Johnson, T. W. | bioRxiv Science

bioRxiv2025

Insights from the lack of an enigmatic trait: monomorphic sperm in evergreen bagworm moths and the evolution of sperm dimorphism

Reproductive traits contain some of the most bizarre and unintuitive innovations seen across the tree of life. Chief among these is the sperm dimorphism of butterflies and moths (Lepidoptera). Males make two types of sperm: traditional fertilizing sperm (eupyrene) and a second, non-fertilizing type (apyrene) that lacks a nucleus entirely. Despite decades of study, the function and evolution of this second sperm type has remained unclear. Here we explore the sperm biology of the evergreen bagworm moth, Thyridopteryx ephemeraeformis (Lepidoptera: Tineoidea: Psychidae), and find no evidence for non-fertilizing sperm in this species. We generate genomic, transcriptomic, and proteomic resources to characterize the apparently monomorphic sperm of this species and compare it to that of other Lepidoptera. The fertilizing sperm of the evergreen bagworm shows key differences from other studied species, especially a lack of proteolytic enzymes used to break down sperm bundles in other species. Combining this and other evidence, we offer new hypotheses for the evolution and function of this enigmatic reproductive trait. Notably, early diverging moths appear to produce far less non-fertilizing sperm in general than later diverging Lepidoptera. We infer that non-fertilizing sperm are not necessary in these taxa, perhaps because less robust packaging of fertilizing sperm enables greater mobility than in later diverging moths.

evolutionary biology↗

bioRxiv2024

Pharmacological inhibition of 11βhydroxysteroid dehydrogenase type 1 after myocardial infarction targets extracellular matrix processing and preserves cardiac function in a translational mini-pig model

Background and PurposePlasma glucocorticoids (GCs) increase acutely after myocardial infarction (MI), thereafter tissue levels are amplified selectively within cells expressing 11{beta}Hydroxysteroid Dehydrogenase type 1 (11{beta}HSD1) that regenerates active GCs from circulating metabolites. GCs initially protect cardiomyocytes and prevent excessive inflammation after MI but can also suppress subsequent wound repair leading to functional decline. The present study aimed to investigate the potential of pharmacological 11{beta}HSD1 inhibition after MI to prevent deterioration of cardiac function and its impact on wound repair. Experimental ApproachAdult female Gottingen mini-pigs underwent percutaneous balloon MI/reperfusion and were randomised to receive either oral 11{beta}HSD1 inhibitor AZD8329 (n=11), or vehicle (n=9), from 2 until 27 days later, with concurrent administration of clinically relevant therapeutic intervention (anti-platelet, statin and ACE inhibitor). Key ResultsAZD8329 treatment increased plasma accumulation of cortisone substrate consistent with successful 11{beta}HSD1 inhibition. Gadolinium-enhanced MRI showed equivalent infarct size in both groups prior to commencing treatment. 28 days after MI cardiac function and LV area were preserved in the AZD8329 treated group relative to vehicle. There was no impact of 11{beta}HSD1 inhibitor on neovascularisation or infarct area. Mass spectrometry imaging revealed AZD8329 binding to the healing infarct and altered regulation of extracellular matrix (ECM) processing was highlighted by birefringence microscopy and proteomic analysis. Conclusions and ImplicationsPharmacological inhibition of 11{beta}HSD1 after MI prevents deterioration of cardiac function and detrimental remodelling. 11{beta}HSD1 inhibitors have safely reached phase 2 clinical trials in diabetes and dementia and could be repurposed as an addition to standard care after MI to prevent the development of heart failure. Bullet Point Summary What is already known?O_LIGCs are released from the adrenal gland after MI, but also regenerated within the heart from circulating precursors by the enzyme 11{beta}HSD1 in cardiomyocytes, fibroblasts and macrophages. C_LIO_LIGenetic suppression of Hsd11b1 expression in the mouse promotes neovascularisation, prevents infarct expansion during infarct repair after MI and the development of heart failure. C_LI What does this study add?O_LIOral pharmacological inhibition of 11{beta}HSD1 after MI/reperfusion in a translational mini-pig model of MI receiving concurrent clinically relevant therapy prevents cardiac functional deterioration and adverse ventricular remodelling over the following 4 weeks. C_LIO_LIMass spectrometry imaging reveals target engagement of the 11{beta}HSD1i in the repairing infarct. C_LIO_LIThe mechanism is independent of neovascularisation but does involve modification of extracellular matrix remodelling during repair and scar formation. C_LI What is the clinical significance?O_LITissue 11{beta}HSD1 expression is increased in aging when the risk of MI is higher. C_LIO_LIPharmacological inhibitors of 11{beta}HSD1 have safely reached phase 2 clinical trials for dementia and metabolic disease and could be repurposed for use post-MI to prevent the development of heart failure. C_LI

pharmacology and toxicology↗

bioRxiv2021

Structural and functional analysis of lorlatinib analogs reveals roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer

The treatment approach to advanced, ALK-positive non-small cell lung cancer (NSCLC) utilizing sequential ALK tyrosine kinase inhibitors (TKIs) represents a paradigm of precision oncology. Lorlatinib is currently the most advanced, potent and selective ALK tyrosine kinase inhibitor (TKI) in the clinic. However, tumors invariably acquire resistance to lorlatinib, and after sequential ALK TKIs culminating with lorlatinib, diverse refractory compound ALK mutations can emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations identified in patients after treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. By assessing a panel of lorlatinib analogs against compound ALK mutant in vitro and in vivo models, we identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R- versus I1171N/S/T-based compound ALK mutations. Structural analysis revealed that increased potency against compound mutations was achieved primarily through two different mechanisms of improved targeting of either G1202R- or I1171N/S/T-mutant kinases. Based on these results, we propose a classification of heterogenous ALK compound mutations designed to focus the development of distinct therapeutic strategies for precision targeting of compound resistance mutations following sequential TKIs.

cancer biology↗