Biology subjects

Young, A. A.

Publications and source records attributed to Young, A. A..

4 recordsLinked to original sources

bioRxiv2025

PACT suppresses PKR activation through dsRNA binding and dimerization, and is a therapeutic target for triple-negative breast cancer

Triple-negative breast cancer (TNBC), the deadliest breast cancer subtype, lacks broadly applicable targeted therapies. Induction of viral mimicry by activation of viral double-stranded RNA (dsRNA) sensors has potential therapeutic applications for TNBC and other cancers. Suppressors of dsRNA sensing prevent sensing of endogenous dsRNAs and resulting autoimmunity. Depletion of the suppressor of dsRNA sensing ADAR1 causes activation of dsRNA sensors and cell death in many cancer cell lines. These ADAR1-dependent cells are generally also dependent on the dsRNA-binding protein PACT, which is highly expressed and essential in many TNBC cell lines. While PACT is known as an activator of the dsRNA sensor PKR, overexpression of PACT had no effect on activation of PKR in multiple TNBC cell lines. Conversely, depletion of PACT in PACT-dependent cell lines caused robust activation of the dsRNA sensor PKR and cell death, in addition to induction of integrated stress response genes and NF-{kappa}B targets. These phenotypes were entirely dependent on PKR. Rescue experiments revealed that PACT dimerization and dsRNA binding is required to suppress PKR activation. While depletion of PACT alone in ADAR1/ PACT-independent cell lines had no effect on PKR activation, combined depletion of both PACT and ADAR1 in those cell lines caused robust PKR activation and cell death, supporting a partially redundant role for ADAR1 and PACT in suppression of dsRNA sensing. Taken together, these findings support a vital role for PACT in suppressing PKR activation and highlight the therapeutic potential of targeting PACT to treat TNBC.

cancer biology↗

bioRxiv2022

Ultraviolet Dosage and Decontamination Efficacy was Widely Variable Across 14 UV Devices after Testing a Dried Enveloped Ribonucleic Acid Virus Surrogate for SARS-CoV-2

AbstractO_ST_ABSAimsC_ST_ABSThe dosages and efficacy of 14 ultraviolet (UV) decontamination technologies were measured against a SARS-CoV-2 surrogate virus that was dried on to different materials for lab and field testing. Methods and ResultsA live enveloped, ribonucleic acid (RNA) virus surrogate for SARS- CoV-2 was dried on stainless steel 304 (SS304), Navy Top Coat-painted SS304 (NTC), cardboard, polyurethane, polymethyl methacrylate (PMMA), and acrylonitrile butadiene styrene (ABS) at > 8.0 log10 plaque-forming units (PFU) per test coupon. The coupons were then exposed to UV radiation during both lab and field testing. Commercial and prototype UV- emitting devices were measured for efficacy: 4 handheld devices, 3 room/surface-disinfecting machines, 5 air-disinfection devices, and 2 larger custom-made machines. UV device dosages ranged from 0.01-729 mJ cm-2. Anti-viral efficacy among the different UV devices ranged from no decontamination up to nearly achieving sterilization. Importantly, cardboard required far more dosage than SS304. ConclusionsEnormous variability in dosage and efficacy was measured among the different UV devices. Porous materials limit the utility of UV decontamination. Significance and Impact of the StudyUV devices have wide variability in dosages, efficacy, hazards, and UV output over time indicating that each UV device needs independent technical measurement and assessment for product development, prior to, and during use.

microbiology↗

bioRxiv2021

Cerebrovascular super-resolution 4D Flow MRI - using deep learning to non-invasively quantify velocity, flow, and relative pressure

The development of cerebrovascular disease is tightly coupled to changes in cerebrovascular hemodynamics, with altered flow and relative pressure indicative of the onset, development, and acute manifestation of pathology. Image-based monitoring of cerebrovascular hemodynamics is, however, complicated by the narrow and tortuous vasculature, where accurate output directly depends on sufficient spatial resolution. To address this, we present a method combining dedicated deep learning and state-of-the-art 4D Flow MRI to generate super-resolution full-field images with coupled quantification of relative pressure using a physics-driven image processing approach. The method is trained and validated in a patient-specific in-silico cohort, showing good accuracy in estimating velocity (relative error: 12.0 {+/-} 0.1%, mean absolute error (MAE): 0.07 {+/-} 0.06 m/s at peak velocity), flow (relative error: 6.6 {+/-} 4.7%, root mean square error (RMSE): 0.5 {+/-} 0.1 mL/s at peak flow), and with maintained recovery of relative pressure through the circle of Willis (relative error: 11.0 {+/-} 7.3%, RMSE: 0.3 {+/-} 0.2 mmHg). Furthermore, the method is applied to an in-vivo volunteer cohort, effectively generating data at <0.5mm resolution and showing potential in reducing low-resolution bias in relative pressure estimation. Our approach presents a promising method to non-invasively quantify cerebrovascular hemodynamics, applicable to dedicated clinical cohorts in the future.

bioengineering↗

bioRxiv2020

Hot, humid air decontamination of aircraft confirmed that high temperature and high humidity are critical for inactivation of infectious, enveloped ribonucleic acid (RNA) virus

AimsTo develop infectious (live/dead) enveloped virus test indicators and Response Surface Methodology (RSM) models that evaluate survival of an enveloped ribonucleic acid (RNA) virus on contaminated aircraft materials after exposure to hot, humid air (HHA). Methods and ResultsEnveloped RNA bacteriophage Phi6 ({Phi}6) was dried on wiring insulation, aircraft performance coating (APC), polypropylene, and nylon at [≥] 8 log10 plaque-forming units (PFU) test coupon-1. Only 2.4 log10 inactivation was measured on APC at 70{degrees}Celsius ({degrees}C), 5% relative humidity (RH) after 24 h. In contrast, HHA RSM models showed a 90% probability of a 7-log10 inactivation at [≥]63{degrees}C, 90% RH after 1 h, and decontamination kinetics were similar across different materials. HHA decontamination of C-130 and C-17 aircraft showed >7 log10 and [≥]5.9 log10 inactivation of enveloped virus on 100 and 110 test indicators, respectively, with a 1-h treatment, excluding ramp-up and ramp-down times. ConclusionsEnveloped RNA virus test indicators were successfully developed, lab tested for HHA decontamination, analyzed for RSM, and field-tested in aircraft demonstrations. Significance and Impact of the StudyThe utility of HHA decontamination was demonstrated after inactivating enveloped RNA virus on aircraft with a 1-h HHA treatment within aircraft temperature and RH limits.

microbiology↗