Publications by authors named "Kazutaka Ikeda"

306 Publications

Atomic-level characterization of free volume in the structure of CuZramorphous alloy.

J Phys Condens Matter 2021 Apr 27. Epub 2021 Apr 27.

Institute of Materials Structure Science, KEK, 1-1 Oho, Tsukuba, Ibaraki, 305-0801, JAPAN.

The structure of CuZramorphous alloy was investigated in terms of packing density and free volume by using neutron, X-ray diffraction and reverse Monte Carlo (RMC) modelling. The RMC model was analysed by a method of decomposing the three-dimensional atomic configuration into fundamental polyhedral units (termed as 'holes' referencing the Bernal's works) whose faces are all triangles consisting of chemical bonds. Not only tetrahedral and octahedral holes but also other larger holes were identified. Moreover, the atomic packing fractions and free volumes in the respective polyhedral holes were evaluated with reference to those for the corresponding crystal structures. The results show that the distribution of free volumes for the larger holes can be described by the exponential function assuming that there are no energetic interactions between each other. On the other hand, the local structural fluctuations due to densely and loosely packed tetrahedral holes were observed, leading to the negative free volume spaces.
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http://dx.doi.org/10.1088/1361-648X/abfc12DOI Listing
April 2021

Future direction of addiction research-An expert questionnaire survey in Japan.

Neuropsychopharmacol Rep 2021 Apr 6. Epub 2021 Apr 6.

Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Addiction has become a major worldwide medical, public health, and social problem. Because the prevalence of addiction varies widely geographically, due to differences in ethnicity, culture, education, social environment, and regulation, each country or region needs to understand its current state of addiction and to take appropriate measures, in multidisciplinary collaboration. In order to understand the direction of addiction research in Japan, we analyzed 50 research and development topics and their characteristics, based on an expert questionnaire survey. The topics were placed in five categories, as follows. Category 1: Basic science; all 10 topics were of the Long-term project and International cooperation types. Category 2: Translational and clinical research; 6 out of 10 topics were of the Long-term project. Category 3: Fact-finding surveys; 8 out of 10 topics were of the Japan-specific type. Category 4: Health system and service; 8 out of 10 topics were of the Japan-specific type and Short-term project. Category 5: Study on society, culture, environment, education, and regulation; 7 out of 10 topics were of the Short-term project (similar to Category 4). As far as we know, this is the first systematic questionnaire survey on the direction of addiction research. The results of this study might support developing a strategy for addiction research, not only in Japan, but also in other countries.
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http://dx.doi.org/10.1002/npr2.12175DOI Listing
April 2021

Cold pain sensitivity is associated with single-nucleotide polymorphisms of / and .

Mol Pain 2021 Jan-Dec;17:17448069211002009

Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Pain sensitivity differs individually, but the mechanisms and genetic factors that underlie these differences are not fully understood. To investigate genetic factors that are involved in sensing cold pain, we applied a cold-induced pain test and evaluated protease-activated receptor 2 (PAR2/F2RL1) and transient receptor potential melastatin 8 (TRPM8), which are related to pain. We statistically investigated the associations between genetic polymorphisms and cold pain sensitivity in 461 healthy patients who were scheduled to undergo cosmetic orthognathic surgery for mandibular prognathism. We found an association between cold pain sensitivity and the rs2243057 polymorphism of the gene. We also found a significant association between cold pain sensitivity and the rs12992084 polymorphism of the gene. Carriers of the minor A allele of the rs2243057 polymorphism of and minor C allele of the rs12992084 polymorphism of exhibited a longer latency to pain perception in the cold-induced pain test, reflecting a decrease in cold pain sensitivity. These results suggest that genetic polymorphisms of both and are involved in individual differences in cold pain sensitivity.
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http://dx.doi.org/10.1177/17448069211002009DOI Listing
March 2021

Filopodium-derived vesicles produced by MIM enhance the migration of recipient cells.

Dev Cell 2021 Mar;56(6):842-859.e8

Division of Biological Science, Nara Institute of Science and Technology, Ikoma 630-0192, Japan; Data Science Center, Nara Institute of Science and Technology, Ikoma 630-0192, Japan. Electronic address:

Extracellular vesicles (EVs) are classified as large EVs (l-EVs, or microvesicles) and small EVs (s-EVs, or exosomes). S-EVs are thought to be generated from endosomes through a process that mainly depends on the ESCRT protein complex, including ALG-2 interacting protein X (ALIX). However, the mechanisms of l-EV generation from the plasma membrane have not been identified. Membrane curvatures are generated by the bin-amphiphysin-rvs (BAR) family proteins, among which the inverse BAR (I-BAR) proteins are involved in filopodial protrusions. Here, we show that the I-BAR proteins, including missing in metastasis (MIM), generate l-EVs by scission of filopodia. Interestingly, MIM-containing l-EV production was promoted by in vivo equivalent external forces and by the suppression of ALIX, suggesting an alternative mechanism of vesicle formation to s-EVs. The MIM-dependent l-EVs contained lysophospholipids and proteins, including IRS4 and Rac1, which stimulated the migration of recipient cells through lamellipodia formation. Thus, these filopodia-dependent l-EVs, which we named as filopodia-derived vesicles (FDVs), modify cellular behavior.
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http://dx.doi.org/10.1016/j.devcel.2021.02.029DOI Listing
March 2021

Polygenic risk scores differentiating schizophrenia from bipolar disorder are associated with premorbid intelligence in schizophrenia patients and healthy subjects.

Int J Neuropsychopharmacol 2021 Mar 19. Epub 2021 Mar 19.

Department of Psychiatry and Psychotherapy, Gifu University Graduate School of Medicine, Gifu, Japan.

