El Liber de educatione de Alonso Ortiz: un estudio sobre el diálogo para la educación del príncipe en el contexto del humanismo castellano del siglo XV

[ES]En este trabajo de investigación, pretendemos realizar un análisis y estudio de la teoría de la educación de Alonso Ortiz (¿?-1507) expuesta en el Liber de educatione Iohannis serenissimi principis et primogeniti regum potentissimorum Castellae Aragoni et Siciliae, Fernandi et Helisabet inclyta prosapia coniugum clarissimorum (Liber de educatione, en adelante) traducido por Giovannni Maria Bertini al castellano. Intentamos delinear la figura del autor, considerándole como uno de los hombres que formaban parte del ámbito cultural-intelectual de la época, que siempre ha sido y es una época discutible en relación con el Renacimiento español. Tratamos de esclarecer sus ideas antropológicas y pedagógicas que constituyen su teoría de la educación para el joven príncipe y resaltar sus características en relación a dos coordenadas: el contexto del género literario espejos de príncipes y el desarrollo del humanismo castellano. El trabajo está dividido en tres partes. La primera parte tiene la función de dar una introducción al contexto cultural de la Castilla del siglo XV en el que nos fijamos en dos cuestiones: una se trata de la polémica en torno a la génesis del humanismo en Castilla, especialmente una discusión desarrollada entre los investigadores especialistas del campo acerca del año 1480, y la otra es la cuestión de la diversidad de los movimientos del humanismo que se manifestó en el caso de Castilla. De este modo, fijamos nuestra comprensión del término humanismo desde la cual parte nuestro análisis del pensamiento humanista en este trabajo. En la segunda parte, presentamos algunas características generales del humanismo como pensamiento, centrándonos en dos factores clave para nuestro trabajo: Hombre y Educación. Luego, mediante un estudio del tratado de Pier Paolo Vergerio vemos cómo se aplicaron esas ideas características a la hora de construir una teoría de educación para jóvenes. A continuación, observamos el caso de Castilla: exponemos la proliferación de producción en el género literario espejos de príncipes en relación con el humanismo. Con la ubicación en estas coordenadas, investigamos dos obras escritas antes de la de Ortiz: El Vergel de los príncipes (1456 o 1457) de Rodrigo Sánchez de Arévalo y el Doctrinal de príncipes (1476 o 1477) de Diego de Valera, con la idea de realizar una observación comparativa con la obra de Ortiz. En la tercera y última parte, nos ocupamos de nuestro objeto de investigación: el Liber de educatione y su autor Alonso Ortiz. Sintetizamos los datos biográficos para dar un perfil a la figura borrosa del autor. Y después, con el apoyo del texto castellano traducido por Bertini, Diálogo sobre la educación del Príncipe Don Juan, Hijo de los Reyes Católicos Diálogo (en adelante, Diálogo), estudiamos su diálogo sobre la educación del príncipe en los siguientes pasos: 1) describimos la visión conjunta del tratado exponiendo el itinerario del diálogo; 2) analizamos la teoría del hombre de Ortiz, que es una base teórica sobre la cual se despliegan los argumentos acerca de la educación del príncipe; 3) estudiamos el tema principal del tratado, que es la educación del príncipe don Juan, deteniéndonos en los siguientes puntos: el momento más oportuno para iniciar la primera educación del niño; el contenido de la educación que se trata principalmente de los temas sobre lectura, el cuidado del cuerpo y del alma; las circunstancias ideales en que debe ser educado el niño, fijando la atención en las personas que rodean al educando. Finalmente concluimos este trabajo de investigación explicitando las características del Diálogo de Ortiz desde el punto de vista de la educación para los príncipes y a la luz del humanismo

Genetic deficiency of carnitine/organic cation transporter 2 (slc22a5) is associated with altered tissue distribution of its substrate pyrilamine in mice

