Yasushi Kishimoto

Background Lean mass is positively associated with bone mineral density (BMD), and this relationship may vary according to age and sex. Sedentary behavior has also been associated with BMD, although findings differ across populations and skeletal sites. However, it remains unclear whether sedentary time modifies the relationship between regional lean mass and BMD and whether such modification varies across sex and age. These relationships were explored using nationally representative U.S. data. Methods Adults aged 18-59 years from the 2017-2018 National Health and Nutrition Examination Survey (NHANES) were analyzed. Mean bilateral leg lean mass and mean bilateral leg BMD were derived from dual-energy X-ray absorptiometry measurements, and sedentary time was obtained from self-report. Survey-weighted regression models incorporated NHANES examination weights, strata, and primary sampling units. The primary model examined the four-way interaction among leg lean mass, sedentary time, sex, and continuous age, with adjustment for race/ethnicity and height. Quadratic lean-mass terms were examined in sensitivity analyses. Results The primary complete-case analysis included 2,543 adults (1,191 men and 1,352 women). Women showed a more apparent decline in both leg lean mass and leg BMD at ages 50-59 years, whereas sedentary time did not increase in parallel with these age-related changes. Leg lean mass was positively associated with leg BMD in both sexes, with modest nonlinearity, particularly among women. In the primary survey-weighted model, the four-way interaction among leg lean mass, sedentary time, sex, and age was positive (beta = 0.000111 per year, 95% CI 0.000039-0.000183; P = 0.0051), indicating increasing sex divergence in sedentary-time modification of the lean mass-BMD association with age. At younger ages, conditional interaction estimates were similar between sexes; at older ages, estimates became increasingly positive in women while remaining negative but imprecise in men. Quadratic sensitivity analyses attenuated the four-way interaction estimate by approximately 9-12% and reduced its statistical precision, while broadly preserving its direction and magnitude. Conclusions In this exploratory cross-sectional analysis, sedentary-time modification of the association between DXA-derived leg lean mass and leg BMD varied according to sex and age. The sex difference was small at younger ages and became progressively more apparent with increasing age. These findings suggest that behavioral and demographic context may contribute to variation in the muscle-bone relationship itself, although confirmation in independent and longitudinal datasets is needed.

This dataset provides synchronized multimodal behavioral measurements from 36 mice across four experimental groups: wild-type and rTg4510 tauopathy mice, each tested with or without doxycycline-mediated suppression of mutant tau expression. Of these, 34 mice had complete measurements across all three behavioral paradigms and were used for analyses requiring full cross-task linkage. At six months of age, all animals underwent three standardized behavioral paradigms: home cage monitoring, ten-day trace eyeblink conditioning, and contextual fear conditioning. The individual-level data included locomotor activity, rearing duration, conditioned response metrics, eyelid closure latencies, and contextual freezing percentages. All measurements were linked using unique mouse identifiers, enabling cross-task analysis without preprocessing or imputation. The dataset was accompanied by a complete data dictionary, processing workflow diagram, and validation analyses demonstrating cross-paradigm correlations. The cross-task associations are illustrated in the main figures, with additional early phase acquisition and temporal processing correlations provided in the main figures. Provided in an open CSV format with detailed metadata, this resource supports behavioral phenotyping, machine learning applications, and the investigation of learning mechanisms in tauopathy models.

This dataset provides synchronized multimodal behavioral measurements from 36 mice across four experimental groups: wild-type and rTg4510 tauopathy mice, each tested with or without doxycycline-mediated suppression of mutant tau expression. At six months of age, all animals underwent three standardized behavioral paradigms: home-cage monitoring, ten-day trace eyeblink conditioning, and contextual fear conditioning. Individual-level data include locomotor activity, rearing duration, conditioned response metrics, eyelid closure latencies, and contextual freezing percentages. All measurements are linked by unique mouse identifiers, enabling cross-task analyses without preprocessing or imputation. The dataset is accompanied by a complete data dictionary, processing workflow diagram, and validation analyses demonstrating cross-paradigm correlations. Cross-task associations are illustrated in main figures, with additional early-phase acquisition and temporal processing correlations provided in supplementary appendices. Provided in open CSV format with detailed metadata, this resource supports behavioral phenotyping, machine learning applications, and investigations of learning mechanisms in tauopathy models.

