Copper exposure induces trafficking of the Menkes protein in intestinal epithelium of ATP7A transgenic mice

The final steps in the absorption and excretion of copper at the molecular level are accomplished by 2 closely related proteins that catalyze the ATP-dependent transport of copper across the plasma membrane. These proteins, ATP7A and ATP7B, are encoded by the genes affected in human genetic copper-transport disorders, namely, Menkes and Wilson diseases. We studied the effect of copper perfusion of an isolated segment of the jejunum of ATP7A transgenic mice on the intracellular distribution of ATP7A by immunofluorescence of frozen sections. Our results indicate that ATP7A is retained in the trans-Golgi network under copper-limiting conditions, but relocalized to a vesicular compartment adjacent to the basolateral membrane in intestines perfused with copper. The findings support the hypothesis that the basolateral transport of copper from the enterocyte into the portal blood may involve ATP7A pumping copper into a vesicular compartment followed by exocytosis to release the copper, rather than direct pumping of copper across the basolateral membrane.

Trafficking of the copper-ATPases, ATP7A and ATP7B: Role in copper homeostasis

Copper is essential for human health and copper imbalance is a key factor in the aetiology and pathology of several neurodegenerative diseases. The copper-transporting P-type ATPases, ATP7A and ATP7B are key molecules required for the regulation and maintenance of mammalian copper homeostasis. Their absence or malfunction leads to the genetically inherited disorders, Menkes and Wilson diseases, respectively. These proteins have a dual role in cells, namely to provide copper to essential cuproenzymes and to mediate the excretion of excess intracellular copper. A unique feature of ATP7A and ATP7B that is integral to these functions is their ability to sense and respond to intracellular copper levels, the latter manifested through their copper-regulated trafficking from the transGolgi network to the appropriate cellular membrane domain (basolateral or apical, respectively) to eliminate excess copper from the cell. Research over the last decade has yielded significant insight into the enzymatic properties and cell biology of the copper-ATPases. With recent advances in elucidating their localization and trafficking in human and animal tissues in response to physiological stimuli, we are progressing rapidly towards an integrated understanding of their physiological significance at the level of the whole animal. This knowledge in turn is helping to clarify the biochemical and cellular basis not only for the phenotypes conferred by individual Menkes and Wilson disease patient mutations, but also for the clinical variability of phenotypes associated with each of these diseases. Importantly, this information is also providing a rational basis for the applicability and appropriateness of certain diagnostic markers and therapeutic regimes. This overview will provide an update on the current state of our understanding of the localization and trafficking properties of the copper-ATPases in cells and tissues, the molecular signals and posttranslational interactions that govern their trafficking activities, and the cellular basis for the clinical phenotypes associated with disease-causing mutations.

Illegal migrants, tourism and welfare : a trade theoretic approach

Many countries receive illegal migrants but are reluctant to accept them due to possible negative externalities. We provide a rationale for not policing illegal migration by linking it to the tourism industry. By paying illegal migrants less than local workers, the relative price of the non-traded goods is shown to be lower than it would be in the absence of such workers. An expansion in tourist trade, under certain intensity conditions, necessarily raises resident welfare and employment. This tourist boom necessarily lowers the welfare of the illegal migrants. It is established that an increase in tourism increases the supply of illegal migrants.

Endosomal trafficking of the Menkes copper ATPase ATP7A is mediated by vesicles containing the Rab7 and Rab5 GTPase proteins

The Cu-ATPase ATP7A (MNK) is localized in the trans-Golgi network (TGN) and relocalizes in the plasma membrane via vesicle-mediated traffic following exposure of the cells to high concentrations of copper. Rab proteins are organelle-specific GTPases, markers of different endosomal compartments; their role has been recently reviewed (Trends Cell Biol. 11(2001) 487). In this article we analyze the endosomal pathway of trafficking of the MNK protein in stably transfected clones of CHO cells, expressing chimeric Rab5-myc or Rab7-myc proteins, markers of early or late endosome compartments, respectively. We demonstrate by immunofluorescence and confocal and electron microscopy techniques that the increase in the concentration of copper in the medium (189 μM) rapidly induces a redistribution of the MNK protein from early sorting endosomes, positive for Rab5-myc protein, to late endosomes, containing the Rab7-myc protein. Cell fractionation experiments confirm these results; i.e., the MNK protein is recruited to the endosomal fraction on copper stimulation and colocalizes with Rab5 and Rab7 proteins. These findings allow the first characterization of the vesicles involved in the intracellular routing of the MNK protein from the TGN to the plasma membrane, a key mechanism allowing appropriate efflux of copper in cells grown in high concentrations of the metal.

