ORCID Profile
0000-0001-5045-819X
Current Organisations
University of Oxford
,
University of Wollongong
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Natural Resource Management | Environment Policy | Environmental Science and Management | Aboriginal and Torres Strait Islander Environmental Knowledge |
Ecosystem Assessment and Management of Marine Environments | Coastal and Estuarine Water Management
Publisher: Elsevier BV
Date: 2004
DOI: 10.1016/J.BCP.2003.07.016
Abstract: Platinum(II)-based anticancer drugs are associated with high reactivity and thus a poor biological stability. The platinum(IV)-complexes display potential advantages due to their greater stability and bioreductive activation, thereby allowing a greater proportion of the drug to arrive at the target intact. All compounds tested were able to produce cytotoxicity in monolayer cell cultures, however, the potencies of platinum(IV) drugs were lower than that observed for the platinum(II) compounds or established organic chemotherapeutic agents. There was no significant alteration in the potency of platinum(II) or (IV) compounds to produce cytotoxicity in multicellular tumour spheroids (MCTS) compared to monolayer cultures. All the organic and platinum-based cytotoxic agents produced, to varying degrees, either a retardation or reduction in MCTS growth. Proliferating cells were restricted to the outer two to three cellular layers in intermediate (d=350 microm) and large (d=600 microm) MCTS. Regardless of MCTS size, drug treatment produced a larger and more widely distributed proliferating cell population, consistent with the recruitment of quiescent cells to the proliferating pool following cytotoxic damage. Histology indicated that the predominant morphological change was that of apoptosis, although there was some drug-dependent effects such as the metaphase arrest produced by vinblastine and chromatin dispersal to the periphery of nuclei produced by doxorubicin. In summary, whilst the platinum(IV) derivatives were able to produce cytotoxicity via apoptosis, the introduction of a stable axial group significantly retarded the rate at which this occurred.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 16-12-2009
Publisher: Royal Zoological Society of New South Wales
Date: 2017
DOI: 10.7882/AZ.2015.029
Publisher: Springer Science and Business Media LLC
Date: 14-10-2019
Publisher: Informa UK Limited
Date: 04-07-2015
Publisher: Elsevier BV
Date: 11-2019
Publisher: Wiley
Date: 10-06-2014
DOI: 10.1002/AQC.2363
Publisher: Frontiers Media SA
Date: 09-07-2021
DOI: 10.3389/FMARS.2021.710088
Abstract: Regional fisheries meetings that support the management of Western and Central Pacific Ocean (WCPO) capture fisheries are usually held face-to-face and in-person. In 2020, the travel and gathering bans due to the global COVID-19 pandemic meant that these meetings were held “virtually,” primarily via videoconferencing. But can virtual meetings perform the same functions and deliver the same management outcomes as face-to-face meetings? This study is an initial investigation of the experiences, perceptions and attitudes of WCPO region government participants in a number of virtual regional fisheries meetings in 2020. Results indicate a strong preference for face-to-face regional meetings, with the perception that virtual meetings performed comparatively poorly at supporting a number of key meeting processes and outcomes. However, one-quarter to one-third of study participants consistently found no difference between format performance for many meeting processes and outcomes. Virtual formats were considered more appropriate for smaller and non-regional meetings, and allowed for greater staff attendance at meetings as well as cost and time savings for some, but not all, participants. Study participants believe that virtual regional meetings will be more common in the region in the future, despite nearly half indicating that virtual meeting are not a good fit for the region generally. Many of these experiences and perceptions are consistent with organizational behavior, communications media, and information systems literature. Some results appear unique to the region’s socially and culturally erse Pacific island countries and territories, which are relative newcomers to the global information and communication technology “revolution.” A greater use of virtual regional fisheries meetings in the future requires meeting hosts and facilitators to carefully consider the potential impacts of virtual meetings on effective communication and inclusive participation in WCPO regional fisheries management and other governance outcomes.
