Signals 1, 2 and B cell fate or: Where, when and for how long?

Diverse B cell responses are important for generating antibody‐mediated protection against highly variable pathogens. While some antigens can trigger T‐independent B cell proliferation and short‐term antibody production, development of long‐term humoral immunity requires T‐dependent B cell responses. The “two‐signal” model of B cell activation has long been invoked to explain alternate B cell recruitment into immune response to foreign antigens vs. induction of tolerance to self‐antigens. However, a number of other factors appear to influence the fate of mature B cells responding to antigen in vivo. In this review, we will discuss how various spatiotemporal scenarios of antigen access into secondary lymphoid organs, antigen valency and cellular environment of antigen acquisition by B cells, duration of B cell access to antigen and the timing of T cell help may affect follicular B cell fate, including death, survival, anergy, and recruitment into T‐dependent responses. We will also highlight unresolved questions related to B cell activation and tolerance in vivo that may have important implications for vaccine development and autoimmunity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156186/2/imr12865.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156186/1/imr12865_am.pd

Linking Hydrogen (δ2H) Isotopes in Feathers and Precipitation: Sources of Variance and Consequences for Assignment to Isoscapes

Background: Tracking small migrant organisms worldwide has been hampered by technological and recovery limitations and sampling bias inherent in exogenous markers. Naturally occurring stable isotopes of H (d 2 H) in feathers provide an alternative intrinsic marker of animal origin due to the predictable spatial linkage to underlying hydrologically driven flow of H isotopes into foodwebs. This approach can assess the likelihood that a migrant animal originated from a given location(s) within a continent but requires a robust algorithm linking H isotopes in tissues of interest to an appropriate hydrological isotopic spatio-temporal pattern, such as weighted-annual rainfall. However, a number of factors contribute to or alter expected isotopic patterns in animals. We present results of an extensive investigation into taxonomic and environmental factors influencing feather d 2 H patterns across North America. Principal Findings: Stable isotope data were measured from 544 feathers from 40 species and 140 known locations. For d 2 H, the most parsimonious model explaining 83 % of the isotopic variance was found with amount-weighted growingseason precipitation d 2 H, foraging substrate and migratory strategy. Conclusions/Significance: This extensive H isotopic analysis of known-origin feathers of songbirds in North America and elsewhere reconfirmed the strong coupling between tissue d 2 H and global hydrologic d 2 H patterns, and accounting for variance associated with foraging substrate and migratory strategy, can be used in conservation and research for th

TGF-beta 1 induces human alveolar epithelial to mesenchymal cell transition (EMT)

Background: Fibroblastic foci are characteristic features in lung parenchyma of patients with idiopathic pulmonary fibrosis (IPF). They comprise aggregates of mesenchymal cells which underlie sites of unresolved epithelial injury and are associated with progression of fibrosis. However, the cellular origins of these mesenchymal phenotypes remain unclear. We examined whether the potent fibrogenic cytokine TGF-β1 could induce epithelial mesenchymal transition (EMT) in the human alveolar epithelial cell line, A549, and investigated the signaling pathway of TGF-β1-mediated EMT. Methods: A549 cells were examined for evidence of EMT after treatment with TGF-β1. EMT was assessed by: morphology under phase-contrast microscopy; Western analysis of cell lysates for expression of mesenchymal phenotypic markers including fibronectin EDA (Fn-EDA), and expression of epithelial phenotypic markers including E-cadherin (E-cad). Markers of fibrogenesis, including collagens and connective tissue growth factor (CTGF) were also evaluated by measuring mRNA level using RT-PCR, and protein by immunofluorescence or Western blotting. Signaling pathways for EMT were characterized by Western analysis of cell lysates using monoclonal antibodies to detect phosphorylated Erk1/2 and Smad2 after TGF-β1 treatment in the presence or absence of MEK inhibitors. The role of Smad2 in TGF-β1-mediated EMT was investigated using siRNA. Results: The data showed that TGF-β1, but not TNF-α or IL-1β, induced A549 cells with an alveolar epithelial type II cell phenotype to undergo EMT in a time-and concentration-dependent manner. The process of EMT was accompanied by morphological alteration and expression of the fibroblast phenotypic markers Fn-EDA and vimentin, concomitant with a downregulation of the epithelial phenotype marker E-cad. Furthermore, cells that had undergone EMT showed enhanced expression of markers of fibrogenesis including collagens type I and III and CTGF. MMP-2 expression was also evidenced. TGF-β1-induced EMT occurred through phosphorylation of Smad2 and was inhibited by Smad2 gene silencing; MEK inhibitors failed to attenuate either EMT-associated Smad2 phosphorylation or the observed phenotypic changes. Conclusion: Our study shows that TGF-β1 induces A549 alveolar epithelial cells to undergo EMT via Smad2 activation. Our data support the concept of EMT in lung epithelial cells, and suggest the need for further studies to investigate the phenomenon

