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BACKGROUND: Shifting enables flexible switch between tasks or mental sets. It is a component of the executive function that plays critical roles in human behaviour control. However, shifting ability in individuals with intellectual disability (ID) has not been well clarified because of the use of intellectually demanding tasks in previous studies. The present study invented a novel shifting task with minimal intellectual demands and aimed to clarify the characteristics of shifting in adolescents with ID. METHODS: Adolescents with ID (n = 21) and chronological-age-matched (n = 10) and mental-age-matched controls (n = 33) performed a novel shifting task with simple rule switching (i.e. change in direction). Analyses focused on the switch cost or the increase in the reaction time associated with rule switching. RESULTS: Two subtypes of adolescents with ID were found with respect to the switch cost: one that lacks it and another with an increased switch cost. The lack of a switch cost was unique to the subgroup adolescents with ID and was not indicated in the control group. CONCLUSIONS: The present study indicated that shifting in adolescents with ID does not depend solely on their intellectual function and is highly heterogeneous. This finding further implies that executive functions, including shifting, must be evaluated separately from their intellectual functions.
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Discapacidad Intelectual , Adolescente , Niño , Cognición , Función Ejecutiva , Humanos , Inteligencia , Tiempo de ReacciónRESUMEN
BACKGROUND: Mutations in GDAP1 are responsible for heterogeneous clinical and electrophysiological phenotypes of Charcot-Marie-Tooth disease (CMT), with autosomal dominant or recessive inheritance pattern. The aim of this study is to identify the clinical and mutational spectrum of CMT patients with GDAP1 variants in Japan. MATERIALS AND METHODS: From April 2007 to October 2014, using three state-of-art technologies, we conducted gene panel sequencing in a cohort of 1,030 patients with inherited peripheral neuropathies (IPNs), and 398 mutation-negative cases were further analyzed with whole-exome sequencing. RESULTS: We identified GDAP1 variants from 10 patients clinically diagnosed with CMT. The most frequent recessive variant in our cohort (5/10), c.740C>T (p.A247V), was verified to be associated with a founder event. We also detected three novel likely pathogenic variants: c.928C>T (p.R310W) and c.546delA (p.E183Kfs*23) in Case 2 and c.376G>A (p.E126K) in Case 8. Nerve conduction study or sural nerve biopsy of all 10 patients indicated axonal type peripheral neuropathy. CONCLUSION: We identified GDAP1 variants in approximately 1% of our cohort with IPNs, and established a founder mutation in half of these patients. Our study originally described the mutational spectrum and clinical features of GDAP1-related CMT patients in Japan.
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Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Mutación , Proteínas del Tejido Nervioso/genética , Fenotipo , Adolescente , Adulto , Alelos , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Efecto Fundador , Estudios de Asociación Genética , Genotipo , Haplotipos , Humanos , Japón , Masculino , Persona de Mediana Edad , Proteínas de la Mielina/genética , Linaje , Reproducibilidad de los Resultados , Secuenciación del Exoma , Adulto JovenRESUMEN
Ultrasmall-angle synchrotron X-ray scattering measurements showed that a three-dimensional polymer lattice of a few 100 nm order with body-centered cubic O(8-) symmetry was formed in a polymer-stabilized blue phase liquid crystal. We obtained clear experimental evidence that the polymer chains condensed selectively in the disclinations within the blue phase during photo-polymerization of monomers in the blue phase.
