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Vanadium-based solid solution alloys potentially serve as safe, high-capacity hydrogen storage materials. Low-vanadium-concentration alloys have low durability, and their hydrogen absorption and desorption amounts decrease by 20 % after 100 cycles. In this study, we conducted reverse Monte Carlo modeling on X-ray diffraction patterns and neutron pair distribution functions of the hydrogen-absorbed and desorbed samples of a V 0.10 Ti 0.36 Cr 0.54 alloy to analyze the variations in the local structure. The local structure surrounding the hydrogen atom in the hydrogen-absorbed phase exhibited minimal changes. In contrast, hydrogen occupied both tetrahedral and octahedral sites of the hydrogen-desorbed phase almost equally during the early cycles; however, the amount of hydrogen occupying the tetrahedral sites increased with the number of cycles. It is speculated that hydrogen absorption and desorption cycling induced grain refinement and/or introduced dislocations, which altered both the amount of hydrogen and the sites occupied in the desorbed phase, thereby decreasing the hydrogen storage capacity. [Display omitted] • Degradation mechanism of V–Ti–Cr hydrogen storage alloy revealed by local structure. • Decrease in hydrogen storage consistent with PDF refinements and p – c isotherms. • Cr–H and Ti–H correlations reproduced by a large atomic ensemble in RMC modeling. • Change in hydrogen occupation positions supplemented by inelastic neutron scattering. [ABSTRACT FROM AUTHOR]

The serotonin transporter (5-HTT) plays a critical role in the regulation of serotonin neurotransmission. Mice genetically deficient in 5-HTT expression have been used to study the physiological functions of 5-HTT in the brain and have been proposed as a potential animal model for neuropsychiatric and neurodevelopmental disorders. Recent studies have provided evidence for a link between the gut-brain axis and mood disorders. However, the effects of 5-HTT deficiency on gut microbiota, brain function, and behavior remain to be fully characterized. Here we investigated the effects of 5-HTT deficiency on different types of behavior, the gut microbiome, and brain c-Fos expression as a marker of neuronal activation in response to the forced swim test for assessing depression-related behavior in male 5-HTT knockout mice. Behavioral analysis using a battery of 16 different tests showed that 5-HTT−/− mice exhibited markedly reduced locomotor activity, decreased pain sensitivity, reduced motor function, increased anxiety-like and depression-related behavior, altered social behavior in novel and familiar environments, normal working memory, enhanced spatial reference memory, and impaired fear memory compared to 5-HTT+/+ mice. 5-HTT+/− mice showed slightly reduced locomotor activity and impaired social behavior compared to 5-HTT+/+ mice. Analysis of 16S rRNA gene amplicons showed that 5-HTT−/− mice had altered gut microbiota abundances, such as a decrease in Allobaculum, Bifidobacterium, Clostridium sensu stricto, and Turicibacter, compared to 5-HTT+/+ mice. This study also showed that after exposure to the forced swim test, the number of c-Fos-positive cells was higher in the paraventricular thalamus and lateral hypothalamus and was lower in the prefrontal cortical regions, nucleus accumbens shell, dorsolateral septal nucleus, hippocampal regions, and ventromedial hypothalamus in 5-HTT−/− mice than in 5-HTT+/+ mice. These phenotypes of 5-HTT−/− mice partially recapitulate clinical observations in humans with major depressive disorder. The present findings indicate that 5-HTT-deficient mice serve as a good and valid animal model to study anxiety and depression with altered gut microbial composition and abnormal neuronal activity in the brain, highlighting the importance of 5-HTT in brain function and the mechanisms underlying the regulation of anxiety and depression. [ABSTRACT FROM AUTHOR]

In situ gas‐loading sample holders for two‐dimensionally arranged detectors in time‐of‐flight neutron total scattering experiments have been developed to investigate atomic arrangements during deuterium absorption using time and real‐space resolution. A single‐crystal sapphire container was developed that allows conditions of 473 K and 10 MPa hydrogen gas pressure. High‐resolution transient measurements detected deuterium absorption by palladium that proceeded within a few seconds. A double‐layered container with thick‐ and thin‐walled vanadium allowed conditions of 423 K and 10 MPa hydrogen gas pressure. The deuterium occupation sites of a lanthanum–nickel–aluminium alloy are discussed in detail on the basis of real‐space high‐resolution data obtained from in situ neutron scattering measurements and reverse Monte Carlo structural modeling. [ABSTRACT FROM AUTHOR]

In order to further improve the productivity of manufacturing equipment, it is indispensable to monitor the conditions of all the manufacturing equipment and not just the processing chambers. In this paper, we present a robust machine learning based deterioration diagnosis technology with harmonic sensor, which has frequency characteristics that have high sensitivity to deterioration and low sensitivity to torque. The robust deterioration diagnosis using a small amount of data is possible by limiting the input data to be trained and inferred to signals and motion patterns, and inferring with neural network models that do not require developments for manufacturing equipment. The example of wafer transfer robots in the ion implanter and the Low-Pressure Chemical Vapor Deposition (LP-CVD) and the coater/developer show that wear deterioration of machine components can be detected from the level of deterioration output and it is possible to prevent errors of the wafer transfer robots because of maintenance based on increases in the level of deterioration. [ABSTRACT FROM AUTHOR]

We report structural and optical properties of Dy3+ doped Na 0.5 Bi 0.5 TiO 3 (NBT), labeled as Dy x :NBT (x = 0.00–0.14). X-ray and neutron diffraction results of Dy x :NBT (x = 0.06 and 0.08) show the occupation of Dy3+ in both Bi and Ti-sites. Such behavior of a dopant ion occupying both in A and B-sites of ABO 3 is called " amphotericity ". In conjunction with the above, Raman spectra show additional breathing vibrational (A 1g) modes in the region of 700–900 cm−1. It confirms the asymmetry in TiO 6 polyhedra and random distribution of Dy3+ and Ti4+ ions. Photoluminescence (PL) spectra show blue (484 nm; 4F 9/2 →6H 15/2 ; magnetic dipole (MD) transition) and yellow (575 nm; 4F 9/2 →6H 13/2 ; electric dipole (ED) transition) emissions. The asymmetric ratio (ED/MD) of emission transitions further confirms the amphoteric distribution of Dy3+ ions. Amphotericity and site-dependent luminescence variation show a strong correlation in structure-property relationships. [Display omitted] • Amphoteric behavior of Dy3+ ions in NBT's structure is explained. • Neutron diffraction confirms the occupation of Dy3+ ions in both Bi and Ti-sites. • Multiple A 1g breathing modes represent the random distribution of Dy3+ and Ti4+ ions. • Asymmetric ratio shows the crystal field around amphoteric Dy3+ ion is symmetrical. • All the phosphors show yellowish-white emission and good CCT values. [ABSTRACT FROM AUTHOR]

