Home-Based Cognitive Intervention for Healthy Older Adults Through Asking Robots Questions: Randomized Controlled Trial.

Background: Asking questions is common in conversations, and while asking questions, we need to listen carefully to what others say and consider the perspective our questions adopt. However, difficulties persist in verifying the effect of asking questions on older adults' cognitive function due to the lack of a standardized system for conducting experiments at participants' homes. Objective: This study examined the intervention effect of cognitive training moderated by robots on healthy older adults. A focus on the feasibility of the intervention at participants' homes was also maintained. Feasibility was evaluated by considering both the dropout rate during the intervention and the number of questions posed to each participant during the experiment. Methods: We conducted a randomized controlled trial with 81 adults older than 65 years. Participants were recruited through postal invitations and then randomized into 2 groups. The intervention group (n=40) received sessions where participants listened to photo-integrated stories and posed questions to the robots. The control group (n=41) received sessions where participants listened to photo-integrated stories and only thanked the robots for confirming participation. The participants participated in 12 dialogue sessions for 2-3 weeks. Scores of global cognitive functioning tests, recall tests, and verbal fluency tasks measured before and after the intervention were compared between the 2 groups. Results: There was no significant intervention effect on the Telephone Interview for Cognitive Status-Japanese scores, recall tests, and verbal fluency tasks. Additionally, our study successfully concluded with no participant dropouts at follow-up, confirming the feasibility of our approach. Conclusions: There was no statistically significant evidence indicating intervention benefits for cognitive functioning. Although the feasibility of home-based interventions was demonstrated, we identified areas for improvement in the future, such as setting up more efficient session themes. Further research is required to identify the effectiveness of an improved cognitive intervention involving the act of asking questions.

Impaired glycosylation of gastric mucins drives gastric tumorigenesis and serves as a novel therapeutic target.

BACKGROUND: Gastric cancer is often accompanied by a loss of MUC6, but its pathogenic role in gastric carcinogenesis remains unclear. METHOD: Muc6 knockout (Muc6-/-) mice and Muc6-dsRED mice were newly generated. Tff1Cre, Golph3-/-, R26-Golgi-mCherry, Hes1flox/flox, Cosmcflox/flox, A4gnt-/- mice were also used. Histology, DNAs and RNAs, proteins, and sugar chains were analyzed by whole exon DNA sequence, RNA sequence, immunohistochemistry, lectin-binding assays, and LC-MS analysis. Gastric organoids and cell lines were used for in vitro assays and xenograft experiments. RESULT: Deletion of Muc6 in mice spontaneously causes pan-gastritis and invasive gastric cancers. Muc6-deficient tumor growth was dependent on MAPK activation, mediated by Golgi stress-induced upregulation of GOLPH3. Glycomic profiling revealed aberrant expression of mannose-rich N-linked glycans in gastric tumors, detected with Banana lectin in association with lack of MUC6 expression. We identified a precursor of clusterin as a binding partner of mannose glycans. MAPK activation, Golgi stress responses, aberrant mannose expression are found in a separate Cosmc- and A4gnt-deficient mouse models which lack normal O-glycosylation. Banana lectin-drug conjugates proved an effective treatment for mannose-rich murine and human gastric cancer. CONCLUSION: We propose that Golgi stress responses and aberrant glycans are important drivers of, and promising new therapeutic targets for gastric cancer.

Adapting the Number of Questions Based on Detected Psychological Distress for Cognitive Behavioral Therapy With an Embodied Conversational Agent: Comparative Study.

