The Candida albicans factor MNN9 modulates cytokine production in distinct epithelial cell types

The opportunistic fungal pathogen Candida albicans colonizes mucosal surfaces of the majority of healthy human individuals. However, the fungus can cause superficial infections in otherwise healthy people and could develop life-threatening systemic candidiasis in immunocompromised patients. Mucosal epithelial cells can discriminate between the commensal and pathogenic lifestyle of C. albicans by the activation of a biphasic MAPK mediated by pattern recognition receptors resulting in a cytokine response. This study aimed to compare the cytokine release from oral mucosal epithelial cells with parenchymal hepatic and renal epithelial cells. As a result, C. albicans infection caused epithelial damage with susceptibility differing between cell lines, and induced an innate immune response by a core secretion of the inflammatory cytokines IL-6 and IL-8, and additionally by the secretion of cell line-specific cytokines. Furthermore, the epithelial immune response can be modulated by C. albicans factors that was observed during a large-scale host response screening. This study focused on Mnn9 that is crucial for the N-mannosylation of the cell wall and therefore has an influence on host recognition. A deletion in the MNN9 gene induced stronger inflammatory cytokine releases by hepatic and oral epithelial cells without altering the damage potential, suggesting differences in the activation of MAPK signaling. Indeed, while the MNN9 mutant induced a delayed activation of oral MKP1, ERK1/2 and JNK, consistent phosphorylation indicates stronger and prolonged activation of all three MAPK pathways during infection that could explain the increased cytokine release. Taken together, this study could show that the epithelial immune activation in response to C. albicans differs not only between mucosal and parenchymal cells, it is also cell type-specific. Moreover, the cytokine secretion can be modulated by alterations in the fungal cell wall in the absence of Mnn9

Research and Design of a Routing Protocol in Large-Scale Wireless Sensor Networks

无线传感器网络，作为全球未来十大技术之一，集成了传感器技术、嵌入式计算技术、分布式信息处理和自组织网技术，可实时感知、采集、处理、传输网络分布区域内的各种信息数据，在军事国防、生物医疗、环境监测、抢险救灾、防恐反恐、危险区域远程控制等领域具有十分广阔的应用前景。 本文研究分析了无线传感器网络的已有路由协议，并针对大规模的无线传感器网络设计了一种树状路由协议，它根据节点地址信息来形成路由，从而简化了复杂繁冗的路由表查找和维护，节省了不必要的开销，提高了路由效率，实现了快速有效的数据传输。 为支持此路由协议本文提出了一种自适应动态地址分配算——ADAR（AdaptiveDynamicAddre...As one of the ten high technologies in the future, wireless sensor network, which is the integration of micro-sensors, embedded computing, modern network and Ad Hoc technologies, can apperceive, collect, process and transmit various information data within the region. It can be used in military defense, biomedical, environmental monitoring, disaster relief, counter-terrorism, remote control of haz...学位：工学硕士院系专业：信息科学与技术学院通信工程系_通信与信息系统学号：2332007115216

Candida albicans-induced epithelial damage mediates translocation through intestinal barriers

