New Highly Selective BACE1 Inhibitors and Their Effects on Dendritic Spine Density In Vivo

& beta;-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is considered a therapeutic target to combat Alzheimer's disease by reducing & beta;-amyloid in the brain. To date, all clinical trials involving the inhibition of BACE1 have been discontinued due to a lack of efficacy or undesirable side effects such as cognitive worsening. The latter could have been the result of the inhibition of BACE at the synapse where it is expressed in high amounts. We have previously shown that prolonged inhibition of BACE interferes with structural synaptic plasticity, most likely due to the diminished processing of the physiological BACE substrate Seizure protein 6 (Sez6) which is exclusively processed by BACE1 and is required for dendritic spine plasticity. Given that BACE1 has significant amino acid similarity with its homolog BACE2, the inhibition of BACE2 may cause some of the side effects, as most BACE inhibitors do not discriminate between the two. In this study, we used newly developed BACE inhibitors that have a different chemotype from previously developed inhibitors and a high selectivity for BACE1 over BACE2. By using longitudinal in vivo two-photon microscopy, we investigated the effect on dendritic spine dynamics of pyramidal layer V neurons in the somatosensory cortex in mice treated with highly selective BACE1 inhibitors. Treatment with those inhibitors showed a reduction in soluble Sez6 (sSez6) levels to 27% (elenbecestat, Biogen, Eisai Co., Ltd., Tokyo, Japan), 17% (Shionogi compound 1) and 39% (Shionogi compound 2), compared to animals fed with vehicle pellets. We observed a significant decrease in the number of dendritic spines with Shionogi compound 1 after 21 days of treatment but not with Shionogi compound 2 or with elenbecestat, which did not show cognitive worsening in clinical trials. In conclusion, highly selective BACE1 inhibitors do alter dendritic spine density similar to non-selective inhibitors if soluble (sSez6) levels drop too much. Low-dose BACE1 inhibition might be reasonable if dosing is carefully adjusted to the amount of Sez6 cleavage, which can be easily monitored during the first week of treatment

Pericardial Effusion in Association With Periodontitis: Case Report and Review of 8 Patients in Literature

Periodontal diseases are well-known background for infective endocarditis. Here, we show that pericardial effusion or pericarditis might have origin also in periodontal diseases. An 86-year-old man with well-controlled hypertension and diabetes mellitus developed asymptomatic increase in pericardial effusion. Two weeks previously, he took oral new quinolone antibiotics for a week because he had painful periodontitis along a dental bridge in the mandibular teeth on the right side and presented cheek swelling. The sputum was positive for Streptococcus species. He was healthy and had a small volume of pericardial effusion for the previous 5 years after drug-eluting coronary stents were inserted at the left anterior descending branch 10 years previously. The differential diagnoses listed for pericardial effusion were infection including tuberculosis, autoimmune diseases, and metastatic malignancy. Thoracic to pelvic computed tomographic scan demonstrated no mass lesions, except for pericardial effusion and a small volume of pleural effusion on the left side. Fluorodeoxyglucose positron emission tomography disclosed many spotty uptakes in the pericardial effusion. The patient denied pericardiocentesis, based on his evaluation of the risk of the procedure. He was thus discharged in several days and followed at outpatient clinic. He underwent dental treatment and pericardial effusion resolved completely in a month. He was healthy in 6 years until the last follow-up at the age of 92 years. We also reviewed 8 patients with pericarditis in association with periodontal diseases in the literature to reveal that periodontal diseases would be the background for developing infective pericarditis and also mediastinitis on some occasions

A liquid crystalline phase in spermidine-condensed DNA

Over a large range of salt and spermidine concentrations, short DNA fragments precipitated by spermidine (a polyamine) sediment in a pellet from a dilute isotropic supernatant. We report here that the DNA-condensed phase consists of a cholesteric liquid crystal in equilibrium with a more concentrated phase. These results are discussed according to Flory's theory for the ordering of rigid polymers. The liquid crystal described here corresponds to an ordering in the presence of attractive interactions, in contrast with classical liquid crystalline DNA. Polyamines are often used in vitro to study the functional properties of DNA. We suggest that the existence of a liquid crystalline state in spermidine-condensed DNA is relevant to these studies

A proposed combination of flat-panel detector and mobile X-ray systems for low-dose image-guided central venous catheter insertion

A central venous catheter (CVC) should be inserted at the optimum position to infuse medicines, blood products, nutrients, or fluids. Positioning of the catheter tip is commonly performed under landmark or fluoroscopic guidance. However, Japanese regulations do not allow the performing of fluoroscopy-guided procedures outside of the fluoroscopy room. We hypothesized that a new image-guided CVC placement technique by combining a wireless flat-panel detector (FPD) and a mobile X-ray system could be applied at the bedside to support CVC insertion. A CVC attached to a chest phantom in conjunction with the polymethyl methacrylate (PMMA) phantom was imaged, contrast-to-noise ratio (CNR) was measured with images, and radiologists and emergency physicians rated the catheter images using a Likert scale for visual evaluation. The minimum dose of the FPD and mobile X-ray system was reduced by at least 98% compared with that of the X-ray fluoroscopy system. The CNR decreased with the increasing PMMA phantom thickness. However, results of the visual evaluation were maintained at the clinically usable score with low-dose imaging up to a 6-cm thickness of the PMMA phantom. In conclusion, the combination of FPD and mobile X-ray systems is particularly effective in the emergency room setting where such procedures are required to be performed with urgency

