Biology subjects

Smith, M. R.

Publications and source records attributed to Smith, M. R..

4 recordsLinked to original sources

bioRxiv2018

Low-dose cadmium potentiates lung inflammatory response to 2009 pandemic H1N1 influenza virus in mice

BACKGROUNDCadmium (Cd) is a toxic, pro-inflammatory metal ubiquitous in the diet that accumulates in body organs due to inefficient elimination. Many individuals exposed to dietary Cd are also infected by seasonal influenza virus. The H1N1 strain causes mild to severe pneumonia which can be fatal.\n\nOBJECTIVESTo determine the influence of low-dose Cd exposure on inflammatory responses to H1N1 influenza A virus.\n\nMETHODSWe exposed mice to low-dose (1 mg CdCl2/l) Cd or vehicle (water) for 16 weeks prior to infection with a sub-lethal dose of H1N1. Lung inflammation was assessed by histopathology and flow cytometry. We used a combination of transcriptomics, metabolomics and bioinformatics to determine the molecular associations of inflammatory cells important in Cd-exacerbated responses.\n\nRESULTSCd-treated mice had increased lung tissue inflammatory cells, including neutrophils, monocytes, T lymphocytes and dendritic cells, following H1N1 infection. Lung genetic responses to infection (increasing TNF-a, interferon and complement, and decreasing myogenesis) were also exacerbated. Global correlations with immune cell counts, leading edge gene transcripts and metabolites revealed that Cd increased correlation of myeloid immune cells with pro-inflammatory genes, particularly interferon-{gamma}, and metabolites in amino acid, nucleobase, glycerophospholipid and vitamin B3 pathways.\n\nDISCUSSIONCd burden in mice increased inflammation in response to sub-lethal H1N1 challenge, which was coordinated by genetic and metabolic responses, and could provide new targets for intervention against lethal inflammatory pathology of clinical H1N1 infection.

pharmacology and toxicology↗

bioRxiv2017

Quantifying and visualising divergence between pairs of phylogenetic trees: implications for phylogenetic reconstruction

Tree topologies are a primary output of phylogenetic analysis. It is important to understand how such outputs are influenced by the choice of phylogenetic method, and the nature and quality of input data. This often entails the measurement of how closely an output corresponds to an ideal tree topology. The symmetric difference (partition) metric is the only widely-used measure that is defined for trees that contain polytomies, but expresses undesirable behaviour in certain situations.\n\nHere I propose a divergence metric for unweighted tree topologies based on quartet statements, which measures the topological information common to two trees. This metric reflects the contributions of both accuracy and precision to tree quality; these components can be decomposed through the use of ternary diagrams. This approach is implemented in a new package for the R statistical environment, and applied to a recent controversy, where it provides a new perspective on the relative merits of Bayesian and parsimony approaches to morphological phylogenetics.

evolutionary biology↗

bioRxiv2017

Morphological phylogenetic analysis with inapplicable data

Non-independence of characters is a real phenomenon in phylogenetic data matrices, even though phylogenetic reconstruction algorithms generally assume character independence. In morphological datasets, the problem results in characters that cannot be applied to certain terminal taxa, with this inapplicability treated as \"missing data\" in a popular method of character coding. However, this treatment is known to create spurious tree length estimates on certain topologies, potentially leading to erroneous results in phylogenetic searches. Here we present a single-character algorithm for ancestral states reconstruction in datasets that have been coded using reductive coding. The algorithm uses up to four traversals on a tree to resolve final ancestral states - which are required in full before a tree can be scored. The algorithm employs explicit criteria for the resolution of ambiguity in applicable/inapplicable dichotomies and the optimization of missing data. We score trees following a previously published procedure that minimizes homoplasy over all characters. Our analysis of published datasets shows that, compared to traditional methods, our new method identifies different trees as \"optimal\"; as such, correcting for inapplicable data may significantly alter the outcome of tree searches.

evolutionary biology↗

bioRxiv2017

Activation of Somatostatin Inhibitory Neurons by Lypd6-nAChRα2 System Restores Juvenile-like Plasticity in Adult Visual Cortex

The limitation of plasticity in the adult brain impedes functional recovery later in life from brain injury or disease. This pressing clinical issue may be resolved by enhancing plasticity in the adult brain. One strategy for triggering robust plasticity in adulthood is to reproduce one of the hallmark physiological events of experience-dependent plasticity observed during the juvenile critical period - rapidly reduce the activity of parvalbumin (PV)-expressing interneurons and disinhibit local excitatory neurons. This may be achieved through enhancement of local inhibitory inputs, particularly those of somatostatin (SST)-expressing interneurons. However, to date the means for manipulating SST interneurons for enhancing cortical plasticity in the adult brain are not known. We show that SST interneuron-selective overexpression of Lypd6, an endogenous nicotinic signaling modulator, enhances ocular dominance plasticity in the adult primary visual cortex (V1). Lypd6 overexpression mediates a rapid experience-dependent increase in the visually evoked activity of SST interneurons as well as a simultaneous reduction in PV interneuron activity and disinhibition of excitatory neurons. Recapitulating this transient activation of SST interneurons using chemogenetics similarly enhanced V1 plasticity. Notably, we show that SST-selective Lypd6 overexpression restores visual acuity in amblyopic mice that underwent early long-term monocular deprivation. Our data in both male and female mice reveal selective modulation of SST interneurons and a putative downstream circuit mechanism as an effective method for enhancing experience-dependent cortical plasticity as well as functional recovery in adulthood. Significance StatementThe decline of cortical plasticity after closure of juvenile critical period consolidates neural circuits and behavior, but this limits functional recovery from brain diseases and dysfunctions in later life. Here we show that activation of cortical SST interneurons by Lypd6, an endogenous modulator of nicotinic acetylcholine receptors (nAChRs), enhances experience-dependent plasticity and recovery from amblyopia in adulthood. This manipulation triggers rapid reduction of PV interneuron activity and disinhibition of excitatory neurons, which are known hallmarks of cortical plasticity during juvenile critical periods. Our study demonstrates modulation of SST interneurons by Lypd6 to achieve robust levels of cortical plasticity in the adult brain and may provide promising targets for restoring brain function in the event of brain trauma or disease.

neuroscience↗