[A Bibliometric Analysis of Research Paper Productivity of Japanese Pharmacy Schools].

Since the early 2000s, Japan has been frequently noted as being the only country among about 20 major countries where the publication of academic papers has stagnated. During this period, there have been major changes especially with regards to the Japanese pharmacy schools, such as the shift to a six-year schooling system and the rapid increase in the number of private pharmacy schools. However, few studies have focused on academic productivity specifically among pharmacy schools. Therefore, this study analyzed the outputs associated with the publication of peer-reviewed scholarly articles in Scopus search engine per faculty member in pharmacy schools nationwide in 2020. Professors, associate professors, and lecturers were considered as faculty members. The average number of papers published per the faculty member was 3.13 for national and public universities and 1.15 for private universities, with a significant difference between these universities. Dividing the pharmacy schools of private universities into schools established in and after 2003 and schools established before that, the production coefficient of the former was 0.98 and that of the latter was 1.33. Newly established pharmacy schools were thus found to be slightly less productive in terms of published papers than traditional schools. The paper productivity of private university pharmacy schools is stagnant; the increase in the number of private schools that have adopted a six-year schooling system has contributed to large extent to the creation of clinically competent pharmacists, but it has also brought to light concerns related to the decline in basic research capabilities of Japanese pharmaceutical academia.

Use of Nuclear and Chromatin Enrichment Procedures for Quantitation of Yeast DNA Replication Proteins Using SILAC.

DNA replication is a highly complex process that achieves the faithful transmission of genetic information from parent to progeny. Recruitment of DNA replication proteins to DNA is dynamically regulated during the cell cycle and in response to replication stresses. For a large-scale analysis of DNA replication proteins, I established a method for analysis of chromatin-bound proteins by SILAC (stable isotope labeling by amino acids in cell culture)-based quantitative proteomics. Here I describe a detailed methodology for SILAC labeling of budding yeast Saccharomyces cerevisiae, then nuclear isolation and chromatin preparation from synchronized yeast cells, prior to quantitative proteomic analysis of DNA replication proteins.

SWI/SNF and the histone chaperone Rtt106 drive expression of the Pleiotropic Drug Resistance network genes.

The Pleiotropic Drug Resistance (PDR) network is central to the drug response in fungi, and its overactivation is associated with drug resistance. However, gene regulation of the PDR network is not well understood. Here, we show that the histone chaperone Rtt106 and the chromatin remodeller SWI/SNF control expression of the PDR network genes and confer drug resistance. In Saccharomyces cerevisiae, Rtt106 specifically localises to PDR network gene promoters dependent on transcription factor Pdr3, but not Pdr1, and is essential for Pdr3-mediated basal expression of the PDR network genes, while SWI/SNF is essential for both basal and drug-induced expression. Also in the pathogenic fungus Candida glabrata, Rtt106 and SWI/SNF regulate drug-induced PDR gene expression. Consistently, loss of Rtt106 or SWI/SNF sensitises drug-resistant S. cerevisiae mutants and C. glabrata to antifungal drugs. Since they cooperatively drive PDR network gene expression, Rtt106 and SWI/SNF represent potential therapeutic targets to combat antifungal resistance.

Spatial and latent memory data in PS2Tg2576 alzheimer's disease mouse model after memantine treatment.

We herein present behavioral data on whether memantine, an adamantane derivative and medical NMDA-receptor antagonist, improves spatial and latent learning deficits in amyloid precursor protein/presenilin 2 double-transgenic mice (PS2Tg2576 mice). In PS2Tg2576 mice, early amyloid-ß protein (Aß) deposition at 2-3 months of age and progressive accumulation at about 5 months of age has been shown. Thus, PS2Tg2576 mice were subjected to Morris water maze (MWM) test for spatial memory and the water-finding test for latent memory testing at ages 3 and 5-6 months. In addition, memantine (30 mg/kg/day, p.o.) was administered 3-4 weeks before commencing the behavioral tasks to check for effects on cognitive function. The information provided in this paper adds to the literature and can be used for the selection of animal models and behavioral paradigms for Alzheimer's disease (AD) research.

