Characterization of Urate Transport System in JAR and JEG-3 Cells, Human Trophoblast-derived Cell Lines

Urate (uric acid) is the major inert end product of purine metabolism in humans. Since it is water soluble, it requires a membranous protein called transporter for its permeation across the plasma membrane. Increased blood urate level is often seen in preeclampsia, but its precise mechanism remains unknown. Syncytiotrophoblasts function as a barrier between maternal blood and fetal one so called “blood-placental barrier”. So far, the expression of several urate transporters was identified in these cells, but it is still unclear about their contribution to urate handling in blood-placental barrier. In this study, we investigated the expression of urate transporters and the properties of ［14C］urate transport in both JAR and JEG-3, human choriocarcinoma cells as a model of human placenta. Conventional PCR analysis revealed that both JAR and JEG-3 cells express strongly breast cancer resistance protein (BCRP/ABCG2) mRNA. Uptake of ［14C］urate by these cells is time-dependent with Na＋- and Cl－-independent and voltage-insensitive manner and is not inhibited by benzbromarone, a representative renal urate transport inhibitor. Then, we focused on BCRP which shows strong mRNA expression and found that these cells have urate efflux property that is sensitive to fumitremorgin C (FMC), a BCRP inhibitor. These results suggest that BCRP is one of the important components for urate handling in human placenta in pathophysiological condition such as preeclampsia

Development of split-force-controlled body weight support (SF-BWS) robot for gait rehabilitation

This study introduces a body-weight-support (BWS) robot actuated by two pneumatic artificial muscles (PAMs). Conventional BWS devices typically use springs or a single actuator, whereas our robot has a split force-controlled BWS (SF-BWS), in which two force-controlled actuators independently support the left and right sides of the user’s body. To reduce the experience of weight, vertical unweighting support forces are transferred directly to the user’s left and right hips through a newly designed harness with an open space around the shoulder and upper chest area to allow freedom of movement. A motion capture evaluation with three healthy participants confirmed that the proposed harness does not impede upper-body motion during laterally identical force-controlled partial BWS walking, which is quantitatively similar to natural walking. To evaluate our SF-BWS robot, we performed a force-tracking and split-force control task using different simulated load weight setups (40, 50, and 60 kg masses). The split-force control task, providing independent force references to each PAM and conducted with a 60 kg mass and a test bench, demonstrates that our SF-BWS robot is capable of shifting human body weight in the mediolateral direction. The SF-BWS robot successfully controlled the two PAMs to generate the desired vertical support forces

In vivo radioactive metabolite analysis for individualized medicine: A basic study of a new method of CYP activity assay using 123I-IMP

Introduction: 123I-N-isopropyl-p-iodoamphetamine (123I-IMP) is metabolized and converted to 123I-p-iodoamphetamine (123I-PIA) by CYP2C19 in humans. Since variations in 123I-PIA levels reflect variations in CYP2C19 activity, CYP2C19 activity can be estimated by quantitative analysis of 123I-PIA levels. Thus, 123I-IMP administration can provide diagnostic information not only regarding cerebral blood flow (rCBF) but also regarding metabolic function. The aim of the present study was to detect variations in CYP activity in mice using metabolite analysis. Methods: Metabolism of 125I-IMP in pooled homogenates of mouse liver (MLH) was analyzed by high-performance liquid chromatography (HPLC) in the presence or absence of NADPH. The amount of 125I-PIA generated was calculated as the normalized peak area of the chromatogram. Inhibition of 125I-IMP metabolism was evaluated using the inhibitor SKF-525A. A biodistribution study of 125I-IMP was performed to determine the organ distribution of 125I-IMP/125I-IMP metabolites and the effect of SKF-525A. Variations in CYP activity in vivo were detected by administration of 123I-IMP and/or SKF-525A to mice. The liver and the kidney were then excised, homogenized and analyzed using HPLC. Results: 125I-IMP was metabolized by MLH in the presence of NADPH, and the production of 125I-PIA was inhibited by SKF-525A. SKF-525A did not greatly affect the biodistribution of 125I-IMP/125I-IMP metabolites in vivo. Both 123I-IMP and 123I-PIA were detected in organs of control mice. However, 123I-PIA was not detected in the livers or kidneys of mice treated with SKF-525A. Conclusions: CYP activity in vivo was inhibited by SKF-525A treatment. Variations in CYP activity could be detected in the blood, liver and kidney as changes in the peak area of 123I-PIA. Advances in knowledge and implications for patient care: 123I-IMP metabolite analysis has the potential to provide beneficial information for prediction of the effect of medicines, in addition to its contribution to more accurate rCBF diagnosis that reflects individual CYP activity

