Mutations in RAB39B Cause X-Linked Intellectual Disability and Early-Onset Parkinson Disease with alpha-Synuclein Pathology

Advances in understanding the etiology of Parkinson disease have been driven by the identification of causative mutations in families. Genetic analysis of an Australian family with three males displaying clinical features of early-onset parkinsonism and intellectual disability identified a approximately 45 kb deletion resulting in the complete loss of RAB39B. We subsequently identified a missense mutation (c.503C>A [p.Thr168Lys]) in RAB39B in an unrelated Wisconsin kindred affected by a similar clinical phenotype. In silico and in vitro studies demonstrated that the mutation destabilized the protein, consistent with loss of function. In vitro small-hairpin-RNA-mediated knockdown of Rab39b resulted in a reduction in the density of alpha-synuclein immunoreactive puncta in dendritic processes of cultured neurons. In addition, in multiple cell models, we demonstrated that knockdown of Rab39b was associated with reduced steady-state levels of alpha-synuclein. Post mortem studies demonstrated that loss of RAB39B resulted in pathologically confirmed Parkinson disease. There was extensive dopaminergic neuron loss in the substantia nigra and widespread classic Lewy body pathology. Additional pathological features included cortical Lewy bodies, brain iron accumulation, tau immunoreactivity, and axonal spheroids. Overall, we have shown that loss-of-function mutations in RAB39B cause intellectual disability and pathologically confirmed early-onset Parkinson disease. The loss of RAB39B results in dysregulation of alpha-synuclein homeostasis and a spectrum of neuropathological features that implicate RAB39B in the pathogenesis of Parkinson disease and potentially other neurodegenerative disorders

New, simplified and improved interpretation of the Vaiont landslide mechanics

Both the occurrence and behaviour of the Vaiont landslide have not been satisfactorily explained previously because of difficulties arising from the assumption that the failure surface was ‘chair’ shaped. It is now known that there was no ‘chair’, which means that the 1963 landslide could not have been a reactivated ancient landslide because the residual strength of the clay interbeds would have been insufficient for stability prior to 1963. Furthermore, the moderately translational geometry reduces the influence of reservoir-induced groundwater and hence of submergence. Standard stability analyses now show that prior to 1960, the average shear strength must have significantly exceeded the peak shear strength of the clay interbeds known to have formed the majority of the failure surface. Three-dimensional stability analyses confirm these results and show that at the time of the first significant movements in 1960, the rising reservoir level had a negligible effect on the Factor of Safety. According to these results, the Vaiont landslide was most likely initiated by pore water pressures associated with transient rainfall-induced ‘perched’ groundwater above the clay layers, in combination with a smaller than hitherto assumed effect of reservoir impounding, then developed by brittle crack propagation within the clay beds, thus displaying progressive failure. Further, very heavy rainfall accelerated the process, possibly due to reservoir-induced groundwater impeding drainage of the rainwater, until the limestone beds at the northeast margin failed. With the shear strength suddenly reduced to residual throughout, the entire mass was released and was able to accelerate as observed

The Galaxy platform for accessible, reproducible, and collaborative data analyses: 2024 update

YesGalaxy (https://galaxyproject.org) is deployed globally, predominantly through free-to-use services, supporting user-driven research that broadens in scope each year. Users are attracted to public Galaxy services by platform stability, tool and reference dataset diversity, training, support and integration, which enables complex, reproducible, shareable data analysis. Applying the principles of user experience design (UXD), has driven improvements in accessibility, tool discoverability through Galaxy Labs/subdomains, and a redesigned Galaxy ToolShed. Galaxy tool capabilities are progressing in two strategic directions: integrating general purpose graphical processing units (GPGPU) access for cutting-edge methods, and licensed tool support. Engagement with global research consortia is being increased by developing more workflows in Galaxy and by resourcing the public Galaxy services to run them. The Galaxy Training Network (GTN) portfolio has grown in both size, and accessibility, through learning paths and direct integration with Galaxy tools that feature in training courses. Code development continues in line with the Galaxy Project roadmap, with improvements to job scheduling and the user interface. Environmental impact assessment is also helping engage users and developers, reminding them of their role in sustainability, by displaying estimated CO2 emissions generated by each Galaxy job.NIH [U41 HG006620, U24 HG010263, U24 CA231877, U01 CA253481]; US National Science Foundation [1661497, 1758800, 2216612]; computational resources are provided by the Advanced Cyberinfrastructure Coordination Ecosystem (ACCESS-CI), Texas Advanced Computing Center, and the JetStream2 scientific cloud. Funding for open access charge: NIH. ELIXIR IS and Travel grants; EU Horizon Europe [HORIZON-INFRA-2021-EOSC-01-04, 101057388]; EU Horizon Europe under the Biodiversity, Circular Economy and Environment program (REA.B.3, BGE 101059492); German Federal Ministry of Education and Research, BMBF [031 A538A de.NBI-RBC]; Ministry of Science, Research and the Arts Baden-Württemberg (MWK) within the framework of LIBIS/de.NBI Freiburg. Galaxy Australia is supported by the Australian BioCommons which is funded through Australian Government NCRIS investments from Bioplatforms Australia and the Australian Research Data Commons, as well as investment from the Queensland Government RICF program.Please note, contributors are listed in alphabetical order