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BACKGROUND: Oestrogens usually stimulate the progression of oestrogen receptor (ER)-positive breast cancer. Paradoxically, high-dose oestrogens suppress the growth of these tumours in certain circumstances. METHODS: We prospectively examined the efficacy and safety of ethinylestradiol treatment (3 mg per day oral) in postmenopausal patients with advanced or recurrent ER-positive breast cancer who had previously received endocrine therapies, especially those with resistance to aromatase inhibitors. RESULTS: Eighteen patients were enrolled with the median age of 63 years and the mean observation time of 9.2 months. Three cases withdrew within 1 week due to oestrogen flare reactions with nausea, fatigue and muscle-skeletal pain. The response rate was 50% (9 out of 18), and the clinical benefit rate was 56% (10 out of 18). The stable disease (<6 months) was 17% (3 out of 18) and another 2 cases were judged as progressive disease. Time-to-treatment failure including 2 on treatment was a median of 5.6 months (range 0.1 to 14.5(+)). Although vaginal bleeding or endometrial thickening was observed in patients receiving long-term treatment, there were no severe adverse events, such as deep venous thrombosis or other malignancies. CONCLUSION: Although the mechanism of this treatment has not been fully understood, our data may contribute to change the common view of late-stage endocrine therapy.
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Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Estrógenos/uso terapéutico , Etinilestradiol/uso terapéutico , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/efectos adversos , Inhibidores de la Aromatasa/administración & dosificación , Neoplasias de la Mama/patología , Estrógenos/efectos adversos , Etinilestradiol/efectos adversos , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Metástasis de la Neoplasia , Proyectos Piloto , Posmenopausia , Estudios ProspectivosRESUMEN
Congenital loco in chicks is characterized by an apparent lack of control of the muscles of the neck. This disorder is inherited as a simple Mendelian recessive disease, caused by an autosomal recessive gene, lo. To date, there are no reports on the localization of this gene. The objective of this study was therefore to identify the genomic region of the lo locus. The experimental congenital loco population used here were selected from a Rhode Island Red (RIR) line and consisted of six generations, resulting in 124 chickens. A total of 113 DNA samples from offspring of four generations (G3, G4, G5, and G6) were used for genotyping. At first, genome-wide linkage mapping was performed using 122 microsatellite markers on 22 autosomal chromosomes, and the lo locus was mapped to chromosome 12. We then performed fine mapping in two steps on chromosome 12. First, the lo locus was mapped to the interval between GGA12_5 and GGA12_11 using 13 new polymorphic markers. In the second step, fine mapping was performed by adding new families and 11 additional new polymorphic markers. Linkage mapping and haplotype information enabled the localization of the lo locus to a 1.1-Mb region between GGA12_28 and GGA12_30. Genetic markers between GGA12_28 and GGA12_30 may be used to remove the carriers of congenital loco through this RIR line.
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Pollos , Sitios Genéticos/genética , Equilibrio Postural/genética , Enfermedades de las Aves de Corral/genética , Trastornos de la Sensación/veterinaria , Animales , Mapeo Cromosómico/veterinaria , Marcadores Genéticos/genética , Genotipo , Repeticiones de Microsatélite/genética , Trastornos de la Sensación/genéticaRESUMEN
The ornithine decarboxylase (ODC) gene is a candidate gene for growth and carcass traits. It is located on chicken chromosome 3 in a region where QTL for growth and carcass traits have previously been detected in the F2 population. The objectives of this study were to identify polymorphisms of the ODC gene in an F2 resource population and to examine the effects of these ODC polymorphisms on growth and carcass traits. The F2 resource population was obtained by crossing a Shamo male and White Plymouth Rock females. The F2 population was then measured for growth and carcass traits and used for positional candidate gene analysis. A total of 6 novel SNP and a novel indel mutation were identified in the parental population. Three SNP (g.-638A>G, g.-465C>T, and g.-353C>T) and a 4-bp indel mutation (g.-633_-632ins) in the promoter region of the ODC gene were identified in the parental population, and 2 haplotypes composed of these mutations were segregated in the parental population. A QTL analysis was performed, and the QTL for some growth and carcass traits were detected at a significant level and on a similar position to the ODC gene. Significant associations were found between haplotypes in the promoter region of the ODC gene and these traits in the F2 population, and the effect of haplotype on BW at 9 wk of age was the most significant. The haplotypes of the ODC gene found in this study might help in understanding the genetic structure of growth and carcass traits and in improving these traits directly by MAS. Therefore, further functional studies are necessary to evaluate the effects of promoter mutations at a molecular level.
