The Ordered Extension of Pseudopodia by Amoeboid Cells in the Absence of External Cues

Eukaryotic cells extend pseudopodia for movement. In the absence of external cues, cells move in random directions, but with a strong element of persistence that keeps them moving in the same direction Persistence allows cells to disperse over larger areas and is instrumental to enter new environments where spatial cues can lead the cell. Here we explore cell movement by analyzing the direction, size and timing of ∼2000 pseudopodia that are extended by Dictyostelium cells. The results show that pseudpopod are extended perpendicular to the surface curvature at the place where they emerge. The location of new pseudopods is not random but highly ordered. Two types of pseudopodia may be formed: frequent splitting of an existing pseudopod, or the occasional extension of a de novo pseudopod at regions devoid of recent pseudopod activity. Split-pseudopodia are extended at ∼60 degrees relative to the previous pseudopod, mostly as alternating Right/Left/Right steps leading to relatively straight zigzag runs. De novo pseudopodia are extended in nearly random directions thereby interrupting the zigzag runs. Persistence of cell movement is based on the ratio of split versus de novo pseudopodia. We identify PLA2 and cGMP signaling pathways that modulate this ratio of splitting and de novo pseudopodia, and thereby regulate the dispersal of cells. The observed ordered extension of pseudopodia in the absence of external cues provides a fundamental insight into the coordinated movement of cells, and might form the basis for movement that is directed by internal or external cues

Antibody landscapes after influenza virus infection or vaccination.

We introduce the antibody landscape, a method for the quantitative analysis of antibody-mediated immunity to antigenically variable pathogens, achieved by accounting for antigenic variation among pathogen strains. We generated antibody landscapes to study immune profiles covering 43 years of influenza A/H3N2 virus evolution for 69 individuals monitored for infection over 6 years and for 225 individuals pre- and postvaccination. Upon infection and vaccination, titers increased broadly, including previously encountered viruses far beyond the extent of cross-reactivity observed after a primary infection. We explored implications for vaccination and found that the use of an antigenically advanced virus had the dual benefit of inducing antibodies against both advanced and previous antigenic clusters. These results indicate that preemptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals.This is the author’s version of the work. It will be under embargo for 6 months following publication. It is posted here by permission of the AAAS for personal use, not for redistribution. The final version is available from AAAS in Science at http://www.sciencemag.org/content/346/6212/996.long

The alpha 7 nicotinic receptor agonist PHA-543613 hydrochloride inhibits <i>Porphyromonas gingivalis</i>-induced expression of interleukin-8 by oral keratinocytes

Objective: The alpha 7 nicotinic receptor (α7nAChR) is expressed by oral keratinocytes. α7nAChR activation mediates anti-inflammatory responses. The objective of this study was to determine if α7nAChR activation inhibited pathogen-induced interleukin-8 (IL-8) expression by oral keratinocytes.&lt;p&gt;&lt;/p&gt; Materials and methods: Periodontal tissue expression of α7nAChR was determined by real-time PCR. OKF6/TERT-2 oral keratinocytes were exposed to &lt;i&gt;Porphyromonas gingivalis&lt;/i&gt; in the presence and absence of a α7nAChR agonist (PHA-543613 hydrochloride) alone or after pre-exposure to a specific α7nAChR antagonist (α-bungarotoxin). Interleukin-8 (IL-8) expression was measured by ELISA and real-time PCR. Phosphorylation of the NF-κB p65 subunit was determined using an NF-κB p65 profiler assay and STAT-3 activation by STAT-3 in-cell ELISA. The release of ACh from oral keratinocytes in response to &lt;i&gt;P. gingivalis&lt;/i&gt; lipopolysaccharide was determined using a GeneBLAzer M3 CHO-K1-blacell reporter assay.&lt;p&gt;&lt;/p&gt; Results: Expression of α7nAChR mRNA was elevated in diseased periodontal tissue. PHA-543613 hydrochloride inhibited &lt;i&gt;P. Gingivalis&lt;/i&gt;-induced expression of IL-8 at the transcriptional level. This effect was abolished when cells were pre-exposed to a specific α7nAChR antagonist, α-bungarotoxin. PHA-543613 hydrochloride downregulated NF-κB signalling through reduced phosphorylation of the NF-κB p65-subunit. In addition, PHA-543613 hydrochloride promoted STAT-3 signalling by maintenance of phosphorylation. Furthermore, oral keratinocytes upregulated ACh release in response to &lt;i&gt;P. Gingivalis&lt;/i&gt; lipopolysaccharide.&lt;p&gt;&lt;/p&gt; Conclusion: These data suggest that α7nAChR plays a role in regulating the innate immune responses of oral keratinocytes.&lt;p&gt;&lt;/p&gt

