Pharmacologically blocking p53-dependent apoptosis protects intestinal stem cells and mice from radiation.

Exposure to high levels of ionizing radiation (IR) leads to debilitating and dose-limiting gastrointestinal (GI) toxicity. Using three-dimensional mouse crypt culture, we demonstrated that p53 target PUMA mediates radiation-induced apoptosis via a cell-intrinsic mechanism, and identified the GSK-3 inhibitor CHIR99021 as a potent radioprotector. CHIR99021 treatment improved Lgr5+ cell survival and crypt regeneration after radiation in culture and mice. CHIR99021 treatment specifically blocked apoptosis and PUMA induction and K120 acetylation of p53 mediated by acetyl-transferase Tip60, while it had no effect on p53 stabilization, phosphorylation or p21 induction. CHIR99021 also protected human intestinal cultures from radiation by PUMA but not p21 suppression. These results demonstrate that p53 posttranslational modifications play a key role in the pathological and apoptotic response of the intestinal stem cells to radiation and can be targeted pharmacologically

The Schr\"odinger system H=-{1/2}e^{\Upsilon(t-t_o)}\partial_{xx} +\lfrac{1}{2}\omega^2e^{-\Upsilon(t-t_o)}x^2

In this paper, we attack the specific time-dependent Hamiltonian problem H=-{1/2}e^{\Upsilon(t-t_o)}\partial_{xx} +\lfrac{1}{2}\omega^2e^{-\Upsilon(t-t_o)}x^2. This corresponds to a time-dependent mass (TM) Schr\"odinger equation. We give the specific transformations to i) the more general quadratic (TQ) Schr\"odinger equation and to ii) a different time-dependent oscillator (TO) equation. For each Schr\"odinger system, we give the Lie algebra of space-time symmetries, the number states, the coherent states, the squeezed-states and the time-dependent , , (\Delta x)^2, (\Delta p)^2, and uncertainty product.Comment: Latex, 24 pages, including 3 figures and 8 tables. New title and format for journal. Conclusion adde

The topography of transmembrane segment six is altered during the catalytic cycle of P-glycoprotein

Structural evidence has demonstrated that P-glycoprotein (P-gp) undergoes considerable conformational changes during catalysis, and these alterations are important in drug interaction. Knowledge of which regions in P-gp undergo conformational alterations will provide vital information to elucidate the locations of drug binding sites and the mechanism of coupling. A number of investigations have implicated transmembrane segment six (TM6) in drug-P-gp interactions, and a cysteine-scanning mutagenesis approach was directed to this segment. Introduction of cysteine residues into TM6 did not disturb basal or drug-stimulated ATPase activity per se. Under basal conditions the hydrophobic probe coumarin maleimide readily labeled all introduced cysteine residues, whereas the hydrophilic fluorescein maleimide only labeled residue Cys-343. The amphiphilic BODIPY-maleimide displayed a more complex labeling profile. The extent of labeling with coumarin maleimide did not vary during the catalytic cycle, whereas fluorescein maleimide labeling of F343C was lost after nucleotide binding or hydrolysis. BODIPY-maleimide labeling was markedly altered during the catalytic cycle and indicated that the adenosine 5'-(beta,gamma-imino)triphosphate-bound and ADP/vanadate-trapped intermediates were conformationally distinct. Our data are reconciled with a recent atomic scale model of P-gp and are consistent with a tilting of TM6 in response to nucleotide binding and ATP hydrolysis

Quantum Interference: From Kaons to Neutrinos (with Quantum Beats in between)

Using the vehicle of resolving an apparent paradox, a discussion of quantum interference is presented. The understanding of a number of different physical phenomena can be unified, in this context. These range from the neutral kaon system to massive neutrinos, not to mention quantum beats, Rydberg wave packets, and neutron gravity.Comment: 12 pages, LaTeX, 3 figure

Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor

Until recently it was assumed that hereditary angioedema is a disease that results exclusively from a genetic deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity and protein in plasma were described. Since then numerous patients and families with that condition have been reported. Most of the patients by far were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. Recently, in some families mutations in the coagulation factor XII (Hageman factor) gene were detected in the affected persons

Producing Adulthood: Adolescent Employment, Fertility, and the Life Course

Adolescent employment is typically framed as having either positive or negative effects. Yet cutting edge research yields apparently contradictory results; work lowers delinquency but also increases school dropout. Both opportunity cost and life course development theories could explain these results. This study investigates effects of employment on fertility among adolescent women, which pits life course development against opportunity cost theory. Using 2006 and 2007 American Community Surveys, individual instrumental variable and state-level difference-in-difference models (following the same cohort over time) control for self-selection and find a positive effect of employment on adolescent fertility. National Vital Statistics birth data confirm state-level results. Results for fertility (and some evidence for other early transitions) indicate that youth employment speeds the transition to adulthood, supporting life course theory. Findings suggest adolescent employment should be reconceived as promoting adult rather than positive or negative behavior