Gastroesophageal reflux disease is a risk factor for sputum production in the general population: the Nagahama study

Background: Chronic sputum production in the general population is historically associated with clinical indices including male sex and smoking history. However, its relationship with gastroesophageal reflux disease (GERD), which may prove an underlying factor in sputum production, is unclear. We aimed to clarify factors associated with sputum production in the general population in cross-sectional and longitudinal manners. Methods: In the Nagahama study, a community-based cohort study, 9804 subjects were recruited between 2008 and 2010 (baseline assessment), 8293 of whom were followed from 2013 to 2015 (follow-up assessment). This study contained a self-completed questionnaire which included medical history, assessment of sputum production, and a frequency scale for symptoms of GERD. A Frequency Scale for Symptoms of Gastroesophageal Reflux Disease score of ≥ 8 was defined as GERD. In addition to the frequency of sputum production at each assessment, frequency of persistent sputum production defined as sputum production at both assessments was examined. Results: Frequency of sputum production was 32.0% at baseline and 34.5% at follow-up. Multivariable analysis demonstrated that sputum production at baseline was significantly associated with GERD [odds ratio (OR), 1.92; 95% confidence interval (CI) 1.73-2.13] and post-nasal drip (PND) (OR, 2.40; 95% CI 2.15-2.68), independent of other known factors such as older age, male sex and smoking history. These associations between sputum production and GERD or PND were also observed at follow-up. In longitudinal analysis, 19.4% had persistent sputum production and 12.3% had transient sputum production, i.e., at baseline only. Multivariable analysis for risk of persistence of sputum production revealed that persistent sputum production was associated with GERD and PND, in addition to the known risk factors listed above. The proportion of subjects with GERD at both assessments was highest among subjects with persistent sputum production. Conclusions: Cross-sectional and longitudinal analysis demonstrated an association in the general population between sputum production and GERD, as well as PND, independent of known risk factors. The presence of GERD should be assessed in patients complaining of sputum production

GALAXY CRUISE: Deep Insights into Interacting Galaxies in the Local Universe

We present the first results from GALAXY CRUISE, a community (or citizen) science project based on data from the Hyper Suprime-Cam Subaru Strategic Program (HSC-SSP). The current paradigm of galaxy evolution suggests that galaxies grow hierarchically via mergers, but our observational understanding of the role of mergers is still limited. The data from HSC-SSP are ideally suited to improve our understanding with improved identifications of interacting galaxies thanks to the superb depth and image quality of HSC-SSP. We have launched a community science project, GALAXY CRUISE, in 2019 and collected over 2 million independent classifications of 20,686 galaxies at z < 0.2. We first characterize the accuracy of the participants' classifications and demonstrate that it surpasses previous studies based on shallower imaging data. We then investigate various aspects of interacting galaxies in detail. We show that there is a clear sign of enhanced activities of super massive black holes and star formation in interacting galaxies compared to those in isolated galaxies. The enhancement seems particularly strong for galaxies undergoing violent merger. We also show that the mass growth rate inferred from our results is roughly consistent with the observed evolution of the stellar mass function. The 2nd season of GALAXY CRUISE is currently under way and we conclude with future prospects. We make the morphological classification catalog used in this paper publicly available at the GALAXY CRUISE website, which will be particularly useful for machine-learning applications.Comment: 23 pages, 22 figures, PASJ in press. Data available at https://galaxycruise.mtk.nao.ac.jp/en/for_researchers.htm

‘Politics’ of Site and Display: The Korean Comics Exhibition ‘Flowers that Never Wilt’ at the Angouleme International Comics Festival

This paper reports on the special exhibition of Korean comics ‘Flowers that Never Wilt’ at the 2014 Angouleme International Comics Festival. It also analyzes the ‘politics’ involved in the festival site and the exhibition display. The exhibition, which dealt with the issues of ‘comfort women’, raised disputes among the three involved countries: Korea, Japan and France. This paper tries to carefully examine the cause of these disputes, and to clarify the differences or the gaps in their perspectives towards exhibiting such political issues.本稿は、フランス・アングレーム市で毎年開催されるアングレーム国際ＢＤフェスティバルに出展された韓国漫画の展覧会「枯れない花」展を、現場のレポートを交えて概観するとともに、そこにおいて顕在化した場と展示の〈政治性〉についての考察を行うものである。これによって、日韓仏三国には、〈政治性〉をめぐる解釈に齟齬があること、またここには日韓間の問題だけではなく、ヨーロッパからみた「オリエント」としてのアジアという問題も、影を落としていることが明らかになった。※ 本研究の一部は、平成24年度関西大学在外研究による成果である。※本論文は、2013年度仁愛大学共同研究費およびJSPS 科学研究費・若手研究（B）研究課題番号：24730047 （代表 山中千恵）による研究成果の一部である