TCF-1 is a key transcription factor in progenitor exhausted CD8 T cells (Tex). Moreover, this Tex cell subset mediates responses to PD-1 checkpoint pathway blockade. However, the role of the transcription factor TCF-1 in early fate decisions and initial generation of Tex cells is unclear. Single-cell RNA sequencing (scRNA-seq) and lineage tracing identified a TCF-1 + Ly108 + PD-1 + CD8 T cell population that seeds development of mature Tex cells early during chronic infection. TCF-1 mediated the bifurcation between divergent fates, repressing development of terminal KLRG1 Hi effectors while fostering KLRG1 Lo Tex precursor cells, and PD-1 stabilized this TCF-1 + Tex precursor cell pool. TCF-1 mediated a T-bet-to-Eomes transcription factor transition in Tex precursors by promoting Eomes expression and drove c-Myb expression that controlled Bcl-2 and survival. These data define a role for TCF-1 in early-fate-bifurcationdriving Tex precursor cells and also identify PD-1 as a protector of this early TCF-1 subset.

Collisions of 0-4 eV electrons with thin DNA films are shown to produce single strand breaks. The yield is sharply structured as a function of electron energy and indicates the involvement of pi* shape resonances in the bond breaking process. The cross sections are comparable in magnitude to those observed in other compounds in the gas phase in which pi* electrons are transferred through the molecule to break a remote bond. The results therefore support aspects of a theoretical study by Barrios et al. [J. Phys. B 106, 7991 (2002)]] indicating that such a mechanism could produce strand breaks in DNA.

To better understand the cause of the diversity in reported values of the electron affinities (EAs) for DNA bases, we performed a series of DFT (B3LYP functional) calculations at different basis set sizes. Through investigation of (1) trends in the values of EAs, (2) the excess electron spin distribution of the anion radical dependence on basis set size, (3) effect of the excess electron on ZPEs, we are able to identify the features of a basis set that allows for dipole-bound and continuum states to compete with molecular states for the electron. Smaller basis sets that confine the excess electron to the molecule allow for reasonable estimates of relative valence electron affinities excluding dipole-bound states and suggest the order of adiabatic valence electron affinities to be U ≈ T > C ≈ I (hypoxanthine) > A > G with G nearly 1 eV less electron affinic than U. Combining the best estimates from theory and experiment we place the adiabatic valence electron affinities of the pyrimidines as zero to +0.2 eV, whereas the purines A and G are predicted to be clearly negative with electron affinities of ca. -0.35 and -0.75 eV, respectively. The virtual states (i.e., negative electron affinities) for A and G in the gas-phase become relevant to biology when their energies are lowered to bound states in solvated systems. Indeed, our calculations performed including the effect of solvation (PCM model) show that all EAs for the DNA bases are positive and have the same relative order as found with the compact basis sets in the gas-phase calculations.

Proton-transfer reactions in two DNA base pair anion and cation radicals are treated by density functional theory to aid our understanding of the possible contributions of these reactions to electron and hole transfer in DNA. The proton-transfer transition structures for both the GC and IC anion and cation radicals are found. For both anion and cation radicals, it is the proton at the N1 guanine (G) site, or hypoxanthine (I) site, that transfers to cytosine. The forward and reverse activation energies as well as reaction enthalpies and free energy changes are calculated. These calculations show that small activation energies of 1 and 3 kcal/mol are present for the GC anion and cation, respectively. The predicted free energy change for the proton transfer is favorable for GC anion radical (-3 kcal/mol) but is slightly unfavorable for the GC cation radical (1.4 kcal/mol). Both of these values compare well with experimental estimates. Remarkably, the IC anion radical system shows no activation energy toward proton transfer and a large free energy change favoring the proton transferred state (-7 kcal). Electron affinities (EA) and ionization potentials (IP) of the two base pairs are also calculated and reported.

Gold nanoparticle (AuNP) radiosensitization represents a novel approach to enhance the effectiveness of ionizing radiation. Its efficiency varies widely with photon source energy and AuNP size, concentration, and intracellular localization. In this Monte Carlo study we explored the effects of those parameters to define the optimal clinical use of AuNPs. Photon sources included (103)Pd and (125)I brachytherapy seeds; (169)Yb, (192)Ir high dose rate sources, and external beam sources 300 kVp and 6 MV. AuNP sizes were 1.9, 5, 30, and 100 nm. We observed a 10(3) increase in the rate of photoelectric absorption using (125)I compared to 6 MV. For a (125)I source, to double the dose requires concentrations of 5.33-6.26 mg g(-1) of Au or 7.10 × 10(4) 30 nm AuNPs per tumor cell. For 6 MV, concentrations of 1560-1760 mg g(-1) or 2.17 × 10(7) 30 nm AuNPs per cell are needed, which is not clinically achievable. Examining the proportion of energy transferred to escaping particles or internally absorbed in the nanoparticle suggests two clinical strategies: the first uses photon energies below the k-edge and takes advantage of the extremely localized Auger cascade. It requires small AuNPs conjugated to tumor targeted moieties and nuclear localizing sequences. The second, using photon sources above the k-edge, requires a higher gold concentration in the tumor region. In this approach, energy deposited by photoelectrons is the main contribution to radiosensitization; AuNP size and cellular localization are less relevant.