Mesenchymal to epithelial transition in development and disease

Cellular plasticity is fundamental to embryonic development. The importance of cellular transitions in development is first apparent during gastrulation when the process of epithelial to mesenchymal transition transforms polarized epithelial cells into migratory mesenchymal cells that constitute the embryonic and extraembryonic mesoderm. It is now widely accepted that this developmental pathway is exploited in various disease states, including cancer progression. The loss of epithelial characteristics and the acquisition of a mesenchymal-like migratory phenotype are crucial to the development of invasive carcinoma and metastasis. However, given the morphological similarities between primary tumour and metastatic lesions, it is likely that tumour cells re-activate certain epithelial properties through a mesenchymal to epithelial transition (MET) at the secondary site, although this is yet to be proven. MET is also an essential developmental process and has been extensively studied in kidney organogenesis and somitogenesis. In this review we describe the process of MET, highlight important mediators, and discuss their implication in the context of cancer progression.

Psychosocial correlates of physical activity in white and African-American girls

Purpose To evaluate the relative utility of the Theory of Reasoned Action (TRA) and the Theory of Planned Behavior (TPB) in explaining intentions and physical activity behavior in white and African-American eighth-grade girls. Methods One-thousand-thirty white and 1114 African-American eighth-grade girls (mean age 13.6 ± 0.7 years) from 31 middle schools in South Carolina completed a 3-day physical activity recall and a questionnaire assessing attitudes, subjective norms, perceived behavioral control, self-efficacy, and intentions related to regular participation in moderate-to-vigorous physical activity (MVPA). Results Among Whites, 17% of the variance in intentions was contributed by subjective norms and attitude, with intentions accounting for 8% of the variance in MVPA. The addition of perceived behavioral control and self-efficacy to the TRA significantly improved the prediction of intentions and MVPA accounting for 40% and 10% of the variance, respectively. Among African-Americans, subjective norms and attitude accounted for 13% of the variance in intentions, with intentions accounting for only 3% of the variance in MVPA. The addition of perceived behavioral control and self-efficacy to the TRA significantly improved the prediction of intentions and MVPA accounting for 28% and 5% of the variance, respectively. Conclusions The results provided limited empirical support for the TPB among white adolescent girls; however, our findings suggest that the planned behavior framework has limited utility among African-American adolescent girls. The relatively weak link between intentions and MVPA observed in both population groups suggest that constructs external to the TPB may be more important mediators of physical activity behavior in adolescent girls.

Physical activity correlates in adolescent girls who differ by weight status

Objective This study compared correlates of physical activity (PA) among African-American and white girls of different weight groups to guide future interventions. Research Methods and Procedures Participants were 1015 girls (mean age, 14.6 years; 45% African-American) from 12 high schools in South Carolina who served as control subjects for a school-based intervention. Post-intervention measures obtained at the end of ninth grade were used. PA was measured using the Three-Day PA Recall, and a questionnaire measured social-cognitive and environmental variables thought to mediate PA. Height and weight were measured, and BMI was calculated. Girls were stratified by race and categorized into three groups, based on BMI percentiles for girls from CDC growth charts: normal (BMI < 85th percentile), at risk (BMI, 85th to 94th percentile), and overweight (BMI ≥ 95th percentile). Girls were further divided into active and low-active groups, based on a vigorous PA standard (average of one or more 30-minute blocks per day per 3-day period). Mixed-model ANOVA was used to compare factors among groups, treating school as a random effect Results None of the social-cognitive or environmental variables differed by weight status for African-American or white girls. Perceived behavioral control and sports team participation were significantly higher in girls who were more active, regardless of weight or race group. In general, social-cognitive variables seem to be more related to activity in white girls, whereas environmental factors seem more related to activity in African-American girls. Discussion PA interventions should be tailored to the unique needs of girls based on PA levels and race, rather than on weight status alone.

Time pressure and coworker support mediate the curvilinear relationship between age and occupational well-being

As the proportion of older employees in the workforce is growing, researchers have become increasingly interested in the association between age and occupational well-being. The curvilinear nature of relationships between age and job satisfaction and between age and emotional exhaustion is well-established in the literature, with employees in their late 20s to early 40s generally reporting lower levels of occupational well-being than younger and older employees. However, the mechanisms underlying these curvilinear relationships are so far not well understood due to a lack of studies testing mediation effects. Based on an integration of role theory and research from the adult development and career literatures, this study examined time pressure, work–home conflict, and coworker support as mediators of the relationships between age and job satisfaction and between age and emotional exhaustion. Data came from 771 employees between 17 and 74 years of age in the construction industry. Results showed that employees in their late 20s to early 40s had lower job satisfaction and higher emotional exhaustion than younger and older employees. Time pressure and coworker support fully mediated both the U-shaped relationship between age and job satisfaction and the inversely U-shaped relationship between age and emotional exhaustion. These findings suggest that organizational interventions may help increase the relatively low levels of occupational well-being in certain age groups.

