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Find video protocols related to scientific articles indexed in Pubmed.
Individual reactions to stress predict performance during a critical aviation incident.
Anxiety Stress Coping
PUBLISHED: 11-15-2014
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Background: Understanding the influence of stress on human performance is of theoretical and practical importance. An individual's reaction to stress predicts their subsequent performance; with a 'challenge' response to stress leading to better performance than a 'threat' response. However, this contention has not been tested in truly stressful environments with highly skilled individuals. Furthermore, the effect of challenge and threat responses on attentional control during visuomotor tasks is poorly understood.Design: Thus, this study aimed to examine individual reactions to stress, and their influence on attentional control, among a cohort of commercial pilots performing a stressful flight assessment.Methods: Sixteen pilots performed an 'engine failure on take-off' scenario, in a high-fidelity flight simulator. Reactions to stress were indexed via self-report; performance was assessed subjectively (flight instructor assessment) and objectively (simulator metrics); gaze behaviour data were captured using a mobile eye tracker, and measures of attentional control were subsequently calculated (search rate, stimulus driven attention, and entropy).Results: Hierarchical regression analyses revealed that a threat response was associated with poorer performance and disrupted attentional control.Conclusion: The findings add to previous research showing that individual reactions to stress influence performance, and shed light on the processes through which stress influences performance.
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Prognosis of patients with bilateral fixed dilated pupils secondary to traumatic extradural or subdural haematoma who undergo surgery: a systematic review and meta-analysis.
Emerg Med J
PUBLISHED: 11-12-2014
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To review the prognosis of patients with bilateral fixed and dilated pupils secondary to traumatic extradural (epidural) or subdural haematoma who undergo surgery.
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Injury-induced MRP8/MRP14 stimulates IP-10/CXCL10 in monocytes/macrophages.
FASEB J.
PUBLISHED: 10-25-2014
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Trauma/hemorrhagic shock is associated with morbidity and mortality due to dysregulated inflammation, which is driven in part by monocytes/macrophages stimulated by injury-induced release of damage-associated molecular pattern (DAMP) molecules. MRP8/MRP14 is an endogenous DAMP involved in various inflammatory diseases, though its mechanism of action is unclear. Circulating MRP8/MRP14 levels in human blunt trauma nonsurvivors were significantly lower than those of survivors (P < 0.001). Human monocytic THP-1 cells stimulated with MRP8/MRP14 expressed the chemokine IFN-? inducible protein 10 (IP-10)/CXCL10. Circulating IP-10 levels in human blunt trauma patients were correlated positively with MRP8/MRP14 levels (r = 0.396, P < 0.001), and were significantly lower in trauma nonsurvivors than in survivors (P < 0.001). We therefore sought to determine the mechanisms by which MRP8/MRP14 stimulates IP-10 in monocytes/macrophages, and found that induction of IP-10 by MRP8/MRP14 required Toll-like receptor 4 and TRIF but not MyD88. Full induction of IP-10 by MRP8/MRP14 required synergy between the transcription factors NF-?B and IFN regulatory factor 3 (IRF3). The receptor for IP-10 is CXCR3, and MRP8/MRP14-induced chemotaxis of CXCR3(+) cells was dependent on the production of IP-10 in monocytes/macrophages. Furthermore, in vivo study with a mouse trauma/hemorrhagic shock model showed that administration of neutralizing antibody against MRP8 prevented activation of NF-?B and IRF3 as well as IP-10 production. Thus, the current study identified a novel signaling mechanism that controls IP-10 expression in monocytes/macrophages by MRP8/MRP14, which may play an important role in injury-induced inflammation.-Wang, J., Vodovotz, Y., Fan, L., Li, Y., Liu, Z., Namas, R., Barclay, D., Zamora, R., Billiar, T. R., Wilson, M. A., Fan, J., Jiang, Y. Injury-induced MRP8/MRP14 stimulates IP-10/CXCL10 in monocytes/macrophages.
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Neutrophils counteract autophagy-mediated anti-inflammatory mechanisms in alveolar macrophage: role in posthemorrhagic shock acute lung inflammation.
J. Immunol.
PUBLISHED: 09-29-2014
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Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome after hemorrhagic shock (HS) resulting from major surgery and trauma. The increased susceptibility in HS patients to the development of ALI suggests not yet fully elucidated mechanisms that enhance proinflammatory responses and/or suppress anti-inflammatory responses in the lung. Alveolar macrophages (AM?) are at the center of the pathogenesis of ALI after HS. We have previously reported that HS-activated polymorphonuclear neutrophils (PMNs) interact with macrophages to influence inflammation progress. In this study, we explore a novel function of PMNs regulating AM? anti-inflammatory mechanisms involving autophagy. Using a mouse "two-hit" model of HS/resuscitation followed by intratracheal injection of muramyl dipeptide, we demonstrate that HS initiates high mobility group box 1/TLR4 signaling, which upregulates NOD2 expression in AM? and sensitizes them to subsequent NOD2 ligand muramyl dipeptide to augment lung inflammation. In addition, upregulated NOD2 signaling induces autophagy in AM?, which negatively regulates lung inflammation through feedback suppression of NOD2-RIP2 signaling and inflammasome activation. Importantly, we further demonstrate that HS-activated PMNs that migrate in alveoli counteract the anti-inflammatory effect of autophagy in AM?, possibly through NAD(P)H oxidase-mediated signaling to enhance I-?B kinase ? phosphorylation, NF-?B activation, and nucleotide-binding oligomerization domain protein 3 inflammasome activation, and therefore augment post-HS lung inflammation. These findings explore a previously unidentified complexity in the mechanisms of ALI, which involves cell-cell interaction and receptor cross talk.
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Self-assembly and mesophase formation in a non-ionic chromonic liquid crystal system: insights from dissipative particle dynamics simulations.
Phys Chem Chem Phys
PUBLISHED: 09-25-2014
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Results are presented from a dissipative particle dynamics (DPD) simulation of a model non-ionic chromonic system, TP6EO2M, composed of a poly(ethylene glycol) functionalised aromatic (triphenylene) core. The simulations demonstrate self-assembly of chromonic molecules to form single molecule stacks in solution at low concentrations, the formation of a nematic mesophase at higher concentrations and a columnar phase in the more concentrated regime. The simulation model used allows very large system sizes, of many thousands of particles, to be studied. This provides, for the first time, an opportunity to study chromonic phase behaviour by simulation without severe restrictions imposed by system size. In the low concentration limit, the simulations demonstrate approximate isodesmic association from which a binding energy can be obtained, allowing the simulations to be tuned to reproduce the behaviour of the real experimental system.
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High-Pressure Transformation of SiO_{2} Glass from a Tetrahedral to an Octahedral Network: A Joint Approach Using Neutron Diffraction and Molecular Dynamics.
Phys. Rev. Lett.
PUBLISHED: 09-23-2014
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A combination of in situ high-pressure neutron diffraction at pressures up to 17.5(5) GPa and molecular dynamics simulations employing a many-body interatomic potential model is used to investigate the structure of cold-compressed silica glass. The simulations give a good account of the neutron diffraction results and of existing x-ray diffraction results at pressures up to ?60??GPa. On the basis of the molecular dynamics results, an atomistic model for densification is proposed in which rings are "zipped" by a pairing of five- and/or sixfold coordinated Si sites. The model gives an accurate description for the dependence of the mean primitive ring size ?n? on the mean Si-O coordination number, thereby linking a parameter that is sensitive to ordering on multiple length scales to a readily measurable parameter that describes the local coordination environment.
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Low frequency vibrational dynamics and polyamorphism in Y?O?-Al?O? glasses.
Phys Chem Chem Phys
PUBLISHED: 09-12-2014
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Glass formation, and associated potential polyamorphism are investigated for the key ceramic Y2O3-Al2O3 using a combination of experimental and theoretical techniques. Liquid samples are rapidly cooled by drop quenching and high and low density amorphous regions (LDA and HDA respectively) are identified using reflected light microscopy. Raman spectra are obtained to low frequency focussed on regions identified as pure LDA or HDA. The respective compositions of these regions are confirmed by electron microprobe analysis. These spectra are used to extract the vibrational densities of states and these are compared with those generated for the liquid oxide using polarizable-ion molecular dynamics simulations. The experimental and simulated spectra are used to determine the low temperature heat capacities. The low frequency regions of the spectra display an excess of states (boson peaks) which are different for the two glasses. Thermodynamic modelling is used to demonstrate how samples of the same composition my vitrify or not depending upon the quench rate.
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Ring statistics of silica bilayers.
J Phys Condens Matter
PUBLISHED: 09-05-2014
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The recent synthesis and characterisation of bilayers of vitreous silica has produced valuable new information on ring sizes and distributions. In this paper, we compare the ring statistics of experimental samples with computer generated samples. The average ring size is fixed at six by topology, but the width, skewness and other moments of the distribution of ring edges are characteristics of particular samples. We examine the Aboav-Weaire law that quantifies the propensity of smaller rings to be adjacent to larger rings, and find similar results for available experimental samples which however differ somewhat from computer-generated bilayers. We introduce a new law for the areas of rings of various sizes.
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Cadmium alters the formation of benzo[a]pyrene DNA adducts in the RPTEC/TERT1 human renal proximal tubule epithelial cell line.
