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Our understanding about the genetic influences on human disease has increased dramatically with the technological developments in genome and DNA analysis and the discovery of the human genome sequence. Whilst much remains unexplained, it is obvious that normal cardiac development is controlled by the genome and there is significant evidence that a proportion of cardiac malformations are caused by genetic factors. This is important for clinicians as an understanding of confirmed genetic factors is essential to estimate recurrence risks of congenital heart disease (CHD) within families and also screen for predicted associated anomalies. An accurate genetic diagnosis can provide important prognostic information for both the initial patient (proband) and other family members, for whom further genetic investigations may be indicated. There is likely to be a continued increase in demand for such investigations as improvement in surgical and medical management allows more individuals with CHD to survive to reproductive age and have families of their own. For some, the recurrence risk for a cardiac malformation may be as high as 50%; the actual figure varies with different genetic diagnoses. Accurate risk stratification is likely to become increasingly important and the rapidly developing technologies to detect genetic variation mean that genome-wide investigation is becoming more widely available in the clinical setting. An aim of this chapter is to introduce clinicians to principles that will help them embrace and understand the results from these investigations and appreciate the implications they have for their patients.
Looking to evolutionary biology for lessons applicable to cultural and political evolution, David Sloan Wilson brings the book to a conclusion with his discussion of symbolic systems as the most effective and organic model for societal transformation. Building on the literature of professors of genetics and evolution, and on his own earlier work on evolutionary theory and economics, Wilson demonstrates that many of the assumptions undergirding the national security state are due for reform as a matter of future existence, beginning with ideas about theories of governance.
The essays in this volume of Fourteenth Century England engage with many of the themes and subjects which make the period so attractive to scholars and the wider public alike. The authors reflect on issues of kingship and changing theories of power at a number of levels; they tackle questions concerning loyalty and rebellion; examine the role of law, both domestic and international; give consideration to the nature of memory – legal, historical and fabricated; and they address the relationship between the Plantagenets and the rulers of those nations and territories over which England claimed dominion.
In so doing, the essays draw on a vibrant array of new scholarship, some of which was published in earlier volumes of FCE, that is transforming our understanding of and approach to the later Middle Ages. They also take advantage of sources which are now much easier to access and which can be interrogated in new ways. The digital revolution has shaped the direction of a good deal of recent research both in terms of international collaborations and what individual scholars may study and how they conduct their studies. The establishment of major databases and digitized source collections has been a key feature of this process. In addition to opening new avenues of enquiry such resources have also prompted a return to more familiar subjects by allowing investigations to be carried out in wholly new ways. Prosopographical work using such materials and employing data analysis software in order to explore the relationships between members of various groups is only one example of this.
As with earlier volumes in this series, several contributions to this collection originated in papers sponsored by the Society for Fourteenth Century Studies at the International Medieval Congress (University of Leeds) and the Society of the White Hart at the International Conference on Medieval Studies (University of Western Michigan). Over many years, these meetings have helped shape broader scholarly agendas as well as individual research projects while maintaining a tradition of friendly collegiality. They have ensured that the fourteenth century, a period of intense and often brutal change, is a very welcoming one to study.
During the French Revolutionary and Napoleonic Wars, the British Empire grew through its invasion of Dutch colonies around the Indian Ocean rim. The incursions entwined British and Dutch politics, cultures, and social networks. These developments were significant for the Dutch East Indies, but have received relatively little attention in histories of the Second British Empire. In light of recent interest in Anglo-Dutch interaction, connectivity across empires, and the uses of prosopography to question the boundaries of imperial history, this article uses Dutch biographies to interrogate the relationship between the politics of liberal reform and despotism in the Cape Colony and Java under the British. A dialectic between despotism and liberalism dominates the Second Empire's historiography. Conversely, tracing the biographies of two interstitial figures who passed between the Dutch Empire and that of Britain shows how despotism and reform were connected. The Dutch drew notions of reform from their social networks into the Cape and Java through their manipulation of loyalist rhetoric. Concurrently, the use of such rhetoric legitimized societies and controls linked to the entrenchment of autocracy. This article thus reveals links between connectivity and control in Britain's Indian Ocean empire.