Atmosphere : a framework for contextual awareness

This article enhances existing approaches to present-day asynchronous awareness concepts by providing the means to explicitly represent and mediate contextual information. The resulting concept of contextual awareness takes different notions of the term context into account. Following a human-centered approach, the proposed methods serve as mediators for context between persons rather than automatically detecting context. Based on this variant of awareness, the atmosphere framework is introduced to provide mechanisms to deal with the problem of workload in tandem with contextual information. Atmosphere provides a highly tailorable structure and interface to deal with a wide variance of user and organizational requirements. The article closes with the description of a partial implementation of the framework and its evaluation.

Myeloma-induced alloreactive T cells arising in myeloma-infiltrated bones include double-positive CD8+CD4+ T cells : evidence from myeloma-bearing mouse model

The graft-versus-myeloma (GVM) effect represents a powerful form of immune attack exerted by alloreactive T cells against multiple myeloma cells, which leads to clinical responses in multiple myeloma transplant recipients. Whether myeloma cells are themselves able to induce alloreactive T cells capable of the GVM effect is not defined. Using adoptive transfer of T naive cells into myeloma-bearing mice (established by transplantation of human RPMI8226-TGL myeloma cells into CD122(+) cell-depleted NOD/SCID hosts), we found that myeloma cells induced alloreactive T cells that suppressed myeloma growth and prolonged survival of T cell recipients. Myeloma-induced alloreactive T cells arising in the myeloma-infiltrated bones exerted cytotoxic activity against resident myeloma cells, but limited activity against control myeloma cells obtained from myeloma-bearing mice that did not receive T naive cells. These myeloma-induced alloreactive T cells were derived through multiple CD8(+) T cell divisions and enriched in double-positive (DP) T cells coexpressing the CD8alphaalpha and CD4 coreceptors. MHC class I expression on myeloma cells and contact with T cells were required for CD8(+) T cell divisions and DP-T cell development. DP-T cells present in myeloma-infiltrated bones contained a higher proportion of cells expressing cytotoxic mediators IFN-gamma and/or perforin compared with single-positive CD8(+) T cells, acquired the capacity to degranulate as measured by CD107 expression, and contributed to an elevated perforin level seen in the myeloma-infiltrated bones. These observations suggest that myeloma-induced alloreactive T cells arising in myeloma-infiltrated bones are enriched with DP-T cells equipped with cytotoxic effector functions that are likely to be involved in the GVM effect.

On mind, mediation and meaning-making

This paper takes inspiration from the integrative model of human mind proposed by Brinkmann (2011, 2012) and argues that the kind of integration that he seeks to attain can only be achieved if the model focuses on the processes that underlie the functioning of the human mind and not on the entities that these processes produce or function by. An alternative integrative model is thus proposed. In the first part of the paper the process of meaning-making will be explored. It will be argued that an integrative conceptualisation of human mind needs to take into account pre-reflective and unmediated as well as reflective and mediated states through which meanings become constructed. In the second part of the paper the idea of semiotic mediation will be explored. It will be argued that an integrative model of human mind needs to focus not only on different kinds of mediators, but also explain how these are used reflectively and non-reflectively by individuals themselves and visibly or invisibly by others in our everyday interactions.

