大腸菌二成分制御系情報伝達ネットワークの研究

For survival, organisms adapt to environmental changes by switch the gene expression. Simple unicellular organisms that possess only thousands of genes such as bacteria shows the amazing adaptation ability against a variety of environment. Therefore, in bacteria, limited gene regulation mechanism may forms the transduction network with others for multiply the gene regulation pathway. Two component system which is the major signal transduction pathway employed in wide varieties of bacteria, is generally composed of the sensor kinase (SK) that monitors an external signal(s) and the response regulator (RR) that controls physiological activities for response against external signals. A total of about 30 unique TCS pairs of SK and RR have been identified in E. coli based on the gene organization and the further genetic and/or biochemical data. In addition to these, there is the several RRs which pairing partner SK are not found and its function are unkown in E.coli. The process of TCS signal transduction generally show a high level of specificity, while a certain level of cross-regulation has been identified at the signal transduction pathways in E. coli: cross talk in recognition of signals by the sensor SK (stage 1); cross talk in phosphorylation of RRs by SKs (stage 2); and cross talk in recognition of regulation target promoters between RRs (stage 3). Cross talk between TCS pairs has been established at three stages of the signal transduction pathways. Network formation between the TCSs may contribute for the bacterial adaptation to various environment. However, the perspective of the TCS network does not yet become clear. Especially, there are few reports for the cross recognition of the promoter by RRs. And E. coli possesses function unknown orphan RRs. In this study, for the elucidation of the entire signal transduction network of E. coli, I performed the comprehensive analysis of the stage 3 cross talk among RRs. And I investigated the role and activation mechanism of uncharacterized orphan RR. The study of the stage 3 cross talk between NarL-family RRs is described in the chapter 2. In the same line study, the cross talk between OmpR family RRs were also analyzed and described in chapter 3. The chapter 4 focuses on the uncharacterized RR YgeK. Taking all the chapter together, my thesis presents the specific and complicated promoter recognition by RRs and function of atypical RR YgeK that plays the role of growth in acetate medium and biofilm formation. These findings provide the insight into the perspective of TCS signal transduction network and contribute for understanding the mechanism how bacteria adapt and survive againt to environment change.博士(生命科学)法政大学 (Hosei University

Primary Mediastinal (Thymic) Large B-Cell Lymphoma

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is one of the primary extranodal tumors and originates from thymic medulla B cells. The disease is more common in young women and declares itself by mainly locally advanced growth within the anterior upper mediastinum with frequent involvement of chest organs. PMBCL has specific morphological, immunological, and genetic characteristics that permit to differentiate it from other similar diseases: diffuse large В-cell lymphoma, nodular sclerosis Hodgkin’s lymphoma, and mediastinal gray zone lymphoma. Immunochemotherapy with subsequent irradiation of the residual mediastinal tumor is the standard treatment of PMBCL. No benefits of one drug therapy over another have been demonstrated to date in controlled studies. Application of new imaging techniques (PET/CT) may result in withdrawal of the radiotherapy in some PMBCL patients without impairment of delayed survival rates

A Review of the ACHS Clinical Indicator Program after 20 years

The Clinical Indicator Program, which was introduced into the Australian Council on Healthcare Standards’ accreditation program two decades ago, has grown from one set addressed by 115 healthcare organisations to 22 sets with data received from over 800 healthcare organisations, resulting in a national database which is unique in its clinical diversity, reflecting every major medical discipline involved in hospital practice. The process for Clinical Indicator selection and review remains with the providers of the care, but the selection criteria are better defined and the evidence base strengthened. Early responses to their introduction were encouraging as improvements in patient management and outcomes were sought and achieved following review of comparative data, and some examples of these are provided. Clinical Indicator revision remains an important and major task and the original Hospital- Wide set of Clinical Indicators is now in its 12th version. The development and use of Clinical Indicators is increasing world-wide, and in Australia there are other organisations, including the Australian Commission on Safety and Quality in Healthcare, looking at Clinical Indicators to further understand the performance of healthcare organisations. As clinical care changes, the challenges for the Australian Council on Healthcare Standards are to ensure the Clinical Indicators continue to reflect current practice, to retain clinician support, and also to ensure that the existence of its extensive and long-standing national clinical database is more widely known and utilised. Abbreviations: ACHS: Australian Council of Healthcare Standards; ACIR – Australasian Clinical Indicator Report; ANZICS – Australian and New Zealand Intensive Care Society; APD – Adult Patient Database; CI – Clinical Indicators; HCO – HealthCare Organisation; PIRT – Performance Indicator Reporting Tool; RACMA - Royal Australian College of Medical Administrators

Atomic-scale images of charge ordering in a mixed-valence manganite

Transition-metal perovskite oxides exhibit a wide range of extraordinary but imperfectly understood phenomena. Charge, spin, orbital, and lattice degrees of freedom all undergo order-disorder transitions in regimes not far from where the best-known of these phenomena, namely high-temperature superconductivity of the copper oxides, and the 'colossal' magnetoresistance of the manganese oxides, occur. Mostly diffraction techniques, sensitive either to the spin or the ionic core, have been used to measure the order. Unfortunately, because they are only weakly sensitive to valence electrons and yield superposition of signals from distinct mesoscopic phases, they cannot directly image mesoscopic phase coexistence and charge ordering, two key features of the manganites. Here we describe the first experiment to image charge ordering and phase separation in real space with atomic-scale resolution in a transition metal oxide. Our scanning tunneling microscopy (STM) data show that charge order is correlated with structural order, as well as with whether the material is locally metallic or insulating, thus giving an atomic-scale basis for descriptions of the manganites as mixtures of electronically and structurally distinct phases.Comment: 8 pages, 4 figures, 19 reference

