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本研究は、ダイバーシティをキーワードとして開発された単元の円滑な実践や目標達成の可否を探ることを目的としている。まず、この単元の主要部分を大学の教職課程科目である「総合的な学習の時間の指導法」に組み込み、受講生の学修活動の観察と受講後のアンケート調査を行った。その結果、「ルール作り」を自分事として取り組むなど積極的な受講生の活動が観察された。アンケート調査では、ダイバーシティへの対応能力育成のためには、「ルール作り」の学修が適切であること、また、その学修が楽しかったとの認識を多くの受講生が持っていることが明らかになった。これらの結果から、「ルール作り」の単元は、将来社会で必要とする資質・能力の育成を目指す総合的な学習の時間での実践に適切であると判断した。また、受講生の反応から大学での「ルール作り」の実践は、法の理解やマイノリティへの配慮など、これからの教員が獲得すべき資質・能力に気付く機会にもなると考えた。, The purpose of this research is to determine the practicability and the attainability of the learning purpose in the new course unit. The main content of the new unit was incorporated into the“Teaching methods of Integrated Study”which is one of the classes in a teacher-training course. Then, we conducted classroom observation and executed pre and post-surveys about the activities in the class. As a result of classroom observation, students are actively involved in rule making activities. Survey results showed that most of the students believed that the ability of rulemaking is important to deal with a diverse society and that the learning process of rulemaking is enjoyable.The new unit of Integrated Study on the basis of rulemaking is appropriate to foster qualities and abilities which will be needed in future society. Furthermore, the practice of rulemaking gives students a chance and ideas to understand Law and minority people which will be necessary for the future teacher.

２０１７年に改訂された学習指導要領においては、総合的な学習の時間の目標として、自己の生き方を考えていくための資質・能力を育成することを目指すことが明示され、その資質・能力の一つとして、実社会や実生活の中から問いを見出し、自分で課題を立て、情報を集め、整理・分析して、まとめ・表現することができるようにすることが掲げられた１）。この資質・能力の文言は、２０１６年の中央教育審議会答申の中で用いられており２）、そのねらいを実現する場として総合的な学習の時間が位置づけられた形になっている。ただ、総合的な学習の時間のテーマや学習内容を具体的に示してきた例示では、国際理解、情報、環境など従来通りの表記がなされており、その資質・能力育成のための学習の姿が示されていない。そこで本研究では、現在の子どもたちが活躍する将来社会のキーワードを、ダイバーシティと捉え、その資質・能力を育成するための総合的な学習の時間の例示となるテーマや学習内容の開発を追究することにした。ダイバーシティが進む社会の中で、人々が平和で安全に暮らしていくためには、現在以上に個の尊厳が社会の基盤にならなければならない。この考えに従い、個の尊厳が基点となっている法の基本理念に沿った「ルール作り」をテーマとする単元の開発を行った。, A learning goal of Integrated Study was set to foster qualities and abilities in order to consider a way of life in a revision of the Courses of Study in ２０１７. Qualities and abilities mentioned were to put forward questions, to find one’s challenge, to gather and organize information, and to express one’s ideas in real society and actual life. These qualities and abilities were also presented in the recommendation report issued by the Central Council for Education in ２０１６. Therefore, this recommendation by the Central Council for Education was implemented into Integrated Study in a revision of the Courses of Study in ２０１７. However, the revised Courses of Study in ２０１７ illustrated only traditional learning content of Integrated Study such as global understanding, information and environment, and it did not give any concrete ideas to foster the targeted qualities and abilities.We consider real society and actual life in the present as diversity and develop learning contents of new Integrated Learning to foster the qualities and abilities to live there. Furthermore, it is more important than ever to live together with diverse populations to respect each individual safely and peacefully. Therefore, we focused on rulemaking as the content of Integrated Learning.

The aim of this study was to investigate the relationship between the swallowing/physical/cognitive function on admission and the feeding status on discharge for dysphagia patients in the convalescent rehabilitation ward. The subjects were 163 hospitalized for cerebrovascular disease in our convalescent rehabilitation ward from June 2017 to May 2018. For these patients, we investigated background factors, cognitive functions, swallowing functions, daily living activities (ADL), etc. at admission. Two groups were compared: one that was orally available at the time of discharge and one that was tube fed. There were 128 oral intake groups at discharge and 35 non-oral intake groups at discharge. In the oral intake group, the number of days until hospitalization was longer, and the consciousness disorder remained (JCS II digit or more) more than the parenteral intake group. The parenteral group had lower nutritional status than the oral group, and fewer VE and VF were performed. SIAS showed significant differences between the two groups in visuospatial recognition, grip strength, and quadriceps strength on the healthy side. As a result of logistic regression analysis using these factors, JCS (p < 0.05, OR 6.06, 95%CI 1.39–26.4), presence/absence of VE/VF (p < 0.05, OR 0.21, 95%CI 0.05–0.88), and MNA-SF (p < 0.05, OR 1.30, 95%CI 1.02–1.71) were extracted as significant predictors of oral intake. In the convalescent rehabilitation ward, it seems possible to infer whether or not oral intake is possible at the time of discharge by performing appropriate evaluation at the time of admission for patients with dysphagia.

