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1.  β2-Adrenergic agonists augment air pollution–induced IL-6 release and thrombosis 
The Journal of Clinical Investigation  2014;124(7):2935-2946.
Acute exposure to particulate matter (PM) air pollution causes thrombotic cardiovascular events, leading to increased mortality rates; however, the link between PM and cardiovascular dysfunction is not completely understood. We have previously shown that the release of IL-6 from alveolar macrophages is required for a prothrombotic state and acceleration of thrombosis following exposure to PM. Here, we determined that PM exposure results in the systemic release of catecholamines, which engage the β2-adrenergic receptor (β2AR) on murine alveolar macrophages and augment the release of IL-6. In mice, β2AR signaling promoted the development of a prothrombotic state that was sufficient to accelerate arterial thrombosis. In primary human alveolar macrophages, administration of a β2AR agonist augmented IL-6 release, while the addition of a beta blocker inhibited PM-induced IL-6 release. Genetic loss or pharmacologic inhibition of the β2AR on murine alveolar macrophages attenuated PM-induced IL-6 release and prothrombotic state. Furthermore, exogenous β2AR agonist therapy further augmented these responses in alveolar macrophages through generation of mitochondrial ROS and subsequent increase of adenylyl cyclase activity. Together, these results link the activation of the sympathetic nervous system by β2AR signaling with metabolism, lung inflammation, and an enhanced susceptibility to thrombotic cardiovascular events.
PMCID: PMC4071386  PMID: 24865431
2.  Wind Speed during Migration Influences the Survival, Timing of Breeding, and Productivity of a Neotropical Migrant, Setophaga petechia 
PLoS ONE  2014;9(5):e97152.
Over the course of the annual cycle, migratory bird populations can be impacted by environmental conditions in regions separated by thousands of kilometers. We examine how climatic conditions during discrete periods of the annual cycle influence the demography of a nearctic-neotropical migrant population of yellow warblers (Setophaga petechia), that breed in western Canada and overwinter in Mexico. We demonstrate that wind conditions during spring migration are the best predictor of apparent annual adult survival, male arrival date, female clutch initiation date and, via these timing effects, annual productivity. We find little evidence that conditions during the wintering period influence breeding phenology and apparent annual survival. Our study emphasizes the importance of climatic conditions experienced by migrants during the migratory period and indicates that geography may play a role in which period most strongly impacts migrant populations.
PMCID: PMC4020938  PMID: 24828427
3.  Individual quality explains association between plumage colouration, arrival dates and mate acquisition in yellow warblers (Setophaga petechia) 
BMC Ecology  2014;14:13.
In many bird species colour traits influence social dominance and breeding success. In our study we first evaluated whether the colour of the basic plumage (tail feathers grown at the end of the breeding season), that provides an index of individual quality, influenced winter habitat use by yellow warblers. We then evaluated whether winter habitat use (inferred using δ13C and δ15N signatures of winter grown greater-coverts) influenced alternate plumage colouration, after controlling for individual quality using basic plumage colouration. Finally, we investigated whether basic and alternate plumage colouration influenced arrival dates, mate acquisition, breeding phenology and reproductive success of yellow warblers breeding in southern (Revelstoke, B.C.) and arctic (Inuvik, N.W.T.) Canada.
The colour (chroma and hue) of tail feathers, grown on the breeding grounds, was not related to subsequent winter habitat use. Greater covert and tail feather colour (chroma and hue) were correlated, suggesting genetics and/or individual quality played a role in pigment deposition. After controlling for individual difference in tail colour, δ13C values did not explain any variation in greater covert colour, but birds with high δ15N signatures had greater coverts with higher chroma. Male arrival dates varied with tail chroma in Revelstoke and tail hue in Inuvik. Males that arrived early paired with older and/or more colourful mates that initiated clutches earlier, and at one site (Revelstoke) were more likely to fledge young. In addition, in Revelstoke (but not Inuvik) males with high tail hue also acquired more colourful mates. In contrast, after controlling for individual differences in tail colour, greater covert colour did not affect male arrival date, the quality of the mate obtained or reproductive success in either population.
Our results suggest that plumage colour effects on breeding phenology and mate acquisition result from differences in the intrinsic quality of individuals rather than a carry-over effect of winter habitat use.
PMCID: PMC4024118  PMID: 24886073
Carry-over effects; Seasonal interactions; Breeding phenology; Plumage colour; Carotenoid-based colouration; Yellow warbler; American redstart
4.  Cognitive control for language switching in bilinguals: A quantitative meta-analysis of functional neuroimaging studies 
Language and cognitive processes  2011;27(10):1479-1488.