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Ornitina Descarboxilasa/genética , Animales , Composición Corporal , Cruzamiento , Pollos , Cruzamientos Genéticos , Femenino , Genotipo , Análisis de los Mínimos Cuadrados , Masculino , Ornitina Descarboxilasa/metabolismo , Polimorfismo Genético , Sitios de Carácter CuantitativoRESUMEN
PURPOSE: Elastase, produced by Aspergillus fumigatus and A. flavus, is an important pathogenic factor in pulmonary aspergillosis. We investigated the possibility of using A. fumigatus-derived A. fumigatus elastase inhibitor (AFUEI) as a therapeutic agent. As native-AFUEI (N-AFUEI) has an extremely low yield, we generated a synthetic-AFUEI (S-AFUEI) and investigated whether S-AFUEI has a biological activity against A. fumigatus elastase (AFUE) and inhibits cytotoxicity. METHODOLOGY: A. fumigatus was cultured in Yeast Carbon Base (YCB) -elastin culture medium for 3-7 days, and AFUE was purified by chromatography using DE52 cellulose and Sephadex G-75 column. Elastolytic activity was examined using Glt-Ala-Ala-Pro-Leu-pNA (GAAPLNA) as the substrate. The hydrolytic activity of AFUE was determined using the characteristic substrates, fibrinogen and collagen (Type IV), and human cell cytotoxicity was measured colorimetrically. Furthermore, the inhibitory effect of S-AFUEI on these activities was examined. RESULTS: We confirmed that S-AFUEI demonstrated elastase inhibitory activity and heat stability equivalent to that demonstrated by N-AFUEI, and inhibited human collagen hydrolytic activity and human fibrinogen hydrolytic activity. Further, S-AFUEI inhibited cytotoxicity in AFUE human pulmonary artery endothelial cells (HPAEC), human small airway epithelial cells (HSAEC), and human pulmonary alveolar epithelial cells (HPAEpiC). CONCLUSION: As S-AFUEI strongly inhibited cytotoxicity induced by elastase in human-derived cells, it could prove beneficial for the treatment of pulmonary aspergillosis.
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Antifúngicos/síntesis química , Aspergillus fumigatus/química , Aspergillus fumigatus/enzimología , Elastasa Pancreática/antagonistas & inhibidores , Células Epiteliales Alveolares/efectos de los fármacos , Antifúngicos/farmacología , Colágeno/metabolismo , Medios de Cultivo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Fibrinógeno/metabolismo , Calor , Humanos , Hidrólisis , Arteria Pulmonar/citología , Aspergilosis Pulmonar/tratamiento farmacológico , Aspergilosis Pulmonar/microbiologíaRESUMEN
A major problem with allergen-specific immunotherapy involving repeated injection of allergens is the risk of an anaphylactic reaction. We engineered the major house dust mite allergen, Der f 2, to reduce its capacity to induce skin test reactivity and histamine release from peripheral blood basophils in allergic patients. The engineered allergen, in which the disulfide bond that linked the N- and C-terminal sequences of Der f 2 was disrupted, retained T-cell epitopes essential for immunotherapy and ability to stimulate T-cell proliferation. Such engineered allergens are potentially useful for safer and more effective immunotherapy for allergies.
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Alérgenos/genética , Antígenos/genética , Desensibilización Inmunológica , Ingeniería Genética , Glicoproteínas/genética , Ácaros/inmunología , Alérgenos/inmunología , Alérgenos/metabolismo , Animales , Antígenos/inmunología , Antígenos/metabolismo , Antígenos Dermatofagoides , Basófilos/efectos de los fármacos , Basófilos/inmunología , División Celular/efectos de los fármacos , Cisteína/genética , Cisteína/metabolismo , Disulfuros/química , Disulfuros/metabolismo , Epítopos de Linfocito T/inmunología , Glicoproteínas/inmunología , Glicoproteínas/metabolismo , Liberación de Histamina/efectos de los fármacos , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/terapia , Inmunoglobulina E/metabolismo , Mutagénesis Sitio-Dirigida , Pruebas CutáneasRESUMEN
The standard surgical procedure for patients with malignant pleural mesothelioma (MPM) is extrapleural pneumonectomy (EPP). However, high morbidity and mortality rates have been reported in patients who received EPP, whereas survival rates after EPP remain unsatisfactory. Thus, a carefully and precise preoperative assessment to select appropriate candidates for EPP is essential in patients with MPM, and we conducted a surgical staging with laparoscopy, mediastinoscopy and contralateral thoracoscopy for potentially resectable MPM patients. Among 5 consective patients who received the preoperative surgical staging during past 10 months, 1 patient was judged not to be a surgical candidate due to the presence of contralateral pleural metastasis. In conclusion, this surgical staging is a useful preoperative evaluation to prevent an unnecessary operation.