Age-dependent impairment of memory and neurofibrillary tangle formation and clearance in a mouse model of tauopathy.

Insoluble, fibrillar intraneuronal accumulation of the tau protein termed neurofibrillary tangles (NFTs), are characteristic hallmarks of Alzheimer's disease (AD). They play a significant role in the behavioral phenotypes of AD. Certain mice (rTg4510) constitutively express mutant human tau until transgene expression is inactivated by the administration of doxycycline (DOX). The present study aimed to determine the timing of the onset of memory impairment in rTg4510 mice and define the relationship between the extent of memory deficit and the duration of NFT overexpression. In 6-month-old (young) rTg4510 mice, both spatial memory and object recognition memory were impaired. These impairments were prevented by pre-treatment with DOX for 2 months. In parallel, the expression of NFTs decreased in the DOX-treated group. Ten-month-old (aged) rTg4510 mice showed severe impairments in memory performance. Pretreatment with DOX did not prevent these impairments. Increasing levels of NFTs were observed in aged rTg4510 mice. DOX treatment did not prevent tau pathology in aged rTg4510 mice. Expression of the autophagy markers LC3A and LC3B increased in rTg4510 mice, along with an increase in NFT formation. These results suggest that the clearance mechanisms of NFTs are impaired at 10 months of age.

Ligation of newly replicated DNA controls the timing of DNA mismatch repair.

Mismatch repair (MMR) safeguards genome stability through recognition and excision of DNA replication errors.1-4 How eukaryotic MMR targets the newly replicated strand in vivo has not been established. MMR reactions reconstituted in vitro are directed to the strand containing a preexisting nick or gap,5-8 suggesting that strand discontinuities could act as discrimination signals. Another candidate is the proliferating cell nuclear antigen (PCNA) that is loaded at replication forks and is required for the activation of Mlh1-Pms1 endonuclease.7-9 Here, we discovered that overexpression of DNA ligase I (Cdc9) in Saccharomyces cerevisiae causes elevated mutation rates and increased chromatin-bound PCNA levels and accumulation of Pms1 foci that are MMR intermediates, suggesting that premature ligation of replication-associated nicks interferes with MMR. We showed that yeast Pms1 expression is mainly restricted to S phase, in agreement with the temporal coupling between MMR and DNA replication.10 Restricting Pms1 expression to the G2/M phase caused a mutator phenotype that was exacerbated in the absence of the exonuclease Exo1. This mutator phenotype was largely suppressed by increasing the lifetime of replication-associated DNA nicks, either by reducing or delaying Cdc9 ligase activity in vivo. Therefore, Cdc9 dictates a window of time for MMR determined by transient DNA nicks that direct the Mlh1-Pms1 in a strand-specific manner. Because DNA nicks occur on both newly synthesized leading and lagging strands,11 these results establish a general mechanism for targeting MMR to the newly synthesized DNA, thus preventing the accumulation of mutations that underlie the development of human cancer.

Flexible electrochromic devices based on tungsten oxide and Prussian blue nanoparticles for automobile applications.

Smart windows, which control the amount of light entering buildings, houses, and automobiles, are promising in terms of energy conservation and their low environmental impact. Particularly, a next-generation smart window for automobiles will require high optical modulation, along with flexibility to adapt to various intelligent designs. We have previously fabricated electrochromic devices (ECDs) by wet coating glass substrates with nanoparticles (NPs), such as water-dispersive ink containing tungsten oxide (WO3), and Prussian blue (PB), and have evaluated and confirmed the various electrochromic (EC) properties, such as optical modulation, cyclic durability, and colouration efficiency, of the ECDs. However, glass substrates are heavy and difficult to adapt by deformation to meet the demand of next-generation automobiles. In this study, we aim to prepare complementary ECDs by wet coating WO3 and PB thin films on indium tin oxide (ITO)-coated flexible polyethylene terephthalate (PET) substrates. Chromaticity and haze of ECDs were investigated in detail as evaluation indexes to verify specifications for practical use in automotive applications. Repeated switching, bending, and twisting did not degrade the ECD properties, thereby demonstrating its durability and mechanical robustness. These excellent electrochromic properties of the flexible ECDs suggest that they are promising materials for application in next-generation smart windows for automobiles.