In a quantitative meta-analysis, using the activation likelihood estimation method, we examined the neural regions involved in bilingual cognitive control, particularly when engaging in switching between languages. The purpose of this study was to evaluate the bilingual cognitive control model based on a qualitative analysis [Abutalebi, J., & Green, D. W. (2008). Control mechanisms in bilingual language production: Neural evidence from language switching studies. Language and Cognitive Processes, 23, 557–582.]. After reviewing 128 peer-reviewed articles, ten neuroimaging studies met our inclusion criteria and in each study, bilinguals switched between languages in response to cues. We isolated regions involved in voluntary language switching, by including reported contrasts between the switching conditions and high level baseline conditions involving similar tasks but requiring the use of only one language. Eight brain regions showed significant and reliable activation: left inferior frontal gyrus, left middle temporal gyrus, left middle frontal gyrus, right precentral gyrus, right superior temporal gyrus, midline pre-SMA and bilateral caudate nuclei. This quantitative result is consistent with bilingual aphasia studies that report switching deficits associated with lesions to the caudate nuclei or prefrontal cortex. It also extends the previously reported qualitative model. We discuss the implications of the findings for accounts of bilingual cognitive control.
PMCID: PMC4006828  PMID: 24795491 CAMSID: cams2989
bilingualism; meta-analysis; functional neuroimaging; cognitive control; language switching
5.  Evolving Marine Biomimetics for Regenerative Dentistry 
Marine Drugs  2014;12(5):2877-2912.
New products that help make human tissue and organ regeneration more effective are in high demand and include materials, structures and substrates that drive cell-to-tissue transformations, orchestrate anatomical assembly and tissue integration with biology. Marine organisms are exemplary bioresources that have extensive possibilities in supporting and facilitating development of human tissue substitutes. Such organisms represent a deep and diverse reserve of materials, substrates and structures that can facilitate tissue reconstruction within lab-based cultures. The reason is that they possess sophisticated structures, architectures and biomaterial designs that are still difficult to replicate using synthetic processes, so far. These products offer tantalizing pre-made options that are versatile, adaptable and have many functions for current tissue engineers seeking fresh solutions to the deficiencies in existing dental biomaterials, which lack the intrinsic elements of biofunctioning, structural and mechanical design to regenerate anatomically correct dental tissues both in the culture dish and in vivo.
PMCID: PMC4052322  PMID: 24828293
regenerative dentistry; biomimetics; marine invertebrates; bone; dentine
6.  Inspiratory High Frequency Airway Oscillation Attenuates Resistive Loaded Dyspnea and Modulates Respiratory Function in Young Healthy Individuals 
PLoS ONE  2014;9(3):e91291.
Direct chest-wall percussion can reduce breathlessness in Chronic Obstructive Pulmonary Disease and respiratory function may be improved, in health and disease, by respiratory muscle training (RMT). We tested whether high-frequency airway oscillation (HFAO), a novel form of airflow oscillation generation can modulate induced dyspnoea and respiratory strength and/or patterns following 5 weeks of HFAO training (n = 20) compared to a SHAM-RMT (conventional flow-resistive RMT) device (n = 15) in healthy volunteers (13 males; aged 20–36 yrs). HFAO causes oscillations with peak-to-peak amplitude of 1 cm H2O, whereas the SHAM-RMT device was identical but created no pressure oscillation. Respiratory function, dyspnoea and ventilation during 3 minutes of spontaneous resting ventilation, 1 minute of maximal voluntary hyperventilation and 1 minute breathing against a moderate inspiratory resistance, were compared PRE and POST 5-weeks of training (2×30 breaths at 70% peak flow, 5 days a week). Training significantly reduced NRS dyspnoea scores during resistive loaded ventilation, both in the HFAO (p = 0.003) and SHAM-RMT (p = 0.005) groups. Maximum inspiratory static pressure (cm H2O) was significantly increased by HFAO training (vs. PRE; p<0.001). Maximum inspiratory dynamic pressure was increased by training in both the HFAO (vs. PRE; p<0.001) and SHAM-RMT (vs. PRE; p = 0.021) groups. Peak inspiratory flow rate (L.s−1) achieved during the maximum inspiratory dynamic pressure manoeuvre increased significantly POST (vs. PRE; p = 0.001) in the HFAO group only. HFAO reduced inspiratory resistive loading–induced dyspnoea and augments static and dynamic maximal respiratory manoeuvre performance in excess of flow-resistive IMT (SHAM-RMT) in healthy individuals without the respiratory discomfort associated with RMT.
PMCID: PMC3961233  PMID: 24651392
7.  RCP-driven α5β1 recycling suppresses Rac and promotes RhoA activity via the RacGAP1–IQGAP1 complex 
The Journal of Cell Biology  2013;202(6):917-935.
RCP-driven α5β1 recycling suppresses Rac activity through the RacGAP1–IQGAP1 complex to permit local activation of RhoA and drive invasive migration.