Background: Impairments in intelligence are more severe in patients with schizophrenia (SCZ) than in patients with bipolar disorder (BD) despite clinical and genetic similarities between the disorders. Genetic loci differentiating SCZ from BD, i.e., SCZ-specific risk, have been identified. Polygenetic [risk] scores (PGSs) for SCZ-specific risk are higher in SCZ patients than in healthy controls (HCs). However, the influence of genetic risk on impaired intelligence is poorly understood. Here, we investigated whether SCZ-specific risk could predict impairments in intelligence in SCZ patients and HCs.

Methods: Large-scale genome-wide association study (GWAS) datasets related to SCZ vs BD, childhood intelligence (CHI) and adulthood intelligence (n=12,441-282,014) were utilized to compute PGSs. PGSs derived from the GWASs were calculated for 130 patients with SCZ and 146 HCs. Premorbid and current intelligence and the decline were measured in SCZ patients and HCs. Correlations between PGSs and intelligence functions were investigated.

Results: High PGSs for SCZ-specific risk were correlated with low premorbid intelligence in SCZ patients and HCs (β=-0.17, p=4.12×10 -3). The correlation was still significant after adjusting for diagnostic status (β=-0.13, p=0.024). There were no significant correlations between PGSs for SCZ-specific risk and current intelligence or intelligence decline (p>0.05). PGSs for CHI were lower in SCZ patients than in HCs (R 2=0.025, p=0.025), while the PGSs for CHI were not significantly correlated with premorbid and current intelligence, the decline or the PGSs for SCZ-specific risk (p>0.05).

Conclusions: These findings suggest that genetic factors differentiating SCZ from BD might affect the pathogenesis of SCZ and/or pathological differences between SCZ and BD via the impairment of premorbid intelligence, i.e., crystallized intelligence, while genetic factors for CHI might affect the pathogenesis of SCZ not via impaired impairments in intelligence.
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http://dx.doi.org/10.1093/ijnp/pyab014DOI Listing
March 2021

Stage-Specific Synthesis of Very-Long-Chain Dihydroceramides Confers Dormancy to Parasites.

mSphere 2021 03 17;6(2). Epub 2021 Mar 17.

Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

Amoebiasis is a parasitic disease caused by infection and is a serious public health problem worldwide due to ill-prepared preventive measures as well as its high morbidity and mortality rates. Amoebiasis transmission is solely mediated by cysts. Cysts are produced by the differentiation of proliferative trophozoites in a process termed "encystation." encystation is a fundamental cell differentiation process and proceeds with substantial changes in cell metabolites, components, and morphology, which occur sequentially in an orchestrated manner. Lipids are plausibly among these metabolites that function as key factors for encystation. However, a comprehensive lipid analysis has not been reported, and the involved lipid metabolic pathways remain largely unknown. Here, we exploited the state-of-the-art untargeted lipidomics and characterized 339 molecules of 17 lipid subclasses. Of these, dihydroceramide (Cer-NDS) was found to be among the most induced lipid species during encystation. Notably, in encysting cells, amounts of Cer-NDS containing very long -acyl chains (≥26 carbon) were more than 30-fold induced as the terminal product of a metabolic pathway. We also identified three ceramide synthase genes responsible for producing the very-long-chain Cer-NDS molecules. These genes were upregulated during encystation. Furthermore, these ceramide species were shown to be indispensable for generating membrane impermeability, a prerequisite for becoming dormant cyst that shows resistance to environmental assault inside and outside the host for transmission. Hence, the lipid subclass of Cer-NDS plays a crucial role for cell differentiation and morphogenesis by alternating the membrane properties. is a protozoan parasite that thrives in its niche by alternating its two forms between a proliferative trophozoite and dormant cyst. Cysts are the only form able to transmit to a new host and are differentiated from trophozoites in a process termed "encystation." During encystation, cell metabolites, components, and morphology drastically change, which occur sequentially in an orchestrated manner. Lipids are plausibly among these metabolites. However, the involved lipid species and their metabolic pathways remain largely unknown. Here, we identified dihydroceramides (Cer-NDSs) containing very long -acyl chains (C to C) as a key metabolite for encystation by our state-of-the-art untargeted lipidomics. We also showed that these Cer-NDSs are critical to generate the membrane impermeability, a prerequisite for this parasite to show dormancy as a cyst that repels substances and prevents water loss. Hence, ceramide metabolism is essential for to maintain the parasitic lifestyle.
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http://dx.doi.org/10.1128/mSphere.00174-21DOI Listing
March 2021

Correction to: Increase in excitability of hippocampal neurons during novelty-induced hyperlocomotion in dopamine-deficient mice.

Mol Brain 2021 Mar 11;14(1):51. Epub 2021 Mar 11.

Department of Psychiatry and Behavioral Sciences, Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.

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http://dx.doi.org/10.1186/s13041-021-00741-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953761PMC
March 2021

Genome-wide association study identifies candidate loci associated with chronic pain and postherpetic neuralgia.

Mol Pain 2021 Jan-Dec;17:1744806921999924

Addictive Substance Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Background: Human twin studies and other studies have indicated that chronic pain has heritability that ranges from 30% to 70%. We aimed to identify potential genetic variants that contribute to the susceptibility to chronic pain and efficacy of administered drugs. We conducted genome-wide association studies (GWASs) using whole-genome genotyping arrays with more than 700,000 markers in 191 chronic pain patients and a subgroup of 89 patients with postherpetic neuralgia (PHN) in addition to 282 healthy control subjects in several genetic models, followed by additional gene-based and gene-set analyses of the same phenotypes. We also performed a GWAS for the efficacy of drugs for the treatment of pain.