Toxicol Rep
PUBLISHED: 08-30-2014
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Previously, we demonstrated the sensitivity of RPTEC/TERT1 cells, an immortalized human renal proximal tubule epithelial cell line, to two common environmental carcinogens, cadmium (Cd) and benzo[a]pyrene (B[a]P). Here, we measured BPDE-DNA adducts using a competitive ELISA method after cells were exposed to 0.01, 0.1, and 1 ?M B[a]P to determine if these cells, which appear metabolically competent, produce BPDE metabolites that react with DNA. BPDE-DNA adducts were most significantly elevated at 1 ?M B[a]P after 18 and 24 hours with 36.34 +/- 9.14 (n = 3) and 59.75 +/- 17.03 (n = 3) adducts/10(8) nucleotides respectively. For mixture studies, cells were exposed to a non-cytotoxic concentration of Cd, 1 ?M, for 24 hours and subsequently exposed to concentrations of B[a]P for 24 hours. Under these conditions, adducts detected at 1 ?M B[a]P after 24 hours were significantly reduced, 17.28 +/- 1.30 (n = 3) adducts/10(8) nucleotides, in comparison to the same concentration at previous time points without Cd pre-treatment. We explored the NRF2 antioxidant pathway and total glutathione levels in cells as possible mechanisms reducing adduct formation under co-exposure. Results showed a significant increase in the expression of NRF2-responsive genes, GCLC, HMOX1, NQO1, after 1 ?M Cd × 1 ?M B[a]P co-exposure. Additionally, total glutathione levels were significantly increased in cells exposed to 1 ?M Cd alone and 1 ?M Cd × 1 ?M B[a]P. Together, these results suggest that Cd may antagonize the formation of BPDE-DNA adducts in the RPTEC/TERT1 cell line under these conditions. We hypothesize that this occurs through priming of the antioxidant response pathway resulting in an increased capacity to detoxify BPDE prior to BPDE-DNA adduct formation.
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0125?The effects of acute and chronic mental stress on cardiac function.
Occup Environ Med
PUBLISHED: 07-15-2014
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The main objective of this study is to investigate the effects of chronic and acute stress on blood pressure, heart rate variability and an indicator of cardiac contractility. The study also aims to describe the degree to which various demographic and lifestyle factors modify the observed effect.
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Quantifying tissue mechanical properties using photoplethysmography.
Biomed Opt Express
PUBLISHED: 07-01-2014
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Photoplethysmography (PPG) is a non-invasive optical method that can be used to detect blood volume changes in the microvascular bed of tissue. The PPG signal comprises two components; a pulsatile waveform (AC) attributed to changes in the interrogated blood volume with each heartbeat, and a slowly varying baseline (DC) combining low frequency fluctuations mainly due to respiration and sympathetic nervous system activity. In this report, we investigate the AC pulsatile waveform of the PPG pulse for ultimate use in extracting information regarding the biomechanical properties of tissue and vasculature. By analyzing the rise time of the pulse in the diastole period, we show that PPG is capable of measuring changes in the Young's Modulus of tissue mimicking phantoms with a resolution of 4 KPa in the range of 12 to 61 KPa. In addition, the shape of the pulse can potentially be used to diagnose vascular complications by differentiating upstream from downstream complications. A Windkessel model was used to model changes in the biomechanical properties of the circulation and to test the proposed concept. The modeling data confirmed the response seen in vitro and showed the same trends in the PPG rise and fall times with changes in compliance and vascular resistance.
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Intracranial pressure at altitude.
High Alt. Med. Biol.
PUBLISHED: 06-28-2014
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Rapid ascent to high altitude can result in high altitude headache, acute mountain sickness, and less commonly, high altitude cerebral or pulmonary edema. The exact mechanisms by which these clinical syndromes develop remain to be fully elucidated. Direct and indirect measures of intracranial pressure (ICP) usually demonstrate a rise in pressure when human subjects and animals are exposed to acute hypoxia. However, the correlation of ICP changes to symptoms and altitude-related illnesses has been difficult to establish. Headache, for example, may occur with vessel distension prior to a rise in ICP. This article reviews the literature both supporting and refuting an increase in ICP as the underlying mechanism of headaches and other related neurological sequelae experienced at high altitude.
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The use of simulation in neurosurgical education and training.
J. Neurosurg.
PUBLISHED: 06-20-2014
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There is increasing evidence that simulation provides high-quality, time-effective training in an era of resident duty-hour restrictions. Simulation may also permit trainees to acquire key skills in a safe environment, important in a specialty such as neurosurgery, where technical error can result in devastating consequences. The authors systematically reviewed the application of simulation within neurosurgical training and explored the state of the art in simulation within this specialty. To their knowledge this is the first systematic review published on this topic to date.
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A Targeted Health Risk Assessment Following the Deep Water Horizon Oil Spill: Polycyclic Aromatic Hydrocarbon Exposure in Vietnamese-American Shrimp Consumers.
Environ. Health Perspect.
PUBLISHED: 05-13-2014
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The Deep Water Horizon oil spill of 2010, prompted concern about health risks among seafood consumers exposed to polycyclic aromatic hydrocarbons (PAHs) via consumption of contaminated seafood.
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Visual control strategies of surgeons: a novel method of establishing the construct validity of a transurethral resection of the prostate surgical simulator.
J Surg Educ
PUBLISHED: 05-07-2014
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To examine novice and expert differences in visual control strategies while performing a virtual reality transurethral resection of the prostate (TURP) task and to determine if these differences could provide a novel method for assessing construct validity of the simulator.
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Hypochlorite-induced structural modifications enhance the chaperone activity of human ?2-macroglobulin.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 05-05-2014
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Hypochlorite, an oxidant generated in vivo by the innate immune system, kills invading pathogens largely by inducing the misfolding of microbial proteins. Concomitantly, the nonspecific activity of hypochlorite also damages host proteins, and the accumulation of damaged (misfolded) proteins is implicated in the pathology of a variety of debilitating human disorders (e.g., Alzheimer's disease, atherosclerosis, and arthritis). It is well-known that cells respond to oxidative stress by up-regulating proteostasis machinery, but the direct activation of mammalian chaperones by hypochlorite has not, to our knowledge, been previously reported. In this study, we show that hypochlorite-induced modifications of human ?2-macroglobulin (?2M) markedly increase its chaperone activity by generating species, particularly dimers formed by dissociation of the native tetramer, which have enhanced surface hydrophobicity. Moreover, dimeric ?2M is generated in whole-blood plasma in the presence of physiologically relevant amounts of hypochlorite. The chaperone activity of hypochlorite-modified ?2M involves the formation of stable soluble complexes with misfolded client proteins, including heat-denatured enzymes, oxidized fibrinogen, oxidized LDL, and native or oxidized amyloid ?-peptide (A?1-42). Here, we show that hypochlorite-modified ?2M delivers its misfolded cargo to lipoprotein receptors on macrophages and reduces A?1-42 neurotoxicity. Our results support the conclusion that ?2M is a specialized chaperone that prevents the extracellular accumulation of misfolded and potentially pathogenic proteins, particularly during innate immune system activity.
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Activation of aryl hydrocarbon receptor signaling by extracts of teak and other wood dusts.
Environ. Toxicol.
PUBLISHED: 04-18-2014
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Wood dusts, as a group, are categorized as known human carcinogens, but the risks of exposure to specific types of wood dusts and the carcinogenic chemicals they contain are not well studied. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is linked to the carcinogenic action of specific classes of chemicals. Here we examined whether chemicals in various wood dusts had the potential to activate AhR signaling as a potential toxic mechanism of action. We found that methanol extracts of teak, walnut, mahogany, and poplar dusts contained a wide range of AhR ligand activity, whereas extracts of oak, pine, and other softwoods did not contain appreciable activity. Teak dust extract, being particularly potent, was subjected to chemical analysis. The 2-methylanthraquinone (2-MAQ) accounted for the AhR ligand activity and was present at an average concentration of 0.27 parts per hundred in teak dust. Pure 2-MAQ potently induced AhR signaling (EC50 115 nM), confirming that this was the active ligand. Aqueous extracts of teak dust made using yeast or mammalian cell culture medium also contained robust AhR activity, suggesting the 2-MAQ ligand is soluble at bioactive concentrations in physiologically relevant fluids. The high concentration and potency of 2-MAQ in teak wood suggest it may mediate toxic effects through activation of AhR signaling in exposed wood workers. © 2014 Wiley Periodicals, Inc. Environ Toxicol, 2014.
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Simultaneous detection of human mitochondrial DNA and nuclear-inserted mitochondrial-origin sequences (NumtS) using forensic mtDNA amplification strategies and pyrosequencing technology.
J. Forensic Sci.
PUBLISHED: 04-16-2014
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Next-generation sequencing technologies enable the identification of minor mitochondrial DNA variants with higher sensitivity than Sanger methods, allowing for enhanced identification of minor variants. In this study, mixtures of human mtDNA control region amplicons were subjected to pyrosequencing to determine the detection threshold of the Roche GS Junior(®) instrument (Roche Applied Science, Indianapolis, IN). In addition to expected variants, a set of reproducible variants was consistently found in reads from one particular amplicon. A BLASTn search of the variant sequence revealed identity to a segment of a 611-bp nuclear insertion of the mitochondrial control region (NumtS) spanning the primer-binding sites of this amplicon (Nature 1995;378:489). Primers (Hum Genet 2012;131:757; Hum Biol 1996;68:847) flanking the insertion were used to confirm the presence or absence of the NumtS in buccal DNA extracts from twenty donors. These results further our understanding of human mtDNA variation and are expected to have a positive impact on the interpretation of mtDNA profiles using deep-sequencing methods in casework.
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Rare individual amyloid-? oligomers act on astrocytes to initiate neuronal damage.
