satisfaction. Social support alone mediated the relationship between role strain and marital satisfaction, and no variable moderated the relationship. These findings support prior research that shows that these husbands are significantly impacted by their wives condition, and suggest the need to focus more attention on this population, possibly targeting social support for interventions.
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Are synucleinopathies prion-like disorders?
Lancet Neurol
PUBLISHED: 09-16-2010
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A shared neuropathological feature of idiopathic Parkinsons disease, dementia with Lewy bodies, and multiple system atrophy is the development of intracellular aggregates of ?-synuclein that gradually engage increasing parts of the nervous system. The pathogenetic mechanisms underlying these neurodegenerative disorders, however, are unknown. Several studies have highlighted similarities between classic prion diseases and these neurological proteinopathies. Specifically, identification of Lewy bodies in fetal mesencephalic neurons transplanted in patients with Parkinsons disease raised the hypothesis that ?-synuclein, the main component of Lewy bodies, could be transmitted from the host brain to a graft of healthy neurons. These results and others have led to the hypothesis that a prion-like mechanism might underlie progression of synucleinopathy within the nervous system. We review experimental findings showing that misfolded ?-synuclein can transfer between cells and, once transferred into a new cell, can act as a seed that recruits endogenous ?-synuclein, leading to formation of larger aggregates. This model suggests that strategies aimed at prevention of cell-to-cell transfer of ?-synuclein could retard progression of symptoms in Parkinsons disease and other synucleinopathies.
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Cognitive-behavioral therapy attenuates nociceptive responding in patients with fibromyalgia: a pilot study.
Arthritis Care Res (Hoboken)
PUBLISHED: 03-02-2010
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To explore the possibility that cognitive-behavioral therapy (CBT) influences fibromyalgia symptoms via descending inhibition of nociception, we evaluated the effects of CBT on the nociceptive flexion reflex (NFR) threshold, an objective measure of spinal nociceptive transmission.
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Depression in husbands of breast cancer patients: relationships to coping and social support.
Support Care Cancer
PUBLISHED: 02-08-2010
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The purpose of the present study was to examine depression in husbands of women with breast cancer, as depression is typically as high in husbands as in patients, and impacts functioning in both.
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Modeling rare gene variation to gain insight into the oldest biomarker in autism: construction of the serotonin transporter Gly56Ala knock-in mouse.
J Neurodev Disord
PUBLISHED: 12-05-2009
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Alterations in peripheral and central indices of serotonin (5-hydroxytryptamine, 5-HT) production, storage and signaling have long been associated with autism. The 5-HT transporter gene (HTT, SERT, SLC6A4) has received considerable attention as a potential risk locus for autism-spectrum disorders, as well as disorders with overlapping symptoms, including obsessive-compulsive disorder (OCD). Here, we review our efforts to characterize rare, nonsynonymous polymorphisms in SERT derived from multiplex pedigrees carrying diagnoses of autism and OCD and present the initial stages of our effort to model one of these variants, Gly56Ala, in vivo. We generated a targeting vector to produce the Gly56Ala substitution in the Slc6a4 locus by homologous recombination. Following removal of a neomycin resistance selection cassette, animals exhibiting germline transmission of the Ala56 variant were bred to establish a breeding colony on a 129S6 background, suitable for initial evaluation of biochemical, physiological and behavioral alterations relative to SERT Gly56 (wild-type) animals. SERT Ala56 mice were achieved and exhibit a normal pattern of transmission. The initial growth and gross morphology of these animals is comparable to wildtype littermate controls. The SERT Ala56 variant can be propagated in 129S6 mice without apparent disruption of fertility and growth. We discuss both the opportunities and challenges that await the physiological/behavioral analysis of Gly56Ala transgenic mice, with particular reference to modeling autism-associated traits.
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cGMP-dependent protein kinase Ialpha associates with the antidepressant-sensitive serotonin transporter and dictates rapid modulation of serotonin uptake.
