Ramin M. Abolfath

Ku and DNA-dependent Protein Kinase Dynamic Conformations and Assembly Regulate DNA Binding and the Initial Non-homologous End Joining Complex

DNA double strand break (DSB) repair by non-homologous end joining (NHEJ) is initiated by DSB detection by Ku70/80 (Ku) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) recruitment, which promotes pathway progression through poorly defined mechanisms. Here, Ku and DNA-PKcs solution structures alone and in complex with DNA, defined by x-ray scattering, reveal major structural reorganizations that choreograph NHEJ initiation. The Ku80 C-terminal region forms a flexible arm that extends from the DNA-binding core to recruit and retain DNA-PKcs at DSBs. Furthermore, Ku- and DNA-promoted assembly of a DNA-PKcs dimer facilitates trans-autophosphorylation at the DSB. The resulting site-specific autophosphorylation induces a large conformational change that opens DNA-PKcs and promotes its release from DNA ends. These results show how protein and DNA interactions initiate large Ku and DNA-PKcs rearrangements to control DNA-PK biological functions as a macromolecular machine orchestrating assembly and disassembly of the initial NHEJ complex on DNA.

Optical control of DNA-base radio-sensitivity

We describe manipulation of the radio sensitivity of the nucleotide base driven by the spin blockade mechanism of diffusive free radicals against ionizing radiation. We theoretically propose a mechanism which uses the simultaneous application of circularly polarized light and an external magnetic field to control the polarization of the free radicals and create S=1 electron-hole spin excitations (excitons) on a nucleotide base. We deploy an ab initio molecular dynamics model to calculate the characteristic parameters of the light needed for optical transitions. As a specific example, we present the numerical results calculated for a guanine in the presence of an OH free radical. To increase the radio resistivity of this system, an energy gap for the optical pumping and induction of excitons on guanine is predicted. The effect of spin injection on the formation of a free energy barrier in diffusion-controlled chemical reaction pathways leads to the control of radiation-induced base damage. The proposed method allows us to manipulate and partially suppress the damage induced by ionizing radiation.

General strategy for the protection of organs at risk in IMRT therapy of a moving body

We investigated protection strategies of organs at risk (OARs) in intensity modulated radiation therapy (IMRT). These strategies apply to delivery of IMRT to moving body anatomies that show relative displacement of OAR in close proximity to a tumor target. We formulated an efficient genetic algorithm which makes it possible to search for global minima in a complex landscape of multiple irradiation strategies delivering a given, predetermined intensity map to a target. The optimal strategy was investigated with respect to minimizing the dose delivered to the OAR. The optimization procedure developed relies on variability of all parameters available for control of radiation delivery in modern linear accelerators, including adaptation of leaf trajectories and simultaneous modification of beam dose rate during irradiation. We showed that the optimization algorithms lead to a significant reduction in the dose delivered to OAR in cases where organs at risk move relative to a treatment target.

Spin transitions induced by a magnetic field in quantum dot molecules

We study the many-body effects in the spin flip transitions by incorporating systematically the inter-dot and intra-dot electron-electron Coulomb interactions using real space Hartree-Fock Configuration Interaction (HFCI) technique. We find quantum Hall droplets with zero and full spin polarization, identified as ν = 2 and ν = 1 quantum Hall droplets 12 , in analogy with single quantum dots and quantum Hall ferromagnets 20 . Between these two states, we find series of continuous transitions among partially spin polarized phases. These partially polarized phases correspond to spin flips. Simultaneous spin flip in each isolated dot must lead to even number of spin flips in a double dot. Recently, we have found partially spin polarized phases which correspond to odd number of spin flips 21 in a double quantum dot. In Ref. [21], we have identified these correlated states as quantum Hall ferrimagnets.

Variable beam dose rate and DMLC IMRT to moving body anatomy

Derivation of formulas relating leaf speeds and beam dose rates for delivering planned intensity profiles to static and moving targets in dynamic multileaf collimator (DMLC) intensity modulated radiation therapy (IMRT) is presented. The analysis of equations determining algorithms for DMLC IMRT delivery under a variable beam dose rate reveals a multitude of possible delivery strategies for a given intensity map and for any given target motion patterns. From among all equivalent delivery strategies for DMLC IMRT treatments specific subclasses of strategies can be selected to provide deliveries that are particularly suitable for clinical applications providing existing delivery devices are used. Special attention is devoted to the subclass of beam dose rate variable DMLC delivery strategies to moving body anatomy that generalize existing techniques of such deliveries in Varian DMLC irradiation methodology to static body anatomy. Few examples of deliveries from this subclass of DMLC IMRT irradiations are investigated to illustrate the principle and show practical benefits of proposed techniques.

Extend distance treatment for stereotactic body radiation therapy of lung cancer

Purpose: We investigate a delivery method in stereotactic body radiation therapy using an Extend Distance Source to Virtual Axis (EDSVA) method. This approach significantly expands the range of beam angles and improves the target confomality and the normal tissue avoidance.

Para-ortho transition of artificial H 2 molecule in lateral quantum dots doped with magnetic impurities

We present the magnetic phase diagram of artificial H

Optical Enhancement of DNA-Base Radio-Resistivity

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SU‐GG‐T‐107: Genetic Optimizers and Control of DMLC IMRT Delivery to Moving Body Anatomy

molecule in lateral quantum dots doped with magnetic impurities as a function of external magnetic field and plunger gate voltage. The onset of Mn-Mn antiferromagnetic-ferromagnetic transition follows the electron spin singlet-triplet transition. We deploy a configuration-interaction method to exactly diagonalize the electron-Mn Hamiltonian and map it to an effective Mn-Mn Heisenberg Hamiltonian. We find that Mn-Mn exchange coupling can be described by RKKY-interaction/magnetic-polaron in weak/strong electron-Mn coupling at low/high magnetic fields.

SU‐GG‐T‐87: Variable Beam Dose Rate and DMLC IMRT to Moving Body Anatomy

We propose a mechanism which uses the simultaneous application of circularly polarized light and an external magnetic field to control the polarization of the free radicals and create S=1 electron-hole spin excitations (excitons) on nucleotide-base. We deploy an ab-initio molecular dynamics model to calculate the characteristic parameters of the light needed for optical transitions. The effect of spin-injection on the formation of a free energy barrier in diffusion controlled chemical reaction pathways leads to the control of radiation-induced base damage. The proposed method allows us to manipulate and partially suppress the damage induced by ionizing radiation.