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Find video protocols related to scientific articles indexed in Pubmed.
Hospital admission for community-acquired pneumonia in a First Nations population.
Can J Rural Med
PUBLISHED: 10-08-2014
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Northwestern Ontario is a large rural area with a high concentration of remote First Nations communities. In Ontario, the highest hospital admission rates for pneumonia are reported from northern and rural regions. However, data are lacking on the epidemiology of community-acquired pneumonia in northwestern Ontario. We sought to characterize cases of community-acquired pneumonia requiring admission at the Sioux Lookout Meno Ya Win Health Centre, which serves a primarily First Nations population of 28 000.
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Detection of Glaucoma and Its Association With Diabetic Retinopathy in a Diabetic Retinopathy Screening Program.
J. Glaucoma
PUBLISHED: 09-30-2014
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To determine the type of glaucoma in subjects with diabetes mellitus detected during a diabetic retinopathy screening program and to determine any association between diabetic retinopathy (DR) and glaucoma.
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A cognitive-balance control training paradigm using wii fit to reduce fall risk in chronic stroke survivors.
J Neurol Phys Ther
PUBLISHED: 09-09-2014
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The impaired ability to maintain balance while performing higher-level cognitive tasks (cognitive-motor interference) significantly predisposes stroke survivors to risk of falls. We investigated adherence and intervention-related effects of gaming to improve balance control and decrease cognitive-motor interference in stroke survivors.
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Hyaluronan in aged collagen matrix increases prostate epithelial cell proliferation.
In Vitro Cell. Dev. Biol. Anim.
PUBLISHED: 08-15-2014
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The extracellular matrix (ECM) of the prostate, which is comprised primarily of collagen, becomes increasingly disorganized with age, a property that may influence the development of hyperplasia and cancer. Collageous ECM extracted from the tails of aged mice exhibits many characteristics of collagen in aged tissues, including the prostate. When polymerized into a 3-dimensional (3D) gel, these collagen extracts can serve as models for the study of specific cell-ECM interactions. In the present study, we examined the behaviors of human prostatic epithelial cell lines representing normal prostate epithelial cells (PEC), benign prostatic hyperplasia (BPH-1), and adenocarcinoma (LNCaP) cultured in contact with 3D gels made from collagen extracts of young and aged mice. We found that proliferation of PEC, BPH-1, and LNCaP cells were all increased by culture on aged collagen gels relative to young collagen gels. In examining age-associated differences in the composition of the collagen extracts, we found that aged and young collagen had a similar amount of several collagen-associated ECM components, but aged collagen had a much greater content of the glycosaminoglycan hyaluronan (HA) than young collagen. The addition of HA (of similar size and concentration to that found in aged collagen extracts) to cells placed in young collagen elicited significantly increased proliferation in BPH-1 cells, but not in PEC or LNCaP cells, relative to controls not exposed to HA. Of note, histochemical analyses of human prostatic tissues showed significantly higher expression of HA in BPH and prostate cancer stroma relative to stroma of normal prostate. Collectively, these results suggest that changes in ECM involving increased levels of HA contribute to the growth of prostatic epithelium with aging.
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CREB modulates calcium signaling in cAMP-induced bone marrow stromal cells (BMSCs).
Cell Calcium
PUBLISHED: 08-06-2014
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Calcium signaling has a versatile role in many important cellular functions. Despite its importance, regulation of calcium signaling in bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) has not been explored extensively. Our previous study revealed that cyclic adenosine monophosphate (cAMP) enabled BMSCs to generate calcium signal upon stimulation by dopamine, KCl and glutamate. Concurrently, cAMP transiently activated the transcription factor cAMP response element binding protein (CREB) in BMSCs. Activity of CREB can be modulated by the calcium/calmodulin-dependent kinase signaling pathway, however, whether the calcium signaling observed in cAMP-induced BMSCs requires CREB has not been investigated. In an effort to uncover the role of CREB in the generation of calcium signaling in response to modulators such as dopamine and KCl, we knocked down CREB activity in BMSCs. Our study indicated that BMSCs, but not its close relative fibroblasts, are responsive to dopamine and KCl after cAMP treatment. Calcium signal elicited by dopamine depends, in part, on calcium influx whereas that elicited by KCl depends completely on calcium influx. Knock-down of CREB activity significantly reduced or abolished the cAMP-induced calcium response, and reintroducing a constitutively active CREB partially restored the calcium response.
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The effects of practicing sitting Tai Chi on balance control and eye-hand coordination in the older adults: a randomized controlled trial.
Disabil Rehabil
PUBLISHED: 07-26-2014
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Abstract Purpose: The purpose of this study was to examine the effects of 3 months of sitting Tai Chi training on the sitting balance control and eye-hand coordination of older adults subjects. Methods: We randomly assigned 59 older adults from four residential care facilities to either sitting Tai Chi group or mobilizing exercises group as control. The sitting Tai Chi group underwent 3 months of training with a total of 36 sessions (1 hour/session, 3 sessions/week). The outcome measures included sitting balance tests (testing sequential weight shifting and forward reaching in a sitting position) and eye-hand coordination tests (reaction time, movement time and accuracy in finger pointing task). Results: The Tai Chi practitioners showed significant improvement in their sequential weight shifting while sitting (improved by 29.0%, p???0.05) and in their maximum reaching distance from a sitting position (improved by 21.2%, p???0.05). No such improvements were found in the control group. In the eye-hand coordination test, the sitting Tai Chi practitioners had significant improvements in accuracy (improved by 17.3%, p???0.05). Also, no improvement was found in the control group. Conclusions: The results demonstrate 3-months of sitting Tai Chi training can improve sitting balance and accuracy in finger pointing task in the older adults. Implications for Rehabilitation Traditional Tai Chi poses difficulties for older adults with poor standing balance. This pilot study showed that a 3 months sitting Tai Chi training can improve sitting balance and accuracy in the finger pointing task in the older adults. Sitting Tai Chi can be a therapy option for older adults with poor standing balance.
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Effects of Tai Chi on a Functional Arm Reaching Task in Older Adults: A Cross-Sectional Study.
J Aging Phys Act
PUBLISHED: 07-11-2014
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This study quantified the effect of aging and the long-term practice of Tai Chi on upper limb movement control, indicated by performance-outcome (temporal) and performance-production (amplitude) measures, on a multi-planar, stand-reaching (i.e. functional) task. Twelve Tai Chi practitioners (TCP), 11 age-matched, older non-practitioners (ONP) and 12 young subjects performed cued, flexion- and abduction-reaching tasks using a custom set-up. Surface-EMG and acceleration data sampled from wireless sensors rendered performance-outcome (reaction time, burst duration, time-to-peak and movement time) and performance-production (normalized EMG amplitude and peak acceleration) measures. Young subjects and TCP demonstrated better performance-outcome and performance-production than ONP. Relative-effect computations (i.e. the effect of Tai Chi expressed as a percentage of the effect of aging) showed that TCP exhibited approximately 20-60% (flexion) and 20-100% (abduction) improvement in reaching task performance compared to ONP. Tai Chi practitioners displayed better arm movement control than ONP on a relatively challenging and functional stand-reaching task.
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One-year follow-up of the 2011 Christchurch Earthquake stress cardiomyopathy cases.
N. Z. Med. J.
PUBLISHED: 07-06-2014
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A major earthquake struck Christchurch on 22 February 2011 causing extensive damage to the city and 185 direct fatalities. Within 4 days 21 postmenopausal women presented to Christchurch Hospital with stress cardiomyopathy. We were able to closely examine these patients in the immediate phase of presentation and at 12 months.
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Effect of dual tasking on intentional vs. reactive balance control in people with hemiparetic stroke.
J. Neurophysiol.
PUBLISHED: 05-28-2014
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To examine the effect of a cognitive task on intentional vs. reactive balance control in people with hemiparetic stroke (PwHS). Community-dwelling PwHS (n = 10) and healthy, age-similar controls performed two tests, which included the Limits of Stability Test (intentional control) and the Motor Control Test (reactive control), under single-task (ST) and dual-task (DT) conditions (addition of a cognitive task). Cognitive ability was measured on a word list generation task by recording the number of words enumerated in sitting (ST; for cognition) and during the balance tasks. The difference in response time between the ST and DT, defined as the "balance cost" was obtained [(ST - DT)/ST × 100] and compared between tests and across groups. The "cognitive cost" was similarly defined and compared. For both groups, the response time under DT condition was significantly greater for intentional than the reactive balance control task, leading to a higher balance cost for this task (P < 0.05). However, the cognitive cost was significantly greater for the intentional than the reactive balance control task for only the PwHS. DT significantly affected intentional than reactive balance control for PwHS. The significant decrease in both balance and cognitive performance under DT compared with ST conditions during intentional balance control suggests sharing of attentional resources between semantic memory and intentional balance control. Decreased performance on the cognitive task only during the reactive balance test indicates possible central nervous system's prioritization of reactive balance control over cognition.
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Internal consistency and test-retest reliability of an instrumented functional reaching task using wireless electromyographic sensors.
J Electromyogr Kinesiol
PUBLISHED: 05-07-2014
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The purpose of this study was to establish the internal consistency and test-retest reliability of the electromyographic and accelerometric data sampled from the prime movers of the dominant arm during an antigravity, within-arm's length stand-reaching task without trunk restraint. Ten healthy young adults participated in two experimental sessions, approximately 7-10days apart. During each session, subjects performed 15 trials of both a flexion- and an abduction-reaching task. Surface EMG and acceleration using wireless sensors were sampled from the anterior and middle deltoid. Reliability was established using Cronbach's alpha, intraclass correlation coefficients (ICC 2, k) and standard error of measurements (SEM) for electromyographic reaction time, burst duration and normalized amplitude along with peak acceleration. Results indicated high degrees of inter-trial and test-retest reliability for flexion (Cronbach's ? range=0.92-0.99; ICC range=0.82-0.92) as well as abduction (Cronbach's ? range=0.94-0.99; ICC range=0.81-0.94) reaching. The SEM associated with response variables for flexion and abduction ranged from 1.55-3.26% and 3.33-3.95% of means, respectively. Findings from this study revealed that electromyographic and accelerometric data collected from prime movers of the arm during the relatively functional stand-reaching task were highly reproducible. Given its high reliability and portability, the proposed test could have applications in clinical and laboratory settings to quantify upper limb function.
