Gammadelta T cells are present in the mucosal intestinal epithelia and secrete factors necessary to maintain tissue integrity. Ags recognized by these cells are poorly defined, although in mice non-classical MHC class I molecules have been implicated. Since MHC class I-like CD1 receptors are widely expressed at the surface of epithelial and dendritic intestinal cells and have the capacity to present lipid Ags to T cells, we hypothesized that these molecules might present autologous and/or exogenous phospholipids to intestinal gammadelta T lymphocytes. Intraepithelial T lymphocytes from normal human duodenal mucosal biopsies were cloned and exposed to natural and synthetic phospholipids using CD1a-, CD1b-, CD1c- or CD1d-transfected C1R lymphoblastoid or HeLa cell lines as APCs. Their cytolytic properties and regulatory cytokine secretion were also examined. Most clones obtained from duodenal mucosa (up to 70%) were TCRalphabeta+, and either CD4+ or CD8+, whereas 20% were CD4-CD8- (6 clones) or TCRgammadelta+ (12 clones). A relevant percentage (up to 66%) of TCRgammadelta+ but few (<5%) TCRalphabeta+ T cell clones responded to synthetic and/or natural phospholipids presented by CD1 molecules, as measured by both [(3)H]thymidine incorporation and IL-4 release assays. A Th1-like cytolytic and functional activity along with the ability to secrete regulatory cytokines was observed in most phospholipid-specific gammadelta T cell clones. Thus, a substantial percentage of TCRgammadelta+ but few TCRalphabeta+ from human duodenal mucosa recognize exogenous phospholipids in a CD1-restricted fashion. This adaptive response could contribute to mucosal homeostasis, but could also favor the emergence of inflammatory or allergic intestinal diseases. 相似文献
We herein report the optimization of cyclopentane- and cyclohexane-1,3-diamine derivatives as novel and potent MCH-R1 antagonists. Structural modifications of the 2-amino-quinoline and thiophene moieties found in the initial lead compound served to improve its metabolic stability profile and MCH-R1 affinity, and revealed unprecedented SAR when compared to other 2-amino-quinoline-containing MCH-R1 antagonists. 相似文献
Land abandonment is causing woodland expansion and loss of open habitats in the Alps, coupled with a shift in forestry practices
from coppice management to high forest. Despite such rapid large-scale changes, there has been very little investigation of
the environmental predictors of biodiversity in the Alpine landscape. We assessed the richness of amphibians, reptiles and
breeding birds (n = 189 species), used as a surrogate of biodiversity, in 58 quadrats of 100 km2, located within a well surveyed area of the province of Trento (central-eastern Italian Alps). The surrogates were then related
to a series of environmental variables by means of stepwise multiple regression. Depending on the surrogate analysed, species
richness declined linearly or quadratically with elevation, and increased with habitat heterogeneity and the availability
of grassland and arid-rocky habitats. The same results were obtained when incorporating a measure of species threat into the
biodiversity estimates. Different surrogates were positively inter-correlated, probably because of a common response to the
same factor, namely elevation, which was the only variable to enter all models. Such elevational gradient produced a clear
biodiversity peak in low-elevation areas, generating potential conflict between efficient biodiversity conservation and economic
interests linked to human development, a scenario which probably applies to many mountain regions worldwide. The current network
of protected areas was quite satisfactory in terms of area covered but biased towards high-elevation areas, of high scenic
beauty but relatively low in animal biodiversity value. Low-elevation reserves were small and isolated. Proposed conservation
targets include the establishment of corridors increasing the connectivity of low-elevation reserves and the promotion of
incentives for the extensive management of grassland, an agro-ecosystem of high historical and biological value. 相似文献
T(H)17 lymphocytes appear to be essential in the pathogenesis of numerous inflammatory diseases. We demonstrate here the expression of IL-17 and IL-22 receptors on blood-brain barrier endothelial cells (BBB-ECs) in multiple sclerosis lesions, and show that IL-17 and IL-22 disrupt BBB tight junctions in vitro and in vivo. Furthermore, T(H)17 lymphocytes transmigrate efficiently across BBB-ECs, highly express granzyme B, kill human neurons and promote central nervous system inflammation through CD4+ lymphocyte recruitment. 相似文献
MOTIVATION: Several kernel-based methods have been recently introduced for the classification of small molecules. Most available kernels on molecules are based on 2D representations obtained from chemical structures, but far less work has focused so far on the definition of effective kernels that can also exploit 3D information. RESULTS: We introduce new ideas for building kernels on small molecules that can effectively use and combine 2D and 3D information. We tested these kernels in conjunction with support vector machines for binary classification on the 60 NCI cancer screening datasets as well as on the NCI HIV data set. Our results show that 3D information leveraged by these kernels can consistently improve prediction accuracy in all datasets. AVAILABILITY: An implementation of the small molecule classifier is available from http://www.dsi.unifi.it/neural/src/3DDK. 相似文献
The present study investigates the survival and fate of neural stem cells/progenitor cells (NSC/NPCs) homografted into the
hippocampus of rats treated with trimethyltin (TMT), a potent neurotoxicant considered a useful tool to obtain a well characterized
model of neurodegeneration, to evaluate their possible role in the reparative mechanisms that accompany neurodegenerative
events. NSC/NPCs expressing eGFP by lentivirus-mediated infection were stereotaxically grafted into the hippocampus of TMT-treated
animals and controls. Two weeks after transplantation surviving NSC/NPCs were detectable in 60% of TMT-treated animals and
30% of controls, while 30 days after transplantation only 40% of TMT-treated animals showed surviving grafted cells, which
were undetectable in controls. At both times investigated, while grafted NSC/NPCs differentiated into neurons or astrocytes
could be observed in addition to undifferentiated NSC/NPCs, we did not find evidence of structural integration of grafted
cells into the main site of hippocampal lesion leading to appreciable repair.
