Einfluss des Treg-Aktivierungsmarkers GARP auf die Differenzierung und Funktion von T-Zellen

CD4+CD25+FoxP3+ regulatorische T-Zellen (Treg) spielen eine essentielle Rolle bei der Unterdrückung von schädlichen Immunreaktionen. Da aktivierte CD4+ T-Helferzellen auch CD25 und FoxP3 exprimieren, können diese nicht als spezifische Marker zur Identifikation von Treg verwendet werden. Die Analyse der Membranproteinexpression beider Populationen führte zur Identifikation von GARP (glycoprotein A repetitions predominant) als spezifischer Marker auf aktivierten Treg. GARP bindet LAP und TGF-beta, welches für die Unterdrückung von entzündlichen T-Zellantworten von Bedeutung ist. Um die Funktion von GARP unabhängig von Treg zu untersuchen, wurde ein lösliches GARP Protein (sGARP) synthetisiert und sein Effekt auf die Aktivierung und Differenzierung von humanen T-Zellen untersucht. Die Ergebnisse zeigen, dass sGARP die Proliferation von naiven CD4+ T-Zellen supprimiert und zu einer Phosphorylierung von SMAD2/3 sowie zu der Induktion von FoxP3 führt. Zusätzlich inhibiert sGARP die Produktion von Effektorzytokinen wie IL-2 und IFN-gamma. Die Stimulation von naiven CD4+ T-Zellen mit sGARP induziert die Differenzierung zu Treg, welche in Kokultur die Aktivierung von T-Effektorzellen supprimieren. Die Wirkung war vergleichbar in naiven CD4+ und ruhenden CD4+CD45RA+ T-Zellen, konnte aber in differenzierten CD4+CD45RO+ T-Zellen nicht nachgewiesen werden. Die Induktion von FoxP3 und die Phosphorylierung von SMAD2/3 konnte durch eine Blockade des TGF-beta-Signalweges inhibiert werden. Dies lässt vermuten, dass die Funktion von sGARP zumindest teilweise von TGF-beta abhängig ist. Zusätzlich zu seiner passiven Rolle als TGF-beta-Transporter, induzierte sGARP die TGF-beta-Produktion in naiven T-Zellen und trägt so zum Mechanismus der infektiösen Toleranz bei. Des Weiteren fördert die Stimulation von sGARP in Anwesenheit von IL-6 und IL-23 die Differenzierung zu Th17 Zellen. rnNeben dem Einfluss von sGARP auf die Differenzierung von CD4+ T-Zellen, supprimiert sGARP die Proliferation und Granzyme B-Expression in CD8+ T-Zellen. rnFür die Analyse der immunmodulatorischen Funktion von sGARP in vivo wurde ein Modell einer xenogenen GvHD (graft-versus-host disease) verwendet. Der Transfer von humanen PBMC in neugeborene, immundefiziente Rag2-/-gamma-chain-/--Mäuse führt zu einer letalen GvHD, welche durch die Applikation von humanen Treg dosisabhängig unterdrückt werden kann. In diesem Modell konnte die repetitive Gabe von sGARP, ohne zusätzliche Zugabe von Treg, ebenfalls die GvHD unterdrücken. Dies lässt auf einen synergistischen Effekt von sGARP und Treg bei der Suppression inflammatorischer T-Zellantworten schließen. rnZusammengefasst lassen die Ergebnisse auf eine entscheidende Rolle von GARP in der Modulation der peripheren Toleranz folgern und zeigen sGARP als potentes Biological für die Behandlung von unerwünschten inflammatorischen Immunantworten.

Radiation balance of the tropical ocean surface measured during Atlantic Expedition GARP 1974 (Table 1)

The net flux of all irreversible fluxes of radiation and heat crossing the ocean surface is determined for phase III of GATE at position no. 27 (WFS "Planet", FRG). The radiation fluxes have been measured directly, while the heat fluxes have been parameterized with the bulk formula however with bulk coefficients depending on stability. The heat loss of the ocean due to warming of the cooler precipitation is included for the determination of the net flux at the ocean surface. Some examples of hourly mean values of different fluxes during different weather conditions are additionally shown.