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Mesotelioma/cirugía , Neoplasias Pleurales/cirugía , Femenino , Humanos , Mesotelioma/diagnóstico , Persona de Mediana Edad , Neoplasias Pleurales/diagnóstico , Cuidados PreoperatoriosRESUMEN
The murine severe combined immune deficiency mutation (scid) is characterized by a lack of B- and T-lymphoid cells due to a defect in lymphoid V(D)J recombination. Moreover, defective rejoining of DNA double-strand breaks (dsb) in scid cells also results in a marked increase in sensitivity to ionizing radiation. Recently, the putative human homologue of the murine scid gene locus, HYRC1, was assigned to human chromosome 8q11, based on the radiation sensitivity of scid cells as compared to scid:human cell hybrids carrying portions of human chromosome 8. Given the precedent (e.g., ataxia-telangiectasia) for genes other than the affected one being able to complement radiation defects, we were interested in determining if the V(D)J recombination defect was also corrected by the HYRC1 locus. The V(D)J recombination analysis using extrachromosomal DNA substrates in control scid cells (SC3VA2) versus complemented cells (RD13B2) indicates that the radiation sensitivity-complemented cells (RD13B2) are also fully complemented for the V(D)J recombination reaction, whereas the control (uncomplemented) cells (SC3VA2) fail to carry out V(D)J recombination normally. Slightly over 60% of the radiation-induced dsb are rejoined even in scid cells, and this alternative pathway is temperature sensitive. Only the remaining 30-35% of dsb require the introduction of the HYRC1 locus, and this pathway is not temperature sensitive. This merely partial contribution of the scid factor to the repair process suggests the presence of another pathway of dsb repair. Our results indicate that the HYRC1 locus, assigned to human chromosome 8q11, encodes the scid factor, which is involved in all V(D)J recombination coding joint formation and in 30-35% of dsb repair by the temperature-resistant pathway.
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Cromosomas Humanos Par 8 , ADN Nucleotidiltransferasas/genética , Reparación del ADN , Animales , Linfocitos B/inmunología , Supervivencia Celular/efectos de la radiación , ADN Nucleotidiltransferasas/biosíntesis , Relación Dosis-Respuesta en la Radiación , Prueba de Complementación Genética , Humanos , Ratones , Ratones SCID/genética , Linfocitos T/inmunología , Transfección , VDJ RecombinasasRESUMEN
The Werner syndrome (WS) gene (WRN) was isolated by positional cloning, based on mapping to chromosome 8p12, and the WRN protein was recently shown to encode an active helicase. To examine functional complementation of WS phenotypes by expression of the WRN gene, we introduced a normal human chromosome 8 into a SV40-transformed WS fibroblastoid cell line (WS780) by microcell fusion and studied several cellular phenotypes associated previously with WS cell lines, including cell growth rate, 4-nitroquinoline-1-oxide (4NQO) sensitivity, and spontaneous mutation rate and type of mutation at the hypoxanthine-guanine phosphoribosyl transferase locus. The WRN gene was expressed in two of three microcell hybrids introduced with chromosome 8. We failed to observe a difference between normal and WS cell lines in terms of growth rates and spontaneous mutation rates. However, we found that the WS cell line was highly sensitive to 4NQO-induced cytotoxicity and showed an unusually high proportion of deletion mutations at the hypoxanthine-guanine phosphoribosyl transferase locus as compared to a control cell line, as shown previously. Here, we report that these phenotypes were not corrected by introduction of the WRN gene, although the WRN protein was expressed. Our results suggest that the hypersensitivity to 4NQO and the extensive deletion mutations observed in the WS cell line are caused by a defect that is secondary to the WRN gene mutation, possibly a repair gene defect that controls the phenotypes of hypersensitivity to carcinogen(s) and/or the extensive deletion mutations.