BACKGROUND: The high prevalence of mental illness is a critical social problem. The limited availability of mental health services is a major factor that exacerbates this problem. One solution is to deliver cognitive behavioral therapy (CBT) using an embodied conversational agent (ECA). ECAs make it possible to provide health care without location or time constraints. One of the techniques used in CBT is Socratic questioning, which guides users to correct negative thoughts. The effectiveness of this approach depends on a therapist's skill to adapt to the user's mood or distress level. However, current ECAs do not possess this skill. Therefore, it is essential to implement this adaptation ability to the ECAs. OBJECTIVE: This study aims to develop and evaluate a method that automatically adapts the number of Socratic questions based on the level of detected psychological distress during a CBT session with an ECA. We hypothesize that this adaptive approach to selecting the number of questions will lower psychological distress, reduce negative emotional states, and produce more substantial cognitive changes compared with a random number of questions. METHODS: In this study, which envisions health care support in daily life, we recruited participants aged from 18 to 65 years for an experiment that involved 2 different conditions: an ECA that adapts a number of questions based on psychological distress detection or an ECA that only asked a random number of questions. The participants were assigned to 1 of the 2 conditions, experienced a single CBT session with an ECA, and completed questionnaires before and after the session. RESULTS: The participants completed the experiment. There were slight differences in sex, age, and preexperimental psychological distress levels between the 2 conditions. The adapted number of questions condition showed significantly lower psychological distress than the random number of questions condition after the session. We also found a significant difference in the cognitive change when the number of questions was adapted based on the detected distress level, compared with when the number of questions was fewer than what was appropriate for the level of distress detected. CONCLUSIONS: The results show that an ECA adapting the number of Socratic questions based on detected distress levels increases the effectiveness of CBT. Participants who received an adaptive number of questions experienced greater reductions in distress than those who received a random number of questions. In addition, the participants showed a greater amount of cognitive change when the number of questions matched the detected distress level. This suggests that adapting the question quantity based on distress level detection can improve the results of CBT delivered by an ECA. These results illustrate the advantages of ECAs, paving the way for mental health care that is more tailored and effective.

Transcription factor Nrf2 activation regulates NETosis, endothelial injury, and kidney disease in myeloperoxidase-positive antineutrophil cytoplasmic antibody-associated vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease pathologically characterized by vascular necrosis with inflammation. During AAV development, activated neutrophils produce reactive oxygen species (ROS), leading to the aberrant formation of neutrophil extracellular traps (NETs) via NETosis and subsequent fibrinoid vascular necrosis. Nuclear factor-erythroid 2-related factor 2 (Nrf2) functions as an intracellular defense system to counteract oxidative stress by providing antioxidant properties. Herein, we explored the role of Nrf2 in the pathogenesis of AAV. The role and mechanism of Nrf2 in ANCA-stimulated neutrophils and subsequent endothelial injury were evaluated in vitro using Nrf2 genetic deletion and Nrf2 activator treatment. In corresponding in vivo studies, the role of Nrf2 in ANCA-transfer AAV and spontaneous AAV murine models was examined. Pharmacological activation of Nrf2 in vitro suppressed ANCA-induced NET formation via the inhibition of ROS. In contrast, NET formation was enhanced in Nrf2-deficient neutrophils. Furthermore, Nrf2 activation protected endothelial cells from ANC-induced NETs-mediated injury. In vivo, Nrf2 activation ameliorated glomerulonephritis in two AAV models by upregulating antioxidants and inhibiting ROS-mediated NETs. Furthermore, Nrf2 activation restrained the expansion of splenic immune cells, including T lymphocytes and limited the infiltration of Th17 cells into the kidney. In contrast, Nrf2 genetic deficiency exacerbated vasculitis in a spontaneous AAV model. Thus, the pathophysiological process in AAV may be downregulated by Nrf2 activation, potentially leading to a new therapeutic strategy by regulating NETosis.

Radiation Exposure Characteristics among Healthcare Workers: Before and After Japan's Ordinance Revision.

ABSTRACT: Radioactive materials and ionizing radiation have both medical value and disease risks, necessitating radiation dose measurement and risk reduction strategies. The International Commission on Radiological Protection (ICRP) lowered the lens of the eye exposure limit, leading to Japan's revised "Ionizing Radiation Ordinance." However, the effects on radiation exposure in medical settings and compliance feasibility remain unclear. To examine the impact of the revision to the "Ionizing Radiation Ordinance" and use it for measures to reduce exposure to radiation, a comprehensive analysis was conducted on data collected from Nagasaki University Hospital, Hiroshima University Hospital, and Fukushima Medical University Hospital in 2018, 2020, and April to September 2021. This included information on age, sex, occupation, department, and monthly radiation doses of workers, aiming to assess the impact of the revision to the "Ionizing Radiation Ordinance" on radiation exposure before and after its enforcement. Out of 9,076 cases studied, 7,963 (87.7%) had radiation doses below the measurable limit throughout the year. Only 292 cases (3.2%) exceeded 1 mSv y -1 , with 9 doctors and 2 radiological technologists surpassing 5 mSv y -1 . Radiological technologists showed significantly higher doses compared to doctors, dentists, and nurses (p < 0.01), while male subjects had significantly higher exposure doses than females (p < 0.01). No significant changes in radiation exposure were observed before and after the revision of the Ionizing Radiation Ordinance; however, variations in radiation exposure control were noted, particularly among nurses and radiological technologists, suggesting the impact of the revision and the need for tailored countermeasures to reduce radiation dose in each group.