The flow of reality’s development: from postmodernism to post-postmodernism in John Irving’s The World According to Garp and Last Night in Twisted River

In this master’s thesis, I examine the development of writer-characters and metafiction from John Irving’s The World According to Garp to Last Night in Twisted River and how this development relates to the development of late twentieth century postmodern literary theory to twenty-first century post-postmodern literary theory. The purpose of my study is to determine how the prominently postmodern feature metafiction, created through the writer-character’s stories-within-stories, has changed in form and function in the two novels published thirty years apart from one another, and what possible features this indicates for future post-postmodern theory. I establish my theoretical framework on the development of metafiction largely on late twentieth-century models of author and authorship as discussed by Roland Barthes, Wayne Booth and Michel Foucault. I base my close analysis of metafiction mostly on Linda Hutcheon’s model of overt and covert metafiction. At the end of my study, I examine Irving’s later novel through Suzanne Rohr’s models of reality constitution and fictional reality. The analysis of the two novels focuses on excerpts that feature the writer-characters, their stories-within-stories and the novels’ other characters and the narrators’ evaluations of these two. I draw examples from both novels, but I illustrate my choice of focus on the novels at the beginning of each section. Through this, I establish a method of analysis that best illustrates the development as a continuum from pre-existing postmodern models and theories to the formation of new post-postmodern theory. Based on my findings, the thesis argues that twenty-first century literary theory has moved away from postmodern overt deconstruction of the narrative and its meaning. New post-postmodern literary theory reacquires the previously deconstructed boundaries that define reality and truth and re-establishes them as having intrinsic value that cannot be disputed. In establishing fictional reality as self-governing and non-intrudable, post-postmodern theory takes a stance against postmodern nihilism, which indicates the re-founded, non-questionable value of the text’s reality. To continue mapping other possible features of future post-postmodern theory, I recommend further analysis solely on John Irving’s novels’ published in the twenty-first century.

Identification of IL6R and chromosome 11q13.5 as risk loci for asthma

We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26 475), and these were tested in an additional 25 358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57 800): rs4129267 (OR 1·09, combined p= 2·4×10-8) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10-8) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10-4), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2. The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma. National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix. © 2011 Elsevier Ltd.

Landslide Susceptible Locations in Western Ghats: Prediction through openModeller

Many shallow landslides are triggered by heavy rainfall on hill slopes resulting in enormous casualties and huge economic losses in mountainous regions. Hill slope failure usually occurs as soil resistance deteriorates in the presence of the acting stress developed due to a number of reasons such as increased soil moisture content, change in land use causing slope instability, etc. Landslides triggered by rainfall can possibly be foreseen in real time by jointly using rainfall intensity-duration and information related to land surface susceptibility. Terrain analysis applications using spatial data such as aspect, slope, flow direction, compound topographic index, etc. along with information derived from remotely sensed data such as land cover / land use maps permit us to quantify and characterise the physical processes governing the landslide occurrence phenomenon. In this work, the probable landslide prone areas are predicted using two different algorithms – GARP (Genetic Algorithm for Rule-set Prediction) and Support Vector Machine (SVM) in a free and open source software package - openModeller. Several environmental layers such as aspect, digital elevation data, flow accumulation, flow direction, slope, land cover, compound topographic index, and precipitation data were used in modelling. A comparison of the simulated outputs, validated by overlaying the actual landslide occurrence points showed 92% accuracy with GARP and 96% accuracy with SVM in predicting landslide prone areas considering precipitation in the wettest month whereas 91% and 94% accuracy were obtained from GARP and SVM considering precipitation in the wettest quarter of the year.

Predictive distribution modeling for rare Himalayan medicinal plant Berberis aristata DC

Predictive distribution modelling of Berberis aristata DC, a rare threatened plant with high medicinal values has been done with an aim to understand its potential distribution zones in Indian Himalayan region. Bioclimatic and topographic variables were used to develop the distribution model with the help of three different algorithms viz. GeneticAlgorithm for Rule-set Production (GARP), Bioclim and Maximum entroys(MaxEnt). Maximum entropy has predicted wider potential distribution (10.36%) compared to GARP (4.63%) and Bioclim (2.44%). Validation confirms that these outputs are comparable to the present distribution pattern of the B. atistata. This exercise highlights that this species favours Western Himalaya. However, GARP and MaxEnt's prediction of Eastern Himalayan states (i.e. Arunachal Pradesh, Nagaland and Manipur) are also identified as potential occurrence places require further exploration.