金沢大学医薬保健研究域薬学系Carnitine/organic cation transporter 2 (OCTN2) recognizes various cationic compounds as substrates in vitro, but information on its pharmacokinetic role in vivo is quite limited. This paper demonstrates altered tissue distribution of the OCTN2 substrate pyrilamine in juvenile visceral steatosis (jvs) mice, which have a hereditary defect of the octn2 gene. At 30 min after intravenous injection of pyrilamine, the tissue-to-plasma concentration ratio (K p) in the heart and pancreas was higher, whereas the Kp in kidney and testis was lower in jvs mice compared with wild-type mice. Pyrilamine transport studies in isolated heart slices confirmed higher accumulation, together with lower efflux, of pyrilamine in the heart of jvs mice. The higher accumulation in heart slices of jvs mice was abolished by lowering the temperature, by increasing the substrate concentration, and in the presence of other H1 antagonists or another OCTN2 substrate, carnitine, suggesting that OCTN2 extrudes pyrilamine from heart tissue. On the other hand, the lower distribution to the kidney of jvs mice was probably due to down-regulation of a basolateral transporter coupled with OCTN2, because, in jvs mice, (i) the Kp of pyrilamine in kidney assessed immediately after intravenous injection (∼1 min) was also lower, (ii) the urinary excretion of pyrilamine was lower, and (iii) the uptake of pyrilamine in kidney slices was lower. The renal uptake of pyrilamine was saturable (K m∼236 μM) and was strongly inhibited by cyproheptadine, astemizole, ebastine and terfenadine. The present study thus indicates that genetic deficiency of octn2 alters pyrilamine disposition tissue-dependently. Copyright © 2009 John Wiley & Sons, Ltd

Involvement of Multidrug Resistance-Associated Protein 1 in Intestinal Toxicity of Methotrexate

金沢大学医薬保健研究域薬学系Purpose: Methotrexate (MTX) causes dose-limiting gastrointestinal toxicity due to exposure of intestinal tissues, and is a substrate of the multidrug resistance-associated protein (MRP) 1. Here we examine the involvement of MRP1, which is reported to be highly expressed in the proliferative crypt compartment of the small intestine, in the gastrointestinal toxicity of MTX. Methods: MTX was intraperitonealy administered to mrp1 gene knockout (mrp1(-/-)) and wild-type (mrp1(+/+)) mice. Body weight, food and water intake were monitored, intestinal histological studies and pharmacokinetics of MTX were examined. Results: mrp1(-/-) mice more severely decreased body weight, food and water intake than mrp1(+/+) mice. Almost complete loss of villi throughout the small intestine in mrp1(-/-) mice was observed, whereas the damage was only partial in mrp1(+/+) mice. Plasma concentration and biliary excretion profiles of MTX were similar in mrp1(-/-) and mrp1(+/+) mice, though accumulation of MTX in immature proliferative cells isolated from mrp1(-/-) mice was much higher compared to mrp1(+/+) mice. Immunostaining revealed localization of Mrp1 in plasma membrane of the intestinal crypt compartment in mrp1(+/+) mice, but not in mrp1(-/-) mice. Conclusion: Mrp1 determines the exposure of proliferative cells in the small intestine to MTX, followed by gastrointestinal toxicity. © 2009 Springer Science+Business Media, LLC

Bacterial adaptation to high pressure: a respiratory system in the deep-sea bacterium Shewanella violacea DSS12

Abstract Shewanella violacea DSS12 is a psychrophilic facultative piezophile isolated from the deep sea. In a previous study, we have shown that the bacterium adapted its respiratory components to alteration in growth pressure. This appears to be one of the bacterial adaptation mechanisms to high pressures. In this study, we measured the respiratory activities of S. violacea grown under various pressures. There was no significant difference between the cells grown under atmospheric pressure and a high pressure of 50 MPa relative to oxygen consumption of the cell-free extracts and inhibition patterns in the presence of KCN and antimycin A. Antimycin A did not inhibit the activity completely regardless of growth pressure, suggesting that there were complex III-containing and -eliminating pathways operating in parallel. On the other hand, there was a difference in the terminal oxidase activities. Our results showed that an inhibitor-and pressure-resistant terminal oxidase was expressed in the cells grown under high pressure. This property should contribute to the high-pressure adaptation mechanisms of S. violacea

