Biology subjects

Parker, K. A.

Publications and source records attributed to Parker, K. A..

4 recordsLinked to original sources

bioRxiv2026

Dual inhibition of GTP-bound (ON) and GDP-bound (OFF) KRASG12C suppresses PI3Kα and leads to potent tumor inhibition

Current approved KRASG12C inhibitors covalently bind the inactive GDP-bound (OFF) form of KRASG12C. Recently, KRASG12C inhibitors that selectively bind to the GTP-bound (ON) form of both KRASG12C (ON) and (OFF) forms have been reported and entered clinical testing. In principle, KRASG12C (ON) inhibitors may be less susceptible to adaptive mechanisms that promote resistance to (OFF) inhibitors, however the specific mechanisms that differentiate the activity of (ON) versus (OFF) inhibition are not well understood. We profiled the activity of BBO-8520, a covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C, in KRASG12C-mutant non-small cell lung cancer models. BBO-8520 exerted more potent and sustained inhibition of KRASG12C and anti-tumor activity in vitro and in vivo compared with sotorasib, a KRASG12C (OFF)-only inhibitor. While cells treated with BBO-8520 or sotorasib both exhibited feedback reactivation of MAPK signaling driven by wild-type HRAS/NRAS isoforms, more durable suppression of KRASG12C by BBO-8520 was associated with decreased PI3K-AKT activation in vitro. Disruption of the interaction between RAS and PI3K using a novel protein:protein interaction inhibitor suppressed PI3K-AKT activation and increased the tumor response to sotorasib to a similar level as BBO-8520. Moreover, in some contexts, disruption of RAS-PI3K further increased the anti-tumor activity of BBO-8520 monotherapy. These results reveal mechanistic differences between KRAS (ON) and (OFF) inhibitors, highlight the importance of PI3K-AKT signaling in driving resistance to KRAS inhibition in lung cancer, and suggest combination strategies that suppress PI3K-AKT to improve the response to KRAS inhibitors.

cancer biology↗

bioRxiv2025

Foraging ecology drives viral community structure in New Zealand's aquatic birds

Wild migratory birds play a major role in the global spread of viruses, yet the diversity, host range and transmission patterns of viruses harboured by migratory species in Aotearoa/New Zealand remain largely unknown. This knowledge gap is critical given New Zealands position along major migratory flyways spanning Oceania, Antarctica and east Asia, where understanding viral diversity is key to assessing the risk of viral introductions such as highly pathogenic avian influenza virus and viral dispersal across these regions. To address this, we conducted the first large-scale metatranscriptomic survey of wild birds from New Zealand and its subantarctic islands, collecting 1,348 samples from 31 host species spanning four avian orders. We identified 118 avian viruses from 17 families, including 107 novel species, greatly expanding our knowledge of avian viral diversity. Viral communities differed significantly by host order and foraging behaviour, with scavenger birds harbouring more diverse viromes than non-scavengers. Although no HPAI subtypes were detected, we recovered a low-pathogenic avian influenza A/H1N9 virus from red knots (Calidris canutus) and a divergent tobanivirus from Auckland Island teal (Anas aucklandica), the first putative avian member of the Tobaniviridae. Notably, we detected 12 mammalian-associated viruses, primarily in scavenger birds, including Hedgehog hepatovirus, Rabbit haemorrhagic disease virus 2, and sea lion astroviruses, with mammalian host reads confirming their dietary origin. This study establishes the first virome baseline for New Zealands migratory birds, highlighting the ecological role of foraging in shaping viral communities and improving regional preparedness for HPAI and other emerging avian pathogens.

microbiology↗

bioRxiv2022

Novel Viral and Microbial Species in a Translocated Toutouwai (Petroica longipes) Population from Aotearoa/New Zealand

BackgroundTranslocation is a common tool in wildlife management and been responsible for many conservation successes. During translocations, any associated infectious agents are moved with their wildlife hosts. Accordingly, translocations can present a risk of infectious disease emergence, although they also provide an opportunity to restore natural infectious communities ( infectome) and mitigate the long-term risks of reduced natural resistance. MethodsWe used metatranscriptomic sequencing to characterise the infectome of 41 toutouwai (North Island robin, Petroica longipes) that were translocated to establish a new population within the North Island of New Zealand. We also screened for pathogenic bacteria, fungi and parasites. ResultsAlthough we did not detect any known avian diseases, which is a positive outcome for the translocated toutouwai population, we identified a number of novel viruses of interest, including a novel avian hepatovirus, as well as a divergent calici-like virus and four hepe-like viruses of which the host species is unknown. We also revealed a novel spirochete bacterium and a coccidian eukaryotic parasite. ConclusionsThe presumably non-pathogenic viruses and microbial species identified here support the idea that the majority of microorganisms likely do not cause disease in their hosts, and that translocations could serve to help restore and maintain native infectious communities. We advise greater surveillance of infectious communities of both native and non-native wildlife before and after translocations to better understand the impact, positive or negative, that such movements may have on both host and infectome ecology.

microbiology↗

bioRxiv2018

Changes in social groups across reintroductions and effects on post-release survival

Reintroductions are essential to many conservation programmes, and thus much research has focussed on understanding what determines the success of these translocation interventions. However, while reintroductions disrupt both the abiotic and social environments, there has been less focus on the consequences of social disruption. Therefore, here we investigate if moving familiar social groups may help animals (particularly naive juveniles) adjust to their new environment and increase the chances of population establishment. We used social network analysis to study changes in group composition and individual sociality across a reintroduction of 40 juvenile hihi (Notiomystis cincta), a threatened New Zealand passerine. We collected observations of groups before a translocation to explore whether social behaviour before the reintroduction predicted associations after, and whether reintroduction influenced individual sociality (degree). We also assessed whether grouping familiar birds during temporary captivity in aviaries maintained group structure and individual sociality, compared to our normal translocation method (aviaries of random familiarity). Following release, we measured if survival depended on how individual sociality had changed. By comparing these analyses with birds that remained at the source site, we found that translocation lead to re-assortment of groups: non-translocated birds maintained their groups, but translocated juveniles formed groups with both familiar and unfamiliar birds. Aviary holding did not improve group cohesion; instead, juveniles were less likely to associate with aviary-mates. Finally, we found that translocated juveniles that lost the most associates experienced a small but significant tendency for higher mortality. This suggests sociality loss may have represented a disruption that affected their ability to adapt to a new site.

animal behavior and cognition↗