Biology subjects

Swift, K.

Publications and source records attributed to Swift, K..

5 recordsLinked to original sources

bioRxiv2025

Hypoxia-inducible factor 1 protects neurons from Sarm1-mediated neurodegeneration

The Sarm1 NAD+ hydrolase drives neurodegeneration in many contexts, but how Sarm1 activity is regulated remains poorly defined. Using CRISPR/Cas9 screening, we found loss of VHL suppressed Sarm1-mediated cellular degeneration. VHL normally promotes O2-dependent constitutive ubiquitination and degradation of hypoxia-inducible factor 1 (HIF-1), but during hypoxia, HIF-1 is stabilized and regulates gene expression. We observed neuroprotection after depletion of VHL or other factors required for HIF-1 degradation, and expression of a non-ubiquitinated HIF-1 variant led to even stronger blockade of axon degeneration in mammals and Drosophila. Neuroprotection required HIF-1 DNA binding, prolonged expression, and resulted in broad gene expression changes. Unexpectedly, stabilized HIF-1 prevented the precipitous NAD+ loss driven by Sarm1 activation in neurons, despite NAD+ hydrolase activity being intrinsic to the Sarm1 TIR domain. Our work argues hypoxia inhibits Sarm1 activity through HIF-1 driven transcriptional changes, rendering neurons less sensitive to Sarm1-mediated neurodegeneration when in a hypoxic state. Competing interestsMarc Freeman is co-founder of Nura Bio, a biotech startup pursuing novel neuroprotective therapies including SARM1 inhibition. The remaining authors declare no competing interests.

neuroscience↗

bioRxiv2022

The evolution of two transmissible cancers in Tasmanian devils

Tasmanian devils have spawned two transmissible cancer lineages, named devil facial tumour 1 (DFT1) and devil facial tumour 2 (DFT2). We investigated the genetic diversity and evolution of these clones by analysing 78 DFT1 and 41 DFT2 genomes relative to a newly assembled chromosome-level reference. Time-resolved phylogenetic trees reveal that DFT1 first emerged in 1986 (1982-1989), and DFT2 in 2011 (2009-2012). Subclone analysis documents transmission of heterogeneous cell populations. DFT2 has faster mutation rates than DFT1 across all variant classes, including substitutions, indels, rearrangements, transposable element insertions and copy number alterations, and we identify a hypermutated DFT1 lineage with defective DNA mismatch repair. Several loci show plausible evidence of positive selection in DFT1 or DFT2, including loss of chromosome Y and inactivation of MGA, but none are common to both cancers. This study illuminates the parallel long-term evolution of two transmissible cancers inhabiting a common niche in Tasmanian devils.

cancer biology↗

bioRxiv2021

Decreased overall neuronal activity in a rodent model of impaired consciousness during absence seizures

Absence seizures are characterized by a brief behavioural impairment including apparent loss of consciousness. Neuronal mechanisms determining the behavioural impairment of absence seizures remain unknown, and their elucidation might highlight therapeutic options for reducing seizure severity. However, recent studies have questioned the similarity of animal spike-wave-discharges (SWD) to human absence seizures both behaviourally and neuronally. Here, we report that Genetic Absence Epilepsy Rats from Strasbourg recapitulate the decreased neuroimaging signals and loss of consciousness characteristic of human absence seizures. Overall neuronal firing is decreased but rhythmic in the somatosensory cortex and thalamus during these seizures. Interestingly, individual neurons in both regions tend to consistently express one of four distinct patterns of seizure-associated activity. These patterns differ in firing rate dynamics and in rhythmicity during seizure. One group of neurons showed a transient initial peak in firing at SWD onset, accounting for the brief initial increase in overall neuronal firing seen in cortex and thalamus. The largest group of neurons in both cortex and thalamus showed sustained decreases in firing during SWD. Other neurons showed either sustained increases or no change in firing. These findings suggest that certain classes of cortical and thalamic neurons may be particularly responsible for the paroxysmal oscillations and consequent loss of consciousness in absence epilepsy.

neuroscience↗

bioRxiv2020

Post release immune responses of Tasmanian devils vaccinated with an experimental devil facial tumour disease vaccine

Disease is increasingly becoming a driver of wildlife population declines and extinction risk. Vaccines have been one of the most successful health interventions in human history, but few have been tested for mitigating wildlife disease. The transmissible cancer, devil facial tumour disease (DFTD), triggered the Tasmanian devils (Sarcophilus harrisii) inclusion on the international endangered species list. Development of a protective DFTD vaccine would provide a valuable management approach for conservation of the species. In 2016, 33 devils from a DFTD-free insurance population were given an experimental DFTD vaccination prior to their release on the north coast of Tasmania. The release site was already home to an incumbent population of devils, including some individuals with DFTD. To determine the efficacy of the vaccination protocol and the longevity of the response it induced, six trapping trips took place at the site over the 2.5 years following release. Eight of the 33 vaccinated devils were re-trapped, and six of those developed DFTD within the monitoring period. Despite the apparent lack of protection provided by the vaccine for the re-trapped devils, we observed several signs of immune activation not usually found in unvaccinated devils. Firstly, sera collected from the eight devils showed that anti-DFTD antibodies persisted for up to two years post vaccination. Secondly, tumour infiltrating lymphocytes were found in three out of four biopsies collected from vaccinated devils which contrasts with the "immune deserts" typical of DFTs; only one out of twenty incumbent devils with DFTD trapped during the same period had a tumour biopsy exhibiting immune cell infiltrate. Thirdly, immunohistochemical analysis of tumour biopsies from the vaccinated devils identified the functional immune molecules associated with antigen presenting cells (MHC-II) and T cells (CD3), and the immune checkpoint molecule PD-1, all associated with anti-tumour immunity in other species. These results correlate with our previous study on captive devils in which a prophylactic vaccine primed the devil immune system and, following DFTD challenge and tumour growth, immunotherapy induced complete tumour regressions. The field trial results presented here provide further evidence that the devil immune system can be primed to recognise DFTD cells, but additional immune manipulation could be needed for complete protection or induction of tumour regressions.

immunology↗

bioRxiv2019

Differential and Age Dependent Expression of Specific Sialoglycans on HeLa Cells -Revealed by Direct Fluorescent Glycan Labeling

Cells are covered with glycans. The expression and distribution of specific glycans on cell surface are important for various cellular functions. Imaging these glycans is essential to elucidate their biological roles. Here, utilizing enzymatic incorporation of fluorophore-conjugated sialic acids, dubbed as direct fluorescent glycan labeling (DFGL), we report the imaging of N- and O-glycans and particularly tumor specific sialyl T antigen on HeLa cells. It is found that while Core-1 O-glycans are relatively evenly distributed on cells, the expression of N-glycans tend to be more peripheral. More interestingly, the expression of sialyl T antigen displays random and sporadic patterns. In technique side, DFGL allows convenient labeling or imaging of various glycans on intact glycoproteins or cell surfaces with variety of fluorescent dyes.

cancer biology↗