Biochemistry
PUBLISHED: 04-09-2014
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Oligomers of the amyloid-? (A?) peptide have been implicated in the neurotoxicity associated with Alzheimer's disease. We have used single-molecule techniques to examine quantitatively the cellular effects of adding well characterized A? oligomers to primary hippocampal cells and hence determine the initial pathway of damage. We found that even picomolar concentrations of A? (1-40) and A? (1-42) oligomers can, within minutes of addition, increase the levels of intracellular calcium in astrocytes but not in neurons, and this effect is saturated at a concentration of about 10 nM of oligomers. Both A? (1-40) and A? (1-42) oligomers have comparable effects. The rise in intracellular calcium is followed by an increase in the rate of ROS production by NADPH oxidase in both neurons and astrocytes. The increase in ROS production then triggers caspase-3 activation resulting in the inhibition of long-term potentiation. Our quantitative approach also reveals that only a small fraction of the oligomers are damaging and that an individual rare oligomer binding to an astrocyte can initiate the aforementioned cascade of responses, making it unlikely to be due to any specific interaction. Preincubating the A? oligomers with an extracellular chaperone, clusterin, sequesters the oligomers in long-lived complexes and inhibits all of the physiological damage, even at a ratio of 100:1, total A? to clusterin. To explain how A? oligomers are so damaging but that it takes decades to develop Alzheimer's disease, we suggest a model for disease progression where small amounts of neuronal damage from individual unsequestered oligomers can accumulate over time leading to widespread tissue-level dysfunction.
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Preliminary joint X-ray and neutron protein crystallographic studies of ecDHFR complexed with folate and NADP+.
Acta Crystallogr F Struct Biol Commun
PUBLISHED: 04-08-2014
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A crystal of Escherichia coli dihydrofolate reductase (ecDHFR) complexed with folate and NADP+ of 4×1.3×0.7?mm (3.6?mm3) in size was obtained by sequential application of microseeding and macroseeding. A neutron diffraction data set was collected to 2.0?Å resolution using the IMAGINE diffractometer at the High Flux Isotope Reactor within Oak Ridge National Laboratory. A 1.6?Å resolution X-ray data set was also collected from a smaller crystal at room temperature. The neutron and X-ray data were used together for joint refinement of the ecDHFR-folate-NADP+ ternary-complex structure in order to examine the protonation state, protein dynamics and solvent structure of the complex, furthering understanding of the catalytic mechanism.
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Exploring the utility of analogies in motor learning after stroke: a feasibility study.
Int J Rehabil Res
PUBLISHED: 04-01-2014
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Individuals who have experienced a stroke need to (re)learn motor skills. Analogy learning has been shown to facilitate motor learning in sports and may also be an attractive alternative to traditional approaches in therapy. The aim of this study was to assess the feasibility and utility of analogies to improve the walking performance in long-term stroke survivors. Three men aged 76, 87 and 70 years who were 6, 1 and 3 years poststroke, respectively, presented with different walking deficits. An analogy, targeted at improving the walking performance was designed with the help of each participant. During a 3-week intervention period, the analogy was practiced once weekly under supervision and daily at home. To assess feasibility, a structured interview was conducted at the end of the intervention period. To assess utility, walking performance was assessed using the 10-Metre Walking Test. All three participants were supportive of the feasibility and benefits of analogy learning. Two of the participants had a meaningful improvement on the 10-Metre Walking Test (0.1 and 0.3 m/s). The third participant did not improve most likely because of medication issues during the week of the retest. Developing analogies in therapy is a creative and challenging process, as analogies must not only guide the correct movement pattern, but also be meaningful to the individual. However, as participants were supportive of the use of analogies, and positive trends were seen in walking speed it seems worthwhile to pursue the use of analogies in future research.
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Microbial heterotrophic production in an oligotrophic acidic geothermal lake: responses to organic amendments and terrestrial plant litter.
FEMS Microbiol. Ecol.
PUBLISHED: 03-30-2014
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Boiling Springs Lake (BSL) is an oligotrophic, acidic geothermal feature where even very low levels of microbial heterotrophic production still exceed autotrophy. To test whether allochthonous leaf litter (LL) inputs fuel this excess, we quantified leaf litterfall, leaching and decomposition kinetics, and measured the impact of organic amendments on production, germination and cell growth, using pyrosequencing to track changes in microbial community composition. Coniferous leaves in BSL exhibited high mass loss rates during leaching and decomposition, likely due to a combination of chemical hydrolysis and contributions of both introduced and endemic microbes. We measured very low in situ (3)H-thymidine incorporation over hours by the dominant chemolithotroph Acidimicrobium (13-65 ?g C L(-1) day(-1)), which was inhibited by simple C sources (acetate, glucose). Longer term incubations with additions of 0.01-0.02% complex C/N sources induced germination of the Firmicute Alicyclobacillus within 1-2 days, as well as growth of Acetobacteraceae after 3-4 days. LL additions yielded the opposite successional patterns of these r-selected heterotrophs, boosting production to 30-150 ?g C L(-1) day(-1). Growth and germination studies suggest both prokaryotes and fungi likely consume allochthonous organics, and might be novel sources of lignocellulose-degrading enzymes. A model of BSL's C budget supports the hypothesis that allochthonous inputs fuel seasonal microbial heterotrophy, but that dissolved organic C sources greatly exceed direct LL inputs.
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Crystal cryocooling distorts conformational heterogeneity in a model michaelis complex of DHFR.
Structure
PUBLISHED: 03-10-2014
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Most macromolecular X-ray structures are determined from cryocooled crystals, but it is unclear whether cryocooling distorts functionally relevant flexibility. Here we compare independently acquired pairs of high-resolution data sets of a model Michaelis complex of dihydrofolate reductase (DHFR), collected by separate groups at both room and cryogenic temperatures. These data sets allow us to isolate the differences between experimental procedures and between temperatures. Our analyses of multiconformer models and time-averaged ensembles suggest that cryocooling suppresses and otherwise modifies side-chain and main-chain conformational heterogeneity, quenching dynamic contact networks. Despite some idiosyncratic differences, most changes from room temperature to cryogenic temperature are conserved and likely reflect temperature-dependent solvent remodeling. Both cryogenic data sets point to additional conformations not evident in the corresponding room temperature data sets, suggesting that cryocooling does not merely trap preexisting conformational heterogeneity. Our results demonstrate that crystal cryocooling consistently distorts the energy landscape of DHFR, a paragon for understanding functional protein dynamics.
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Examining the antecedents of challenge and threat states: the influence of perceived required effort and support availability.
Int J Psychophysiol
PUBLISHED: 03-03-2014
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To date, limited research has explicitly examined the antecedents of challenge and threat states proposed by the biopsychosocial model. Thus, the aim of the present study was to examine the influence of perceived required effort and support availability on demand/resource evaluations, challenge and threat states, and motor performance. A 2 (required effort; high, low)×2 (support availability; available, not available) between-subjects design was used with one hundred and twenty participants randomly assigned to one of four experimental conditions. Participants received instructions designed to manipulate perceptions of required effort and support availability before demand/resource evaluations and cardiovascular responses were assessed. Participants then performed the novel motor task (laparoscopic surgery) while performance was recorded. Participants in the low perceived required effort condition evaluated the task as more of a challenge (i.e., resources outweighed demands), exhibited a cardiovascular response more indicative of a challenge state (i.e., higher cardiac output and lower total peripheral resistance), and performed the task better (i.e., quicker completion time) than those in the high perceived required effort condition. However, perceptions of support availability had no significant impact on participants' demand/resource evaluations, cardiovascular responses, or performance. Furthermore, there was no significant interaction effect between perceptions of required effort and support availability. The findings suggest that interventions aimed at promoting a challenge state should include instructions that help individuals perceive that the task is not difficult and requires little physical and mental effort to perform effectively.
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Time course variations in the mechanisms by which cerebral oxygen delivery is maintained on exposure to hypoxia/altitude.
High Alt. Med. Biol.
PUBLISHED: 02-21-2014
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Normal cerebral function is dependent upon an adequate and continuous supply of oxygen. This study calculated cerebral blood flow based on assessment of the right middle cerebral artery (MCA) velocity (MCAVel) and MCA diameter (MCADiam) by trans-cranial Doppler and trans-cranial Duplex in normoxia, during acute exposure to 12% normobaric hypoxia for up to 6 hours, and after 3 days exposure to the equivalent altitude, 4392?m, in nine subjects. Mean (SD) MCAVel increased both after 6 hours hypoxia from 76.8 (11.4) to 97.2 (17.4) cms/sec (p<0.001), and after 3 days at altitude from 68.1 (7.5) [sea level] to 76.2 (10.2) [4392 m] (p=0.015). MCADiam increased from 5.07 (0.6) to 6.1 (0.6) mm (p<0.001) after 6 hours of 12% hypoxia. Calculated mean MCA blood flow increased after 6 hours of 12% hypoxia from 5.0 (0.6) mL/sec to 8.9 (1.2) mL/sec, but there was no difference between sea level and 4392?m. Calculated mean cerebral oxygen delivery increased from 72.4 (14.4) to 107 (20.1) mL/sec (p<0.001) after 6 hours of 12% hypoxia and was maintained unchanged at 4392?m. An increase in MCA caliber, rather than blood velocity, was a major contributor to increased oxygen delivery accompanying within the first few hours of exposure to acute hypoxia. During more long-term exposure, increases in MCA velocity and a rise in hemoglobin appeared to be the more important mechanisms in maintaining cerebral oxygen delivery. The implication of this observed change in MCA diameter questions the widely held assumption that MCA velocity is a surrogate for flow during acute hypoxic exposure.