Publisher: Public Library of Science (PLoS)
Date: 23-01-2009
Publisher: Springer Science and Business Media LLC
Date: 21-01-2022
Publisher: Springer Science and Business Media LLC
Date: 25-06-1998
DOI: 10.1038/31723
Abstract: Parasites of the phylum Apicomplexa cause substantial morbidity, mortality and economic losses, and new medicines to treat them are needed urgently. The shikimate pathway is an attractive target for herbicides and antimicrobial agents because it is essential in algae, higher plants, bacteria and fungi, but absent from mammals. Here we present biochemical, genetic and chemotherapeutic evidence for the presence of enzymes of the shikimate pathway in apicomplexan parasites. In vitro growth of Toxoplasma gondii, Plasmodium falciparum (malaria) and Cryptosporidium parvum was inhibited by the herbicide glyphosate, a well-characterized inhibitor of the shikimate pathway enzyme 5-enolpyruvyl shikimate 3-phosphate synthase. This effect on T. gondii and P. falciparum was reversed by treatment with p-aminobenzoate, which suggests that the shikimate pathway supplies folate precursors for their growth. Glyphosate in combination with pyrimethamine limited T. gondii infection in mice. Four shikimate pathway enzymes were detected in extracts of T. gondii and glyphosate inhibited 5-enolpyruvyl shikimate 3-phosphate synthase activity. Genes encoding chorismate synthase, the final shikimate pathway enzyme, were cloned from T. gondii and P. falciparum. This discovery of a functional shikimate pathway in apicomplexan parasites provides several targets for the development of new antiparasite agents.
Publisher: eLife Sciences Publications, Ltd
Date: 29-10-2015
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.CMET.2012.10.017
Abstract: Metabolic reprogramming of cancer cells provides energy and multiple intermediates critical for cell growth. Hypoxia in tumors represents a hostile environment that can encourage these transformations. We report that glycogen metabolism is upregulated in tumors in vivo and in cancer cells in vitro in response to hypoxia. In vitro, hypoxia induced an early accumulation of glycogen, followed by a gradual decline. Concordantly, glycogen synthase (GYS1) showed a rapid induction, followed by a later increase of glycogen phosphorylase (PYGL). PYGL depletion and the consequent glycogen accumulation led to increased reactive oxygen species (ROS) levels that contributed to a p53-dependent induction of senescence and markedly impaired tumorigenesis in vivo. Metabolic analyses indicated that glycogen degradation by PYGL is important for the optimal function of the pentose phosphate pathway. Thus, glycogen metabolism is a key pathway induced by hypoxia, necessary for optimal glucose utilization, which represents a targetable mechanism of metabolic adaptation.
Publisher: Frontiers Media SA
Date: 23-11-2022
DOI: 10.3389/FMARS.2022.1043881
Abstract: The proliferation of the blue economy in political discourse has gained traction in recent years, however, there remains no standardized definition. The triple bottom line goals of economic development, social equity, and environmental conservation are at the center of the blue economy vision. Yet the ambiguities surrounding the term have resulted in considerable variation in how the blue economy is implemented and what is prioritized. This paper takes a global snapshot of current approaches to national level blue economy governance. In doing so this paper provides the first global assessment of blue economy implementation approaches, through the development of a global blue economy database. Using the best available information from policy documents, media releases and other publicly available online information, we comparatively analyzed each country’s governance strategy to assess the level of blue economy development in coastal states around the world. Throughout this paper we outline the novel methodological approach we took in order to develop a tool for analyzing national level blue economy implementation on the global scale. This approach will allow for ongoing and continued analysis of blue economy operationalization as the concept continues to evolve.
