Biology subjects

Healy, A.

Publications and source records attributed to Healy, A..

3 recordsLinked to original sources

bioRxiv2026

The Effects of Mean Temperature and Diurnal Temperature Range on West Nile Virus Transmission

Temperature is a major driver of arbovirus transmission, and a changing climate is expected to affect this process significantly. Most experimental studies rely on constant temperatures and overlook realistic daily temperature fluctuations that impact vector-pathogen interactions. The nonlinear relationship between temperature and vector traits responsible for pathogen transmission suggests that daily fluctuating temperatures produce phenotypes important for transmission distinct from those at constant temperatures. Here, we tested whether realistic variations in mean temperature and diurnal temperature range (DTR) influence West Nile virus (WNV) transmission. We experimentally infected colonized Culex tarsalis with WNV-infectious blood meals and maintained them under constant and fluctuating temperature regimes. We quantified how temperature, DTR, and incubation time shaped several outcomes (infection, dissemination, infectiousness, WNV loads in mosquito saliva and mosquito survival). We also integrated survival and infectiousness probabilities to infer implications for transmission. We observed strong effects of temperature on the WNV infection dynamics, viral loads and mosquito survival. Although the probability of initial infection was similar among all temperature regimes, dissemination and infectiousness were constrained by temperature. Dissemination and infectiousness were highest at 26{degrees}C and reduced at cooler (22{degrees}C) and warmer (30{degrees}C) temperatures. Fluctuating temperatures significantly decreased infection and dissemination probabilities, while the probability of becoming infectious was driven primarily by mean temperature rather than DTR. Mosquito survival probability was temperature dependent, and fluctuating regimes increased mortality risk by 1.95-fold. Integrating mosquito survival and infectiousness dynamics demonstrated that, although at higher temperatures the extrinsic incubation period is shorter, reduced mosquito lifespan can limit viral transmission. Together, these results indicate that overall WNV transmission is affected by temperature-dependent viral dynamics and host physiological constraints. Fluctuating temperature regimes significantly delay viral dissemination within the host, especially at the optimal temperature (26{degrees}C). Measurement of infection outcomes under constant temperatures treatments may lead to over/under estimation of transmission parameters in epidemiological models, therefore integrating fluctuating temperature treatments into mechanistic models of transmission can improve estimates of when and where WNV transmission is most likely to occur.

ecology↗

bioRxiv2023

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed DrugMap, an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF{kappa}B1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF{kappa}B1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription factor activity.

systems biology↗

bioRxiv2023

Development and validation of a high throughput screening platform to enable target identification in skeletal muscle cells from Duchenne Muscular Dystrophy (DMD) patients

Duchenne muscular dystrophy (DMD) is a progressive and fatal muscle degenerating disease caused by dystrophin deficiency. Effective methods for drug discovery for the treatment of DMD requires systems to be physiologically relevant, scalable, and effective. To this end, the Myoscreen platform offers a scalable and physiologically relevant system for generating and characterizing patient-derived myotubes. Morphological profiling is a powerful technique involving the simultaneous measurement of hundreds of morphological parameters from fluorescence microscopy images and using machine learning to predict cellular activity. Here, we describe combining the Myoscreen platform and high dimensional morphological profiling to accurately predict a phenotype associated with the lack of Dystrophin expression in patient derived myotubes. Using this methodology, we evaluated a series of Dystrophin-associated protein complex (DAPC) candidates and identified that the combination of Utrophin and - Sarcoglycan yielded highest morphological differences between DMD and non-DMD donors. Finally, we validated this methodology by knocking down Dystrophin expression in non-DMD cells as well as introducing Dystrophin expression in DMD cells. Knocking down Dystrophin in non- DMD cells shifted their morphological profile to one that is similar to DMD cells while introducing Dystrophin in DMD cells shifted their morphological profile towards non-DMD cells. In conclusion, we have developed a platform that accurately predicts the DMD disease phenotype in a disease relevant cell type. Ultimately this platform may have wide applications in the drug development process include identification of disease modifier genes, screening of novel therapeutic moieties, and as a potency assay for future therapeutics.

cell biology↗