Inhibition of αvβ3 or expression of mutant p53 promotes invasion into fibronectin (FN)-containing extracellular matrix (ECM) by enhancing Rab-coupling protein (RCP)–dependent recycling of α5β1 integrin. RCP and α5β1 cooperatively recruit receptor tyrosine kinases, including EGFR1, to regulate their trafficking and downstream signaling via protein kinase B (PKB)/Akt, which, in turn, promotes invasive migration. In this paper, we identify a novel PKB/Akt substrate, RacGAP1, which is phosphorylated as a consequence of RCP-dependent α5β1 trafficking. Phosphorylation of RacGAP1 promotes its recruitment to IQGAP1 at the tips of invasive pseudopods, and RacGAP1 then locally suppresses the activity of the cytoskeletal regulator Rac and promotes the activity of RhoA in this subcellular region. This Rac to RhoA switch promotes the extension of pseudopodial processes and invasive migration into FN-containing matrices, in a RhoA-dependent manner. Thus, the localized endocytic trafficking of α5β1 within the tips of invasive pseudopods elicits signals that promote the reorganization of the actin cytoskeleton, protrusion, and invasion into FN-rich ECM.
PMCID: PMC3776348  PMID: 24019536
8.  13-Year Long-Term Associations between Changes in Traditional Cardiovascular Risk Factors and Changes in Fibrinogen Levels: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Atherosclerosis  2012;226(1):214-219.
Cross-sectional and prospective studies have linked cardiovascular events and traditional risk factors (TRFs) with higher plasma fibrinogen levels. In a young cohort, we sought to determine longitudinal associations between changes in/development of TRFs and fibrinogen levels over 13 years.
We included 2525 adults from the CARDIA study, aged 25-37 with fibrinogen and TRFs measured at year 7 (study baseline; 1992-1993); and year 20 (follow-up). Multiple linear regressions were used to compare mean changes in fibrinogen to TRFs.
Mean fibrinogen increased by 71mg/dL vs. 70mg/dL (p=NS) in black vs. white men, and 78mg/dL vs. 68mg/dL (p<0.05) in black vs. white women, respectively over 13 years. After multivariable adjustments, fibrinogen generally rose with increasing BMI (p<0.001; all sex/race groups), LDL-cholesterol, log triglycerides and diastolic blood pressure; and fell with increasing HDL-cholesterol and physical activity. 13-year increase in fibrinogen for persons who quit smoking or became non-obese were comparable (p=NS) to that of never-smokers and never-obese persons.
Among young black and white men and women with few baseline cardiovascular risk factors, fibrinogen tracked longitudinally with changes in TRFs over 13 years through middle-age. There was a strong inverse longitudinal relationship between modifiable risk factors (weight loss/smoking cessation) and 13-year change in fibrinogen. Our study helps provide some insight into the role of fibrinogen as a disease marker in the associations between fibrinogen and CVD.
PMCID: PMC3529787  PMID: 23177973
Fibrinogen; risk factors; cardiovascular disease prevention; obesity; smoking; sex; race
9.  Sensory-to-motor integration during auditory repetition: a combined fMRI and lesion study 
The aim of this paper was to investigate the neurological underpinnings of auditory-to-motor translation during auditory repetition of unfamiliar pseudowords. We tested two different hypotheses. First we used functional magnetic resonance imaging in 25 healthy subjects to determine whether a functionally defined area in the left temporo-parietal junction (TPJ), referred to as Sylvian-parietal-temporal region (Spt), reflected the demands on auditory-to-motor integration during the repetition of pseudowords relative to a semantically mediated nonverbal sound-naming task. The experiment also allowed us to test alternative accounts of Spt function, namely that Spt is involved in subvocal articulation or auditory processing that can be driven either bottom-up or top-down. The results did not provide convincing evidence that activation increased in either Spt or any other cortical area when non-semantic auditory inputs were being translated into motor outputs. Instead, the results were most consistent with Spt responding to bottom up or top down auditory processing, independent of the demands on auditory-to-motor integration. Second, we investigated the lesion sites in eight patients who had selective difficulties repeating heard words but with preserved word comprehension, picture naming and verbal fluency (i.e., conduction aphasia). All eight patients had white-matter tract damage in the vicinity of the arcuate fasciculus and only one of the eight patients had additional damage to the Spt region, defined functionally in our fMRI data. Our results are therefore most consistent with the neurological tradition that emphasizes the importance of the arcuate fasciculus in the non-semantic integration of auditory and motor speech processing.
PMCID: PMC3908611  PMID: 24550807
fMRI; lesions; language; speech; aphasia
10.  Dissecting the functional anatomy of auditory word repetition 
This fMRI study used a single, multi-factorial, within-subjects design to dissociate multiple linguistic and non-linguistic processing areas that are all involved in repeating back heard words. The study compared: (1) auditory to visual inputs; (2) phonological to non-phonological inputs; (3) semantic to non-semantic inputs; and (4) speech production to finger-press responses. The stimuli included words (semantic and phonological inputs), pseudowords (phonological input), pictures and sounds of animals or objects (semantic input), and colored patterns and hums (non-semantic and non-phonological). The speech production tasks involved auditory repetition, reading, and naming while the finger press tasks involved one-back matching. The results from the main effects and interactions were compared to predictions from a previously reported functional anatomical model of language based on a meta-analysis of many different neuroimaging experiments. Although many findings from the current experiment replicated many of those predicted, our within-subject design also revealed novel results by providing sufficient anatomical precision to dissect several different regions within the anterior insula, pars orbitalis, anterior cingulate, SMA, and cerebellum. For example, we found one part of the pars orbitalis was involved in phonological processing and another in semantic processing. We also dissociated four different types of phonological effects in the left superior temporal sulcus (STS), left putamen, left ventral premotor cortex, and left pars orbitalis. Our findings challenge some of the commonly-held opinions on the functional anatomy of language, and resolve some previously conflicting findings about specific brain regions—and our experimental design reveals details of the word repetition process that are not well captured by current models.
