Gigaxonin-controlled degradation of MAP1B light chain is critical to neuronal survival

Giant axonal neuropathy (GAN) is a devastating sensory and motor neuropathy caused by mutations in the GAN gene, which encodes the ubiquitously expressed protein gigaxonin. Cytopathological features of GAN include axonal degeneration, with accumulation and aggregation of cytoskeletal components. Little is currently known about the molecular mechanisms underlying this recessive disorder. Here we show that gigaxonin controls protein degradation, and is essential for neuronal function and survival. We present evidence that gigaxonin binds to the ubiquitin-activating enzyme E1 through its amino-terminal BTB domain, while the carboxy-terminal kelch repeat domain interacts directly with the light chain (LC) of microtubule-associated protein 1B (MAP1B). Overexpression of gigaxonin leads to enhanced degradation of MAP1B-LC, which can be antagonized by proteasome inhibitors. Ablation of gigaxonin causes a substantial accumulation of MAP1B-LC in GAN-null neurons. Moreover, we show that overexpression of MAP1B in wild-type cortical neurons leads to cell death characteristic of GAN-null neurons, whereas reducing MAP1B levels significantly improves the survival rate of null neurons. Our results identify gigaxonin as a ubiquitin scaffolding protein that controls MAP1B-LC degradation, and provide insight into the molecular mechanisms underlying human neurodegenerative disorders.     

Extreme winds and waves in the aftermath of a Neoproterozoic glaciation

The most severe excursions in the Earth's climatic history are thought to be associated with Proterozoic glaciations. According to the 'Snowball Earth' hypothesis, the Marinoan glaciation, which ended about 635 million years ago, involved global or nearly global ice cover. At the termination of this glacial period, rapid melting of continental ice sheets must have caused a large rise in sea level. Here we show that sediments deposited during this sea level rise contain remarkable structures that we interpret as giant wave ripples. These structures occur at homologous stratigraphic levels in Australia, Brazil, Canada, Namibia and Svalbard. Our hydrodynamic analysis of these structures suggests maximum wave periods of 21 to 30 seconds, significantly longer than those typical for today's oceans. The reconstructed wave conditions could only have been generated under sustained high wind velocities exceeding 20 metres per second in fetch-unlimited ocean basins. We propose that these extraordinary wind and wave conditions were characteristic of the climatic transit, and provide observational targets for atmospheric circulation models.     

Uncertainty in predictions of the climate response to rising levels of greenhouse gases

The range of possibilities for future climate evolution needs to be taken into account when planning climate change mitigation and adaptation strategies. This requires ensembles of multi-decadal simulations to assess both chaotic climate variability and model response uncertainty. Statistical estimates of model response uncertainty, based on observations of recent climate change, admit climate sensitivities--defined as the equilibrium response of global mean temperature to doubling levels of atmospheric carbon dioxide--substantially greater than 5 K. But such strong responses are not used in ranges for future climate change because they have not been seen in general circulation models. Here we present results from the 'climateprediction.net' experiment, the first multi-thousand-member grand ensemble of simulations using a general circulation model and thereby explicitly resolving regional details. We find model versions as realistic as other state-of-the-art climate models but with climate sensitivities ranging from less than 2 K to more than 11 K. Models with such extreme sensitivities are critical for the study of the full range of possible responses of the climate system to rising greenhouse gas levels, and for assessing the risks associated with specific targets for stabilizing these levels.     

A single-nucleotide polymorphism tagging set for human drug metabolism and transport

Interindividual variability in drug response, ranging from no therapeutic benefit to life-threatening adverse reactions, is influenced by variation in genes that control the absorption, distribution, metabolism and excretion of drugs. We genotyped 904 single-nucleotide polymorphisms (SNPs) from 55 such genes in two population samples (European and Japanese) and identified a set of tagging SNPs that represents the common variation in these genes, both known and unknown. Extensive empirical evaluations, including a direct assessment of association with candidate functional SNPs in a new, larger population sample, validated the performance of these tagging SNPs and confirmed their utility for linkage-disequilibrium mapping in pharmacogenetics. The analyses also suggest that rare variation is not amenable to tagging strategies.     

Abrupt rise in atmospheric CO2 overestimates community response in a model plant-soil system

Attempts to understand the ecological effect of increasing atmospheric CO2 concentration, [CO2], usually involve exposing today's ecosystems to expected future [CO2] levels. However, a major assumption of these approaches has not been tested--that exposing ecosystems to a single-step increase in [CO2] will yield similar responses to those of a gradual increase over several decades. We tested this assumption on a mycorrhizal fungal community over a period of six years. [CO2] was either increased abruptly, as is typical of most [CO2] experiments, or more gradually over 21 generations. The two approaches resulted in different structural and functional community responses to increased [CO2]. Some fungi were sensitive to the carbon pulse of the abrupt [CO2] treatment. This resulted in an immediate decline in fungal species richness and a significant change in mycorrhizal functioning. The magnitude of changes in fungal diversity and functioning in response to gradually increasing [CO2] was smaller, and not significantly different to those with ambient [CO2]. Our results suggest that studies may overestimate some community responses to increasing [CO2] because biota may be sensitive to ecosystem changes that occur as a result of abrupt increases.     

Coproduction in Practice: Participatory Action Research to Develop a Model of Community Aged Care

Coproduction has become synonymous with innovative approaches to public service delivery in European Union countries as well as in Australia. Coproduction has the potential to bring together individuals, communities, and organisations in a process to collaboratively develop new models and services which improve public services. Yet, Australian policy makers and practitioners who would like to deploy coproduction within the context of older adult social care can only draw on a handful of papers and reports that could guide implementation. This paper fills this gap by reporting on the implementation of a multi-stakeholder coproduction approach to the development of a consumer directed care model for older people with complex health issues. The paper describes and critically highlights methodological challenges encountered during the 12 month-long participatory action research phase of a larger project involving older people with complex care needs, their carers, and government and non-government stakeholders. The paper outlines key considerations regarding (1) the involvement of older people with complex needs, (2) collaboration with industry partners, (3) engagement of government representatives, and (4) reflects on implementing participatory research projects within a context of outsourcing and interlinked supply chains. While not all challenges encountered could be resolved, the coproduction approach was successful in bringing together a wide range of stakeholders with competing agendas in an iterative process geared to resolve a plethora of concerns raised by older people, carers and services providers. This paper provides an example for others seeking to use coproduction and participatory methods to provide person-centred care services for older people.