Publisher: Wiley
Date: 06-2017
DOI: 10.1111/FAF.12229
Publisher: Elsevier BV
Date: 02-2019
Publisher: Elsevier BV
Date: 06-1995
DOI: 10.1046/J.1432-0436.1995.5850361.X
Abstract: The present work describes a severe-combined immunodeficient murine xenograft model used to investigate human gastrointestinal ontogenesis. Specifically, the study has tested whether carefully selected regions of human fetal gut are able to undergo region-specific morphogenesis and epithelial cytodifferentiation when transplanted subcutaneously into immunodeficient mice. In addition, double-label in situ hybridisation techniques, utilising specific human and mouse DNA probes, have been adopted to characterise host and donor cell types and to investigate the potential developmental roles for non-epithelial cells in the regulation of epithelial differentiation pathways in vivo. Human fetal small and large bowel developed to form a characteristic mucosa 10 weeks after transplantation, which displayed clear region-specific structural and functional gradients. The initial phase of xenograft epithelialisation closely resembled the stratified type of epithelium which is present during early fetal gastrointestinal development. Idiosyncratic epithelial differentiation pathways were recorded during xenograft regeneration, with an absence of Paneth cells and an abundance of enteroendocrine cells when compared with developed xenograft and paediatric intestine. Such differences may, therefore, be important in ensuring rapid and region-specific development in the absence of conventional luminal stimuli and hormonal changes that occur normally during pregnancy. In situ hybridisation demonstrated an exclusively human origin for the intestinal xenograft epithelium and muscularis mucosa and externa. Although the submucosa and lamina propria were comprised of a chimeric mixture, murine cells were rarely seen to contact with the epithelium, which interacted primarily with human myofibroblasts and human intraepithelial lymphocytes. It is proposed that a 'selection' process operates to maintain species-specific cellular interactions, and this mechanism may subsequently play an important role in regulating epithelial cell differentiation, orchestrated in part by juxtaposed non-epithelial cell types.
Publisher: Informa UK Limited
Date: 05-04-2021
Publisher: Elsevier BV
Date: 02-2010
Publisher: Elsevier BV
Date: 06-2004
Publisher: Elsevier BV
Date: 2014
Publisher: Cambridge University Press (CUP)
Date: 19-08-2013
DOI: 10.1017/S0031182013000838
Abstract: Eimeria is a common genus of apicomplexan parasites that infect erse vertebrates, most notably poultry, causing serious disease and economic loss. Like all apicomplexans, eimerians have a complex life cycle characterized by asexual isions that lify the parasite population in preparation for sexual reproduction. This can be ided into three events: gametocytogenesis, producing gametocytes from merozoites gametogenesis, producing microgametes and macrogametes from gametocytes and fertilization of macrogametes by microgametes, producing diploid zygotes with ensuing meiosis completing the sexual phase. Sexual development in Eimeria depends on the differential expression of stage-specific genes, rather than presence or absence of sex chromosomes. Thus, it involves the generation of specific structures and, implicitly, storage of proteins and regulation of protein expression in macrogametes, in preparation for fertilization. In Eimeria , the formation of a unique, resilient structure, the oocyst wall, is essential for completion of the sexual phase and parasite transmission. In this review, we piece together the molecular events that underpin sexual reproduction in Eimeria and use additional details from analogous events in Plasmodium to fill current knowledge gaps. The mechanisms governing sexual stage formation and subsequent fertilization may represent targets for counteracting parasite transmission.
Publisher: Elsevier BV
Date: 09-2007
Publisher: Public Library of Science (PLoS)
Date: 07-03-2013
Publisher: Elsevier BV
Date: 02-2017
Publisher: Frontiers Media SA
Date: 12-2022
DOI: 10.3389/FPOS.2022.1040318
Abstract: The blue economy has emerged as an influential global concept. It is commonly understood to relate to the development of the ocean in a manner which also addresses concerns about ocean health in the face of increasing demands on ocean resources, marine pollution, and climate change. While the blue economy holds potential to act as an integrating policy framework for the sustainable development of the ocean, to date, there are limited ex les of implementation in practice to test the usefulness of the concept. Based on a typology of “good governance” adapted from existing global typologies, we investigated the role of blue economy governance in enabling integration. We used a mixed methods approach to explore the experience of Seychelles, a blue economy early adopter, combining policy and institutional analysis, semistructured interviews with key actors and partners, and country fieldwork. Our analysis shows that from its inception, Seychelles' vision of blue economy was a transformative model of development based on the protection and sustainable use of ocean resources for the benefit of Seychellois, consistent with the SDGs. Thanks to early political leadership and international engagement, the adoption of the blue economy concept was successful in raising awareness of the ocean health and its connection to people and the economy, and in establishing the basis of a national blue economy “architecture,” which helped secure innovative finance for implementation. Transitioning to implementation, several governance challenges emerged, which included maintaining high-level political momentum, stakeholder engagement, and institutional coordination and capacity. While some governance barriers to effective integration may be unique to Seychelles, some are common to SIDS, and others are found in a range of governance settings. Seychelles international visibility has brought high expectations, not always commensurate with local aspirations, capabilities, and jurisdictional responsibilities. Bridging the gap between global expectations and local realities will require support for locally driven institutional reforms, which take account of issues of scale, culture, and capacity.