Results: Although none of the single-nucleotide polymorphisms (SNPs) were found to be genome-wide significantly associated with chronic pain ( ≥ 1.858 × 10), the GWAS of PHN patients revealed that the rs4773840 SNP within the gene region was significantly associated with PHN in the trend model (nominal  = 1.638 × 10). In the additional gene-based analysis, one gene, , was significantly associated with chronic pain in the trend model (adjusted  = 0.03722). In the gene-set analysis, several gene sets were significantly associated with chronic pain and PHN. No SNPs were significantly associated with the efficacy of any of types of drugs in any of the genetic models.

Conclusions: These results suggest that the gene and rs4773840 SNP within the gene region may be related to the susceptibility to chronic pain conditions and PHN, respectively.
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http://dx.doi.org/10.1177/1744806921999924DOI Listing
March 2021

Enhancement of morphine-induced antinociception after electroconvulsive shock in mice.

Mol Pain 2021 Jan-Dec;17:1744806921992628

Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Electroconvulsive therapy (ECT) has been applied for chronic pain for decades. The amounts of opioids to treat pain are sometimes reduced after a series of ECT. The effect of ECT on morphine-induced analgesia and its mechanism underlying the reduction of morphine requirement has yet to be clarified. Therefore, we administered electroconvulsive shocks (ECS) to mice and investigated the antinociceptive effect of morphine in a hot plate test. We examined the expression level of µ-opioid receptor in the thalami of mice 25 h after administration of ECS compared to the thalami of mice without ECS administration using western blotting. ECS disturbed the development of a decrease in the percentage of maximal possible effect (%MPE), which was observed 24 h after a morphine injection, when ECS was applied 25, 23, 21, and 12 h before the second administration of morphine. We also examined the effect of ECS on the dose-response curve of %MPE to morphine-antinociception. Twenty-five hours after ECS, the dose-response curve was shifted to the left, and the EC of morphine given to ECS-pretreated mice decreased by 30.1% compared to the mice that were not pretreated with ECS. We also found that the expression level of µ-opioid receptors was significantly increased after ECS administration. These results confirm previous clinical reports showing that ECT decreased the required dose of opioids in neuropathic pain patients and suggest the hypothesis that this effect of ECT works through the thalamus.
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http://dx.doi.org/10.1177/1744806921992628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897827PMC
February 2021

Adolescent Problem Gaming and Loot Box Purchasing in Video Games: Cross-sectional Observational Study Using Population-Based Cohort Data.

JMIR Serious Games 2021 Feb 9;9(1):e23886. Epub 2021 Feb 9.

Research Center for Social Science & Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Background: Video game loot boxes, which can typically be purchased by players or are given as reward, contain random virtual items, or loot, ranging from simple customization options for a player's avatar or character, to game-changing equipment such as weapons and armor. Loot boxes have drawn concern, as purchasing loot boxes might lead to the development of problematic gambling for adolescents. Although parental problem gambling is associated with adolescent problem gambling, no studies have evaluated the prevalence of loot box purchases in adolescents' parents.

Objective: This study investigated the association between loot box purchasing among adolescents and parents, and problem online gaming in population-based samples.

Methods: In total, 1615 adolescent (aged 14 years) gamers from Japan responded to a questionnaire regarding their loot box purchasing and problem online gaming behaviors. Problem online gaming was defined as four or more of the nine addictive behaviors from the Diagnostic and Statistical Manual of Mental Disorders. The adolescents' primary caregivers were asked about their loot box purchasing.

Results: Of the 1615 participants, 57 (3.5%) reported loot box purchasing. This prevalence did not differ according to primary caregivers' loot box purchasing, but adolescents who purchased loot boxes were significantly more likely to exhibit problem online gaming (odds ratio 3.75, 95% CI 2.17-6.48).

Conclusions: Adolescent loot box purchasing is linked to problem online gaming, but not with parents' loot box purchasing. Measures to reduce these behaviors should target reducing addictive symptoms in young video gamers.
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http://dx.doi.org/10.2196/23886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902198PMC
February 2021

Dual actions of 5-MeO-DIPT at the serotonin transporter and serotonin 5-HT receptor in the mouse striatum and prefrontal cortex.

Neuropsychopharmacol Rep 2021 03 6;41(1):91-101. Epub 2021 Feb 6.

Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Aims: 5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is a synthetic orally active hallucinogenic tryptamine analogue. The present study examined whether the effects of 5-MeO-DIPT involve the serotonin transporter (SERT) and serotonin 5-hydroxytryptamine-1A (5-HT ) receptor in the striatum and prefrontal cortex (PFC).

Methods: We investigated the effects of 5-MeO-DIPT on extracellular 5-HT (5-HT ) and dopamine (DA ) levels in the striatum and PFC in wildtype and SERT knockout (KO) mice using in vivo microdialysis, and for comparison the effects of the 5-HT receptor antagonist WAY100635 and the 5-HT receptor agonist 8-OH-DPAT on 5-HT .

Results: 5-MeO-DIPT decreased 5-HT levels in the striatum, but not PFC. In SERT-KO mice, 5-MeO-DIPT did not affect 5-HT levels in the striatum or PFC. In the presence of WAY100635, 5-MeO-DIPT substantially increased 5-HT levels, suggesting that 5-MeO-DIPT acts on SERT and these effects are masked by its 5-HT actions in the absence of WAY100635. 8-OH-DPAT decreased 5-HT levels in the striatum and PFC in wildtype mice. WAY100635 antagonized the 8-OH-DPAT-induced decrease in 5-HT levels. In SERT-KO mice, 8-OH-DPAT did not decrease 5-HT levels in the striatum and PFC. 5-MeO-DIPT dose-dependently increased DA levels in the PFC, but not striatum, in wildtype and SERT-KO mice. The increase in DA levels that was induced by 5-MeO-DIPT was not antagonized by WAY100635.