Mol Brain
PUBLISHED: 08-05-2009
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The Na(+)/Cl(-)-dependent serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) is a critical element in neuronal 5-HT signaling, being responsible for the efficient elimination of 5-HT after release. SERTs are not only targets for exogenous addictive and therapeutic agents but also can be modulated by endogenous, receptor-linked signaling pathways. We have shown that neuronal A3 adenosine receptor activation leads to enhanced presynaptic 5-HT transport in vitro and an increased rate of SERT-mediated 5-HT clearance in vivo. SERT stimulation by A3 adenosine receptors derives from an elevation of cGMP and subsequent activation of both cGMP-dependent protein kinase (PKG) and p38 mitogen-activated protein kinase. PKG activators such as 8-Br-cGMP are known to lead to transporter phosphorylation, though how this modification supports SERT regulation is unclear.
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Effects of carbohydrate supplementation on the RPE-blood lactate relationship.
Med Sci Sports Exerc
PUBLISHED: 05-23-2009
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To examine the effects of carbohydrate (CHO) ingestion on the RPE-blood lactate relationship during incremental and constant-effort exercise.
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Enhanced activity of human serotonin transporter variants associated with autism.
Philos. Trans. R. Soc. Lond., B, Biol. Sci.
PUBLISHED: 03-04-2009
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Rare, functional, non-synonymous variants in the human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT) gene (SLC6A4) have been identified in both autism and obsessive-compulsive disorder (OCD). Within autism, rare hSERT coding variants associate with rigid-compulsive traits, suggesting both phenotypic overlap with OCD and a shared relationship with disrupted 5-HT signalling. Here, we document functional perturbations of three of these variants: Ile425Leu; Phe465Leu; and Leu550Val. In transiently transfected HeLa cells, the three variants confer a gain of 5-HT transport phenotype. Specifically, enhanced SERT activity was also observed in lymphoblastoid lines derived from mutation carriers. In contrast to previously characterized Gly56Ala, where increased transport activity derives from catalytic activation, the three novel variants exhibit elevated surface density as revealed through both surface antagonist-binding and biotinylation studies. Unlike Gly56Ala, mutants Ile425Leu, Phe465Leu and Leu550Val retain a capacity for acute PKG and p38 MAPK regulation. However, both Gly56Ala and Ile425Leu demonstrate markedly reduced sensitivity to PP2A antagonists, suggesting that deficits in trafficking and catalytic modulation may derive from a common basis in perturbed phosphatase regulation. When expressed stably from the same genomic locus in CHO cells, both Gly56Ala and Ile425Leu display catalytic activation, accompanied by a striking loss of SERT protein.
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Linking tumor-associated macrophages, inflammation, and intestinal tumorigenesis: role of MCP-1.
Am. J. Physiol. Gastrointest. Liver Physiol.
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Tumor-associated macrophages are associated with poor prognosis in certain cancers. Monocyte chemoattractant protein 1 (MCP-1) is thought to be the most important chemokine for recruitment of macrophages to the tumor microenvironment. However, its role on tumorigenesis in a genetic mouse model of colon cancer has not been explored. We examined the role of MCP-1 on tumor-associated macrophages, inflammation, and intestinal tumorigenesis. Male Apc(Min/+), Apc(Min/+)/MCP-1(-/-) or wild-type mice were euthanized at 18 wk of age and intestines were analyzed for polyp burden, apoptosis, proliferation, ?-catenin, macrophage number and phenotype, markers for cytotoxic T lymphocytes and regulatory T cells, and inflammatory mediators. MCP-1 deficiency decreased overall polyp number by 20% and specifically large polyp number by 45% (P < 0.05). This was consistent with an increase in apoptotic cells (P < 0.05), but there was no change detected in proliferation or ?-catenin. MCP-1 deficiency decreased F4/80-positive cells in both the polyp tissue and surrounding intestinal tissue (P < 0.05) as well as expression of markers associated with M1 (IL-12 and IL-23) and M2 macrophages (IL-13, CD206, TGF-?, and CCL17) (P < 0.05). MCP-1 knockout was also associated with increased cytotoxic T lymphocytes and decreased regulatory T cells (P < 0.05). In addition, MCP-1(-/-) offset the increased mRNA expression of IL-1? and IL-6 in intestinal tissue and IL-1? and TNF-? in polyp tissue (P < 0.05), and prevented the decrease in SOCS1 expression (P < 0.05). We demonstrate that MCP-1 is an important mediator of tumor growth and immune regulation that may serve as an important biomarker and/or therapeutic target in colon cancer.
