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Long-term habitation in space leads to physiological alterations such as bone loss, muscle atrophy, and cardiovascular deconditioning. Two predominant factors—namely space radiation and microgravity—have a crucial impact on oxidative stress in living organisms. Oxidative stress is also involved in the aging process, and plays important roles in the development of cardiovascular diseases including hypertension, left ventricular hypertrophy, and myocardial infarction. Here, we discuss the effects of space radiation, microgravity, and a combination of these two factors on oxidative stress. Future research may facilitate safer living in space by reducing the adverse effects of oxidative stress.

The egg coat including mammalian zona pellucida (ZP) and the avian equivalent, i.e., inner-perivitelline layer (IPVL), is a specialized extracellular matrix being composed of the ZP glycoproteins and surrounds both pre-ovulatory oocytes and ovulated egg cells in vertebrates. The egg coat is well known for its potential importance in both the reproduction and early development, although the underlying molecular mechanisms remain to be fully elucidated. Interestingly, ZP3, one of the ZP-glycoprotein family members forming scaffolds of the egg-coat matrices with other ZP glycoproteins, exhibits extreme but distinctive microheterogeneity to form a large number of isoelectric-point isoforms at least in the chicken IPVL. In the present study, we performed three-dimensional confocal imaging and two-dimensional polyacrylamide-gel electrophoresis (2D-PAGE) of chicken IPVLs that were isolated from the ovarian follicles at different growth stages before ovulation. The results suggest that the relative proportions of the ZP3 isoforms are differentially altered during the structural maturation of the egg-coat matrices. Furthermore, tandem mass spectrometry (MS/MS) analyses and ZP1 binding assays against separated ZP3 isoforms demonstrated that each ZP3 isoform contains characteristic modifications, and there are large differences among ZP3 isoforms in the ZP1 binding affinities. These results suggest that the microheterogeneity of chicken ZP3 might be regulated to be associated with the formation of egg-coat matrices during the structural maturation of chicken IPVL. Our findings may provide new insights into molecular mechanisms of egg-coat assembly processes.

Recent genetic studies have found common genomic risk variants among psychiatric disorders, strongly suggesting the overlaps in their molecular and cellular mechanism. Our research group identified the variant in ASTN2 as one of the candidate risk factors across these psychiatric disorders by whole-genome copy number variation analysis. However, the alterations in the human neuronal cells resulting from ASTN2 variants identified in patients remain unknown. To address this, we used patient-derived and genome-edited iPS cells with ASTN2 deletion; cells were further differentiated into neuronal cells. A comprehensive gene expression analysis using genome-edited iPS cells with variants on both alleles revealed that the expression level of ZNF558 , a gene specifically expressed in human forebrain neural progenitor cells, was greatly reduced in ASTN2 -deleted neuronal cells. Furthermore, the expression of the mitophagy-related gene SPATA18 , which is repressed by ZNF558 , and mitophagy activity were increased in ASTN2 -deleted neuronal cells. These phenotypes were also detected in neuronal cells differentiated from patient-derived iPS cells with heterozygous ASTN2 deletion. Our results suggest that ASTN2 deletion is related to the common pathogenic mechanism of psychiatric disorders by regulating mitophagy via ZNF558 .

Background Antipsychotics are essential in the acute treatment of and maintenance therapy for schizophrenia, but medication adherence and long-term treatment continuity are needed to maximize their effectiveness. Each antipsychotic has various side effects, which may affect adherence. Some patients with schizophrenia are reluctant to take asenapine because of its unique oral-related side effects, such as the bitter taste caused by sublingual administration. Our previous basic research found that D-sorbitol lowered the bitterness parameters of the taste sensors. However, whether D-sorbitol has the same effect in patients remains unclear. Therefore, using a D-sorbitol solution, we aim to evaluate changes in the bitterness of asenapine among patients with schizophrenia. Methods In this single-blind, placebo-controlled, crossover trial, we plan to recruit 20 adult patients with schizophrenia spectrum disorder who take sublingual asenapine tablets. The participants will be divided into two groups ( n  = 10 each). Each group will be given a D-sorbitol or placebo solution on the first day for rinsing before taking the sublingual asenapine tablets. After a 1-day interval, the participants will rinse their mouths again with a different liquid. Questionnaires regarding changes in taste and the willingness to continue asenapine will be conducted before the start of the study and after each rinse. The primary and secondary end points will be a taste evaluation of bitterness, and the willingness to continue asenapine, respectively. Differences in questionnaire scores between the D-sorbitol and placebo solutions will be calculated and analyzed using a McNemar test. Discussion This study aims to determine the efficacy of D-sorbitol in masking the bitter taste of asenapine. To our knowledge, it is the first intervention study using D-sorbitol for bitter taste of asenapine in patients with schizophrenia. Evidence of the efficacy of D-sorbitol could result in D-sorbitol pretreatment being an easy and inexpensive means of improving adherence to asenapine. Trial registration This study was registered in the Japan Registry of Clinical Trials jRCTs041210019, on May 14, 2021. Ethics approval was obtained from the Nagoya University Clinical Research Review Board.

