Neuroendocrine immunity in patients with Alzheimer's disease: toward translational epigenetics

The emerging domain of epigenetics in molecular medicine finds application for a variety of patient populations. Here, we present fundamental neuroendocrine immune evidence obtained in patients with senile dementia of the Alzheimer's type (sDAT), and discuss the implications of these data from the viewpoint of translational epigenetics of Alzheimer's disease. We followed 18 subjects with mild sDAT treated with acetylcholinesterase inhibitors, and 10 control subjects matched for age in a repeated measure design every six months for 18 months. We monitored psychosocial profile (Mini-Mental State Examination, Functional Assessment Staging, Independence in Activities of Daily Living, Depression, Profile of Moods States) in parallel to immunophenotypic parameters of T cell subpopulations by flow cytometry. Based on change in the mini-mental state score at entry and at 18 months, patients with sDAT were assigned to a "fast progression" (delta greater than 2 points) or to a "slow progression" group (delta less than or equal to 2 points). The change in circulating activated T cells (CD3+Dr+) with time in patients with sDAT was significantly inversely correlated with the change in time in natural killer (NK) cytotoxic activity to cortisol modulation in these patients, which was greater in patients with fast progression, compared to slow progression sDAT. These data indicate underlying neuroendocrine immune processes during progression of sDAT. Our observations suggest that psychoimmune measures such as those we have monitored in this study provide relevant information about the evolving physiological modulation in patients with sDAT during progression of Alzheimer's disease, and point to new or improved translational epigenetic treatment interventions.     

Physiologic modulation of natural killer cell activity as an index of Alzheimer's disease progression

Patients with Alzheimer's disease (AD) are characterized by an altered sensitivity to cortisol-mediated modulation of circulating lymphocytes. Longitudinal studies are needed to address the clinical applicability of these abnormalities as prognostic factors. Therefore, we designed a longitudinal study to address the clinical applicability of physiologic modulation of Natural Killer (NK) cell activity as a prognostic factor in AD. NK activity was assessed as baseline measurement and in response to modulation by cortisol at 10(-6)M. To verify the immunophysiological integrity of the NK cell population, we tested augmentation of NK cytotoxicity by human recombinant interleukin (IL)-2 (100 IU/ml) as control. The response to modulation by cortisol or by IL-2 was significantly greater in patients with AD. Based on change in the Mini-Mental State score at entry and at 18 months, patients with AD could be assigned to a "fast progression" (Delta > 2 points) or to a "slow progression" group (Delta 相似文献   

Dendronized hydroxypropyl cellulose: synthesis and characterization of biobased nanoobjects

Dendronized polymers containing a cellulose backbone have been synthesized with the aim of producing complex molecules with versatile functionalization possibilites and high molecular weight from biobased starting materials. The dendronized polymers were built by attaching premade acetonide-protected 2,2-bis(methylol)propionic acid functional dendrons of generation one to three to a hydroxypropyl cellulose backbone. Deprotection or functionalization of the end groups of the first generation dendronized polymer to hydroxyl groups and long alkyl chains was performed, respectively. The chemical structures of the dendronized polymers were confirmed through analysis using (1)H NMR and FT-IR spectroscopies. From SEC analysis, the dendronized polymers were found to have an increasing polystyrene-equivalent molecular weight up to the second generation ( M n = 50 kg mol (-1)), whereas the polystyrene-equivalent molecular weight for the third generation was lower than for the second, although the same grafting density was obtained from (1)H NMR spectroscopy for the second and third generations. Tapping-mode atomic force microscopy was used to characterize the properties of the dendronized polymers in the dry state, exploring both the effect of the polar substrate mica and the less polar substrate highly oriented pyrolytic graphite (HOPG). It was found that the molecules were in the size range of tens of nanometers and that they were apt to undertake a more elongated conformation on the HOPG surfaces when long alkyl chains were attached as the dendron end-groups.     

Overexpression of the trichodiene synthase gene tri5 increases trichodermin production and antimicrobial activity in Trichoderma brevicompactum

Trichoderma brevicompactum produces trichodermin, a simple trichothecene-type toxin that shares the first steps of the sesquiterpene biosynthetic pathway with other phytotoxic trichothecenes from Fusarium spp. Trichodiene synthase catalyses the conversion of farnesyl pyrophosphate to trichodiene and it is encoded by the tri5 gene that was cloned and analysed functionally by homologous overexpression in T. brevicompactum. tri5 expression was up-regulated in media with glucose, H(2)O(2) or glycerol. tri5 repression was observed in cultures supplemented with the antioxidants ferulic acid and tyrosol. Acetone extracts of tri5-overexpressing transformants displayed higher antifungal activity than those from the wild-type. Chromatographic and spectroscopic analyses revealed that tri5 overexpression led to an increased production of trichodermin and tyrosol. Agar diffusion assays with these two purified metabolites from the tri5-overexpressing transformant T. brevicompactum Tb41tri5 showed that only trichodermin had antifungal activity against Saccharomyces cerevisiae, Kluyveromyces marxianus, Candida albicans, Candida glabrata, Candida tropicalis and Aspergillus fumigatus, in most cases such activity being higher than that observed for amphotericin B and hygromycin. Our results point to the significant role of tri5 in the production of trichodermin and in the antifungal activity of T. brevicompactum.     

