Hoang, T. T. | Search bioRxiv

bioRxiv2023

Nuclear Transformation In Metalloenzyme. A Novel And High Potential Cancer Treatment Research.

In this study, we have introduced a novel approach to cancer treatment involving the deactivation of metalloenzymes through the utilization of radioisotopes. The concept of leveraging radioisotopes to interact with metalloenzymes represents a groundbreaking theoretical advancement. Through simulations utilizing the MIRD code and based on the consistent concentration of stable Mg within stage 2A cancerous tissue, we have quantified the potential success rates. To conduct these simulations, we employed 0.1 nanograms (ng) of stable Mg, which corresponds to an activity of 19.7 MBq of Mg-28. This data was input into the MIRD calculations to estimate the absorbed doses within various organs, employing diverse methods of radioisotope administration into the body. Remarkably, even with a mere 1{per thousand} probability of effectively reaching the intended cancerous tissues, this quantity of Mg-28 demonstrates the capability to render billions of Mg-containing metalloenzymes inactive. The remarkable efficiency achieved through precise radioisotope targeting underscores the promise of this methodology. Nevertheless, the findings underscore the necessity of undertaking both in vitro and in vivo research initiatives prior to embarking on clinical trials.

cancer biology↗

bioRxiv2023

Quantitative classification of energy landscapes inferred from single nanoparticle tracking of membrane receptors inside nanodomains reveals confinement functional and molecular features

The cell membrane organization has been hypothesized for a long time to have an essential functional role, through the control of membrane receptor confinement in micro- or nanodomains. Several mechanisms have been proposed to account for these properties, though some features of the resulting organization have remained controversial, notably the nature, size, and stability of cholesterol- and sphingolipid-rich domains called rafts. Here, we quantitatively probed the energy landscape experienced by single nanoparticle-labeled membrane receptors - epidermal growth factor receptors (EGFR), transferrin receptors (TfR), and receptors of {varepsilon}-toxin produced by C. perfringens and -toxin of C.Septicum (CP{varepsilon}TR and CSTR, respectively) - through the development of new computational methods. By establishing a new analysis pipeline combining Bayesian inference, decision trees and clustering approaches, we indeed systematically classified single protein trajectories according to the type of confining energy landscape. This revealed the existence of only two distinct organization modalities: (A) confinement in a quadratic energy landscape for EGF, CP{varepsilon}T and CST receptors and (B) free diffusion in confinement domains resulting from the steric hindrance due to F-actin barriers for transferrin receptors. The characterization of confinement energy landscapes by Bayesian inference furthermore revealed the role of interactions with the domain environment in cholesterol- and sphingolipid-rich domains with (in the case of EGFR) or without (for CP{varepsilon}T and CST receptors) parallel interactions with F-actin, to regulate the confinement energy depth. Strikingly, these two distinct mechanisms result in the same organization type (A). We furthermore revealed that the apparent domain sizes for these receptor trajectories resulted from Brownian exploration of the energy landscape in a steady-state like regime at a common effective temperature, independently of the underlying molecular mechanisms. These results highlight that the membrane organization in confinement domains may be more adequately described as interaction hotspots rather than rafts with abrupt domain boundaries. Altogether, these results establish a new computational approach, which paves the way to the constitution of an atlas of energy landscape of membrane proteins and of their control mechanisms, and support a new general model for functional receptor confinement in membrane nanodomains.

biophysics↗