[Research Material] How to Use the Legal Online Data Base LEXIS

In the class of "legal information processing", students are studying how to use LEXIS (Legal text Retrieval System) and Prolog-programming. LEXIS is a legal online data base in the United States of America. This data base is serviceable to lawyers in the world, and serves several purposes for legal information processing. As there is not a manual for the new version of the access software, we have inconvenience in teaching LEXIS. So, we planned to make a manual on using LEXIS for students, graduate students, and teachers of related subjects in order for them to master how to handle it We shall be happy to be of any service to them for the understanding of LEXIS

Decreased responsiveness of naturally occurring mutants of human estrogen receptor α to estrogens and antiestrogens

金沢大学大学院医学系研究科機能分子医薬学Estrogen receptor α (ERα) is a ligand-inducible transcription factor that mediates the biological effects of estrogens and antiestrogens. Many point mutations in the human ERα gene have been reported to be associated with breast cancer, endometrial cancer, and psychiatric diseases. However, functional analyses for most mutants with amino acid changes are still lacking. In the present study, to investigate the effects of point mutations on the function, gel-shift assays and luciferase assays were performed for eight kinds of mutated ERα proteins, including a single nucleotide change of C207G (N69K), G478T (G160C), T887C (L296P), A908G (K303R), C926T (S309F), A1058T (E353V), A1186G (M396V), and G1231deletion (411fsX7). The mutated ERα expression plasmids were constructed by site-directed mutagenesis. With gel-shift assays using in vitro translated ERα proteins, binding to the consensus estrogen response element (ERE) was observed for the mutated ERα proteins except ERα (G160C) and ERα (411fsX7), the binding of which was comparable with that of the wild type. Western blot analyses showed that ERα (G160C) could not be efficiently translated with the in vitro transcription/translation system and that ERα (411fsX7) produced a truncated protein. To investigate the transactivation potency, wild-type or mutated ERα expression plasmids were co-transfected with pGL3-3EREc38 reporter plasmid into human breast adenocarcinoma MDA-MB-435 cells. The concentration-response curves (10 pM-100 nM E2) of the mutant ERα proteins except ERα (E353V) and ERα (411fsX7) were similar to that of wild-type ERα. However, at a low level of E2 (100 pM), the mutants ERα (N69K), ERα (L296P), ERα (S309F), and ERα (M396V) showed a significant decrease of transactivation compared with that of the wild-type ERα. The mutants ERα (E353V) and ERα (411fsX7) did not show responsiveness to E2 and antiestrogens, 4-hydroxytamoxifen (4OHT) and ICI 182,780. The mutant ERα (S309F) showed decreased responsiveness for the antiestrogenicity of 4OHT. In conclusion, we found that some of the naturally occurring human ERα mutants with amino acid changes may have an altered responsiveness to estrogen and antiestrogens. © 2006 Elsevier Ltd. All rights reserved

Effect of Salivation by Facial Somatosensory Stimuli of Facial Massage and Vibrotactile Apparatus

We studied the effects of salivary promotion of fluid secretion after hand massage, and the apparatus of vibrotactile stimulation (89 Hz frequency, 15 min) in normal humans. Personal massage cannot be performed on handicap and stroke patients, and then giving hand massage to them for 5 min massage gives a tired feeling. So, we focused 3 min stranger massage. Salivary glands can discharge the accumulated saliva by extrusion from the acinus glands’ massages as described in the recent Japanese textbook. We think that this method may not produce realistic recovery. Our aim ideas are to relieve stress and increase temperature with lightly touch massage of the skin and for a 1 cycle of 1 s. We recorded RR interval of ECG, total salivation, facial skin temperature, OxyHb of fNIRS on the frontal cortex, and amylase activity for the autonomic changes. In increased 2°C of the facial skin temperature, the hand massage had a need for 3 min and the vibrotactile stimulation for 15 min. Increase from 700 to 1000 ms of RR intervals had a need for 3 min in the hand massage and had 15 min in the vibrotactile stimulation. Although vibrotactile stimulation needs long time of 4–7 years as effective recovery, hand massage may have more effect with a repetition of day after day