Conclusion: 5-MeO-DIPT influences both 5-HT and DA levels in the striatum and PFC. 5-MeO-DIPT dually acts on SERT and 5-HT receptors so that elevations in 5-HT levels produced by reuptake inhibition are limited by actions of the drug on 5-HT receptors.
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http://dx.doi.org/10.1002/npr2.12161DOI Listing
March 2021

Effects of rs958804 and rs7858836 single-nucleotide polymorphisms of the ASTN2 gene on pain-related phenotypes in patients who underwent laparoscopic colectomy and mandibular sagittal split ramus osteotomy.

Neuropsychopharmacol Rep 2021 03 21;41(1):82-90. Epub 2021 Jan 21.

Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan.

Background: Opioids are widely used as effective analgesics, but opioid sensitivity varies widely among individuals. The underlying genetic and nongenetic factors are not fully understood. Based on the results of our previous genome-wide association study, we investigated the effects of single nucleotide polymorphisms (SNPs) of the astrotactin 2 (ASTN2) gene on pain-related phenotypes in surgical patients.

Methods: We investigated the effects of two SNPs, rs958804 T/C and rs7858836 C/T, of the ASTN2 gene on eight and seven pain-related phenotypes in 350 patients who underwent laparoscopic colectomy (LAC) and 358 patients who underwent mandibular sagittal split ramus osteotomy (SSRO), respectively. In both surgical groups, intravenous fentanyl patient-controlled analgesia (PCA) was used for postoperative analgesia, and 24-hour postoperative PCA fentanyl use was the primary endpoint.

Results: The association analyses among the two SNPs and pain-related traits showed that 24-hour fentanyl use was significantly associated with the two SNP genotypes in both surgical groups. The Mann-Whitney test showed that 24-hour fentanyl use was lower in patients with the C allele than in patients with the TT genotype of the rs958804 T/C SNP (P = .0019 and .0200 in LAC and SSRO patients, respectively), and it was lower in patients with the T allele than in patients with the CC genotype of the rs7858836 C/T SNP (P = .0017 and .0098 in LAC and SSRO patients, respectively).

Conclusion: The two SNPs of the ASTN2 gene were consistently associated with fentanyl requirements after two different types of surgery. These findings may contribute to personalized pain control.
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http://dx.doi.org/10.1002/npr2.12159DOI Listing
March 2021

Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders.

Science 2021 01;371(6526):265-270

Division of Cancer Cell Biology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, we identified glutaminase 1 () as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.
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http://dx.doi.org/10.1126/science.abb5916DOI Listing
January 2021

Functional lipidomics of vascular endothelial cells in response to laminar shear stress.

FASEB J 2021 Feb;35(2):e21301

Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Laminar shear stress generated by blood flow stimulates endothelial cells and activates signal transduction, which plays an important role in vascular homeostasis. Several lines of evidence indicate that membrane and intracellular lipids are involved in the signal transduction of biomechanical stresses. In this study, we performed global profiling of cellular lipids from human pulmonary artery endothelial cells (HPAEC) exposed to laminar shear stress. A total of 761 species of lipids were successfully annotated, with 198 of these species significantly changed in response to shear stress for 24 hours. Ether-linked lipids containing an alkyl moiety with a medium chain length (C11-C14) were uniquely upregulated, and the administration of their biosynthetic precursor 1-O-dodecyl-rac-glycerol attenuated phorbol 12-myristate 13-acetate (PMA) induced vascular cell adhesion molecule-1 (VCAM-1) expression. Given the pro-inflammatory and atherogenic roles of VCAM-1, our findings suggest that the induction of a specific group of lipids (ie, ether-linked lipids with medium length alkyl side chain) may confer atheroprotective and anti-inflammatory roles to vascular endothelial cells under flow conditions.
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http://dx.doi.org/10.1096/fj.202002144RDOI Listing
February 2021

Crystal Structural Investigations for Understanding the Hydrogen Storage Properties of YMgNi-Based Alloys.

ACS Omega 2020 Dec 30;5(48):31192-31198. Epub 2020 Nov 30.

Institute for Materials Research, Tohoku University, Miyagi 980-8577, Japan.

The hydrogen storage properties and crystal structures of YMgNi-based alloys, which were synthesized from (2 - )YNi and MgNi (0.6 ≤ ≤ 1.2), were investigated by pressure-composition-temperature measurements and powder neutron diffraction at a deuterium gas pressure to understand the hydrogen absorption and desorption reactions viewed from atomic arrangements around H atoms. Reducing the amounts of MgNi, which was utilized as a Mg source in YMgNi-based alloys, has been observed to lower the hydrogen absorption and desorption pressures and increase the hydrogen storage capacities. However, the reversible hydrogen capacity attained a maximum value of 1.2 mass % at = 0.8 because of the formation of a thermodynamically stable hydride in which hydrogen was not released at = 0.6. In the case of = 0.6, the presence of excessive Y atoms around the H atoms in the hydrogen-absorbed phase would lead to the formation of a hydride with stronger interaction between Y and H because of the affinity between them. Moreover, the presence of small amounts of D atoms with short interatomic D-D distances (1.6 and 1.9 Å) in the deuterium-absorbed phase (YMgNiD and YMgNiD) at <5 MPa and 323 K was proposed by the crystal structural investigations. The D atoms with short D-D interatomic distances were located in the same local atomic arrangements of D atoms in a deuterium-absorbed phase, which were formed at a higher-pressure range, and had higher hydrogen storage capacities than the deuterium-absorbed phases in this study.
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http://dx.doi.org/10.1021/acsomega.0c04535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726944PMC
December 2020

Elucidation of Gut Microbiota-Associated Lipids Using LC-MS/MS and 16S rRNA Sequence Analyses.

iScience 2020 Dec 23;23(12):101841. Epub 2020 Nov 23.

RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.

