15 research outputs found
偽エクソン生成を標的とした嚢胞性線維症に対する個別化医療
京都大学新制・課程博士博士(医学)甲第23065号医博第4692号新制||医||1049(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 村川 泰裕, 教授 平井 豊博, 教授 小川 誠司学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA
On the Theory of Vibronic Laser
Some aspects of lasing at vibronic transitions in impurity crystals are
theoretically studied. The threshold conditions for a vibronic laser are shown
to be dependent on the strength of interaction of optical centers with a local
vibration, which forms the vibronic spectrum, and the crystal lattice
temperature. The theory can be easily generalized to the spectrum containing a
structureless phonon sideband and well agrees with the experimental temperature
dependence of the output power of a Mg2SiO4:Cr4+ forsterite laser.Comment: 6 pages, 1 figur
Conformational diversity of dynactin
Dynactin is a principal regulator of the minus-end directed microtubule motor dynein. The sidearm of dynactin is essential for binding to microtubules and regulation of dynein activity. Although our understanding of the structure of the dynactin backbone (Arp1 rod) has greatly improved recently, structural details of the sidearm subcomplex remain elusive. Here, we report the flexible nature and diverse conformations of dynactin sidearm observed by electron microscopy. Using nanogold labeling and deletion mutant analysis, we determined the domain organization of the largest subunit p150 and discovered that its coiled-coil (CC1), dynein-binding domain, adopted either a folded or an extended form. Furthermore, the entire sidearm exhibited several characteristic forms, and the equilibrium among them depended on salt concentrations. These conformational diversities of the dynactin complex provide clues to understanding how it binds to microtubules and regulates dynein
Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia.
Approximately half of genetic disease-associated mutations cause aberrant splicing. However, a widely applicable therapeutic strategy to splicing diseases is yet to be developed. Here, we analyze the mechanism whereby IKBKAP-familial dysautonomia (FD) exon 20 inclusion is specifically promoted by a small molecule splice modulator, RECTAS, even though IKBKAP-FD exon 20 has a suboptimal 5' splice site due to the IVS20 + 6 T > C mutation. Knockdown experiments reveal that exon 20 inclusion is suppressed in the absence of serine/arginine-rich splicing factor 6 (SRSF6) binding to an intronic splicing enhancer in intron 20. We show that RECTAS directly interacts with CDC-like kinases (CLKs) and enhances SRSF6 phosphorylation. Consistently, exon 20 splicing is bidirectionally manipulated by targeting cellular CLK activity with RECTAS versus CLK inhibitors. The therapeutic potential of RECTAS is validated in multiple FD disease models. Our study indicates that small synthetic molecules affecting phosphorylation state of SRSFs is available as a new therapeutic modality for mechanism-oriented precision medicine of splicing diseases
On the Theory of Vibronic Superradiance
The Dicke superradiance on vibronic transitions of impurity crystals is
considered. It is shown that parameters of the superradiance (duration and
intensity of the superradiance pulse and delay times) on each vibronic
transition depend on the strength of coupling of electronic states with the
intramolecular impurity vibration (responsible for the vibronic structure of
the optical spectrum in the form of vibrational replicas of the pure electronic
line) and on the crystal temperature through the Debye-Waller factor of the
lattice vibrations. Theoretical estimates of the ratios of the time delays, as
well as of the superradiance pulse intensities for different vibronic
transitions well agree with the results of experimental observations of
two-color superradiance in the polar dielectric KCl:O2-. In addition, the
theory describes qualitatively correctly the critical temperature dependence of
the superradiance effect.Comment: 8 pages, 1 figur