Splanchnic blood flow changes dramatically after meal ingestion. The present study evaluated physiologic interactions between meal ingestion and hemodynamics with respect to renal blood flow on duplex sonography, assessing the possible influence on Doppler parameters used as diagnostic criteria for renal artery stenosis. Subjects comprised 26 healthy young men (mean age: 22 ± 2 y). Sonographic measurements were made shortly after breakfast and every 1 h thereafter and were compared with values measured before the meal. Peak systolic velocity in the renal artery was elevated post-prandially, peaking at 1 h (90 ± 12 cm/s), compared with pre-prandially (73 ± 10 cm/s, p < 0.01). Similarly, acceleration time at the intra-renal segmental artery shortened to a minimum at 1 h (45 ± 5 ms) compared with baseline (51 ± 6 ms, p < 0.01). The present study indicates that renal blood flow is altered for a few hours after meal ingestion. Attention should be paid to the interpretation of data measured after meals on duplex sonography for diagnosis of renal artery stenosis.

PURPOSE To evaluate the distribution and progression of glaucomatous visual field (VF) defects with binocular vision. PATIENTS AND METHODS Subjects were 167 patients (average age, 67±10.7 y) with glaucoma who received the Humphrey 24-2 VF test (SITA-Standard) for the 2 eyes. Using the Best Location Algorithm, patient's binocular integrated VF (IVF) was calculated from their Humphrey 24-2 results. Of 167, 77 subjects (average age, 68±11.0 y) also underwent monocular/binocular Humphrey Esterman tests. Patient's stage of glaucomatous VF loss was classified by the Esterman Disability Score for each test, and the distribution and progression of the defects with binocular vision was evaluated for each stage. The frequencies of the defects in the upper and lower halves of the VF were also investigated. RESULTS With the IVF, the glaucomatous VF defects were most frequently found around the Mariotte blind spots and the Bjerrum areas and extended to the periphery. With the binocular Humphrey Esterman VF, the defects were most frequently found around the bitemporal and Bjerrum areas. The IVF results showed 31%, 49%, and 20% of the patients with the earliest glaucoma having defects in the upper, lower, and both halves of the VF, respectively. CONCLUSIONS Glaucomatous VF defects with binocular vision were frequently found at the Mariotte blind spots in the central VF and around the bitemporal areas in the periphery. They appeared to have distributions and progression different from those of the defects with monocular vision previously reported.

The purpose of this study is to evaluate the suitable visual field (VF) test conditions (target size, test type, and eccentricity) for the macular region, we investigated the correlations between the ganglion cell layer (GCL) thickness and 6 VF test results.We tested 32 eyes of patients (61.1±9.2 y) with preperimetric (6), early-stage (16), and moderate-stage (10) glaucoma. The VF tests included 3 SAP (the 10-2 HFA using SITA with target size III [HFA SITA (III)], full threshold with size III [HFA FULL (III)] and size I [HFA FULL (I)]) and 3 visual function-specific perimetry tests (the 10-2 SWAP, 10-2 flicker, and 10-2 Humphrey Matrix). The GCL and inner plexiform layer (GCL+IPL) thickness was measured by Spectral Domain Optical Coherence Tomography (SD-OCT) with a macular 7×7 mm cube scan (3D OCT-2000, Topcon). The coefficient of determination (r) for the correlation between visual sensitivity and the GCL+IPL thickness was calculated for each test at eccentricities 0 to 5 degrees, 5 to 7 degrees, and 7 to 10 degrees using linear and quadratic regressions.All 6 tests showed the strongest correlation with the GCL+IPL thickness at 5 to 7 degrees. The respective r (linear) and R (quadratic) for HFA SITA (III), HFA FULL (III), HFA FULL (I), SWAP, Flicker, and Matrix were (0.40, 0.50), (0.43, 0.53), (0.44, 0.46), (0.51, 0.51), (0.33, 0.34), and (0.52, 0.52).As compared with the frequently-used SAP with a size III, SAP with size I and the function-specific perimetry tests (especially the Matrix) could be more suitable for testing the macular region.

Identifying the target molecules of antimicrobial agents is essential for assessing their mode of action. Here, we propose Acquired Resistance induced by Gene Overexpression (ARGO) as a novel in vivo approach for exploring target proteins of antimicrobial agents. The principle of the method is based on the fact that overexpression of the expected target protein leads to reduced sensitivity to the antimicrobial agent. We applied this approach to identify target proteins of the antimicrobial peptide apidaecin, which is specifically effective against Gram-negative bacteria. To this end, a set of overexpression Escherichia coli clones was tested, and peptide chain release factor 1, which directs the termination of translation, was found as a candidate, suggesting that apidaecin inhibits the termination step of translation. This finding was confirmed in vivo and in vitro by evaluating the inhibitory activity of apidaecin towards lacZ reporter gene expression, which is tightly dependent on its stop codon. The results of this study demonstrate that apidaecin exerts its antimicrobial effects partly by inhibiting release factors.

AimsTo clarify the anatomical relation between the optic disc and temporal raphe and to examine how these are related to test points in the 10-2 visual field test pattern.Subjects and methodsFor 22 eyes of volunteers with normal vision (+0.75 D spherical equivalent 7.88 D), a volume scan was used to obtain en-face images from a plane fitted to the inner limiting membrane using optical coherence tomography (OCT). The clearest en-face retinal nerve fibre (RNF) image was chosen for each subject and superimposed on fundus photographs using blood vessels for alignment. Individual landmarks (disc, fovea and visual field blind spot) were then used to superimpose the Humphrey Field Analyzer 10-2 visual field on the OCT image to compare with the RNF image.ResultsThe average disc–fovea–raphe angle was 169.4°±3.2°. Both the disc and temporal raphe were located above the horizontal midline (ie, were inferior in visual field space). For the 10-2 test pattern superimposed on the OCT image, in 54.5% of eyes, the temporal inferior test points adjacent to the horizontal midline mapped to the anatomical inferior hemifield. In 22.7% of eyes, nasal inferior test points adjacent to the horizontal midline mapped to the anatomical inferior hemifield. This mapping is opposite to typically assumed.ConclusionThe position of the disc and raphe affects the mapping between structure and function with respect to superior and inferior hemifields. Individual differences in the position of the temporal raphe should be considered when mapping between structure and function for the 10-2 test pattern.

