Biology subjects

Dean, C.

Publications and source records attributed to Dean, C..

6 recordsLinked to original sources

bioRxiv2018

A Proof-of-Principle of Nanoscale Optogenetics

Optogenetics has revolutionized the study of circuit function in the brain, by allowing activation of specific ensembles of neurons by light. However, this technique has not yet been exploited extensively at the subcellular level. Here we propose a novel focal stimulation approach using STED/RESOLFT-like illumination, whereby switchable light-gated channels are focally activated by a laser beam of one wavelength and deactivated by an overlapping donut-shaped beam of a different wavelength, confining activation to a center focal region. We demonstrate the utility of current optogenetic tools to achieve highly focal depolarization using this method and further examine a proof-of-principle of nanoscale optogenetic activation using an initial macroscale approach. When employed at the nanoscale, this approach will allow unprecedented optogenetic control of nanodomains within cells.

neuroscience↗

bioRxiv2018

Non-canonical Wnt signalling initiates scarring in biliary disease

Cholangiopathies, or biliary diseases, account for a significant proportion of adult and paediatric liver disease. In these pathologies, iterative cycles of damage and repair result in the development of a regenerative microenvironment surrounding the bile ducts, which orchestrates both epithelial proliferation and also biliary fibrosis. Ultimately, fibrosis at the cost of repair results in cholestasis and liver failure, necessitating liver transplantation. Whilst the fibrogenic mechanisms in hepatocellular disease have been widely studied, little is known about the processes that regulate biliary scarring. We sought to determine how the injured biliary epithelium communicates to adjacent stromal cells to regulate scar formation, and to identify therapeutically targetable pathways that could be inhibited to reduce biliary scarring, whilst maintaining the pro-regenerative stroma. Using human tissue, bile duct organoids and animal models of biliary disease, we show that non-canonical Wnt signalling is important in initiating biliary scarring. This process is driven by myeloid Wnt5a and acts through epithelial Vangl2, which is upstream of Jnk/cJun signalling. Activation of this pathway drives a pro-fibrotic signalling process which instructs portal fibroblasts to synthesise collagen. Finally, we determine that therapeutic Wnt ligand inhibition reduces biliary scarring, identifying non-canonical Wnt signalling as a novel target for anti-fibrotic therapy in cholestatic biliary disease.

physiology↗

bioRxiv2018

Tychus: a whole genome sequencing pipeline for assembly, annotation and phylogenetics of bacterial genomes

SummaryTychus is a tool that allows researchers to perform massively parallel whole genome sequence (WGS) analysis with the goal of producing a high confidence and comprehensive description of the bacterial genome. Key features of the Tychus pipeline include the assembly, annotation, alignment, variant discovery and phylogenetic inference of large numbers of WGS isolates in parallel using open-source bioinformatics tools and virtualization technology. All prerequisite tools and dependencies come packaged together in a single suite that can be easily downloaded and installed on Linux and Mac operating systems.\n\nAvailabilityTychus is freely available as an open-source package under the MIT license, and can be downloaded via GitHub (https://github.com/Abdo-Lab/Tychus).\n\nContactzaid.abdo@colostate.edu

bioinformatics↗

bioRxiv2018

Visualizing BDNF cell-to-cell transfer reveals astrocytes are the primary recipient of neuronal BDNF

Brain-derived neurotrophic factor (BDNF) is essential for neuronal growth, differentiation, and synaptic plasticity. Although the release and effects of BDNF have been well-studied separately, the transfer of BDNF between cells has not been investigated. Using a four-fluorophore imaging approach to identify both the cell of origin and target cells, we quantified the transfer of BDNF. Surprisingly, we found that astrocytes are the main recipient of neuronally expressed BDNF. We further found that astrocytes specifically take up mature (not pro) BDNF released by neurons. Over-expression of TrkB in neurons redirects released BDNF from astrocytes to neurons, indicating that TrkB levels determine neuronal versus astrocytic BDNF uptake. Increased neuronal activity further increased astrocytic (but not neuronal) uptake of neuronally expressed BDNF. Finally, we demonstrate that astrocytes are not simply a sink for excess BDNF, but that BDNF taken up by astrocytes mediates physiological effects on the astrocytic population by increasing astrocytic territory.

neuroscience↗

bioRxiv2017

Plant genes influence microbial hubs that shape beneficial leaf communities

Although complex interactions between hosts and microbial associates are increasingly well documented, we still know little about how and why hosts shape microbial communities in nature. In addition, host genetic effects on microbial communities vary widely depending on the environment, obscuring conclusions about which microbes are impacted and which plant functions are important. We characterized the leaf microbiota of 200 A. thaliana genotypes in eight field experiments and detected consistent host effects on specific, broadly distributed microbial OTUs. Host genetics disproportionately influenced hubs within the microbial communities, with their impact then percolating through the community, as evidenced by a decline in the heritability of particular OTUs with their distance to the nearest hub. By simultaneously measuring host performance, we found that host genetics associated with microbial hubs explained over 10% of the variation in lifetime seed production among host genotypes across sites and years. We successfully cultured one of these microbial hubs and demonstrated its growth-promoting effects on plants grown in sterile conditions. Finally, genome-wide association mapping identified many putatively causal genes with small effects on the relative abundance of microbial hubs across sites and years, and these genes were enriched for those involved in the synthesis of specialized metabolites, auxins and the immune system. Using untargeted metabolomics, we corroborate the consistent association of variation in specialized metabolites and microbial hubs across field sites. Together, our results reveal that host natural variation impacts the microbial communities in consistent ways across environments and that these effects contribute to fitness variation among host genotypes.

microbiology↗

bioRxiv2017

RNA-dependent intergenerational inheritance of enhanced synaptic plasticity after environmental enrichment

Physical exercise in combination with cognitive training is known to enhance synaptic plasticity and lower the risk for various complex diseases including Alzheimers disease. Here we show that exposure of adult male mice to an environmental enrichment paradigm leads to long-lasting enhancement of synaptic plasticity that is also passed on to the next generation. We show that the effect is mediated through sperm RNA and is explained by microRNAs 212/132. In conclusion, our study reports intergenerational inheritance of an acquired cognitive benefit and points to specific microRNAs as candidates mechanistically involved in this type of transmission.

neuroscience↗