Geography's medieval history: A neglected enterprise?

This paper examines the marginal place of ‘medieval geography’ in contemporary geographical scholarship. Over the past two decades, geographers' studies of the subject’s historiography have tended to focus mainly on ‘modern’ and ‘early-modern’ rather than medieval geographies. This contrasts with the early 20th century when ‘medieval geography’ was seen by geographers to be part of the discipline’s long history. Set within the context of current discussion on writing geography’s histories, the paper examines how geographers, and latterly historians, have sought to characterize and represent medieval geographies. This reveals that the subject of geography in the Middle Ages shared in the same fluidities and ambivalences that characterize geography today. The paper thus helps to challenge orthodox views of geography’s history, and argues that the connections and continuities that have shaped geography for over two millennia cautions us against taking a compartmentalized approach to historiographies of geography.

Folklore’s Timeless Past, Ireland’s Present Past, and the Perception of Rural Houses in Early Historic Ireland

This study examines how the archaeology of historic Ireland has been interpreted. Two approaches to the history and archaeology of Ireland are identified. The first, the timeless past, has its roots in a neo-Lamarckian view of the past. This perspective was particularly developed in the work of geographer and ethnographer, Estyn Evans. The second view, associated in particular with a nationalist approach to Ireland’s past, looked to the west of the country where it was believed the culture had been preserved largely unchanged and in its purest form. The continuing impact of these frameworks upon the interpretation of rural settlement in the period 1200– 1700 is examined. It is argued that historians and archaeologists alike have underestimated the quality of buildings.

Clathrin adaptor epsinR is required for retrograde sorting on early endosomal membranes

Retrograde transport links early/recycling endosomes to the trans-Golgi network (TGN), thereby connecting the endocytic and the biosynthetic/secretory pathways. To determine how internalized molecules are targeted to the retrograde route, we have interfered with the function of clathrin and that of two proteins that interact with it, AP1 and epsinR. We found that the glycosphingolipid binding bacterial Shiga toxin entered cells efficiently when clathrin expression was inhibited. However, retrograde transport of Shiga toxin to the TGN was strongly inhibited. This allowed us to show that for Shiga toxin, retrograde sorting on early/recycling endosomes depends on clathrin and epsinR, but not AP1. EpsinR was also involved in retrograde transport of two endogenous proteins, TGN38/46 and mannose 6-phosphate receptor. In conclusion, our work reveals the existence of clathrin-independent and -dependent transport steps in the retrograde route, and establishes a function for clathrin and epsinR at the endosome-TGN interface.

Involvement of the endosomal autoantigen EEA1 in homotypic fusion of early endosomes

In mammalian cells, fusion between early endocytic vesicles has been shown to require the ubiquitous intracellular fusion factors N-ethylmaleimide-sensitive factor (NSF) and alpha-SNAP, as well as a factor specific for early endosomes, the small GTPase Rab5 [1-3]. We have previously demonstrated an additional requirement for phosphatidylinositol 3-kinase (PI 3-kinase) activity [4]. The membrane association of early endosomal antigen 1 (EEA1), a specific marker of early endosomes [5,6], has recently been shown to be similarly dependent on PI 3-kinase activity [7], and we therefore postulated that it might be involved in endosome fusion. Here, we present evidence that EEA1 has an important role in determining the efficiency of endosome fusion in vitro. Both the carboxy-terminal domain of EEA1 (residues 1098-1411) and specific antibodies against EEA1 inhibited endosome fusion when included in an in vitro assay. Furthermore, depletion of EEA1, both from the membrane fraction used in the assay by washing with salt and from the cytosol using an EEA1-specific antibody, resulted in inhibition of endosome fusion. The involvement of EEA1 in endosome fusion accounts for the sensitivity of the endosome fusion assay to inhibitors of PI 3-kinase.

The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer

The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of α-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression).

PATIENT SUMMARY: This first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Expression levels of the genes that the androgen receptor regulates are predictive of treatment outcome. Upregulation of oestrogen receptor 1 is a mechanism by which PCa cells may survive despite castration.