Host-microbiota interactions create a unique metabolic milieu that modulates intestinal environments. Integration of 16S ribosomal RNA (rRNA) sequences and mass spectrometry (MS)-based lipidomics has a great potential to reveal the relationship between bacterial composition and the complex metabolic network in the gut. In this study, we conducted untargeted lipidomics followed by a feature-based molecular MS/MS spectral networking to characterize gut bacteria-dependent lipid subclasses in mice. An estimated 24.8% of lipid molecules in feces were microbiota-dependent, as judged by > 10-fold decrease in antibiotic-treated mice. Among these, there was a series of unique and microbiota-related lipid structures, including acyl alpha-hydroxyl fatty acid (AAHFA) that was newly identified in this study Based on the integrated analysis of 985 lipid profiles and 16S rRNA sequence data providing 2,494 operational taxonomic units, we could successfully predict the bacterial species responsible for the biosynthesis of these unique lipids, including AAHFA.
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http://dx.doi.org/10.1016/j.isci.2020.101841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721639PMC
December 2020

Transomics analysis reveals allosteric and gene regulation axes for altered hepatic glucose-responsive metabolism in obesity.

Sci Signal 2020 12 1;13(660). Epub 2020 Dec 1.

Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Impaired glucose tolerance associated with obesity causes postprandial hyperglycemia and can lead to type 2 diabetes. To study the differences in liver metabolism in healthy and obese states, we constructed and analyzed transomics glucose-responsive metabolic networks with layers for metabolites, expression data for metabolic enzyme genes, transcription factors, and insulin signaling proteins from the livers of healthy and obese mice. We integrated multiomics time course data from wild-type and leptin-deficient obese (/) mice after orally administered glucose. In wild-type mice, metabolic reactions were rapidly regulated within 10 min of oral glucose administration by glucose-responsive metabolites, which functioned as allosteric regulators and substrates of metabolic enzymes, and by Akt-induced changes in the expression of glucose-responsive genes encoding metabolic enzymes. In / mice, the majority of rapid regulation by glucose-responsive metabolites was absent. Instead, glucose administration produced slow changes in the expression of carbohydrate, lipid, and amino acid metabolic enzyme-encoding genes to alter metabolic reactions on a time scale of hours. Few regulatory events occurred in both healthy and obese mice. Thus, our transomics network analysis revealed that regulation of glucose-responsive liver metabolism is mediated through different mechanisms in healthy and obese states. Rapid changes in allosteric regulators and substrates and in gene expression dominate the healthy state, whereas slow changes in gene expression dominate the obese state.
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http://dx.doi.org/10.1126/scisignal.aaz1236DOI Listing
December 2020

Polygenic risk scores for late smoking initiation associated with the risk of schizophrenia.

NPJ Schizophr 2020 Nov 23;6(1):36. Epub 2020 Nov 23.

Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Patients with schizophrenia display characteristic smoking-related behaviors and genetic correlations between smoking behaviors and schizophrenia have been identified in European individuals. However, the genetic etiology of the association remains to be clarified. The present study investigated transethnic genetic overlaps between European-based smoking behaviors and the risk of Japanese schizophrenia by conducting polygenic risk score (PRS) analyses. Large-scale European genome-wide association study (GWAS) datasets (n = 24,114-74,035) related to four smoking-related intermediate phenotypes [(i) smoking initiation, (ii) age at smoking initiation, (iii) smoking quantity, and (iv) smoking cessation] were utilized as discovery samples. PRSs derived from these discovery GWASs were calculated for 332 Japanese subjects [schizophrenia patients, their unaffected first-degree relatives (FRs), and healthy controls (HCs)] as a target sample. Based on GWASs of European smoking phenotypes, we investigated the effects of PRSs on smoking phenotypes and the risk of schizophrenia in the Japanese population. Of the four smoking-related behaviors, the PRSs for age at smoking initiation in Europeans significantly predicted the age at smoking initiation (R = 0.049, p = 0.026) and the PRSs for smoking cessation significantly predicted the smoking cessation (R = 0.092, p = 0.027) in Japanese ever-smokers. Furthermore, the PRSs related to age at smoking initiation in Europeans were higher in Japanese schizophrenia patients than in the HCs and those of the FRs were intermediate between those of patients with schizophrenia and those of the HCs (R = 0.015, p = 0.015). In our target subjects, patients with schizophrenia had a higher mean age at smoking initiation (p = 0.018) and rate of daily smoking initiation after age 20 years (p = 0.023) compared with the HCs. A total of 60.6% of the patients started to smoke before the onset of schizophrenia. These findings suggest that genetic factors affecting late smoking initiation are associated with the risk of schizophrenia.
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http://dx.doi.org/10.1038/s41537-020-00126-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684279PMC
November 2020

Strain-induced creation and switching of anion vacancy layers in perovskite oxynitrides.

Nat Commun 2020 Nov 23;11(1):5923. Epub 2020 Nov 23.

Department of Energy and Hydrocarbon Chemistry, Graduate school of Engineering, Graduate School of Engineering, Nishikyo-ku, Kyoto, 615-8510, Japan.

Perovskite oxides can host various anion-vacancy orders, which greatly change their properties, but the order pattern is still difficult to manipulate. Separately, lattice strain between thin film oxides and a substrate induces improved functions and novel states of matter, while little attention has been paid to changes in chemical composition. Here we combine these two aspects to achieve strain-induced creation and switching of anion-vacancy patterns in perovskite films. Epitaxial SrVO films are topochemically converted to anion-deficient oxynitrides by ammonia treatment, where the direction or periodicity of defect planes is altered depending on the substrate employed, unlike the known change in crystal orientation. First-principles calculations verified its biaxial strain effect. Like oxide heterostructures, the oxynitride has a superlattice of insulating and metallic blocks. Given the abundance of perovskite families, this study provides new opportunities to design superlattices by chemically modifying simple perovskite oxides with tunable anion-vacancy patterns through epitaxial lattice strain.
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http://dx.doi.org/10.1038/s41467-020-19217-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683707PMC
November 2020

Genetic implications in quality palliative care and preventing opioid crisis in cancer-related pain management.