Abstract Reelin is a secreted protein essential for the development and function of the mammalian brain. The receptors for Reelin, apolipoprotein E receptor 2 and very low-density lipoprotein receptor, belong to the low-density lipoprotein receptor family, but it is not known whether Reelin is involved in the brain lipid metabolism. In the present study, we performed lipidomic analysis of the cerebral cortex of wild-type and Reelin-deficient (reeler) mice, and found that reeler mice exhibited several compositional changes in phospholipids. First, the ratio of phospholipids containing one saturated fatty acid (FA) and one docosahexaenoic acid (DHA) or arachidonic acid (ARA) decreased. Secondly, the ratio of phospholipids containing one monounsaturated FA (MUFA) and one DHA or ARA increased. Thirdly, the ratio of phospholipids containing 5,8,11-eicosatrienoic acid, or Mead acid (MA), increased. Finally, the expression of stearoyl-CoA desaturase-1 (SCD-1) increased. As the increase of MA is seen as an index of polyunsaturated FA (PUFA) deficiency, and the expression of SCD-1 is suppressed by PUFA, these results strongly suggest that the loss of Reelin leads to PUFA deficiency. Hence, MUFA and MA are synthesized in response to this deficiency, in part by inducing SCD-1 expression. This is the first report of changes of FA composition in the reeler mouse brain and provides a basis for further investigating the new role of Reelin in the development and function of the brain. [ABSTRACT FROM AUTHOR]

Extraction and analysis of sphingolipids from biological samples is a critical step in lipidomics, especially for minor species such as sphingoid bases and sphingosine-1-phosphate. Although several liquid chromatography-mass spectrometry methods enabling the determination of sphingolipid molecular species have been reported, they were limited in analytical sensitivity and reproducibility by causing significant peak tailing, especially by the presence of phosphate groups, and most of the extraction techniques are laborious and do not cover a broad range of sphingolipid metabolites. In this study, we developed a rapid single-phase extraction and highly sensitive analytical method for the detection and quantification of sphingolipids (including phosphates) comprehensively using liquid chromatography-triple quadruple mass spectrometry. After validating the reliability of the method, we analyzed the intestinal tissue sphingolipids of germ-free (GF) and specific pathogen-free (SPF) mice and found significantly higher levels of free sphingoid bases and sphingosine-1-phosphate in the GF condition as compared to the SPF condition. This method enables a rapid extraction and highly sensitive determination of sphingolipids comprehensively at low femtomolar ranges.Diagrammatic comparision of sphingolipid (phosphates) analysis between conventional and this method. [ABSTRACT FROM AUTHOR]

The formation process from the intermetallic compound LaMg 2 Ni to a complex hydride (deuteride) LaMg 2 NiD 7 composed of La 3+ , 2 × Mg 2+ , [NiD 4 ] 4− , and 3 × D − was investigated by in-situ powder neutron diffraction under deuterium gas pressure at room temperature. Below 0.001 MPa, small amount of deuterium was initially dissolved in the lattice of LaMg 2 Ni forming LaMg 2 NiD 0.05 and two new hydride phases (LaMg 2 NiD x 1 and LaMg 2 NiD x 2 ) were continuously yielded. Furthermore, LaMg 2 NiD 4.6 with NiD 1.9 and NiD 3.3 units and interstitial deuterium atoms was formed prior to appearing of LaMg 2 NiD 7 . From their Bragg peak positions, the deuterium contents x 1, and x 2 were inferred as 0.05 < x 1 < x 2 < 4.6. At approximately 0.001 MPa, LaMg 2 NiD 7 started forming. Since the intermediate deuterides had similar metal atomic framework of LaMg 2 Ni, we revealed that LaMg 2 NiD 7 formation proceeded through multiple deuteride phases with maintaining of the metal atomic framework of LaMg 2 Ni. [ABSTRACT FROM AUTHOR]

Background: Liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) is used for comprehensive metabolome and lipidome analyses. Compound identification relies on similarity matching of the retention time (RT), precursor m/z, isotopic ratio, and MS/MS spectrum with reference compounds. For sphingolipids, however, little information on the RT and MS/MS references is available. Results: Negative-ion ESI-MS/MS is a useful method for the structural characterization of sphingolipids. We created theoretical MS/MS spectra for 21 sphingolipid classes in human and mouse (109,448 molecules), with substructure-level annotation of unique fragment ions by MS-FINDER software. The existence of ceramides with β-hydroxy fatty acids was confirmed in mouse tissues based on cheminformatic- and quantum chemical evidences. The RT of sphingo- and glycerolipid species was also predicted for our LC condition. With this information, MS-DIAL software for untargeted metabolome profiling could identify 415 unique structures including 282 glycerolipids and 133 sphingolipids from human cells (HEK and HeLa) and mouse tissues (ear and liver). Conclusions: MS-DIAL and MS-FINDER software programs can identify 42 lipid classes (21 sphingo- and 21 glycerolipids) with the in silico RT and MS/MS library. The library is freely available as Microsoft Excel files at the software section of our RIKEN PRIMe website (). [ABSTRACT FROM AUTHOR]

N-3 polyunsaturated fatty acids (PUFA), such as docosahexaenoic acid (DHA, 22:6n-3), have been reported to play roles in preventing cardiovascular diseases. The major source of DHA is fish oils but a recent increase in the global demand of DHA and decrease in fish stocks require a substitute. Thraustochytrids, unicellular marine protists belonging to the Chromista kingdom, can synthesize large amounts of DHA, and, thus, are expected to be an alternative to fish oils. DHA is found in the acyl chain(s) of phospholipids as well as triacylglycerols in thraustochytrids; however, how thraustochytrids incorporate DHA into phospholipids remains unknown. We report here a novel lysophospholipid acyltransferase (PLAT1), which is responsible for the generation of DHA-containing phosphatidylcholine and phosphatidylethanolamine in thraustochytrids. The PLAT1 gene, which was isolated from the genomic DNA of Aurantiochytrium limacinum F26-b, was expressed in Saccharomyces cerevisiae, and the FLAG-tagged recombinant enzyme was characterized after purification with anti-FLAG affinity gel. PLAT1 shows wide specificity for donor substrates as well as acceptor substrates in vitro, i.e, the enzyme can adopt lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylserine and lysophosphatidylinositol as acceptor substrates, and 15:0/16:0-CoA and DHA-CoA as donor substrates. In contrast to the in vitro experiment, only lysophosphatidylcholine acyltransferase and lysophosphatidylethanolamine acyltransferase activities were decreased in plat1-knockout mutants, resulting in a decrease of 16:0-DHA-phosphatidylcholine (PC) [PC(38∶6)] and 16:0-DHA-phosphatidylethanolamine (PE) [PE(38∶6)], which are two major DHA-containing phospholipids in A. limacinum F26-b. However, the amounts of other phospholipid species including DHA-DHA-PC [PC(44∶12)] and DHA-DHA-PE [PE(44∶12)] were almost the same in plat-knockout mutants and the wild-type. These results indicate that PLAT1 is the enzyme responsible for the generation of 16:0-DHA-PC and 16:0-DHA-PE in the thraustochytrid. [ABSTRACT FROM AUTHOR]