Water and sodium intake habits and status of ultra-endurance runners during a multi-stage ultra-marathon conducted in a hot ambient environment: an observational field based study

<p>Abstract</p> <p>Background</p> <p>Anecdotal evidence suggests ultra-runners may not be consuming sufficient water through foods and fluids to maintenance euhydration, and present sub-optimal sodium intakes, throughout multi-stage ultra-marathon (MSUM) competitions in the heat. Subsequently, the aims were primarily to assess water and sodium intake habits of recreational ultra-runners during a five stage 225 km semi self-sufficient MSUM conducted in a hot ambient environment (T_max range: 32°C to 40°C); simultaneously to monitor serum sodium concentration, and hydration status using multiple hydration assessment techniques.</p> <p>Methods</p> <p>Total daily, pre-stage, during running, and post-stage water and sodium ingestion of ultra-endurance runners (UER, <it>n</it> = 74) and control (CON, <it>n</it> = 12) through foods and fluids were recorded on Stages 1 to 4 by trained dietetic researchers using dietary recall interview technique, and analysed through dietary analysis software. Body mass (BM), hydration status, and serum sodium concentration were determined pre- and post-Stages 1 to 5.</p> <p>Results</p> <p>Water (overall mean (SD): total daily 7.7 (1.5) L/day, during running 732 (183) ml/h) and sodium (total daily 3.9 (1.3) g/day, during running 270 (151) mg/L) ingestion did not differ between stages in UER (<it>p</it> < 0.001 <it>vs</it>. CON). Exercise-induced BM loss was 2.4 (1.2)% (<it>p</it> < 0.001). Pre- to post-stage BM gains were observed in 26% of UER along competition. Pre- and post-stage plasma osmolality remained within normal clinical reference range (280 to 303 mOsmol/kg) in the majority of UER (<it>p</it> > 0.05 <it>vs</it>. CON pre-stage). Asymptomatic hyponatraemia (<135 mmol/L) was evident pre- and post-stage in <it>n</it> = 8 UER, corresponding to 42% of sampled participants. Pre- and post-stage urine colour, urine osmolality and urine/plasma osmolality ratio increased (<it>p</it> < 0.001) as competition progressed in UER, with no change in CON. Plasma volume and extra-cellular water increased (<it>p</it> < 0.001) 22.8% and 9.2%, respectively, from pre-Stage 1 to 5 in UER, with no change in CON.</p> <p>Conclusion</p> <p>Water intake habits of ultra-runners during MSUM conducted in hot ambient conditions appear to be sufficient to maintain baseline euhydration levels. However, fluid over-consumption behaviours were evident along competition, irrespective of running speed and gender. Normonatraemia was observed in the majority of ultra-runners throughout MSUM, despite sodium ingestion under benchmark recommendations.</p

Suitability of PSA-detected localised prostate cancers for focal therapy: Experience from the ProtecT study

This article is available through a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. Copyright @ 2011 Cancer Research UK.Background: Contemporary screening for prostate cancer frequently identifies small volume, low-grade lesions. Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial. Methods: Surgical specimens from 525 men who underwent prostatectomy within the ProtecT study were analysed to determine tumour volume, location and grade. These findings were compared with information available in the biopsy specimen to examine whether focal therapy could be provided appropriately. Results: Solitary cancers were found in prostatectomy specimens from 19% (100 out of 525) of men. In addition, 73 out of 425 (17%) men had multiple cancers with a solitary significant tumour focus. Thus, 173 out of 525 (33%) men had tumours potentially suitable for focal therapy. The majority of these were small, well-differentiated lesions that appeared to be pathologically insignificant (38–66%). Criteria used to select patients for focal prostatic ablation underestimated the cancer's significance in 26% (34 out of 130) of men and resulted in overtreatment in more than half. Only 18% (24 out of 130) of men presumed eligible for focal therapy, actually had significant solitary lesions. Conclusion: Focal therapy appears inappropriate for the majority of men presenting with prostate-specific antigen-detected localised prostate cancer. Unifocal prostate cancers suitable for focal ablation are difficult to identify pre-operatively using biopsy alone. Most lesions meeting criteria for focal ablation were either more aggressive than expected or posed little threat of progression.National Institute for Health Researc

Cognitive function, social integration and mortality in a U.S. national cohort study of older adults