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Systematic modeling for the insulin signaling network mediated by IRS(1) and IRS(2).
J. Theor. Biol.
PUBLISHED: 02-26-2014
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The hepatic insulin signaling mediated by insulin receptor substrates IRS1 and IRS2 plays a central role in maintaining glucose homeostasis under different physiological conditions. Although functions of individual components in the signaling network have been extensively studied, our knowledge is still limited with regard to how the signals are integrated and coordinated in the complex network to render their functional roles. In this study, we construct systematic models for the insulin signaling network mediated by IRS1 and IRS2, through the integration of current knowledge in the literature into mathematical models of insulin signaling pathways. We hypothesize that the specificity of the IRS signaling mechanisms emerges from the wiring and kinetics of the entire network. A discrete dynamic model is first constructed to account for the numerous dynamic features in the system, i.e., complex feedback circuits, different regulatory time-scales and cross-talks between pathways. Our simulation shows that the wiring of the network determines different functions of IRS1 and IRS2. We further collate and reconstruct a kinetic model of the network as a system of ordinary differential equations to provide an informative model for predicting phenotypes. A sensitivity analysis is applied to identify essential regulators for the signaling process.
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The role of inflammasome in Alzheimer's disease.
Ageing Res. Rev.
PUBLISHED: 02-19-2014
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Alzheimer's disease (AD) is a chronic, progressive and irreversible neurodegenerative disease with clinical characteristics of memory loss, dementia and cognitive impairment. Although the pathophysiologic mechanism is not fully understood, inflammation has been shown to play a critical role in the pathogenesis of AD. Inflammation in the central nervous system (CNS) is characterized by the activation of glial cells and release of proinflammatory cytokines and chemokines. Accumulating evidence demonstrates that inflammasomes, which cleave precursors of interleukin-1? (IL-1?) and IL-18 to generate their active forms, play an important role in the inflammatory response in the CNS and in AD pathogenesis. Therefore, modulating inflammasome complex assembly and activation could be a potential strategy for suppressing inflammation in the CNS. This review aims to provide insight into the role of inflammasomes in the CNS, with respect to the pathogenesis of AD, and may provide possible clues for devising novel therapeutic strategies.
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Augmenting protein release from layer-by-layer functionalized agarose hydrogels.
Carbohydr Polym
PUBLISHED: 02-18-2014
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Recent work demonstrated the efficacy of combining layer-by-layer assembly with hydrogels to provide the controlled delivery of proteins for use in nerve repair scaffolds. In this work, we augmented the protein dose response by controlling and increasing the hydrogel internal surface area. Sucrose was added to agarose during gelation to homogenize the nanopore morphology, resulting in increased surface area per unit volume of hydrogel. The surface area of a range of compositions (1.5-5.0 wt% agarose and 0, 50 and 65 wt% sucrose) was measured. Gels were supercritically dried to preserve porosity enabling detailed pore morphology measurements using nitrogen adsorption and high resolution scanning electron microscopy. The resulting surface area, normalized by superficial gel volume, ranged between 6m(2)/cm(3)gel and 56 m(2)/cm(3)gel. Using the layer-by-layer process to load lysozyme, a neurotrophic factor analog, a relationship was observed between surface area and cumulative dose response ranging from 176 to 2556 ?g/mL, which is in the range of clinical relevance for the delivery of growth factors. In this work, we demonstrated that the ability to control porosity is key in tuning drug delivery dose response from layer-by-layer modified hydrogels.
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Reprint of: A rapid increase in macrophage-derived versican and hyaluronan in infectious lung disease.
Matrix Biol.
PUBLISHED: 01-21-2014
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The goals of this study were to characterize the changes in chondroitin sulfate proteoglycans and hyaluronan in lungs in acute response to gram-negative bacterial infection and to identify cellular components responsible for these changes. Mice were treated with intratracheal (IT) live Escherichia coli, E. coli lipopolysaccharide (LPS), or PBS. Both E. coli and LPS caused rapid selective increases in mRNA expression of versican and hyaluronan synthase (Has) isoforms 1 and 2 associated with increased immunohistochemical and histochemical staining for versican and hyaluronan in the lungs. Versican was associated with a subset of alveolar macrophages. To examine whether macrophages contribute to versican and hyaluronan accumulation, in vitro studies with primary cultures of bone marrow-derived and alveolar macrophages were performed. Unstimulated macrophages expressed very low levels of versican and hyaluronan synthase mRNA, with no detectible versican protein or hyaluronan product. Stimulation with LPS caused rapid increases in versican mRNA and protein, a rapid increase in Has1 mRNA, and concomitant inhibition of hyaluronidases 1 and 2, the major hyaluronan degrading enzymes. Hyaluronan could be detected following chloroquine pre-treatment, indicating rapid turnover and degradation of hyaluronan by macrophages. In addition, the effects of LPS, the M1 macrophage classical activation agonist, were compared to those of IL-4/IL-13 or IL-10, the M2a and M2c alternative activation agonists, respectively. Versican and Has1 increased only in response to M1 activation. Finally, the up-regulation of versican and Has1 in the whole lungs of wild-type mice following IT LPS was completely abrogated in TLR-4(-/-) mice. These findings suggest that versican and hyaluronan synthesis may play an important role in the innate immune response to gram-negative lung infection.
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A rapid increase in macrophage-derived versican and hyaluronan in infectious lung disease.
Matrix Biol.
PUBLISHED: 01-21-2014
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The goals of this study were to characterize the changes in chondroitin sulfate proteoglycans and hyaluronan in lungs in acute response to gram-negative bacterial infection and to identify cellular components responsible for these changes. Mice were treated with intratracheal (IT) live Escherichia coli, E. coli lipopolysaccharide (LPS), or PBS. Both E. coli and LPS caused rapid selective increases in mRNA expression of versican and hyaluronan synthase (Has) isoforms 1 and 2 associated with increased immunohistochemical and histochemical staining for versican and hyaluronan in the lungs. Versican was associated with a subset of alveolar macrophages. To examine whether macrophages contribute to versican and hyaluronan accumulation, in vitro studies with primary cultures of bone marrow-derived and alveolar macrophages were performed. Unstimulated macrophages expressed very low levels of versican and hyaluronan synthase mRNA, with no detectible versican protein or hyaluronan product. Stimulation with LPS caused rapid increases in versican mRNA and protein, a rapid increase in Has1 mRNA, and concomitant inhibition of hyaluronidases 1 and 2, the major hyaluronan degrading enzymes. Hyaluronan could be detected following chloroquine pre-treatment, indicating rapid turnover and degradation of hyaluronan by macrophages. In addition, the effects of LPS, the M1 macrophage classical activation agonist, were compared to those of IL-4/IL-13 or IL-10, the M2a and M2c alternative activation agonists, respectively. Versican and Has1 increased only in response to M1 activation. Finally, the up-regulation of versican and Has1 in the whole lungs of wild-type mice following IT LPS was completely abrogated in TLR-4(-/-) mice. These findings suggest that versican and hyaluronan synthesis may play an important role in the innate immune response to gram-negative lung infection.
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Binding site multiplicity with fatty acid ligands: implications for the regulation of PKR kinase autophosphorylation with palmitate.
Proteins
PUBLISHED: 01-10-2014
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Saturated long chain-free fatty acids (FFAs), especially palmitate, have been implicated in apoptosis by inhibiting the activity of PKR (double-stranded RNA-dependent protein kinase). We recently found evidence that palmitate interacts directly with the kinase domain of PKR, subsequently inhibiting the autophosphorylation of PKR. To investigate the interactions of palmitate with PKR and its effects on PKR autophosphorylation, we performed extensive unbiased MD simulations combined with biochemical and biophysical experiments. The simulations predict multiple putative binding sites of palmitate on both the phosphorylated and unphosphorylated PKR with similar binding affinities. Ligand-protein interactions involving a large variety of different binding modes challenge the conventional view of highly specific, single binding sites. Key interactions of palmitate involve the ?C-helix of PKR, especially near residue R307. Experimental mutation of R307 was found to affect palmitate binding and reduce its inhibitory effect. Based on this study a new allosteric mechanism is proposed where palmitate binding to the ?C-helix prevents the inactive-to-active transition of PKR and subsequently reduces its ability to autophosphorylate.
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Improved asymmetry prediction for short interfering RNAs.
FEBS J.
PUBLISHED: 01-08-2014
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In the development of RNA interference therapeutics, merely selecting short interfering RNA (siRNA) sequences that are complementary to the mRNA target does not guarantee target silencing. Current algorithms for selecting siRNAs rely on many parameters, one of which is asymmetry, often predicted through calculation of the relative thermodynamic stabilities of the two ends of the siRNA. However, we have previously shown that highly active siRNA sequences are likely to have particular nucleotides at each 5'-end, independently of their thermodynamic asymmetry. Here, we describe an algorithm for predicting highly active siRNA sequences based only on these two asymmetry parameters. The algorithm uses end-sequence nucleotide preferences and predicted thermodynamic stabilities, each weighted on the basis of training data from the literature, to rank the probability that an siRNA sequence will have high or low activity. The algorithm successfully predicts weakly and highly active sequences for enhanced green fluorescent protein and protein kinase R. Use of these two parameters in combination improves the prediction of siRNA activity over current approaches for predicting asymmetry. Going forward, we anticipate that this approach to siRNA asymmetry prediction will be incorporated into the next generation of siRNA selection algorithms.
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Prediction of therapeutic microRNA based on the human metabolic network.
