イヌ尺骨神経損傷モデルにおける、自家皮膚線維芽細胞から作製したscaffold-free Bio 3D conduitの末梢神経再生に対する有効性：前臨床概念実証研究

京都大学新制・課程博士博士(医学)甲第23056号医博第4683号新制||医||1048(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 戸口田 淳也, 教授 森本 尚樹, 教授 伊佐 正学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Variable Selection in Maximum Mean Discrepancy for Interpretable Distribution Comparison

Two-sample testing decides whether two datasets are generated from the same distribution. This paper studies variable selection for two-sample testing, the task being to identify the variables (or dimensions) responsible for the discrepancies between the two distributions. This task is relevant to many problems of pattern analysis and machine learning, such as dataset shift adaptation, causal inference and model validation. Our approach is based on a two-sample test based on the Maximum Mean Discrepancy (MMD). We optimise the Automatic Relevance Detection (ARD) weights defined for individual variables to maximise the power of the MMD-based test. For this optimisation, we introduce sparse regularisation and propose two methods for dealing with the issue of selecting an appropriate regularisation parameter. One method determines the regularisation parameter in a data-driven way, and the other aggregates the results of different regularisation parameters. We confirm the validity of the proposed methods by systematic comparisons with baseline methods, and demonstrate their usefulness in exploratory analysis of high-dimensional traffic simulation data. Preliminary theoretical analyses are also provided, including a rigorous definition of variable selection for two-sample testing

Instrumentos e dificuldades de implantação da ISO 14001 em empresas

O período pós Revolução Industrial é marcado pelo crescimento desordenado das cidades, o aumento na exploração dos recursos naturais e da poluição ao meio ambiente. A partir da década de 80 os movimentos ambientalistas ganham força e acabam pressionando os países a melhorarem as suas legislações ambientais. A série ISO 14000 foi criada para padronizar o gerenciamento ambiental. Esta série possui várias normas, dentre elas a ISO 14001, que é o documento base para a série ISO 14000. A ISO 14001 se refere ao sistema de gestão ambiental, que possui ferramentas mínimas para serem implantadas, como: política ambiental, requisitos legais e outros requisitos, objetivos e metas, programa de gestão ambiental, estrutura e responsabilidade, treinamento, conscientização e competência, comunicação, documentação do sistema de gestão ambiental, preparação e atendimento à emergência, monitoramento, ação corretiva e auditoria do sistema de gestão ambiental. O principal problema encontrado na implantação da ISO 14001 é o mau planejamento do processo, que gera problemas como a falta de treinamento, sensibilização e comprometimento dos envolvidos. O planejamento deve ser minucioso para que gere o levantamento de pontos fortes e oportunidades de melhorias, estes deverão ser sanados através de projetos desenvolvidos pela empresa. Se a implantação for bem planejada, elaborada e seus problemas forem identificados e sanados com rapidez, a empresa obterá a certificação da Norma ISO 14001. Apesar de ser um processo que envolve custos financeiros a certificação traz inúmeras vantagens para a empresa tanto do ponto de vista econômico como ambiental

Hypothermia Due to an Ascending Impairment of Shivering in Hyperacute Experimental Allergic Encephalomyelitis in the Lewis Rat

Severe hypothermia and an ascending impairment of shivering are previously undescribed clinical signs in hyperacute experimental allergic encephalomyelitis (EAE) in the Lewis rat. These occurred in hyperacute EAE induced by inoculation with guinea pig spinal cord homogenate and heat-killed Bordetella pertussis. Hypothermia was first detected on day 6-7 post-inoculation, within 12-24 h of the onset of neurological signs, and became more severe as the disease progressed. Rectal temperatures less than or equal to 30 degrees C were common at ambient temperatures of 19-22 degrees C. Shivering was assessed by palpation and by cold tremor electromyography. Shivering was absent in the tail by day 6-7 post-inoculation. The impairment then progressed to affect the hindlimbs, thorax and occasionally the forelimbs. Shivering was absent in hindlimbs with only mild or moderate weakness. Histological studies revealed perivascular inflammation with polymorphonuclear and mononuclear cells, oedema, fibrin deposition, haemorrhage, primary demyelination and axonal degeneration in the spinal cord, dorsal root ganglia and spinal roots. The brainstem was also involved but the cerebral hemispheres, including the hypothalamus, were spared. The close relationship between the severity of hypothermia and the extent of shivering impairment indicates that reduced shivering is an important cause of hypothermia in hyperacute EAE. It is concluded that this impairment of shivering is due not to hypothalamic damage but to lesions elsewhere in the central and peripheral nervous systems

The fission yeast Rpb4 subunit of RNA polymerase II plays a specialized role in cell separation

RNA polymerase II is a complex of 12 subunits, Rpb1 to Rpb12, whose specific roles are only partly understood. Rpb4 is essential in mammals and fission yeast, but not in budding yeast. To learn more about the roles of Rpb4, we expressed the rpb4 gene under the control of regulatable promoters of different strength in fission yeast. We demonstrate that below a critical level of transcription, Rpb4 affects cellular growth proportional to its expression levels: cells expressing lower levels of rpb4 grew slower compared to cells expressing higher levels. Lowered rpb4 expression did not affect cell survival under several stress conditions, but it caused specific defects in cell separation similar to sep mutants. Microarray analysis revealed that lowered rpb4 expression causes a global reduction in gene expression, but the transcript levels of a distinct subset of genes were particularly responsive to changes in rpb4 expression. These genes show some overlap with those regulated by the Sep1-Ace2 transcriptional cascade required for cell separation. Most notably, the gene expression signature of cells with lowered rpb4 expression was highly similar to those of mcs6, pmh1, sep10 and sep15 mutants. Mcs6 and Pmh1 encode orthologs of metazoan TFIIH-associated cyclin-dependent kinase (CDK)-activating kinase (Cdk7-cyclin H-Mat1), while Sep10 and Sep15 encode mediator components. Our results suggest that Rpb4, along with some other general transcription factors, plays a specialized role in a transcriptional pathway that controls the cell cycle-regulated transcription of a specific subset of genes involved in cell division. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00438-006-0161-5 and is accessible for authorized users