<p>Abstract</p> <p>Background</p> <p>Prior research suggests an interaction between social networks and Alzheimer's disease pathology and cognitive function, all predictors of survival in the elderly. We test the hypotheses that both social integration and cognitive function are independently associated with subsequent mortality and there is an interaction between social integration and cognitive function as related to mortality in a national cohort of older persons.</p> <p>Methods</p> <p>Data were analyzed from a longitudinal follow-up study of 5,908 American men and women aged 60 years and over examined in 1988–1994 followed an average 8.5 yr. Measurements at baseline included self-reported social integration, socio-demographics, health, body mass index, C-reactive protein and a short index of cognitive function (SICF).</p> <p>Results</p> <p>Death during follow-up occurred in 2,431. In bivariate analyses indicators of greater social integration were associated with higher cognitive function. Among persons with SICF score of 17, 22% died compared to 54% of those with SICF score of 0–11 (p < 0.0001). After adjusting for confounding by baseline socio-demographics and health status, the hazards ratio (HR) (95% confidence limits) for low SICF score was 1.43 (1.13–1.80, p < 0.001). After controlling for health behaviors, blood pressure and body mass, C-reactive protein and social integration, the HR was 1.36 (1.06–1.76, p = 0.02). Further low compared to high social integration was also independently associated with increased risk of mortality: HR 1.24 (1.02–1.52, p = 0.02).</p> <p>Conclusion</p> <p>In a cohort of older Americans, analyses demonstrated a higher risk of death independent of confounders among those with low cognitive function and low social integration with no significant interaction between them.</p

The developmental effects of media-ideal internalization and self-objectification processes on adolescents’ negative body-feelings, dietary restraint, and binge eating

Despite accumulated experimental evidence of the negative effects of exposure to media-idealized images, the degree to which body image, and eating related disturbances are caused by media portrayals of gendered beauty ideals remains controversial. On the basis of the most up-to-date meta-analysis of experimental studies indicating that media-idealized images have the most harmful and substantial impact on vulnerable individuals regardless of gender (i.e., “internalizers” and “self-objectifiers”), the current longitudinal study examined the direct and mediated links posited in objectification theory among media-ideal internalization, self-objectification, shame and anxiety surrounding the body and appearance, dietary restraint, and binge eating. Data collected from 685 adolescents aged between 14 and 15 at baseline (47 % males), who were interviewed and completed standardized measures annually over a 3-year period, were analyzed using a structural equation modeling approach. Results indicated that media-ideal internalization predicted later thinking and scrutinizing of one’s body from an external observer’s standpoint (or self-objectification), which then predicted later negative emotional experiences related to one’s body and appearance. In turn, these negative emotional experiences predicted subsequent dietary restraint and binge eating, and each of these core features of eating disorders influenced each other. Differences in the strength of these associations across gender were not observed, and all indirect effects were significant. The study provides valuable information about how the cultural values embodied by gendered beauty ideals negatively influence adolescents’ feelings, thoughts and behaviors regarding their own body, and on the complex processes involved in disordered eating. Practical implications are discussed

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer

Design of the DIRECT-project: interventions to increase job resources and recovery opportunities to improve job-related health, well-being, and performance outcomes in nursing homes

Background Because of high demands at work, nurses are at high risk for occupational burnout and physical complaints. The presence of job resources (such as job autonomy or social support) and recovery opportunities could counteract the adverse effect of high job demands. However, it is still unclear how job resources and recovery opportunities can be translated into effective workplace interventions aiming to improve employee health, well-being, and performance-related outcomes. The aim of the current research project is developing and implementing interventions to optimize job resources and recovery opportunities, which may lead to improved health, well-being and performance of nurses. Methods/design The DIRECT-project (DIsc Risk Evaluating Controlled Trial) is a longitudinal, quasi-experimental field study. Nursing home staff of 4 intervention wards and 4 comparison wards will be involved. Based on the results of a base-line survey, interventions will be implemented to optimize job resources and recovery opportunities. After 12 and 24 month the effect of the interventions will be investigated with follow-up surveys. Additionally, a process evaluation will be conducted to map factors that either stimulated or hindered successful implementation as well as the effectiveness of the interventions. Discussion The DIRECT-project fulfils a strong need for intervention research in the field of work, stress, performance, and health. The results could reveal (1) how interventions can be tailored to optimize job resources and recovery opportunities, in order to counteract job demands, and (2) what the effects of these interventions will be on health, well-being, and performance of nursing staff