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Use of cysteine-reactive cross-linkers to probe conformational flexibility of human DJ-1 demonstrates that Glu18 mutations are dimers.
J. Neurochem.
PUBLISHED: 02-13-2014
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The oxidation of a key cysteine residue (Cys106) in the parkinsonism-associated protein DJ-1 regulates its ability to protect against oxidative stress and mitochondrial damage. Cys106 interacts with a neighboring protonated Glu18 residue, stabilizing the Cys106-SO2 (-) (sulfinic acid) form of DJ-1. To study this important post-translational modification, we previously designed several Glu18 mutations (E18N, E18D, E18Q) that alter the oxidative propensity of Cys106. However, recent results suggest these Glu18 mutations cause loss of DJ-1 dimerization, which would severely compromise the protein's function. The purpose of this study was to conclusively determine the oligomerization state of these mutants using X-ray crystallography, NMR spectroscopy, thermal stability analysis, circular dichroism spectroscopy, sedimentation equilibrium ultracentrifugation, and cross-linking. We found that all of the Glu18 DJ-1 mutants were dimeric. Thiol cross-linking indicates that these mutant dimers are more flexible than the wild-type protein and can form multiple cross-linked dimeric species due to the transient exposure of cysteine residues that are inaccessible in the wild-type protein. The enhanced flexibility of Glu18 DJ-1 mutants provides a parsimonious explanation for their lower observed cross-linking efficiency in cells. In addition, thiol cross-linkers may have an underappreciated value as qualitative probes of protein conformational flexibility. DJ-1 is a homodimeric protein that protects cells against oxidative stress. Designed mutations that influence the regulatory oxidation of a key cysteine residue have recently been proposed to disrupt DJ-1 dimerization. We use cysteine cross-linking and various biophysical techniques to show that these DJ-1 mutants form dimers with increased conformational flexibility.
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Changes in hormones and biomarkers in polycystic ovarian syndrome treated with gastric bypass.
Surg Obes Relat Dis
PUBLISHED: 01-29-2014
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Small retrospective studies have demonstrated reduction in weight and co-morbid hirsutism and diabetes in women with polycystic ovary syndrome (PCOS) treated with Roux-en-Y gastric bypass. The objective of this study was to prospectively determine clinical improvements in obese women with PCOS treated with gastric bypass and identify postoperative biomarker changes.
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Conscious Motor Processing and Movement Self-Consciousness: Two Dimensions of Personality That Influence Laparoscopic Training.
J Surg Educ
PUBLISHED: 01-27-2014
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Identifying personality factors that account for individual differences in surgical training and performance has practical implications for surgical education. Movement-specific reinvestment is a potentially relevant personality factor that has a moderating effect on laparoscopic performance under time pressure. Movement-specific reinvestment has 2 dimensions, which represent an individual's propensity to consciously control movements (conscious motor processing) or to consciously monitor their 'style' of movement (movement self-consciousness).
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Assessing visual control during simulated and live operations: gathering evidence for the content validity of simulation using eye movement metrics.
Surg Endosc
PUBLISHED: 01-11-2014
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Although virtual reality (VR) simulators serve an important role in the training and assessment of surgeons, they need to be evaluated for evidence of validity. Eye-tracking technology and measures of visual control have been used as an adjunct to the performance parameters produced by VR simulators to help in objectively establishing the construct validity (experts vs. novices) of VR simulators. However, determining the extent to which VR simulators represent the real procedure and environment (content validity) has largely been a subjective process undertaken by experienced surgeons. This study aimed to examine the content validity of a VR transurethral resection of the prostate (TURP) simulator by comparing visual control metrics taken during simulated and real TURP procedures.
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Wireless monitoring of liver hemodynamics in vivo.
PLoS ONE
PUBLISHED: 01-01-2014
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Liver transplants have their highest technical failure rate in the first two weeks following surgery. Currently, there are limited devices for continuous, real-time monitoring of the graft. In this work, a three wavelengths system is presented that combines near-infrared spectroscopy and photoplethysmography with a processing method that can uniquely measure and separate the venous and arterial oxygen contributions. This strategy allows for the quantification of tissue oxygen consumption used to study hepatic metabolic activity and to relate it to tissue stress. The sensor is battery operated and communicates wirelessly with a data acquisition computer which provides the possibility of implantation provided sufficient miniaturization. In two in vivo porcine studies, the sensor tracked perfusion changes in hepatic tissue during vascular occlusions with a root mean square error (RMSE) of 0.135 mL/min/g of tissue. We show the possibility of using the pulsatile wave to measure the arterial oxygen saturation similar to pulse oximetry. The signal is also used to extract the venous oxygen saturation from the direct current (DC) levels. Arterial and venous oxygen saturation changes were measured with an RMSE of 2.19% and 1.39% respectively when no vascular occlusions were induced. This error increased to 2.82% and 3.83% when vascular occlusions were induced during hypoxia. These errors are similar to the resolution of a commercial oximetry catheter used as a reference. This work is the first realization of a wireless optical sensor for continuous monitoring of hepatic hemodynamics.
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Using a Delphi technique to seek consensus regarding definitions, descriptions and classification of terms related to implicit and explicit forms of motor learning.
PLoS ONE
PUBLISHED: 01-01-2014
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Motor learning is central to domains such as sports and rehabilitation; however, often terminologies are insufficiently uniform to allow effective sharing of experience or translation of knowledge. A study using a Delphi technique was conducted to ascertain level of agreement between experts from different motor learning domains (i.e., therapists, coaches, researchers) with respect to definitions and descriptions of a fundamental conceptual distinction within motor learning, namely implicit and explicit motor learning.
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The earliest giant Osprioneides borings from the Sandbian (late ordovician) of Estonia.
PLoS ONE
PUBLISHED: 01-01-2014
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The earliest Osprioneides kampto borings were found in bryozoan colonies of Sandbian age from northern Estonia (Baltica). The Ordovician was a time of great increase in the quantities of hard substrate removed by single trace makers. Increased predation pressure was most likely the driving force behind the infaunalization of larger invertebrates such as the Osprioneides trace makers in the Ordovician. It is possible that the Osprioneides borer originated in Baltica or in other paleocontinents outside of North America.
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Expression and purification of chaperone-active recombinant clusterin.
PLoS ONE
PUBLISHED: 01-01-2014
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Clusterin was the first described secreted mammalian chaperone and is implicated as being a key player in both intra- and extracellular proteostasis. Its unique combination of structural features and biological chaperone activity has, however, previously made it very challenging to express and purify the protein in a correctly processed and chaperone-active form. While there are multiple reports in the literature describing the use of recombinant clusterin, all of these reports suffer from one or more of the following shortcomings: details of the methods used to produce the protein are poorly described, the product is incompletely (if at all) characterised, and purity (if shown) is in many cases inadequate. The current report provides the first well validated method to economically produce pure chaperone-active recombinant clusterin. The method was developed after trialling expression in cultured bacterial, yeast, insect and mammalian cells, and involves the expression of recombinant clusterin from stably transfected HEK293 cells in protein-free medium. The product is expressed at between 7.5 and 10 µg/ml of culture, and is readily purified by a combination of immunoaffinity, cation exchange and size exclusion chromatography. The purified product was shown to be glycosylated, correctly proteolytically cleaved into ?- and ?-subunits, and have chaperone activity similar to that of human plasma clusterin. This new method creates the opportunity to use mutagenesis and metabolic labelling approaches in future studies to delineate functionally important sites within clusterin, and also provides a theoretically unlimited supply of recombinant clusterin which may in the future find applications in the development of therapeutics.
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The Role of Religion and Spirituality in Coping with Type 2 Diabetes: A Qualitative Study among Black Men.
J Relig Health
PUBLISHED: 12-21-2013
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Religion and spirituality are instrumental to coping with health; however, there is limited literature on the use of religion and spirituality among Black men with type 2 diabetes. The purpose of this study is to explore how Black men use religion or spirituality to cope with diabetes management. We conducted in-depth interviews with 30 Black men recruited from a diabetes clinic in Atlanta, Georgia as part of a larger study. This article reports on data from 12 of the 30 Black men who reported the use of religion and spirituality as a coping strategy for diabetes management. The following coping strategies were reported: prayer and belief in God, keeping me alive, turning things over to God, changing my unhealthy behaviors, supplying my needs, reading the Bible, and religious or spiritual individuals helping me. Healthcare professionals and researchers involved in diabetes management among Black men should consider these findings in their efforts.
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Champ or chump?: challenge and threat States during pressurized competition.
J Sport Exerc Psychol
PUBLISHED: 12-17-2013
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The present research examined the immediate impact of challenge and threat states on golf performance in both real competition and a laboratory-based task. In Study 1, 199 experienced golfers reported their evaluations of competition demands and personal coping resources before a golf competition. Evaluating the competition as a challenge (i.e., sufficient resources to cope with demands) was associated with superior performance. In Study 2, 60 experienced golfers randomly received challenge or threat manipulation instructions and then performed a competitive golf-putting task. Challenge and threat states were successfully manipulated and the challenge group outperformed the threat group. Furthermore, the challenge group reported less anxiety, more facilitative interpretations of anxiety, less conscious processing, and displayed longer quiet eye durations. However, these variables failed to mediate the group-performance relationship. These studies demonstrate the importance of considering preperformance psychophysiological states when examining the influence of competitive pressure on motor performance.
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Ensembl 2014.