We demonstrate a 4.8-μVrms noise microelectrode array (MEA) based on the complementary-metal-oxide-semiconductor active-pixel-sensors readout technique with disaggregated differential amplifier implementation. The circuit elements of the differential amplifier are divided into a readout pixel, a reference pixel, and a column circuit. This disaggregation contributes to the small area of the readout pixel, which is less than 81 μm2. We observed neuron signals around 100 μV with 432 electrodes in a fabricated prototype chip. The implementation has technological feasibility of up to 12-μm-pitch electrode density and 6,912 readout channels for high-spatial resolution mapping of neuron network activity.

To extrapolate the optimal test point resolution for assessment of glaucomatous visual field (VF) defects including subtle functional defects, we performed high-resolution perimetry with the 0.5 degrees test point resolution.Subjects were 11 eyes of 11 normal volunteers and 16 eyes of 16 glaucomatous patients. Octopus 900 custom test was used to measure 61 points with the test point resolution of 0.5 degrees on the temporal meridian of 45 degrees within the eccentricity of 30 degrees. In the glaucoma cases, VF profiles were extracted in 17 patterns of the test point resolutions that ranged from 0.5 to 8.5 degrees and the mean defect (MD), square root of loss variance (sLV), and maximum sensitivity loss (Max loss) were calculated. The influence of the test point resolution on MD, sLV, and Max loss was examined. In addition, the test range from the fixation point to the eccentricity of 30 degrees was divided into 3 zones. Similarly, each zone was investigated if the test point resolution exerted influence on the MD, sLV, and Max loss.Our glaucoma cases did not show any significant differences in MD and sLV regardless of the resolution. Max loss showed significant difference at resolution ≥1.0 degree. MD and sLV did not show significant differences by the change of resolution in each zone. Max loss showed significant differences at resolution ≥1.5 degrees within the central 10 degrees.To detect subtle VF defects within the eccentricity of 10 degrees, high-resolution perimetry with the test point resolution of1.5 degrees is necessary.

We demonstrate a 4.8-μVrms noise microelectrode array (MEA) based on the complementary-metal-oxide-semiconductor active-pixel-sensors readout technique with disaggregated differential amplifier implementation. The circuit elements of the differential amplifier are divided into a readout pixel, a reference pixel, and a column circuit. This disaggregation contributes to the small area of the readout pixel, which is less than 81 μm2. We observed neuron signals around 100 μV with 432 electrodes in a fabricated prototype chip. The implementation has technological feasibility of up to 12-μm-pitch electrode density and 6,912 readout channels for high-spatial resolution mapping of neuron network activity.

Background/aimsCar accidents caused by drivers unaware of their visual field (VF) defects under binocular vision have become an issue. We developed a simple self-check chart (CLOCK CHART binocular edition (CCBE)) to help patients with glaucoma recognise their abnormalities in the binocular VF and evaluated its usefulness.MethodsThe chart has four targets displayed at 10°, 15°, 20° and 25° eccentricities. The examinee gradually rotates the chart 360° clockwise. At every 30°, the examinee confirms the fixation and indicates if all four targets can be seen. This study enrolled 88 eyes of 44 patients with glaucoma (mean age, 64.4±13.1 years) and 64 eyes of 32 visually normal individuals (mean age, 32.0±8.4 years). Except the CCBE test, static VF testing using the Humphrey field analyser (HFA) Swedish Interactive Threshold Algorithm-Standard 30-2 and binocular Esterman programmes was also performed for the subjects with glaucoma.ResultsVF abnormality was defined as two or more contiguous points with a sensitivity of ConclusionThe CCBE test enables drivers with glaucoma to notice their VF abnormalities under binocular condition. The application of this simple self-check method appears promising for occasions such as driver licensing.

A 24-μm-pitch microelectrode array (MEA) with 6912 readout channels at 12 kHz and 23.2-μVrms random noise is presented. The aim is to reduce noise in a “highly scalable” MEA with a complementary metal-oxide-semiconductor integration circuit (CMOS-MEA), in which a large number of readout channels and a high electrode density can be expected. Despite the small dimension and the simplicity of the in-pixel circuit for the high electrode-density and the relatively large number of readout channels of the prototype CMOS-MEA chip developed in this work, the noise within the chip is successfully reduced to less than half that reported in a previous work, for a device with similar in-pixel circuit simplicity and a large number of readout channels. Further, the action potential was clearly observed on cardiomyocytes using the CMOS-MEA. These results indicate the high-scalability of the CMOS-MEA. The highly scalable CMOS-MEA provides high-spatial-resolution mapping of cell action potentials, and the mapping can aid understanding of complex activities in cells, including neuron network activities.A 24-μm-pitch microelectrode array (MEA) with 6912 readout channels at 12 kHz and 23.2-μVrms random noise is presented. The aim is to reduce noise in a “highly scalable” MEA with a complementary metal-oxide-semiconductor integration circuit (CMOS-MEA), in which a large number of readout channels and a high electrode density can be expected. Despite the small dimension and the simplicity of the in-pixel circuit for the high electrode-density and the relatively large number of readout channels of the prototype CMOS-MEA chip developed in this work, the noise within the chip is successfully reduced to less than half that reported in a previous work, for a device with similar in-pixel circuit simplicity and a large number of readout channels. Further, the action potential was clearly observed on cardiomyocytes using the CMOS-MEA. These results indicate the high-scalability of the CMOS-MEA. The highly scalable CMOS-MEA provides high-spatial-resolution mapping of cell action potentials, and the mapping can aid u...