Bioinformatics
PUBLISHED: 01-07-2014
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MicroRNA (miRNA) expression has been found to be deregulated in human cancer, contributing, in part, to the interest of the research community in using miRNAs as alternative therapeutic targets. Although miRNAs could be potential targets, identifying which miRNAs to target for a particular type of cancer has been difficult due to the limited knowledge on their regulatory roles in cancer. We address this challenge by integrating miRNA-target prediction, metabolic modeling and context-specific gene expression data to predict therapeutic miRNAs that could reduce the growth of cancer.
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Association between Mycoplasma-specific polymerase chain reaction assay results and oral bacterial contamination of bronchoalveolar lavage fluid samples from dogs with respiratory tract disease: 121 cases (2005-2012).
J. Am. Vet. Med. Assoc.
PUBLISHED: 11-23-2013
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Objective-To determine whether an association exists between oral bacterial contamination of bronchoalveolar lavage fluid (BALF) and positive PCR assay results for the detection of Mycoplasma spp in BALF samples of dogs with lower respiratory tract (LRT; portion from the trachea to the lungs) disease. Design-Retrospective case series. Animals-121 dogs with LRT disease. Procedures-Medical records from January 2005 to April 2012 were reviewed. Dogs with LRT disease that had BALF samples evaluated by use of Mycoplasma-specific PCR assay, bacterial culture, and cytologic examination were included. Information on signalment, final diagnoses, and BALF testing results was extracted. Results-83 (68.6%) dogs had BALF samples with negative PCR assay results for Mycoplasma spp, and 38 (31.4%) had positive results. The BALF samples with cytologic evidence of oral bacterial contamination were 5.1 times as likely to have positive Mycoplasma-specific PCR assay results as were noncontaminated samples. Compared with hound or herding dogs, other breeds were 13.6 times as likely to have positive PCR assay results. Dogs with bronchitis were less likely than dogs with other LRT diseases to have positive Mycoplasma-specific PCR assay results. No significant association was found between Mycoplasma-specific PCR assay results and bacterial culture results. Conclusions and Clinical Relevance-In dogs with LRT disease, Mycoplasma-specific PCR assay results for BALF samples should be interpreted in terms of possible oral bacterial contamination. Mycoplasma-specific PCR assay of BALF samples from herding dogs, hound dogs, and dogs with bronchitis may be less rewarding than for other dogs with LRT disease.
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ADAMTS-4 and Biglycan are Expressed at High Levels and Co-Localize to Podosomes During Endothelial Cell Tubulogenesis In Vitro.
J. Histochem. Cytochem.
PUBLISHED: 09-18-2013
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Proteolysis of the extracellular matrix influences vascular growth. We examined the expression of ADAMTS-1, -4, and -5 metalloproteinases and their proteoglycan substrates versican, decorin, and biglycan as human umbilical vein endothelial cells (HUVECs) formed tubes within type I collagen gels in vitro. Tubulogenic and control HUVEC cultures expressed low levels of ADAMTS-1 and -5 mRNAs, but ADAMTS-4 mRNA was relatively abundant and was significantly elevated (as was ADAMTS-4 protein) in tubulogenic cultures versus controls. Immunocytochemistry revealed ADAMTS-4 in f-actin- and cortactin-positive podosome-like puncta in single cells and mature tubes. Tubulogenic and control cultures expressed low levels of versican and decorin mRNAs; however, peak levels of biglycan mRNA were 400- and 16,000-fold that of versican and decorin, respectively. Biglycan mRNA was highest at 3 hr, declined steadily through day 7 and, at 12 hr and beyond, was significantly lower in tubulogenic cultures than in controls. Western blots of extracellular matrix from tubulogenic cultures contained bands corresponding to biglycan and its cleavage products. By immunocytochemistry, biglycan was found in the pericellular matrix surrounding endothelial tubes and in cell-associated puncta that co-localized with ADAMTS-4 and cortactin. Collectively, our results suggest that ADAMTS-4 and its substrate biglycan are involved in tubulogenesis by endothelial cells.
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Challenges in the practice of human milk nutrition in the neonatal intensive care unit.
Early Hum. Dev.
PUBLISHED: 08-30-2013
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The use of human milk for preterm infants has increased over the past decade reflecting an improved awareness of the benefits of human milk. Inherent in this paradigm shift is the recognition that human milk is a living tissue; full of immune cells, probiotics and hundreds of compounds that confer bioactivity and immune protective properties. Together these factors deliver a powerful effect in reducing clinical morbidities such as necrotizing enterocolitis and sepsis in the preterm infant. However, as breastfeeding is not possible for the very premature infant, human milk needs to be introduced in the neonatal intensive care unit through alternative means, resulting in significant handling and manipulation of maternal milk. This presents risks in quality control and provision of optimal nutrition delivery. Therefore, a comprehensive approach to standardizing preterm infant nutrition is essential to optimize the collection, storage, fortification and delivery of human milk to preterm neonates. In this paper we discuss the challenges presented by supporting human milk nutrition, and the rationale for the development of the Supporting Premature Infant Nutrition (SPIN) program at our institution.
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Design of siRNA Therapeutics from the Molecular Scale.
Pharmaceuticals (Basel)
PUBLISHED: 08-27-2013
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While protein-based therapeutics is well-established in the market, development of nucleic acid therapeutics has lagged. Short interfering RNAs (siRNAs) represent an exciting new direction for the pharmaceutical industry. These small, chemically synthesized RNAs can knock down the expression of target genes through the use of a native eukaryotic pathway called RNA interference (RNAi). Though siRNAs are routinely used in research studies of eukaryotic biological processes, transitioning the technology to the clinic has proven challenging. Early efforts to design an siRNA therapeutic have demonstrated the difficulties in generating a highly-active siRNA with good specificity and a delivery vehicle that can protect the siRNA as it is transported to a specific tissue. In this review article, we discuss design considerations for siRNA therapeutics, identifying criteria for choosing therapeutic targets, producing highly-active siRNA sequences, and designing an optimized delivery vehicle. Taken together, these design considerations provide logical guidelines for generating novel siRNA therapeutics.
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Gains and Losses in Creative Personality as Perceived by Adults Across the Life Span.
Dev Psychol
PUBLISHED: 08-26-2013
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In this study, we used a life span model to study the subjective perception of creative personality (CP) in emerging, young, middle-aged, and older Hong Kong Chinese adults. We also asked participants to estimate the approximate age by which people develop and lose CP across adulthood. We expected an interesting interplay between internalized age stereotypes and age-related differentiation in beliefs about personality development. Older adults perceived increases in both gains and losses in CP in old age. But they still maintained a similar level of self-perceived CP traits when compared with young participants. Emerging, young, and middle-aged adults were less optimistic about their creativity development into old age. Young adults, in contrast to older adults, believed that gains in CP began and ceased at an earlier age. Positive perceptions of CP in ones aging process may have implications for aging successfully. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
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Evaluating New York Citys smoke-free parks and beaches law: a critical multiplist approach to assessing behavioral impact.
Am J Community Psychol
PUBLISHED: 08-24-2013
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This article describes the evaluation of the law banning smoking in New York Citys parks and beaches that went into effect in 2011. We discuss the practical and methodological challenges that emerged in evaluating this law, and describe how we applied the principles of critical multiplism to address these issues. The evaluation uses data from three complementary studies, each with a unique set of strengths and weaknesses that can provide converging evidence for the effectiveness of the law. Results from a litter audit and an observational study suggest the ban reduced smoking in parks and beaches. The purpose, methodology and baseline results from an ongoing survey that measures how frequently adults in NYC and across New York State notice people smoking in parks and on beaches are presented and discussed. Limitations are considered and suggestions are offered for future evaluations of similar policies.
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Human Milk Galectin-3 Binding Protein and Breastfeeding-Associated HIV Transmission.
Pediatr. Infect. Dis. J.
PUBLISHED: 08-01-2013
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Analysis of milk from 247 HIV-infected Zambian mothers showed that Galectin-3 Binding Protein (Gal3BP) concentrations were significantly higher among HIV-infected mothers who transmitted HIV through breastfeeding (6.51±2.12 ug/mL) than among non-transmitters but were also correlated with higher milk and plasma HIV RNA copies/ml and lower CD4+ cell counts. The association between Gal3BP and postnatal transmission was attenuated after adjustment for milk and plasma HIV load and CD4+ cell counts. This suggests that although milk Gal3BP is a marker of advanced maternal disease, it does not independently modify transmission risk.
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Electrical acupoint stimulation of the affected arm in acute stroke: a placebo-controlled randomized clinical trial.
Clin Rehabil
PUBLISHED: 07-31-2013
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Objectives:To determine whether adding electrical stimulation of upper limb acupoints to conventional rehabilitation during acute stroke could produce greater and longer lasting motor improvements of the arm.Design:Double-blind, randomized, placebo-controlled trial.Setting:Acute stroke wards, followed by rehabilitation hospitals and subjects residences.Participants:Seventy-three patients ? 46 hours post stroke onset with moderate to severe weakness in the arm contralateral to the side of stroke.Intervention:All subjects received conventional rehabilitation. Twenty-nine received additional electrical stimulation, 21 received additional placebo-electrical stimulation and 23 received conventional rehabilitation only, as control. Electrical stimulation or placebo-electrical stimulation was applied to acupoints GB20, LI15, LI11, LI10 and LI4, 60 minutes a day, five days a week, for four weeks.Measurements:Primary outcome measures were hand grip and pinch strength, with Action Research Arm Test (ARAT) as secondary outcome measure. These were assessed on the affected arm at recruitment, then 4 (W4), 12 (W12) and 24 weeks (W24) afterwards.Results:Post-hoc analysis showed that the electrical stimulation group had greater improvements than the control group in hand grip (P = 0.015) and pinch strength (P = 0.007) at W4, with the gains maintained at W12 and W24. In contrast, the placebo-electrical stimulation group did not differ from either the control or the electrical stimulation group. Between-group improvements in ARAT scores from baseline to W24 (by 16.8 in control, 27.6 in placebo-electrical stimulation group and 26.3 in electrical stimulation group) were not significant.Conclusions:Adding four weeks of electrical stimulation during acute stroke appears to produce greater and longer lasting hand grip and pinch strength improvements than administering conventional rehabilitation alone.