J Neurosci Res 2020 Nov 11. Epub 2020 Nov 11.

Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

The prevalence of cancer-related pain is 64% among patients with metastatic, advanced, or terminal cancer, 59% among patients undergoing anticancer treatment, and 33% among patients who completed curative treatment. According to the World Health Organization cancer pain relief guidelines, opioid analgesics are the mainstay analgesic therapy in addition to conventional first-step analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen. The indications for strong opioids have recently been expanded to include mild-to-moderate pain in addition to moderate-to-severe pain. The U.S. Centers for Disease Control and Prevention guidelines emphasize that realistic expectations should be weighed against potential serious harm from opioids, rather than relying on the unrealized long-term benefits of these drugs. Therefore, treatment strategies for both cancer-related chronic or acute pain have been unfortunately deviated from opioid analgesics. The barriers hindering adequate cancer-related pain management with opioid analgesics are related to the inadequate knowledge of opioid analgesics (e.g., effective dose, adverse effects, and likelihood of addiction or tolerance). To achieve adequate opioid availability, these barriers should be overcome in a clinically suitable manner. Genetic assessments could play an important role in overcoming challenges in opioid management. To balance the improvement in opioid availability and the prevention of opioid misuse and addiction, the following two considerations concerning opioids and genetic polymorphisms warrant attention: (A) pain severity, opioid sensitivity, and opioid tolerance; and (B) vulnerability to opioid dependence and addiction.
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http://dx.doi.org/10.1002/jnr.24756DOI Listing
November 2020

Solvation Structure of Li in Concentrated Acetonitrile and ,-Dimethylformamide Solutions Studied by Neutron Diffraction with Li/Li Isotopic Substitution Methods.

J Phys Chem B 2020 11 8;124(46):10456-10464. Epub 2020 Nov 8.

Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan.

Neutron diffraction measurements on Li/Li isotopically substituted 10 and 33 mol % *LiTFSA (lithium bis(trifluoromethylsulfonyl)amide)-AN- (acetonitrile-) and 10 and 33 mol % *LiTFSA-DMF-(-dimethylformamide-) solutions have been carried out in order to obtain structural insights on the first solvation shell of Li in highly concentrated organic solutions. Structural parameters concerning the local structure around Li have been determined from the least squares fitting analysis of the first-order difference function derived from the difference between carefully normalized scattering cross sections observed for Li-enriched and natural abundance solutions. In 10 mol % LiTFSA-AN- solution, 3.25 ± 0.04 AN molecules are coordinated to Li with a intermolecular Li···N(AN) distance of 2.051 ± 0.007 Å. It has been revealed that 1.67 ± 0.07 AN molecules and 2.00 ± 0.01 TFSA are involved in the first solvation shell of Li in the 33 mol % LiTFSA-AN solution. The nearest neighbor Li···N and Li···O distances are obtained to be (Li···N) = 2.09 ± 0.01 Å and (Li···O) = 1.88 ± 0.01 Å, respectively. The first solvation shell of Li in the 10 mol % LiTFSA-DMF- solutions contains 3.4 ± 0.1 DMF molecules with an intermolecular Li···O distance of 1.95 ± 0.02 Å. In highly concentrated 33 mol % LiTFSA-DMF- solutions, there are 1.3 ± 0.2 DMF molecules and 3.2 ± 0.2 TFSA in the first solvation shell of Li with intermolecular distances of (Li···O) = 1.90 ± 0.02 Å and (Li···O) = 2.01 ± 0.01 Å, respectively. The Li···TFSA contact ion pair stably exists in highly concentrated 33 mol % LiTFSA-AN and -DMF solutions.
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http://dx.doi.org/10.1021/acs.jpcb.0c08021DOI Listing
November 2020

Increase in excitability of hippocampal neurons during novelty-induced hyperlocomotion in dopamine-deficient mice.

Mol Brain 2020 09 18;13(1):126. Epub 2020 Sep 18.

Department of Psychiatry and Behavioral Sciences, Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.

Dopamine is involved in many important brain functions, including voluntary motor movement. Dysfunction of the dopaminergic system can induce motor impairments, including Parkinson's disease. We previously found that dopamine-deficient (DD) mice became hyperactive in a novel environment 72 h after the last injection of L-3,4-dihydroxyphenylalanine (L-DOPA) when dopamine was almost completely depleted. In the present study, we investigated neuronal activity in hippocampal subregions during hyperactivity by measuring Fos expression levels using immunohistochemistry. Dopamine-deficient mice were maintained on daily intraperitoneal injections of 50 mg/kg L-DOPA. Seventy-two hours after the last L-DOPA injection, DD mice were exposed to a novel environment for 1, 2, or 4 h, and then brains were collected. In wildtype mice, the number of Fos-immunopositive neurons significantly increased in the hippocampal CA1 region after 1 h of exposure to the novel environment and then decreased. In DD mice, the number of Fos-immunopositive neurons gradually increased and then significantly increased after 4 h of exposure to the novel environment. The number of Fos-immunopositive neurons also significantly increased in the CA3 region and dentate gyrus in DD mice after 4 h of exposure to the novel environment. These results indicate that the delayed and prolonged excitation of hippocampal neurons in the CA1, CA3, and dentate gyrus that is caused by dopamine depletion might be involved in hyperactivity in DD mice.
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http://dx.doi.org/10.1186/s13041-020-00664-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501682PMC
September 2020

Distance-Selected Topochemical Dehydro-Diels-Alder Reaction of 1,4-Diphenylbutadiyne toward Crystalline Graphitic Nanoribbons.