Nucleic Acids Res.
PUBLISHED: 12-06-2013
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Ensembl (http://www.ensembl.org) creates tools and data resources to facilitate genomic analysis in chordate species with an emphasis on human, major vertebrate model organisms and farm animals. Over the past year we have increased the number of species that we support to 77 and expanded our genome browser with a new scrollable overview and improved variation and phenotype views. We also report updates to our core datasets and improvements to our gene homology relationships from the addition of new species. Our REST service has been extended with additional support for comparative genomics and ontology information. Finally, we provide updated information about our methods for data access and resources for user training.
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A Glutathione-Independent Glyoxalase of the DJ-1 Superfamily Plays an Important Role in Managing Metabolically Generated Methylglyoxal in Candida albicans.
J. Biol. Chem.
PUBLISHED: 12-03-2013
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Methylglyoxal is a cytotoxic reactive carbonyl compound produced by central metabolism. Dedicated glyoxalases convert methylglyoxal to D-lactate using multiple catalytic strategies. In this study, the DJ-1 superfamily member orf 19.251/GLX3 from Candida albicans is shown to possess glyoxalase activity, making this the first demonstrated glutathione-independent glyoxalase in fungi. The crystal structure of Glx3p indicates that the protein is a monomer containing the catalytic triad Cys136-His137-Glu168. Purified Glx3p has an in vitro methylglyoxalase activity (Km = 5.5 mM and kcat = 7.8 s-1) that is significantly greater than that of more distantly related members of the DJ-1 superfamily. A close Glx3p homolog from Saccharomyces cerevisiae (YDR533C/Hsp31) also has glyoxalase activity, suggesting that fungal members of the Hsp31 clade of the DJ-1 superfamily are all probable glutathione-independent glyoxalases. A homozygous glx3 null mutant in C. albicans strain SC5314 displays greater sensitivity to millimolar levels of exogenous methylglyoxal, elevated levels of intracellular methylglyoxal, and carbon source-dependent growth defects, especially when grown on glycerol. These phenotypic defects are complemented by restoration of the wild-type GLX3 locus. The growth defect of Glx3-deficient cells in glycerol is also partially complemented by added inorganic phosphate, which is not observed for wild-type or glucose-grown cells. Therefore, C. albicans Glx3 and its fungal homologs are physiologically relevant glutathione-independent glyoxalases that are not redundant with the previously characterized glutathione-dependent GLO1/GLO2 system. In addition to its role in detoxifying glyoxals, Glx3 and its close homologs may have other important roles in stress response.
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Applying the chronic care model to an employee benefits program: a qualitative inquiry.
J. Occup. Environ. Med.
PUBLISHED: 11-26-2013
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To assess how employee benefits programs may strengthen and/or complement elements of the chronic care model (CCM), a framework used by health systems to improve chronic illness care.
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Rapid intrinsic fluorescence method for direct identification of pathogens in blood cultures.
MBio
PUBLISHED: 11-21-2013
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A positive blood culture is a critical result that requires prompt identification of the causative agent. This article describes a simple method to identify microorganisms from positive blood culture broth within the time taken to perform a Gram stain (<20 min). The method is based on intrinsic fluorescence spectroscopy (IFS) of whole cells and required development of a selective lysis buffer, aqueous density cushion, optical microcentrifuge tube, and reference database. A total of 1,121 monomicrobial-positive broth samples from 751 strains were analyzed to build a database representing 37 of the most commonly encountered species in bloodstream infections or present as contaminants. A multistage algorithm correctly classified 99.6% of unknown samples to the Gram level, 99.3% to the family level, and 96.5% to the species level. There were no incorrect results given at the Gram or family classification levels, while 0.8% of results were discordant at the species level. In 8/9 incorrect species results, the misidentified isolate was assigned to a species of the same genus. This unique combination of selective lysis, density centrifugation, and IFS can rapidly identify the most common microbial species present in positive blood cultures. Faster identification of the etiologic agent may benefit the clinical management of sepsis. Further evaluation is now warranted to determine the performance of the method using clinical blood culture specimens.
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IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation.
J. Exp. Med.
PUBLISHED: 11-18-2013
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IL-9 fate reporter mice established type 2 innate lymphoid cells (ILC2s) as major producers of this cytokine in vivo. Here we focus on the role of IL-9 and ILC2s during the lung stage of infection with Nippostrongylus brasiliensis, which results in substantial tissue damage. IL-9 receptor (IL-9R)-deficient mice displayed reduced numbers of ILC2s in the lung after infection, resulting in impaired IL-5, IL-13, and amphiregulin levels, despite undiminished numbers of Th2 cells. As a consequence, the restoration of tissue integrity and lung function was strongly impaired in the absence of IL-9 signaling. ILC2s, in contrast to Th2 cells, expressed high levels of the IL-9R, and IL-9 signaling was crucial for the survival of activated ILC2s in vitro. Furthermore, ILC2s in the lungs of infected mice required the IL-9R to up-regulate the antiapoptotic protein BCL-3 in vivo. This highlights a unique role for IL-9 as an autocrine amplifier of ILC2 function, promoting tissue repair in the recovery phase after helminth-induced lung inflammation.
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Proposal for establishment of the UK Cranial Reconstruction Registry (UKCRR).
Br J Neurosurg
PUBLISHED: 11-18-2013
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Background. The increasing utilisation of decompressive craniectomy for traumatic brain injury and stroke has led to an increase in the number of cranioplasties undertaken. Cranioplasty is also undertaken following excision of tumours originating from or invading the skull vault, removal of bone flaps due to post-operative infection, and decompressive craniectomy for the management of rarer causes of brain oedema and/or refractory intracranial hypertension. The existing literature which mainly consists of single-centre, retrospective studies, shows a significant variation in practice patterns and a wide range of morbidity. There also exists a need to measure the outcome as perceived by the patients themselves with patient reported outcome measures (PROMs; functional outcome, quality of life, satisfaction with cosmesis). In the UK, the concept of long-term surveillance of neurosurgical implants is well established with the UK shunt registry. Based on this background, we propose to establish the UK Cranial Reconstruction Registry (UKCRR). Aim. The overarching aim of the UKCRR is to collect high-quality data about cranioplasties undertaken across the UK and Ireland in order to improve outcomes for patients. Methods. Any patient undergoing reconstruction of the skull vault with autologous bone, titanium, or synthetic material in participating units will be eligible for inclusion. Data will be submitted directly by participating units to the Outcome Registry Intervention and Operation Network secure platform. A Steering Committee will be responsible for overseeing the strategic direction and running of the UKCRR. Outcome measures. These will include re-operation due to a cranioplasty-related issue, surgical site infection, re-admission due to a cranioplasty-related issue, unplanned post-operative escalation of care, adverse events, length of stay in admitting unit, destination at discharge from admitting unit, mortality at discharge from admitting unit, neurological status and PROMs during routine follow-up. Conclusion. The UKCRR will be an important pillar in the ongoing efforts to optimise the outcomes of patients undergoing cranioplasty.
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Well-tempered metadynamics as a tool for characterizing multi-component, crystalline molecular machines.
J Phys Chem B
PUBLISHED: 10-01-2013
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The well-tempered, smoothly converging form of the metadynamics algorithm has been implemented in classical molecular dynamics simulations and used to obtain an estimate of the free energy surface explored by the molecular rotations in the plastic crystal, octafluoronaphthalene. The biased simulations explore the full energy surface extremely efficiently, more than 4 orders of magnitude faster than unbiased molecular dynamics runs. The metadynamics collective variables used have also been expanded to include the simultaneous orientations of three neighboring octafluoronaphthalene molecules. Analysis of the resultant three-dimensional free energy surface, which is sampled to a very high degree despite its significant complexity, demonstrates that there are strong correlations between the molecular orientations. Although this correlated motion is of limited applicability in terms of exploiting dynamical motion in octafluoronaphthalene, the approach used is extremely well suited to the investigation of the function of crystalline molecular machines.
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Management of malignant middle cerebral artery infarction following a cardiac stab wound - the role of early decompressive craniectomy.
Br J Neurosurg
PUBLISHED: 09-25-2013
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We report the presentation, investigation and management of a 22-year-old male who developed a right malignant middle cerebral artery infarct following a cardiac stab wound. This case exemplifies that early identification and timely decompression of young patients with embolic infarcts as a result of penetrating trauma can lead to a favourable clinical outcome.
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Evaluating stress as a challenge is associated with superior attentional control and motor skill performance: testing the predictions of the biopsychosocial model of challenge and threat.
J Exp Psychol Appl
PUBLISHED: 09-25-2013
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The biopsychosocial model of challenge and threat (Blascovich, 2008) suggests that individuals who evaluate a performance situation as a challenge will perform better than those who evaluate it as a threat. However, limited research has examined (a) the influence of challenge and threat evaluations on learned motor performance under pressure and (b) the attentional processes by which this effect occurs. In the present study 52 novices performed a motor task (laparoscopic surgery), for which optimal visual attentional control has been established. Participants performed a Baseline trial (when the task was novel) and were then trained to proficiency before performing under pressurized conditions designed to increase anxiety (Pressure). At Baseline, regression analyses were performed to examine the relationship between challenge/threat evaluations and the outcome variables (performance, cardiovascular response, and visual attention). At Pressure, hierarchical regression analyses (controlling for the degree of learning) were performed to examine the relationship between challenge/threat evaluations and the outcome variables. At both Baseline and Pressure tests evaluating the task as more of a challenge was associated with more effective attentional control and superior performance. In the Baseline test, evaluating the task as more of a challenge was associated with differential cardiovascular responses. Although there is some support for an attentional explanation of differential performance effects, additional analyses did not reveal mediators of the relationship between challenge/threat evaluations and motor performance. The findings have implications for the training and performance of motor skills in pressurized environments (e.g., surgery, sport, aviation).