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Early phosphoproteomic changes in the mouse spleen during deoxynivalenol-induced ribotoxic stress.
Toxicol. Sci.
PUBLISHED: 06-29-2013
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The trichothecene mycotoxin deoxynivalenol (DON) targets the innate immune system and is of public health significance because of its frequent presence in human and animal food. DON-induced proinflammatory gene expression and apoptosis in the lymphoid tissue have been associated with a ribotoxic stress response (RSR) that involves rapid phosphorylation of mitogen-activated protein kinases (MAPKs). To better understand the relationship between protein phosphorylation and DONs immunotoxic effects, stable isotope dimethyl labeling-based proteomics in conjunction with titanium dioxide chromatography was employed to quantitatively profile the immediate (? 30min) phosphoproteome changes in the spleens of mice orally exposed to 5mg/kg body weight DON. A total of 90 phosphoproteins indicative of novel phosphorylation events were significantly modulated by DON. In addition to critical branches and scaffolds of MAPK signaling being affected, DON exposure also altered phosphorylation of proteins that mediate phosphatidylinositol 3-kinase/AKT pathways. Gene ontology analysis revealed that DON exposure affected biological processes such as cytoskeleton organization, regulation of apoptosis, and lymphocyte activation and development, which likely contribute to immune dysregulation associated with DON-induced RSR. Consistent with these findings, DON impacted phosphorylation of proteins within diverse immune cell populations, including monocytes, macrophages, T cells, B cells, dendritic cells, and mast cells. Fuzzy c-means clustering analysis further indicated that DON evoked several distinctive temporal profiles of regulated phosphopeptides. Overall, the findings from this investigation can serve as a template for future focused exploration and modeling of cellular responses associated with the immunotoxicity evoked by DON and other ribotoxins.
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Curcumin-induced upregulation of the anti-tau cochaperone BAG2 in primary rat cortical neurons.
Neurosci. Lett.
PUBLISHED: 06-20-2013
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Alzheimers disease (AD) is a progressive, neurodegenerative disease characterized by extracellular deposits of amyloid beta (A?) protein and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. Various studies suggest that the tau tangle pathology, which lies downstream to A? pathology, is essential to produce AD-associated clinical phenotype and thus treatments targeting tau pathology may prevent or delay disease progression effectively. In this context, our present study examined three polyphenol compounds (curcumin, EGCG and resveratrol) for their possible activity against two endogenous proteins (BAG2 and LAMP1) that are shown to play a vital role in clearing tau tangles from neurons. Human epidemiological and animal data suggest potential positive effects of these polyphenols against AD. Here, primary rat cortical neurons treated with these polyphenols significantly up-regulated BAG2 levels at different concentrations, while only EGCG upregulated LAMP1 levels, although at higher concentrations. Importantly, curcumin doubled BAG2 levels at low micromolar concentrations that are clinically relevant. In addition, curcumin also downregulated levels of phosphorylated tau, which may be potentially attributed to the curcumin-induced upregulation in BAG2 levels in the neurons. The present results demonstrate novel activity of polyphenol curcumin in up-regulating an anti-tau cochaperone BAG2 and thus, suggest probable benefit of curcumin against AD-associated tauopathy.
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A classification framework applied to cancer gene expression profiles.
J Healthc Eng
PUBLISHED: 06-20-2013
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Classification of cancer based on gene expression has provided insight into possible treatment strategies. Thus, developing machine learning methods that can successfully distinguish among cancer subtypes or normal versus cancer samples is important. This work discusses supervised learning techniques that have been employed to classify cancers. Furthermore, a two-step feature selection method based on an attribute estimation method (e.g., ReliefF) and a genetic algorithm was employed to find a set of genes that can best differentiate between cancer subtypes or normal versus cancer samples. The application of different classification methods (e.g., decision tree, k-nearest neighbor, support vector machine (SVM), bagging, and random forest) on 5 cancer datasets shows that no classification method universally outperforms all the others. However, k-nearest neighbor and linear SVM generally improve the classification performance over other classifiers. Finally, incorporating diverse types of genomic data (e.g., protein-protein interaction data and gene expression) increase the prediction accuracy as compared to using gene expression alone.
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Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes.
Exp. Neurol.
PUBLISHED: 05-28-2013
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Deregulation of calcium has been implicated in neurodegenerative diseases, including Alzheimers disease (AD). Previously, we showed that saturated free-fatty acid, palmitate, causes AD-like changes in primary cortical neurons mediated by astrocytes. However, the molecular mechanisms by which conditioned medium from astrocytes cultured in palmitate induce AD-like changes in neurons are unknown. This study demonstrates that this condition medium from astrocytes elevates calcium level in the neurons, which subsequently increases calpain activity, a calcium-dependent protease, leading to enhance p25/Cdk5 activity and phosphorylation and activation of the STAT3 (signal transducer and activator of transcription) transcription factor. Inhibiting calpain or Cdk5 significantly reduces the upregulation in nuclear level of pSTAT3, which we found to transcriptionally regulate both BACE1 and presenilin-1, the latter is a catalytic subunit of ?-secretase. Decreasing pSTAT3 levels reduced the mRNA levels of both BACE1 and presenilin-1 to near control levels. These data demonstrate a signal pathway leading to the activation of STAT3, and the generation of the amyloid peptide. Thus, our results suggest that STAT3 is an important potential therapeutic target of AD pathogenesis.
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A multi-layer inference approach to reconstruct condition-specific genes and their regulation.
Bioinformatics
PUBLISHED: 04-22-2013
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An important topic in systems biology is the reverse engineering of regulatory mechanisms through reconstruction of context-dependent gene networks. A major challenge is to identify the genes and the regulations specific to a condition or phenotype, given that regulatory processes are highly connected such that a specific response is typically accompanied by numerous collateral effects. In this study, we design a multi-layer approach that is able to reconstruct condition-specific genes and their regulation through an integrative analysis of large-scale information of gene expression, protein interaction and transcriptional regulation (transcription factor-target gene relationships). We establish the accuracy of our methodology against synthetic datasets, as well as a yeast dataset. We then extend the framework to the application of higher eukaryotic systems, including human breast cancer and Arabidopsis thaliana cold acclimation. Our study identified TACSTD2 (TROP2) as a target gene for human breast cancer and discovered its regulation by transcription factors CREB, as well as NFkB. We also predict KIF2C is a target gene for ER-/HER2- breast cancer and is positively regulated by E2F1. The predictions were further confirmed through experimental studies.
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The impact of cigarette excise tax increases on purchasing behaviors among New York city smokers.
Am J Public Health
PUBLISHED: 04-18-2013
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We examined the relationship between cigarette excise tax increases and tax-avoidant purchasing behaviors among New York City adult smokers.
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Chronic back problems and labor force participation in a national population survey: impact of comorbid arthritis.
BMC Public Health
PUBLISHED: 03-26-2013
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Back problems and arthritis are common chronic conditions, while having back problems is a frequent reason for lost work time. The objective of this study was to investigate employment status amongst individuals who report having both back problems and arthritis, compared to having either condition alone.
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Tai Chi practitioners have better postural control and selective attention in stepping down with and without a concurrent auditory response task.
Eur. J. Appl. Physiol.
PUBLISHED: 03-03-2013
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To compare the performance of older experienced Tai Chi practitioners and healthy controls in dual-task versus single-task paradigms, namely stepping down with and without performing an auditory response task, a cross-sectional study was conducted in the Center for East-meets-West in Rehabilitation Sciences at The Hong Kong Polytechnic University, Hong Kong. Twenty-eight Tai Chi practitioners (73.6 ± 4.2 years) and 30 healthy control subjects (72.4 ± 6.1 years) were recruited. Participants were asked to step down from a 19-cm-high platform and maintain a single-leg stance for 10 s with and without a concurrent cognitive task. The cognitive task was an auditory Stroop test in which the participants were required to respond to different tones of voices regardless of their word meanings. Postural stability after stepping down under single- and dual-task paradigms, in terms of excursion of the subjects center of pressure (COP) and cognitive performance, was measured for comparison between the two groups. Our findings demonstrated significant between-group differences in more outcome measures during dual-task than single-task performance. Thus, the auditory Stroop test showed that Tai Chi practitioners achieved not only significantly less error rate in single-task, but also significantly faster reaction time in dual-task, when compared with healthy controls similar in age and other relevant demographics. Similarly, the stepping-down task showed that Tai Chi practitioners not only displayed significantly less COP sway area in single-task, but also significantly less COP sway path than healthy controls in dual-task. These results showed that Tai Chi practitioners achieved better postural stability after stepping down as well as better performance in auditory response task than healthy controls. The improved performance that was magnified by dual motor-cognitive task performance may point to the benefits of Tai Chi being a mind-and-body exercise.
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A prospective, assessor-blind evaluation of surgeon-performed transcutaneous laryngeal ultrasonography in vocal cord examination before and after thyroidectomy.
Surgery
PUBLISHED: 03-01-2013
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Transcutaneous laryngeal ultrasonography (TLUSG) is a promising alternative to direct laryngoscopy in assessing perioperative vocal cord function. This study sought to evaluate the accuracy of TLUSG in assessing vocal cord function.
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IPAF inflammasome is involved in interleukin-1? production from astrocytes, induced by palmitate; implications for Alzheimers Disease.