Although endogenous ligands for Toll-like receptor (TLR)4–myeloid differentiation factor 2 (MD2) have not been well-understood, we here report that a globo-series glycosphingolipid, globotetraosylceramide (Gb4), attenuates the toxicity of lipopolysaccharides (LPSs) by binding to TLR4–MD-2. Because α1,4-galactosyltransferase (A4galt)-deficient mice lacking globo-series glycosphingolipids showed higher sensitivity to LPS than wild-type mice, we examined mechanisms by which globo-series glycosphingolipids attenuate LPS toxicity. Cultured endothelial cells lacking A4galt showed higher expression of LPS-inducible genes upon LPS treatment. In turn, introduction of A4galt cDNA resulted in the neo expression of Gb4, leading to the reduced expression of LPS-inducible genes. Exogenous Gb4 induced similar effects. As a mechanism for the suppressive effects of Gb4 on LPS signals, specific binding of Gb4 to the LPS receptor TLR4–MD-2 was demonstrated by coprecipitation of Gb4 with recombinant MD-2 and by native PAGE. A docking model also supported these data. Taken together with colocalization of TLR4–MD-2 with Gb4 in lipid rafts after LPS stimulation, it was suggested that Gb4 competes with LPS for binding to TLR4–MD-2. Finally, administration of Gb4 significantly protected mice from LPS-elicited mortality. These results suggest that Gb4 is an endogenous ligand for TLR4–MD-2 and is capable of attenuating LPS toxicity, indicating the possibility for its therapeutic application in endotoxin shock. [ABSTRACT FROM AUTHOR]

Lipids are key components in the viral life cycle that affect host-pathogen interactions. In this study, we investigated the effect of HCV infection on sphingolipid metabolism, especially on endogenous SM levels, and the relationship between HCV replication and endogenous SM molecular species. We demonstrated that HCV induces the expression of the genes (SGMS1 and 2) encoding human SM synthases 1 and 2. We observed associated increases of both total and individual sphingolipid molecular species, as assessed in human hepatocytes and in the detergent-resistant membrane (DRM) fraction in which HCV replicates. SGMS1 expression had a correlation with HCV replication. Inhibition of sphingolipid biosynthesis with a hepatotropic serine palmitoyltransferase (SPT) inhibitor, NA808, suppressed HCV-RNA production while also interfering with sphingolipid metabolism. Further, we identified the SM molecular species that comprise the DRM fraction and demonstrated that these endogenous SM species interacted with HCV nonstructural 5B polymerase to enhance viral replication. Our results reveal that HCV alters sphingolipid metabolism to promote viral replication, providing new insights into the formation of the HCV replication complex and the involvement of host lipids in the HCV life cycle. [ABSTRACT FROM AUTHOR]

A fungus-specific glucosylceramide (GlcCer), which contains a unique sphingoid base possessing two double bonds and a methyl substitution, is essential for pathogenicity in fungi. Although the biosynthetic pathway of the GlcCer has been well elucidated, little is known about GlcCer catabolism because a GlcCer-degrading enzyme (glucocerebrosidase) has yet to be identified in fungi. We found a homologue of endoglycoceramidase tentatively designated endoglycoceramidase-related protein 1 (EGCrP1) in several fungal genomic databases. The recombinant EGCrP1 hydrolyzed GlcCer but not other glycosphingolipids, whereas endoglycoceramidase hydrolyzed oligosaccharide-linked glycosphingolipids but not GlcCer. Disruption of egcrp1 in Cryptococcus neoformans, a typical pathogenic fungus causing cryptococcosis, resulted in the accumulation of fungus-specific GlcCer and immature GlcCer that possess sphingoid bases without a methyl substitution concomitant with a dysfunction of polysaccharide capsule formation. These results indicated that EGCrP1 participates in the catabolism of GlcCer and especially functions to eliminate immature GlcCer in vivo that are generated as by-products due to the broad specificity of GlcCer synthase. We conclude that EGCrP1, a glucocerebrosidase identified for the first time in fungi, controls the quality of GlcCer by eliminating immature GlcCer incorrectly generated in C. neoformans, leading to accurate processing of fungus-specific GlcCer. [ABSTRACT FROM AUTHOR]

Fatty liver is one of the typical manifestations in homocysteinemia/homocystinuria patients and their genetic animal model, mice lacking cystathionine β-synthase ( Cbs). The vast majority of Cbs die within 4 weeks after birth via yet unknown mechanisms, whereas a small portion survive to adulthood, escaping fatty degeneration of the liver during lactation periods, through regeneration. To investigate the molecular basis of such fatty changes, we analyzed lipid components in fatty livers of 2-week-old Cbs and regenerated non-fatty livers of 8-week-old Cbs survivors using a chip-based nanoESI (electrospray ionization)-MS system, which allows quantitative detection of triacylglycerol/phospholipid molecular species. Hepatic levels of all major triacylglycerol species were much higher in Cbs than in wild-type mice at 2 weeks, although not at 8 weeks. Levels of some phospholipid species were either up- or downregulated in 2-week-old Cbs; e.g. saturated (16:0 and 18:0) or mono-unsaturated (16:1 and 18:1) fatty acids-containing phosphatidylcholine/phosphatidylethanolamine species were upregulated, while poly-unsaturated fatty acids-containing phosphatidylcholine (18:2-18:2 and 18:2-20:5), phosphatidylethanolamine (18:1-20:4), and phosphatidylinositol (18:0-20:4) were downregulated. Capillary electrophoresis-MS analysis identified high-level accumulation of S-adenosylmethionine and S-adenosylhomocysteine in fatty livers of 2-week-old Cbs but much less in non-fatty livers of 8-week-old Cbs. Although hepatic S-adenosylmethionine/ S-adenosylhomocysteine ratios were comparable between 2-week-old Cbs and wild-type, global protein arginine methylation was disturbed in fatty livers of Cbs. Our results suggest that cellular signaling mediated by altered phospholipid contents might be involved in pathogenesis of fatty liver in Cbs. [ABSTRACT FROM AUTHOR]

