A Monte Carlo Model of Stochastic Alpha Particle Microdosimetry in 3D Multicellular Aggregates

Targeted alpha therapy (TAT) is an emerging new approach to radionuclide therapy, and promises to be especially valuable in the treatment of metastatic disease and radioresistant tumors. However, the dosimetry of TAT presents challenges not seen in photon therapy, due to uncertainties in the relative biological effectiveness (RBE) of alpha radiation. One of the most dominant sources of this uncertainty is the stochasticity originating from the discrete nature of alpha particles, resulting in nonuniform cellular uptake patterns at low specific activities. Current approaches to alpha particle internal dosimetry, based on the MIRD formalism, typically assume that activity is uniformly distributed in subcellular compartments, with resulting absorbed dose distributions being unrealistically homogeneous and isotropic. We develop a Monte Carlo generalization of the MIRD-based formalism that explicitly accounts for stochastic nonuniform localization of alpha emitters in a general 3D multicellular aggregate. In the limit of averaging over many replicates, our approach reduces to the MIRD-based one, which we verify by comparing our code’s results with those of MIRDcell, a commonly used software for TAT dosimetry based on the MIRD formalism. At low specific activity, stochasticity manifests itself as an increase in cell survival beyond that expected from MIRD-based calculations, along with corresponding shifts in the generalized equivalent uniform dose. The magnitude of this effect strongly depends on the cellular localization of alpha emission, a parameter that can be experimentally controlled by altering the chemistry of the conjugate delivery vehicle of the radionuclide.M.S

5‑Methylation of Cytosine in CG:CG Base-Pair Steps: A Physicochemical Mechanism for the Epigenetic Control of DNA Nanomechanics

van der Waals density functional theory is integrated with analysis of a non-redundant set of protein–DNA crystal structures from the Nucleic Acid Database to study the stacking energetics of CG:CG base-pair steps, specifically the role of cytosine 5-methylation. Principal component analysis of the steps reveals the dominant collective motions to correspond to a tensile “opening” mode and two shear “sliding” and “tearing” modes in the orthogonal plane. The stacking interactions of the methyl groups globally inhibit CG:CG step overtwisting while simultaneously softening the modes locally via potential energy modulations that create metastable states. Additionally, the indirect effects of the methyl groups on possible base-pair steps neighboring CG:CG are observed to be of comparable importance to their direct effects on CG:CG. The results have implications for the epigenetic control of DNA mechanics

MathIOmica: An Integrative Platform for Dynamic Omics

Job file for the creation/design of stained glass from either the Charles J. Connick Studio (1912-1945) or the Charles J. Connick Associates studio (1945-1986). The job file contains a job number, location information, date of completion, size, contact information, price, and a description of the project. This particular job file contains information on a job located at: Springfield, Massachusetts. Saint Michael's Church