Viral infection switches non-plasmacytoid dendritic cells into high interferon producers

Type I interferons (IFN-I) are important cytokines linking innate and adaptive immunity. Plasmacytoid dendritic cells make high levels of IFN-I in response to viral infection and are thought to be the major source of the cytokines in vivo. Here, we show that conventional non-plasmacytoid dendritic cells taken from mice infected with a dendritic-cell-tropic strain of lymphocytic choriomeningitis virus make similarly high levels of IFN-I on subsequent culture. Similarly, non-plasmacytoid dendritic cells secrete high levels of IFN-I in response to double-stranded RNA (dsRNA), a major viral signature, when the latter is introduced into the cytoplasm to mimic direct viral infection. This response is partially dependent on the cytosolic dsRNA-binding enzyme protein kinase R and does not require signalling through toll-like receptor (TLR) 3, a surface receptor for dsRNA. Furthermore, we show that sequestration of dsRNA by viral NS1 (refs 6, 7) explains the inability of conventional dendritic cells to produce IFN-I on infection with influenza. Our results suggest that multiple dendritic cell types, not just plasmacytoid cells, can act as specialized interferon-producing cells in certain viral infections, and reveal the existence of a TLR-independent pathway for dendritic cell activation that can be the target of viral interference.     

Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination

Myelination of axons by oligodendrocytes enables rapid impulse propagation in the central nervous system. But long-term interactions between axons and their myelin sheaths are poorly understood. Here we show that Cnp1, which encodes 2',3'-cyclic nucleotide phosphodiesterase in oligodendrocytes, is essential for axonal survival but not for myelin assembly. In the absence of glial cyclic nucleotide phosphodiesterase, mice developed axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death. But, in contrast to previously studied myelin mutants, the ultrastructure, periodicity and physical stability of myelin were not altered in these mice. Genetically, the chief function of glia in supporting axonal integrity can thus be completely uncoupled from its function in maintaining compact myelin. Oligodendrocyte dysfunction, such as that in multiple sclerosis lesions, may suffice to cause secondary axonal loss.     

Cicuta bulbifera L. (Umbelliferae) in Alaska

Cited are distribution records for Alaska of Cicuta bulbifera L. It was discovered growing in the Nowitna National Wildlife Refuge in north central Alaska in 1984 and again in 1987. An earlier record is also known from near Fairbanks.     

Differential lethality in developmental stages ofDrosophila following X-irradiation

Summary ADrosophila melanogaster line has been treated with ionizing radiations. The dose-response relationship has been studied upon separate treatment of male and female gametes. The results show that while the total survival is similar, at different developmental stages differences can be observed between progenies from treated male and female gametes. It is suggested that developmental patterns may affect the expression of induced mutations.     

Intercepting the first rat ashore

A single Norway rat released on to a rat-free island was not caught for more than four months, despite intensive efforts to trap it. The rat first explored the 9.5-hectare island and then swam 400 metres across open water to another rat-free island, evading capture for 18 weeks until an aggressive combination of detection and trapping methods were deployed simultaneously. The exceptional difficulty of this capture indicates that methods normally used to eradicate rats in dense populations are unlikely to be effective on small numbers, a finding that could have global implications for conservation on protected islands.     

Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer

A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.     

基于人类行为下的多目标跟踪视觉时序注意控制算法研究(英文)

由于移动式机器人所携带的传感器资源有限,能够在时间维度上共享传感器资源,实现多目标跟踪,是智能化机器人重要的研究领域之一.本文提出了一个基于人类行为模型的时序注意控制算法,能够实现使用单个2自由度摄像头实时监控多个自由移动的目标物体.该算法基于以下三个控制原则:①最小化监控目标位置预测的不确定性以及各个目标物预测效果的差异;②最小化多目标跟踪过程中摄像头切换视角所需的能量消耗;③最大化能够呈现在摄像头视觉范围内的目标物体的个数.算法根据当前检测到目标信息,通过卡尔曼滤波,预测目标物的运动规律,选择下一时刻摄像头的最佳注意视角.该算法通过matlab仿真以及在移动式机器人实体上进行了实验验证,结果显示,该算法能够在时间顺序有效的共享单个摄像头资源,检测摄像头视角范围内的目标的位置,并根据上一个时间点的检测信息预测视角范围外的目标,实现跟踪多个目标物体,降低预测及跟踪的误差,并优化跟踪过程中切换摄像头视角的能量损耗.     

An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection

Herpes simplex virus 2 (HSV-2) infection causes significant morbidity and is an important cofactor for the transmission of HIV infection. A microbicide to prevent sexual transmission of HSV-2 would contribute substantially to controlling the spread of HIV and other infections. Because RNA interference (RNAi) provides effective antiviral defence in plants and other organisms, several studies have focused on harnessing RNAi to inhibit viral infection. Here we show that vaginal instillation of small interfering RNAs (siRNAs) targeting HSV-2 protects mice from lethal infection. siRNAs mixed with lipid are efficiently taken up by epithelial and lamina propria cells and silence gene expression in the mouse vagina and ectocervix for at least nine days. Intravaginal application of siRNAs targeting the HSV-2 UL27 and UL29 genes (which encode an envelope glycoprotein and a DNA binding protein, respectively) was well tolerated, did not induce interferon-responsive genes or cause inflammation, and protected mice when administered before and/or after lethal HSV-2 challenge. These results suggest that siRNAs are attractive candidates for the active component of a microbicide designed to prevent viral infection or transmission.