Prediction of Shallow Landslide prone regions in Undulating Terrains

Genetic Algorithm for Rule-set Prediction (GARP) and Support Vector Machine (SVM) with free and open source software (FOSS) - Open Modeller were used to model the probable landslide occurrence points. Environmental layers such as aspect, digital elevation, flow accumulation, flow direction, slope, land cover, compound topographic index and precipitation have been used in modeling. Simulated output of these techniques is validated with the actual landslide occurrence points, which showed 92% (GARP) and 96% (SVM) accuracy considering precipitation in the wettest month and 91% and 94% accuracy considering precipitation in the wettest quarter of the year.

Note sur les biomasses pélagiques évaluées par écho-intégration dans la zone équatoriale du Golfe de Guinée: premiers résultats

An Echo-Integration survey on the equator made during he GARP Atlantic Tropical Experiment indicated an important biomass in the layer 0/100m. The changes of that biomass have been connected to hydrological conditions. Measurements of target strength have been made, and the biggest schools have been measured.

苋属入侵种的可能分布区预测及相关环境因子分析

苋属（Amaranthus）约40种，世界均有分布。我国有20种，分布很广，其中外来种为17种(11种为入侵种)，危害旱田作物、果树、茶树和蔬菜。反枝苋（Amaranthus retroflexus L.）是苋属入侵种中发生频率最多、分布最广、危害最严重的杂草。本文首先基于反枝苋在世界范围内4207个实际分布点及其对应的气候、地形和土壤三类要素28个环境因子的定量关系，利用主成分分析确定了影响其分布的主要环境因子，据此估测其中心可能分布区和最大可能分布区，并与实际分布点进行比较;然后利用GARP生态位模型和地理信息系统(GIS)对影响苋属8个入侵种地理分布的环境因子进行分析并对其全球可能分布区进行预测，并根据苋属入侵种与环境因子的关系对8个苋属入侵种进行聚类分析;最后基于Receiver Operating Characteristics(ROC)分析对GARP模型及GIS模型对反枝苋全球可能分布区的预测结果进行精度检验和比较，结果表明： (1) GIS模型预测显示14个环境因子在决定反枝苋全球分布格局中起着重要作用。反枝苋中心可能分布区位于新西兰南部、澳大利亚东南部、南美洲北部少数地区、北美洲西北部及东南部部分地区、欧洲大部分地区和中国东南部。最大可能分布区位于南美洲中南部、北美洲大部分、非洲北部小部分、澳大利亚南部及北部少数区域、欧洲大部分地区和亚洲大部分地区及中国除西藏、青海、新疆、四川西部以外的地区。中心可能分布区的预测结果与实际分布点吻合较好，而最大可能分布区则过于广阔。 (2) GARP模型预测显示14个环境因子中雨日频率，极端低温，海拔这三个环境因子的影响较为重要，是苋属8个入侵种分布的主要限制因子。聚类分析表明8种苋属入侵种按欧式距离的长度可分为三类：第一类：反枝苋、凹头苋;第二类：刺苋、皱果苋、尾穗苋;第三类：绿穗苋、白苋、北美苋。 ROC分析结果显示GARP模型对反枝苋的可能分布区模拟效果（AUCGARP=0.857）好于GIS模型，其中GIS模型对反枝苋中心可能分布区的模拟效果(AUCGIS-CENTER=0.832)好于最大可能分布区(AUCGIS-MAX=0.778)。 苋属8个入侵种均有分布的地区为澳大利亚沿海地区，新西兰，中国东南沿海，欧洲西部，南美洲部分国家，美国，非洲中部。 (3)两种模型所预测的反枝苋的可能分布区有很大程度的重合性，GARP模型预测的可能分布区大于GIS模型预测出的中心可能分布区，但小于GIS模型预测出的最大可能分布区，且和实际分布点拟合程度较好。