Endogenous oxytocin levels in extracted saliva elevates during breastfeeding correlated with lower postpartum anxiety in primiparous mothers

Background: Breastfeeding in the early postpartum period is expected to have mental benefits for mothers; however, the underlying sychobiological mechanisms remain unclear. Previously, we hypothesized that the release of oxytocin in response to the suckling stimuli during breastfeeding would mediate a calming effect on primiparous mothers, and we examined salivary oxytocin measurements in primiparous mothers at postpartum day 4 using saliva samples without extraction, which was erroneous. Thus, further confirmation of this hypothesis with a precise methodology was needed.Methods: We collected saliva samples at three time points (baseline, feeding, and post-feeding) to measure oxytocin in 24 primiparous mothers on postpartum day 2 (PD2) and 4 (PD4) across the breastfeeding cycle. Salivary oxytocin levels using both extracted and unextracted methods were measured and compared to determine the qualitative differences. State and trait anxiety and clinical demographics were evaluated to determine their association with oxytocin changes.Results: Breastfeeding elevated salivary oxytocin levels; however, it was not detected to a significant increase in the extraction method at PD4. We found a weak but significant positive correlation between changes in extracted and unextracted oxytocin levels during breastfeeding (feeding minus baseline); there were no other significant positive correlations. Therefore, we used the extracted measurement index for subsequent analysis. We showed that the greater the increase in oxytocin during breastfeeding, the lower the state anxiety, but not trait anxiety. Mothers who exclusively breastfed at the 1-month follow-up tended to be associated with slightly higher oxytocin change at PD2 than those who did not.Conclusions: Breastfeeding in early postpartum days could be accompanied by the frequent release of oxytocin and lower state anxiety, potentially contributing to exclusive breastfeeding

Isotopic evidence for acidity-driven enhancement of sulfate formation after SO2 emission control

After the 1980s, atmospheric sulfate reduction is slower than the dramatic reductions in sulfur dioxide (SO2) emissions. However, a lack of observational evidence has hindered the identification of causal feedback mechanisms. Here, we report an increase in the oxygen isotopic composition of sulfate (Δ17OSO42-) in a Greenland ice core, implying an enhanced role of acidity-dependent in-cloud oxidation by ozone (up to 17 to 27 in sulfate production since the 1960s. A global chemical transport model reproduces the magnitude of the increase in observed Δ17OSO42- with a 10 to 15 to sulfate in Eastern North America and Western Europe. With an expected continued decrease in atmospheric acidity, this feedback will continue in the future and partially hinder air quality improvements

Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs

There is a high death rate of lung cancer patients. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in some lung adenocarcinoma patients with EGFR mutations. However, a significant number of patients show primary and acquire resistance to EGFR-TKIs. Although the Akt kinase is commonly activated due to various resistance mechanisms, the key targets of Akt remain unclear. Here, we show that the Akt-β-catenin pathway may be a common resistance mechanism. We analyzed gene expression profiles of gefitinib-resistant PC9M2 cells that were derived from gefitinib-sensitive lung cancer PC9 cells and do not have known resistance mechanisms including EGFR mutation T790M. We found increased expression of Axin, a β-catenin target gene, increased phosphorylation of Akt and GSK3, accumulation of β-catenin in the cytoplasm/nucleus in PC9M2 cells. Both knockdown of β-catenin and treatment with a β-catenin inhibitor at least partially restored gefitinib sensitivity to PC9M2 cells. Lung adenocarcinoma tissues derived from gefitinib-resistant patients displayed a tendency to accumulate β-catenin in the cytoplasm. We provide a rationale for combination therapy that includes targeting of the Akt-β-catenin pathway to improve the efficacy of EGFR-TKIs