Optimizing cardiac amyloidosis assessment: utility of 1-h and 3-h 99mTc-PYP imaging.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM), characterized by the extracellular deposition of an insoluble amyloid protein in the heart, is one of the main causes of heart failure in elderly patients. In this study, our primary objective was to explore the diverse applications and temporal significance of 1-h and 3-h imaging using 99mTc-PYP in the context of ATTR-CM. Additionally, we compared tracer kinetics in the heart and bone to comprehensively assess the diagnostic advantages and time-related considerations associated with these two incubation periods. METHODS: Twenty-seven patients at Nagasaki University Hospital who underwent 99mTc-PYP planar, and SPECT cardiac imaging were classified into two groups (ATTR-CM-positive and -negative groups) based on the American Heart Association statement. Cardiac retention was assessed with both a semiquantitative visual score and a quantitative analysis. To assess bone accumulation, a ROI with an equal volume was drawn on the sternum and calculated as the bone-to-contralateral ratio (B/CL). We also evaluated correlation between heart-to-contralateral lung (H/CL) ratio and left ventricular wall thickness. RESULTS: Among patients who underwent 99mTc-PYP imaging, the H/CL ratio was significantly higher at 1 h than at 3 h regardless of the group (from 2.20 ± 0.36 to 1.99 ± 0.35, p < 0.01 in the positive group and from 1.35 ± 0.12 to 1.19 ± 0.21, p = 0.01 in the negative group). The gap of H/CL between highest H/CL of negative case and lowest H/CL of positive case was narrower in 3 h. On the other hand, correlation between H/CL and left ventricular posterior wall thickness tends to be clearer in 3 h (p = 0.12, r = 0.30 for 1 h, p = 0.04, r = 0.39 at 3 h). CONCLUSION: Our study suggests that both 1-h and 3-h incubation times for 99mTc-PYP imaging have different benefits for ATTR cardiac amyloidosis. A one-hour incubation may be preferable for differential diagnostic purposes, while a three-hour incubation may provide greater utility in evaluating disease severity.

Practice recommendation for measuring washout rates in 123I-BMIPP fatty acid images.

The purpose of this practice recommendation is to specifically identify the critical steps involved in performing and interpreting 123I-ß-methyl-iodophenyl-pentadecanoic acid (BMIPP) single-photon emission computed tomography (SPECT) and measurement of washout rate (WR) from the heart. This document will cover backgrounds, patient preparation, testing procedure, visual image interpretation, quantitation methods using planar and SPECT studies, and reporting of WR. The pitfall and some tips for the calculation of 123I-BMIPP WR are also included. The targets of global and regional WR calculation include ischemic heart disease, cardiomyopathy, heart failure, and triglyceride deposit cardiomyovasculopathy, an emerging rare heart disease.

Living Arrangements Predict Frequent Alcohol Consumption Among University Students: A Retrospective Cohort Study.

PURPOSE: This study aimed to confirm the clinical impact of living arrangements on incidence of frequent alcohol consumption in university students. DESIGN: A retrospective cohort study. SETTING: A national university in Japan. SUBJECTS: 17,774 university students. MEASURES: The association between living arrangements on admission and the incidence of frequent alcohol consumption (≥4 days/week) was assessed using multivariable-adjusted Cox proportional-hazards models. RESULTS: Among 5,685, 692, and 5,151 male students living with family, living in the dormitory, and living alone, 5.0%, 6.2%, and 5.8% reported frequent alcohol consumption during the median observational period of 3.0 years, respectively. Living in the dormitory and living alone were identified as significant predictors of frequent alcohol consumption (multivariable-adjusted hazard ratios: 1.00 [reference], 1.39 [1.01-1.92], and 1.21 [1.03-1.42], respectively). On the contrary, living arrangements were not associated with the incidence of frequent alcohol consumption among of 6,091 female students, partly because of low incidence of frequent alcohol consumption (2.3%, 1.4%, and 2.6%, respectively). CONCLUSIONS: Living arrangements predicted frequent alcohol consumption among male university students, whereas not among female university students.