PURPOSE Test-retest variability (TRV) of visual field (VF) data seriously degrades our capacity to recognize true VF progression. We conducted repeated high-resolution perimetry with a test interval of 0.5° to investigate the sources of TRV. In particular, we examined whether the spatial variance of the observed sensitivity changes or if their absolute magnitude was of more importance. METHODS Sixteen eyes of 16 glaucoma patients were each tested three times at 61 VF locations along the superior-temporal 45° meridian using a modified protocol of the Octopus 900 perimeter. TRV was quantified as the standard deviation of the repeats at each point (retest-SD). We also computed the mean sensitivity at each point (retest-MS) and the running spatial-SD along the tested meridian. Multiple regression models investigated whether any of those variables (and also age, sex, and VF eccentricity) were significant independent determinants of TRV. RESULTS The main independent determinants of TRV were the retest-MS at -0.04 dB TRV/dB loss (P < 0.0001, t-statistic 5.05), and the retest-SD at 0.47 dB spatial variance/dB loss (P < 0.0001, t-statistic 12.5). CONCLUSIONS The larger effect for the spatial-SD suggested that it was perhaps a stronger determinant of TRV than scotoma depth per se. This might support the hypothesis that interactions between small perimetric stimuli, rapidly varying sensitivity across the field, and normal fixational jitter are strong determinants of TRV. TRANSLATIONAL RELEVANCE Our study indicates that methods that might reduce the effects of jagged sensitivity changes, such as increasing stimulus size or better gaze tracking, could reduce TRV.

Background Candida species are clinically important causes of bloodstream infections because their mortality is very high. Given that some species of Candida are azole-resistant, identifying the distributions of Candida species could facilitate the formulation of an appropriate empirical antifungal therapy. It has been shown that the distribution varies depending on the continent, country, city, and hospital. In this paper, we describe the distributions of species in hospitals in northern Osaka, Japan. Method We evaluated blood culture results obtained from six tertiary hospitals in the northern Osaka area between 2004 and 2011. We also obtained comorbidity information from the patients' hospital medical records. Kaplan–Meier curves were drawn to compare the risk of death related to the different species. Results Of the 165 cases of candidemia confirmed by blood culture, 66% were male and the mean age was 62 years (range = 0–96). Overall, Candida albicans comprised 70 cases (43%), followed by Candida parapsilosis with 36 cases (22%), Candida glabrata with 25 cases (15%), Candida tropicalis with 11 cases (7%), Candida krusei with 10 cases (6%), and other Candida species with 13 cases (8%). C. tropicalis had higher associated mortality than other species, although it was not statistically significant. Conclusions C. albicans was the most frequently isolated species, but the proportion of non-albicans Candida species was not negligible. The relatively high frequency of non-albicans Candida species distinguished the Japanese distribution from other areas. This characteristic distribution may have important implications when formulating an empirical antifungal therapy for Japanese clinical practice.

9060 Background: Various gene alterations occur during the development of squamous cell lung cancer (SqLC), but specific gene alterations for SqLC and their clinical significance remain unknown. Methods: In a nationwide genome screening project (LC-SCRUM-Japan), we have prospectively analyzed lung cancer patients for genetic alterations using a next-generation sequencing (NGS) system, Oncomine Comprehensive Assay, and have established a large-scale clinico-genomic database. Results: Since February 2013 to December 2018, a total of 6692 lung cancer patients (686 SqLCs, 5360 non-squamous non-small cell lung cancers [Non-sq] and 646 small cell lung cancers [SCLCs]) had been enrolled in the LC-SCRUM-Japan. The success rate of the NGS assay was 91%. Of 639 SqLCs analyzed, 274 (48%) had potentially targetable gene alterations, including 77 NFE2L2 (encoding NRF2) mut, 50 PIK3CA mut, 46 FGFR1 amp, 40 EGFRmut/amp, 36 PTEN mut, 23 KRAS mut, 6 AKT1 mut, 6 MET ex14skip, 5 ALK fusions, 2 FGFR3 fusions. Among the alterations detected, NFE2L2 mut and FGFR1 amp were significantly frequent in SqLC than Non-sq or SCLC (NFE2L2, 12.1% vs. 1.0% vs. 1.3%; p < 0.001, and FGFR1, 7.2% vs. 1.1% vs. 3.4%; p < 0.001). In advanced SqLC patients who received platinum-containing chemotherapies, the median progression-free survival (mPFS) was significantly shorter in NFE2L2-mutated patients (NRF2-type) than NFE2L2/FGFR1-negative patients (nonNF-type) (3.8 [95%CI, 2.9-5.1] vs. 4.5 [95%CI, 3.8-5.4] months, p = 0.03), and similarly, the mPFS of FGFR1-amplified patients (FGFR1-type) (3.5 months [95%CI, 1.5-4.9]) tended to be shorter than that of nonNF-type (p = 0.07), although the response rates were equivalent among the three types. NRF2-type also showed shorter overall survival (OS) than nonNF-type (median OS, 10.4 [95%CI, 6.9-22.3] vs. 16.6 [95%CI, 13.6-21.7] months, p = 0.10). Therapeutic efficacy of nivolumab or pembrolizumab was not different among these types in the current follow-up data. Conclusions: Our large scale genome screening identified specific gene alterations for SqLC and the alterations were associated with a less efficacy of chemotherapy and worse prognosis, suggesting the need for the development of genotype-directed therapeutic strategy for SqLC patients.