Publisher: Wiley
Date: 12-09-2013
DOI: 10.1111/TRA.12102
Publisher: Elsevier BV
Date: 09-2022
Publisher: Elsevier BV
Date: 02-2017
Publisher: Elsevier BV
Date: 03-2012
Publisher: Informa UK Limited
Date: 15-05-2018
Publisher: Elsevier BV
Date: 08-2009
Publisher: Elsevier BV
Date: 07-2020
Publisher: Elsevier BV
Date: 09-2006
Abstract: Coccidian parasites are transmitted between hosts by the ingestion of food or water contaminated with oocysts, followed by the release of infectious sporozoites and invasion of the gastro-intestinal tract. In the external environment, sporozoites are protected from desiccation and chemical disinfection by the oocyst wall. This unique structure guarantees successful disease transmission and is as vital to the coccidian parasite as the exoskeleton is to insects--without it they would die. Here, we revisit the early work and combine it with newer molecular data to describe our present understanding of the coccidian oocyst wall.
Publisher: Informa UK Limited
Date: 14-12-2021
Publisher: Public Library of Science (PLoS)
Date: 10-01-2012
Publisher: Springer Science and Business Media LLC
Date: 30-09-2015
DOI: 10.1038/SREP14552
Abstract: Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82%, respectively, when expressed in Xenopus oocytes. These data provide, at least in part, a mechanistic explanation for the increased sensitivity of the mutant parasite lines to chloroquine. Taken together, these findings provide new insights into PfCRT function and PfCRT-mediated drug resistance, as well as the food vacuole, which is an important target of many antimalarial drugs.
Publisher: Elsevier BV
Date: 12-2015
Publisher: Center for Open Science
Date: 19-09-2018
Abstract: The ‘Blue Economy’ is an increasingly popular term in modern marine and ocean governance. The concept seeks to marry ocean-based development opportunities with environmental stewardship and protection. Yet different actors are co-opting this term in competing, and often conflicting ways. Four conceptual interpretations of the Blue Economy are identified, through examination of dominant discourses within international Blue Economy policy documents and key ‘grey’ literature. The way the Blue Economy is enacted is also examined, through an analysis of the Blue Economy ‘in practice’, and the actors involved. Finally, the scope of the Blue Economy is explored, with a particular focus on which particular marine industries are included or excluded from different conceptualizations. This analysis reveals areas of both consensus and conflict. Areas of consensus reflect the growing trend towards commodification and valuation of nature, the designation and delimitation of spatial boundaries in the oceans and increasing securitization of the world's oceans. Areas of conflict exist most notably around a ergence in opinions over the legitimacy of in idual sectors as components of the ‘Blue Economy’, in particular, carbon-intensive industries like oil and gas, and the emerging industry of deep seabed mining.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Elsevier BV
Date: 02-2014
Publisher: Authorea, Inc.
Date: 08-10-2020
Publisher: Elsevier BV
Date: 03-2018
Publisher: Oxford University Press (OUP)
Date: 15-02-2002
DOI: 10.1086/338004
Abstract: The shikimate pathway is essential for production of a plethora of aromatic compounds in plants, bacteria, and fungi. Seven enzymes of the shikimate pathway catalyze sequential conversion of erythrose 4-phosphate and phosphoenol pyruvate to chorismate. Chorismate is then used as a substrate for other pathways that culminate in production of folates, ubiquinone, napthoquinones, and the aromatic amino acids tryptophan, phenylalanine, and tyrosine. The shikimate pathway is absent from animals and present in the apicomplexan parasites Toxoplasma gondii, Plasmodium falciparum, and Cryptosporidium parvum. Inhibition of the pathway by glyphosate is effective in controlling growth of these parasites. These findings emphasize the potential benefits of developing additional effective inhibitors of the shikimate pathway. Such inhibitors may function as broad-spectrum antimicrobial agents that are effective against bacterial and fungal pathogens and apicomplexan parasites.