Background Asenapine has unique orally-related side effects, such as a bitter taste induced by sublingual administration, which often results in discontinuation of the medication. While the FDA has approved black-cherry-flavored asenapine, several countries have prescribed only unflavored versions. Specifically, Asians commonly report experiencing the bitterness of asenapine because they are more sensitive to bitter tastes than other ethnic groups. In this study, with the aim of improving adherence by reducing the bitterness of asenapine, we investigated the effects of d -sorbitol, which reduced the bitterness parameters of taste sensors in our previous basic study on the bitterness and continuity of asenapine among patients with schizophrenia. Methods Twenty adult patients with schizophrenia were included in this single-blind, placebo-controlled, crossover trial. Participants rinsed their mouths with single-administration of d -sorbitol or a placebo prior to each administration of asenapine. We then conducted the questionnaires and assessed changes in the bitterness of asenapine (primary end point) and willingness to continue its use (secondary end point). Results d -sorbitol significantly improved the bitterness of asenapine ( p  = 0.038). Although it did not significantly increase the willingness to continue asenapine ( p  = 0.180), it did show improvement over the placebo in enhancing willingness to continue, especially in patients who were not accustomed to its taste. Conclusion Our findings indicate that single-administration of d -sorbitol significantly reduces the bitterness of asenapine. In countries where flavored asenapine is not available, this finding could benefit patients who were not accustomed to its bitter taste. Trial registration This study was registered in the Japan Registry of Clinical Trials (jRCTs041210019) on May 14, 2021.

Purpose This study examined the incidence of hypermagnesemia in patients with eating disorders, its associations with renal function, body mass index, and magnesium oxide use, and the correlation between different methods of estimating renal function and serum magnesium levels. Methods This retrospective cohort study was conducted in female patients with eating disorders treated at Nagoya University Hospital between January 2018 and December 2022. Patients diagnosed as eating disorders, based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision, were included. Serum magnesium levels, estimated glomerular filtration rate, body mass index, and magnesium oxide prescriptions were collected. Linear mixed-effects models were used to analyze factors affecting serum magnesium levels. Renal function screening methods were compared in underweight patients. Results Among 194 patients, 42 (21.6%) developed hypermagnesemia (≥ 2.5 mg/dL; maximum 5.3 mg/dL). Younger age, lower body mass index, and reduced estimated glomerular filtration rate were linked to higher magnesium levels, whereas magnesium oxide use showed no clear association. Further analysis showed that the alternative estimated glomerular filtration rate method, adjusted for body size, negatively correlated with elevated serum magnesium levels in underweight patients. Conclusion The incidence of hypermagnesemia in patients with eating disorders receiving magnesium oxide was comparable to previous studies. Risk factors include low body mass index, impaired renal function, and younger age. Although monitoring is warranted, severe complications were not observed, suggesting magnesium oxide need not be avoided. The use of body size-adjusted estimated glomerular filtration rate may improve the screening for hypermagnesemia in underweight patients. Level of Evidence: Level III, well-designed cohort or case–control analytic studies.

Whole genome analysis has identified rare copy number variations (CNV) that are strongly involved in the pathogenesis of psychiatric disorders, and 3q29 deletion has been found to have the largest effect size. The 3q29 deletion mice model (3q29-del mice) has been established as a good pathological model for schizophrenia based on phenotypic analysis; however, circadian rhythm and sleep, which are also closely related to neuropsychiatric disorders, have not been investigated. In this study, our aims were to reevaluate the pathogenesis of 3q29-del by recreating model mice and analyzing their behavior and to identify novel new insights into the temporal activity and temperature fluctuations of the mouse model using a recently developed small implantable accelerometer chip, Nano-tag. We generated 3q29-del mice using genome editing technology and reevaluated common behavioral phenotypes. We next implanted Nano-tag in the abdominal cavity of mice for continuous measurements of long-time activity and body temperature. Our model mice exhibited weight loss similar to that of other mice reported previously. A general behavioral battery test in the model mice revealed phenotypes similar to those observed in mouse models of schizophrenia, including increased rearing frequency. Intraperitoneal implantation of Nano-tag, a miniature acceleration sensor, resulted in hypersensitive and rapid increases in the activity and body temperature of 3q29-del mice upon switching to lights-off condition. Similar to the 3q29-del mice reported previously, these mice are a promising model animals for schizophrenia. Successive quantitative analysis may provide results that could help in treating sleep disorders closely associated with neuropsychiatric disorders.

Hepatitis B virus (HBV) specifically infects human hepatocytes and increases the risks of cirrhosis and liver cancer. Currently, nucleic acid analogs are the main therapeutics for chronic hepatitis caused by HBV infection. Although nucleic acid analogs can eliminate HBV DNA by inhibiting HBV reverse transcriptase, they cannot lead to negative conversion of covalently closed circular DNA (cccDNA) and hepatitis B surface antigen (HBsAg). In this study, we revealed that the antifilarial drug ivermectin suppresses HBV production by a different mechanism from the nucleic acid analog entecavir or Na+ taurocholate co-transporting polypeptide-mediated entry inhibitor cyclosporin A. Ivermectin reduced the levels of several HBV markers, including HBsAg, in HBV-infected human hepatocellular carcinoma cells (HepG2-hNTCP-C4 cells) and humanized mouse hepatocytes (PXB hepatocytes). In addition, ivermectin significantly decreased the expression of HBV core protein and the nuclear transporter karyopherin α2 (KPNA2) in the nuclei of HepG2-hNTCP-C4 cells. Furthermore, depletion of KPNA1–6 suppressed the production of cccDNA. These results suggest that KPNA1–6 is involved in the nuclear import of HBV and that ivermectin suppresses the nuclear import of HBV by inhibiting KPNA2. This study demonstrates the potential of ivermectin as a novel treatment for hepatitis B.

Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 ( PCDH15 ) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15 . Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion ( Pcdh15 -null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15- null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice ( Pcdh15 -het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15 -null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15 -null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15 -deletion mice. Therefore, Pcdh15 -deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.