Background: Hyperphosphorylated tau accumulation and neurofibrillary tangles (NFTs) are hallmarks of tauopathies, including Alzheimer’s disease (AD), and are strongly associated with cognitive decline. The rTg4510 mouse model, which expresses mutant human tau (P301L), develops progressive tauopathy in the absence of amyloid-β pathology, providing a valuable tool for investigating tau-driven neurodegeneration. Previous studies have demonstrated spatial and object-recognition memory deficits at six months of age, which can be prevented by doxycycline (DOX)-mediated suppression of tau expression. However, it remained unclear whether non-spatial hippocampal learning, particularly temporal associative learning, would be similarly affected. Methods: We evaluated six-month-old rTg4510 mice with or without DOX treatment. To control for potential motor confounds, we first assessed spontaneous home cage activity. We then tested hippocampus-dependent non-spatial learning using two paradigms: trace eyeblink conditioning (500-ms trace interval) and contextual fear conditioning. Results: General motor function remained intact; however, rTg4510 mice without DOX treatment exhibited increased rearing behavior. These mice demonstrated significant deficits in trace eyeblink conditioning acquisition, with particularly clear impairment on the final day of training. Contextual fear conditioning showed milder deficits. Analysis of response peak latency revealed subtle temporal processing abnormalities during early learning. Two months of DOX treatment initiated at four months of age prevented these learning deficits, confirming their association with tau overexpression. Conclusions: Our findings demonstrate that rTg4510 mice exhibit deficits in non-spatial temporal associative learning alongside previously reported spatial and object-recognition impairments. Trace eyeblink conditioning serves as a sensitive behavioral assay for detecting tau-related hippocampal dysfunction, and the prevention of learning deficits by DOX treatment highlights its potential utility as a translational biomarker for evaluating tau-targeted interventions.

The maintenance of proper brain function relies heavily on the balance of excitatory and inhibitory neural circuits, governed in part by synaptic adhesion molecules. Among these, MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor 1) acts as a suppressor of synapse formation by interfering with Neuroligin-mediated interactions, crucial for maintaining the excitatory–inhibitory (E/I) balance. Mdga1^−/− mice exhibit selectively enhanced inhibitory synapse formation in their hippocampal pyramidal neurons, leading to impaired hippocampal long-term potentiation (LTP) and hippocampus-dependent learning and memory function; however, it has not been fully investigated yet if the reduction in MDGA1 protein levels would alter brain function. Here, we examined the behavioral and synaptic consequences of reduced MDGA1 protein levels in Mdga1^+/− mice. As observed in Mdga1^−/− mice, Mdga1^+/− mice exhibited significant deficits in hippocampus-dependent learning and memory tasks, such as the Morris water maze and contextual fear-conditioning tests, along with a significant deficit in the long-term potentiation (LTP) in hippocampal Schaffer collateral CA1 synapses. The acute administration of D-cycloserine, a co-agonist of NMDAR (N-methyl-d-aspartate receptor), significantly ameliorated memory impairments and restored LTP deficits specifically in Mdga1^+/− mice, while having no such effect on Mdga1^−/− mice. These results highlight the critical role of MDGA1 in regulating inhibitory synapse formation and maintaining the E/I balance for proper cognitive function. These findings may also suggest potential therapeutic strategies targeting the E/I imbalance to alleviate cognitive deficits associated with neuropsychiatric disorders.