Assessment of Interobserver Agreement in the Interpretation of 99mTc-PYP SPECT Imaging of Cardiac Amyloidosis.

Background: Technetium-99m pyrophosphate single photon emission computed tomography (99mTc-PYP SPECT) imaging is widely used to diagnose cardiac amyloidosis, a disease characterized by amyloid protein deposits in the myocardium. The effects of viewing perspectives on interobserver agreement in the interpretation of 99mTc-PYP SPECT images for the diagnosis of cardiac amyloidosis remain unclear. Methods: A retrospective analysis of 32 consecutive patients who underwent 99mTc-PYP imaging for the diagnosis of cardiac amyloidosis at Nagasaki University Hospital between October 2017 and February 2020 was performed. Four evaluators independently reviewed coronal, sagittal, and transaxial images and then all images together and made a categorical diagnosis based on predefined criteria. Interobserver agreement was analyzed using Cohen's Kappa analysis. Results: Kappa coefficient values in the four-grade grading system (grades 0-3) ranged between 0.31 and 0.95, while those in the binary grading system (positive/negative) ranged between 0.88 and 1. The sagittal view showed the highest value in the four-grade grading system (0.95) and the lowest in the binary grading system (0.88). The transaxial view was more likely to show a consistently high kappa value in both the four-grade and binary grading systems. The use of the multiplanar view reduced the number of subjects classified as grade 1. Conclusion: Our study demonstrates that the transaxial view provides the most consistent interpretation of 99mTc-PYP SPECT images for the diagnosis of cardiac amyloidosis. The use of the multiplanar view may also reduce equivocal interpretations, which are graded as grade 1. Further studies with larger sample sizes and a quantitative analysis are needed to confirm the present results.

Practice Recommendation for Measuring Washout Rates in 123I-BMIPP Fatty Acid Images.

The purpose of this practice recommendation is to specifically identify the critical steps involved in performing and interpreting 123I-ß-methyl-iodophenyl-pentadecanoic acid (BMIPP) single-photon emission computed tomography (SPECT) and measurement of washout rate (WR) from the heart. This document will cover backgrounds, patient preparation, testing procedure, visual image interpretation, quantitation methods using planar and SPECT studies, and reporting of WR. The pitfall and some tips for the calculation of 123I-BMIPP WR are also included. The targets of global and regional WR calculation include ischemic heart disease, cardiomyopathy, heart failure, and triglyceride deposit cardiomyovasculopathy, an emerging rare heart disease.

Inhibition of Toll-like receptor 4 and Interleukin-1 receptor prevent SARS-CoV-2 mediated kidney injury.

Acute kidney injury (AKI) is a common and severe complication of the coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly affects the glomerular and tubular epithelial cells to induce AKI; however, its pathophysiology remains unclear. Here, we explored the underlying mechanisms and therapeutic targets of renal involvement in COVID-19. We developed an in vitro human kidney cellular model, including immortalized tubular epithelial and endothelial cell lines, demonstrating that SARS-CoV-2 directly triggers cell death. To identify the molecular targets in the process of SARS-CoV-2-mediated cell injury, we performed transcriptional analysis using RNA sequencing. Tubular epithelial cells were more prone to dying by SARS-CoV-2 than endothelial cells; however, SARS-CoV-2 did not replicate in renal cells, distinct from VeroE6/transmembrane protease serine 2 cells. Transcriptomic analysis revealed increased inflammatory and immune-related gene expression levels in renal cells incubated with SARS-CoV-2. Toll-like receptor (TLR) 3 in renal cells recognized viral RNA and underwent cell death. Furthermore, analysis of upstream regulators identified several key transcriptional regulators. Among them, inhibition of the interleukin-1 receptor (IL-1R) and TLR4 pathways protects tubular epithelial and endothelial cells from injury via regulation of the signal transducer and activator of transcription protein-3/nuclear factor-kB pathway. Our results reveal that SARS-CoV-2 directly injures renal cells via the proinflammatory response without viral replication, and that IL-1R and TLR4 may be used as therapeutic targets for SARS-CoV-2 mediated kidney injury.

