An oncogenic tyrosine kinase inhibits DNA repair and DNA-damage-induced Bcl-xL deamidation in T cell transformation

AbstractA transgenic mouse model of T cell lymphoma was used to investigate the transforming events mediated by an oncogenic tyrosine kinase in pretumorigenic CD4−CD8− (DN) thymocytes. Parental CD45−/− and p56lck-F505Y mice do not develop tumors, whereas their CD45−/−p56lck-F505Y progeny develop T lymphomas. Increased but nononcogenic p56lck kinase activity in p56lck-F505Y mice DN thymocytes causes cell-cycle progression, survival, and Bcl-XL upregulation. Additional unique oncogenic signals occur in pretumorigenic CD45−/−p56lck-F505Y thymocytes in which p56lck kinase activity is 2- to 3-fold higher relative to p56lck-F505Y: inhibition of DNA repair, inhibition of DNA-damage-induced Bcl-XL deamidation, Bax conformational change and mitochondrial translocation, cytochrome c release, and the apoptotic caspase execution cascade. Inhibition of Bcl-XL deamidation may be a critical switch in oncogenic kinase-induced T cell transformation

Quantum dynamics of wave packets in a non-stationary parabolic potential and the Kramers escape rate theory

At sufficiently low temperatures, the reaction rates in solids are controlled by quantum rather than by thermal fluctuations. We solve the Schrödinger equation for a Gaussian wave packet in a non-stationary harmonic oscillator and derive simple analytical expressions for the increase of its mean energy with time induced by the time-periodic modulation. Applying these expressions to the modified Kramers theory, we demonstrate a strong increase of the rate of escape out of a potential well under the time-periodic driving, when the driving frequency of the well position equals its eigenfrequency, or when the driving frequency of the well width exceeds its eigenfrequency by a factor of ~2~2. Such regimes can be realized near localized anharmonic vibrations (LAVs), in which the amplitude of atomic oscillations greatly exceeds that of harmonic oscillations (phonons) that determine the system temperature. LAVs can be excited either thermally or by external triggering, which can result in strong catalytic effects due to amplification of the Kramers rate

The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses

SummaryThe molecular mechanisms whereby the CD45 tyrosine phosphatase (PTPase) regulates T cell receptor (TCR) signaling responses remain to be elucidated. To investigate this question, we have reconstituted CD45 (encoded by Ptprc)-deficient mice, which display severe defects in thymic development, with five different expression levels of transgenic CD45RO, or with mutant PTPase null or PTPase-low CD45R0. Whereas CD45 PTPase activity was absolutely required for the reconstitution of thymic development, only 3% of wild-type CD45 activity restored T cell numbers and normal cytotoxic T cell responses. Lowering the CD45 expression increased CD4 lineage commitment. Peripheral T cells with very low activity of CD45 phosphatase displayed reduced TCR signaling, whereas intermediate activity caused hyperactivation of CD4+ and CD8+ T cells. These results are explained by a rheostat mechanism whereby CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56lck tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56lck pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity

Bilim ve Din İlişkisi İçin Modeller

Bilim ve din arasındaki etkileşimler hem tarihsel olarak hem de günümüzde çeşitli ve karmaşıktır. Modeller, verileri anlamlandırmak için faydalı olabilir. Bu makale, bilim-din etkileşimlerini tanımlamak için önerilen dört ana model türünü karşılaştırarak, onların güçlü ve zayıf yönlerini vurgulamaktadır. Bilimsel ve dini bilgiyi ilişkilendirme görevinde 'bütünleyici' modelin en verimli olduğu sonucuna varılmıştır