Abstract: Recently, global analysis of triacylglycerols (TAGs) has become increasingly important in studies of abnormality of lipid metabolism in metabolic syndrome. TAGs consist of various molecular species, caused by their three fatty acyl chains with a large variety of carbon chain lengths and degrees of unsaturation. Therefore, most previously reported methods have been insufficient in global detection of TAGs including their structural isomers and TAGs with oxidized or odd number acyl carbon chain. Here we report an effective method for global analysis of TAG molecular species from complex lipid mixtures of mouse liver and white adipose tissue (WAT) using reverse-phased high resolution liquid chromatography (LC) coupled with electrospray ionization (ESI)-quadrapole/time of flight hybrid mass spectrometer (QTOF-MS). For effective profiling of TAG molecular species, sensitive two-dimensional (2D) maps were constructed and individual structures were correctly identified by the elution profile and MS/MS. As a result, TAGs including their structural isomers and TAGs with an odd number acyl carbon chain were separated and detected effectively on the 2D map as compared with conventional high performance LC. It was also found that our 2D profiling method was useful in searching characteristic molecular species globally. In mouse WAT, novel oxidized TAGs, which were mainly formed by hydroperoxidation of one of their linoleic acyl chains, were effectively detected in comparison with TAG molecular species of mouse liver. [Copyright &y& Elsevier]

Opiate analgesics are widely used and abused drugs. Individual differences in opiate sensitivity can hamper effective pain treatments and increase risks of drug abuse. Although genetic factors might affect individual differences in opiate sensitivity, scientific evidence for specific genetic mechanisms that underlie these differences has been sparse. Recent studies using inbred and knockout mice have revealed that the mu opioid peptide (MOP) receptor encoded by the Oprm1 gene has a mandatory role in the analgesic and addictive properties of opiate drugs. Increasing evidence suggests that differences in Oprm1 gene sequences affect the amount of Oprm1 mRNA and sensitivity to opiates, and >100 polymorphisms have been identified in the human OPRM1 gene, some of which are related to vulnerability to drug dependence in some populations. Rapid advances in this research field are leading to improved understanding of the relationships between gene polymorphisms and opiate sensitivities that will enable more-accurate prediction of the opiate sensitivity and opiate requirements in individual patients. [Copyright &y& Elsevier]

Opioids and ethanol have been used since ancient times for pain relief. Opioid signaling is mediated by various effectors, including G protein-activated inwardly rectifying potassium (GIRK) channels, adenylyl cyclases, voltage-dependent calcium channels, phospholipase Cβ(PLCβ), and mitogen-activated protein kinases, although it has been unclear which effector mediates the analgesic effects of opioids. Ethanol induces a variety of physiological phenomena via various proteins, including GIRK channels rather than via membrane lipids. GIRK channel activation by either G proteins or ethanol is impaired in weaver mutant mice. The mutant mice may therefore serve as a useful animal model for studying the role of GIRK channels in vivo. Reduced analgesia by using either opioids or ethanol in weaver mutant mice suggests that GIRK channels are important effectors in both opioid- and ethanol-induced analgesia. This hypothesis is supported by similar findings in GIRK2 knockout mice. Among the various effectors coupled with opioid receptors and various targets of ethanol, GIRK channels are the only molecules whose involvement in opioid- and ethanol-induced analgesia has been demonstrated in vivo. The GIRK channel is potentially one of the key molecules in furthering the understanding of the pain control system and in developing advanced analgesics with fewer adverse effects. [Copyright &y& Elsevier]

1 To investigate the effects of adenosine on endogenous Xenopus oocyte receptors, we analysed defolliculated oocytes injected with mRNAs for the G protein-activated inwardly rectifying K[sup +] (GIRK) channels. 2 In oocytes injected with mRNAs for either GIRK1/GIRK2 or GIRK1/GIRK4 subunits, application of adenosine or ATP reversibly induced inward K[sup +] currents, although ATP was less potent than adenosine. The responses were attenuated by caffeine, a non-selective adenosine receptor antagonist. Furthermore, in uninjected oocytes from the same donor, adenosine produced no significant current. 3 The endogenous receptor was activated by two selective A[sub 1] adenosine receptor agonists, N[sup 6]cyclopentyladenosine (CPA) and N[sup 6]-cyclohexyladenosine (CHA), and antagonized by a selective A[sub 1] adenosine receptor antagonist, 1,3-dipropyl-8-cyclopenylxanthine (DPCPX) at moderate nanomolar concentrations, but insensitive to micromolar concentrations of selective A[sub 2A] and A[sub 3] adenosine receptor agonists, 2-[p-(2-carbonyl-ethyl)-phenytethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680) and N[sup 6]-(3-iodobenzyl)-5'-(N-methylcarbamoyl)adenosine (IB-MECA), respectively. However, the pharmacological characteristics of the receptor were different from those of the cloned Xenopus A[sub 1] adenosine receptor and previously proposed adenosine receptors. 4 The adenosine-induced GIRK currents were abolished by injection of pertussis toxin and CPA inhibited forskolin-stimulated cyclic AMP accumulation. 5 We conclude that an adenosine receptor on the Xenopus oocyte membrane can activate GIRK channels and inhibit adenylyl cyclase via G[sub i/o] proteins. Moreover, our results suggest the existence of an endogenous adenosine receptor with the unique pharmacological characteristics. As the receptor was activated by nanomolar concentrations of adenosine, which is a normal constituent of extracellular fluid, the receptor may be involved in some effects through... [ABSTRACT FROM AUTHOR]

Recent studies have highlighted the significance of cellular metabolism in the initiation of clonal expansion and effector differentiation of T cells. Upon exposure to antigens, naïve CD4+ T cells undergo metabolic reprogramming to meet their metabolic requirements. However, only few studies have simultaneously evaluated the changes in protein and metabolite levels during T cell differentiation. Our research seeks to fill the gap by conducting a comprehensive analysis of changes in levels of metabolites, including sugars, amino acids, intermediates of the TCA cycle, fatty acids, and lipids. By integrating metabolomics and proteomics data, we discovered that the quantity and composition of cellular lipids underwent significant changes in different effector Th cell subsets. Especially, we found that the sphingolipid biosynthesis pathway was commonly activated in Th1, Th2, Th17, and iTreg cells and that inhibition of this pathway led to the suppression of Th17 and iTreg cells differentiation. Additionally, we discovered that Th17 and iTreg cells enhance glycosphingolipid metabolism, and inhibition of this pathway also results in the suppression of Th17 and iTreg cell generation. These findings demonstrate that the utility of our combined metabolomics and proteomics analysis in furthering the understanding of metabolic transition during Th cell differentiation. Using metabolomics and proteomics data, the quantity and composition of cellular lipid underwent notable changes in different eff Th cell subsets. Especially, Th17 and iTreg cells enhance glycosphingolipid metabolism to sustain their differentiation. [ABSTRACT FROM AUTHOR]