Publisher: Elsevier BV
Date: 2021
Publisher: Cold Spring Harbor Laboratory
Date: 13-09-2019
DOI: 10.1101/767830
Abstract: Eukaryotic cell proliferation requires chromosome replication and precise segregation to ensure daughter cells have identical genomic copies. The genus Plasmodium , the causative agent of malaria, displays remarkable aspects of nuclear ision throughout its lifecycle to meet some peculiar and unique challenges of DNA replication and chromosome segregation. The parasite undergoes atypical endomitosis and endoreduplication with an intact nuclear membrane and intranuclear mitotic spindle. To understand these erse modes of Plasmodium cell ision, we have studied the behaviour and composition of the outer kinetochore NDC80 complex, a key part of the mitotic apparatus that attaches the centromere of chromosomes to microtubules of the mitotic spindle. Using NDC80-GFP live-cell imaging in Plasmodium berghei we observe dynamic spatiotemporal changes during proliferation, including highly unusual kinetochore arrangements during sexual stages. We identify a very ergent candidate for the SPC24 subunit of the NDC80 complex, previously thought to be missing in Plasmodium , which completes a canonical, albeit unusual, NDC80 complex structure. Altogether, our studies reveal the kinetochore as an ideal tool to investigate the non-canonical modes of chromosome segregation and cell ision in Plasmodium. The dynamic localization of kinetochore marker NDC80 protein complex during proliferative stages of the malaria parasite life cycle reveals unique modes of chromosome segregation.
Publisher: Elsevier BV
Date: 11-2021
Publisher: Elsevier BV
Date: 07-2014
Publisher: Elsevier BV
Date: 02-2022
Publisher: Elsevier BV
Date: 02-1996
DOI: 10.1046/J.1432-0436.1996.5950321.X
Abstract: The present work describes the pattern of human intestinal proliferation in an immunodeficient murine xenograft model, which we have shown to closely mimic cell ision in normal paediatric gut. Cellular proliferation was measured using a double-label technique combining MIB-1 immunohistochemistry and [3H]thymidine autoradiography, to critically compare values for the tissue growth fraction (G1, G2, S- and M-phase cells) and DNA synthesizing (S-phase) cells in xenograft epithelium, lamina propria, muscularis externa and intraepithelial lymphocytes. The MIB-1 monoclonal antibody (which recognises the cell-cycle dependent nuclear antigen Ki-67) specifically labelled proliferating human cells within the xenografts and did not cross-react with iding murine cells. This was confirmed using ultrastructural in situ hybridisation with human- and mouse-specific DNA probes to identify the genetic origin of proliferating cells. In general, we found a good tissue correlation between MIB-1 and [3H]thymidine labelling, the only exception being an apparent dysregulation of Ki-67 antigen expression in regenerating xenograft epithelium. In developed xenograft intestine, the highest levels of proliferation were consistently recorded within the crypt epithelium, where 15.7%-26.7% of cells were actively cycling and S-phase occupied approximately half of the cell cycle. The frequency distribution of proliferating epithelial cells within small and large intestinal xenograft crypts was clearly tissue-specific, showing typical patterns of cell ision. Therefore, the presence of functional pluripotent epithelial stem cells and conventional spatio-temporal patterns in cellular proliferation, migration, de-cycling, lineage commitment and cytodifferentiation now makes this an attractive experimental model with which to study human intestinal crypt responses to various types of tissue manipulation, e.g. cytotoxic, radiotherapeutic, dietary, endocrine and gene-targeting therapy.
Publisher: Springer Science and Business Media LLC
Date: 07-1999
DOI: 10.1038/21900
Abstract: The malaria parasite Plasmodium falciparum is one of the most successful human pathogens. Specific virulence factors remain poorly defined, although the adhesion of infected erythrocytes to the venular endothelium has been associated with some of the syndromes of severe disease. Immune responses cannot prevent the development of symptomatic infections throughout life, and clinical immunity to the disease develops only slowly during childhood. An understanding of the obstacles to the development of protective immunity is crucial for developing rational approaches to prevent the disease. Here we show that intact malaria-infected erythrocytes adhere to dendritic cells, inhibit the maturation of dendritic cells and subsequently reduce their capacity to stimulate T cells. These data demonstrate both a novel mechanism by which malaria parasites induce immune dysregulation and a functional role beyond endothelial adhesion for the adhesive phenotypes expressed at the surface of infected erythrocytes.