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A coarse-grained model for polyethylene glycol in bulk water and at a water/air interface.
Phys Chem Chem Phys
PUBLISHED: 09-06-2013
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A coarse-grained model for polyethylene glycol (PEG) in water has been developed using a combination of the iterative Boltzmann inversion (IBI) methodology and a suitable coarse-grained water potential. The combined coarse-grained model is shown to be effective in reproducing the properties of single chains in bulk water and multiple chains across a series of chain lengths and concentrations, and is transferable to PEG chains at a water/air interface. Good agreement is achieved with both experiment and reference atomistic simulations in an explicit solvent. Simulations of a single chain in aqueous solution yield a molecular weight (MW)-radius of gyration (Rg) relation that compares favourably with the reported scaling law from experiment. Simulations of multiple chains across a wide concentration range show no concentration dependence of Rg, in agreement with previous atomistic simulations. The model we develop is shown to be transferable between polymer in bulk water and at a water/air interface. For interfacial simulations, PEG chains are found to spontaneously migrate to the surface and adsorb to form a thin surface layer, which thickens with increasing surface concentration. The point at which the surface is fully saturated with polymer, and the polymer layer thicknesses obtained from simulations, are both in good agreement with experimental findings. At high surface concentrations, when the surface is fully saturated with polymer, ethylene oxide (EO) segments are found to extend into the water subphase as loop and tail conformations, with this extension increasing with further increases in the surface concentration. The coarse-grained model is noted to provide very large increases in simulation speed, with equilibration times of <1000× the reference atomistic models. We also consider a number of different coarse-grained models for water in this study, showing that the CSJ model adopted in this work [Chiu et al., J. Chem. Theory Comput., 2010, 6, 851] is far superior for studying water at a water/air surface, than many of the previous coarse-grained models of water.
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Modulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors.
PLoS Biol.
PUBLISHED: 09-01-2013
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Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distinct site. There is growing evidence that allosteric cooperativity can be communicated by modulation of protein dynamics without conformational change. The mechanisms, however, for communicating dynamic fluctuations between sites are debated. We provide a foundational theory for how allostery can occur as a function of low-frequency dynamics without a change in structure. We have generated coarse-grained models that describe the protein backbone motions of the CRP/FNR family transcription factors, CAP of Escherichia coli and GlxR of Corynebacterium glutamicum. The latter we demonstrate as a new exemplar for allostery without conformation change. We observe that binding the first molecule of cAMP ligand is correlated with modulation of the global normal modes and negative cooperativity for binding the second cAMP ligand without a change in mean structure. The theory makes key experimental predictions that are tested through an analysis of variant proteins by structural biology and isothermal calorimetry. Quantifying allostery as a free energy landscape revealed a protein "design space" that identified the inter- and intramolecular regulatory parameters that frame CRP/FNR family allostery. Furthermore, through analyzing CAP variants from diverse species, we demonstrate an evolutionary selection pressure to conserve residues crucial for allosteric control. This finding provides a link between the position of CRP/FNR transcription factors within the allosteric free energy landscapes and evolutionary selection pressures. Our study therefore reveals significant features of the mechanistic basis for allostery. Changes in low-frequency dynamics correlate with allosteric effects on ligand binding without the requirement for a defined spatial pathway. In addition to evolving suitable three-dimensional structures, CRP/FNR family transcription factors have been selected to occupy a dynamic space that fine-tunes biological activity and thus establishes the means to engineer allosteric mechanisms driven by low-frequency dynamics.
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Intestinal perfusion monitoring using photoplethysmography.
J Biomed Opt
PUBLISHED: 08-15-2013
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In abdominal trauma patients, monitoring intestinal perfusion and oxygen consumption is essential during the resuscitation period. Photoplethysmography is an optical technique potentially capable of monitoring these changes in real time to provide the medical staff with a timely and quantitative measure of the adequacy of resuscitation. The challenges for using optical techniques in monitoring hemodynamics in intestinal tissue are discussed, and the solutions to these challenges are presented using a combination of Monte Carlo modeling and theoretical analysis of light propagation in tissue. In particular, it is shown that by using visible wavelengths (i.e., 470 and 525 nm), the perfusion signal is enhanced and the background contribution is decreased compared with using traditional near-infrared wavelengths leading to an order of magnitude enhancement in the signal-to-background ratio. It was further shown that, using the visible wavelengths, similar sensitivity to oxygenation changes could be obtained (over 50% compared with that of near-infrared wavelengths). This is mainly due to the increased contrast between tissue and blood in that spectral region and the confinement of the photons to the thickness of the small intestine. Moreover, the modeling results show that the source to detector separation should be limited to roughly 6 mm while using traditional near-infrared light, with a few centimeters source to detector separation leads to poor signal-to-background ratio. Finally, a visible wavelength system is tested in an in vivo porcine study, and the possibility of monitoring intestinal perfusion changes is showed.
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The use of immobilised metal affinity chromatography (IMAC) to compare expression of copper-binding proteins in control and copper-exposed marine microalgae.
Anal Bioanal Chem
PUBLISHED: 08-13-2013
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Toxicity of metals to aquatic organisms is dependent on both external factors, such as exposure concentration and water quality parameters, and intracellular processes including specific metal-binding sites and detoxification. Current models used to predict copper toxicity in microalgae do not adequately consider these intracellular processes. This study compared the copper-binding proteins from four species of marine microalgae, Dunaliella tertiolecta, Tetraselmis sp., Phaedactylum tricornutum and Ceratoneis closterium, in controls (no added copper) and following a 72-h exposure to copper (sufficient to inhibit growth by approximately 50 %). Cells were lysed by sonication, which was optimised to obtain 54-94 % cell rupture for the different algae. Cell lysates were processed by immobilised metal affinity chromatography (IMAC) using Cu(2+) as the bound metal (i.e. Cu-IMAC). Bound proteins were subsequently analysed by SDS-PAGE, comparing proteins recovered from algae that were exposed to copper versus untreated control cells. Individual proteins for which copper exposure resulted in changes to proteins present were excised from gels and further analysed by nano LC ESI-MS/MS; proteins were identified using the Mascot database. Proteins identified in this way included heat-shock proteins, rubisco, ?- and ?-tubulins and ATP synthase (? subunit). The results established that Cu-IMAC is a useful approach to identify proteins involved in copper binding in algae. This study identified several proteins that may play an active role in responses to copper toxicity in marine microalgae.
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Increased mortality associated with cerebral contusions following trauma in the elderly: bad patients or bad management?
J. Neurotrauma
PUBLISHED: 07-17-2013
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Age has been identified as an independent risk factor for poor outcome following head injury in the elderly, and postulated reasons for this include nature, nurture, and variations in management. Do elderly head injuries do worse because of a self-fulfilling prophecy of poorer management? The aim of this study was to review the management of patients with cerebral contusions according to age to identify any trends. We retrospectively reviewed prospectively collected national data on cerebral contusion admissions between March 14, 1988, and May 4, 2012, to UK hospitals held in the Trauma Audit and Research Network database. Patients were included in the study if they had cerebral contusion(s) with an abbreviated injury score (AIS) of 3 or more; no other head injury with a AIS score of 4 or more, or no injury in any other body region with AIS score of 3 or more, and known outcome data. In total, 4387 patients met the inclusion criteria. Mortality was found to increase with increasing age (p<0.001). However, time from admission to CT head imaging (p=0.003) and the likelihood of not being transferred to a center with acute neurosurgical care facilities (p<0.001) increased with increasing age, too. Further, there was a significant trend for the most senior grade of doctor to review more younger patients and for only the most junior grade of doctor to review more older patients (both, p<0.001). To conclude, our data suggest differences in management practice may contribute to the observed differences in mortality between younger and older patients suffering brain contusions.
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Associations between insulin and heart rate variability in police officers.
Am. J. Hum. Biol.
PUBLISHED: 07-16-2013
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Low heart rate variability (HRV) has been linked to cardiovascular disease. Our objective was to examine the cross-sectional association between insulin and HRV.
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Exploring the impact of expertise, clinical history, and visual search on electrocardiogram interpretation.
Med Decis Making
PUBLISHED: 06-27-2013
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The primary aim of this study is to understand more about the perceptual-cognitive mechanisms underpinning the expert advantage in electrocardiogram (ECG) interpretation. While research has examined visual search processes in other aspects of medical decision making (e.g., radiology), this is the first study to apply the paradigm to ECG interpretation. The secondary aim is to explore the role that clinical history plays in influencing visual search behavior and diagnostic decision making. While clinical history may aid diagnostic decision making, it may also bias the visual search process.
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TLR4 Signaling augments monocyte chemotaxis by regulating G protein-coupled receptor kinase 2 translocation.