Nonfibrillar assemblies of amyloid β-protein (Aβ) are considered to play primary roles in Alzheimer disease (AD). Elucidating the assembly pathways of these specific aggregates is essential for understanding disease pathogenesis and developing knowledge-based therapies. However, these assemblies cannot be monitored in vivo, and there has been no reliable in vitro monitoring method at low protein concentration. We have developed a highly sensitive in vitro monitoring method using fluorescence correlation spectroscopy (FCS) combined with transmission electron microscopy (TEM) and toxicity assays. Using Aβ labeled at the N terminus or Lys(16), we uncovered two distinct assembly pathways. One leads to highly toxic 10-15-nm spherical Aβ assemblies, termed amylospheroids (ASPDs). The other leads to fibrils. The first step in ASPD formation is trimerization. ASPDs of ∼330 kDa in mass form from these trimers after 5 h of slow rotation. Up to at least 24 h, ASPDs remain the dominant structures in assembly reactions. Neurotoxicity studies reveal that the most toxic ASPDs are ∼128 kDa (∼32-mers). In contrast, fibrillogenesis begins with dimer formation and then proceeds to formation of 15-40-nm spherical intermediates, from which fibrils originate after 15 h. Unlike ASPD formation, the Lys(16)-labeled peptide disturbed fibril formation because the Aβ(16-20) region is critical for this final step. These differences in the assembly pathways clearly indicated that ASPDs are not fibril precursors. The method we have developed should facilitate identifying Aβ assembly steps at which inhibition may be beneficial.

9070Background: PD-L1 high expression and high tumor mutation burden (TMB) are reported to be correlated with high sensitivity to immune checkpoint inhibitor (ICI) in non-small cell lung cancer (NS...

Contributing factors for the antimicrobial activity enhancement of N-terminally engineered mutants of cell-penetrating apidaecins were analyzed based on their cell-penetration efficiency. The flow cytometric analysis of the engineered apidaecins labeled with carboxyfluorescein (FAM) revealed their enhanced cell-penetrating efficiencies into Escherichia coli that should be one of key factors causing the enhanced antimicrobial activity. It is noteworthy that, for one mutant, the enhancement in antimicrobial activity (18-fold higher than wild type) was greater than that of cell penetration (5.9-fold), suggesting that the N-terminal mutation may reinforce both interaction with unidentified intracellular target(s) and cell-penetration efficiency.

Activity improvement of an antimicrobial peptide, thanatin, has been achieved up to 4-fold higher than natural original one by site-specific chemical modifications with tert-butyl group at two cysteine residues which form an intramoleular disulfide bridge. The chemically modified thanatin (C11tBu/C18tBu) exhibited improved antimicrobial activity toward Gram-positive bacteria, Micrococcus luteus, whereas lowered activity toward Gram-negative bacteria, Escherichia coli. This finding suggests that disulfide-bridge formation is not only indispensable for exhibition of antimicrobial activity of thanatin but also closely related to the activity specificity towards bacteria. NMR analysis indicates that thanatin acts against E.coli stereospecifically by taking advantage of its C-terminal beta-hairpin structure, while the activity against M. luteus does not relate to structures and correlates very well to side-chain hydrophobicity.

The bleomycins (BLMs) are clinically used glycopeptide antitumor antibiotics that have been shown to mediate the sequence-selective oxidative damage of both DNA and RNA. Previously, we described the solid-phase synthesis of a library of 108 unique analogues of deglycoBLM A6, a congener that cleaves DNA analogously to BLM itself. Each member of the library was assayed for its ability to effect single- and double-strand nicking of duplex DNA, sequence-selective DNA cleavage, and RNA cleavage in the presence and absence of a metal ion cofactor. All of the analogues tested were found to mediate concentration-dependent plasmid DNA relaxation to some extent, and a number exhibited double-strand cleavage with an efficiency comparable to or greater than deglycoBLM A6. Further, some analogues having altered linker and metal-binding domains mediated altered sequence-selective cleavage, and a few were found to cleave a tRNA3Lys transcript both in the presence and in the absence of a metal cofactor. The results provide insights into structural elements within BLM that control DNA and RNA cleavage. The present study also permits inferences to be drawn regarding the practicality of a selection strategy for the solid-phase construction and evaluation of large libraries of BLM analogues having altered properties.

Purpose: We evaluated the clinical usefulness of flicker perimetry in glaucoma and glaucoma suspect patients using the new Octopus 311 automated perimeter. Methods: A total of 52 eyes of 52 glaucoma patients, 26 eyes of 26 glaucoma suspect patients and 61 eyes of 61 normal subjects were examined using standard automated perimetry (SAP), flicker perimetry and frequency doubling technology (FDT) perimetry. Flicker perimetry was performed using the Octopus 311 and its remote software package. Suprathreshold four-zone probability strategy was used to classify the critical fusion frequency probability level. The classified levels were set at 5% and 1% of probability of normality and 5 Hz. Frequency doubling technology perimetry was performed using 24-2-5, 24-2-1, N-30–5, N-30–1 screening programs using Humphrey Matrix perimetry. Standard automated perimetry was performed using the Humphrey field analyser program 24–2 full threshold. Optical coherence tomography using Stratus OCT was used for evaluating the retinal nerve fibre layer thickness in all glaucoma and glaucoma suspect patients. Results: Receiver operating characteristic (ROC) curves were calculated. In the early stage of glaucoma, the areas under the ROC curve (AUCs) were 0.96 in flicker and 0.90 in Matrix perimetry. In the moderate and advanced stages of glaucoma, the AUCs were almost 1.0 in all tests. In glaucoma suspect patients, the AUC of the 5% probability level in flicker was significantly higher than in Matrix perimetry. Conclusion: The four-zone probability strategy using the Octopus 311 is a useful method for evaluating the flicker field in early glaucoma and glaucoma suspect patients.