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Cromosomas Humanos Par 8/genética , ADN Helicasas/genética , Hipoxantina Fosforribosiltransferasa/genética , Síndrome de Werner/genética , 4-Nitroquinolina-1-Óxido/farmacología , Animales , Carcinógenos/farmacología , Fusión Celular , Línea Celular Transformada/efectos de los fármacos , Transformación Celular Viral , Cromosomas Humanos Par 9/genética , ADN Helicasas/metabolismo , Exodesoxirribonucleasas , Eliminación de Gen , Prueba de Complementación Genética/métodos , Humanos , Ratones , Repeticiones de Microsatélite/genética , Mutación , Fenotipo , Polimorfismo Genético , RecQ Helicasas , Virus 40 de los Simios , Síndrome de Werner/patología , Helicasa del Síndrome de WernerRESUMEN
A filament driven multi-cusp negative ion source has been developed for proton cyclotrons in medical applications. In Cs-free operation, continuous H(-) beam of 10 mA and D(-) beam of 3.3 mA were obtained stably at an arc-discharge power of 3 kW and 2.4 kW, respectively. In Cs-seeded operation, H(-) beam current reached 22 mA at a lower arc power of 2.6 kW with less co-extracted electron current. The optimum gas flow rate, which gives the highest H(-) current, was 15 sccm in the Cs-free operation, while it decreased to 4 sccm in the Cs-seeded operation. The relationship between H(-) production and the design/operating parameters has been also investigated by a numerical study with KEIO-MARC code, which gives a reasonable explanation to the experimental results of the H(-) current dependence on the arc power.
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Aniones , Cesio , Ciclotrones , DeuterioRESUMEN
INTRODUCTION: Mastectomy is the current standard surgical procedure for ipsilateral breast tumor recurrence (IBTR). However, there is little evidence about the prognostic impact of the surgical procedure (mastectomy versus repeat lumpectomy) for IBTR. PATIENTS AND METHODS: A total of 271 consecutive patients who had histologically confirmed IBTR without distant metastases and underwent definitive surgery for IBTR between 1989 and 2008 were included from eight institutions in Japan. The impact of the surgical procedure for IBTR on distant disease-free survival (DDFS) and overall survival (OS) was evaluated using and multivariable proportional hazards regression and propensity score matching methods. RESULTS: Of the 271 patients, 149 patients (55%) underwent repeat lumpectomy and 122 patients (45%) underwent mastectomy after IBTR. The median follow-up period from definitive surgery for IBTR was 55 months. There was no difference in terms of DDFS and OS between repeat lumpectomy and mastectomy after IBTR, adjusted for various clinical and tumor characteristics. In addition, for the matched patient cohort, no difference in DDFS and OS was seen between the 2 groups. CONCLUSION: In our study, both multivariate analysis and the propensity score matching method demonstrated that there was no difference in terms of DDFS and OS between repeat lumpectomy and mastectomy after IBTR. Further studies are warranted (UMIN-CTR number UMIN000008136).