MDGA1-deficiency attenuates prepulse inhibition with alterations of dopamine and serotonin metabolism: An ex vivo HPLC-ECD analysis.

MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor) has recently been linked to schizophrenia and bipolar disorder. Dysregulation of dopamine (DA) and serotonin (5-HT) systems has long been associated with schizophrenia and other neuropsychiatric disorders. Here, we measured prepulse inhibition (PPI) of the startle response and ex vivo tissue content of monoamines and their metabolites in the frontal cortex, striatum and hippocampus of Mdga1 homozygous (Mdga1-KO), Mdga1 heterozygous (Mdga1-HT) and wild-type (WT) male mice. We found that Mdga1-KO mice exhibited statistically significant impairment of PPI, and had higher levels of homovanillic acid in all three brain regions studied compared with Mdga1-HT and WT mice (P < 0.05), while levels of norepinephrine, DA and its metabolites 3,4-dihydroxyphenylacetic acid and 3-methoxytyramine remained unchanged. Mdga1-KO mice also had a lower 5-hydroxyindoleacetic acid level in the striatum (P < 0.05) compared with WT mice. 5-HT levels remained unchanged with the exception of a significant increase in the level in the cortex. These data are the first evidence suggesting that MDGA1 deficiency leads to a pronounced deficit in PPI and plays an important role in perturbation of DA and 5-HT metabolism in mouse brain; such changes may contribute to a range of neuropsychiatric disorders.

Effective mismatch repair depends on timely control of PCNA retention on DNA by the Elg1 complex.

Proliferating cell nuclear antigen (PCNA) is a sliding clamp that acts as a central co-ordinator for mismatch repair (MMR) as well as DNA replication. Loss of Elg1, the major subunit of the PCNA unloader complex, causes over-accumulation of PCNA on DNA and also increases mutation rate, but it has been unclear if the two effects are linked. Here we show that timely removal of PCNA from DNA by the Elg1 complex is important to prevent mutations. Although premature unloading of PCNA generally increases mutation rate, the mutator phenotype of elg1Δ is attenuated by PCNA mutants PCNA-R14E and PCNA-D150E that spontaneously fall off DNA. In contrast, the elg1Δ mutator phenotype is exacerbated by PCNA mutants that accumulate on DNA due to enhanced electrostatic PCNA-DNA interactions. Epistasis analysis suggests that PCNA over-accumulation on DNA interferes with both MMR and MMR-independent process(es). In elg1Δ, over-retained PCNA hyper-recruits the Msh2-Msh6 mismatch recognition complex through its PCNA-interacting peptide motif, causing accumulation of MMR intermediates. Our results suggest that PCNA retention controlled by the Elg1 complex is critical for efficient MMR: PCNA needs to be on DNA long enough to enable MMR, but if it is retained too long it interferes with downstream repair steps.

Identification of Elg1 interaction partners and effects on post-replication chromatin re-formation.

Elg1, the major subunit of a Replication Factor C-like complex, is critical to ensure genomic stability during DNA replication, and is implicated in controlling chromatin structure. We investigated the consequences of Elg1 loss for the dynamics of chromatin re-formation following DNA replication. Measurement of Okazaki fragment length and the micrococcal nuclease sensitivity of newly replicated DNA revealed a defect in nucleosome organization in the absence of Elg1. Using a proteomic approach to identify Elg1 binding partners, we discovered that Elg1 interacts with Rtt106, a histone chaperone implicated in replication-coupled nucleosome assembly that also regulates transcription. A central role for Elg1 is the unloading of PCNA from chromatin following DNA replication, so we examined the relative importance of Rtt106 and PCNA unloading for chromatin reassembly following DNA replication. We find that the major cause of the chromatin organization defects of an ELG1 mutant is PCNA retention on DNA following replication, with Rtt106-Elg1 interaction potentially playing a contributory role.

Interfacility variation in treatment planning parameters in tomotherapy: field width, pitch, and modulation factor.

