Transcriptional Profile of Cohesin Complex Mutations in the Background of NPM1 AND RUNX1-RUNX1T1 AML

Acute Myeloid Leukemia is a cancer of the blood, characterized by a heterogenous mixture of disease causing mutations. Mutations of the cohesin complex is a group of such mutations and occur alongside several other driving mutations in the development of Acute Myeloid Leukemia. This thesis specifically focuses on cohesin complex mutations in the context of concurrence with NPM1 mutation and the Core Binding Factor (CBF) mutation RUNX1-RUNX1T1 in three distinct components. The first two components involved Differential Expression Analysis (DEA) to identify significantly differentiated genes in each model, followed by Gene Set Enrichment Analysis (GSEA) to identify Gene Ontology (GO) terms associated with the significantly expressed genes. The third component involved a cross analyses of the significantly expressed genes from both the NPM1 and CBF analyses to identify genes enriched in both primary analyses and further Gene Ontology Overrepresentation Analysis was used to characterize the gene ontology terms shared in the identified gene set.In the DEA of NPM1mutatant + cohesin mutant vs. NPM1 wild-type mice there were 239 genes up-regulated NPM1-cohesin mutant model and 126 down- regulated genes identified. DEA of cohesin mutant + RUNX1-RUNX1T1 vs. cohesin wild-type RUNX1-RUNX1T1 from a cohort of pediatric and adolescent patients revealed 212 upregulated genes and 472 downregulated significantly differentiated genes identified. The cross analyses of differentially expressed genes from both the NPM1 and CBF analyses completed with an analyses for enrichment of the CBF gene set in the NPM1 up and down regulated gene sets revealed 55 genes that were of the core GSEA enrichment. From the 55 genes a number of GO terms were identified from the Biological Process, KEGG and Reactome GO collections. Network and clustering analyses further was used to identify patterns in the representation of the Biological Process GO terms identified. The predominant cluster was representative of GO terms involving immune, inflammatory, and leukocyte processes. The emphasis on immune/inflammatory dysregulation from the outcome in the analyses serves as a potential point of interest in characterizing the functional role of the cohesin complex in future studies

Wrestling with Neptune: The Political Consequences of the Military Inundations during the Dutch Revolt

Over the course of several centuries during the High and Late Middle Ages the people of Holland developed a vast water-management infrastructure to protect themselves against flooding. Enormous sections of the province lay at or below sea-level, so it was only through constant diligence that they kept their lands dry. They found that the best way to maintain these flood defenses was through cooperation and consensus forming at the local and regional level. Those who would be affected an inundation were given a chance to participate in the decision-making process about how to prevent floods from occurring. These environmental influences led those in Holland to develop a culture based on discussion, debate, compromise, and consensus forming. In the historiography this approach is known as the poldermodel. In the late sixteenth century a series of natural and human-made floods would test the limits of the poldermodel in Holland. In November 1570 the All Saints Day Flood struck the province and several others located along the North Sea. This natural disaster was arguably the worst flood ever to hit Holland, devastating the flood defenses across the province. Before they had time to repair all the damages, war erupted in 1572 as those in Holland revolted against their Spanish Habsburg sovereign. Since the rebel forces in Holland were outmatched by the Habsburg forces they frequently used floods for strategic ends. These military inundations were carried out almost indiscriminately and with little to no regard of the long-term consequences. During the siege of Leiden in 1574 the rebels set roughly half of the province temporarily underwater so they could reach the city with ships and prevent it from falling into Spanish hands. That the rebels adopted the motto “better broken lands than lost lands” demonstrates how far they were willing to go with the use of the military inundations. These floods essentially broke the poldermodel in Holland. Many of the different cities represented in the provincial assembly the States of Holland placed civic priorities above all else. The city of Gouda in particular simply refused to send delegates to the meetings until the Leidschendam was repaired which had been breached during the siege of Leiden. In the end the city sent out its militia and closed the opening itself, without the States’ permission. This civic particularism prevented discussion, debate, and the ability to form consensus. It was the individuals with water-management experience which ultimately repaired the poldermodel. They developed a number of ways to satisfy the civic interests and rebuild the discussion culture in the province. When the war resumed following a short truce from 1576 to 1579 known as the Pacification of Ghent, the States of Holland maintained the poldermodel by shifting the burden of the inundations onto neighboring provinces, and constructing fortifications to keep the enemy out of Holland