Global macroecology of bird assemblages in urbanized and semi‐natural ecosystems

Aim Despite the increasing pace of urbanization, little is known about how this process affects biodiversity globally. We investigate macroecological patterns of bird assemblages in urbanized areas relative to semi‐natural ecosystems. Location World‐wide. Methods We use a database of quantitative bird surveys to compare key assemblage structure parameters for plots in urbanized and semi‐natural ecosystems controlling for spatial autocorrelation and survey methodology. We use the term ‘urbanized’ instead of ‘urban’ ecosystems as many of the plots were not located in the centre of towns but in remnant habitat patches within conurbations. Results Some macroecological relationships were conserved in urbanized landscapes. Species–area, species–abundance and species–biomass relationships did not differ significantly between urbanized and non‐urbanized environments. However, there were differences in the relationships between productivity and assemblage structure. In forests, species richness increased with productivity; in both forests and open habitats, the evenness of species abundances declined as productivity increased. Among urbanized plots, instead, both species richness and the evenness of species abundances were independent of variation in productivity. Main conclusions Remnant habitats within urbanized areas are subject to many ecological alterations, yet key macroecological patterns differ remarkably little in urbanized versus non‐urbanized plots. Our results support the need for increased conservation activities in urbanized landscapes, particularly given the additional benefits of local experiences of biodiversity for the human population. With increasing urbanization world‐wide, broad‐scale efforts are needed to understand and manage the effects of this driver of change on biodiversity.     

Differential bone marrow homing capacity of VLA-4 and CD38 high expressing chronic lymphocytic leukemia cells

Background

VLA-4 and CD38 predict a poor clinical outcome in chronic lymphocytic leukemia (CLL). We used CLL samples with discordant VLA-4/CD38 risk to address their individual roles in human bone marrow infiltration (BM), CLL cell homing to murine BM, and in supportive CLL cell-stromal cell interactions.

Methods

VLA-4, CD38, and Ki-67 expression was measured in CLL cells from peripheral blood (PB) and bone marrow (BM) aspirates. CLL BM infiltration rates, routinely determined by Pathology, were correlated to VLA-4 and CD38 expression. Short-term homing capacity of CLL cells was evaluated by adoptive transfer experiments. CLL cell viability and adhesion in stromal cell co-culture was determined.

Results

About 20% of CLL samples in our cohort displayed discordant VLA-4 and CD38 risk, with either high VLA-4 and low CD38 risk or vice versa. Using particularly such samples, we observed that VLA-4, and not CD38, was responsible for recirculation of CLL cells to murine BM. Human BM infiltration was also significantly higher in patients with high VLA-4 risk but not high CD38 risk. However, both molecules acted as independent prognostic markers. While both VLA-4 and CD38 expression were increased in BM-derived CLL cells, and VLA-4+ and CD38+ subpopulations showed enriched Ki-67 expression, VLA-4 did not contribute to CLL cell protection by stromal cells in vitro.

Conclusions

Our data argue for a prominent role of VLA-4 but not CD38 expression in the homing of CLL cells to BM niches and in human BM infiltration,but only a limited role in their protection by stromal cells.     

Transgenic trees for a new era

Summary Traditional breeding has been widely used in forestry. However, this technique is inefficient because trees have a long and complex life cycle that is not amenable to strict control by man. Fortunately, the development of genetic engineering is offering new ways of breeding and allowing the incorporation of new traits in plant species through the introduction of foreign genes (transgenes). The introduction of selected traits can be used to increase the productivity and commercial value of trees and other plants. For example, some species have been endowed with resistance to herbicide and pathogens such as insects and fungi. Also, it has been possible to introduce genes that modify development and wood quality, and induce sexual sterility. The development of transgenic trees has required the implementation of in vitro regeneration techniques such as organogenesis and somatic embryogenesis. Release of transgenic species into the agricultural market requires a standardized biosafety regulatory frame and effective communication between the scientific community and society to dissipate the suspicions associated with transgenic products.     

Vascular function and sphingosine-1-phosphate regulate development of the dorsal pancreatic mesenchyme

Early growth and differentiation of the pancreatic endoderm is regulated by soluble factors from the pancreatic mesenchyme. Previously, we demonstrated that N-cadherin-deficient mice lack a dorsal pancreas, due to a critical role of N-cadherin in dorsal pancreatic mesenchymal cell survival. Here, we show that restoring cardiac and circulatory function in N-cadherin null mice by cardiac-specific expression of N-cadherin, rescues formation of the dorsal pancreas, indicating that the phenotype is secondary to defects related to cardiac/vascular function. Based on this observation, we demonstrate that soluble factors present in plasma, such as sphingosine-1-phosphate, rescue formation of the dorsal pancreas in N-cadherin-deficient mice. We also show that sphingosine-1-phosphate indirectly promotes budding of the pancreatic endoderm by stimulating pancreatic mesenchymal cell proliferation. Finally, we identify sphingosine-1-phosphate receptors within the mesenchyme and show that pertussis toxin blocks the sphingosine-1-phosphate-induced actions, suggesting the involvement of G-protein-coupled sphingosine-1-phosphate receptors. Thus, we propose a new model where blood vessel-derived sphingosine-1-phosphate stimulates growth and budding of the dorsal pancreatic endoderm by induction of mesenchymal cell proliferation.