Several studies have reported changes in dose distribution and delivery time based on the value of specific planning parameters [field width (FW), pitch, and modulation factor (MF)] in tomotherapy. However, the variation in the parameters between different facilities is unknown. The purpose of this study was to determine standard values of the above parameters for cases of head and neck cancer (HNC) and prostate cancer (PC) in Japan. In this survey, a web-based questionnaire was sent to 48 facilities performing radiation therapy with tomotherapy in March 2016. The deadline for data submission was April 2016. In the questionnaire, the values of the planning parameters usually used were requested and 23 responses were received, representing a response rate of 48% (23/48). The FW selected was 2.5 cm in most facilities, and facilities with a tomoEDGE license used dynamic FW rather than fixed FW. Facilities changed the pitch based on FW, dose per fraction, or target offset more frequently in HNC than in PC. In contrast, >50% of the facilities used the magic number proposed by Kissick et al. Median preset MFs (range, min to max) in HNC and PC were 2.4 (1.8-2.8) and 2.0 (1.8-3.0), respectively, and MF values showed large variations between the facilities. Our results are likely to be useful to several facilities designing treatment plans in tomotherapy.

Analysis of modulation factor to shorten the delivery time in helical tomotherapy.

A low modulation factor (MF) maintaining a good dose distribution contributes to the shortening of the delivery time and efficiency of the treatment plan in helical tomotherapy. The purpose of this study was to reduce the delivery time using initial values and the upper limit values of MF. First, patients with head and neck cancer (293 cases) or prostate cancer (181 cases) treated between June 2011 and July 2015 were included in the analysis of MF values. The initial MF value (MFinitial ) was defined as the average MFactual value, and the upper limit of the MF value (MFUL ) was defined according the following equation: MFUL = 2 × standard deviation of MFactual value + the average MFactual Next, a treatment plan was designed for patients with head and neck cancer (62 cases) and prostate cancer (13 cases) treated between December 2015 and June 2016. The average MFactual value for the nasopharynx, oropharynx, hypopharynx, and prostate cases decreased from 2.1 to 1.9 (p = 0.0006), 1.9 to 1.6 (p < 0.0001), 2.0 to 1.7 (p < 0.0001), and 1.8 to 1.6 (p = 0.0004) by adapting the MFinitial and the MFUL values, respectively. The average delivery time for the nasopharynx, oropharynx, hypopharynx, and prostate cases also decreased from 19.9 s cm-1 to 16.7 s cm-1 (p < 0.0001), 15.0 s cm-1 to 13.9 s cm-1 (p = 0.025), 15.1 s cm-1 to 13.8 s cm-1 (p = 0.015), and 23.6 s cm-1 to 16.9 s cm-1 (p = 0.008) respectively. The delivery time was shortened by the adaptation of MFinitial and MFUL values with a reduction in the average MFactual for head and neck cancer and prostate cancer cases.

Data on amyloid precursor protein accumulation, spontaneous physical activity, and motor learning after traumatic brain injury in the triple-transgenic mouse model of Alzheimer׳s disease.

This data article contains supporting information regarding the research article entitled "Traumatic brain injury accelerates amyloid-ß deposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer׳s disease" (H. Shishido, Y. Kishimoto, N. Kawai, Y. Toyota, M. Ueno, T. Kubota, Y. Kirino, T. Tamiya, 2016) [1]. Triple-transgenic (3×Tg)-Alzheimer׳s disease (AD) model mice exhibited significantly poorer spatial learning than sham-treated 3×Tg-AD mice 28 days after traumatic brain injury (TBI). Correspondingly, amyloid-ß (Aß) deposition within the hippocampus was significantly greater in 3×Tg-AD mice 28 days after TBI. However, data regarding the short-term and long-term influences of TBI on amyloid precursor protein (APP) accumulation in AD model mice remain limited. Furthermore, there is little data showing whether physical activity and motor learning are affected by TBI in AD model mice. Here, we provide immunocytochemistry data confirming that TBI induces significant increases in APP accumulation in 3×Tg-AD mice at both 7 days and 28 days after TBI. Furthermore, 3×Tg-AD model mice exhibit a reduced ability to acquire conditioned responses (CRs) during delay eyeblink conditioning compared to sham-treated 3×Tg-AD model mice 28 days after TBI. However, physical activity and motor performance are not significantly changed in TBI-treated 3×Tg-AD model mice.