Promiscuity, pheromones and pathogenicity : why all Enterococci are not created equal

Enterococcus faecalis is a Gram-positive, coccus shaped, lactic acid bacterium, with demonstrated ubiquity across multiple anatomical sites. Enterococcus faecalis isolates have been isolated from clinical samples as the etiological agent in patients with overt infections, and from body sites previously thought to be sterile but absent of signs and symptoms of infection. E. faecalis is implicated in both human health and disease, recognized as a commensal, a probiotic and an opportunistic multiply resistant pathogen. E. faecalis has emerged as a key pathogen in nosocomial infections. E. faecalis is well equipped to avert recognition by host cell immune mediators. Antigenic cell wall components including lipotechoic acids are concealed from immune detection by capsular polysaccharides produced by some strains. Thereby preventing complement activation, the pro-inflammatory response, opsonisation and phagocytosis. E. faecalis also produces a suite of enzymes including gelatinase and cytolysin, which aid in both virulence and host immune evasion. The ability of enterococci to form biofilms in vivo further increases virulence, whilst simultaneously preventing detection by host cells. E. faecalis exhibits high levels of both intrinsic and acquired antimicrobial resistance. The mobility of the E. faecalis genome is a significant contributor to antimicrobial resistance, with this species also transferring resistance to other Gram-positive bacteria. Whilst E. faecalis is of increasing concern in nosocomial infections, its role as a member of the endogenous microbiota cannot be underestimated. As a commensal and probiotic, E. faecalis plays an integral role in modulating the immune response, and in providing endogenous antimicrobial activity to enhance exclusion or inhibition of opportunistic pathogens in certain anatomical niches. In this chapter we will review possible mediators of enterococcal transition from commensal microbe to opportunistic pathogen, considering isolates obtained from patients diagnosed with pathogenic infections and those obtained from asymptomatic patients.

Cytokine secretion in macrophages : SNAREs, Rabs and membrane trafficking

Macrophages have the capacity to rapidly secrete a wide range of inflammatory mediators that influence the development and extent of an inflammatory response. Newly synthesized and/or preformed stored cytokines and other inflammatory mediators are released upon stimulation, the timing, and volume of which is highly regulated. To finely tune this process, secretion is regulated at many levels; at the level of transcription and translation and post-translationally at the endoplasmic reticulum (ER), Golgi, and at or near the cell surface. Here, we discuss recent advances in deciphering these cytokine pathways in macrophages, focusing on recent discoveries regarding the cellular machinery and mechanisms implicated in the synthesis, trafficking, and secretion of cytokines. The specific roles of trafficking machinery including chaperones, GTPases, cytoskeletal proteins, and SNARE membrane fusion proteins will be discussed.

Cytokine expression and secretion by skeletal muscle cells : regulatory mechanisms and exercise effects

Cytokines are important mediators of various aspects of health and disease, including appetite, glucose and lipid metabolism, insulin sensitivity, skeletal muscle hypertrophy and atrophy. Over the past decade or so, considerable attention has focused on the potential for regular exercise to counteract a range of disease states by modulating cytokine production. Exercise stimulates moderate to large increases in the circulating concentrations of interleukin (IL)-6, IL-8, IL-10, IL-1 receptor antagonist, granulocyte-colony stimulating factor, and smaller increases in tumor necrosis factor-α, monocyte chemotactic protein-1, IL-1β, brain-derived neurotrophic factor, IL-12p35/p40 and IL-15. Although many of these cytokines are also expressed in skeletal muscle, not all are released from skeletal muscle into the circulation during exercise. Conversely, some cytokines that are present in the circulation are not expressed in skeletal muscle after exercise. The reasons for these discrepant cytokine responses to exercise are unclear. In this review, we address these uncertainties by summarizing the capacity of skeletal muscle cells to produce cytokines, analyzing other potential cellular sources of circulating cytokines during exercise, and discussing the soluble factors and intracellular signaling pathways that regulate cytokine synthesis (e.g., RNA-binding proteins, microRNAs, suppressor of cytokine signaling proteins, soluble receptors).

Towards a potential model to enhance language learner autonomy in the Vietnamese higher education context

This constructivist theory-led case study explored how the term language learner autonomy (LLA) is interpreted and the appropriate pedagogy to foster LLA in the Vietnamese higher education context. Evidence through the exploration of the government policies and the cases of three EFL classes confirms the interpretation that learner autonomy and language acquisition are mutually supported. The study has proposed project work as a potential model while demonstrating the role of the teacher and the use of target language as mediators to enhance LLA in the local context. Findings of the study contribute a theoretical and pedagogical justification for encouraging LLA in Vietnam and other similar contexts.

Modulating exercise-induced hormesis: Does less equal more?