The Galaxy platform for accessible, reproducible, and collaborative data analyses: 2024 update

YesGalaxy (https://galaxyproject.org) is deployed globally, predominantly through free-to-use services, supporting user-driven research that broadens in scope each year. Users are attracted to public Galaxy services by platform stability, tool and reference dataset diversity, training, support and integration, which enables complex, reproducible, shareable data analysis. Applying the principles of user experience design (UXD), has driven improvements in accessibility, tool discoverability through Galaxy Labs/subdomains, and a redesigned Galaxy ToolShed. Galaxy tool capabilities are progressing in two strategic directions: integrating general purpose graphical processing units (GPGPU) access for cutting-edge methods, and licensed tool support. Engagement with global research consortia is being increased by developing more workflows in Galaxy and by resourcing the public Galaxy services to run them. The Galaxy Training Network (GTN) portfolio has grown in both size, and accessibility, through learning paths and direct integration with Galaxy tools that feature in training courses. Code development continues in line with the Galaxy Project roadmap, with improvements to job scheduling and the user interface. Environmental impact assessment is also helping engage users and developers, reminding them of their role in sustainability, by displaying estimated CO2 emissions generated by each Galaxy job.NIH [U41 HG006620, U24 HG010263, U24 CA231877, U01 CA253481]; US National Science Foundation [1661497, 1758800, 2216612]; computational resources are provided by the Advanced Cyberinfrastructure Coordination Ecosystem (ACCESS-CI), Texas Advanced Computing Center, and the JetStream2 scientific cloud. Funding for open access charge: NIH. ELIXIR IS and Travel grants; EU Horizon Europe [HORIZON-INFRA-2021-EOSC-01-04, 101057388]; EU Horizon Europe under the Biodiversity, Circular Economy and Environment program (REA.B.3, BGE 101059492); German Federal Ministry of Education and Research, BMBF [031 A538A de.NBI-RBC]; Ministry of Science, Research and the Arts Baden-Württemberg (MWK) within the framework of LIBIS/de.NBI Freiburg. Galaxy Australia is supported by the Australian BioCommons which is funded through Australian Government NCRIS investments from Bioplatforms Australia and the Australian Research Data Commons, as well as investment from the Queensland Government RICF program

Habitat partitioning and vulnerability of sharks in the Great Barrier Reef Marine Park

Sharks present a critical conservation challenge, but little is known about their spatial distribution and vulnerability, particularly in complex seascapes such as Australia's Great Barrier Reef Marine Park (GBRMP). We review (1) the distribution of shark species among the primary habitats of the GBRMP (coral reefs, inshore/shelf, pelagic and deep-water habitats) (2) the relative exploitation of each species by fisheries, and (3) how current catch rates interact with their vulnerability and trophic index. Excluding rays and chimaeras, we identify a total of 82 shark species in the GBRMP. We find that shark research in the GBRMP has yielded little quantitative information on most species. Reef sharks are largely site-fidelic, but can move large distances and some regularly use non-reef habitats. Inshore and shelf sharks use coastal habitats either exclusively or during specific times in their life cycle (e.g. as nurseries). Virtually nothing is known about the distribution and habitat use of the GBRMP's pelagic and deep-water sharks. At least 46 species (53.5 %) are caught in one or more fisheries, but stock assessments are lacking for most. At least 17 of the sharks caught are considered highly vulnerable to exploitation. We argue that users of shark resources should be responsible for demonstrating that a fishery is sustainable before exploitation is allowed to commence or continue. This fundamental change in management principle will safeguard against stock collapses that have characterised many shark fisheries