Evaluating the importance of metamorphism in the foundering of continental crust

The metamorphic conditions and mechanisms required to induce foundering in deep arc crust are assessed using an example of representative lower crust in SW New Zealand. Composite plutons of Cretaceous monzodiorite and gabbro were emplaced at ~1.2 and 1.8 GPa are parts of the Western Fiordland Orthogneiss (WFO); examples of the plutons are tectonically juxtaposed along a structure that excised ~25 km of crust. The 1.8 GPa Breaksea Orthogneiss includes suitably dense minor components (e.g. eclogite) capable of foundering at peak conditions. As the eclogite facies boundary has a positive dP/dT, cooling from supra-solidus conditions (T > 950 ºC) at high-P should be accompanied by omphacite and garnet growth. However, a high monzodioritic proportion and inefficient metamorphism in the Breaksea Orthogneiss resulted in its positive buoyancy and preservation. Metamorphic inefficiency and compositional relationships in the 1.2 GPa Malaspina Pluton meant it was never likely to have developed densities sufficiently high to founder. These relationships suggest that the deep arc crust must have primarily involved significant igneous accumulation of garnet–clinopyroxene (in proportions >75%). Crustal dismemberment with or without the development of extensional shear zones is proposed to have induced foundering of excised cumulate material at P > 1.2 GPa

The role of the genetic counsellor: a systematic review of research evidence

In Europe, genetic counsellors are employed in specialist genetic centres or other specialist units. According to the European Board of Medical Genetics, the genetic counsellor must fulfil a range of roles, including provision of information and facilitation of psychosocial adjustment of the client to their genetic status and situation. To evaluate the extent to which genetic counsellors fulfil their prescribed roles, we conducted a systematic review of the published relevant scientific evidence. We searched five relevant electronic databases (Medline, CINAHL, SocIndex, AMED and PsychInfo) using relevant search terms and handsearched four subject-specific journals for research-based papers published in English between 1 January 2000 and 30 June 2013. Of 419 potential papers identified initially, seven satisfied the inclusion criteria for the review. Themes derived from the thematic analysis of the data were: (i) rationale for genetic counsellors to provide care, (ii) appropriate roles and responsibilities and (iii) the types of conditions included in the genetic counsellor caseload. The findings of this systematic review indicate that where genetic counsellors are utilised in specialist genetic settings, they undertake a significant workload associated with direct patient care and this appears to be acceptable to patients. With the burden on genetic services, there is an argument for the increased use of genetic counsellors in countries where they are under-utilised. In addition, roles undertaken by genetic counsellors in specialist genetic settings could be adapted to integrate genetic counsellors into multi-disciplinary teams in other specialisms

Relationship between craving and personality in treatment-seeking women with substance-related disorders

BACKGROUND: Individual differences may impact susceptibility to addiction. The impact of personality features on drug craving, however, has not been studied, particularly in women. METHODS: Ninety-five treatment-seeking women with substance dependence, abstinent for at least 5 and no more than 21 days, were investigated regarding the correlation between personality factors and craving. Personality was assessed using the Temperament and Character Inventory (TCI), the NEO Personality Inventory Revised (NEO-PI-R), and the Barratt Impulsiveness Scale version 11 (BIS-11). Cravings were assessed through the Pennsylvania Craving Scale (PCS), and the Craving Questionnaire (CQ). Anxiety and depressive symptomatology were also recorded. RESULTS: Craving scores were positively correlated with depression and negatively correlated with number of days abstinent from substance use. Also, craving scores were positively associated with the novelty-seeking factor from the TCI and the total score on the BIS-11, and negatively associated with the conscientiousness and agreeableness facets of the NEO-PI-R. CONCLUSION: Findings suggest that personality features, particularly impulsiveness, can be important predictors of craving in women, which has important implications for treatment planning