PMCID: PMC4018561  PMID: 24834043
fMRI; language; auditory word repetition
11.  Carbohydrate recognition by the antiviral lectin cyanovirin-N 
Journal of the American Chemical Society  2012;134(48):19639-19651.
Cyanovirin-N is a cyanobacterial lectin with potent antiviral activity, and has been the focus of extensive pre-clinical investigation as a potential prophylactic for the prevention of the sexual transmission of the human immunodeficiency virus (HIV). Here we present a detailed analysis of carbohydrate recognition by this important protein, using a combination of computational methods, including extensive molecular dynamics simulations and Molecular-Mechanics/ Poisson–Boltzmann/Surface-Area (MM/PBSA) energetic analysis. The simulation results strongly suggest that the observed tendency of wildtype CVN to form domain-swapped dimers is the result of a previously unidentified cis-peptide bond present in the monomeric state. The energetic analysis additionally indicates that the highest-affinity ligand for CVN characterized to date (α-Man-(1,2)-α-Man-(1,2)-α-Man) is recognized asymmetrically by the two binding sites. Finally, we are able to provide a detailed map of the role of all binding site functional groups (both backbone and side chain) to various aspects of molecular recognition: general affinity for cognate ligands, specificity for distinct oligosaccharide targets and the asymmetric recognition of α-Man-(1,2)-α-Man-(1,2)-α-Man. Taken as a whole, these results complement past experimental characterization (both structural and thermodynamic) to provide the most complete understanding of carbohydrate recognition by CVN to date. The results also provide strong support for the application of similar approaches to the understanding of other protein–carbohydrate complexes.
PMCID: PMC3531799  PMID: 23057413
molecular recognition; glycobiology; continuum electrostatics; virucide; microbicide; protein therapeutics; biotherapeutics
12.  Hypoxia Mediates Mutual Repression between microRNA-27a and PPARγ in the Pulmonary Vasculature 
PLoS ONE  2013;8(11):e79503.
Pulmonary hypertension (PH) is a serious disorder that causes significant morbidity and mortality. The pathogenesis of PH involves complex derangements in multiple pathways including reductions in peroxisome proliferator-activated receptor gamma (PPARγ). Hypoxia, a common PH stimulus, reduces PPARγ in experimental models. In contrast, activating PPARγ attenuates hypoxia-induced PH and endothelin 1 (ET-1) expression. To further explore mechanisms of hypoxia-induced PH and reductions in PPARγ, we examined the effects of hypoxia on selected microRNA (miRNA or miR) levels that might reduce PPARγ expression leading to increased ET-1 expression and PH. Our results demonstrate that exposure to hypoxia (10% O2) for 3-weeks increased levels of miR-27a and ET-1 in the lungs of C57BL/6 mice and reduced PPARγ levels. Hypoxia-induced increases in miR-27a were attenuated in mice treated with the PPARγ ligand, rosiglitazone (RSG, 10 mg/kg/d) by gavage for the final 10 d of exposure. In parallel studies, human pulmonary artery endothelial cells (HPAECs) were exposed to control (21% O2) or hypoxic (1% O2) conditions for 72 h. Hypoxia increased HPAEC proliferation, miR-27a and ET-1 expression, and reduced PPARγ expression. These alterations were attenuated by treatment with RSG (10 µM) during the last 24 h of hypoxia exposure. Overexpression of miR-27a or PPARγ knockdown increased HPAEC proliferation and ET-1 expression and decreased PPARγ levels, whereas these effects were reversed by miR-27a inhibition. Further, compared to lungs from littermate control mice, miR-27a levels were upregulated in lungs from endothelial-targeted PPARγ knockout (ePPARγ KO) mice. Knockdown of either SP1 or EGR1 was sufficient to significantly attenuate miR-27a expression in HPAECs. Collectively, these studies provide novel evidence that miR-27a and PPARγ mediate mutually repressive actions in hypoxic pulmonary vasculature and that targeting PPARγ may represent a novel therapeutic approach in PH to attenuate proliferative mediators that stimulate proliferation of pulmonary vascular cells.