Publisher: Cambridge University Press (CUP)
Date: 13-05-2004
DOI: 10.1017/S0031182004005025
Abstract: Human serum high-density lipoprotein (HDL) is necessary and sufficient for the short-term maintenance of Plasmodium falciparum in in vitro culture. However, at high concentrations it is toxic to the parasite. A heat-labile component is apparently responsible for the stage-specific toxicity to parasites within infected erythrocytes 12–42 h after invasion, i.e. during trophozoite maturation. The effects of HDL on parasite metabolism (as determined by nucleic acid synthesis) are evident at about 30 h after invasion. Parasites treated with HDL show gross abnormalities by light and electron microscopy.
Publisher: Elsevier BV
Date: 11-2019
Publisher: The Royal Society
Date: 16-05-2022
Abstract: The Blue Economy is a catch all term that is used to describe a wide variety of development approaches and priorities in the ocean and coastal areas. A number of distinct, and sometimes conflicting discourses have emerged in relation to the Blue Economy, which are distinguished by the degree to which they prioritize different development objectives. This paper explores the range of Blue Economy interpretations, governance strategies and implementation approaches that exist across Commonwealth countries. Key Blue Economy policy statements and governance instruments are analysed in order to ascertain the way the Blue Economy is being institutionalized at a national level, with reference to the Sustainable Development Goals and the Commonwealth Blue Charter. High-level Blue Economy objectives appear to prioritize economic and environmental objectives, with limited engagement with equity objectives including food security and gender equality. Blue Economy objectives are primarily being institutionalized through a erse array of strategies, plans and policies with limited information on mechanisms for implementation. Finally, there are signs that the Blue Economy may be facilitating a greater degree of integration across sectoral management, with the emergence of range of boundary-crossing arrangements in a number of the countries examined. This article is part of the theme issue ‘Nurturing resilient marine ecosystems’.
Publisher: Elsevier BV
Date: 02-2009
Publisher: Springer Science and Business Media LLC
Date: 26-10-2023
Publisher: Elsevier BV
Date: 10-2003
DOI: 10.1016/S0020-7519(03)00185-1
Abstract: We have identified, and followed the development of three macrogamete organelles involved in the formation of the oocyst wall of Eimeria maxima. The first were small lucent vacuoles that cross-reacted with antibodies to the apple domains of the Toxoplasma gondii microneme protein 4. They appeared early in development and were secreted during macrogamete maturation to form an outer veil and were termed veil forming bodies. The second were the wall forming bodies type 1, large, electron dense vacuoles that stained positively only with antibodies raised to an enriched preparation of the native forms of 56 (gam56), 82 (gam82) and 230 kDa (gam230) gametocyte antigens (termed anti-APGA). The third were the wall forming bodies type 2, which appeared before the wall forming bodies type 1 but remain enclosed within the rough endoplasmic reticulum and stained positively with antibodies raised to recombinant versions of gam56 (anti-gam56), gam82 (anti-gam82) and gam230 (anti-gam230) plus anti-APGA. At the initiation of oocyst wall formation, the anti-T. gondii microneme protein 4 positive outer veil detached from the surface. The outer layer of the oocyst wall was formed by the release of the contents of wall forming bodies type 1 at the surface to form an electron dense, anti-APGA positive layer. The wall forming bodies type 2 appeared, subsequently, to give rise to the electron lucent inner layer. Thus, oocyst wall formation in E. maxima represents a sequential release of the contents of the veil forming bodies, wall forming bodies types 1 and 2 and this may be controlled at the level of the rough endoplasmic reticulum/Golgi body.
Publisher: Springer Science and Business Media LLC
Date: 02-11-2017
DOI: 10.1038/S41467-017-01342-5
Abstract: AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as αβγ complexes, whose regulatory γ subunit confers energy sensor function by binding adenine nucleotides. Humans bearing activating mutations in the γ2 subunit exhibit a phenotype including unexplained slowing of heart rate (bradycardia). Here, we show that γ2 AMPK activation downregulates fundamental sinoatrial cell pacemaker mechanisms to lower heart rate, including sarcolemmal hyperpolarization-activated current ( I f ) and ryanodine receptor-derived diastolic local subsarcolemmal Ca 2+ release. In contrast, loss of γ2 AMPK induces a reciprocal phenotype of increased heart rate, and prevents the adaptive intrinsic bradycardia of endurance training. Our results reveal that in mammals, for which heart rate is a key determinant of cardiac energy demand, AMPK functions in an organ-specific manner to maintain cardiac energy homeostasis and determines cardiac physiological adaptation to exercise by modulating intrinsic sinoatrial cell behavior.