应用SVM预测杜鹃属（Rhododendron L.）在中国的潜在分布中心

杜鹃属(Rhododendron L.)是中国种子植物中最大的属，其现代分布和分化中心是我国西南部的横断山区和东喜马拉雅地区。我国西部、西南部的云南、四川、西藏等地共有杜鹃达450种，仅特有种就有约300种。对杜鹃属分布的深入研究是横断山区生物多样性保护不可缺少的重要部分。 由于物种分布与环境因子之间存在着紧密的联系，利用环境因子作为预测物种分布模型的变量是当前最普遍的建模思路。但是绝大多数物种分布预测模型都遇到了难以解决的“高维小样本”问题――模型在标本数据不足时无法给出合理的预测，或者模型无法处理大量的环境变量。机器学习领域的理论和实践已经证明，基于结构风险最小化原理的支持向量机(Support Vector Machine, SVM)算法非常适合“高维小样本”的分类问题。为了探索其应用在物种分布预测问题上的可能性，本文创新性的实现了基于SVM算法的物种分布预测系统。然后，本文以30个杜鹃属(Rhododendron L.)物种为检验对象，利用其标本数据和11个1km的栅格环境变量图层作为模型变量，预测其在中国的潜在分布区。本文通过全面的模型评估——专家评估，ROC (Receiver Operator Characteristic)曲线和曲线下方面积AUC (Area Under the Curve)——来比较模型的性能。试验结果表明，我们所实现的以SVM为核心的物种分布预测系统无论在计算速度还是预测效果上都远远优于当前广泛使用的GARP (Genetic Algorithm for Rule-Set Prediction)预测系统。 之后，本文进一步探讨了SVM预测系统预测效果与环境变量维数和标本点个数的关系。试验结果表明，对于只有少量标本点的物种SVM的预测结果仍然具有相当的合理性。由此可见， SVM预测系统很好的解决了以前众多模型无法克服的稀有种和标本点稀少的物种的潜在分布区模拟问题。同时本文发现大的环境维数（高维）对于物种潜在分布区的预测有着决定性的作用，因此模型处理高维问题的能力显得至关重要。 最后，我们使用中国所有可获取的杜鹃属标本数据，以及83个1km的栅格环境变量图层，对400种杜鹃属物种的潜在分布区进行预测。根据预测出来的物种潜在分布区，我们得到了中国杜鹃属物种潜在多样性分布格局，特有物种潜在多样性分布格局，濒危杜物种潜在的分布格局，各亚属物种潜在分布格局，以及不同生活型物种潜在多样性分布格局。这些分布区图不仅可以对杜鹃属起源研究提供分析验证的条件，还能为其引种、保护和新种的搜寻提供有利的空间依据。