PMCID: PMC3828382  PMID: 24244514
13.  The Nox4 Inhibitor GKT137831 Attenuates Hypoxia-Induced Pulmonary Vascular Cell Proliferation 
Increased NADP reduced (NADPH) oxidase 4 (Nox4) and reduced expression of the nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) contribute to hypoxia-induced pulmonary hypertension (PH). To examine the role of Nox4 activity in pulmonary vascular cell proliferation and PH, the current study used a novel Nox4 inhibitor, GKT137831, in hypoxia-exposed human pulmonary artery endothelial or smooth muscle cells (HPAECs or HPASMCs) in vitro and in hypoxia-treated mice in vivo. HPAECs or HPASMCs were exposed to normoxia or hypoxia (1% O2) for 72 hours with or without GKT137831. Cell proliferation and Nox4, PPARγ, and transforming growth factor (TGF)β1 expression were measured. C57Bl/6 mice were exposed to normoxia or hypoxia (10% O2) for 3 weeks with or without GKT137831 treatment during the final 10 days of exposure. Lung PPARγ and TGF-β1 expression, right ventricular hypertrophy (RVH), right ventricular systolic pressure (RVSP), and pulmonary vascular remodeling were measured. GKT137831 attenuated hypoxia-induced H2O2 release, proliferation, and TGF-β1 expression and blunted reductions in PPARγ in HPAECs and HPASMCs in vitro. In vivo GKT137831 inhibited hypoxia-induced increases in TGF-β1 and reductions in PPARγ expression and attenuated RVH and pulmonary artery wall thickness but not increases in RVSP or muscularization of small arterioles. This study shows that Nox4 plays a critical role in modulating proliferative responses of pulmonary vascular wall cells. Targeting Nox4 with GKT137831 provides a novel strategy to attenuate hypoxia-induced alterations in pulmonary vascular wall cells that contribute to vascular remodeling and RVH, key features involved in PH pathogenesis.
PMCID: PMC3547100  PMID: 22904198
rosiglitazone; PPARγ; TGF-β; pulmonary hypertension
14.  Ionic Strength Effects on Amyloid Formation by Amylin Are a Complicated Interplay between Debye Screening, Ion Selectivity, and Hofmeister Effects 
Biochemistry  2012;51(43):8478-8490.
Amyloid formation plays a role in a wide range of human diseases. The rate and extent of amyloid formation depends on solution conditions including pH and ionic strength. Amyloid fibrils often adopt structures with parallel, in-register β-sheets, which generate quasi-infinite arrays of aligned side chains. These arrangements can lead to significant electrostatic interactions between adjacent polypeptide chains. The effect of ionic strength and ion composition on the kinetics of amyloid formation by islet amyloid polypeptide (IAPP) is examined. IAPP is a basic 37-residue polypeptide responsible for islet amyloid formation in type 2 diabetes. Poisson–Boltzmann calculations revealed significant electrostatic repulsion in a model of the IAPP fibrillar state. The kinetics of IAPP amyloid formation are strongly dependent on ionic strength, varying by more than a factor of 10 over the range of 20 to 600 mM NaCl at pH 8.0, but the effect is not entirely due to Debye screening. At low ionic strength the rate depends strongly on the identity of the anion, nearly varying by a factor of four and scales with the electroselectivity series, implicating anion binding. At high ionic strength the rate varies by only 8% and scales with the Hofmeister series. At intermediate ionic strength no clear trend is detected, likely because of convolution of different effects. The effects of salts on the growth phase and lag phase of IAPP amyloid formation are strongly correlated. At pH 5.5, where the net charge on IAPP is larger, the effect of different anions scales with the electroselectivity series at all salt concentrations.
PMCID: PMC3753197  PMID: 23016872
Amyloid; Amylin; Debye–Hückel; electroselectivity series; Hofmeister effect; ionic strength; IAPP; Poisson–Boltzmann
15.  Computer/gaming station use in youth: Correlations among use, addiction and functional impairment 
Paediatrics & Child Health  2012;17(8):427-431.
Computer/gaming station use is ubiquitous in the lives of youth today. Overuse is a concern, but it remains unclear whether problems arise from addictive patterns of use or simply excessive time spent on use. The goal of the present study was to evaluate computer/gaming station use in youth and to examine the relationship between amounts of use, addictive features of use and functional impairment.
A total of 110 subjects (11 to 17 years of age) from local schools participated. Time spent on television, video gaming and non-gaming recreational computer activities was measured. Addictive features of computer/gaming station use were ascertained, along with emotional/behavioural functioning. Multiple linear regressions were used to understand how youth functioning varied with time of use and addictive features of use.
Mean (± SD) total screen time was 4.5±2.4 h/day. Addictive features of use were consistently correlated with functional impairment across multiple measures and informants, whereas time of use, after controlling for addiction, was not.
Youth are spending many hours each day in front of screens. In the absence of addictive features of computer/gaming station use, time spent is not correlated with problems; however, youth with addictive features of use show evidence of poor emotional/ behavioural functioning.