Neurobiol. Aging
PUBLISHED: 02-05-2013
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Inflammatory response has been strongly implicated in the pathogenesis of numerous diseases, including Alzheimers disease (AD). However, little is known about the molecular mechanisms initiating the generation of inflammatory molecules in the central nervous system, such as interleukin-1? (IL-1?). Previously we identified that palmitate can induce primary astrocytes to produce cytokines, causing AD-like changes in primary neurons. Here we investigated and identified that palmitate induced the activation of ice protease-activating factor (IPAF)-apoptosis-associated speck-like protein containing a caspase activation and recruitment domains (CARD) (ASC) inflammasome in astrocytes leading to the maturation of IL-1?, thereby implicating that not only pathogen-related factors can activate the IPAF-ASC inflammasome. Moreover, downregulating IPAF (which was found to be regulated by cAMP response element-binding protein) in astrocytes through silencing to decrease IL-1? secretion from the astrocytes reduced the generation of amyloid-?42 by primary neurons. Furthermore, the expression levels of IPAF and ASC were found significantly elevated in a subgroup of sporadic AD patients, suggesting an involvement of the IPAF-ASC inflammasome in the inflammatory response associated with AD, and thus could be a potential therapeutic target for AD.
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Inhibition of serine palmitoyltransferase reduces A? and tau hyperphosphorylation in a murine model: a safe therapeutic strategy for Alzheimers disease.
Neurobiol. Aging
PUBLISHED: 01-31-2013
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The contribution of the autosomal dominant mutations to the etiology of familial Alzheimers disease (AD) is well characterized. However, the molecular mechanisms contributing to sporadic AD are less well understood. Increased ceramide levels have been evident in AD patients. We previously reported that increased ceramide levels, regulated by increased serine palmitoyltransferase (SPT), directly mediate amyloid ? (A?) levels. Therefore, we inhibited SPT in an AD mouse model (TgCRND8) through subcutaneous administration of L-cylcoserine. The cortical A??? and hyperphosphorylated tau levels were down-regulated with the inhibition of SPT/ceramide. Positive correlations were observed among cortical SPT, ceramide, and A??? levels. With no evident toxic effects observed, inhibition of SPT could be a safe therapeutic strategy to ameliorate the AD pathology. We previously observed that miR-137, -181c, -9, and 29a/b post-transcriptionally regulate SPT levels, and the corresponding miRNA levels in the blood sera are potential diagnostic biomarkers for AD. Here, we observe a negative correlation between cortical A??? and sera A???, and a positive correlation between cortical miRNA levels and sera miRNA levels suggesting their potential as noninvasive diagnostic biomarkers.
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Signaling dynamics of palmitate-induced ER stress responses mediated by ATF4 in HepG2 cells.
BMC Syst Biol
PUBLISHED: 01-17-2013
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Palmitic acid, the most common saturated free fatty acid, has been implicated in ER (endoplasmic reticulum) stress-mediated apoptosis. This lipoapotosis is dependent, in part, on the upregulation of the activating transcription factor-4 (ATF4). To better understand the mechanisms by which palmitate upregulates the expression level of ATF4, we integrated literature information on palmitate-induced ER stress signaling into a discrete dynamic model. The model provides an in silico framework that enables simulations and predictions. The model predictions were confirmed through further experiments in human hepatocellular carcinoma (HepG2) cells and the results were used to update the model and our current understanding of the signaling induced by palmitate.
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Effects of aging and tai chi on a finger-pointing task with a choice paradigm.
Evid Based Complement Alternat Med
PUBLISHED: 01-14-2013
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Background. This cross-sectional study examined the effect of aging on performing finger-pointing tasks involving choices and whether experienced older Tai Chi practitioners perform better than healthy older controls in such tasks. Methods. Thirty students and 30 healthy older controls were compared with 31 Tai Chi practitioners. All the subjects performed a rapid index finger-pointing task. The visual signal appeared randomly under 3 conditions: (1) to touch a black ball as quickly and as accurately as possible, (2) not to touch a white ball, (3) to touch only the white ball when a black and a white ball appeared simultaneously. Reaction time (RT) of anterior deltoid electromyogram, movement time (MT) from electromyogram onset to touching of the target, end-point accuracy from the center of the target, and the number of wrong movements were recorded. Results. Young students displayed significantly faster RT and MT, achieving significantly greater end-point accuracy and fewer wrong movements than older controls. Older Tai Chi practitioners had significantly faster MT than older controls. Conclusion. Finger-pointing tasks with a choice paradigm became slower and less accurate with age. Positive findings suggest that Tai Chi may slow down the aging effect on eye-hand coordination tasks involving choices that require more cognitive progressing.
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Global protein phosphorylation dynamics during deoxynivalenol-induced ribotoxic stress response in the macrophage.
Toxicol. Appl. Pharmacol.
PUBLISHED: 01-12-2013
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Deoxynivalenol (DON), a trichothecene mycotoxin produced by Fusarium that commonly contaminates food, is capable of activating mononuclear phagocytes of the innate immune system via a process termed the ribotoxic stress response (RSR). To encapture global signaling events mediating RSR, we quantified the early temporal (?30min) phosphoproteome changes that occurred in RAW 264.7 murine macrophage during exposure to a toxicologically relevant concentration of DON (250ng/mL). Large-scale phosphoproteomic analysis employing stable isotope labeling of amino acids in cell culture (SILAC) in conjunction with titanium dioxide chromatography revealed that DON significantly upregulated or downregulated phosphorylation of 188 proteins at both known and yet-to-be functionally characterized phosphosites. DON-induced RSR is extremely complex and goes far beyond its prior known capacity to inhibit translation and activate MAPKs. Transcriptional regulation was the main target during early DON-induced RSR, covering over 20% of the altered phosphoproteins as indicated by Gene Ontology annotation and including transcription factors/cofactors and epigenetic modulators. Other biological processes impacted included cell cycle, RNA processing, translation, ribosome biogenesis, monocyte differentiation and cytoskeleton organization. Some of these processes could be mediated by signaling networks involving MAPK-, NF?B-, AKT- and AMPK-linked pathways. Fuzzy c-means clustering revealed that DON-regulated phosphosites could be discretely classified with regard to the kinetics of phosphorylation/dephosphorylation. The cellular response networks identified provide a template for further exploration of the mechanisms of trichothecenemycotoxins and other ribotoxins, and ultimately, could contribute to improved mechanism-based human health risk assessment.
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Endothelial deletion of ADAM17 in mice results in defective remodeling of the semilunar valves and cardiac dysfunction in adults.
Mech. Dev.
PUBLISHED: 01-07-2013
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Global inactivation of the metalloproteinase ADAM17 during mouse development results in perinatal lethality and abnormalities of the heart, including late embryonic cardiomegaly and thickened semilunar and atrioventricular valves. These defects have been attributed in part to a lack of ADAM17-mediated processing of HB-EGF, as absence of soluble HB-EGF results in similar phenotypes. Because valvular mesenchymal cells are largely derived from cardiac endothelial cells, we generated mice with a floxed Adam17 allele and crossed these animals with Tie2-Cre transgenics to focus on the role of endothelial ADAM17 in valvulogenesis. We find that although hearts from late-stage embryos with ablation of endothelial ADAM17 appear normal, an increase in valve size and cell number is evident, but only in the semilunar cusps. Unlike Hbegf(-/-) valves, ADAM17-null semilunar valves do not differ from controls in acute cell proliferation at embryonic day 14.5 (E14.5), suggesting compensatory processing of HB-EGF. However, levels of the proteoglycan versican are significantly reduced in mutant hearts early in valve remodeling (E12.5). After birth, aortic valve cusps from mutants are not only hyperplastic but also show expansion of the glycosaminoglycan-rich component, with the majority of adults exhibiting aberrant compartmentalization of versican and increased deposition of collagen. The inability of mutant outflow valve precursors to transition into fully mature cusps is associated with decreased postnatal viability, progressive cardiomegaly, and systolic dysfunction. Together, our data indicate that ADAM17 is required in valvular endothelial cells for regulating cell content as well as extracellular matrix composition and organization in semilunar valve remodeling and homeostasis.
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Historical epidemiology of the second cholera pandemic: relevance to present day disease dynamics.
PLoS ONE
PUBLISHED: 01-01-2013
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Despite nearly two centuries of study, the fundamental transmission dynamic properties of cholera remain incompletely characterized. We used historical time-series data on the spread of cholera in twelve European and North American cities during the second cholera pandemic, as reported in Amariah Brighams 1832 A Treatise on Epidemic Cholera, to parameterize simple mathematical models of cholera transmission. Richards growth models were used to derive estimates of the basic reproductive number (R0) (median: 16.0, range: 1.9 to 550.9) and the proportion of unrecognized cases (mean: 96.3%, SD: 0.04%). Heterogeneity in model-generated R0 estimates was consistent with variability in cholera dynamics described by contemporary investigators and may represent differences in the nature of cholera spread. While subject to limitations associated with measurement and the absence of microbiological diagnosis, historical epidemic data are a potentially rich source for understanding pathogen dynamics in the absence of control measures, particularly when used in conjunction with simple and readily interpretable mathematical models.
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Acute myocardial infarction and stress cardiomyopathy following the Christchurch earthquakes.
PLoS ONE
PUBLISHED: 01-01-2013
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Christchurch, New Zealand, was struck by 2 major earthquakes at 4:36 am on 4 September 2010, magnitude 7.1 and at 12:51 pm on 22 February 2011, magnitude 6.3. Both events caused widespread destruction. Christchurch Hospital was the regions only acute care hospital. It remained functional following both earthquakes. We were able to examine the effects of the 2 earthquakes on acute cardiac presentations.
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Core groups, antimicrobial resistance and rebound in gonorrhoea in North America.
Sex Transm Infect
PUBLISHED: 12-14-2011
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Genital tract infections caused by Neisseria gonorrhoeae are a major cause of sexually transmitted disease worldwide. Surveillance data suggest that incidence has increased in recent years after initially falling in the face of intensified control efforts.
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A case of recurrent earthquake stress cardiomyopathy with a differing wall motion abnormality.