The bleomycins (BLMs) are structurally related glycopeptide antibiotics isolated from Streptomyces verticillus that mediate the sequence-selective oxidative damage of DNA and RNA. Deglycobleomycin, which lacks the carbohydrate moiety, cleaves DNA analogously to bleomycin itself, albeit less potently, and has been used successfully for analyzing the functional domains of bleomycin. Although structural modifications to bleomycin and deglycobleomycin have been reported, no bleomycin or deglycobleomycin analogue having enhanced DNA cleavage activity has yet been described. The successful synthesis of a deglycobleomycin on a solid support has permitted the facile solid-phase synthesis of 108 unique deglycobleomycin analogues through parallel solid-phase synthesis. Each of the deglycobleomycin analogues was synthesized efficiently; the purity of each crude product was greater than 60%, as determined by HPLC integration. The solid-phase synthesis of the deglycobleomycin library provided near-milligram to milligram quantities of each deglycobleomycin, thereby permitting characterization by (1)H NMR and high-resolution mass spectrometry. Each analogue demonstrated supercoiled plasmid DNA relaxation above background cleavage; the library included two analogues that mediated plasmid relaxation to a greater extent than the parent deglycobleomycin molecule.

Deglycobleomycin analogues having different length polyamine side chains at the C-terminus were synthesized using a novel solid-phase synthesis strategy that produces fully deprotected deglycobleomycin congeners attached to the resin. Detailed studies of DNA cleavage by these compounds and their resin-bound counterparts using supercoiled plasmid DNAs and DNA restriction fragments as substrates revealed that (i) the length of the polyamine side chain of free deglycoBLM had limited effect on its DNA cleavage potency or sequence selectivity, and (ii) the nature of the linker moiety between the resin and attached deglycobleomycin had a more substantial effect on the potency of DNA cleavage, but no effect on sequence selectivity of resin-bound deglycoBLMs. Resin-bound 4 exhibited efficient DNA cleavage, indicating that its tetraamine linker moiety could be used for the elaboration and direct evaluation of bleomycin congeners attached to resins.

[structure: see text] A greatly improved solid-phase synthesis of deglycobleomycin using a Dde-based linker is reported. The resin-bound deglycobleomycin could be completely deblocked and assayed for DNA plasmid relaxation, sequence-selective DNA cleavage, and light production from a molecular beacon.

Purpose A newly developed head-mounted perimeter termed “imo” enables visual field (VF) testing without a fixed head position. Because the positional relationship between the subject’s head and the imo is fixed, the effects of head position changes on the test results are small compared with those obtained using a stationary perimeter. However, only ocular counter-roll (OCR) induced by head tilt might affect VF testing. To quantitatively reveal the effects of head tilt and OCR on the VF test results, we investigated the associations among the head-tilt angle, OCR amplitude and VF testing results. Subjects and methods For 20 healthy subjects, we binocularly recorded static OCR (s-OCR) while tilting the subject’s head at an arbitrary angle ranging from 0° to 60° rightward or leftward in 10° increments. By monitoring iris patterns, we evaluated the s-OCR amplitude. We also performed blind spot detection while tilting the subject’s head by an arbitrary angle ranging from 0° to 50° rightward or leftward in 10° increments to calculate the angle by which the blind spot rotates because of head tilt. Results The association between s-OCR amplitude and head-tilt angle showed a sinusoidal relationship. In blind spot detection, the blind spot rotated to the opposite direction of the head tilt, and the association between the rotation angle of the blind spot and the head-tilt angle also showed a sinusoidal relationship. The rotation angle of the blind spot was strongly correlated with the s-OCR amplitude (R2≥0.94, p

In 1995, the Act on Welfare of Physically Disabled Persons was revised and the visual impairment grading methods were modified. In this revision, the target size for peripheral visual field measurements was changed from V/4 to I/4. We compared the area of I/4 and V4 visual fields in normal eyes and evaluated its influence on the decision of the visual impairment grade 5.Goldmann kinetic perimetry results obtained from 137 eyes of 137 subjects (age 10-79, average ± SD: 47.0 ± 17.5) at Kinki University Hospital were retrospectively evaluated. The V/4 and I/4 isopter areas were calculated using Image J and compared with the normal visual field range in the visual impairment criteria.The V/4 isopter area decreased from age 70 and the I/4 isopter area decreased significantly from age 50. The aging slope of the isopter areas were significantly larger in I/4 than in V/4. In age 60 to 69, 19% showed a smaller I/4 isopter area than that of the grade 5 criteria. In age 70 to 79, 75% showed a smaller I/4 isopter area than that of the grade 5 criteria.In some elderly people, the binocular I/4 isopter area is smaller than the visual impairment grade 5 criteria.

CLOCK CHART(®) is a multi-stimulus-type self-check visual field screening sheet developed by our group. The test chart is rotated during the examination, and the visual field abnormalities are pointed out by the patients themselves. In this study, we evaluated the clinical usefulness of this chart in patients with glaucoma.We studied 114 eyes of 114 glaucoma patients (average age 60.0 ± 11.1 years) and 45 eyes of 45 normal individuals (average age 45.0 ± 16.4 years) using CLOCK CHART(®). The static visual fields were obtained using the Octopus 101 G2 program and classified using the Aulhorn classification as modified by Greve (stages 0-I to IV) and by mean defect (MD; early6 dB; moderate 6 ≤ MD ≤12 dB; severe12 dB).The sensitivity and specificity of CLOCK CHART(®) for detecting visual field abnormalities were evaluated within the entire 25° field and at the 5°, 10°, 15°, 20°, and 25° eccentricity zones. The visual field agreement between the results of CLOCK CHART(®) and the static visual fields were also evaluated.In glaucomatous eyes, the sensitivity of CLOCK CHART(®) was 85, 93, and 100 % for Greve stages I, II and III-VI, respectively, and 87, 93, and 97 % for the MD value in early, moderate, and severe eyes, respectively. The agreement of the visual field defect area in CLOCK CHART(®) with the static fields was 85 and 100 % with Greve stages 0-I to I and II-VI, respectively, and 91, 96, and 96 % in early, moderate and severe glaucomatous eyes according to MD, respectively. The specificity of CLOCK CHART(®) was 89 %.CLOCK CHART(®) is a simple and reliable self-check screening chart for detecting visual field abnormalities in patients with glaucoma.

