This thesis presents algorithms for performing the next two reduction steps, namely orthogonalization and extraction. More specifically, this thesis addresses the following research question: What are proper methods of orthogonalizing spectral images in preparation for extraction?

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18183号 / 医博第3903号 / 新制||医||1004(附属図書館) / 31041 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邉 大, 教授 髙橋 良輔, 教授 髙橋 淳, 教授 江藤 浩之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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We carried out a near-infrared radial velocity search for Jupiter-mass planets around 36 late M dwarfs. This survey was the first of its kind undertaken to monitor radial velocity variability of these faint dwarfs. For this unique survey we employed the 10-m Keck II on Mauna Kea in Hawaii. With a resolution of 20,000 on the near-infrared spectrograph, NIRSPEC, we monitored these stars over four epochs in 2007. In addition to the measurement of relative radial velocity we established physical properties of these stars. The physical properties of M dwarfs we determined included the identification of neutral atomic lines, the measurement of pseudo-equivalent widths, masses, surface gravity, effective temperature, absolute radial velocities, rotational velocities and rotation periods. The identification of neutral atomic lines was carried out using the Vienna Atomic line Database. We were able to confirm these lines that were previously identified. We also found that some of the lines observed in the K-type stars, such as Mg I though weak, still persist in late M dwarfs. Using the measurement of pseudo-equivalent widths (p-EW) of 13 neutral atomic lines, we have established relations between p-EW and spectral type. Such relations serve as a tool in determining the spectral type of an unknown dwarf star by means of measuring its p-EW. We employed the mass-luminosity relation to compute the masses of M dwarfs. Our calculations indicate these dwarfs to be in the range of 0.1 to 0.07 solar masses. This suggests that some of the late M dwarfs appear to be in the Brown dwarf regime. Assuming their radii of 0.1 solar radii, we calculated their surface gravity. The mean surface gravity is, log g = 5.38. Finally their effective temperature was determined by using the spectral-type iii temperature relationship. Our calculations show effective temperatures in the range of 3000 2300 K. Comparison of these values with models in literature show a good agreement. The absolute radial and rotational velocities of our targets were also calculated. Values of rotational velocities indicate that M dwarfs are, in general, slow rotators. Using our result and that from literature, we extended our study of rotational velocities to L dwarfs. Our observations show an increase in rotational velocities from late M to L dwarfs. We also find that the mean periods of M dwarfs are less than 10 hours. In order to improve our precision in measuring relative radial velocity (RV), we employed the use of deconvolution method. With this method we were able to ameliorate relative RV precision from 300 m/s to 200 m/s. This was a substantial improvement in our ability to detect gas-giant planets. However none of the 15 dwarfs we monitored indicate a presence of companions. This null result was then used to compute the upper limit to the binary frequency and close-in Jupiter mass planetary frequency. We find the binary frequency to be 11% while the planetary frequency was 1.20%.

The outer membrane (OM) of P. aeruginosa is a semi-permeable barrier that contributes to antibiotic resistance by reducing uptake. Finding strategies to circumvent this barrier is a major challenge. One approach involves screening in physiologically relevant conditions to identify novel activity in existing molecules. We discovered that thiostrepton (TS), a thiopeptide antibiotic with no reported activity against Gram-negative bacteria, hijacks the pyoverdine siderophore transporters FpvA and FpvB to cross the OM under iron limitation to inhibit translation. Using TS, we subsequently showed that FpvB is not primarily a pyoverdine transporter, but rather a promiscuous transporter for siderophores ferrichrome and ferrioxamine B. Our work with TS suggested that other thiopeptides may use siderophore transporters for entry into the cell. This hypothesis led to a screen to identify other thiopeptides with activity against P. aeruginosa, uncovering two other thiopeptides, thiocillin and micrococcin, that use the ferrioxamine transporter FoxA for uptake. We discovered another siderophore, bisucaberin, could also use FoxA for uptake and our collaborators solved the crystal structure of bisucaberin bound to FoxA. Through biochemical approaches, we characterized how FoxA accommodates structurally distinct ligands. Finally, we screened known large natural product antibiotics with no pseudomonal activity under nutrient limitation and discovered that the glycopeptide vancomycin inhibits growth by blocking peptidoglycan crosslinking. This pilot screen emphasizes the importance of screening for antibiotics under physiologically relevant conditions to avoid overlooking potential hits. Overall, the findings from these studies can be used to guide medicinal chemistry efforts to develop novel siderophore-antibiotic conjugates for the treatment of P. aeruginosa infections. These results also help us gain a deeper understanding of the mechanism of binding and uptake through siderophore transporters and the range of substrates that can be taken up. / Dissertation / Doctor of Philosophy (PhD) / Antibiotic resistance is a growing crisis that threatens modern medicine, and it is becoming more challenging to discover truly new antibiotics to combat this threat. Intrinsic resistance conferred by the outer membrane of Gram-negative bacteria restricts the entry of many antibiotics, especially larger antibiotics that would otherwise inhibit the growth of Gram-positive bacteria. Consequently, there are fewer treatment options for infections caused by Gram-negative bacteria and developing new antibiotics that can cross the outer membrane remains a significant challenge in drug discovery. My work describes the discovery of a class of antibiotics that can bypass the outer membrane using specific outer-membrane nutrient transporters. Using biochemical, structural biology, fluorescence microscopy, and molecular biology techniques, we uncover the molecular determinants of uptake of these antibiotics for their respective transporters. These results can inform the design of novel narrow-spectrum antibiotics that can overcome the outer membrane barrier to combat antimicrobial resistance.

Hair follicles harbor a heterogeneous regenerative cell pool and represent a putative low-to-non-invasively available source of stem cells. We previously reported a technology for culturing human melanocytes from the hair follicle outer root sheath (ORS) for autologous pigmentation of tissue engineered skin equivalents. This study translated the ORS technology to horses. We de-veloped a culture of equine melanocytes from the ORS (eMORS) from equine forelock hair follicles cultured by means of an analogue human hair follicle-based in vitro methodology. The procedure was adjusted to equine physiology by addition of equine serum to the culture medium. The hair follicles were isolated by macerating forelock skin rests, enzymatically digested and subjected to air-medium-interface cultivation method. The procedure resulted in differentiated equine melanocytes, which exhibited typical morphology, presence of melanosomes, expression of cytoskeleton proteins vimentin, α-SMA, Sox2, S100ß and tyrosinase as well as tyrosinase activity followed by production of melanin. According to all assessed parameters, eMORS could be ranked as partially melanotic melanocytes. The results of the study offer an experimental base for further insight into hair follicle biology in equine and for comparative studies of hair follicles across different species.

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