PMCID: PMC3474382  PMID: 24082802
Adolescence; Computer addiction; Internet addiction; Video games
17.  The maintenance of sex: Ronald Fisher meets the Red Queen 
Sex in higher diploids carries a two-fold cost of males that should reduce its fitness relative to cloning, and result in its extinction. Instead, sex is widespread and clonal species face early obsolescence. One possible reason is that sex is an adaptation that allows organisms to respond more effectively to endless changes in their environment. The purpose of this study was to model mutation and selection in a diploid organism in an evolving environment and ascertain their support for sex.
We used a computational approach to model finite populations where a haploid environment subjects a diploid host to endlessly evolving change. Evolution in both populations is primarily through adoption of novel advantageous mutations within a large allele space. Sex outcompetes cloning by two complementary mechanisms. First, sexual diploids adopt advantageous homozygous mutations more rapidly than clonal ones under conditions of lag load (the gap between the actual adaptation of the diploid population and its theoretical optimum). This rate advantage can offset the higher fecundity of cloning. Second, a relative advantage to sex emerges where populations are significantly polymorphic, because clonal polymorphism runs the risk of clonal interference caused by selection on numerous lines of similar adaptation. This interference extends allele lifetime and reduces the rate of adaptation. Sex abolishes the interference, making selection faster and elevating population fitness. Differences in adaptation between sexual and clonal populations increase markedly with the number of loci under selection, the rate of mutation in the host, and a rapidly evolving environment. Clonal interference in these circumstances leads to conditions where the greater fecundity of clones is unable to offset their poor adaptation. Sexual and clonal populations then either co-exist, or sex emerges as the more stable evolutionary strategy.
Sex can out-compete clones in a rapidly evolving environment, such as that characterized by pathogens, where clonal interference reduces the adaptation of clonal populations and clones adopt advantageous mutations more slowly. Since all organisms carry parasitic loads, the model is of potentially general applicability.
PMCID: PMC3765275  PMID: 23962342
Maintenance of sex; Advantageous mutation; Frequency-dependent selection; Red Queen; Computational model
18.  Auditory–motor interactions for the production of native and non-native speech 
During speech production, auditory processing of self-generated speech is used to adjust subsequent articulations. The current study investigated how the proposed auditory–motor interactions are manifest at the neural level in native and non-native speakers of English who were overtly naming pictures of objects and reading their written names. Data were acquired with fMRI and analysed with dynamic causal modelling (DCM). We found that: (1) higher activity in articulatory regions caused activity in auditory regions to decrease (i.e., auditory suppression); and (2) higher activity in auditory regions caused activity in articulatory regions to increase (i.e., auditory feedback). In addition, we were able to demonstrate that: (3) speaking in a non-native language involves more auditory feedback and less auditory suppression than speaking in a native language. The difference between native and non-native speakers was further supported by finding that, within non-native speakers, there was less auditory feedback for those with better verbal fluency. Consequently, the networks of more fluent non-native speakers looked more like those of native speakers. Together, these findings provide a foundation on which to explore auditory–motor interactions during speech production in other human populations, particularly those with speech difficulties.
PMCID: PMC3593607  PMID: 23392667
19.  Effect of Orthostasis on Endothelial Function: A Gender Comparative Study 
PLoS ONE  2013;8(8):e71655.
As the vascular endothelium has multiple functions, including regulation of vascular tone, it may play a role in the pathophysiology of orthostatic intolerance. We investigated the effect of orthostasis on endothelial function using EndoPAT®, a non-invasive and user-independent method, and across gender. As sex steroid hormones are known to affect endothelial function, this study examined the potential effect of these hormones on the endothelial response to orthostasis by including females at different phases of the menstrual cycle (follicular and luteal—where the hormone balance differs), and females taking an oral contraceptive. A total of 31 subjects took part in this study (11 males, 11 females having normal menstrual cycles and 9 females taking oral contraceptive). Each subject made two visits for testing; in the case of females having normal menstrual cycles the first session was conducted either 1–7 (follicular) or 14–21 days (luteal) after the start of menstruation, and the second session two weeks later, i.e., during the other phase, respectively. Endothelial function was assessed at baseline and following a 20-min orthostatic challenge (active standing). The EndoPAT® index increased from 1.71 ± 0.09 (mean ± SEM) at baseline to 2.07 ± 0.09 following orthostasis in females (p<0.001). In males, the index increased from 1.60 ± 0.08 to 1.94 ± 0.13 following orthostasis (p<0.001). There were no significant differences, however, in the endothelial response to orthostasis between females and males, menstrual cycle phases and the usage of oral contraceptive. Our results suggest an increased vasodilatatory endothelial response following orthostasis in both females and males. The effect of gender and sex hormones on the endothelial response to orthostasis appears limited. Further studies are needed to determine the potential role of this post orthostasis endothelial response in the pathophysiology of orthostatic intolerance.
PMCID: PMC3798144  PMID: 24147147
20.  Long-term change in alcohol-consumption status and variations in fibrinogen levels: the coronary artery risk development in young adults (CARDIA) study 
BMJ Open  2013;3(7):e002944.
To examine long-term associations between change in alcohol-consumption status and cessation of alcohol use, and fibrinogen levels in a large, young, biracial cohort.