OBJECTIVES/SPECIFIC AIMS: Chlamydia trachomatis (CT) infection can lead to reproductive morbidity in women. Animal models suggest that protection against CT is mediated through the cytokine interferon-gamma (IFN-γ), produced by CD4+ T-cells, which clears CT through intracellular tryptophan depletion. In humans, correlates of protection remain to be elucidated, which hinders chlamydia vaccine development. Natural clearance of CT infection (e.g., clearance before antibiotics) may be an immunological correlate of protection, evidenced by (1) CT clearance without antibiotics; and (2) a 4-fold reduced risk of CT reinfection within 6 months. We have identified women with and without natural clearance of CT infection. By comparing these two groups of women, the role of IFN-γ-mediated natural clearance of CT infection will be investigated. METHODS/STUDY POPULATION: Through collaboration with a cohort study of CT-infected women, we have access to stored specimens from women who naturally cleared CT or had persisting CT infection. Using peripheral blood mononuclear cell (PBMC), we will assess whether natural clearance of CT infection is associated with IFN-γ-producing CD4+ T-cells by stimulating PBMC ex vivo with CT antigens using intracellular cytokine staining. We will also use cervicovaginal lavage (CVL) and untargeted High-Performance Liquid Chromatography-Mass Spectrometry to assess for tryptophan-dependent and -independent metabolic pathways associated with natural clearance of CT infection. RESULTS/ANTICIPATED RESULTS:: To date, IFN-γ has been measured in 10 women who did not clear CT infection, demonstrating that <20% of these women produced significant levels of IFN-γ. Women who naturally cleared CT have yet to be studied. Untargeted HPLC-MS has been performed on 6 women (3 who cleared matched to 3 with persisting CT infection). To date, 11 pathways that are significantly associated with natural clearance have been identified. DISCUSSION/SIGNIFICANCE OF IMPACT: The outcome of natural clearance of CT infection is distinct from women with persisting chlamydia. These studies may inform whether IFN-γ, produced by CD4+ T-cells, or tryptophan-dependent or -independent metabolic pathways are associated with natural clearance, which may advance chlamydia vaccine development.
Whereas seventeenth-century piracy has been recognised as an integrated component of the developing European Atlantic world, eighteenth-century pirates have been marginalised as an isolated group with few ties to landed communities. Such evaluations have stressed the heightened extension of state authority to the colonial theatre in the eighteenth century and, by doing so, have overlooked how pirates continued to interact with colonial actors operating in contested and unclaimed regions throughout the Atlantic commons. It is imperative that the Atlantic commons is given full consideration in any discussion of Atlantic maritime activity as it was within these expanses that inter-imperial, inter-colonial, and cross-border colonial actors converged. This article utilises the piratical voyage captained by Howell Davies (and later Bartholomew Roberts) to demonstrate that it was within this commons that eighteenth-century piratical voyages were sustained and facilitated through the forced acquisition of supplies, through markets for plundered goods, and through the opportunities available for dispersing amongst landed communities at the end of expeditions. Continued connections between colonial denizens and pirates in the eighteenth century compels a reassessment of pirates’ isolation to instead place them within the wider population of coastal traders, sojourning mariners, and marginal colonial settlers who existed both within and outside of the imperial framework espoused by state and colonial centres. Ultimately, this questions the overall ability of European states to regulate maritime traffic when vessels sailed out of sight of established colonial ports, and beyond the practical reach of imperial authority.
The nexus between an increasing global population, the demand for food and the land on which it is cultivated, and emerging climate variability poses one of today's greatest societal challenges (Rudel et al. 2009). Understanding the dynamics and drivers of global land-use change is as important now as ever. As agricultural and pasture lands expand into remaining forests, previously fertile land is lost to desertification and intensified soil degradation. The latest report from the Intergovernmental Panel on Climate Change Fifth Assessment Report (IPCC-AR5) suggests that land-use change may also be responsible for as much as 24 per cent of global greenhouse gas (GHG) emissions (IPCC 2014b). This poses challenges for decision-makers and farmers alike and requires a coordinated effort that balances the need to meet rising food demand with the protection of our fragile and depleted natural resource base. Underpinning this is the need for accurate information on global, regional, national, and subnational dynamics and drivers of land-use change. Increasingly, this needs to be viewed and considered through the lens of climate change.
A tension between two major land-use types — forests and agricultural land — also exists. Prevailing opinion is that expansion of agricultural land comes at the expense of forested areas; indeed, evidence exists suggesting this was, is, and most likely will continue to be one of the major drivers of forest loss and land-use change globally (Rudel et al. 2005; Chomitz 2006; Lambin and Meyfroidt 2011; Hosonuma et al. 2012). This is not necessarily the case in all countries, however, and local contexts are often more complex and ambiguous, as is discussed in this chapter focusing on the Philippines.
Agricultural lands and agroecosystems provide essential benefits to human society and, in addition to being crucial to subsistence and economic activity, are deeply embedded culturally. For developing nations, poorer, often smallholder farmers rely on agriculture to meet their daily needs, and as populations grow so too does demand for land. At the same time, forests also offer benefits to those dependent on their goods and services (who may also be smallholder farmers). Direct benefits such as food, fodder, and timber are obvious. Perhaps less tangible, but no less important, are trees and forests and the role they play in supporting agricultural activities such as micro-climatic regulation, soil nutrient cycling, and stabilization, as well as improving water retention.