Maria Concetta Geloso and Stefano Giannetti contributed equally to this work. 相似文献
Occupational and chronic exposure to solvents and metals is considered a possible risk factor for Parkinson's disease and
essential tremor. While manufacturing dental prostheses, dental technicians are exposed to numerous chemicals that contain
toxins known to affect the central nervous system, such as solvents (which contain n-hexane in particular) and metals (which
contain mercury, iron, chromium, cobalt and nickel). 相似文献
The number of completely sequenced plastid genomes available is growing rapidly. This array of sequences presents new opportunities to perform comParative analyses. In comParative studies, it is often useful to compare across wide phylogenetic spans and, within angiosperms, to include representatives from basally diverging lineages such as the genomes reported here: Nuphar advena (from a basal-most lineage) and Ranunculus macranthus (a basal eudicot). We report these two new plastid genome sequences and make comparisons (within angiosperms, seed plants, or all photosynthetic lineages) to evaluate features such as the status of ycf15 and ycf68 as protein coding genes, the distribution of simple sequence repeats (SSRs) and longer dispersed repeats (SDR), and patterns of nucleotide composition.
Results
The Nuphar [GenBank:NC_008788] and Ranunculus [GenBank:NC_008796] plastid genomes share characteristics of gene content and organization with many other chloroplast genomes. Like other plastid genomes, these genomes are A+T-rich, except for rRNA and tRNA genes. Detailed comparisons of Nuphar with Nymphaea, another Nymphaeaceae, show that more than two-thirds of these genomes exhibit at least 95% sequence identity and that most SSRs are shared. In broader comparisons, SSRs vary among genomes in s of abundance and length and most contain repeat motifs based on A and T nucleotides.
Conclusion
SSR and SDR abundance varies by genome and, for SSRs, is proportional to genome size. Long SDRs are rare in the genomes assessed. SSRs occur less frequently than predicted and, although the majority of the repeat motifs do include A and T nucleotides, the A+T bias in SSRs is less than that predicted from the underlying genomic nucleotide composition. In codon usage third positions show an A+T bias, however variation in codon usage does not correlate with differences in A+T-richness. Thus, although plastome nucleotide composition shows "A+T richness", an A+T bias is not apparent upon more in-depth analysis, at least in these aspects. The pattern of evolution in the sequences identified as ycf15 and ycf68 is not consistent with them being protein-coding genes. In fact, these regions show no evidence of sequence conservation beyond what is normal for non-coding regions of the IR. 相似文献
Zinc (Zn2+) is believed to play a relevant role in the physiology and pathophysiology of the brain. Hence, Zn2+ homeostasis is critical and involves different classes of molecules, including Zn2+ transporters. The ubiquitous Zn2+ transporter‐1 (ZNT‐1) is a transmembrane protein that pumps cytosolic Zn2+ to the extracellular space, but its function in the central nervous system is not fully understood. Here, we show that ZNT‐1 interacts with GluN2A‐containing NMDA receptors, suggesting a role for this transporter at the excitatory glutamatergic synapse. First, we found that ZNT‐1 is highly expressed at the hippocampal postsynaptic density (PSD) where NMDA receptors are enriched. Two‐hybrid screening, coimmunoprecipitation experiments and clustering assay in COS‐7 cells demonstrated that ZNT‐1 specifically binds the GluN2A subunit of the NMDA receptor. GluN2A deletion mutants and pull‐down assays indicated GluN2A(1390–1464) domain as necessary for the binding to ZNT‐1. Most importantly, ZNT‐1/GluN2A complex was proved to be dynamic, since it was regulated by induction of synaptic plasticity. Finally, modulation of ZNT‐1 expression in hippocampal neurons determined a significant change in dendritic spine morphology, PSD‐95 clusters and GluN2A surface levels, supporting the involvement of ZNT‐1 in the dynamics of excitatory PSD.