Crystal architectures of a layered silicate on monodisperse spherical silica particles cause the topochemical expansion of the core-shell particles

Anisotropic structural changes in an expandable layered silicate (directed towards the c-axis) occurring on isotropic and monodisperse microspheres were detected by measurable increases in the grain size. The hierarchical changes were observed through pursing the sophisticated growth of expandable layered silicate crystals on monodisperse spherical silica particles with diameters of 1.0 mu m; the core-shell hybrids with a quite uniform grain size were successfully produced using a rotating Teflon-lined autoclave by reacting spherical silica particles in a colloidal suspension with lithium and magnesium ions under alkaline conditions at 373 K. The size distribution of the core-shell particles tended to be uniform when the amount of lithium ions in the initial mixture decreased. The intercalation of dioctadecyldimethylammonium ions into the small crystals through cation-exchange reactions expanded the interlayer space, topochemically increasing the grain size without any change occurring in the shapes of the core-shell particles. (C) 2015 Elsevier Inc. All rights reserved.ArticleMICROPOROUS AND MESOPOROUS MATERIALS. 215:168-174 (2015)journal articl

COVID-19 vaccine effectiveness against severe COVID-19 requiring oxygen therapy, invasive mechanical ventilation, and death in Japan: A multicenter case-control study (MOTIVATE study).

INTRODUCTION: Since the SARS-CoV-2 Omicron variant became dominant, assessing COVID-19 vaccine effectiveness (VE) against severe disease using hospitalization as an outcome became more challenging due to incidental infections via admission screening and variable admission criteria, resulting in a wide range of estimates. To address this, the World Health Organization (WHO) guidance recommends the use of outcomes that are more specific to severe pneumonia such as oxygen use and mechanical ventilation. METHODS: A case-control study was conducted in 24 hospitals in Japan for the Delta-dominant period (August-November 2021; "Delta") and early Omicron (BA.1/BA.2)-dominant period (January-June 2022; "Omicron"). Detailed chart review/interviews were conducted in January-May 2023. VE was measured using various outcomes including disease requiring oxygen therapy, disease requiring invasive mechanical ventilation (IMV), death, outcome restricting to "true" severe COVID-19 (where oxygen requirement is due to COVID-19 rather than another condition(s)), and progression from oxygen use to IMV or death among COVID-19 patients. RESULTS: The analysis included 2125 individuals with respiratory failure (1608 cases [75.7%]; 99.2% of vaccinees received mRNA vaccines). During Delta, 2 doses provided high protection for up to 6 months (oxygen requirement: 95.2% [95% CI:88.7-98.0%] [restricted to "true" severe COVID-19: 95.5% {89.3-98.1%}]; IMV: 99.6% [97.3-99.9%]; fatal: 98.6% [92.3-99.7%]). During Omicron, 3 doses provided high protection for up to 6 months (oxygen requirement: 85.5% [68.8-93.3%] ["true" severe COVID-19: 88.1% {73.6-94.7%}]; IMV: 97.9% [85.9-99.7%]; fatal: 99.6% [95.2-99.97]). There was a trend towards higher VE for more severe and specific outcomes. CONCLUSION: Multiple outcomes pointed towards high protection of 2 doses during Delta and 3 doses during Omicron. These results demonstrate the importance of using severe and specific outcomes to accurately measure VE against severe COVID-19, as recommended in WHO guidance in settings of intense transmission as seen during Omicron