Analysis of covariance models were used to analyse participants within the Coronary Artery Risk Development in Young Adults Study (CARDIA) cohort who had fibrinogen and alcohol use data at year 7 (1992–1993; ages 25–37) and year 20 examinations.
4 urban US cities.
2520 men and women within the CARDIA cohort.
Main outcome measures
13-year changes in alcohol use related to changes in fibrinogen.
Over 13 years, mean fibrinogen increased by 71 vs 70 mg/dL (p=NS) in black men (BM) versus white men (WM), and 78 vs 68 mg/dL (p<0.05) in black women (BW) versus white women (WW), respectively. Compared with never-drinkers, there were smaller longitudinal increases in fibrinogen for BM, BW and WW (but a larger increase in WM) who became or stayed drinkers, after multivariable adjustment. For BM, WM and WW, fibrinogen increased the most among persons who quit drinking over 13 years (p<0.001 for WM (fibrinogen increase=86.5 (7.1) (mean (SE))), compared with never-drinkers (fibrinogen increase=53.1 (5.4)).
In this young cohort, compared with the participants who never drank, those who became/stayed drinkers had smaller increases, while those who quit drinking had the highest increase in fibrinogen over 13 years of follow-up. The results provide a novel insight into the mechanism for the established protective effect of moderate alcohol intake on cardiovascular disease outcomes.
PMCID: PMC3710982  PMID: 23847267
Epidemiology; Preventive Medicine
21.  Will Working Memory Training Generalize to Improve Off-Task Behavior in Children with Attention-Deficit/Hyperactivity Disorder? 
Neurotherapeutics  2012;9(3):639-648.
Computerized working memory and executive function training programs designed to target specific impairments in executive functioning are becoming increasingly available, yet how well these programs generalize to improve functional deficits in disorders, such as attention-deficit/hyperactivity disorder (ADHD), beyond the training context is not well-established. The aim of this study was to examine the extent to which working memory (WM) training in children with ADHD would diminish a core dysfunctional behavior associated with the disorder, “off-task” behavior during academic task performance. The effect of computerized WM training (adaptive) was compared to a placebo condition (nonadaptive) in a randomized, double-blind, placebo-controlled design in 26 children (18 males; age, 7 to 14 years old) diagnosed with ADHD. Participants completed the training in approximately 25 sessions. The Restricted Academic Situations Task (RAST) observational system was used to assess aspects of off-task behavior during the completion of an academic task. Traditional measures of ADHD symptoms (Conners’ Parent Rating Scale) and WM ability (standardized WM tests) were also collected. WM training led to significant reductions in off-task ADHD-associated behavior on the RAST system and improvement on WM tests. There were no significant differences between groups in improvement on parent rating scales. Findings lend insight into the generalizability of the effects of WM training and the relation between deficits in WM and off-task behavioral components of ADHD. These preliminary data suggest WM training may provide a mechanism for indirectly altering academic performance in children with ADHD.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0124-y) contains supplementary material, which is available to authorized users.
PMCID: PMC3441930  PMID: 22752960
Attention; academic behavior; treatment; RAST; children; ADHD; cognitive training.
22.  Polycyclovorans algicola gen. nov., sp. nov., an Aromatic-Hydrocarbon-Degrading Marine Bacterium Found Associated with Laboratory Cultures of Marine Phytoplankton 
A strictly aerobic, halotolerant, rod-shaped bacterium, designated strain TG408, was isolated from a laboratory culture of the marine diatom Skeletonema costatum (CCAP1077/1C) by enrichment with polycyclic aromatic hydrocarbons (PAHs) as the sole carbon source. 16S rRNA gene sequence analysis placed this organism within the order Xanthomonadales of the class Gammaproteobacteria. Its closest relatives included representatives of the Hydrocarboniphaga-Nevskia-Sinobacter clade (<92% sequence similarity) in the family Sinobacteraceae. The strain exhibited a narrow nutritional spectrum, preferring to utilize aliphatic and aromatic hydrocarbon compounds and small organic acids. Notably, it displayed versatility in degrading two- and three-ring PAHs. Moreover, catechol 2,3-dioxygenase activity was detected in lysates, indicating that this strain utilizes the meta-cleavage pathway for aromatic compound degradation. Cells produced surface blebs and contained a single polar flagellum. The predominant isoprenoid quinone of strain TG408 was Q-8, and the dominant fatty acids were C16:0, C16:1 ω7c, and C18:1 ω7c. The G+C content of the isolate's DNA was 64.3 mol% ± 0.34 mol%. On the basis of distinct phenotypic and genotypic characteristics, strain TG408 represents a novel genus and species in the class Gammaproteobacteria for which the name Polycyclovorans algicola gen. nov., sp. nov., is proposed. Quantitative PCR primers targeting the 16S rRNA gene of this strain were developed and used to show that this organism is found associated with other species of marine phytoplankton. Phytoplankton may be a natural biotope in the ocean where new species of hydrocarbon-degrading bacteria await discovery and which contribute significantly to natural remediation processes.