Background: During menopause, bone density decreases, and low-density lipoprotein cholesterol (LDL-C) rapidly increases; a decrease in the estrogen level is a common factor in these phenomena. Methods: In this study, we focused on the fact that menopause is a spontaneous process, and aimed to derive the conditions that mitigate the decline in the osteo sono-assessment index (OSI), an index of bone mineral density (BMD), using a chemical equilibrium model. We attempted to establish the relationship between variables related to female hormone secretion (OSI, LDL-C) and a variable related to work capacity (physical work capacity [PWC] at 75% of maximal heart rate) by analogy, using the fact that Gibbs free energy, a thermodynamic variable related to spontaneous change, is related by three variables. Results: Consequently, if linearity is established between PWC and OSI when LDL-C is used as the standard, then the analogy of chemical equilibrium can be established between the deviation values of these three variables, with equilibrium constant K. Finally, the theoretically determined equilibrium model with constant K was applied to data obtained from the Sports Program Service (SPS) of the Yokohama Sports Medical Center. Conclusions: The present study suggests that the decrease in bone density could be alleviated by promoting an increase in LDL-C or by mitigating the decrease in PWC. In discussing personal health, mitigating bone density loss and maintaining a high work capacity are important components, which should also take into account the appropriate levels of LDL-C.

The modeling of iron porphyrins is essential in the study of heme proteins. These complexes readily undergo autooxidation and dimerization; however, this dimerization process can be inhibited by introducing phenyl groups. Herein, the dimerization of highly substituted iron(III) porphyrins is investigated. The stability of water-insoluble iron(III) hydroxo complexes was monitored via thin-layer chromatography and was found to increase with the number of phenyl groups. Dodecaphenyl-substituted complexes formed hydroxo complexes, tetraphenyl and hexaphenyl complexes formed [ ]-oxo dimers, and octaphenyl and decaphenyl complexes existed as hydroxo complex-[ ]-oxo dimer mixtures. Crystals of the dodecaphenyl-substituted iron(III) hydroxo complexes were successfully isolated. The decaphenyl-substituted complex was unique in that the respective crystals of both the hydroxo complexes and [ ]-oxo dimer could be isolated from the chloride complexes. Furthermore, the synthesis and proton equilibria of the new porphyrin iron(III) water-soluble complexes were investigated. Under neutral to basic conditions, at equilibrium, dodecaphenyl-substituted complexes exclusively formed hydroxo complexes, whereas octaphenyl, hexaphenyl, and tetraphenyl complexes exclusively formed [ ]-oxo dimers, and decaphenyl complexes existed as hydroxo complex-[ ]-oxo dimer mixtures. Additionally, the order of the dimerization reaction was examined using the initial-rate and half-life methods, which confirmed that the dimerization is a second-order reaction that follows a mechanism wherein two hydroxo complexes form a dihydroxo-bridged intermediate. This result was supported by the dimerization of water-soluble iron(III) hydroxo complexes. The new hydroxo complexes with non-planar porphyrin cores synthesized in this study are expected to have a significant impact on heme protein reaction modeling.

Group I metabotropic glutamate receptors (mGluRs) include mGluR1 and mGluR5, which are coupled to the Gq family of heterotrimeric G-proteins and readily activated by their selective agonist 3,5-dihydroxyphenilglycine (DHPG). mGluR1 and mGluR5 exhibit nearly complementary distributions spatially or temporally in the central nervous system (CNS). In adult cerebellar Purkinje cells (PCs), mGluR1 is a dominant group I mGluR and mGluR5 is undetectable. mGluR1 expression increases substantially during the first three weeks of postnatal development and remains high throughout adulthood. On the other hand, mGluR5 expression is observed during the first two postnatal weeks and then decreases. However, functional differences between mGluR1 and mGluR5 in the CNS remains to be elucidated. To address this issue, we generated “mGluR5-rescue” mice in which mGluR5 is specifically expressed in PCs in global mGluR1-knockout (KO) mice. mGluR5-rescue mice exhibited apparently normal motor coordination, developmental elimination of redundant climbing fiber (CF)-PC synapses, and delay eyeblink conditioning, which were severely impaired in mGluR1-KO mice. We concluded that mGluR5 is functionally comparable with mGluR1 in cerebellar PCs.

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 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.