Echocardiography
PUBLISHED: 11-08-2011
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We present the case of a Caucasian woman who survived two major earthquakes, presenting on each occasion with stress cardiomyopathy, but with a different pattern of regional wall motion abnormality on the second occasion. The first Christchurch earthquake struck on September 4, 2010. At 7.1 on the Richter scale, it was larger than the major Haiti quake, but miraculously there were no direct fatalities. In the week following, eight women meeting modified Mayo criteria for stress cardiomyopathy presented to Christchurch Hospital. The second Christchurch earthquake was on February 22, 2011. It measured 6.4 on the Richter scale and caused 180 direct fatalities. In the week following this earthquake, 24 women were admitted with stress cardiomyopathy. One patient presented after both earthquakes. This 76-year-old woman first presented on September 4 with 10 hours of chest pain. Electrocardiogram showed inferolateral deep T-wave inversion and QT prolongation. TnI peaked at 0.81 ?g/L. Coronary angiography demonstrated diffuse atheroma with a moderate mid LAD lesion that was stented at the time. Echocardiography showed a classic takotsubo pattern. Her follow-up echocardiogram on September 28 was normal and she was completely well at that point. However, during the second earthquake of February 22, she again developed chest pain and shortness of breath. TnI peaked at 1.3 ?g/L. Echocardiogram showed a midwall variant takotsubo with apical sparing. She was discharged from hospital on the 25th, planning to leave Christchurch for a new home in another city, but returned for follow-up echocardiogram on July 27. This was normal.
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MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid ?, novel targets in sporadic Alzheimers disease.
J. Neurosci.
PUBLISHED: 10-14-2011
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The contribution of mutations in amyloid precursor protein (APP) and presenilin (PSEN) to familial Alzheimers disease (AD) is well established. However, little is known about the molecular mechanisms leading to amyloid ? (A?) generation in sporadic AD. Increased brain ceramide levels have been associated with sporadic AD, and are a suggested risk factor. Serine palmitoyltransferase (SPT) is the first rate-limiting enzyme in the de novo ceramide synthesis. However, the regulation of SPT is not yet understood. Evidence suggests that it may be posttranscriptionally regulated. Therefore, we investigated the role of miRNAs in the regulation of SPT and amyloid ? (A?) generation. We show that SPT is upregulated in a subgroup of sporadic AD patient brains. This is further confirmed in mouse model studies of risk factors associated with AD. We identified that the loss of miR-137, -181c, -9, and 29a/b-1 increases SPT and in turn A? levels, and provides a mechanism for the elevated risk of AD associated with age, high-saturated-fat diet, and gender. Finally, these results suggest SPT and the respective miRNAs may be potential therapeutic targets for sporadic AD.
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POLYELECTROLYTE MULTILAYER STAMPING IN AQUEOUS PHASE AND NON-CONTACT MODE.
Ind Eng Chem Res
PUBLISHED: 08-24-2011
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Polyelectrolyte multilayer (PEM) transfer printing has been previously achieved by stamping under dry conditions. Here, we show for the first time, that PEM can be transferred from a stamp to the base substrate under aqueous conditions whereby the two surfaces are in a non-contact mode. Degradable multilayers of (PAA/PEG)(10.5) followed by non-degradable multilayers of (PDAC/SPS)(80.5) were fabricated under acidic pH conditions on either PDMS or glass (stamp), and subsequently transferred over top of another multilayer prepared on a different substrate (base substrate), with a spacing of ~ 200 ?m between the stamping surface and the base substrate. This multilayer transfer was performed under physiological pH conditions. This process is referred to herein as non-contact, aqueous-phase multilayer (NAM) transfer. NAM transfer can be useful for applications such as fabricating three-dimensional (3-D) cellular scaffolds. We attempted to create a 3-D cellular scaffold using NAM transfer, and characterized the scaffolds with conventional and fluorescence microscopy.
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Identification of novel targets for breast cancer by exploring gene switches on a genome scale.
BMC Genomics
PUBLISHED: 08-22-2011
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An important feature that emerges from analyzing gene regulatory networks is the "switch-like behavior" or "bistability", a dynamic feature of a particular gene to preferentially toggle between two steady-states. The state of gene switches plays pivotal roles in cell fate decision, but identifying switches has been difficult. Therefore a challenge confronting the field is to be able to systematically identify gene switches.
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Blood serum miRNA: non-invasive biomarkers for Alzheimers disease.
Exp. Neurol.
PUBLISHED: 08-11-2011
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There is an urgent need to identify non-invasive biomarkers for the detection of sporadic Alzheimers disease (AD). We previously studied microRNAs (miRNAs) in AD autopsy brain samples and reported a connection between miR-137, -181c, -9, -29a/b and AD, through the regulation of ceramides. In this study, the potential role of these miRNAs as diagnostic markers for AD was investigated. We identified that these miRNAs were down-regulated in the blood serum of probable AD patients. The levels of these miRNAs were also reduced in the serum of AD risk factor models. Although the ability of these miRNAs to conclusively diagnose for AD is currently unknown, our findings suggest a potential use for circulating miRNAs, along with other markers, as non-invasive and relatively inexpensive biomarkers for the early diagnosis of AD, however, with further research and validation.
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Acute Effects of Acu-TENS on FEV1 and Blood ?-endorphin Level in Chronic Obstructive Pulmonary Disease.
Altern Ther Health Med
PUBLISHED: 07-26-2011
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Background Pharmacotherapy is the mainstay of dyspnea management in patients with chronic obstructive pulmonary disease (COPD). Undesirable side effects have led to the application of alternative treatment strategies such as acupuncture. Our previous study showed that transcutaneous electrical nerve stimulation over acupuncture points (Acu-TENS), a noninvasive modality, can reduce dyspnea symptoms in patients with COPD, but the underlying mechanism is unknown. Primary Study Objective This study investigated the effect of acu-TENS on forced expiratory volume in one second (FEV1), dyspnea, and ?-endorphin levels in patients with COPD. Design A double-blinded randomized controlled trial Setting: Hospital outpatient clinic Participants Forty-four subjects diagnosed with COPD Intervention Participants were randomly assigned to receive either acu-TENS or placebo-TENS on Dingchuan (EX-B1) for 45 minutes. Outcome Measures FEV1, forced vital capacity (FVC), dyspnea visual analogue score (DVAS), respiratory rate (RR), and blood ?-endorphin levels were measured before and after therapeutic intervention. Results Our findings showed that the increase in FEV1 was 24.2% greater in the acu-TENS group than the placebo group (P < .0001). The decrease in RR and DVAS was also more in the acu-TENS group by 14.2% (P < .0001) and 20.7% (P = .006), respectively. The postintervention increase in ?-endorphin was significantly higher in the acu-TENS than the placebo group (18.3%) (P = .027). Furthermore, the percentage reduction in RR correlated with the increase in ?-endorphin (R = -0.477, P = .033). Conclusion An improvement in FEV1 and dyspnea score at the end of Acu-TENS treatment was associated with a concurrent increase in b-endorphin level in patients with COPD.
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Learning transcriptional regulation on a genome scale: a theoretical analysis based on gene expression data.
Brief. Bioinformatics
PUBLISHED: 05-26-2011
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The recent advent of high-throughput microarray data has enabled the global analysis of the transcriptome, driving the development and application of computational approaches to study transcriptional regulation on the genome scale, by reconstructing in silico the regulatory interactions of the gene network. Although there are many in-depth reviews of such reverse-engineering methodologies, most have focused on the practical aspect of data mining, and few on the biological problem and the biological relevance of the methodology. Therefore, in this review, from a biological perspective, we used a set of yeast microarray data as a working example, to evaluate the fundamental assumptions implicit in associating transcription factor (TF)-target gene expression levels and estimating TFs activity, and further explore cooperative models. Finally we confirm that the detailed transcription mechanism is overly-complex for expression data alone to reveal, nevertheless, future network reconstruction studies could benefit from the incorporation of context-specific information, the modeling of multiple layers of regulation (e.g. micro-RNA), or the development of approaches for context-dependent analysis, to uncover the mechanisms of gene regulation.
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Cholera, canals, and contagion: Rediscovering Dr. Becks report.
J Public Health Policy
PUBLISHED: 05-05-2011
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Cholera first appeared in North America (in Montreal and Quebec) in 1832 and spread rapidly across the eastern half of the continent. The dispatch of American disease control experts to Lower Canada in anticipation of choleras spread implies that medical professionals expected spread, possibly from contagion, even though the notion that cholera was contagious was disparaged in medical writings of the time, and would be until John Snows landmark work in London in the 1850s. Snows insights derived largely from his observations on spatial and temporal patterns of cholera cases. We discuss a document from the 1832 epidemic, the report of Dr. Lewis Beck to New Yorks Governor Throop, which anticipates Snow in presenting geospatial data that imply choleras contagiousness. Beck shows that the movements of immigrants along the newly completed New York state canal system resulted in sequential cholera outbreaks along the canals path. Although aware of the degree to which this suggested contagion, Beck argues strenuously against the contagiousness of cholera. We explore the social context of early nineteenth-century medicine that probably led Beck to disbelieve his own observations, and to favor a medical model inconsistent with his data. Themes that emerge from our inquiry include belief in disease as a physical manifestation of defective morality, stigmatization of the poor and immigrant groups, and reluctance to overturn prevailing medical models that themselves reflected the economic position of medical practitioners. We show that these themes continue to serve as obstacles to innovation in medical and public health practice today.
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Effects of Tai Chi on pre-landing muscle response latency during stepping down while performing a concurrent mental task in older adults.
Eur. J. Appl. Physiol.