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Cognitive appraisals, coping and depressive symptoms in breast cancer patients.
Stress Health
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Depression in breast cancer patients and survivors is related to negative disease outcomes and worse quality of life. Factors that explain this depression can serve as targets of intervention. This study, guided by the Transactional Theory of Stress, examined the relationship between cognitive appraisals, coping strategies and depressive symptoms in a group of women with mostly advanced-stage breast cancer (N = 65), who scored mostly within the normal range for depressive symptoms. Path analysis was used to determine the relationships among variables, measured with the Cognitive Appraisals of Illness Scale, the Ways of Coping Questionnaire and the Center for Epidemiological Studies Depression Scale. The results of the path analysis showed that higher appraisals of harm/loss and greater use of escape-avoidance coping predicted higher depressive symptoms. These findings enhance the prediction of depression among breast cancer patients and suggest the need to examine cognitive appraisals when attempting to understand depressive symptoms.
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Importance of chemokine (CC-motif) ligand 2 in breast cancer.
Int. J. Biol. Markers
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Breast cancer is the leading cause of cancer-related death in women in the United States. Chemokine (CC-motif) ligand 2 (CCL2), an inflammatory cytokine and chemokine, is highly expressed within the tumor and stromal cell populations and has been associated with enhanced tumorigenesis. In breast cancer patients, CCL2 has been correlated with high tumor grade and has been shown to have significant prognostic value for relapse-free survival. CCL2 likely exerts its pro-tumorigenic effects through recruitment of tumor-associated macrophages (TAMs); TAMs promote a tumorigenic microenvironment through the induction of growth enhancers, angiogenic factors and inflammatory mediators. CCL2 may also stimulate angiogenesis independently of TAM recruitment as it is closely associated with several endothelial cell growth factors. Additionally, CCL2 has been implicated in several processes leading to metastatic establishment including the development of bone metastasis. It has also been reported to directly upregulate pro-tumorigenic inflammatory mediators, including regulated upon activation, normal T cell expressed and secreted (RANTES) and tumor necrosis factor-alpha (TNF-?). While there is emerging support for a tumor promoting role of CCL2 in breast cancer, additional research is required before CCL2 can be decisively established as a prognostic factor and/or treatment target in breast cancer.
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Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo.
PLoS ONE
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Several people with Parkinsons disease have been treated with intrastriatal grafts of fetal dopaminergic neurons. Following autopsy, 10-22 years after surgery, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. Numerous studies have attempted to explain these findings in cell and animal models. In cell culture, ?-synuclein has been found to transfer from one cell to another, via mechanisms that include exosomal transport and endocytosis, and in certain cases seed aggregation in the recipient cell. In animal models, transfer of ?-synuclein from host brain cells to grafted neurons has been shown, but the reported frequency of the event has been relatively low and little is known about the underlying mechanisms as well as the fate of the transferred ?-synuclein. We now demonstrate frequent transfer of ?-synuclein from a rat brain engineered to overexpress human ?-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying cell-to-cell transfer of ?-synuclein. Thus, we present evidence both for the involvement of endocytosis in ?-synuclein uptake in vivo, and for seeding of aggregation of endogenous ?-synuclein in the recipient neuron by the transferred ?-synuclein. Finally, we show that, at least in a subset of the studied cells, the transmitted ?-synuclein is sensitive to proteinase K. Our new model system could be used to test compounds that inhibit cell-to-cell transfer of ?-synuclein and therefore might retard progression of Parkinson neuropathology.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.