Hormesis enco 16 mpasses the notion that low levels of stress stimulate or upregulate 17 existing cellular and molecular pathways that improve the capacity of cells and organisms to 18 withstand greater stress. This notion underlies much of what we know about how exercise 19 conditions the body and induces long-term adaptations. During exercise, the body is 20 exposed to various forms of stress, including thermal, metabolic, hypoxic, oxidative, and 21 mechanical stress. These stressors activate biochemical messengers, which in turn activate 22 various signaling pathways that regulate gene expression and adaptive responses. 23 Historically, antioxidant supplements, nonsteroidal anti-inflammatory drugs, and 24 cryotherapy have been favored to attenuate or counteract exercise-induced oxidative stress 25 and inflammation. However, reactive oxygen species and inflammatory mediators are key 26 signaling molecules in muscle, and such strategies may mitigate adaptations to exercise. 27 Conversely, withholding dietary carbohydrate and restricting muscle blood flow during 28 exercise may augment adaptations to exercise. In this review article, we combine, integrate, 29 and apply knowledge about the fundamental mechanisms of exercise adaptation. We also 30 critically evaluate the rationale for using interventions that target these mechanisms under 31 the overarching concept of hormesis. There is currently insufficient evidence to establish 32 whether these treatments exert dose-dependent effects on muscle adaptation. However, 33 there appears to be some dissociation between the biochemical/molecular effects and 34 functional/performance outcomes of some of these treatments. Although several of these 35 treatments influence common kinases, transcription factors and proteins, it remains to be 36 determined if these interventions complement or negate each other, and whether such 37 effects are strong enough to influence adaptations to exercise.

The role of inflammation in cutaneous repair

Inflammation is a fundamental component of the normal adult wound healing response occurring even in the absence of infection. It performs many beneficial roles such as the clearing of damaged cells and extracellular matrix (ECM), the removal of pathogens that might other wise multiply and spread, and the secretion of mediators that regulate other aspects of wound healing such as proliferation, re-epithelialisation and wound remodelling. Yet, excess and/or prolonged inflammation is detrimental to wound healing and leads to increased fibrosis and scarring, which can be disfiguring and, in cases such as contractures, can lead to disability. Furthermore, excessive inflammation is a major contributing factor to the persistence of chronic non-healing wounds, which are “stuck” in the inflammatory phase of healing and fail to reepithelialise. Current research suggest that the type of immune cells, their timing and the level of inflammation in a wound could have dramatic effect on whether a wound heals in a timely fashion and the final quality of the repaired tissue. Studies suggest that altering the level of inflammation might be beneficial in terms of reducing scarring and improving the rate of healing in chronic wounds. This review looks at the role of the major immune cells in normal and impaired wound healing and strategies that might be used to reduce inflammation in wounds.

Genetics and genomics of ankylosing spondylitis

Ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the pathogenesis of which is poorly understood. The mechanism by which the main gene for the disease, HLA-B27, leads to AS is unknown. Genetic and genomic studies have demonstrated involvement of the interleukin-23 (IL-23) signaling pathway in AS, a finding which has stimulated much new research into the disease and has led to therapeutic trials. Several other genes and genetic regions, including further major histocompatibility complex (MHC) and non-MHC loci, have been shown to be involved in the disease, but it is not clear yet how they actually induce the condition. These findings have shown that there is a strong genetic overlap between AS and Crohn's disease in particular, although there are also major differences in the genes involved in the two conditions, presumably explaining their different presentations. Genomic and proteomic studies are in an early phase but have potential both as diagnostic/prognostic tools and as a further hypothesis-free tool to investigate AS pathogenesis. Given the slow progress in studying the mechanism of association of HLA-B27 with AS, these may prove to be more fruitful approaches to investigating the pathogenesis of the disease. © 2009 John Wiley & Sons A/S.

Heterogeneity of miR-10b expression in circulating tumor cells

Circulating tumor cells (CTCs) in the blood of cancer patients are recognized as important potential targets for future anticancer therapies. As mediators of metastatic spread, CTCs are also promising to be used as € liquid biopsyto aid clinical decision-making. Recent work has revealed potentially important genotypic and phenotypic heterogeneity within CTC populations, even within the same patient. MicroRNAs (miRNAs) are key regulators of gene expression and have emerged as potentially important diagnostic markers and targets for anti-cancer therapy. Here, we describe a robust in situ hybridization (ISH) protocol, incorporating the CellSearch ® CTC detection system, enabling clinical investigation of important miRNAs, such as miR-10b on a cell by cell basis. We also use this method to demonstrate heterogeneity of such as miR-10b on a cell-by-cell basis. We also use this method to demonstrate heterogeneity of miR-10b in individual CTCs from breast, prostate and colorectal cancer patients.