CD47 blockade ameliorates autoimmune vasculitis via efferocytosis of neutrophil extracellular traps.

Neutrophil extracellular trap (NET) formation contributes to immune defense and is a distinct form of cell death. Excessive NET formation is found in patients with anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) vasculitis (AAV), contributing to disease progression. The clearance of dead cells by macrophages, a process known as efferocytosis, is regulated by the CD47-mediated "don't eat me" signal. Hence, we hypothesized that pathogenic NETs in AAV escape from efferocytosis via the CD47 signaling pathway, resulting in the development of necrotizing vasculitis. Immunostaining for CD47 in human renal tissues revealed high CD47 expression in crescentic glomerular lesions of patients with AAV. In ex vivo studies, ANCA-induced netting neutrophils increased the expression of CD47 with the reduction of efferocytosis. After efferocytosis, macrophages displayed proinflammatory phenotypes. The blockade of CD47 in spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice ameliorated renal disease and reduced myeloperoxidase-ANCA (MPO-ANCA) titers with a reduction in NET formation. Thus, CD47 blockade would protect against developing glomerulonephritis in AAV via restored efferocytosis of ANCA-induced NETs.

Improvement of Protein Expression Profile in Three-Dimensional Renal Proximal Tubular Epithelial Cell Spheroids Selected Based on OAT1 Gene Expression: A Potential In Vitro Tool for Evaluating Human Renal Proximal Tubular Toxicity and Drug Disposition.

The proximal tubule plays an important role in the kidney and is a major site of drug interaction and toxicity. Analysis of kidney toxicity via in vitro assays is challenging, because only a few assays that reflect functions of drug transporters in renal proximal tubular epithelial cells (RPTECs) are available. In this study, we aimed to develop a simple and reproducible method for culturing RPTECs by monitoring organic anion transporter 1 (OAT1) as a selection marker. Culturing RPTECs in spherical cellular aggregates increased OAT1 protein expression, which was low in the conventional two-dimensional (2D) culture, to a level similar to that in human renal cortices. By proteome analysis, it was revealed that the expression of representative two proximal tubule markers was maintained and 3D spheroid culture improved the protein expression of approximately 7% of the 139 transporter proteins detected, and the expression of 2.3% of the 4,800 proteins detected increased by approximately fivefold that in human renal cortices. Furthermore, the expression levels of approximately 4,800 proteins in three-dimensional (3D) RPTEC spheroids (for 12 days) were maintained for over 20 days. Cisplatin and adefovir exhibited transporter-dependent ATP decreases in 3D RPTEC spheroids. These results indicate that the 3D RPTEC spheroids developed by monitoring OAT1 gene expression are a simple and reproducible in vitro experimental system with improved gene and protein expressions compared with 2D RPTECs and were more similar to that in human kidney cortices. Therefore, it can potentially be used for evaluating human renal proximal tubular toxicity and drug disposition. SIGNIFICANCE STATEMENT: This study developed a simple and reproducible spheroidal culture method with acceptable throughput using commercially available RPTECs by monitoring OAT1 gene expression. RPTECs cultured using this new method showed improved mRNA/protein expression profiles to those in 2D RPTECs and were more similar to those of human kidney cortices. This study provides a potential in vitro proximal tubule system for pharmacokinetic and toxicological evaluations during drug development.

Reduction in disialyl-T antigen levels in mice deficient for both St6galnac3 and St6galnac4 results in blood filling of lymph nodes.