J Am Chem Soc 2020 Oct 23;142(41):17662-17669. Epub 2020 Sep 23.

Center for High Pressure Science and Technology Advanced Research, Beijing 100094, P. R. China.

Solid-state topochemical polymerization (SSTP) is a promising method to construct functional crystalline polymeric materials, but in contrast to various reactions that happen in solution, only very limited types of SSTP reactions are reported. Diels-Alder (DA) and dehydro-DA (DDA) reactions are textbook reactions for preparing six-membered rings in solution but are scarcely seen in solid-state synthesis. Here, using multiple cutting-edge techniques, we demonstrate that the solid 1,4-diphenylbutadiyne (DPB) undergoes a DDA reaction under 10-20 GPa with the phenyl as the dienophile. The crystal structure at the critical pressure shows that this reaction is "distance-selected". The distance of 3.2 Å between the phenyl and the phenylethynyl facilitates the DDA reaction, while the distances for other DDA and 1,4-addition reactions are too large to allow the bonding. The obtained products are crystalline armchair graphitic nanoribbons, and hence our studies open a new route to construct the crystalline carbon materials with atomic-scale control.
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http://dx.doi.org/10.1021/jacs.0c08274DOI Listing
October 2020

Absence of methamphetamine-induced conditioned place preference in weaver mutant mice.

Neuropsychopharmacol Rep 2020 12 19;40(4):324-331. Epub 2020 Aug 19.

Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Aims: G protein-activated inwardly rectifying potassium (GIRK) channels are related to rewarding effects of addictive drugs. The GIRK2 subunit is thought to play key roles in the reward system. Weaver mutant mice exhibit abnormal GIRK2 function and different behaviors that are caused by several addictive substances compared with wild-type mice. However, mechanisms of reward-related alterations in weaver mutant mice remain unclear. The present study investigated changes in the rewarding effects of methamphetamine (METH) in weaver mutant mice.

Methods: The rewarding effects of METH (4.0 mg/kg) were investigated using the conditioned place preference (CPP) paradigm. Extracellular dopamine level in the nucleus accumbens (NAc) was measured by in vivo microdialysis. To identify brain regions that were associated with these changes in rewarding effects, METH-induced alterations of Fos expression were investigated by immunohistochemical analysis.

Results: Weaver mutant mice exhibited a significant decrease in METH-induced CPP and dopamine release in the NAc. Methamphetamine significantly increased Fos expression in the posterior NAc (pNAc) shell in wild-type but not in weaver mutant mice.

Conclusions: Methamphetamine did not induce rewarding effects in weaver mutant mice. The pNAc shell exhibited a significant difference in neuronal activity between wild-type and weaver mutant mice. The present results suggest that the absence of METH-induced CPP in weaver mutant mice is probably related to an innate reduction of dopamine and decreased neural activity in the pNAc shell that is partially attributable to the change of GIRK channel function. GIRK channels, especially those containing the GIRK2 subunit, appear to be involved in METH dependence.
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http://dx.doi.org/10.1002/npr2.12130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722684PMC
December 2020

Genetic associations of single nucleotide polymorphisms in the l-DOPA receptor (GPR143) gene with severity of nicotine dependence in Japanese individuals, and attenuation of nicotine reinforcement in Gpr143 gene-deficient mice.

J Pharmacol Sci 2020 Oct 16;144(2):89-93. Epub 2020 Jul 16.

Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. Electronic address:

l-3,4-dihydroxyphenylalanine (l-DOPA) is a candidate neurotransmitter. l-DOPA is released by nicotine through nicotinic receptors. Recently, G-protein coupled receptor GPR143, was identified as a receptor for l-DOPA. In this study, genetic association studies between GPR143 genetic polymorphisms and smoking behaviors revealed that the single-nucleotide polymorphism rs6640499, in the GPR143 gene, was associated with traits of smoking behaviors in Japanese individuals. In Gpr143 gene-deficient mice, nicotine-induced hypolocomotion and rewarding effect were attenuated compared to those in wild-type mice. Our findings suggest the involvement of GPR143 in the smoking behaviors.
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http://dx.doi.org/10.1016/j.jphs.2020.07.003DOI Listing
October 2020

The structural elucidation of aqueous HBO solutions by DFT and neutron scattering studies.

Phys Chem Chem Phys 2020 Aug;22(30):17160-17170

CAS, Key Laboratory of Comprehensive and Highly Efficient Utilization of Salt Lake Resources, Key Laboratory of Salt Lake Resources Chemistry of Qinghai Province, Qinghai Institute of Salt Lakes, Chinese Academy of Sciences, Xining 810008, China.

The micro-structure of aqueous boric acid (H3BO3) solutions is of broad interest in earth sciences, geochemistry, material science, as well as chemical engineering. In the present study, the structure of aqueous H3BO3 solutions was studied via neutron scattering with 2H and 11B isotope labelling combined with empirical potential structure refinement (EPSR) modelling. In aqueous H3BO3 solutions, B(OH)3 is the dominant borate species. Density function theory (DFT) calculations show that the boron hydroxyl has a lower electrostatic potential (ESP), which makes B(OH)3 a relatively weakly hydrated, compared with the bulk water. In the 0.95 mol L-1 H3BO3 solution at 298 K (saturated), ∼18 water molecules enter the hydration sphere of B(OH)3 with the hydration distance (B-O(W)) of 3.75 Å, while only 4.23 of them hydrate with H3BO3 as the hydrogen bond (H-bond) acceptor or H-bond donor. Both neutron scattering and DFT calculations for 2B(OH)3·6H2O clusters at the ωB97XD/6-311++g(3df,3pd) basis level show that B(OH)3 forms molecular clusters in bidentate contact molecular pairs (BCMP), mono-dentate molecular pairs (MCMP), solvent-shared molecular pairs (SMP), and parallel solvent-shared molecular pairs (PSMP) in aqueous solutions. Their relative contents are both concentration- and temperature-sensitive. BCMP with the B-B distance of ∼4.1 Å is the dominant molecular pair in the aqueous solutions. Relatively less content and van der Waals interactions stabilized PSMP, with a B-B distance of ∼3.6 Å between the two parallel layers, which is a crucial species for the crystallization of H3BO3 from aqueous solution.
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http://dx.doi.org/10.1039/d0cp02306jDOI Listing
August 2020

Effects of hyperbaric oxygen treatment on calvarial bone regeneration in young and adult mice.