The Effect of Arc Proximity on Hydrothermal Activity Along Spreading Centers: New Evidence From the Mariana Back Arc (12.7°N-18.3°N)

Back-arc spreading centers (BASCs) form a distinct class of ocean spreading ridges distinguished by steep along-axis gradients in spreading rate and by additional magma supplied through subduction. These characteristics can affect the population and distribution of hydrothermal activity on BASCs compared to mid-ocean ridges (MORs). To investigate this hypothesis, we comprehensively explored 600 km of the southern half of the Mariana BASC. We used water column mapping and seafloor imaging to identify 19 active vent sites, an increase of 13 over the current listing in the InterRidge Database (IRDB), on the bathymetric highs of 7 of the 11 segments. We identified both high and low (i.e., characterized by a weak or negligible particle plume) temperature discharge occurring on segment types spanning dominantly magmatic to dominantly tectonic. Active sites are concentrated on the two southernmost segments, where distance to the adjacent arc is shortest (48 mm/yr), and tectonic extension is pervasive. Re-examination of hydrothermal data from other BASCs supports the generalization that hydrothermal site density increases on segments <90 km from an adjacent arc. Although exploration quality varies greatly among BASCs, present data suggest that, for a given spreading rate, the mean spatial density of hydrothermal activity varies little between MORs and BASCs. The present global database, however, may be misleading. On both BASCs and MORs, the spatial density of hydrothermal sites mapped by high-quality water-column surveys is 2–7 times greater than predicted by the existing IRDB trend of site density versus spreading rate

Gcn5 facilitates Pol II progression, rather than recruitment to nucleosome-depleted stress promoters, in Schizosaccharomyces pombe

In the fission yeast, the MAP kinase Sty1 and the transcription factor Atf1 regulate up to 400 genes in response to environmental signals, and both proteins have been shown to bind to their promoters in a stress-dependent manner. In a genetic search, we have isolated the histone H3 acetyltransferase Gcn5, a component of the SAGA complex, as being essential for oxidative stress survival and activation of those genes. Upon stress, Gcn5 is recruited to promoters and coding sequences of stress genes in a Sty1- and Atf1-dependent manner, causing both an enhanced acetylation of histone H3 and nucleosome eviction. Unexpectedly, recruitment of RNA polymerase II (Pol II) is not impaired in Δgcn5 cells. We show here that stress genes display a 400-bp long nucleosome depleted region upstream of the transcription start site even prior to activation. Stress treatment does not alter promoter nucleosome architecture, but induces eviction of the downstream nucleosomes at stress genes, which is not observed in Δgcn5 cells. We conclude that, while Pol II is recruited to nucleosome-free stress promoters in a transcription factor dependent manner, Gcn5 mediates eviction of nucleosomes positioned downstream of promoters, allowing efficient Pol II progression along the genes

The Yeast Tor Signaling Pathway Is Involved in G2/M Transition via Polo-Kinase

The target of rapamycin (Tor) protein plays central roles in cell growth. Rapamycin inhibits cell growth and promotes cell cycle arrest at G1 (G0). However, little is known about whether Tor is involved in other stages of the cell division cycle. Here we report that the rapamycin-sensitive Tor complex 1 (TORC1) is involved in G2/M transition in S. cerevisiae. Strains carrying a temperature-sensitive allele of KOG1 (kog1-105) encoding an essential component of TORC1, as well as yeast cell treated with rapamycin show mitotic delay with prolonged G2. Overexpression of Cdc5, the yeast polo-like kinase, rescues the growth defect of kog1-105, and in turn, Cdc5 activity is attenuated in kog1-105 cells. The TORC1-Type2A phosphatase pathway mediates nucleocytoplasmic transport of Cdc5, which is prerequisite for its proper localization and function. The C-terminal polo-box domain of Cdc5 has an inhibitory role in nuclear translocation. Taken together, our results indicate a novel function of Tor in the regulation of cell cycle and proliferation

Geological interpretation of volcanism and segmentation of the Mariana back-arc spreading center between 12.7°N and 18.3°N

The relationships between tectonic processes, magmatism, and hydrothermal venting along ∼600 km of the slow-spreading Mariana back-arc between 12.7°N and 18.3°N reveal a number of similarities and differences compared to slow-spreading mid-ocean ridges. Analysis of the volcanic geomorphology and structure highlights the complexity of the back-arc spreading center. Here, ridge segmentation is controlled by large-scale basement structures that appear to predate back-arc rifting. These structures also control the orientation of the chains of cross-arc volcanoes that characterize this region. Segment-scale faulting is oriented perpendicular to the spreading direction, allowing precise spreading directions to be determined. Four morphologically distinct segment types are identified: dominantly magmatic segments (Type I); magmatic segments currently undergoing tectonic extension (Type II); dominantly tectonic segments (Type III); and tectonic segments currently undergoing magmatic extension (Type IV). Variations in axial morphology (including eruption styles, neovolcanic eruption volumes, and faulting) reflect magma supply, which is locally enhanced by cross-arc volcanism associated with N-S compression along the 16.5°N and 17.0°N segments. In contrast, cross-arc seismicity is associated with N-S extension and increased faulting along the 14.5°N segment, with structures that are interpreted to be oceanic core complexes—the first with high-resolution bathymetry described in an active back-arc basin. Hydrothermal venting associated with recent magmatism has been discovered along all segment types