Geodesic motion in the space-time of a cosmic string

We study the geodesic equation in the space-time of an Abelian-Higgs string and discuss the motion of massless and massive test particles. The geodesics can be classified according to the particles energy, angular momentum and linear momentum along the string axis. We observe that bound orbits of massive particles are only possible if the Higgs boson mass is smaller than the gauge boson mass, while massless particles always move on escape orbits. Moreover, neither massive nor massless particles can ever reach the string axis for non-vanishing angular momentum. We also discuss the dependence of light deflection by a cosmic string as well as the perihelion shift of bound orbits of massive particles on the ratio between Higgs and gauge boson mass and the ratio between symmetry breaking scale and Planck mass, respectively.Comment: 20 pages including 14 figures; v2: references added, discussion on null geodesics extended, numerical results adde

Puzzles of Dark Matter - More Light on Dark Atoms?

Positive results of dark matter searches in experiments DAMA/NaI and DAMA/LIBRA confronted with results of other groups can imply nontrivial particle physics solutions for cosmological dark matter. Stable particles with charge -2, bound with primordial helium in O-helium "atoms" (OHe), represent a specific nuclear-interacting form of dark matter. Slowed down in the terrestrial matter, OHe is elusive for direct methods of underground Dark matter detection using its nuclear recoil. However, low energy binding of OHe with sodium nuclei can lead to annual variations of energy release from OHe radiative capture in the interval of energy 2-4 keV in DAMA/NaI and DAMA/LIBRA experiments. At nuclear parameters, reproducing DAMA results, the energy release predicted for detectors with chemical content other than NaI differ in the most cases from the one in DAMA detector. Moreover there is no bound systems of OHe with light and heavy nuclei, so that there is no radiative capture of OHe in detectors with xenon or helium content. Due to dipole Coulomb barrier, transitions to more energetic levels of Na+OHe system with much higher energy release are suppressed in the correspondence with the results of DAMA experiments. The proposed explanation inevitably leads to prediction of abundance of anomalous Na, corresponding to the signal, observed by DAMA.Comment: Contribution to Proceedings of XIII Bled Workshop "What Comes beyond the Standard Model?

Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes.

AIMS: Hypertrophic cardiomyopathy (HCM) is characterised by cardiomyocyte hypertrophy and disarray, and myocardial stiffness due to interstitial fibrosis, which result in impaired left ventricular filling and diastolic dysfunction. The latter manifests as exercise intolerance, angina, and dyspnoea. There is currently no specific treatment for improving diastolic function in HCM. Here, we investigated whether myeloperoxidase (MPO) is expressed in cardiomyocytes and provides a novel therapeutic target for alleviating diastolic dysfunction in HCM. METHODS AND RESULTS: Human cardiomyocytes derived from control induced pluripotent stem cells (iPSC-CMs) were shown to express MPO, with MPO levels being increased in iPSC-CMs generated from two HCM patients harbouring sarcomeric mutations in the MYBPC3 and MYH7 genes. The presence of cardiomyocyte MPO was associated with higher chlorination and peroxidation activity, increased levels of 3-chlorotyrosine-modified cardiac myosin binding protein-C (MYBPC3), attenuated phosphorylation of MYBPC3 at Ser-282, perturbed calcium signalling, and impaired cardiomyocyte relaxation. Interestingly, treatment with the MPO inhibitor, AZD5904, reduced 3-chlorotyrosine-modified MYBPC3 levels, restored MYBPC3 phosphorylation, and alleviated the calcium signalling and relaxation defects. Finally, we found that MPO protein was expressed in healthy adult murine and human cardiomyocytes, and MPO levels were increased in diseased hearts with left ventricular hypertrophy. CONCLUSION: This study demonstrates that MPO inhibition alleviates the relaxation defect in hypertrophic iPSC-CMs through MYBPC3 phosphorylation. These findings highlight cardiomyocyte MPO as a novel therapeutic target for improving myocardial relaxation associated with HCM, a treatment strategy which can be readily investigated in the clinical setting, given that MPO inhibitors are already available for clinical testing. TRANSLATIONAL PERSPECTIVE: There are currently no specific therapies for improving diastolic function in patients with HCM. We show for the first time that myeloperoxidase (MPO) is present in and is up-regulated in cardiomyocytes derived from human iPSCs obtained from HCM patients, where it impairs cardiomyocyte relaxation by reducing phosphorylation of cardiac MYBPC3. Treatment with the MPO inhibitor, AZD5904, restored MYBPC3 phosphorylation and alleviated the relaxation defect, demonstrating cardiomyocyte MPO to be a novel therapeutic target for improving diastolic function in HCM, a treatment strategy which can be evaluated in HCM patients given that MPO inhibitors are already available for clinical testing