Sialic acid (SA) is present at the terminal ends of carbohydrate chains in glycoproteins and glycolipids and is involved in various biological phenomena. The biological function of the disialyl-T (SAα2-3Galß1-3(SAα2-6)GalNAcα1-O-Ser/Thr) structure is largely unknown. To elucidate the role of disialyl-T structure and determine the key enzyme from the N-acetylgalactosaminide α2,6-sialyltransferase (St6galnac) family involved in its in vivo synthesis, we generated St6galnac3- and St6galnac4-deficient mice. Both single-knockout mice developed normally without any prominent phenotypic abnormalities. However, the St6galnac3::St6galnact4 double knockout (DKO) mice showed spontaneous hemorrhage of the lymph nodes (LN). To identify the cause of bleeding in the LN, we examined podoplanin, which modifies the disialyl-T structures. The protein expression of podoplanin in the LN of DKO mice was similar to that in wild-type mice. However, the reactivity of MALII lectin, which recognizes disialyl-T, in podoplanin immunoprecipitated from DKO LN was completely abolished. Moreover, the expression of vascular endothelial cadherin was reduced on the cell surface of high endothelial venule (HEV) in the LN, suggesting that hemorrhage was caused by the structural disruption of HEV. These results suggest that podoplanin possesses disialyl-T structure in mice LN and that both St6galnac3 and St6galnac4 are required for disialyl-T synthesis.

Development and Validation of a Proteomic Correlation Profiling Technique to Detect and Identify Enzymes Involved in Metabolism of Drugs of Concern.

To predict the variation of pharmacological or toxicological effect caused by pharmacokinetic variance, it is important to be able to detect previously unknown and unsuspected enzymes involved in drug metabolism. We investigated the use of proteomic correlation profiling (PCP) as a technique to identify the enzymes involved in metabolism of drugs of concern. By evaluating the metabolic activities of each enzyme (including isoforms of cytochrome P450, uridine 5' diphospho-glucuronosyltransferase, and hydrolases, plus aldehyde oxidase and carbonyl reductase) on their typical substrates using a panel of human liver samples, we were able to show the validity of PCP for this purpose. R or Rs and P values were calculated for the association between the protein abundance profile of each protein and the metabolic rate profile of each typical substrate. For the 18 enzymatic activities examined, 13 of the enzymes reported to be responsible for the reactions had correlation coefficients higher than 0.7 and were ranked first to third. For the remaining five activities, the responsible enzymes had correlation coefficients lower than 0.7 and lower rankings. The reasons for this were diverse, including confounding resulting from low protein abundance ratios, artificially high correlations of other enzymes due to limited sample numbers, the presence of inactive enzyme forms, and genetic polymorphisms. Overall, PCP was able to identify the majority of responsible drug-metabolizing enzymes across several enzyme classes (oxidoreductase, transferase, hydrolase); use of this methodology could allow more timely and accurate identification of unknown drug-metabolizing enzymes. SIGNIFICANCE STATEMENT: Proteomic correlation profiling using samples from individual human donors was proven to be a useful methodology for the identification of enzymes responsible for drug-metabolism. This methodology could accelerate the identification of unknown drug-metabolizing enzymes in the future.

Reduction of thyroid radioactive iodine exposure by oral administration of cyclic oligosaccharides.

Alpha-cyclodextrin, a six D-glucose cyclic oligosaccharide, has several applications in food and pharmaceuticals, but has also been reported to retain iodine in a stable manner for 16 months. Radioactive iodine, which may cause thyroid cancer and hypofunction, must be properly managed. If the absorption of radioactive iodine is suppressed, it can be expected to lead to a reduction in thyroid exposure. This study clarified the inhibition of radioactive iodine absorption by the oral administration of α-cyclodextrin in a murine model using direct measurement of single photon emission computed tomography. The uptake of radioactive iodine into the thyroid gland in mice administered with radioactive iodine and an α-cyclodextrin solution was approximately 40% lower after 24 h. The finding that oral uptake of α-cyclodextrin has an inhibitory effect on the transfer of radioactive iodine to the thyroid gland has potential for application in many fields such as food, pharmaceuticals, nuclear emergency preparedness, and medicine.

Lunar gravity prevents skeletal muscle atrophy but not myofiber type shift in mice.

Skeletal muscle is sensitive to gravitational alterations. We recently developed a multiple artificial-gravity research system (MARS), which can generate gravity ranging from microgravity to Earth gravity (1 g) in space. Using the MARS, we studied the effects of three different gravitational levels (microgravity, lunar gravity [1/6 g], and 1 g) on the skeletal muscle mass and myofiber constitution in mice. All mice survived and returned to Earth, and skeletal muscle was collected two days after landing. We observed that microgravity-induced soleus muscle atrophy was prevented by lunar gravity. However, lunar gravity failed to prevent the slow-to-fast myofiber transition in the soleus muscle in space. These results suggest that lunar gravity is enough to maintain proteostasis, but a greater gravitational force is required to prevent the myofiber type transition. Our study proposes that different gravitational thresholds may be required for skeletal muscle adaptation.