INTRODUCTION: Gangliogliomas (GGs) are neuroepithelial tumours of the central nervous system (CNS) composed of mature ganglion cells or a mixed population of ganglion and glial cells. Microarray data of low grade gliomas (LGG) including GGs revealed overexpression of the Dlx2 gene, a homeobox gene essential for interneuron migration and differentiation. We hypothesized that GGs are arrested in development, and began to explore the role of the Dlx2 gene. BRAF rearrangements and BRAF V600E point mutations have been reported in pediatric LGG. METHODS: DLX2 expression was examined in GGs using immunofluorescence (IF) and immunohistochemistry (IHC) labelling of formalin fixed paraffin embedded (FFPE) tissue sections, along with staining of glial and neuronal markers. BRAF mutations were detected using a commercial antibody and/or sequence verification of the DNA extracted from the FFPE blocks. RESULTS: In the Discovery cohort 10/30 were DLX2+ (33.3%) and in the Validation cohort 15/40 were DLX2+ (37.5%). Of these 15 cases, 15 were GFAP+ (100%), 15 were synaptophysin and/or NeuN+ (100%), and 13 were OLIG2+ (86.7%); 6 had a BRAF V600E mutation (40.0%). For the Validation cohort of 40 GGs, 28 were OLIG2+ (70.0%); 13/28 co-expressed DLX2 (46.4%). 18/40 cases had a BRAF V600 mutation(17 V600E, 1 V600G; 45.0%) and 6/18 were DLX2+ (33.3%). CONCLUSIONS: DLX2 is expressed in GGs in both neuronal and glial marker expressing tumour cells. Our results support that GGs arise from CNS progenitors arrested at the neuronal-glial cell fate “decision” point.
BACKGROUND: IGTS is a rare phenomenon of paradoxical germ cell tumor (GCT) growth during or following treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of IGTS in patients in 21 North-American and Australian institutions. METHODS: Patients with IGTS diagnosed from 2000-2017 were retrospectively evaluated. RESULTS: Out of 739 GCT diagnoses, IGTS was identified in 33 patients (4.5%). IGTS occurred in 9/191 (4.7%) mixed-malignant GCTs, 4/22 (18.2%) immature teratomas (ITs), 3/472 (0.6%) germinomas/germinomas with mature teratoma, and in 17 secreting non-biopsied tumours. Median age at GCT diagnosis was 10.9 years (range 1.8-19.4). Male gender (84%) and pineal location (88%) predominated. Of 27 patients with elevated markers, median serum AFP and Beta-HCG were 70 ng/mL (range 9.2-932) and 44 IU/L (range 4.2-493), respectively. IGTS occurred at a median time of 2 months (range 0.5-32) from diagnosis, during chemotherapy in 85%, radiation in 3%, and after treatment completion in 12%. Surgical resection was attempted in all, leading to gross total resection in 76%. Most patients (79%) resumed GCT chemotherapy/radiation after surgery. At a median follow-up of 5.3 years (range 0.3-12), all but 2 patients are alive (1 succumbed to progressive disease, 1 to malignant transformation of GCT). CONCLUSION: IGTS occurred in less than 5% of patients with GCT and most commonly after initiation of chemotherapy. IGTS was more common in patients with IT-only on biopsy than with mixed-malignant GCT. Surgical resection is a principal treatment modality. Survival outcomes for patients who developed IGTS are favourable.
OBJECTIVES/SPECIFIC AIMS: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a curative procedure for hematological malignancies. Chronic graft Versus host disease (cGVHD) is a lethal complication that often develops after allo-HCT. Fli-1 is an aberrantly expressed protein in cancers including erythroleukemia and melanoma, while being implicated in pathogenesis of systemic lupus in mice and humans, a disease with marked similarity to cGVHD. METHODS/STUDY POPULATION: cGVHD was induced using hematopoietic cells from conditional knock-out mice deficient for the fli-1 gene specifically on T cells and progression of cGVHD in murine allo-HCT recipients was monitored using a clinical scoring system, and changes in activation status of hematopoietic cell populations were quantified using flow cytometry. RESULTS/ANTICIPATED RESULTS: Recipients transplanted with fli-1 deficient T cells exhibited reduced cGVHD clinical scores compared with littermate wild-type controls. Donor-grafts containing fli-1 deficient T cells were associated with restrained T-cell responses including reduced Interferon-y cytokine production, PD-1 expression, and differentiation into follicular helper T cells. fli-1 T-cell deficient donor-grafts also improved donor B-cell reconstitution and reduced plasma cells in allo-HCT recipients relative to littermate wild-type control donor-graft recipients. DISCUSSION/SIGNIFICANCE OF IMPACT: Thus, inhibiting Fli-1 represents a promising therapeutic strategy for the goal of preventing cGVHD after allo-HCT while also directly targeting cancers which aberrantly express Fli-1.