J. Immunol.
PUBLISHED: 06-14-2013
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Monocytes are critical effector cells of the innate immune system that protect the host by migrating to inflammatory sites, differentiating to macrophages and dendritic cells, eliciting immune responses, and killing pathogenic microbes. MCP-1, also known as CCL2, plays an important role in monocyte activation and migration. The chemotactic function of MCP-1 is mediated by binding to the CCR2 receptor, a member of the G protein-coupled receptor (GPCR) family. Desensitization of GPCR chemokine receptors is an important regulator of the intensity and duration of chemokine stimulation. GPCR kinases (GRKs) induce GPCR phosphorylation, and this leads to GPCR desensitization. Regulation of subcellular localization of GRKs is considered an important early regulatory mechanism of GRK function and subsequent GPCR desensitization. Chemokines and LPS are both present during Gram-negative bacterial infection, and LPS often synergistically exaggerates leukocyte migration in response to chemokines. In this study, we investigated the role and mechanism of LPS-TLR4 signaling on the regulation of monocyte chemotaxis. We demonstrate that LPS augments MCP-1-induced monocyte migration. We also show that LPS, through p38 MAPK signaling, induces phosphorylation of GRK2 at serine 670, which, in turn, suppresses GRK2 translocation to the membrane, thereby preventing GRK2-initiated internalization and desensitization of CCR2 in response to MCP-1. This results in enhanced monocyte migration. These findings reveal a novel function for TLR4 signaling in promoting innate immune cell migration.
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The impact of visual illusions on perception, action planning, and motor performance.
Atten Percept Psychophys
PUBLISHED: 06-13-2013
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The present study extended recent research revealing that illusions can influence performance in golf putting (Witt, Linkenauger, & Proffitt Psychological Science, 23, 397-399, 2012), by exploring the potential mediating roles of attention and action planning. Glover and Dixons (Journal of Experimental Psychology. Human Perception and Performance, 27, 560-572, 2001) planning-control model suggests that both perceptual and movement-planning processes are prone to illusion-based bias. We therefore predicted that both the perception of target size and a measure of attentional control related to movement planning in golf putting (the quiet eye) would be influenced by the illusion. Moreover, as performance could not be corrected using online control (once the ball was struck), we predicted that these biases would also influence performance. We therefore proposed a three-stage process by which illusory context biases perceptual processes, which in turn bias subsequent attentional control related to movement planning, which in turn biases motor performance. Forty novice golfers completed an Ebbinghaus illusion putting task that was designed to manipulate their perceptions of target size, while quiet eye duration and performance (mean radial error) were measured. The results indicated that the illusion was effective in facilitating differences in perceived target size, with perceptually bigger holes promoting longer quiet eye durations and more accurate putting. Follow-up mediation analyses revealed that illusion-based differences in size perception partially mediated illusion-based differences in both quiet eye duration and performance. Moreover, the relationship between illusion-based differences in quiet eye duration and performance was also significant. Future research should further test this three-stage process of bias in other far-aiming tasks in which online control cannot be used.
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O-Demethylations catalyzed by Rieske nonheme iron monooxygenases involve the difficult oxidation of a saturated C-H bond.
ACS Chem. Biol.
PUBLISHED: 06-10-2013
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Dicamba monooxygenase (DMO) catalyzes the O-demethylation of dicamba (3,6-dichloro-2-methoxybenzoate) to produce 3,6-dichlorosalicylate and formaldehyde. Recent crystallographic studies suggest that DMO catalyzes the challenging oxidation of a saturated C-H bond within the methyl group of dicamba to form a hemiacetal intermediate. Testing of this hypothesis was made possible by our development of two new independent techniques. As a novel method to allow use of (18)O2 to follow reaction products, bisulfite was used to trap newly formed (18)O-formaldehyde in the stable adduct, hydroxymethanesulfonate (HMS(-)), and thereby prevent the rapid exchange of (18)O in formaldehyde with (16)O in water. The second technique utilized unique properties of Pseudomonas putida formaldehyde dehydrogenase that allow rapid conversion of (18)O-formaldehyde into stable and easily detectable (18)O-formic acid. Experiments using these two new techniques provided compelling evidence for DMO-catalyzed oxidation of the methyl group of dicamba, thus validating a mechanism for DMO [and for vanillate monooxygenase, a related Rieske nonheme iron monooxygenase] that involves the difficult oxidation of a saturated C-H bond.
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??PT: a comprehensive toolbox for the analysis of protein motion.
BMC Bioinformatics
PUBLISHED: 05-24-2013
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Normal Mode Analysis is one of the most successful techniques for studying motions in proteins and macromolecules. It can provide information on the mechanism of protein functions, used to aid crystallography and NMR data reconstruction, and calculate protein free energies.
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Sequestration and histopathology in Plasmodium chabaudi malaria are influenced by the immune response in an organ-specific manner.
Cell. Microbiol.
PUBLISHED: 05-20-2013
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Infection with the malaria parasite, Plasmodium, is associated with a strong inflammatory response and parasite cytoadhesion (sequestration) in several organs. Here, we have carried out a systematic study of sequestration and histopathology during infection of C57Bl/6 mice with Plasmodium chabaudi?AS and determined the influence of the immune response. This parasite sequesters predominantly in liver and lung, but not in the brain, kidney or gut. Histopathological changes occur in multiple organs during the acute infection, but are not restricted to the organs where sequestration takes place. Adaptive immunity, and signalling through the IFN? receptor increased sequestration and histopathology in the liver, but not in the lung, suggesting that there are differences in the adhesion molecules and/or parasite ligands utilized and mechanisms of pathogenesis in these two organs. Exacerbation of pro-inflammatory responses during infection by deletion of the il10 gene resultsin the aggravation of damage to lung and kidney irrespective of the degree of sequestration. The immune response therefore affected both sequestration and histopathology in an organ-specific manner. P.?chabaudi?AS provides a good model to investigate the influence of the host response on the sequestration and specific organ pathology, which is applicable to human malaria.
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Hemorrhagic shock augments Nlrp3 inflammasome activation in the lung through impaired pyrin induction.
J. Immunol.
PUBLISHED: 04-12-2013
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Hemorrhagic shock (HS) promotes the development of systemic inflammatory response syndrome and organ injury by activating and priming the innate immune system for an exaggerated inflammatory response through, as of yet, unclear mechanisms. IL-1? also plays an important role in the development of post-HS systemic inflammatory response syndrome and active IL-1? production is tightly controlled by the inflammasome. Pyrin, a protein of 781 aa with pyrin domain at the N-terminal, negatively regulates inflammasome activation through interaction with nucleotide-binding oligomerization domain-like receptor protein (NLRP). Expression of pyrin can be induced by LPS and cytokines, and IL-10 is a known potent inducer of pyrin expression in macrophages. In the current study, we tested the hypothesis that HS downregulates IL-10 and therefore decreases pyrin expression to promote inflammasome activation and subsequent IL-1? processing and secretion in the lungs. Our results show that LPS, while activating Nlrp3 inflammasome in the lungs, also induced pyrin expression, which in turn suppressed inflammasome activation. More importantly, LPS-mediated upregulation of IL-10 enhanced pyrin expression, which serves, particularly in later phases, as a potent negative-feedback mechanism regulating inflammasome activation. However, HS-mediated suppression of IL-10 expression in alveolar macrophages attenuated the upregulation of pyrin in alveolar macrophages and lung endothelial cells and thereby significantly enhanced inflammasome activation and IL-1? secretion in the lungs. This study demonstrates a novel mechanism by which HS suppresses negative-feedback regulation of Nlrp3 inflammasome to enhance IL-1? secretion in response to subsequent LPS challenge and so primes for inflammation.
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Functional convergence of structurally distinct thioesterases from cyanobacteria and plants involved in phylloquinone biosynthesis.
Acta Crystallogr. D Biol. Crystallogr.
PUBLISHED: 04-08-2013
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The synthesis of phylloquinone (vitamin K1) in photosynthetic organisms requires a thioesterase that hydrolyzes 1,4-dihydroxy-2-naphthoyl-CoA (DHNA-CoA) to release 1,4-dihydroxy-2-naphthoate (DHNA). Cyanobacteria and plants contain distantly related hotdog-fold thioesterases that catalyze this reaction, although the structural basis of these convergent enzymatic activities is unknown. To investigate this, the crystal structures of hotdog-fold DHNA-CoA thioesterases from the cyanobacterium Synechocystis (Slr0204) and the flowering plant Arabidopsis thaliana (AtDHNAT1) were determined. These enzymes form distinct homotetramers and use different active sites to catalyze hydrolysis of DHNA-CoA, similar to the 4-hydroxybenzoyl-CoA (4-HBA-CoA) thioesterases from Pseudomonas and Arthrobacter. Like the 4-HBA-CoA thioesterases, the DHNA-CoA thioesterases contain either an active-site aspartate (Slr0204) or glutamate (AtDHNAT1) that are predicted to be catalytically important. Computational modeling of the substrate-bound forms of both enzymes indicates the residues that are likely to be involved in substrate binding and catalysis. Both enzymes are selective for DHNA-CoA as a substrate, but this selectivity is achieved using divergent predicted binding strategies. The Slr0204 binding pocket is predominantly hydrophobic and closely conforms to DHNA, while that of AtDHNAT1 is more polar and solvent-exposed. Considered in light of the related 4-HBA-CoA thioesterases, these structures indicate that hotdog-fold thioesterases using either an active-site aspartate or glutamate diverged into distinct clades prior to the evolution of strong substrate specificity in these enzymes.
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Quiet eye and choking: online control breaks down at the point of performance failure.
Med Sci Sports Exerc
PUBLISHED: 04-02-2013
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The quiet eye (QE) is a characteristic of highly skilled perceptual and motor performance that has been shown to be sensitive to increases in anxiety. The present study is the first to examine changes in the QE at the precise point of performance failure under heightened anxiety. QE durations were compared for the first, penultimate, and final (missed) putts taken in a pressurized shootout task. To probe the effects of anxiety more specifically, differences in the component of the QE that occurred before (QE-pre), during (QE-online), and after (QE-dwell) putter movement were examined.