Chest pain and Raynaud's phenomenon after COVID-19 vaccination in a patient previously diagnosed with systemic lupus erythematosus: a case report.

Background: Cardiovascular events, including pericarditis, myocarditis, and myocardial ischaemia, have been reported as complications following COVID-19 vaccination. Case summary: A 28-year-old Japanese woman diagnosed 10 years earlier with systemic lupus erythematosus and antiphospholipid syndrome was admitted to our hospital because of chest pain and Raynaud's phenomenon. She had received a second dose of the COVID-19 BNT162b2 mRNA vaccine 28 days earlier. 123I-ß-methyl iodophenyl pentadecanoic acid (BMIPP) and 201thallium dual myocardial single-photon emission computed tomography demonstrated mildly reduced perfusion of BMIPP in the mid-anterior wall of the left ventricle. Coronary angiography revealed normal coronary arteries; additionally, an endomyocardial biopsy was performed. Histopathological evaluation revealed a normal myocardium without cell infiltration. However, immunostaining for the severe acute respiratory coronavirus (SARS-CoV)/severe acute respiratory coronavirus 2 (SARS-CoV-2) spike protein was positive in the small intramural coronary arteries. The administration of azathioprine (50 mg/day) and amlodipine (5 mg/day) and increases in her prednisolone (10 mg/day) and aspirin doses led to improvements in the symptoms of the patient. Discussion: Our data lead us to speculate that two events in the timeline of the patient, namely, receiving COVID-19 vaccination and the presence of SARS-CoV/SARS-CoV-2 spike protein in small intramural coronary arteries, may be related to the myocardial microangiopathy observed in this patient.

Characterization of Enzymes Involved in Nintedanib Metabolism in Humans.

Nintedanib, which is used to treat idiopathic pulmonary fibrosis and non-small cell lung cancer, is metabolized to a pharmacologically inactive carboxylate derivative, BIBF1202, via hydrolysis and subsequently by glucuronidation to BIBF1202 acyl-glucuronide (BIBF1202-G). Since BIBF1202-G contains an ester bond, it can be hydrolytically cleaved to BIBF1202. In this study, we sought to characterize these metabolic reactions in the human liver and intestine. Nintedanib hydrolysis was detected in human liver microsomes (HLMs) (Clearance [CL int]: 102.8 ± 18.9 µL/min per mg protein) but not in small intestinal preparations. CES1 was suggested to be responsible for nintedanib hydrolysis according to experiments using recombinant hydrolases and hydrolase inhibitors as well as proteomic correlation analysis using 25 individual HLM. BIBF1202 glucuronidation in HLM (3.6 ± 0.3 µL/min per mg protein) was higher than that in human intestinal microsomes (1.5 ± 0.06 µL/min per mg protein). UGT1A1 and gastrointestinal UGT1A7, UGT1A8, and UGT1A10 were able to mediate BIBF1202 glucuronidation. The impact of UGT1A1 on glucuronidation was supported by the finding that liver microsomes from subjects homozygous for the UGT1A1*28 allele showed significantly lower activity than those from subjects carrying the wild-type UGT1A1 allele. Interestingly, BIBF1202-G was converted to BIBF1202 in HLS9 at 70-fold higher rates than the rates of BIBF1202 glucuronidation. An inhibition study and proteomic correlation analysis suggested that ß-glucuronidase is responsible for hepatic BIBF1202-G deglucuronidation. In conclusion, the major metabolic reactions of nintedanib in the human liver and intestine were quantitatively and thoroughly elucidated. This information could be helpful to understand the inter- and intraindividual variability in the efficacy of nintedanib. SIGNIFICANCE STATEMENT: To our knowledge, this is the first study to characterize the enzymes responsible for each step of nintedanib metabolism in the human body. This study found that ß-glucuronidase may contribute to BIBF1202-G deglucuronidation.