Traumatic brain injury accelerates amyloid-ß deposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer's disease.

Several pathological and epidemiological studies have demonstrated a possible relationship between traumatic brain injury (TBI) and Alzheimer's disease (AD). However, the exact contribution of TBI to AD onset and progression is unclear. Hence, we examined AD-related histopathological changes and cognitive impairment after TBI in triple transgenic (3×Tg)-AD model mice. Five- to seven-month-old 3×Tg-AD model mice were subjected to either TBI by the weight-drop method or a sham treatment. In the 3×Tg-AD mice subjected to TBI, the spatial learning was not significantly different 7 days after TBI compared to that of the sham-treated 3×Tg-AD mice. However, 28 days after TBI, the 3×Tg-AD mice exhibited significantly lower spatial learning than the sham-treated 3×Tg-AD mice. Correspondingly, while a few amyloid-ß (Aß) plaques were observed in both sham-treated and TBI-treated 3×Tg-AD mouse hippocampus 7 days after TBI, the Aß deposition was significantly greater in 3×Tg-AD mice 28 days after TBI. Thus, we demonstrated that TBI induced a significant increase in hippocampal Aß deposition 28 days after TBI compared to that of the control animals, which was associated with worse spatial learning ability in 3×Tg-AD mice. The present study suggests that TBI could be a risk factor for accelerated AD progression, particularly when genetic and hereditary predispositions are involved.

Establishment of the Commissioning Procedure for Modifying the Beam Model of Helical Tomotherapy.

Although much evidence about the helical tomotherapy system are available, there is not a document about the procedure of quality assurance (QA) for changing the beam model. This study establishes the commissioning procedure for modifying the beam model of helical tomotherapy. Firstly, some intensity-modulated radiotherapy (IMRT) plans were created, and compared them with the calculated dose and the measured dose. Secondly, the absorbed doses to water in the machine-specific reference field and the plan-class specific reference field with a protocol in Japan; Standard Dosimetry of Absorbed Dose to Water in External Beam Radiotherapy (Standard Dosimetry 12) were measured. Thirdly, we reconfirmed patient-specific quality assurance. The recommended commissioning procedure after the change of the beam model was shown through three verification processes. This report would be helpful for not only changing the beam model of helical tomotherapy but also introducing Standard Dosimetry 12 to a clinic.

Ameliorative effect of membrane-associated estrogen receptor G protein coupled receptor 30 activation on object recognition memory in mouse models of Alzheimer's disease.

Membrane-associated estrogen receptor "G protein-coupled receptor 30" (GPR30) has been implicated in spatial recognition memory and protection against neuronal death. The present study investigated the role of GPR30 in object recognition memory in an Alzheimer's disease (AD) mouse model (5XFAD) by using novel object recognition (NOR) test. Impairment of long-term (24 h) recognition memory was observed in both male and female 5XFAD mice. Selective GPR30 agonist, G-1, ameliorated this impairment in female 5XFAD mice, but not in male mice. Our study demonstrated the ameliorative role of GPR30 in NOR memory impaired by AD pathology in female mice.

PCNA Retention on DNA into G2/M Phase Causes Genome Instability in Cells Lacking Elg1.

Loss of the genome maintenance factor Elg1 causes serious genome instability that leads to cancer, but the underlying mechanism is unknown. Elg1 forms the major subunit of a replication factor C-like complex, Elg1-RLC, which unloads the ring-shaped polymerase clamp PCNA from DNA during replication. Here, we show that prolonged retention of PCNA on DNA into G2/M phase is the major cause of genome instability in elg1Δ yeast. Overexpression-induced accumulation of PCNA on DNA causes genome instability. Conversely, disassembly-prone PCNA mutants that relieve PCNA accumulation rescue the genome instability of elg1Δ cells. Covalent modifications to the retained PCNA make only a minor contribution to elg1Δ genome instability. By engineering cell-cycle-regulated ELG1 alleles, we show that abnormal accumulation of PCNA on DNA during S phase causes moderate genome instability and its retention through G2/M phase exacerbates genome instability. Our results reveal that PCNA unloading by Elg1-RLC is critical for genome maintenance.