外来入侵种紫茎泽兰竞争策略与扩散动态

紫茎泽兰（Eupatorium adenophorum Spreng.）作为重要的外来入侵种之一，已严重破坏了入侵地生态系统的结构与功能，同时使当地农林业生产蒙受巨大的损失。因此，明确紫茎泽兰的竞争策略与扩散潜力，对制定合理的控制措施具有重要意义。 土壤氮素增加常常有助于外来种的入侵，那么降氮能否抵制入侵呢？向土壤中添加碳素，增强微生物对氮素的吸收，从而降低土壤中可被植物吸收的氮素是目前常用的降氮方法。为检验这一假说对入侵种紫茎泽兰的适用性，选取入侵种紫茎泽兰和本地种禾本科雀麦（Bromus japonicus）、菊科鱼眼草（Dichrocephala integrifolia），分别单栽或与紫茎泽兰混栽，向各植物组合中添加碳素（按1650克有机质/平方米计）或氮素（按30克氮素/平方米计），并设立对照进行盆栽实验。在碳素添加条件下，紫茎泽兰地上与地下生物量分别比对照降低了71.9% 和 74.9%，而本地种的生物量却没有受到显著影响。同时，碳素添加导致紫茎泽兰对本地种的竞争强度（RII）明显下降。氮素添加则减弱或逆转了上述碳素的作用。因此，向土壤中添加碳素有助于抵抗氮沉降对外来种入侵的促进作用，特别对抵御那些与氮素有亲和力的入侵种更为有效。在不同氮素条件下，紫茎泽兰对本地种竞争中，资源竞争强度均明显大于化感作用。尽管在紫茎泽兰发育早期化感作用较小，但是，碳素添加使紫茎泽兰可利用氮素减少，激发了化感作用在竞争中占有更大的比例，说明资源竞争与化感是相互结合、共同发挥作用的。 去叶作为模拟采食方法之一，至少可以通过两种方式影响植物竞争。一是去叶对目标种生长产生负面影响，二是邻种去叶有利于目标种生长，进而改变种间竞争关系。基于以上假定，对紫茎泽兰与相邻本地种分别单栽、同种合栽和异种混栽，进行去叶处理。结果恰与假定相悖：在整个生长季内，去叶增加目标株生物量的1.0 – 198.9%。对于入侵种而言，当邻居本地种去叶时，紫茎泽兰能完全弥补竞争产生的负面效应，即它与未去叶的单栽紫茎泽兰生长无显著差异;而紫茎泽兰去叶降低了相邻本地种的生长，加剧了原本由于竞争给对本地种带来的负面影响。因此，去叶效应与邻种的存在与否及邻种的类型均有关。在应用生物控制对目标株采食时，特别是在没有造成严重伤害或致死情况下，可以使本来具有竞争优势的入侵种变得更具强势。竞争与去叶之间存在复杂的相互作用，采食带来的间接效应可能比预想的更为复杂。因此，在生物控制措施实施之前，充分地估计生物控制的间接作用至关重要。 为检验反应—扩散模型（reaction–diffusion model）能否正确模拟紫茎泽兰小尺度扩散速率，本研究调查了四川攀枝花山区5个不同的生境的紫茎泽兰群落。对各样地内紫茎泽兰定位和年龄确定，基于克里金插值法做出其入侵格局的等年线图，通过等年线之间的垂直距离即可得到紫茎泽兰扩散速率的经验值。同时，计算内禀增长率和扩散系数，根据模型计算得到扩散速率的预测值。结果表明：紫茎泽兰扩散速率经验值明显小于模型预测值。因此，尽管反应—扩散模型已在大尺度扩散预测方面得到广泛的应用和验证，但在小尺度上，由于没有借助于复杂的生活史模型和分层模型，单凭反应—扩散模型不足以得到准确的预测。另外，在没有遭受干扰的生境中，可以发现紫茎泽兰扩散早期存在明显的时滞期。倘若这种时滞效应在入侵扩散中是频繁发生的，那么在判定物种是否具有入侵性时，很可能由于物种处于时滞期而被误认为非入侵种。 基于紫茎泽兰入侵至中国60年来所收集到的441已知分布记录和23个环境变量，采用GARP模型对其潜在分布范围做出了预测，并通过Kappa和ROC（receiver–operator characteristic）对预测结果进行检验。结果表明紫茎泽兰目前分布以云贵高原为主体，逐渐向四川盆地东部、山东半岛、东南沿海、台湾沿海以及海南岛等地扩散。冷季降水量、年极端低温和年均最高温对分布影响较大。RDA（Redundancy Analysis）分析结果显示温度和降水是限制紫茎泽兰扩散的重要因素。在过去的20年里，紫茎泽兰已经从温度较高、天气波动较小的亚热带气候逐渐向气候温凉、降水减少的高海拔地区扩散。紫茎泽兰可以适应相对较宽的温度和降水梯度，年均温度在10—22 ˚C，年降水量在800—2000 mm区间均有分布。本研究结果为发展早期预警工作、防止紫茎泽兰在中国进一步入侵提供了科学依据。

Identification of immune genes in grass carp Ctenopharyngodon idella in response to infection of the parasitic copepod Sinergasilus major

The parasitic copepod Sinergasilus major is an important pathogen of grass carp Ctenopharyngodon idella. To understand the immune response of grass carp to the copepod infection, suppression subtractive hybridization method was employed to characterize genes up-regulation during the copepod infection in liver and gills of the fish. One hundred and twenty-two dot blot positive clones from infected subtracted library were sequenced. Searching available databases by using these nucleotide sequences revealed that 23 genes are immune-related, including known acute-phase reactants, and four novel genes encoding proteins such as source of immunodominant MHC-associated peptides (SIMP), TNF receptor-associated factor 2 binding protein (T2BP), poliovirus receptor-related protein 1 precursor, glycoprotein A repetitions predominant (GARP). The differential expression of seven immune genes, i.e. GARP, alpha-2-macroglobulin, MHC class I, C3, SIMP, T2BP, transferrin, as a result of infection was further confirmed by RT-PCR, with the up-regulation of alpha-2-macroglobulin, MHC class I, C3, SIMP and T2BP in the liver of infected fish, and down-regulation of SIMP in the gills of infected fish. The present study provides foundation for understanding grass carp immune response and candidate genes for further analysis.