Globally, the rapid aging of the population is predicted to become even more severe in the second half of the 21st century. Thus, it is expected to establish a growing expectation for innovative, non-invasive health indicators and diagnostic methods to support disease prevention, care, and health promotion efforts. In this study, we aimed to establish a new health index and disease diagnosis method by analyzing the minerals and free amino acid components contained in hair shaft. We first evaluated the range of these components in healthy humans and then conducted a comparative analysis of these components in subjects with diabetes, hypertension, androgenetic alopecia, major depressive disorder, Alzheimer's disease, and stroke. In the statistical analysis, we first used a student's t test to compare the hair components of healthy people and those of patients with various diseases. However, many minerals and free amino acids showed significant differences in all diseases, because the sample size of the healthy group was very large compared to the sample size of the disease group. Therefore, we attempted a comparative analysis based on effect size, which is not affected by differences in sample size. As a result, we were able to narrow down the minerals and free amino acids for all diseases compared to t test analysis. For diabetes, the t test narrowed down the minerals to 15, whereas the effect size measurement narrowed it down to 3 (Cr, Mn, and Hg). For free amino acids, the t test narrowed it down to 15 minerals. By measuring the effect size, we were able to narrow it down to 7 (Gly, His, Lys, Pro, Ser, Thr, and Val). It is also possible to narrow down the minerals and free amino acids in other diseases, and to identify potential health indicators and disease-related components by using effect size. [ABSTRACT FROM AUTHOR]

Ethanol affects many functions of the brain and peripheral organs. Here we show that ethanol opens G-protein-activated, inwardly rectifying K[sup +] (GIRK) channels, which has important implications for inhibitory regulation of neuronal excitability and heart rate. At pharmacologically relevant concentrations, ethanol activated both brain-type GIRK½ and cardiac-type GIRK¼ channels without interaction with G proteins or second messengers. Moreover, weaver mutant mice, which have a missense mutation in the GIRK2 channel, showed a loss of ethanol-induced analgesia. These results suggest that the GIRK channels in the brain and heart are important target sites for ethanol. [ABSTRACT FROM AUTHOR]

Examines the physiologic roles of the glutamate receptor (GluR) channel delta subunit. Mice defective in the GluR channel delta2 subunit; Motor coordination; Histology; Purkinje cell responses; Cerebellar long-term depression (LTD).

Combined thermodynamical and structural studies have confirmed the occurrence of multimode hydriding/dehydriding reactions of CaPd that vary depending on temperature, and that these reactions proceed viahydrogen solution/dissolution in the temperature range 273–523 K and viaphase decomposition/recombination in the temperature range 523–773 K. [ABSTRACT FROM AUTHOR]

Abstract: A single-chain variable fragment (scFv) antibody against bisphenol A was refolded using an antigen (bisphenol A)-coupled column. The refolding efficiency was compared with that used in dialysis. The refolding efficiency of the antigen-coupled column was about 50–60%, which was much higher than with dialysis, due to a decrease in the concentration of the refolding molecules and to the suppression of the aggregate formation. [Copyright &y& Elsevier]

Hydrogenation was undertaken in MgNi2 after intense straining by the process of high pressure torsion (HPT). Despite the general acceptance that MgNi2 is not a hydrogen absorber, quantitative analysis demonstrated that the HPT process introduced the capability of hydrogen storage in MgNi2. Although the total hydrogen content was not sufficient, the hydrogen storage performance clearly appeared in the MgNi2. XRD analysis suggested that the hydrogen should be present at grain boundaries. [Copyright &y& Elsevier]

Butorphanol and buprenorphine are mixed opioid receptor agonist‐antagonist drugs widely used as analgesics in people and animals. There are few reports concerning the interaction of multiple opioids, and their antinociceptive effects, when combined with other opioids, remain unclear. Therefore, we report the preliminary findings of the antinociceptive effects of the combined use of butorphanol and buprenorphine in C57BL/6JJcl mice. Both drugs were administered either simultaneously or in different orders. Compared with the baseline values, the tail‐flick and hot‐plate test latencies increased regardless of the order of administration. Furthermore, enhanced latencies were observed on administration of butorphanol followed by buprenorphine. Combined use of these drugs may not attenuate analgesic efficacy. Besides, enhancement of these effects can be obtained by changing the order of the administration of these drugs. It is necessary to further investigate the molecular basis of the underlying mechanism in future definitive studies. [ABSTRACT FROM AUTHOR]

Thermodynamically metastable glasses that can contain metastable species are important functional materials. X-ray absorption near-edge structure (XANES) spectroscopy is an effective technique for determining the valence states of cations, especially for the doping element in phosphors. Herein, we first confirm the valence change of silver cations from monovalent to trivalent in aluminophosphate glasses by X-ray irradiation using a combination of Ag L3-edge XANES, electron spin resonance, and simulated XANES spectra based on first-principles calculations. The absorption edge of the experimental and simulated XANES spectra demonstrate the spectral features of Ag(III), confirming that AgO exists as Ag(I)Ag(III)O2. A part of Ag(I) changes to Ag(III) by X-ray irradiation, and the generation of Ag(III) is saturated after high irradiation doses, in good agreement with conventional radiophotoluminescence (RPL) behaviour. The structural modelling based on a combination of quantum beam analysis suggests that the local coordination of Ag cations is similar to that of Ag(III), which is confirmed by density functional theory calculations. This demonstration of Ag(III) in glass overturns the conventional understanding of the RPL mechanism of silver cations, redefining the science of silver-related materials. [ABSTRACT FROM AUTHOR]

Thermodynamically metastable glasses that can contain metastable species are important functional materials. X-ray absorption near-edge structure (XANES) spectroscopy is an effective technique for determining the valence states of cations, especially for the doping element in phosphors. Herein, we first confirm the valence change of silver cations from monovalent to trivalent in aluminophosphate glasses by X-ray irradiation using a combination of Ag L3-edge XANES, electron spin resonance, and simulated XANES spectra based on first-principles calculations. The absorption edge of the experimental and simulated XANES spectra demonstrate the spectral features of Ag(III), confirming that AgO exists as Ag(I)Ag(III)O2. A part of Ag(I) changes to Ag(III) by X-ray irradiation, and the generation of Ag(III) is saturated after high irradiation doses, in good agreement with conventional radiophotoluminescence (RPL) behaviour. The structural modelling based on a combination of quantum beam analysis suggests that the local coordination of Ag cations is similar to that of Ag(III), which is confirmed by density functional theory calculations. This demonstration of Ag(III) in glass overturns the conventional understanding of the RPL mechanism of silver cations, redefining the science of silver-related materials. [ABSTRACT FROM AUTHOR]

The mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in cell metabolism, growth, and proliferation. The overactivation of mTOR has been implicated in the pathogenesis of syndromic autism spectrum disorder (ASD), such as tuberous sclerosis complex (TSC). Treatment with the mTOR inhibitor rapamycin improved social interaction deficits in mouse models of TSC. Prenatal exposure to valproic acid (VPA) increases the incidence of ASD. Rodent pups that are exposed to VPA in utero have been used as an animal model of ASD. Activation of the mTOR signaling pathway was recently observed in rodents that were exposed to VPA in utero, and rapamycin ameliorated social interaction deficits. The present study investigated the effect of rapamycin on social interaction deficits in both adolescence and adulthood, and gene expressions in mice that were exposed to VPA in utero. We subcutaneously injected 600 mg/kg VPA in pregnant mice on gestational day 12.5 and used the pups as a model of ASD. The pups were intraperitoneally injected with rapamycin or an equal volume of vehicle once daily for 2 consecutive days. The social interaction test was conducted in the offspring after the last rapamycin administration at 5–6 weeks of ages (adolescence) or 10–11 weeks of age (adulthood). Whole brains were collected after the social interaction test in the adulthood, and microarray and Western blot analyses were performed. Mice that were exposed to VPA and treated with vehicle exhibited a decrease in social interaction compared with control mice that were treated with vehicle. Rapamycin treatment in VPA-exposed mice improved social deficits. Mice that were exposed to VPA and treated with vehicle exhibited the aberrant expression of genes in the mTOR signaling pathway, and rapamycin treatment recovered changes in the expression of some genes, including Fyb and A330094K24Rik. Rapamycin treatment suppressed S6 phosphorylation in VPA-exposed mice. Aberrant gene expression was associated with social interaction deficits in VPA-exposed mice. Rapamycin may be an effective treatment for non-syndromic ASD in adolescent and adult patients who present impairments in the mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

The high-intensity neutron total scattering diffractometer NOVA at the Materials and Life Science Experimental Facility in the Japan Proton Accelerator Research Complex has a variety of sample environments. For background reduction, we manufactured and installed the radial collimator NOVARC with a gauge size of ∼ 32 mm. We evaluated its performance and succeeded in eliminating the unwanted scattering from the sample environment equipment and reducing the background signal to less than 4%. We also confirmed that G (r) data, which is important for pair distribution function analysis, is consistent with the one obtained at the sample environment with almost no background. In the future, we plan to combine NOVARC with a radial collimator manufactured using a 3D printer for measuring even smaller specimens or for extreme environments. [ABSTRACT FROM AUTHOR]

Patients with chronic pain are affected psychologically and socially. There are also individual differences in treatment efficacy. Insufficient research has been conducted on genetic polymorphisms that are related to individual differences in the susceptibility to chronic pain. Autoimmune disorders can lead to inflammation and chronic pain; therefore, we focused on the autoimmune-related protease-activated receptor 2 (PAR2/F2RL1) and interleukin 17A (IL-17A/IL17A) genes. PAR2 and IL-17A are associated with autoimmune diseases that lead to chronic pain, and PAR2 regulates T-helper (Th) cell activation and differentiation. We hypothesized that the PAR2 and IL-17A genes are associated with chronic pain. The present study used a case–control design to statistically examine associations between genetic polymorphisms and the vulnerability to chronic pain. The rs2243057 polymorphism of the PAR2 gene and rs3819025 polymorphism of the IL-17A gene were previously reported to be associated with pain- or autoimmune-related phenotypes. Thus, these polymorphisms were investigated in the present study. We found that both rs2243057 and rs3819025 were significantly associated with a susceptibility to chronic pain. The present findings revealed autoimmune-related genetic factors that are involved in individual differences in chronic pain, further aiding understanding of the pathomechanism that underlies chronic pain and possibly contributing to future personalized medicine. [ABSTRACT FROM AUTHOR]

Aims: Cigarette smoking is a preventable risk factor for various diseases such as cancer, ischemic stroke, cardiac stroke, and chronic obstructive pulmonary disease. Smoking cessation is of great importance not only for individual smokers but also for social health. Regarding current cessation therapies, the effectiveness of nicotine replacement is limited, and the cost of varenicline medication is considerable. Thus, a method for screening smokers who are responsive to cessation therapy based on the therapeutic effectiveness is required. Peripheral biomarkers reflecting smoking dependence status are necessary to establish a method for achieving effective cessation therapy. Methods: Methylation status of smokers' blood DNA was evaluated focusing on SHATI/NAT8L, an addiction‐related gene. Eight CpG sites in SHATI/NAT8L were quantified by pyrosequencing. Results: There was no difference in the methylation status of this gene between smokers (n = 129) and non‐smokers (n = 129) at all CpG sites. No correlations between the methylation status of SHATI/NAT8L and indicators of smoking dependence were found. Conclusions: Although the present study found no significance in the DNA methylation of SHATI/NAT8L among smokers, the exploration of predictable peripheral biomarkers for the effectiveness of smoking cessation therapy is required. [ABSTRACT FROM AUTHOR]

Opioid addiction and the opioid overdose epidemic are becoming more serious, and the development of therapeutic agents is essential for the pharmacological treatment of substance use disorders. The κ-opioid receptor (KOP) is a member of the opioid receptor system that has been gaining attention as a promising molecular target for the treatment of numerous human disorders, including pain, depression, anxiety, and drug addiction. Here, we biologically and pharmacologically evaluated a novel azepane-derived ligand, NP-5497-KA, as a selective KOP agonist. NP-5497-KA had 1000-fold higher selectivity for the KOP over the μ-opioid receptor (MOP), which was higher than nalfurafine (KOP/MOP: 65-fold), and acted as a selective KOP full agonist in the 3′,5′-cyclic adenosine monophosphate assay. The oral administration of NP-5497-KA (1–10 mg/kg) dose-dependently suppressed morphine-induced conditioned place preference in C57BL/6 J mice, and its effects were comparable to an intraperitoneal injection of nalfurafine (1–10 μg/kg). Nalfurafine (10 μg/kg) significantly inhibited rotarod performance, whereas NP-5497-KA (10 mg/kg) exerted no effect on rotarod performance. These results indicate that NP-5497-KA may be a novel option for the treatment of opioid use disorder with fewer side effects. [ABSTRACT FROM AUTHOR]

