Kainate Receptors Coexist in a Functional Complex with KCC2 and Regulate Chloride Homeostasis in Hippocampal Neurons

Peer reviewe

Protein Interactions Regulate KCC2-mediated Chloride Homeostasis

KCC2 is the primary Cl- cotransporter which maintains a low [Cl-]i required for inhibitory neurotransmission. Despite intense investigation into the mechanisms governing KCC2 regulation, the underlying mechanisms remain poorly understood. In this thesis I have presented three novel pieces of evidence providing further insight into KCC2 regulation. First, KCC2 membrane expression, and therefore function, require the expression of the KAR-type subunit GluK2. Second, KCC2 membrane recycling can be increased in the presence of GluK2 or by PKC-mediated phosphorylation. Protein interaction with GluK2 and PKC-mediated phosphorylation synergistically increase KCC2 expression and function, demonstrating how this protein can be regulated by functional cross-talk of multiple protein modifications. Finally, KCC2 is dephosphorylated by a calcineurin-dependent mechanism in response to ionic shift plasticity induction. Elucidating the mechanisms which regulate KCC2 function are highly coveted as KCC2 down-regulation is commonly observed in neuropathophysiological conditions such as epilepsy and neuropathic pain. Taken together, my results present novel findings regarding the mechanisms which regulate KCC2 function and surface expression and critically regulate neuronal Cl- homeostasis.Ph.D.2018-02-12 00:00:0

Absence of evidence for the conservation outcomes of systematic conservation planning around the globe: A systematic map

BackgroundSystematic conservation planning is a discipline concerned with the prioritisation of resources for biodiversity conservation and is often used in the design or assessment of terrestrial and marine protected area networks. Despite being an evidence-based discipline, to date there has been no comprehensive review of the outcomes of systematic conservation plans and assessments of the relative effectiveness of applications in different contexts. To address this fundamental gap in knowledge, our primary research question was: what is the extent, distribution and robustness of evidence on conservation outcomes of systematic conservation planning around the globe?MethodsA systematic mapping exercise was undertaken using standardised search terms across 29 sources, including publication databases, online repositories and a wide range of grey literature sources. The review team screened articles recursively, first by title only, then abstract and finally by full-text, using inclusion criteria related to systematic conservation plans conducted at sub-global scales and reported on since 1983. We sought studies that reported outcomes relating to natural, human, social, financial or institutional outcomes and which employed robust evaluation study designs. The following information was extracted from included studies: bibliographic details, background information including location of study and broad objectives of the plan, study design, reported outcomes and context.ResultsOf the approximately 10,000 unique articles returned through our searches, 1209 were included for full-text screening and 43 studies reported outcomes of conservation planning interventions. However, only three studies involved the use of evaluation study designs which are suitably rigorous for inclusion, according to best-practice guidelines. The three included studies were undertaken in the Gulf of California (Mexico), Réunion Island, and The Nature Conservancy’s landholdings across the USA. The studies varied widely in context, purpose and outcomes. Study designs were non-experimental or qualitative, and involved use of spatial landholdings over time, stakeholder surveys and modelling of alternative planning scenarios.ConclusionRigorous evaluations of systematic conservation plans are currently not published in academic journals or made publicly available elsewhere. Despite frequent claims relating to positive implications and outcomes of these planning activities, we show that evaluations are probably rarely conducted. This finding does not imply systematic conservation planning is not effective but highlights a significant gap in our understanding of how, when and why it may or may not be effective. Our results also corroborate claims that the literature on systematic conservation planning is dominated by methodological studies, rather than those that focus on implementation and outcomes, and support the case that this is a problematic imbalance in the literature. We emphasise the need for academics and practitioners to publish the outcomes of systematic conservation planning exercises and to consider employing robust evaluation methodologies when reporting project outcomes. Adequate reporting of outcomes will in turn enable transparency and accountability between institutions and funding bodies as well as improving the science and practice of conservation planning

Research advances and gaps in marine planning: towards a global database in systematic conservation planning

Systematic conservation planning (SCP) has increasingly been used to prioritize conservation actions, including the design of new protected areas to achieve conservation objectives. Over the last 10 years, the number of marine SCP studies has increased exponentially, yet there is no structured or reliable way to find information on methods, trends, and progress. The rapid growth in methods and marine applications warrants an updated analysis of the literature, as well as reflection on the need for continuous and systematic documentation of SCP exercises in general. To address these gaps, we developed a database to document SCP exercises and populated it with 155 marine SCP exercises found in the primary literature. Based on our review, we provide an update on global advances and trends in marine SCP literature. We found accelerating growth in the number of studies over the past decade, with increasing consideration of socioeconomic variables, land-sea planning, and ecological connectivity. While several studies aimed to inform conservation decisions, we found little evidence of input from practitioners. There are important gaps in geographic coverage and little correspondence with areas most threatened. Five countries lead most studies, but their networks suggest potential for capacity building through collaborations. The varying quality and detail in documentation of studies confirmed the limited opportunities to develop and assess the application of best practice in conservation planning. A global database to track the development, implementation, and impact of SCP applications can thus provide numerous benefits. Our database constitutes an important step towards the development of a centralized repository of information on planning exercises and can serve several roles to advance SCP theory and practice: it facilitates assessing geographic coverage and gaps; scientists and practitioners can access information to identify trends in the use of data, methods, and tools; reviewers and editors of journals can assess whether studies have covered important literature and developments; donors and non-government organizations can identify regions needing further work; and practitioners and policy-makers can learn from previous plans

Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity

Glioblastoma (GBM) is a cancer comprised of morphologically, genetically, and phenotypically diverse cells. However, an understanding of the functional significance of intratumoral heterogeneity is lacking. We devised a method to isolate and functionally profile tumorigenic clones from patient glioblastoma samples. Individual clones demonstrated unique proliferation and differentiation abilities. Importantly, naïve patient tumors included clones that were temozolomide resistant, indicating that resistance to conventional GBM therapy can preexist in untreated tumors at a clonal level. Further, candidate therapies for resistant clones were detected with clone-specific drug screening. Genomic analyses revealed genes and pathways that associate with specific functional behavior of single clones. Our results suggest that functional clonal profiling used to identify tumorigenic and drug-resistant tumor clones will lead to the discovery of new GBM clone-specific treatment strategies