PUBLISHED: 04-06-2011
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To investigate whether elderly Tai Chi practitioners are better able to descend a step while performing a concurrent mental task than non-practitioners. The design includes cross-sectional study. The setting includes university-based rehabilitation center. The subjects were 16 young women, 29 elderly women, and 31 elderly women who had been practicing Tai Chi regularly for at least half a year. Pre-landing muscle response latencies in their tibialis anterior (TA) and medial gastrocnemius (MG) muscles were measured during stepping down (single task) and stepping down while performing a concurrent mental activity (dual tasking). The non-practitioners had earlier onset of muscle activity in the TA in preparation for landing than the other subjects. The response latency of the Tai Chi practitioners was not significantly different from that of the young controls. When the cognitive task was added, the pre-landing response in the TA was significantly altered in both elderly groups. Response was significantly delayed among the non-practitioners, but significantly earlier among the Tai Chi subjects. The average change in response latency was significantly greater in the non-Tai Chi group compared with the young subjects and the Tai Chi practitioners (p = 0.006). Such findings suggest that practicing Tai Chi helps the elderly maintain the same strategy as much as younger subjects during stepping down. Tai Chi practitioners seem to have a greater capacity to shift attention between mental and physical tasks than other elderly women.
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Proteolytic cleavage of versican and involvement of ADAMTS-1 in VEGF-A/VPF-induced pathological angiogenesis.
J. Histochem. Cytochem.
PUBLISHED: 03-16-2011
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Malignant tumors and chronic inflammatory diseases induce angiogenesis by overexpressing vascular endothelial growth factor A (VEGF-A/VPF). VEGF-A-induced pathological angiogenesis can be mimicked in immunoincompetent mice with an adenoviral vector expressing VEGF-A(164) (Ad-VEGF-A(164)). The initial step is generation of greatly enlarged "mother" vessels (MV) from preexisting normal venules by a process involving degradation of their rigid basement membranes. Immunohistochemical and Western blot analyses revealed that versican, an extracellular matrix component in the basement membranes of venules, is degraded early in the course of MV formation, resulting in the appearance of a versican N-terminal DPEAAE fragment associated with MV endothelial cells. The protease ADAMTS-1, known to cleave versican near its N terminus to generate DPEAAE, is also upregulated by VEGF-A in parallel with MV formation and localizes to the endothelium of the developing MV. The authors also show that MMP-15 (MT-2 MMP), a protease that activates ADAMTS-1, is upregulated by VEGF-A in endothelial cells in vitro and in vivo. These data suggest VEGF-A initiates MV formation, in part, by inducing the expression of endothelial cell proteases such as ADAMTS-1 and MMP-15 that act in concert to degrade venular basement membrane versican. Thus, versican is actively processed during the early course of VEGF-A-induced pathological angiogenesis.
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Golfers have better balance control and confidence than healthy controls.
Eur. J. Appl. Physiol.
PUBLISHED: 03-05-2011
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In a well-executed golf swing, golfers must maintain good balance and precise control of posture. Golfing also requires prolonged walking over uneven ground such as a hilly course. Therefore, repeated golf practice may enhance balance control and confidence in the golfers. The objective is to investigate whether older golfers had better balance control and confidence than non-golfing older, healthy adults. This is a cross-sectional study, conducted at a University-based rehabilitation center. Eleven golfers and 12 control subjects (all male; mean age: 66.2 ± 6.8 and 71.3 ± 6.6 years, respectively) were recruited. Two balance control tests were administered: (1) functional reach test which measured subjects maximum forward distance in standing; (2) sensory organization test (SOT) which examined subjects abilities to use somatosensory, visual, and vestibular inputs to control body sway during stance. The modified Activities-specific Balance Confidence (ABC) determined subjects balance confidence in daily activities. The golfers were found to achieve significantly longer distance in the functional reach test than controls. They manifested significantly better balance than controls in the visual ratio and vestibular ratio, but not the somatosensory ratio of the SOT. The golfers also reported significantly higher balance confidence score ratios. Furthermore, older adults modified ABC score ratios showed positive correlations with functional reach, visual and vestibular ratios, but not with somatosensory ratio. Golfing is an activity which may enhance both the physical and psychological aspects of balance control. Significant correlations between these measures reveal the importance of the balance control under reduced or conflicting sensory conditions in older adults balance confidence in their daily activities. Since cause-and-effect could not be established in the present cross-sectional study, further prospective intervention design is warranted.
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Acu-TENS and Postexercise Expiratory Flow Volume in Healthy Subjects.
Evid Based Complement Alternat Med
PUBLISHED: 02-06-2011
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Transcutaneous Electrical Nerve Stimulation over acupoints (Acu-TENS) facilitates recovery of resting heart rate after treadmill exercise in healthy subjects. Its effect on postexercise respiratory indices has not been reported. This study investigates the effect of Acu-TENS on forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) in healthy subjects after a submaximal exercise. Eleven male subjects were invited to the laboratory twice, two weeks apart, to receive in random order either Acu-TENS or Placebo-TENS (no electrical output from the TENS unit) over bilateral Lieque (LU7) and Dingchuan (EX-B1) for 45 minutes, before undergoing exercise following the Bruce protocol. Exercise duration, rate of perceived exertion (RPE), and peak heart rate (PHR) were recorded. Between-group FEV1 and FVC, before, immediately after, at 15, 30, and 45minutes postexercise, were compared. While no between-group differences in PHR, RPE, and FVC were found, Acu-TENS was associated with a longer exercise duration (0.9?min (P = .026)) and a higher percentage increase in FEV1 at 15 and 45 minutes postexercise (3.3 ± 3.7% (P = .013) and 5.1 ± 7.5% (P = .047), resp.) compared to Placebo-TENS. We concluded that Acu-TENS was associated with a higher postexercise FEV1 and a prolongation of submaximal exercise.
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Time controlled release of arabinofuranosylcytosine (Ara-C) from agarose hydrogels using layer-by-layer assembly: an in vitro study.
J Biomater Sci Polym Ed
PUBLISHED: 01-28-2011
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Experimentally induced axonal regeneration is compromised by glial scar formation arising from leptomeningeal fibroblasts cells in and around the hydrogel scaffold implanted for nerve repair. Strategies are needed to prevent such fibroblastic reactive cell layer formation for enhanced axonal regeneration. Here, we implement the technique of layer-by-layer assembled degradable, hydrogen bonded multilayers on agarose hydrogels to incorporate an anti-mitotic drug (1-?-D-arabinofuranosylcytosine (Ara-C)) within the agarose hydrogels. We show controlled release of Ara-C under physiological conditions over a period of days. The concentrations of Ara-C released from agarose at the different time points were sufficient to inhibit fibroblast growth in vitro, while not adversely affecting the viability of the neuronal cells.
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Synergy analysis reveals association between insulin signaling and desmoplakin expression in palmitate treated HepG2 cells.
PLoS ONE
PUBLISHED: 01-27-2011
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The regulation of complex cellular activities in palmitate treated HepG2 cells, and the ensuing cytotoxic phenotype, involves cooperative interactions between genes. While previous approaches have largely focused on identifying individual target genes, elucidating interacting genes has thus far remained elusive. We applied the concept of information synergy to reconstruct a "gene-cooperativity" network for palmititate-induced cytotoxicity in liver cells. Our approach integrated gene expression data with metabolic profiles to select a subset of genes for network reconstruction. Subsequent analysis of the network revealed insulin signaling as the most significantly enriched pathway, and desmoplakin (DSP) as its top neighbor. We determined that palmitate significantly reduces DSP expression, and treatment with insulin restores the lost expression of DSP. Insulin resistance is a common pathological feature of fatty liver and related ailments, whereas loss of DSP has been noted in liver carcinoma. Reduced DSP expression can lead to loss of cell-cell adhesion via desmosomes, and disrupt the keratin intermediate filament network. Our findings suggest that DSP expression may be perturbed by palmitate and, along with insulin resistance, may play a role in palmitate induced cytotoxicity, and serve as potential targets for further studies on non-alcoholic fatty liver disease (NAFLD).
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Molecular mechanism by which palmitate inhibits PKR autophosphorylation.
Biochemistry
PUBLISHED: 01-24-2011
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PKR (double-stranded RNA-activated protein kinase) is an important component of the innate immunity, antiviral, and apoptotic pathways. Recently, our group found that palmitate, a saturated fatty acid, is involved in apoptosis by reducing the autophosphorylation of PKR at the Thr451 residue; however, the molecular mechanism by which palmitate reduces PKR autophosphorylation is not known. Thus, we investigated how palmitate affects the phosphorylation of the PKR protein at the molecular and biophysical levels. Biochemical and computational studies show that palmitate binds to PKR, near the ATP-binding site, thereby inhibiting its autophosphorylation at Thr451 and Thr446. Mutation studies suggest that Lys296 and Asp432 in the ATP-binding site on the PKR protein are important for palmitate binding. We further confirmed that palmitate also interacts with other kinases, due to the conserved ATP-binding site. A better understanding of how palmitate interacts with the PKR protein, as well as other kinases, could shed light onto possible mechanisms by which palmitate mediates kinase signaling pathways that could have implications on the efficacy of current drug therapies that target kinases.
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Do older tai chi practitioners have better attention and memory function?
J Altern Complement Med
PUBLISHED: 12-09-2010
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Cognitive declines are common in older people and can be a major health issue in an aging world. One type of body-mind exercises, tai chi, can be a possible means to help maintaining older adults cognitive abilities, in addition to beneficial effects of physical exercises. The purpose of this study was to investigate whether tai chi practitioners had better attention and memory functions than older people with or without regular exercises.
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Transcutaneous electrical stimulation on acupoints combined with task-related training to improve motor function and walking performance in an individual 7 years poststroke: a case study.
J Neurol Phys Ther
PUBLISHED: 11-19-2010
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Impaired walking function and spasticity are common sequelae of stroke. Prior studies have shown that a rehabilitation program combining transcutaneous electrical stimulation (TES) with task-related training (TRT) improves motor function in individuals with stroke. However, it is unclear if this approach is beneficial for individuals with long-standing stroke.
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Designing highly active siRNAs for therapeutic applications.
FEBS J.