Simple Summary: Postoperative nausea and vomiting (PONV) is experienced by approximately 30% of patients who undergo general anesthesia. However, many genetic factors involved in the vulnerability to PONV remain unidentified. The aim of our genome-wide association study (GWAS) was to comprehensively explore genetic variations associated with PONV. We identified several single-nucleotide polymorphisms (SNPs) that may possibly be associated with the frequency of nausea and vomiting, of which the most potent were the rs2776262, rs140703637, rs7212072, rs12444143, rs45574836, and rs1752136 SNPs. These results indicate that these SNPs in the LOC100506403, CNTN5, SHISA6, RBFOX1, ATP8B3, and LOC105370198 gene regions could serve as markers that predict the vulnerability to PONV. Considerable individual differences are widely observed in the incidence of postoperative nausea and vomiting (PONV). We conducted a genome-wide association study (GWAS) to identify potential candidate single-nucleotide polymorphisms (SNPs) that contribute to PONV by utilizing whole-genome genotyping arrays with more than 950,000 markers. The subjects were 806 patients who provided written informed consent and underwent elective surgery under general anesthesia with propofol or desflurane. The GWAS showed that two SNPs, rs2776262 and rs140703637, in the LOC100506403 and CNTN5 gene regions, respectively, were significantly associated with the frequency of nausea. In another GWAS conducted only on patients who received propofol, rs7212072 and rs12444143 SNPs in the SHISA6 and RBFOX1 gene regions, respectively, were significantly associated with the frequency of nausea as well as the rs2776262 SNP, and the rs45574836 and rs1752136 SNPs in the ATP8B3 and LOC105370198 gene regions, respectively, were significantly associated with vomiting. Among these SNPs, clinical and SNP data were available for the rs45574836 SNP in independent subjects who underwent laparoscopic gynecological surgery, and the association was replicated in these subjects. These results indicate that these SNPs could serve as markers that predict the vulnerability to PONV. Our findings may provide valuable information for achieving satisfactory prophylactic treatment for PONV. [ABSTRACT FROM AUTHOR]

A common notion is that essentially all addictive drugs, including opioids, activate dopaminergic pathways in the brain reward system, and the inappropriate use of such drugs induces drug dependence. However, an opioid reward response is reportedly still observed in several models of dopamine depletion, including in animals that are treated with dopamine blockers, animals that are subjected to dopaminergic neuron lesions, and dopamine‐deficient mice. The intracranial self‐stimulation response is enhanced by stimulants but reduced by morphine. These findings suggest that dopaminergic neurotransmission may not always be required for opioid reward responses. Previous findings also indicate the possibility that dopamine‐independent opioid reward may be observed in opioid‐naive states but not in opioid‐dependent states. Therefore, a history of opioid use should be considered when evaluating the dopamine dependency of opioid reward. [ABSTRACT FROM AUTHOR]

Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. The present study focused on the CACNA1C gene, which encodes the α1C subunit of the Cav1.2 L-type Ca2+ channel (LTCC) that has been reported to be associated with neuropathic pain in previous studies. We investigated genetic polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 33 patients with PTP and 118 patients without PTP but with pain or dysesthesia in the orofacial region. From within and around the CACNA1C gene, 155 polymorphisms were selected and analyzed for associations with clinical data. We found that the rs216009 single-nucleotide polymorphism (SNP) of the CACNA1C gene in the recessive model was significantly associated with the vulnerability to PTP. Homozygote carriers of the minor C allele of rs216009 had a higher rate of PTP. Nociceptive transmission in neuropathic pain has been reported to involve Ca2+ influx from LTCCs, and the rs216009 polymorphism may be involved in CACNA1C expression, which regulates intracellular Ca2+ levels, leading to the vulnerability to PTP. Furthermore, psychological factors may lead to the development of PTP by modulating the descending pain inhibitory system. Altogether, homozygous C-allele carriers of the rs216009 SNP were more likely to be vulnerable to PTP, possibly through the regulation of intracellular Ca2+ levels and affective pain systems, such as those that mediate fear memory recall. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder (BD) and schizophrenia (SZ) are complex psychotic disorders (PSY), with both environmental and genetic factors including possible maternal inheritance playing a role. Some studies have investigated whether genetic variants in the mitochondrial chromosome are associated with BD and SZ. However, the genetic variants identified as being associated are not identical among studies, and the participants were limited to individuals of European ancestry. Here, we investigate associations of genome-wide genetic variants in the mitochondrial chromosome with BD, SZ, and PSY in a Japanese population. Methods: After performing quality control for individuals and genetic variants, we investigated whether mitochondrial genetic variants [minor allele frequency (MAF) > 0.01, n = 45 variants) are associated with BD, SZ, and PSY in 420 Japanese individuals consisting of patients with BD (n = 51), patients with SZ (n = 172), and healthy controls (HCs, n = 197). Results: Of mitochondrial genetic variants, three (rs200478835, rs200044200 and rs28359178 on or near NADH dehydrogenase) and one (rs200478835) were significantly associated with BD and PSY, respectively, even after correcting for multiple comparisons (PGC=0.045–4.9 × 10− 3). In particular, individuals with the minor G-allele of rs200044200, a missense variant, were only observed among patients with BD (MAF = 0.059) but not HCs (MAF = 0) (odds ratio=∞). Three patients commonly had neuropsychiatric family histories. Conclusions: We suggest that mitochondrial genetic variants in NADH dehydrogenase-related genes may contribute to the pathogenesis of BD and PSY in the Japanese population through dysfunction of energy production. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder (BD) and schizophrenia (SZ) are complex psychotic disorders (PSY), with both environmental and genetic factors including possible maternal inheritance playing a role. Some studies have investigated whether genetic variants in the mitochondrial chromosome are associated with BD and SZ. However, the genetic variants identified as being associated are not identical among studies, and the participants were limited to individuals of European ancestry. Here, we investigate associations of genome-wide genetic variants in the mitochondrial chromosome with BD, SZ, and PSY in a Japanese population. Methods: After performing quality control for individuals and genetic variants, we investigated whether mitochondrial genetic variants [minor allele frequency (MAF) > 0.01, n = 45 variants) are associated with BD, SZ, and PSY in 420 Japanese individuals consisting of patients with BD (n = 51), patients with SZ (n = 172), and healthy controls (HCs, n = 197). Results: Of mitochondrial genetic variants, three (rs200478835, rs200044200 and rs28359178 on or near NADH dehydrogenase) and one (rs200478835) were significantly associated with BD and PSY, respectively, even after correcting for multiple comparisons (PGC=0.045–4.9 × 10− 3). In particular, individuals with the minor G-allele of rs200044200, a missense variant, were only observed among patients with BD (MAF = 0.059) but not HCs (MAF = 0) (odds ratio=∞). Three patients commonly had neuropsychiatric family histories. Conclusions: We suggest that mitochondrial genetic variants in NADH dehydrogenase-related genes may contribute to the pathogenesis of BD and PSY in the Japanese population through dysfunction of energy production. [ABSTRACT FROM AUTHOR]