We report our recent progress on GaN-based laser diodes (LDs) which will be applied as a light source in high-density optical storage systems. Recently we achieved a lifetime of more than 500 hours under continuous-wave operation with a constant power 20 mW at 25°C using GaN-based LDs with a standard ridge structure. We also report the potential of GaN-based LDs with another structure of a buried-ridge. The far-field pattern of the LDs with a buried-ridge structure strongly depended on the Al content of the AlxGa1−xN burying layer. This dependency showed that the device characteristics change from gain-guiding to refractive index-guiding. The critical point was around x=0.30 of an Al content which corresponds to Δn=0.007 of a lateral index step. It was, therefore, found that the optical transverse mode can be controlled by adjusting the Al content of the AlxGa1−xN burying layer.

The buried-ridge structure was introduced to GaN-based laser diodes for the purpose of realizing an index-guided structure in order to control the difference of effective refractive indexes between the inside and outside of the lasing area and to stabilize the lasing mode. Low-temperature-grown Al x Ga (1− x ) N was used as the burying layer, and it was found that the refractive-index difference can be controlled by adjusting the Al content in the Al x Ga (1− x ) N burying layer independent of the ridge dimensions. As a result of fabricating LDs with different Al contents, we found that Al content should be more than 30% in order to form an index-guided structure. The optimum refractive-index difference was estimated by fitting with the calculation. The LD with a buried-ridge structure, in which Al in the burying layer was more than 30%, had desirable properties as an index-guided waveguide.

In AlGaN growth using low-pressure metalorganic chemical vapor deposition the TMA-flow-rate dependence and reactor-pressure dependence on the Al content were investigated. We found that the reduction of partial pressure of TMA is effective in preventing the reduction of the Al content. To apply AlN and AlGaN films to devices, we fabricated an insulated gate heterostructure field effect transistor (IG-HFET). The AFM image of 4 nm-thick AlN on GaN shows a rough surface composed of approximately 500 nm-size grains. The grain boundary may be the origin of the leakage current between gate and drain during the operation of the IG-HFET. Nevertheless, the device can operate with transconductance gm of 235 mS mm−1 for Lg=1.4 μm.

The well-number dependence of the optical pumping threshold power for stimulated emission of GaInN multiple quantum-well (MQW) laser structures was investigated. The pumping threshold power for a three GaInN MQW sample was found to be as low as 33 kW/cm 2 at room temperature. The room-temperature pulsed operation of a five GaInN MQW laser diode (LD), whose number of wells was determined based on the optical pumping experiment, was also demonstrated. The lowest threshold current density was 9.5 kA/cm 2 . The lasing wavelength was 417.5 nm with a full-width at half-maximum (FWHM) less than the spectrum resolution of 0.2 nm.

The photoreaction of Kemp's imide-linked coumarin 1 and thymine 3 gave two crossadducts, cis-syn 4 cis-anti 5. The yield and ratio of 45 in benzene solution remarkably increased by factors of 4.2 and 10 than those in acetonitrile solution, respectively. On the other hand, the reaction of acetoxycoumarin 2 and 3 gave only the cis-anti crossadduct in each solution.

We examined the effect of HSR-81 ((-)-(R)-alpha-[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol L-tartrate), a newly developed, potent and selective beta 2-adrenoceptor agonist, as well as ritodrine and isoproterenol, on the spontaneous rhythmic contraction in uteri isolated from late pregnant, middle pregnant and non-pregnant (dioestrous and oestrous) rats. The three agonists inhibited the spontaneous rhythmic contraction at all the stages in a concentration-dependent manner. The pD2 value for HSR-81 was greater in late pregnancy than in dioestrus and oestrus. In the uterine preparations of late pregnancy and dioestrus, ICI-118,551 (1-(7-methylindan-4-yloxy)-3-isopropyl-aminobutan-2-ol , a selective beta 2-adrenoceptor antagonist) and atenolol (a selective beta 1-adrenoceptor antagonist) produced a parallel rightward shift of the concentration-response curves for HSR-81. The pKB values for ICI-118,551 and atenolol suggest that the inhibitory effect of HSR-81 was mediated through beta 2-adrenoceptors in the two stages. In the membranes prepared from rat uteri in late pregnancy and dioestrus, the equilibrium dissociation constant for [125I]iodocyanopindolol binding was not significantly different between the two stages. The three beta-adrenoceptor agonists and the two antagonists competed for the specific [125I]iodocyanopindolol binding and the pKi values were not significantly different between the two stages. However, the maximum number of binding sites was significantly greater in late pregnancy than in dioestrus. The configuration of the competition curves and the pKi values for the two antagonists confirmed the fact that these membranes contain predominantly beta 2-adrenoceptor subtype. These results indicate that the potent inhibition of the spontaneous rhythmic contraction by HSR-81 in the pregnant uterus may be due to the increased number of beta 2-adrenoceptors.