ABSTRACT Life-threatening systemic infections often occur due to the translocation of pathogens across the gut barrier and into the bloodstream. While the microbial and host mechanisms permitting bacterial gut translocation are well characterized, these mechanisms are still unclear for fungal pathogens such as Candida albicans, a leading cause of nosocomial fungal bloodstream infections. In this study, we dissected the cellular mechanisms of translocation of C. albicans across intestinal epithelia in vitro and identified fungal genes associated with this process. We show that fungal translocation is a dynamic process initiated by invasion and followed by cellular damage and loss of epithelial integrity. A screen of >2,000 C. albicans deletion mutants identified genes required for cellular damage of and translocation across enterocytes. Correlation analysis suggests that hypha formation, barrier damage above a minimum threshold level, and a decreased epithelial integrity are required for efficient fungal translocation. Translocation occurs predominantly via a transcellular route, which is associated with fungus-induced necrotic epithelial damage, but not apoptotic cell death. The cytolytic peptide toxin of C. albicans, candidalysin, was found to be essential for damage of enterocytes and was a key factor in subsequent fungal translocation, suggesting that transcellular translocation of C. albicans through intestinal layers is mediated by candidalysin. However, fungal invasion and low-level translocation can also occur via non-transcellular routes in a candidalysin-independent manner. This is the first study showing translocation of a human-pathogenic fungus across the intestinal barrier being mediated by a peptide toxin. IMPORTANCE Candida albicans, usually a harmless fungus colonizing human mucosae, can cause lethal bloodstream infections when it manages to translocate across the intestinal epithelium. This can result from antibiotic treatment, immune dysfunction, or intestinal damage (e.g., during surgery). However, fungal processes may also contribute. In this study, we investigated the translocation process of C. albicans using in vitro cell culture models. Translocation occurs as a stepwise process starting with invasion, followed by epithelial damage and loss of epithelial integrity. The ability to secrete candidalysin, a peptide toxin deriving from the hyphal protein Ece1, is key: C. albicans hyphae, secreting candidalysin, take advantage of a necrotic weakened epithelium to translocate through the intestinal layer

Rapid proliferation due to better metabolic adaptation results in full virulence of a filament-deficient Candida albicans strain.

The ability of the fungal pathogen Candida albicans to undergo a yeast-to-hypha transition is believed to be a key virulence factor, as filaments mediate tissue damage. Here, we show that virulence is not necessarily reduced in filament-deficient strains, and the results depend on the infection model used. We generate a filament-deficient strain by deletion or repression of EED1 (known to be required for maintenance of hyphal growth). Consistent with previous studies, the strain is attenuated in damaging epithelial cells and macrophages in vitro and in a mouse model of intraperitoneal infection. However, in a mouse model of systemic infection, the strain is as virulent as the wild type when mice are challenged with intermediate infectious doses, and even more virulent when using low infectious doses. Retained virulence is associated with rapid yeast proliferation, likely the result of metabolic adaptation and improved fitness, leading to high organ fungal loads. Analyses of cytokine responses in vitro and in vivo, as well as systemic infections in immunosuppressed mice, suggest that differences in immunopathology contribute to some extent to retained virulence of the filament-deficient mutant. Our findings challenge the long-standing hypothesis that hyphae are essential for pathogenesis of systemic candidiasis by C. albicans

International Large Detector: Interim Design Report

The ILD detector is proposed for an electron-positron collider with collision centre-of-mass energies from 90~\GeV~to about 1~\TeV. It has been developed over the last 10 years by an international team of scientists with the goal to design and eventually propose a fully integrated detector, primarily for the International Linear Collider, ILC. In this report the fundamental ideas and concepts behind the ILD detector are discussed and the technologies needed for the realisation of the detector are reviewed. The document starts with a short review of the science goals of the ILC, and how the goals can be achieved today with the detector technologies at hand. After a discussion of the ILC and the environment in which the experiment will take place, the detector is described in more detail, including the status of the development of the technologies foreseen for each subdetector. The integration of the different sub-systems into an integrated detector is discussed, as is the interface between the detector and the collider. This is followed by a concise summary of the benchmarking which has been performed in order to find an optimal balance between performance and cost. To the end the costing methodology used by ILD is presented, and an updated cost estimate for the detector is presented. The report closes with a summary of the current status and of planned future actions

The ILD detector at the ILC

The International Large Detector, ILD, is a detector concept which has been developed for the electron-positron collider ILC. The detector has been optimized for precision physics in a range of energies between 90 GeV and 1 TeV. ILD features a high precision, large volume combined silicon and gaseous tracking system, together with a high granularity calorimeter, all inside a 3.5 T solenoidal magnetic field. The paradigm of particle flow has been the guiding principle of the design of ILD. In this document the required performance of the detector, the proposed implementation and the readiness of the different technologies needed for the implementation are discussed. This is done in the framework of the ILC collider proposal, now under consideration in Japan, and includes site specific aspects needed to build and operate the detector at the proposed ILC site in Japan