Interactive Inundation Map

The late 1500s was a difficult period for the Dutch in terms of water management. Over the course of the century, the regional water management boards had difficult maintaining the flood defenses, as a result natural floods became more frequent and devastating, as evidence in the All Saints Day Flood in 1570. At the same time, the Dutch Wars of Independence erupted, which exacerbated the problems through the addition of countless man-made floods, carried out to secure military objectives. These military inundations were ubiquitous and accompanied nearly every single military encounter. This digital history exhibit provides a brief account of the natural and military inundations during the Dutch Wars of Independence. Along with providing a general overview of the nature of the inundations, it examines the strategic floods during the encounters at Brill, Alkmaar, Leiden, Antwerp and numerous others

Application of High Pressure and Near-Critical Fluids, NCF's – a Tool for Novel Processes in Roche

The development of new processes by means of near-critical fluids, NCF's, has gained increasing importance in the last few years. These processes include physical separation processes for especially thermolabile substances as well as chemical reactions in and with NCF's.In this contribution, a short phenomenological description of the physical properties of near-critical fluids is given and their influence on the other compounds is discussed. Some general considerations with respect to high-pressure applications of NCF' s along with a rough overwiew of Roche activities in this field are described

Brief History of Military Inundations During The Dutch Wars of Independence

The Dutch Wars of Independence was as much a religious civil war as it was a revolt against Spanish Habsburg rule. In this tumultuous period of the late sixteenth and early seventeenth century, the rebellious Dutch leaders used the watery landscape to their advantage. Repeatedly throughout the conflict, they used Military Inundations (strategic floods) in order to secure their objectives. Nearly every major encounter, including Brill, Alkmaar, Leiden, and Antwerp involved some form of tactical flooding

Hidden Beneath The Waves: Remembering and Forgetting After The Relief of Leiden

This article analyzes the process of commemoration relating to the relief of Leiden. The siege and subsequent rescue of the city were pivotal moments in early years of the Dutch Revolt. As the Prince of Orange and the rebel forces could not save the city with traditional military maneuvers,they employed military inundations, or the intentional flooding of land,for tactical purposes.Over the course of two months the rebels flooded roughly half of southern Holland through dike breaches and the opening of sluices. This man-­‐made flood only carried the rebels so far, and it took a rain storm and a change in the direction of the wind to finally allow them to save the city. This article focuses on a print produced shortly after the city was saved on October 3,1574. The image highlights the traditional narrative of how the siege was portrayed and commemorated in sixteenth century Holland, focusing on the famine and distress of the city while also showcasing how it was saved through what the rebels interpreted as divine intervention.As a point of departure, this article explores how the military inundations were remembered and memorialized in the image and more broadly in other contemporary accounts.The print, and many other commemorations, interpreted these natural changes in the weather as a sign of God’s blessing.Framing the relief of Leiden as providential served a number of important functions for contemporaries.Most importantly,it allowed the rebels to avoid addressing issues of reparations and compensation resulting from the military inundations.This paper argues that the providential interpretation of the rescue of Leiden helped to hide the uncomfortable truth that the conquest of nature and the domination of humans are intimately connected

Global patterns and drivers of ecosystem functioning in rivers and riparian zones

River ecosystems receive and process vast quantities of terrestrial organic carbon, the fate of which depends strongly on microbial activity. Variation in and controls of processing rates, however, are poorly characterized at the global scale. In response, we used a peer-sourced research network and a highly standardized carbon processing assay to conduct a global-scale field experiment in greater than 1000 river and riparian sites. We found that Earth’s biomes have distinct carbon processing signatures. Slow processing is evident across latitudes, whereas rapid rates are restricted to lower latitudes. Both the mean rate and variability decline with latitude, suggesting temperature constraints toward the poles and greater roles for other environmental drivers (e.g., nutrient loading) toward the equator. These results and data set the stage for unprecedented “next-generation biomonitoring” by establishing baselines to help quantify environmental impacts to the functioning of ecosystems at a global scale

