Biology subjects

Hepburn, C.

Publications and source records attributed to Hepburn, C..

4 recordsLinked to original sources

bioRxiv2023

The complex inhibitory mechanism of glycomimetics with human heparanase

Heparanase (HPSE) is the only mammalian endo-{beta}-glucuronidase known to catalyse the degradation of heparan sulfate. Dysfunction of HPSE activity has been linked to several disease states, resulting in HPSE becoming the target of numerous therapeutic programs, yet no drug has passed clinical trials to date. Pentosan polysulfate sodium (PPS) is a heterogeneous FDA-approved drug for the treatment of interstitial cystitis and a known HPSE inhibitor. However, due to its heterogeneity, characterisation of its mechanism of HPSE inhibition is challenging. Here we show that inhibition of HPSE by PPS is complex, involving multiple overlapping binding events, each influenced by factors such as oligosaccharide length and inhibitor-induced changes in protein secondary structure. The present work advances our molecular understanding of the inhibition of HPSE, which will aid the development of therapeutics for the treatment of a broad range of pathologies associated with enzyme dysfunction including cancer, inflammatory disease and viral infections.

biochemistry↗

bioRxiv2022

Male sex hormone and reduced plakoglobin jointly impair atrial conduction and cardiac sodium currents

Androgenic anabolic steroids (AAS) are commonly abused by young men. Male sex associates with earlier manifestation of common and rare cardiac conditions including atrial fibrillation and arrhythmogenic right ventricular cardiomyopathy (ARVC). Clinical data suggest an atrial involvement in ARVC. The disease is caused by desmosomal gene defects such as reduced plakoglobin expression. Analysis of clinical records from 146 ARVC patients identified male preponderance and increased prevalence of atrial arrhythmias in patients with definite ARVC. Definite patients displayed ECG changes suggesting atrial remodelling. To study mechanisms of atrial remodelling due to desmosomal vulnerability and AAS, young adult male mice, heterozygously deficient for plakoglobin (Plako+/-) and wildtype (WT) littermates, were chronically exposed to 5-dihydrotestosterone (DHT) or placebo. DHT increased atrial expression of pro-hypertrophic, fibrotic and inflammatory transcripts. DHT caused atrial conduction slowing, decreased peak sodium current density, reduced action potential amplitude and lowered the peak depolarisation rate in Plako+/- but not WT atria. Super-resolution microscopy revealed a reduction in Nav1.5 clustering in Plako+/- atrial cardiomyocytes following DHT exposure. These data reveal that AAS combined with plakoglobin deficiency cause pathological atrial electrical remodelling in young male hearts. AAS abuse may increase the risk of atrial myopathy in males with desmosomal gene variants.

molecular biology↗

bioRxiv2022

Environmental DNA reflects common haplotypic variation

Analysis of environmental DNA (eDNA) has gained widespread usage for taxonomically based biodiversity assessment. While interest in applying non-invasive eDNA monitoring for population genetic assessments has grown, its usage in this sphere remains limited. One barrier to uptake is that the effectiveness of eDNA detection below the species level remains to be determined for multiple species and environments. Here, we test the utility of this emergent technology in a population genetic framework using eDNA samples derived from water along New Zealands South Island (Otago Coast: n=9; Kaik[o]ura: n=7) and DNA obtained from tissue samples (n=76) of individual blackfoot p[a]ua (Haliotis iris) sampled from New Zealands Otago coast. We recovered four mitochondrial haplotypes from eDNA versus six from the tissue samples collected. Three common haplotypes were recovered with both eDNA and tissue samples, while only one out of three rare haplotypes - represented in tissue samples by one individual each - was recovered with our eDNA methods. We demonstrate that eDNA monitoring is an effective tool for recovering common genetic diversity from p[a]ua, although rare (< 5%) haplotypes are seldom recovered. Our results show the potential of eDNA to identify population-level haplotypes for gastropods in the marine environment identification below the species level and for studying the population genetic diversity of gastropods. This work supports eDNA methods as effective, non-invasive tools for genetic monitoring. Non-invasive eDNA sampling could minimize target organism stress and human interaction enabling population genetic research for hard-to-sample, delicate, or sensitive species.

genetics↗

bioRxiv2021

Environmental DNA analysis needs local reference data to inform taxonomy-based conservation policy:A case study from Aotearoa / New Zealand

Effective management of biodiversity requires regular surveillance of multiple species. Analysis of environmental DNA by metabarcoding (eDNA) holds promise to achieve this relatively easily. However, taxonomic inquiries into eDNA data need suitable molecular reference data, which are often lacking. We evaluate the impact of this reference data void in a case study of fish diversity in the remote fiords of New Zealand. We compared eDNA-derived species identifications against Baited Remote Underwater Video (BRUV) data collected at the same time and locations as the eDNA data. Furthermore, we cross referenced both eDNA and BRUV data against species lists for the same region obtained from literature surveys and the Ocean Biodiversity Information System (OBIS). From all four data sources, we obtained a total of 116 species records (106 ray-finned fishes, 10 cartilaginous fishes; 59 from literature, 44 from eDNA, 25 from BRUV, 25 from OBIS). Concordance of taxonomies between the data sources dissolved with lowering taxonomic levels, most decisively so for eDNA data. BRUV agreed with local biodiversity information much better and fared better in detecting regional biodiversity dissimilarities. We provide evidence that eDNA metabarcoding will remain a powerful but impaired tool for species-level biodiversity management without locally generated reference data.

ecology↗