マウス腹水肝癌MH134の治療に関与する宿主抵抗性の研究

京都大学0048新制・課程博士医学博士医博第376号新制||医||154(附属図書館)2042京都大学大学院医学研究科外科系専攻(主査)教授 木村 忠司, 教授 伊藤 鉄夫, 教授 本庄 一夫学位規則第5条第1項該当Kyoto UniversityDA

The Circadian Clock Gene Period1 Connects the Molecular Clock to Neural Activity in the Suprachiasmatic Nucleus.

The neural activity patterns of suprachiasmatic nucleus (SCN) neurons are dynamically regulated throughout the circadian cycle with highest levels of spontaneous action potentials during the day. These rhythms in electrical activity are critical for the function of the circadian timing system and yet the mechanisms by which the molecular clockwork drives changes in the membrane are not well understood. In this study, we sought to examine how the clock gene Period1 (Per1) regulates the electrical activity in the mouse SCN by transiently and selectively decreasing levels of PER1 through use of an antisense oligodeoxynucleotide. We found that this treatment effectively reduced SCN neural activity. Direct current injection to restore the normal membrane potential partially, but not completely, returned firing rate to normal levels. The antisense treatment also reduced baseline [Ca(2+)]i levels as measured by Fura2 imaging technique. Whole cell patch clamp recording techniques were used to examine which specific potassium currents were altered by the treatment. These recordings revealed that the large conductance [Ca(2+)]i-activated potassium currents were reduced in antisense-treated neurons and that blocking this current mimicked the effects of the anti-sense on SCN firing rate. These results indicate that the circadian clock gene Per1 alters firing rate in SCN neurons and raise the possibility that the large conductance [Ca(2+)]i-activated channel is one of the targets

ROLE OF RUNX3 IN HEAD AND NECK CANCER

Cumulative evidences show that Runt-related transcription factor 3 (RUNX3) has a tumor suppressive role in various cancers. In particular, RUNX3 appears to be an important component of the transforming growth factor-beta (TGF-ß)-induced tumor suppression pathway. Contrary to reports on this tumor suppressive role of RUNX3, RUNX3 can also function as an oncogene when overexpressed. Recently, we found that RUNX3 overexpression was frequently observed and was well correlated with malignant behaviors in head and neck cancer, which is one of the most common types of human cancer. Moreover, it has been revealed that RUNX3 overexpression promoted cell growth and inhibited apoptosis in head and neck cancer cells. This review introduces the oncogenic role of RUNX3 in certain types of cancer including head and neck cancer

Effect of chronic ethanol exposure on the liver of Clock-mutant mice

In humans, chronic ethanol consumption leads to a characteristic set of changes to the metabolism of lipids in the liver that is referred to as an "alcoholic fatty liver (AFL)". In severe cases, these metabolic changes result in the enlargement and fibrillization of the liver and are considered risk factors for cirrhosis and liver cancer. Clock-mutant mice have been shown to display abnormal lipid metabolism and alcohol preferences. To further understand the potential interactions between ethanol consumption, lipid metabolism, and the circadian clock, we investigated the effect of chronic ethanol intake on the lipid metabolism of Clock-mutant mice. We found that ethanol treatment produced a number of changes in the liver of Clock-mutant mice without impacting the wild-type controls. First, we found that 8 weeks of exposure to ethanol in the drinking water increased the weight of the liver in Clock-mutant mice. Ethanol treatment also increased triglyceride content of liver in Clock-mutant and wild-type mice. This increase was larger in the mutant mice. Finally, ethanol treatment altered the expression of a number of genes related to lipid metabolism in the Clock-mutant mice. Interestingly, this treatment did not impact circadian clock gene expression in the liver of either genotype. Thus, ethanol produces a number of changes in the liver of Clock-mutant mice that are not seen in the wild-type mice. These changes are consistent with the possibility that disturbance of circadian rhythmicity associated with the Clock mutation could be a risk factor for the development of an alcoholic fatty liver

Functional gate metal-oxide-semiconductor field-effect transistors using tunnel injection/ejection of trap charges enabling self-adjustable threshold voltage for ultralow power operation

Metal-oxide-semiconductor field-effect transistors (MOSFETs) with a functional gate, which enables self-adjustment of threshold voltage (Vth), were proposed for ultralow power operation and fabricated with conventional complementary metal-oxide-semiconductor (CMOS) technology. In the on-current state of fabricated nMOSFETs, electron ejection from the charge trap layer by direct tunneling makes Vth low and increases on-current further. In the off-current state, electron injection into the charge trap layer makes Vth high and suppresses subthreshold leakage current. Although the characteristic time of electron transfer of the functional gate from on-current state to off-current state is fairly long, the logic mode operating principle has been verified with the experimental device. Reduction of tunnel oxide thickness (Tox) will reduce the time, which will lead to the practical use of the proposed device for CMOS logic application

Highly sensitive ion detection using Si single-electron transistors

Si single-electron transistors (SETs) were used for highly sensitive ion detection. A multiple-island channel structure was adapted in the SET for room-temperature operation. Clear Coulomb oscillation and diamonds were observed at room temperature. Using the Coulomb oscillation, clear pH responses of drain current (Id)-gate voltage (Vg) characteristics were obtained despite the existence of Id noise. Because Coulomb oscillations have a possibility to increase the slope of Id over Vg near the half-maximum current of the peaks, high resolving power of ion, and/or biomolecule concentration can be expected. A Si-structure will make it possible to integrate the sensors on a single chip

Biomolecule detection based on Si single-electron transistors for highly sensitive integrated sensors on a single chip

Biomolecule detection was achieved using a Si single-electron transistor (SET) for highly-sensitive detection. A multiple-island channel-structure was used for the SET to enable room-temperature operation and to increase sensitivity. Coulomb oscillation shifted against the gate voltage due to biotin-streptavidin binding. Coulomb oscillation has a possibility to increase transconductance (gm), and a higher gm leads to greater sensitivity to a charged target. Since a Si structure is important for integrating label-free-biomolecule and/or ion sensors into large-scale-integrated circuits, a Si SET with multiple islands should enable the integration of a sensor system on a single chip for multiplexed detections and simultaneous diagnoses