Into the protecting arms: the League of Nations and the extension of international assistance to unprotected persons in the Middle East and Europe, 1926 - 1928

The refugee dilemma in Europe in the years between the two world wars had a number of aspects: humanitarian, political, and diplomatic. It raised questions of migration, questions of international law, and questions of the fate of hundreds of thousands of individuals. Refugees were visible from the very last days of the war and remained a matter of serious international concern even beyond the outbreak of war again in September 1939. The refugee dilemma in Europe was, firstly, a humanitarian crisis because the size of the refugee population was without precedent. It was also a political problem because national governments had to contend with questions about the refugees' legal status and their legitimacy under national and international law, as well as balance humanitarian concerns with national political interests. The humanitarian and political aspects together created a crisis for the international community newly united in the League of Nations. One of its first great acts-to take these refugees into its protective care-was not even prescribed for it in its Covenant. But the refugee crisis facing Europe was so great that member states were united in the belief that the League had been established precisely to undertake a task of this kind.

Barriers to cross-fertilization between populations of a widely dispersed Polychaete species are unlikely to have arisen through gametic compatibility arms-races

Although there are theoretical reasons to suspect that gametic incompatibility may develop readily among populations of broadcast spawning marine invertebrates, there have been very few studies documenting geographic patterns of interpopulation incompatibility for any species. To address this we determined how successfully individuals of the intertidal serpulid polychaete, Galeolaria caespitosa, can cross-fertilize within and among populations from across temperate Australia. Fertilization assays revealed asymmetrical differences between very distantly located populations from different coasts, with near-complete incompatibility between eggs from Sydney with sperm from Adelaide, but the reverse cross (Adelaide eggs, Sydney sperm) was reasonably compatible. Although that pattern was congruent with a clear difference in Cytochrome B sequences between worms on the south and east coasts of Australia, we also detected some indication of interpopulation incompatibility within the genetic grouping on east coast, between two populations separated by only 220 km. We then assessed whether commonly proposed gametic compatibility arms-races could account for these patterns. Our results suggest reduced gametic compatibility may reduce a female's maximum fertilization potential, resulting in a cost to this potential mechanism for reducing polyspermy. Consequently, the apparently rapid development of reproductive barriers here seems unlikely to have been driven by arms-races involving sexual conflict over fertilization rate.

Resisting the call to arms : men who did not enlist in World War 1

Historian Dr Bart Ziino has researched thousands of records that give an insight into an often overlooked aspect of World War I – men who chose not to enlist for service.

Nuclear rivalry in South Asia : an examination of post Cold War nuclear arms control initiatives

South Asia has emerged in the post-Cold War era as a region where ongoing nuclear rivalry has the potential to result in a nuclear exchange between India and Pakistan. The United States, together with the global community, is devoting considerable effort to prevent the further development and deployment of nuclear weapons by India and Pakistan. This thesis analyses the underlying reasons for the ongoing nuclear rivalry between India and Pakistan, details post-Cold War initiatives to end the nuclear rivalry and examines the prospect of United States efforts to cap, reduce and eventually eliminate the nuclear arsenals of India and Pakistan. The thesis finds that historical factors form the basis of the continuing hostility and animosity between the two nations. The two nations have been bitter rivals since the time of partition in 1947 and the disputed territory of Kashmir continues to be the manifestation of deep seated antagonism and hostility. Pakistan's geography leaves it extremely vulnerable to conventional Indian attack and possession of nuclear weapons is seen as a means to redress the imbalance. Strong domestic support together with fervent nationalism and international prestige will continue to drive the nuclear programs of each nation. This thesis concludes that the nuclear rivalry between India and Pakistan is regional in nature and the end of the Cold War has done little to improve the prospects for nuclear disarmament in the region. United States led efforts have failed to persuade India or Pakistan to either accede to the Non-Proliferation Treaty (NPT) or dismantle their nuclear weapons. The thesis also notes that the United States has failed to take account of China as a significant regional power and it's impact on the nuclear programs of India and Pakistan. A fresh approach (to include China) with more emphasis on regional dialogue is suggested as a first step to ending the nuclear rivalry.

Over the border and under the radar : can illegal migrants be active citizens?

Active citizens can become a powerful driver of development by holding to popular account those who traditionally wield decision-making power at the local and national levels. Active citizenship draws from a long history of understanding the importance of community participation and ownership of development interventions. However, in spite of its inherent strengths, active citizenship may not be a possible (or optimal) outcome in all circumstances. This article argues for the realistic expectation of active citizenship (and indeed participation) of one specific sub-population in Thailand, where the overwhelming majority of illegal migrants (of an estimated total of 800,000-1.5 million) are Burmese. Their precarious existence as illegal migrants compounds the development needs that confront any poor community. This in turn hinders their ability to engage actively in the development process. This article reviews the lessons learned by a Thai-based NGO that has worked with illegal Burmese migrants for more than 15 years. It discusses the unique strengths and weakness of these illegal communities, whether or not it is appropriate to seek to engage them as active citizens, and the implications for NGOs working with such communities. It suggests that the unique role that NGOs must play, in cases where public participation could endanger the lives of community members, is that of advocate-guardians, whereby they assume the role of active citizen on behalf of the community in question and simultaneously provide development interventions and advocate on its behalf.