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Extracellular chaperones prevent A?42-induced toxicity in rat brains.
Biochim. Biophys. Acta
PUBLISHED: 03-12-2013
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Alzheimers disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, formation of the extracellular amyloid ? (A?42) plaques, neuronal and synapse loss, and activated microglia and astrocytes. Extracellular chaperones, which are known to inhibit amyloid fibril formation and promote clearance of misfolded aggregates, have recently been shown to reduce efficiently the toxicity of HypF-N misfolded oligomers to immortalised cell lines, by binding and clustering them into large species. However, the role of extracellular chaperones on A? oligomer toxicity remains unclear, with reports often appearing contradictory. In this study we microinjected into the hippocampus of rat brains A?42 oligomers pre-incubated for 1h with two extracellular chaperones, namely clusterin and ?2-macroglobulin. The chaperones were found to prevent A?42-induced learning and memory impairments, as assessed by the Morris Water Maze test, and reduce A?42-induced glia inflammation and neuronal degeneration in rat brains, as probed by fluorescent immunohistochemical analyses. Moreover, the chaperones were able to prevent A?42 colocalisation with PSD-95 at post-synaptic terminals of rat primary neurons, suppressing oligomer cytotoxicity. All such effects were not effective by adding pre-formed oligomers and chaperones without preincubation. Molecular chaperones have therefore the potential to prevent the early symptoms of AD, not just by inhibiting A?42 aggregation, as previously demonstrated, but also by suppressing the toxicity of A?42 oligomers after they are formed. These findings elect them as novel neuroprotectors against amyloid-induced injury and excellent candidates for the design of therapeutic strategies against AD.
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Terminology, taxonomy, and facilitation of motor learning in clinical practice: protocol of a delphi study.
JMIR Res Protoc
PUBLISHED: 03-11-2013
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Facilitating motor learning in patients during clinical practice is complex, especially in people with cognitive impairments. General principles of motor learning are available for therapists to use in their practice. However, the translation of evidence from the different fields of motor learning for use in clinical practice is problematic due to lack of uniformity in definition and taxonomy of terms related to motor learning.
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Extracellular chaperones.
Top Curr Chem
PUBLISHED: 03-05-2013
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The maintenance of the levels and correct folding state of proteins (proteostasis) is a fundamental prerequisite for life. Life has evolved complex mechanisms to maintain proteostasis and many of these that operate inside cells are now well understood. The same cannot yet be said of corresponding processes in extracellular fluids of the human body, where inappropriate protein aggregation is known to underpin many serious diseases such as Alzheimers disease, type II diabetes and prion diseases. Recent research has uncovered a growing family of abundant extracellular chaperones in body fluids which appear to selectively bind to exposed regions of hydrophobicity on misfolded proteins to inhibit their toxicity and prevent them from aggregating to form insoluble deposits. These extracellular chaperones are also implicated in clearing the soluble, stabilized misfolded proteins from body fluids via receptor-mediated endocytosis for subsequent lysosomal degradation. Recent work also raises the possibility that extracellular chaperones may play roles in modulating the immune response. Future work will better define the in vivo functions of extracellular chaperones in proteostasis and immunology and pave the way for the development of new treatments for serious diseases.
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Evaluation of Polycyclic Aromatic Hydrocarbons Using Analytical Methods, Toxicology, and Risk Assessment Research: Seafood Safety after a Petroleum Spill as an Example.
Environ. Health Perspect.
PUBLISHED: 02-27-2013
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Polycyclic aromatic hydrocarbons (PAHs) are abundant and widespread environmental chemicals. They are produced naturally and through man-made processes. They are common in organic media including petroleum. Several PAHs are toxic and a subset exhibit carcinogenic activity. PAHs represent a range of chemical structures based on 2 or more benzene rings and depending on their source can exhibit a variety of side modifications resulting from oxygenation, nitrogenation, and alkylation.
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Cerebral venous system and anatomical predisposition to high-altitude headache.
Ann. Neurol.
PUBLISHED: 02-26-2013
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As inspired oxygen availability falls with ascent to altitude, some individuals develop high-altitude headache (HAH). We postulated that HAH results when hypoxia-associated increases in cerebral blood flow occur in the context of restricted venous drainage, and is worsened when cerebral compliance is reduced. We explored this hypothesis in 3 studies.
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Gaze training improves the retention and transfer of laparoscopic technical skills in novices.
Surg Endosc
PUBLISHED: 02-14-2013
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Gaze training is an effective way of training basic laparoscopic skills, resulting in faster acquisition periods and more robust subsequent performance under pressure. The current study is a randomized control trial which examines whether the performance benefits of gaze training stand the test of time (delayed retention) and transfer to more complex skills.
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Legal, Technical, and Interpretational Considerations in the Forensic Analysis of Viruses.
J. Forensic Sci.
PUBLISHED: 02-13-2013
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The forensic evaluation of viruses presents new challenges to the forensic science community. Although many criminal cases have been adjudicated involving the deliberate transmission of viruses, especially HIV, this review provides a general approach to viral forensics, especially in light of significant biodefense challenges. Newly emerging techniques of nucleic acid sequencing are discussed in a forensic context. Human mitochondrial DNA analysis, wherein mixed profiles are routinely assessed in a forensic context, provides the groundwork for an interpretational approach to the issue of mixed DNA sequences. The importance of phylogenetic classification is discussed as both providing an integrated graphical depiction of the structure of viral nucleic acid variation as well as offering a tool that can be used to assess the relatedness of complex populations of nucleic acids.
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On the evolutionary history, population genetics and diversity among isolates of Salmonella Enteritidis PFGE pattern JEGX01.0004.
PLoS ONE
PUBLISHED: 01-30-2013
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Facile laboratory tools are needed to augment identification in contamination events to trace the contamination back to the source (traceback) of Salmonella enterica subsp. enterica serovar Enteritidis (S. Enteritidis). Understanding the evolution and diversity within and among outbreak strains is the first step towards this goal. To this end, we collected 106 new S. Enteriditis isolates within S. Enteriditis Pulsed-Field Gel Electrophoresis (PFGE) pattern JEGX01.0004 and close relatives, and determined their genome sequences. Sources for these isolates spanned food, clinical and environmental farm sources collected during the 2010 S. Enteritidis shell egg outbreak in the United States along with closely related serovars, S. Dublin, S. Gallinarum biovar Pullorum and S. Gallinarum. Despite the highly homogeneous structure of this population, S. Enteritidis isolates examined in this study revealed thousands of SNP differences and numerous variable genes (n?=?366). Twenty-one of these genes from the lineages leading to outbreak-associated samples had nonsynonymous (causing amino acid changes) changes and five genes are putatively involved in known Salmonella virulence pathways. While chromosome synteny and genome organization appeared to be stable among these isolates, genome size differences were observed due to variation in the presence or absence of several phages and plasmids, including phage RE-2010, phage P125109, plasmid pSEEE3072_19 (similar to pSENV), plasmid pOU1114 and two newly observed mobile plasmid elements pSEEE1729_15 and pSEEE0956_35. These differences produced modifications to the assembled bases for these draft genomes in the size range of approximately 4.6 to 4.8 mbp, with S. Dublin being larger (?4.9 mbp) and S. Gallinarum smaller (4.55 mbp) when compared to S. Enteritidis. Finally, we identified variable S. Enteritidis genes associated with virulence pathways that may be useful markers for the development of rapid surveillance and typing methods, potentially aiding in traceback efforts during future outbreaks involving S. Enteritidis PFGE pattern JEGX01.0004.
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Extracellular chaperones and proteostasis.
Annu. Rev. Biochem.
PUBLISHED: 01-23-2013
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There exists a family of currently untreatable, serious human diseases that arise from the inappropriate misfolding and aggregation of extracellular proteins. At present our understanding of mechanisms that operate to maintain proteostasis in extracellular body fluids is limited, but it has significantly advanced with the discovery of a small but growing family of constitutively secreted extracellular chaperones. The available evidence strongly suggests that these chaperones act as both sensors and disposal mediators of misfolded proteins in extracellular fluids, thereby normally protecting us from disease pathologies. It is critically important to further increase our understanding of the mechanisms that operate to effect extracellular proteostasis, as this is essential knowledge upon which to base the development of effective therapies for some of the worlds most debilitating, costly, and intractable diseases.
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Single molecule characterization of the interactions between amyloid-? peptides and the membranes of hippocampal cells.
J. Am. Chem. Soc.
PUBLISHED: 01-22-2013
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Oligomers of the 40 and 42 residue amyloid-? peptides (A?40 and A?42) have been implicated in the neuronal damage and impaired cognitive function associated with Alzheimers disease. However, little is known about the specific mechanisms by which these misfolded species induce such detrimental effects on cells. In this work, we use single-molecule imaging techniques to examine the initial interactions between A? monomers and oligomers and the membranes of live cells. This highly sensitive method enables the visualization of individual A? species on the cell surface and characterization of their oligomerization state, all at biologically relevant, nanomolar concentrations. The results indicate that oligomers preferentially interact with cell membranes, relative to monomers and that the oligomers become immobilized on the cell surface. Additionally, we observe that the interaction of A? species with the cell membrane is inhibited by the presence of ATP-independent molecular chaperones. This study demonstrates the power of this methodology for characterizing the interactions between protein aggregates and the membranes of live neuronal cells at physiologically relevant concentrations and opens the door to quantitative studies of the cellular responses to potentially pathogenic oligomers.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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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.