A stream-to-sea experiment reveals inhibitory effects of freshwater residency on organic-matter decomposition in the sea

One billion tons of carbon are annually transported to the global ocean, and the fate of this carbon hinges not only on marine processing rates, but also on freshwater processing during downstream transport. Using a cotton-strip assay, we assessed the decomposition of organic matter in marine and freshwater sites and simulated its downstream transport from freshwater to the sea by translocating cotton strips approximately half-way through the freshwater incubation period. We observed faster decomposition in the sea relative to the stream and interestingly, an inhibitory effect of stream incubation on subsequent decomposition in the sea. Total nitrogen content and ∂15N in the cotton strips were both greater in the strips incubated entirely in the sea, suggesting greater microbial activity in the marine habitat. Our results lend needed insights into global carbon cycling, the factors that govern organic-carbon processing, and highlight the importance of connections that exist among some of Earth's major ecosystems

Litter decomposition across multiple spatial scales in stream networks

Spatial scale is a critical consideration for understanding ecological patterns and controls of ecological processes, yet very little is known about how rates of fundamental ecosystem processes vary across spatial scales. We assessed litter decomposition in stream networks whose inherent hierarchical nature makes them a suitable model system to evaluate variation in decay rates across multiple spatial scales. Our hypotheses were (1) that increasing spatial extent adds significant variability at each hierarchical level, and (2) that stream size is an important source of variability among streams. To test these hypotheses we let litter decompose in four riffles in each of twelve 3rd-order streams evenly distributed across four 4th-order watersheds, and in a second experiment determined variation in decomposition rate along a stream-size gradient ranging from orders 1 to 4. Differences in decay rates between coarse-mesh and fine-mesh litter bags accounted for much of the overall variability in the data sets, and were remarkably consistent across spatial scales and stream sizes. In particular, variation across watersheds was minor. Differences among streams and among riffles were statistically significant, though relatively small, leaving most of the total variance (51%) statistically unexplained. This result suggests that variability was generated mainly within riffles, decreasing successively with increasing scale. A broad range of physical and chemical attributes measured at the study sites explained little of the variance in decomposition rate. This, together with the strong mesh-size effect and greater variability among coarse-mesh bags, suggests that detritivores account, at least partly, for the unexplained variance. These findings contrast with the widespread perception that variability of ecosystem characteristics, including process rates, invariably increases (1) with spatial extent and (2), in stream networks, when analyses encompass headwaters of various size. An important practical implication is that natural variability need not compromise litter decomposition assays as a means of assessing functional ecosystem integrit

Flood disturbance and riparian species diversity on the Colorado River Delta

We investigated the influence of channel migration and expansion on riparian plant species diversity along the lower Colorado River near the United States-Mexico border. Using repeat aerial photography in a GIS we identified and classed areas of low, moderate, and high disturbance frequency caused by channel expansion and migration. Replicate vegetation plots (12 m × 12 m) were sampled in each of the three disturbance classes. One-way ANOVA was used to test for differences in species richness, species diversity (using the Shannon-Weiner Index) and overall percent ground cover of plants between the three disturbance classes. Regardless of disturbance class, plots were dominated by trees or shrubs, especially the non-native Tamarix ramosissima, as well as Pluchea sericea, Baccharis salicifolia and Salix goodingii. Clearly woody species constitute the great bulk of overall species richness, percent ground cover, and species diversity (H′) in each disturbance group. No overall statistically significant differences were revealed among the disturbance groups for values of species richness, percent ground cover, or the Shannon-Wiener Index, though paired contrasts of means revealed that total percent ground cover on low disturbance plots was significantly higher than on moderately disturbed plots. Spatial and temporal variability in riparian diversity in the study area appears to hinge on factors other than disturbance frequency such as salt or drought stress. Alternately, our results could be interpreted as suggesting that in the presence of intensive flow regulation, disturbance plays a secondary role to ecological stresses, similar to that demonstrated by others. Intentional flood pulses are advocated as a restorative management strategy for improving plant productivity, management of exotic species (particularly T. ramosissima), and restoration of overall biodiversit