Arch Oral Biol 2020 Sep 9;117:104828. Epub 2020 Jul 9.

Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.

Objective: The present study aimed to investigate the effects of hyperbaric oxygen (HBO) treatment on calvarial bone regeneration in young and adult mice.

Methods: Calvarial defects of 6.0 mm diameter were created in sixteen 3-week (young) and sixteen 32-week old (adult) mice. The mice were divided into two groups of eight animals each (HBO-treated and control). The 90-min HBO treatment at 2.5 absolute atmospheric pressure and 100 % oxygen was performed for five days a week for 12 weeks. After 2-weeks from the operation, micro-computerized tomography and video microscopy were used to evaluate the regenerated bone volume and microcirculation every two weeks. The protein concentrations of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in exudates of the calvarial tissue field were measured at 1, 2, 3, and 4 weeks after surgery. After 12 weeks, histochemical examination of regenerated calvarial bone was conducted.

Results: Regenerated bone was formed earlier in young mice than in adult mice treated with HBO. HBO stimulates angiogenesis in the periosteum around regenerated bone area in both young and adult mice at 2 weeks. VEGF concentrations in the calvarial tissue field were lower in the HBO group than in the control 1 week after operation, although bFGF were higher till the 2nd week in the HBO group than in the control.

Conclusions: HBO accelerates bone regeneration earlier in young mice than in adult mice. In the HBO-treated group, bFGF expression was promoted at an early stage, although the expression of VEGF was inhibited.
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http://dx.doi.org/10.1016/j.archoralbio.2020.104828DOI Listing
September 2020

A lipidome atlas in MS-DIAL 4.

Nat Biotechnol 2020 10 15;38(10):1159-1163. Epub 2020 Jun 15.

RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

We present Mass Spectrometry-Data Independent Analysis software version 4 (MS-DIAL 4), a comprehensive lipidome atlas with retention time, collision cross-section and tandem mass spectrometry information. We formulated mass spectral fragmentations of lipids across 117 lipid subclasses and included ion mobility tandem mass spectrometry. Using human, murine, algal and plant biological samples, we annotated and semiquantified 8,051 lipids using MS-DIAL 4 with a 1-2% estimated false discovery rate. MS-DIAL 4 helps standardize lipidomics data and discover lipid pathways.
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http://dx.doi.org/10.1038/s41587-020-0531-2DOI Listing
October 2020

Antioxidant vitamins and lysophospholipids are critical for inducing mouse spermatogenesis under organ culture conditions.

FASEB J 2020 07 31;34(7):9480-9497. Epub 2020 May 31.

Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

In vitro mouse spermatogenesis using a classical organ culture method became possible by supplementing basal culture medium with only the product of bovine serum albumin purified by chromatography (AlbuMAX), which indicated that AlbuMAX contained every chemical factor necessary for mouse spermatogenesis. However, since the identity of these factors was unclear, improvements in culture media and our understanding of the nutritional and signal substances required for spermatogenesis were hindered. In the present study, chemically defined media (CDM) without AlbuMAX was used to evaluate each supplementary factor and their combinations for the induction of spermatogenesis. Similar to in vivo conditions, retinoic acid, triiodothyronine (T ), and testosterone (T) were needed. Based on differences in spermatogenic competence between AlbuMAX, fetal bovine serum, and adult bovine serum, we identified α-tocopherol, which strongly promoted spermatogenesis when combined with ascorbic acid and glutathione. Differences were also observed in the abilities of lipids extracted from AlbuMAX using two different methods to induce spermatogenesis. This led to the identification of lysophospholipids, particularly lysophosphatidylcholine, lysophosphatidic acid, and lysophosphatidylserine, as important molecules for spermatogenesis. New CDM formulated based on these results induced and promoted spermatogenesis as efficiently as AlbuMAX-containing medium. In vitro spermatogenesis with CDM may provide a unique experimental system for research on spermatogenesis that cannot be performed in in vivo experiments.
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http://dx.doi.org/10.1096/fj.202000245RDOI Listing
July 2020

High-pressure Synthesis of BaCoOAgTe with Extended CoO Planes.

Inorg Chem 2020 Jun 21;59(12):8121-8126. Epub 2020 May 21.

Department of Energy and Hydrocarbon Chemistry, Graduate school of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan.

Using a high-pressure synthesis method, we prepared the layered oxychalcogenide BaCoOAgTe (space group: 4/) with alternating stacks of CoO and AgTe layers, separated by Ba atoms. The CoO plane is greatly extended (Co-O = 2.19 Å on average) due to tensile strain from adjacent AgTe layers, causing displacement of oxide anions. Layered cobaltates with -CoOX (X = chalcogen, halogen) coordination feature large spin-orbit coupling, which is linearly scaled by the tetrahedral factor of /. However, applying this relation to BaCoOAgTe yields a magnetic moment of ∼4 μ, which is nearly twice the experimentally observed value of 1.87(17) μ. This result, along with a reduced Néel temperature ( = 60 K), originates from the off-centered position of otherwise under-bonded oxide anions, which changes the crystal field splitting of Co d orbitals.
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http://dx.doi.org/10.1021/acs.inorgchem.0c00429DOI Listing
June 2020