The Leishmania donovani Lipophosphoglycan Excludes the Vesicular Proton-ATPase from Phagosomes by Impairing the Recruitment of Synaptotagmin V

We recently showed that the exocytosis regulator Synaptotagmin (Syt) V is recruited to the nascent phagosome and remains associated throughout the maturation process. In this study, we investigated the possibility that Syt V plays a role in regulating interactions between the phagosome and the endocytic organelles. Silencing of Syt V by RNA interference revealed that Syt V contributes to phagolysosome biogenesis by regulating the acquisition of cathepsin D and the vesicular proton-ATPase. In contrast, recruitment of cathepsin B, the early endosomal marker EEA1 and the lysosomal marker LAMP1 to phagosomes was normal in the absence of Syt V. As Leishmania donovani promastigotes inhibit phagosome maturation, we investigated their potential impact on the phagosomal association of Syt V. This inhibition of phagolysosome biogenesis is mediated by the virulence glycolipid lipophosphoglycan, a polymer of the repeating Galβ1,4Manα1-PO4 units attached to the promastigote surface via an unusual glycosylphosphatidylinositol anchor. Our results showed that insertion of lipophosphoglycan into ganglioside GM1-containing microdomains excluded or caused dissociation of Syt V from phagosome membranes. As a consequence, L. donovani promatigotes established infection in a phagosome from which the vesicular proton-ATPase was excluded and which failed to acidify. Collectively, these results reveal a novel function for Syt V in phagolysosome biogenesis and provide novel insight into the mechanism of vesicular proton-ATPase recruitment to maturing phagosomes. We also provide novel findings into the mechanism of Leishmania pathogenesis, whereby targeting of Syt V is part of the strategy used by L. donovani promastigotes to prevent phagosome acidification

Alternative methods of follow up in breast cancer: a systematic review of the literature

Regular clinical follow up after breast cancer is a common practice. Evidence from retrospective reviews casts doubt on the efficacy of this practice and the various guidelines for follow up show little concordance. Our aim was to investigate what alternative follow-up methods (including reduced frequency of visits) have been subjected to controlled trial and to establish what evidence exists from controlled trials to advise the guidelines. The study involved systematic review of the literature using MEDLINE, Embase, CancerLit, Web of Sciences and EBM reviews as data sources. Methods included reviewing all randomised controlled trials comparing different follow-up frequencies or comparing an alternative method with clinical follow up after breast cancer. All outcome measures addressed in the trials were analysed. Two trials compared frequency of traditional follow up. Five trials assessed alternative methods. All were of inadequate power or duration to establish ideal frequency of clinic visits or safety of alternative follow-up methods. Alternative follow up had no detrimental effect on satisfaction or outcome. Few trials have been conducted, all of which are underpowered to establish safety of reducing or replacing clinic visits. Alternative methods of follow up are acceptable to patients and may be associated with other benefits. Larger trials are required

Systematic pelvic and aortic lymphadenectomy in advanced ovarian cancer patients at the time of interval debulking surgery: a double-institution case-control study

The prognostic role of systematic lymphadenectomy remains unclear in advanced ovarian cancer (AOC). Only few retrospective case series have investigated the percentage of lymph node metastases after neoadjuvant chemotherapy. This multi-institutional case-control study analyzed the prognostic role of systematic lymphadenectomy in AOC patients at the time of interval debulking surgery (IDS)

The Impacts of Climate Change on Ecosystem Services and Resulting Losses and Damages to People and Society

So far, studies of Loss and Damage from climate change have focused primarily on human systems and tended to overlook the mediating role of ecosystems and the services ecosystems provide to society. This is a significant knowledge gap because losses and damages to human systems often result from permanent or temporary disturbances to ecosystems services caused by climatic stressors. This chapter tries to advance understanding of the impacts of climatic stressors on ecosystems and implications for losses and damages to people and society. It introduces a conceptual framework for studying these complex relations and applies this framework to a case study of multi-annual drought in the West-African Sahel. The case study shows that causal links between climate change and a specific event, with subsequent losses and damages, are often complicated. Oversimplification must be avoided and the role of various factors, such as governance or management of natural resources, should be at the centre of future research.</p