To quantify changes in metamorphopsia and retinal contraction in eyes with idiopathic epiretinal membrane (ERM) before and after a spontaneous separation of ERM. Among 92 eyes of 92 patients with idiopathic ERM who were followed up at our hospital, 5 eyes of 5 patients had experienced a spontaneous separation of ERM during the follow-up period. Patient’s metamorphopsia was assessed horizontally and vertically by a metamorphopsia chart developed by our group, M-CHARTS, to obtain the horizontal (MH) and vertical (MV) metamorphopsia scores. Difference in the scores before and after the membrane separation represents change in patient’s metamorphopsia. Changes in retinal contraction were also evaluated horizontally and vertically with our original software for fundus image analysis. The difference between M-CHARTS scores and distances of retinal vessel movements with before and after membrane separation were measured. All five subjects showed a decrease in the retinal contraction. Improved visual acuity was observed in three subjects, and no change was seen in the other two. Four subjects obtained better metamorphopsia scores after the membrane separation, while the other one was not detected with metamorphopsia by M-CHARTS either before or after the separation. In subjects with an improved MV, horizontal retinal movement was seen larger than the vertical movement. Similarly, the subjects with an improved MH indicated a larger vertical retinal movement than the horizontal movement. The direction of patient’s metamorphopsia closely associated with the direction of retinal contraction before and after a spontaneous separation of ERM.

In the presence of adrenergic and cholinergic blocking agents, transmural electrical stimulation evoked a relaxation in isolated dog urethra precontracted with histamine. The response was abolished by tetrodotoxin, indicating its neurogenic origin. The non-adrenergic and non-cholinergic relaxation developed rapidly and was transient at low stimulation frequencies (⪯ 1 Hz). However, at higher frequencies (⪰ 5 Hz ) the recovery phase of the relaxation became slow and often showed a notch, suggesting the presence of transient and slow components. NG-Monomethyl-L-arginine, a nitric oxide synthase inhibitor, inhibited the transient relaxation but did not affect the relaxation evoked at high stimulation frequencies. NG-Nitro-L-arginine, a more potent nitric oxide synthase inhibitor, abolished the transient relaxation produced at low stimulation frequencies and markedly attenuated the transient component at high frequencies. However, NG-nitro-L-arginine did not affect the slow component. The inhibition by NG-monomethyl-L-arginine and NG-nitro-L-arginine was reversed by the addition of L- but not D-arginine. Exogenously applied vasoactive intestinal polypeptide (VIP) produced a slowly developing relaxation. The slow relaxation induced by transmural electrical stimulation and VIP was not affected by [4-Cl-D-Phe6, Leu17]VIP, a reportedly competitive VIP antagonist. NG-Nitro-L-arginine did not effect the relaxation induced by VIP and sodium nitroprusside. These results suggest that the non-adrenergic and non-cholinergic relaxation induced by transmural electrical stimulation is composed of nitric oxide-dependent and -independent components in the isolated dog urethra.

An outdoor experiment is conducted to investigate snowdrift that has much effect on the formation of snow cover depth on roof surface. Three types of model roof with respective roof levels and on existent roof are used to measure changes in snow cover depth and snowdrift with time. At the same time, the wind velocity, temperature and snow cover depth above the ground are measured. The levels of the existent roof surface ranges from 9 to 12 m. The results of this experiment are obtained as follws :1) The higher the roof surface, the more the snowdrift. Snow cover depth on a roof is less than that on the ground.2) Snowdrift on a roof is more likely to occur than that on the ground, because the surface wind has a vertical distribution, which increases in value with height.3) The larger the roof surface is, the more the amount of snowdrift becomes when the wind blows hard. Hence, as roofs increase in area, the distribution of snow cover has become more ununiform.

Purpose To assess the correlations between a patient's subjective perception of metamorphopsia and the clinical measurements of metamorphopsia by M-CHARTS and PreView PHP (PHP). Methods The authors designed a 10-item questionnaire focusing on the symptoms of metamorphopsia and verified its validity with a Rasch analysis. M-CHARTS measured the minimum visual angle of a dotted line needed to detect metamorphopsia, and PHP used the hyperacuity function for detection. Subjects were 39 patients with idiopathic epiretinal membrane (ERM), 22 patients with idiopathic macular hole (M-hole), 19 patients with age-related macular degeneration (AMD), and 51 healthy controls. Results Rasch analysis suggested the elimination of one question. The nine-item questionnaire score significantly correlated to the M-CHARTS score in ERM (r = 0.59; P = 0.0004) but not in M-hole and to the PHP result in AMD (r = -0.29; P = 0.04) but not in ERM. Eighty percent of ERM patients with greater horizontal M-CHARTS score subjectively perceived horizontal metamorphopsia more often. M-CHARTS showed better sensitivities than PHP in both ERM (89% vs. 42%) and AMD (74% vs. 68%) and better specificity (100% vs. 71%) in healthy controls. Rasch analysis indicated that the present form of the questionnaire is better suited for moderate to severe cases of metamorphopsia than for mild cases. Conclusions The questionnaire appears to be a valid assessment of patient subjective perception of metamorphopsia and can be used to supplement the clinical measurements of metamorphopsia by M-CHARTS and PHP in patients with macular diseases.

Carbazolyloxyacetohydroxamic acid (1), 9,9′-decamethylene-bis-carbazolyloxyacetohydroxamic acid (2), benzohydroxamic acid (3) and acetohydroxamic acid (4) without reducing agent under aerobic conditions induced Col E1 DNA strand scissions with increasing of the activities in the order of 4 > 3 > 2 > 1. Inhibition experiments indicated that hydrogen peroxide and superoxide participated in the reactions, but hydroxyl radical or singlet oxygen did not.