Programming the magnitude and persistence of antibody responses with innate immunity

Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic cells via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines. Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines, which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques.     

A Pluto-like radius and a high albedo for the dwarf planet Eris from an occultation

The dwarf planet Eris is a trans-Neptunian object with an orbital eccentricity of 0.44, an inclination of 44 degrees and a surface composition very similar to that of Pluto. It resides at present at 95.7 astronomical units (1?AU is the Earth-Sun distance) from Earth, near its aphelion and more than three times farther than Pluto. Owing to this great distance, measuring its size or detecting a putative atmosphere is difficult. Here we report the observation of a multi-chord stellar occultation by Eris on 6 November 2010 UT. The event is consistent with a spherical shape for Eris, with radius 1,163?±?6?kilometres, density 2.52?±?0.05 grams per cm(3) and a high visible geometric albedo, Pv = 0.96(+0.09)(-0.04). No nitrogen, argon or methane atmospheres are detected with surface pressure larger than ～1?nanobar, about 10,000 times more tenuous than Pluto's present atmosphere. As Pluto's radius is estimated to be between 1,150 and 1,200 kilometres, Eris appears as a Pluto twin, with a bright surface possibly caused by a collapsed atmosphere, owing to its cold environment. We anticipate that this atmosphere may periodically sublimate as Eris approaches its perihelion, at 37.8 astronomical units from the Sun.     

基于加权主成分分析和改进密度峰值聚类的协同训练算法

[目的]针对协同训练算法在视图分割时未考虑噪声影响和两视图分类器对无标记样本标注不一致问题,提出了基于加权主成分分析和改进密度峰值聚类的协同训练算法.[方法]首先引入加权主成分分析对数据进行预处理,通过寻求初始有标记样本中特征和类标记之间的依赖关系求得各特征加权系数,再对加权变换后的数据进行降维并提取高贡献度特征进行视...     

Space use by two arboreal rodent species in a Neotropical cloud forest

Studying animal space use patterns can help increase our understating of ecological processes such as competition and community dynamics. To quantify space and habitat use in an isolated and patchy cloud forest community in Mexico, we evaluate the vertical stratification, home range and habitat selection of two arboreal rodents: Habromys schmidlyi and Reithrodontomys microdon. Using live-traps at ground level and different forest strata, we radio-equipped nine individuals of H. schmidlyi and seven of R. microdon, and evaluated fine-scale space use and broad-scale habitat selection between cloud forest and oak forest. We found an average home range of 0.24 ha for R. microdon males and 0.72 ha for females, with a preference for higher canopy in the cloud forest. For H. schmidlyi the home range was 0.83 ha for males and 0.29 ha for females, with a preference for the understory level in the cloud forest. Home range is three-dimensional for these rodents, so we estimate that on average, individuals of both species used eight trees in the time they were tracked. We characterised the vegetation at the trap sites, and used recursive partitioning to relate the presence of different plants with the probability of finding these two species and Peromyscus aztecus, a third rodent species also present in the area and considered in our analysis of habitat use. The highest probability of finding R. microdon (96%) was related to the presence of Brachythecium occidentale and Renauldia mexicana, while H. schmidlyi (95%) was found in close proximity to Fabronia ciliaris and Everniastrum. We highlight the importance of arboreal trapping in biodiversity assessments, and the role of arboreal rodents in maintaining tropical forest ecosystems. We suggest that these rodent species could avoid or reduce competition by using the vertical strata differentially, and that H. schmidlyi and R. microdon can be biological indicators for cloud forest management and conservation.     

