Biology subjects

Harding, L.

Publications and source records attributed to Harding, L..

3 recordsLinked to original sources

bioRxiv2025

Unravelling the anti-cancer mechanisms elicited by non-covalent thioredoxin reductase inhibitors for triple negative breast cancer therapy.

Thioredoxin reductases (cytosolic TXNRD1 and mitochondrial TXNRD2) are antioxidant enzymes often overexpressed in tumors, including triple negative breast cancer (TNBC), making them promising targets for cancer therapy. Inhibiting these enzymes may worsen the already elevated oxidative stress in cancer cells, ultimately leading to cell death through a pro-oxidant mechanism. However, selectively targeting TXNRDs has been challenging due to the traditional reliance on covalent inhibition strategies. Recent studies have identified a druggable allosteric pocket in this enzyme family, paving the way for the development of novel non-covalent inhibitors, referred to as TXNRD(i)s. These inhibitors have been tested in TNBC models and have demonstrated a range of anti-cancer effects. To understand the molecular and cellular consequences of TXNRD(i)s, we conducted unbiased transcriptomic analyses and found that the gene expression changes induced by TXNRD(i) treatment closely mirror those resulting from TXNRD1 silencing, reinforcing TXNRD1 as the primary therapeutic target. While TXNRD(i) treatment increases redox stress in TNBC cells, this is not the main driver of the anti-cancer effect. Instead, TXNRD(i)s potently inhibit cell proliferation and induce G1 phase cell cycle arrest. Notably, supplementing cells with exogenous deoxynucleotides restores cell viability, cell cycle progression and partially reverses cell death. These findings indicate that TXNRD(i)s deplete endogenous deoxynucleotide pools and impair ribonucleotide reductase activity as the main mechanism of anti-cancer effects. We further demonstrate that TXNRD(i)s inhibit both TXNRD1 and TXNRD2, and that dual inhibition is more effective in suppressing TNBC cell growth. In vivo, TXNRD(i) treatment significantly impairs TNBC xenograft tumor growth and reduces proliferation-related genes. Collectively, these findings challenge the prevailing paradigm that all TXNRD inhibitors function through a pro-oxidant mechanism, instead highlighting that non-covalent TXNRD(i)s exert their effects by blocking proliferation offering a compelling therapeutic strategy for TNBC and potentially other cancers with elevated TXNRD expression. HighlightsNon-covalent TXNRD inhibitors increase intracellular redox stress, but this is not the main driver of anti-cancer effects TXNRD(i)s inhibit both cytosolic TXNRD1 and mitochondrial TXNRD2 enzymes Both TXNRD1 and TXNRD2 are required for growth and proliferation of triple negative breast cancer cells Halted proliferation through ribonucleotide reductase dysfunction emerges as the primary driver of anti-cancer effect Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=174 HEIGHT=200 SRC="FIGDIR/small/674327v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1b5638aorg.highwire.dtl.DTLVardef@19a117eorg.highwire.dtl.DTLVardef@1f27e95org.highwire.dtl.DTLVardef@1549862_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Capacity building needed to reap the benefits of access to biodiversity collections

SummaryO_LIThis research examines biodiversity specimens from two areas of the Caribbean to understand patterns of collection and the roles of the people involved. Using open data from the Global Biodiversity Information Facility (GBIF) and Wikidata, we aimed to uncover geographic and historical trends in specimen use. This study aims to provide concrete evidence to guide collaboration between collection-holding institutions and the communities that need their resources most. C_LIO_LIWe analysed biodiversity specimens from Montserrat and the Cayman Islands in three steps. First, we extracted specimen data from GBIF, disambiguated collector names, and linked them to unique biographical entries. Next, we connected collectors to their publications and specimens. Finally, we analysed the modern use of these specimens through citation data, mapping author affiliations and research themes. C_LIO_LISpecimens are predominantly housed in the Global North and were initially used by their collectors, whose focus was largely on taxonomy and biogeography. With digitisation, use of these collections remains concentrated in the Global North and covers a broader range of subjects, although Brazil and China stand out as significant users of digital collection data compared to other similar countries. C_LIO_LIThe availability of open digital data from collections in the Global North has led to a substantial increase in the reuse of these data across biodiversity science. Nonetheless, most research using these data is still conducted in the Global North. For the non-monetary benefits of digitisation to extend to the countries of origin, capacity building in the Global South is crucial, Open Data alone are insufficient. C_LI Societal Impact StatementDigital biodiversity data from herbaria and museums hold significant potential for nature conservation in the Global South, yet many regions, like Montserrat and the Cayman Islands in the Caribbean, are, for multiple reasons, unable to fully leverage this information. This lack of skills and resources limits local conservation efforts, showing the need for more investment in training, facilities, and expertise. Although past funding has helped improve coordination and build skills, our findings show that more work is needed to make sure conservation in these biodiverse areas can continue in the long term.

scientific communication and education↗

bioRxiv2018

Tool use by four species of Indo-Pacific sea urchins

We compared the covering behavior of four sea urchin species, Tripneustes gratilla, Pseudoboletia maculata, Toxopneutes pileolus, and Salmacis sphaeroides found in the waters of Malapascua Island, Cebu Province and Bolinao, Panagsinan Province, Philippines. Specifically, we measured the amount and type of covering material on each urchin, and, in several cases, the recovery of debris cover after stripping the animal of its cover.\n\nWe found that Tripneustes gratilla and Salmacis sphaeroides have a higher preference for plant material, especially sea-grass, compared to Pseudoboletia maculata and Toxopneutes pileolus, which prefer to cover themselves with coral rubble and other calcified material. Only for Toxopneutes pileolus did we find a decrease in cover with depth, confirming previous work that the covering behavior serves UV protection. We found no dependence of particle size on either species or urchin size, but we observed that larger urchins carried more and heavier debris. We observed a transport mechanism of debris onto the echinoid body surface utilizing a combination of tube feet and spines. The transport speed of individual debris items varied between species.\n\nWe compare our results to previous studies of urchin covering behavior, comment on the phylogeny of urchin covering behavior and discuss the interpretation of this behavior as animal tool use.

animal behavior and cognition↗