PUBLISHED: 11-17-2010
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The discovery of RNA interference (RNAi) generated considerable interest in developing short interfering RNAs (siRNAs) for understanding basic biology and as the active agents in a new variety of therapeutics. Early studies showed that selecting an active siRNA was not as straightforward as simply picking a sequence on the target mRNA and synthesizing the siRNA complementary to that sequence. As interest in applying RNAi has increased, the methods for identifying active siRNA sequences have evolved from focusing on the simplicity of synthesis and purification, to identifying preferred target sequences and secondary structures, to predicting the thermodynamic stability of the siRNA. As more specific details of the RNAi mechanism have been defined, these have been incorporated into more complex siRNA selection algorithms, increasing the reliability of selecting active siRNAs against a single target. Ultimately, design of the best siRNA therapeutics will require design of the siRNA itself, in addition to design of the vehicle and other components necessary for it to function in vivo. In this minireview, we summarize the evolution of siRNA selection techniques with a particular focus on one issue of current importance to the field, how best to identify those siRNA sequences likely to have high activity. Approaches to designing active siRNAs through chemical and structural modifications will also be highlighted. As the understanding of how to control the activity and specificity of siRNAs improves, the potential utility of siRNAs as human therapeutics will concomitantly grow.
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Confocal microscopy for the analysis of siRNA delivery by polymeric nanoparticles.
Microsc. Res. Tech.
PUBLISHED: 08-31-2010
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Clinical applications of genetic therapies, including delivery of short, interfering RNAs (siRNAs) for RNA interference (RNAi), are limited due to the difficulty of delivering nucleic acids to specific cells of interest while at the same time minimizing toxicity and immunogenicity. The use of cationic polymers to deliver nucleic acid therapeutics has the potential to address these complex issues but is currently limited by low-delivery efficiencies. Although cell culture studies have shown that some polymers can be used to deliver siRNAs and achieve silencing, it is still not clear what physical or chemical properties are needed to ensure that the polymers form active polymer-siRNA complexes. In this study, we used multicolor fluorescence confocal microscopy to analyze the cellular uptake of siRNAs delivered by novel propargyl glycolide polymeric nanoparticles (NPs). Delivery by these vehicles was compared with delivery by linear polyethyleneimine (LPEI) and Lipofectamine 2000 (LF2K), which are both known as effective delivery vehicles for siRNAs. Our results showed that when LF2K and LPEI were used, large quantities of siRNA were delivered rapidly, presumably overwhelming the basal levels of mRNA to initiate silencing. In contrast, our novel polymeric NPs showed delivery of siRNAs but at concentrations that were initially too low to achieve silencing. Nonetheless, the exceptionally low cytotoxicity of our NPs, and the simplicity with which they can be modified, makes them good candidates for further study to optimize their delivery profiles and, in turn, achieve efficient silencing.
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The double-stranded RNA-dependent protein kinase differentially regulates insulin receptor substrates 1 and 2 in HepG2 cells.
Mol. Biol. Cell
PUBLISHED: 08-04-2010
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Initially identified to be activated upon virus infection, the double-stranded RNA-dependent protein kinase (PKR) is best known for triggering cell defense responses by phosphorylating eIF-2?, thus suppressing RNA translation. We as well as others showed that the phosphorylation of PKR is down-regulated by insulin. In the present study, we further uncovered a novel function of PKR in regulating the IRS proteins. We found that PKR up-regulates the inhibitory phosphorylation of IRS1 at Ser312, which suppresses the tyrosine phosphorylation of IRS1. This effect of PKR on the phosphorylation of IRS1 is mediated by two other protein kinases, JNK and IKK. In contrast, PKR regulates IRS2, another major IRS family protein in the liver, at the transcriptional rather than the posttranslational level, and this effect is mediated by the transcription factor, FoxO1, which has been previously shown to be regulated by insulin and plays a significant role in glucose homeostasis and energy metabolism. In summary, we found for the first time that initially known as a virus infection response gene, PKR regulates the upstream central transmitters of insulin signaling, IRS1 and IRS2, through different mechanisms.
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Cell adhesive behavior on thin polyelectrolyte multilayers: cells attempt to achieve homeostasis of its adhesion energy.
Langmuir
PUBLISHED: 07-08-2010
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Linearly growing ultrathin polyelectrolyte multilayer (PEM) films of strong polyelectrolytes, poly(diallyldimethylammonium chloride) (PDAC), and sulfonated polystyrene, sodium salt (SPS) exhibit a gradual shift from cytophilic to cytophobic behavior, with increasing thickness for films of less than 100 nm. Previous explanations based on film hydration, swelling, and changes in the elastic modulus cannot account for the cytophobicity observed with these thin films as the number of bilayers increases. We implemented a finite element analysis to help elucidate the observed trends in cell spreading. The simulation results suggest that cells maintain a constant level of energy consumption (energy homeostasis) during active probing and thus respond to changes in the film stiffness as the film thickness increases by adjusting their morphology and the number of focal adhesions recruited and thereby their attachment to a substrate.
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Differentiation of cardiomyocytes from human embryonic stem cells is accompanied by changes in the extracellular matrix production of versican and hyaluronan.
J. Cell. Biochem.
PUBLISHED: 06-22-2010
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Proteoglycans and hyaluronan play critical roles in heart development. In this study, human embryonic stem cells (hESC) were used as a model to quantify the synthesis of proteoglycans and hyaluronan in hESC in the early stages of differentiation, and after directed differentiation into cardiomyocytes. We demonstrated that both hESC and cardiomyocyte cultures synthesize an extracellular matrix (ECM) enriched in proteoglycans and hyaluronan. During cardiomyocyte differentiation, total proteoglycan and hyaluronan decreased and the proportion of proteoglycans bearing heparan sulfate chains was reduced. Versican, a chondroitin sulfate proteoglycan, accumulated in hESC and cardiomyocyte cultures. Furthermore, versican synthesized by hESC contained more N- and O-linked oligosaccharide than versican from cardiomyocytes. Transcripts for the versican variants, V0, V1, V2, and V3, increased in cardiomyocytes compared to hESC, with V1 most abundant. Hyaluronan in hESC had lower molecular weight than hyaluronan from cardiomyocyte cultures. These changes were accompanied by an increase in HAS-1 and HAS-2 mRNA in cardiomyocyte cultures, with HAS-2 most abundant. Interestingly, HAS-3 was absent from the cardiomyocyte cultures, but expressed by hESC. These results indicate that human cardiomyocyte differentiation is accompanied by specific changes in the expression and accumulation of ECM components and suggest a role for versican and hyaluronan in this process.
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Withanolide A and asiatic acid modulate multiple targets associated with amyloid-beta precursor protein processing and amyloid-beta protein clearance.
J. Nat. Prod.
PUBLISHED: 06-18-2010
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Alzheimers disease (AD) is a progressive, neurodegenerative disease histochemically characterized by extracellular deposits of amyloid beta (Abeta) protein and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is considered to be a complex, multifactorial syndrome, with numerous causal factors contributing to its pathogenesis. Thus, for any novel therapeutic molecule to have a "disease-modifying" effect on AD, it must be able to modulate multiple, synergistic targets simultaneously. In this context, we have studied two compounds of plant origin [withanolide A (1) and asiatic acid (2)] for their potential activities against multiple targets associated with Abeta pathways (BACE1, ADAM10, IDE, and NEP). BACE1 is a rate-limiting enzyme in the production of Abeta from amyloid-beta precursor protein (AbetaPP), while ADAM10 is involved in non-amyloidogenic processing of AbetaPP. IDE and NEP are two of the prominent enzymes involved in effectively degrading Abeta. It was found that both 1 and 2 significantly down-regulated BACE1 and also up-regulated ADAM10 in primary rat cortical neurons. In addition, 1 significantly up-regulated IDE levels, which may help in degrading excess Abeta from the AD brain. On the basis of the data obtained, the two multifunctional compounds may prove valuable in developing novel, effective therapeutics for the prevention and treatment of AD-associated amyloid pathology.
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cAMP initiates early phase neuron-like morphology changes and late phase neural differentiation in mesenchymal stem cells.
Cell. Mol. Life Sci.
PUBLISHED: 05-22-2010
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The intracellular second messenger cAMP is frequently used in induction media to induce mesenchymal stem cells (MSCs) into neural lineage cells. To date, an understanding of the role cAMP exerts on MSCs and whether cAMP can induce MSCs into functional neurons is still lacking. We found cAMP initiated neuron-like morphology changes early and neural differentiation much later. The early phase changes in morphology were due to cell shrinkage, which subsequently rendered some cells apoptotic. While the morphology changes occurred prior to the expression of neural markers, it is not required for neural marker expression and the two processes are differentially regulated downstream of cAMP-activated protein kinase A. cAMP enabled MSCs to gain neural marker expressions with neuronal function, such as, calcium rise in response to neuronal activators, dopamine, glutamate, and potassium chloride. However, only some of the cells induced by cAMP responded to the three neuronal activators and further lack the neuronal morphology, suggesting that although cAMP is able to direct MSCs towards neural differentiation, they do not achieve terminal differentiation.
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Culture clash: a missed opportunity.
J Dev Behav Pediatr
PUBLISHED: 04-24-2010
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Erasto is a term infant born by vaginal delivery to a gravida 7 para 7 Somalia woman with full prenatal care in the United States. His mother had gestational diabetes. The delivery was complicated by respiratory distress and an urgent admission to the neonatal intensive care unit for further evaluation for possible pulmonary disease and a congenital heart condition. A female pediatric intern was assigned to update Erastos mother on the babys status and to obtain consent for an intravascular line placement. When she entered the room to talk to the mother, multiple family members spanning at 3 generations were with the babys mother. They were all women with the exception of Erastos father who was apprised of the babys clinical status by the male neonatal physician several minutes earlier. Through a telephone translator, the intern explained to Erastos mother that her baby may have heart and lung problems that may be related to her gestational diabetes. At this point, many family members spoke simultaneously and excitedly. Some accused the intern of keeping the baby in the neonatal intensive care unit "to make more money," and others said they would sue her "if anything happened to Erasto." The mother denied that she had gestational diabetes, and claimed that because she "believed in God...nothing is wrong with my baby." The intern was not prepared for this response and asked herself, "What went wrong?"
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What is Visualize?

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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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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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.