Publisher: eLife Sciences Publications, Ltd
Date: 18-11-2015
DOI: 10.7554/ELIFE.10809
Abstract: Infection by Toxoplasma gondii leads to massive changes to the host cell. Here, we identify a novel host cell effector export pathway that requires the Golgi-resident aspartyl protease 5 (ASP5). We demonstrate that ASP5 cleaves a highly constrained amino acid motif that has similarity to the PEXEL-motif of Plasmodium parasites. We show that ASP5 matures substrates at both the N- and C-terminal ends of proteins and also controls trafficking of effectors without this motif. Furthermore, ASP5 controls establishment of the nanotubular network and is required for the efficient recruitment of host mitochondria to the vacuole. Assessment of host gene expression reveals that the ASP5-dependent pathway influences thousands of the transcriptional changes that Toxoplasma imparts on its host cell. All these changes result in attenuation of virulence of Δasp5 tachyzoites in vivo. This work characterizes the first identified machinery required for export of Toxoplasma effectors into the infected host cell.
Publisher: Informa UK Limited
Date: 02-01-2018
Publisher: Springer Science and Business Media LLC
Date: 19-07-2005
Publisher: Public Library of Science (PLoS)
Date: 11-03-2021
DOI: 10.1371/JOURNAL.PBIO.3001081
Abstract: The apical complex is the instrument of invasion used by apicomplexan parasites, and the conoid is a conspicuous feature of this apparatus found throughout this phylum. The conoid, however, is believed to be heavily reduced or missing from Plasmodium species and other members of the class Aconoidasida. Relatively few conoid proteins have previously been identified, making it difficult to address how conserved this feature is throughout the phylum, and whether it is genuinely missing from some major groups. Moreover, parasites such as Plasmodium species cycle through 3 invasive forms, and there is the possibility of differential presence of the conoid between these stages. We have applied spatial proteomics and high-resolution microscopy to develop a more complete molecular inventory and understanding of the organisation of conoid-associated proteins in the model apicomplexan Toxoplasma gondii . These data revealed molecular conservation of all conoid substructures throughout Apicomplexa, including Plasmodium , and even in allied Myzozoa such as Chromera and dinoflagellates. We reporter-tagged and observed the expression and location of several conoid complex proteins in the malaria model P . berghei and revealed equivalent structures in all of its zoite forms, as well as evidence of molecular differentiation between blood-stage merozoites and the ookinetes and sporozoites of the mosquito vector. Collectively, we show that the conoid is a conserved apicomplexan element at the heart of the invasion mechanisms of these highly successful and often devastating parasites.
Publisher: Public Library of Science (PLoS)
Date: 14-03-2014
Publisher: Elsevier BV
Date: 07-2021
Publisher: Elsevier BV
Date: 02-2020
Publisher: Elsevier BV
Date: 12-2013
Publisher: Springer Science and Business Media LLC
Date: 1995
DOI: 10.1007/BF00164171
Publisher: Elsevier BV
Date: 2004
DOI: 10.1016/J.MOLBIOPARA.2003.07.007
Abstract: Innate immune responses are important in the control of malaria, particularly in those who have not yet mounted an effective adaptive response. Here we report that the human serum acute phase protein, haptoglobin, is toxic to Plasmodium falciparum cultured in vitro. This effect is phenotype dependent and occurs during the trophozoite phase of the asexual life cycle. We propose that the increased levels of haptoglobin seen in the acute phase response may be protective against malaria in humans.
Publisher: Springer Science and Business Media LLC
Date: 06-1993
DOI: 10.1007/BF00157806
Publisher: Elsevier BV
Date: 09-2022
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 04-2022
End Date: 03-2025
Amount: $418,601.00
Funder: Australian Research Council
View Funded Activity