Generation of hypoimmunogenic induced pluripotent stem cells by CRISPR-Cas9 system and detailed evaluation for clinical application

In order to expand the promise of regenerative medicine using allogeneic induced pluripotent stem cells (iPSCs), precise and efficient genome editing of human leukocyte antigen (HLA) genes would be advantageous to minimize the immune rejection caused by mismatches of HLA type. However, clinical-grade genome editing of multiple HLA genes in human iPSC lines remains unexplored. Here, we optimized the protocol for good manufacturing practice (GMP)-compatible CRISPR-Cas9 genome editing to deplete the three gene locus (HLA-A, HLA-B, and CIITA genes) simultaneously in HLA homozygous iPSCs. The use of HLA homozygous iPSCs has one main advantage over heterozygous iPSCs for inducing biallelic knockout by a single gRNA. RNA-seq and flow cytometry analyses confirmed the successful depletion of HLAs, and lineage-specific differentiation into cardiomyocytes was verified. We also confirmed that the pluripotency of genome-edited iPSCs was successfully maintained by the three germ layers of differentiation. Moreover, whole-genome sequencing, karyotyping, and optical genome mapping analyses revealed no evident genomic abnormalities detected in some clones, whereas unexpected copy number losses, chromosomal translocations, and complex genomic rearrangements were observed in other clones. Our results indicate the importance of multidimensional analyses to ensure the safety and quality of the genome-edited cells. The manufacturing and assessment pipelines presented here will be the basis for clinical-grade genome editing of iPSCs

An fMRI Study of an Abnormal Neurovascular Response in the Right Premotor Cortex during Inner Speech and the Relationship to Auditory Hallucinations in Patients with Schizophrenia

There is evidence for sensory and cognitive impairments at multiple levels in schizophrenia, which may be related to the clinical symptoms of the condition. Inner speech involves both auditory and language systems and dysfunction of inner speech and may be associated with auditory hallucinations in schizophrenia. We used functional magnetic resonance imaging to examine this association by measuring brain activation in 23 patients with schizophrenia and 23 healthy control individuals. The participants performed an auditory verbal working memory task that required inner speech in the form of subvocal rehearsal. The control participants showed prominent activation in the inferior frontal cortex (IFC), premotor cortex (PMC), superior temporal cortex (STC), and lateral parietal cortex (LPC) bilaterally, throughout the task. In contrast, patients with schizophrenia showed significant activation in STC bilaterally during encoding phase and in the IFC, PMC, STC, and LPC bilaterally during the recognition phase. A comparison between groups showed that controls had greater activation during rehearsal in the IFC, LPC, and PMC bilaterally than patients with schizophrenia. In the region-of-interest analysis, we observed a significant negative correlation between right PMC activation and Auditory Hallucination Rating Scale scores as well as the hallucination item in the Positive and Negative Syndrome Scale. These observations indicate that inner speech is impaired in schizophrenia and that the severity of auditory hallucinations is associated with abnormal activation in the right PMC during inner speech

Staphylococcus aureus requires cardiolipin for survival under conditions of high salinity

BackgroundThe ability of staphylococci to grow in a wide range of salt concentrations is well documented. In this study, we aimed to clarify the role of cardiolipin (CL) in the adaptation of Staphylococcus aureus to high salinity.ResultsUsing an improved extraction method, the analysis of phospholipid composition suggested that CL levels increased slightly toward stationary phase, but that this was not induced by high salinity. Deletion of the two CL synthase genes, SA1155 (cls1) and SA1891 (cls2), abolished CL synthesis. The cls2 gene encoded the dominant CL synthase. In a cls2 deletion mutant, Cls1 functioned under stress conditions, including high salinity. Using these mutants, CL was shown to be unnecessary for growth in either basal or high-salt conditions, but it was critical for prolonged survival in high-salt conditions and for generation of the L-form.ConclusionsCL is not essential for S. aureus growth under conditions of high salinity, but is necessary for survival under prolonged high-salt stress and for the generation of L-form variants