PMCID: PMC3536080  PMID: 23087039
23.  Using bispectral index and cerebral oximetry to guide hemodynamic therapy in high-risk surgical patients 
High-risk surgery represents 12.5% of cases but contributes 80% of deaths in the elderly population. Reduction in morbidity and mortality by the use of intervention strategies could result in thousands of lives being saved and savings of up to £400m per annum in the UK. This has resulted in the drive towards goal-directed therapy and intraoperative flow optimization of high-risk surgical patients being advocated by authorities such as the National Institute of Health and Care Excellence and the Association of Anaesthetists of Great Britain and Ireland.
Conventional intraoperative monitoring gives little insight into the profound physiological changes occurring as a result of anesthesia and surgery. The build-up of an oxygen debt is associated with a poor outcome and strategies have been developed in the postoperative period to improve outcomes by repayment of this debt. New monitoring technologies such as minimally invasive cardiac output, depth of anesthesia and cerebral oximetry can minimize oxygen debt build-up. This has the potential to reduce complications and lessen the need for postoperative optimization in high-dependency areas.
Flow monitoring has thus emerged as essential during intraoperative monitoring in high-risk surgery. However, evidence suggests that current optimization strategies of deliberately increasing flow to meet predefined targets may not reduce mortality.
Could the addition of depth of anesthesia and cerebral and tissue oximetry monitoring produce a further improvement in outcomes?
Retrospective studies indicate a combination of excessive depth of anesthesia hypotension and low anesthesia requirement results in increased mortality and length of hospital stay.
Near infrared technology allows assessment and maintenance of cerebral and tissue oxygenation, a strategy, which has been associated with improved outcomes. The suggestion that the brain is an index organ for tissue oxygenation, especially in the elderly, indicates a role for this technology in the intraoperative period to assess the adequacy of oxygen delivery and reduce the build-up of an oxygen debt.
The aim of this article is to make the case for depth of anesthesia and cerebral oximetry alongside flow monitoring as a strategy for reducing oxygen debt during high-risk surgery and further improve outcomes in high-risk surgical patients.
PMCID: PMC3964341  PMID: 24472198
BIS; Depth of anesthesia; Cardiac output monitoring; Cerebral oximetry; Triple low; LiDCOrapid; Intraoperative optimization; Goal-directed therapy
24.  Choice of Cell Source in Cell-Based Therapies for Retinal Damage due to Age-Related Macular Degeneration: A Review 
Journal of Ophthalmology  2013;2013:465169.
Background. Age-related macular degeneration (AMD) is a complex disorder that affects primarily the macula involving the retinal pigment epithelium (RPE) but also to a certain extent the photoreceptor layer and the retinal neurons. Cell transplantation is a promising option for AMD and clinical trials are underway using different cell types. Methods. We hypothesize that instead of focusing on a particular cell source for concurrent regeneration of all the retinal layers and also to prevent exhaustive research on an array of cell sources for regeneration of each layer, the choice should depend on, precisely, which layer is damaged. Results. Thus, for a damage limited to the retinal pigment epithelial (RPE) layer, the choice we suggest would be RPE cells. When the damage extends to rods and cones, the choice would be bone marrow stem cells and when retinal neurons are involved, relatively immature stem cell populations with an inherent capacity to yield neuronal lineage such as hematopoietic stem cells, embryonic stem cells, or induced pluripotent stem cells can be tried. Conclusion. This short review will prove to be a valuable guideline for those working on cell therapy for AMD to plan their future directions of research and therapy for this condition.
PMCID: PMC3654320  PMID: 23710332
25.  A Therapeutic Potential for Marine Skeletal Proteins in Bone Regeneration 
Marine Drugs  2013;11(4):1203-1220.
A vital ingredient for engineering bone tissue, in the culture dish, is the use of recombinant matrix and growth proteins to help accelerate the growth of cultivated tissues into clinically acceptable quantities. The skeletal organic matrices of calcifying marine invertebrates are an untouched potential source of such growth inducing proteins. They have the advantage of being ready-made and retain the native state of the original protein. Striking evidence shows that skeleton building bone morphogenic protein-2/4 (BMP) and transforming growth factor beta (TGF-β) exist within various marine invertebrates such as, corals. Best practice mariculture and the latest innovations in long-term marine invertebrate cell cultivation can be implemented to ensure that these proteins are produced sustainably and supplied continuously. This also guarantees that coral reef habitats are not damaged during the collection of specimens. Potential proteins for bone repair, either extracted from the skeleton or derived from cultivated tissues, can be identified, evaluated and retrieved using chromatography, cell assays and proteomic methods. Due to the current evidence for bone matrix protein analogues in marine invertebrates, together with the methods established for their production and retrieval there is a genuine prospect that they can be used to regenerate living bone for potential clinical use.
PMCID: PMC3705399  PMID: 23574983
proteomics; bone tissue engineering; mesenchymal stem cells; marine invertebrate skeletons; bone matrix proteins

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