p16 Mutation Spectrum in the Premalignant Condition Barrett's Esophagus

Background: Mutation, promoter hypermethylation and loss of heterozygosity involving the tumor suppressor gene p16 (CDKN2a/INK4a) have been detected in a wide variety of human cancers, but much less is known concerning the frequency and spectrum of p16 mutations in premalignant conditions. Methods and Findings: We have determined the p16 mutation spectrum for a cohort of 304 patients with Barrett’s esophagus, a premalignant condition that predisposes to the development of esophageal adenocarcinoma. Forty seven mutations were detected by sequencing of p16 exon 2 in 44 BE patients (14.5%) with a mutation spectrum consistent with that caused by oxidative damage and chronic inflammation. The percentage of patients with p16 mutations increased with increasing histologic grade. In addition, samples from 3 out of 19 patients (15.8%) who underwent esophagectomy were found to have mutations. Conclusions: The results of this study suggest the environment of the esophagus in BE patients can both generate an

CD40-CD40 ligand interaction between dendritic cells and CD8+ T cells is needed to stimulate maximal T cell responses in the absence of CD4+ T cell help

Stimulation of CD40 on APCs through CD40L expressed on helper CD4+ T cells activates and licenses the APCs to prime CD8+ T cell responses. Although other stimuli, such as TLR agonists, can also activate APCs, it is unclear to what extent they can replace the signals provided by CD40-CD40L interactions. In this study, we used an adoptive transfer system to re-examine the role of CD40 in the priming of naive CD8+ T cells. We find an approximately 50% reduction in expansion and cytokine production in TCR-transgenic T cells in the absence of CD40 on all APCs, and on dendritic cells in particular. Moreover, CD40-deficient and CD40L-deficient mice fail to develop endogenous CTL responses after immunization. Surprisingly, the role for CD40 and CD40L are observed even in the absence of CD4+ T cells; in this situation, the CD8+ T cell itself provides CD40L. Furthermore, we show that although TLR stimulation improves T cell responses, it cannot fully substitute for CD40. Altogether, these results reveal a direct and unique role for CD40L on CD8+ T cells interacting with CD40 on APCs that affects the magnitude and quality of CD8+ T cell responses

CD40 on APCs is needed for optimal programming, maintenance, and recall of CD8+ T cell memory even in the absence of CD4+ T cell help

CD40 stimulation is one of the many signals that can activate APCs and we have recently shown it to have a unique function in generating maximum primary CD8(+) T cell responses. However, whether CD40 signaling plays a role in memory CD8(+) T cell responses is still not completely understood. In this study, we show that in the absence of CD40 on all APCs or specifically on dendritic cells, memory CD8(+) T cells are generated but at significantly reduced levels. This reduction is due to a contribution of CD40 at several different steps in the generation of CD8(+) memory. In the initial T cell response, CD40 contributes to maximizing not only the number of effector cells that are generated but also the programming of ones that will differentiate into memory. Subsequently, CD40 is needed to maintain maximal numbers of the committed memory cells in a manner that is independent of the immunizing Ag. Finally, when memory CD8(+) T cells are reactivated there is a variable requirement for CD40 depending on whether CD40 or CD4(+) Th cells were present during the primary response. Therefore, CD40 signaling on APCs plays an important role in all phases of a memory CD8(+) T cell response

Evaluation of structure specification in linear mixed models for modeling the spatial effects in tree height-diamater relationships

., 2013. Evaluation of structure specifi cation in linear mixed models for modeling the spatial effects in tree height-diamater relationships. Ann. For. Res. 56(1): 137-148, 2013. Abstract. In recent years, linear mixed models (LMM) have become more popular to deal with spatial effects in forestry and ecological data. In this study, different structure specifications of linear mixed model were applied to model tree height-diameter relationships, including LMM with random blocks only (LMM-block), LMM with spatial covariance only (LMM-covariance), and the combination of the last two (LMM-block-covariance). Further, the betweengroup heterogeneous variances were incorporated into LMM-covariance and LMM-block-covariance. The results indicated that, in general, LMM-covariance significantly reduced spatial autocorrelation in model residuals, while LMM-block was effective in dealing with spatial heterogeneity. LMM-block treated the blocks as random effects and avoided the estimation of parameters of the variogram model. Thus, it produced better model predictions than LMM-covariance. LMM-block-covariance took both block effects and spatial covariance into account, and significantly improve model fitting. However, it did not produce better model predictions due to the increase of model complexity and estimation of the local variogram within each block

A Quantitative Index of Forest Structural Sustainability

Forest health is a complex concept including many ecosystem functions, interactions and values. We develop a quantitative system applicable to many forest types to assess tree mortality with respect to stable forest structure and composition. We quantify impacts of observed tree mortality on structure by comparison to baseline mortality, and then develop a system that distinguishes between structurally stable and unstable forests. An empirical multivariate index of structural sustainability and a threshold value (70.6) derived from 22 nontropical tree species’ datasets differentiated structurally sustainable from unsustainable diameter distributions. Twelve of 22 species populations were sustainable with a mean score of 33.2 (median = 27.6). Ten species populations were unsustainable with a mean score of 142.6 (median = 130.1). Among them, Fagus grandifolia, Pinus lambertiana, P. ponderosa, and Nothofagus solandri were attributable to known disturbances; whereas the unsustainability of Abies balsamea, Acer rubrum, Calocedrus decurrens, Picea engelmannii, P. rubens, and Prunus serotina populations were not. This approach provides the ecological framework for rational management decisions using routine inventory data to objectively: determine scope and direction of change in structure and composition, assess excessive or insufficient mortality, compare disturbance impacts in time and space, and prioritize management needs and allocation of scarce resources

\u3ci\u3eDt2\u3c/i\u3e Is a Gain-of-Function MADS-Domain Factor Gene That Specifies Semideterminacy in Soybean

Similar to Arabidopsis thaliana, the wild soybeans (Glycine soja) and many cultivars exhibit indeterminate stem growth specified by the shoot identity gene Dt1, the functional counterpart of Arabidopsis TERMINAL FLOWER1 (TFL1). Mutations in TFL1 and Dt1 both result in the shoot apical meristem (SAM) switching from vegetative to reproductive state to initiate terminal flowering and thus produce determinate stems. A second soybean gene (Dt2) regulating stem growth was identified, which, in the presence of Dt1, produces semideterminate plants with terminal racemes similar to those observed in determinate plants. Here, we report positional cloning and characterization of Dt2, a dominant MADS domain factor gene classified into the APETALA1/SQUAMOSA (AP1/SQUA) subfamily that includes floral meristem (FM) identity genes AP1, FUL, and CAL in Arabidopsis. Unlike AP1, whose expression is limited to FMs in which the expression of TFL1 is repressed, Dt2 appears to repress the expression of Dt1 in the SAMs to promote early conversion of the SAMs into reproductive inflorescences. Given that Dt2 is not the gene most closely related to AP1 and that semideterminacy is rarely seen in wild soybeans, Dt2 appears to be a recent gain-of-function mutation, which has modified the genetic pathways determining the stem growth habit in soybean