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Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/cirugía , Mastectomía/métodos , Recurrencia Local de Neoplasia/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/mortalidad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Japón/epidemiología , Mastectomía Segmentaria/métodos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Puntaje de Propensión , Estudios Retrospectivos , Tasa de Supervivencia/tendenciasRESUMEN
Ion species ratio of high current positive hydrogen/deuterium ion beams extracted from an electron-cyclotron-resonance ion source for International Fusion Materials Irradiation Facility accelerator was measured by the Doppler shift Balmer-α line spectroscopy. The proton (H(+)) ratio at the middle of the low energy beam transport reached 80% at the hydrogen ion beam extraction of 100 keV/160 mA and the deuteron (D(+)) ratio reached 75% at the deuterium ion beam extraction of 100 keV/113 mA. It is found that the H(+) ratio measured by the spectroscopy gives lower than that derived from the phase-space diagram measured by an Allison scanner type emittance monitor. The H(+)/D(+) ratio estimated by the emittance monitor was more than 90% at those extraction currents.
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INTRODUCTION: Breast-conserving surgery is a standard treatment for early breast cancer. For ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery, salvage mastectomy is the current standard surgical procedure. However, it is not rare for patients with IBTR who have received salvage mastectomy to develop local recurrence. In this study, we examined the risk factors of local recurrence after salvage mastectomy for IBTR. PATIENTS AND METHODS: A total of 118 consecutive patients who had histologically confirmed IBTR without distant metastases and underwent salvage mastectomy without irradiation for IBTR between 1989 and 2008 were included from eight institutions in Japan. The risk factors of local recurrence were assessed. RESULTS: The median follow-up period from salvage mastectomy for IBTR was 4.6 years. Patients with pN2 or higher on diagnosis of the primary tumor showed significantly poorer local recurrence-free survival than those with pN0 or pN1 at primary tumor (p < 0.001). Multivariate analysis showed that the lymph node status of the primary tumor was a significantly independent predictive factor of local recurrence-free survival (p = 0.02). CONCLUSION: The lymph node status of the primary tumor might be a predictive factor of local recurrence-free survival after salvage mastectomy for IBTR. Further research and validation studies are needed. (UMIN-CTR number UMIN000008136).
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Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/cirugía , Ganglios Linfáticos/patología , Mastectomía Radical Modificada , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/cirugía , Terapia Recuperativa , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante , Femenino , Estudios de Seguimiento , Humanos , Japón/epidemiología , Metástasis Linfática , Mastectomía Segmentaria , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/diagnóstico , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Radioterapia Adyuvante , Factores de RiesgoRESUMEN
The objective of linear IFMIF prototype accelerator is to demonstrate 125 mA/CW deuterium ion beam acceleration up to 9 MeV. The injector has been developed in CEA Saclay and already demonstrated 140 mA/100 keV deuterium beam [R. Gobin et al., Rev. Sci. Instrum. 85, 02A918 (2014)]. The injector was disassembled and delivered to the International Fusion Energy Research Center in Rokkasho, Japan. After reassembling the injector, commissioning has started in 2014. Up to now, 100 keV/120 mA/CW hydrogen and 100 keV/90 mA/CW deuterium ion beams have been produced stably from a 10 mm diameter extraction aperture with a low beam emittance of 0.21 π mm mrad (rms, normalized). Neutron production by D-D reaction up to 2.4 × 10(9) n/s has been observed in the deuterium operation.
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The direct transfer of membrane proteins from human platelets to the liposomal fraction was examined, particularly in relation to platelet activation during the process. The incorporation of an artificial boundary lipid, 1,2-dimyristoylamido-1,2-deoxyphosphatidylcholine (DDPC), in the interacting liposome considerably enhanced the efficiency of the protein transfer. The transfer proceeded with neither significant activation nor lysis of the platelet, and the activation of the platelet with thrombin did not affect the amount of the transferred proteins. A wide range of platelet membrane proteins was transferred, and they were almost comparable to those in a sample prepared by glycerol lysis/centrifugation. In addition, they included the major surface glycoproteins GPIIb and GPIIIa without noticeable contamination of soluble cytosol proteins. The protein transfer method is a one-pot process and clearly more convenient than the conventional 'extract and reconstitute' approach. These results strongly support the use of the transfer process, especially with DDPC, as an alternative to the conventional detergent-solubilization or the solvent-extraction methods for preparation of samples of platelet membrane proteins.