Rotational output and beam quality evaluations for helical tomotherapy with use of a third-party quality assurance tool.

Our aim was to determine whether a third-party quality assurance (QA) tool was suitable for the measurement of rotational output and beam quality in place of on-board detector signals. A Rotational Therapy Phantom 507 (507 Phantom) was used as a QA tool. The rotational output constancy (ROC507) and the beam quality index ([Formula: see text]) were evaluated by analysis of signals from an ion chamber inserted into the 507 Phantom. On-board detector signals were obtained for comparisons with the data from the 507 Phantom. The rotational output (ROC(detector)) and beam quality (corrected cone ratio; CCR) were determined by analysis of on-board detector signals that were generated by irradiation. The tissue phantom ratio at depth 20 and 10 cm (TPR20, 10) was measured with a Farmer-type ionization chamber inserted in a plastic-slab phantom. For rotational output measurement, the correlation coefficient between ROC507 and ROC(detector) values was 0.68 (p < 0.001). ROC507 and ROC(detector) values showed a reduced coefficient of variation after magnetron replacement, which was done during the measurement period. In addition, ROC507 values were reduced significantly along with ROC(detector) values after target replacement (p < 0.001). Regarding the beam quality index, [Formula: see text] showed a change similar to CCR and an increase similar to TPR20, 10 after magnetron/target replacement. This QA tool could check for daily rotational output and detect changes in rotational output and beam quality caused by magnetron or target failure as well as when on-board detector signals were used. Without needing a tomotherapy quality assurance license, we could effectively and quantitatively estimate the rotational output and beam quality at a low cost.

Replication-Coupled PCNA Unloading by the Elg1 Complex Occurs Genome-wide and Requires Okazaki Fragment Ligation.

The sliding clamp PCNA is a crucial component of the DNA replication machinery. Timely PCNA loading and unloading are central for genome integrity and must be strictly coordinated with other DNA processing steps during replication. Here, we show that the S. cerevisiae Elg1 replication factor C-like complex (Elg1-RLC) unloads PCNA genome-wide following Okazaki fragment ligation. In the absence of Elg1, PCNA is retained on chromosomes in the wake of replication forks, rather than at specific sites. Degradation of the Okazaki fragment ligase Cdc9 leads to PCNA accumulation on chromatin, similar to the accumulation caused by lack of Elg1. We demonstrate that Okazaki fragment ligation is the critical prerequisite for PCNA unloading, since Chlorella virus DNA ligase can substitute for Cdc9 in yeast and simultaneously promotes PCNA unloading. Our results suggest that Elg1-RLC acts as a general PCNA unloader and is dependent upon DNA ligation during chromosome replication.

Definition of the transcription factor TdIF1 consensus-binding sequence through genomewide mapping of its binding sites.

TdIF1 was originally identified as a protein that directly binds to terminal deoxynucleotidyltransferase, TdT. Through in vitro selection assays (SELEX), we recently showed that TdIF1 recognizes both AT-tract and a specific DNA sequence motif, 5'-TGCATG-3', and can up-regulate the expression of RAB20 through the latter motif. However, whether TdIF1 binds to these sequences in the cells has not been clear and its other target genes remain to be identified. Here, we determined in vivo TdIF1-binding sequences (TdIF1-invivoBMs) on the human chromosomes through ChIP-seq analyses. The result showed a 160-base pair cassette containing 'AT-tract~palindrome (inverted repeat)~AT-tract' as a likely target sequence of TdIF1. Interestingly, the core sequence of the palindrome in the TdIF1-invivoBMs shares significant similarity to the above 5'-TGCATG-3' motif determined by SELEX in vitro. Furthermore, spacer sequences between AT-tract and the palindrome contain many potential transcription factor binding sites. In luciferase assays, TdIF1 can up-regulate transcription activity of the promoters containing the TdIF1-invivoBM, and this effect is mainly through the palindrome. Clusters of this motif were found in the potential target genes. Gene ontology analysis and RT-qPCR showed the enrichment of some candidate targets of TdIF1 among the genes involved in the regulation of ossification. Potential modes of transcription activation by TdIF1 are discussed.