Regulation of primary cilia formation and left-right patterning in zebrafish by a noncanonical Wnt signaling mediator, duboraya

Primary cilia are microtubule-based organelles that project from the surface of nearly every animal cell. Although important functions of primary cilia in morphogenesis and tissue homeostasis have been identified, the mechanisms that control the formation of primary cilia are not understood. Here we characterize a zebrafish gene, termed duboraya (dub), that is essential for ciliogenesis. Knockdown of dub in zebrafish embryos results in both defects in primary cilia formation in Kupffer's vesicle and randomization of left-right organ asymmetries. We show that, at the molecular level, the function of dub in ciliogenesis is regulated by phosphorylation, which in turn depends on Frizzled-2-mediated noncanonical Wnt signaling. We also provide evidence that, at the cellular level, dub function is essential for actin organization in the cells lining Kupffer's vesicle. Taken together, our findings identify a molecular factor that links noncanonical Wnt signaling with the control of left-right axis specification, and provide an entry point for analyzing the mechanisms that regulate primary cilia formation.     

On the mechanism of inhibition of p27 degradation by 15-deoxy-Δ12,14-prostaglandin J 2 in lymphoblasts of Alzheimer’s disease patients

It has been proposed that neuroinflammation, among other factors, may trigger an aberrant neuronal cell cycle re-entry leading to neuronal death. Cell cycle disturbances are also detectable in peripheral cells from Alzheimer’s disease (AD) patients. We previously reported that the anti-inflammatory 15- deoxy-Δ^12,14-prostaglandin J ₂ (15d-PGJ ₂) increased the cellular content of the cyclin-dependent kinase inhibitor p27, in lymphoblasts from AD patients. This work aimed at elucidating the mechanisms of 15d-PGJ ₂-induced p27 accumulation. Phosphorylation, half-life, and the nucleo-cytoplasmic traffic of p27 protein were altered by 15d-PGJ2 by mechanisms dependent on PI3K/Akt activity. 15d-PGJ ₂ prevents the calmodulin-dependent Akt overactivation in AD lymphoblasts by blocking its binding to the 85-kDa regulatory subunit of PI3K. These effects of 15d-PGJ ₂ were not mimicked by 9,10-dihydro-15-deoxy-Δ^12,14- prostaglandin J ₂, suggesting that 15d-PGJ ₂ acts independently of peroxisome proliferator-activated receptor γ activation and that the α,β-unsaturated carbonyl group in the cyclopentenone ring of 15d-PGJ ₂ is a requisite for the observed effects. Received 14 July 2008; received after revision 2 September 2008; accepted 12 September 2008     

Common variants on 1p36 and 1q42 are associated with cutaneous basal cell carcinoma but not with melanoma or pigmentation traits

To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide SNP association study of 930 Icelanders with BCC and 33,117 controls. After analyzing 304,083 SNPs, we observed signals from loci at 1p36 and 1q42, and replicated these associations in additional sample sets from Iceland and Eastern Europe. Overall, the most significant signals were from rs7538876 on 1p36 (OR = 1.28, P = 4.4 x 10(-12)) and rs801114 on 1q42 (OR = 1.28, P = 5.9 x 10(-12)). The 1p36 locus contains the candidate genes PADI4, PADI6, RCC2 and ARHGEF10L, and the gene nearest to the 1q42 locus is the ras-homolog RHOU. Neither locus was associated with fair pigmentation traits that are known risk factors for BCC, and no risk was observed for melanoma. Approximately 1.6% of individuals of European ancestry are homozygous for both variants, and their estimated risk of BCC is 2.68 times that of noncarriers.     

战区物资调运数学模型研究

如何优化分配,合理调运,及时准确地完成后勤保障任务,是现代战争中战区物资调运面临的重要问题之一.基于运输问题,就现代战争条件下战区物资调运问题的各种情况建立了数学模型.该模型可用于后勤物资保障的决策支持系统及指挥自动化系统,为解决战时后勤保障供应问题提供了新的理论方法和思路.     

一种采用混合进制的算术编码

针对许多实际应用中需要同时编码压缩来自多种不同符号集的数据,提出一种采用混合进制的算术编码,提高编码效率的同时增强了算术编码的抗误码扩散能力.从理论上分析了该算法并给出了实现过程.处理小波零树系数以及随机混合数据的实验结果表明,该算法明显优于单一进制的编码算法.