Background: Individuals with schizophrenia (SCZ) and bipolar disorder (BD) display cognitive impairments, but the impairments in those with SCZ are more prominent, supported by genetic overlap between SCZ and cognitive impairments. However, it remains unclear whether cognitive performances differ between individuals at high and low genetic risks for SCZ or BD. Methods: Using the latest Psychiatric Genomics Consortium (PGC) data, we calculated PGC3 SCZ-, PGC3 BD-, and SCZ v. BD polygenic risk scores (PRSs) in 173 SCZ patients, 70 unaffected first-degree relatives (FRs) and 196 healthy controls (HCs). Based on combinations of three PRS deciles, individuals in the genetic SCZ, genetic BD and low genetic risk groups were extracted. Cognitive performance was assessed by the Brief Assessment of Cognition in Schizophrenia. Results: SCZ-, BD-, SCZ v. BD-PRSs were associated with case–control status (R 2 = 0.020–0.061), and SCZ-PRS was associated with relative–control status (R 2 = 0.023). Furthermore, individuals in the highest decile for SCZ PRSs had elevated BD-PRSs [odds ratio (OR) = 6.33] and SCZ v. BD-PRSs (OR = 1.86) compared with those in the lowest decile. Of the three genetic risk groups, the low genetic risk group contained more HCs, whereas the genetic BD and SCZ groups contained more SCZ patients (p < 0.05). SCZ patients had widespread cognitive impairments, and FRs had cognitive impairments that were between those of SCZ patients and HCs (p < 0.05). Cognitive differences between HCs in the low genetic risk group and SCZ patients in the genetic BD or genetic SCZ groups were more prominent (Cohen's d > −0.20) than those between HCs and SCZ patients in the no genetic risk group. Furthermore, SCZ patients in the genetic SCZ group displayed lower scores in verbal fluency and attention than those in the genetic BD group (d > −0.20). Conclusions: Our findings suggest that cognitive impairments in SCZ are partially mediated through genetic loadings for SCZ but not BD. [ABSTRACT FROM AUTHOR]

Sensitivity to opioids varies widely among individuals. To identify potential candidate single-nucleotide polymorphisms (SNPs) that may significantly contribute to individual differences in the minimum effective concentration (MEC) of an opioid, fentanyl, we conducted a three-stage genome-wide association study (GWAS) using whole-genome genotyping arrays in 350 patients who underwent laparoscopic-assisted colectomy. To estimate the MEC of fentanyl, plasma and effect-site concentrations of fentanyl over the 24 h postoperative period were estimated with a pharmacokinetic simulation model based on initial bolus doses and subsequent patient-controlled analgesia doses of fentanyl. Plasma and effect-site MECs of fentanyl were indicated by fentanyl concentrations, estimated immediately before each patient-controlled analgesia dose. The GWAS revealed that an intergenic SNP, rs966775, that mapped to 5p13 had significant associations with the plasma MEC averaged over the 6 h postoperative period and the effect-site MEC averaged over the 12 h postoperative period. The minor G allele of rs966775 was associated with increases in these MECs of fentanyl. The nearest protein-coding gene around this SNP was DRD1, encoding the dopamine D1 receptor. In the gene-based analysis, the association was significant for the SERP2 gene in the dominant model. Our findings provide valuable information for personalized pain treatment after laparoscopic-assisted colectomy. [ABSTRACT FROM AUTHOR]

Autotaxin, encoded by the ENPP2 gene, is a known key element of neuropathic pain; however, its involvement in nociceptive pain processing remains unclear. We explored the associations between postoperative pain intensity, 24-h postoperative opioid dose requirements, and 93 ENNP2-gene single-nucleotide polymorphisms (SNPs) in 362 healthy patients who underwent cosmetic surgery using the dominant, recessive, and genotypic models. Next, we validated the associations between relevant SNPs on the one hand and pain intensity and daily opioid dosages on the other in 89 patients with cancer-related pain. In this validation study, a Bonferroni correction for multiplicity was applied on all relevant SNPs of the ENPP2 gene and their respective models. In the exploratory study, three models of two SNPs (rs7832704 and rs2249015) were significantly associated with postoperative opioid doses, although the postoperative pain intensity was comparable. In the validation study, the three models of the two SNPs were also significantly associated with cancer pain intensity (p < 0.017). Patients with a minor allele homozygosity complained of more severe pain compared with patients with other genotypes when using comparable daily opioid doses. Our findings might suggest that autotaxin is associated with nociceptive pain processing and the regulation of opioid requirements. [ABSTRACT FROM AUTHOR]

A highly complex crystal structure of stoichiometric Mg5(en)6(BH4)10 was solved from single crystal synchrotron X-ray diffraction and confirmed by neutron powder diffraction (NPD) on isotopically substituted Mg(en)1.2(11BD4)2. We highlight the role of the amorphous Mg(BH4)2 in the reactivity of the Mg(BH4)2-en system and characterized a previously overlooked phase, Mg(en)2(BH4)2. [ABSTRACT FROM AUTHOR]

Although opioids are widely used to treat moderate to severe pain, opioid addiction and the opioid overdose epidemic are becoming more serious. Although opioid receptor antagonists/partial agonists, such as naltrexone and buprenorphine, have relatively low selectivity for the μ-opioid receptor (MOP), they have been used for the management of opioid use disorder. The utility of highly selective MOP antagonists remains to be evaluated. Here, we biologically and pharmacologically evaluated a novel nonpeptide ligand, UD-030, as a selective MOP antagonist. UD-030 had more than 100-fold higher binding affinity for the human MOP (Ki = 3.1 nM) than for δ-opioid, κ-opioid, and nociceptin receptors (Ki = 1800, 460, and 1800 nM, respectively) in competitive binding assays. The [35S]-GTPγS binding assay showed that UD-030 acts as a selective MOP full antagonist. The oral administration of UD-030 dose-dependently suppressed the acquisition and expression of morphine-induced conditioned place preference in C57BL/6J mice, and its effects were comparable to naltrexone. These results indicate the UD-030 may be a new candidate for the treatment of opioid use disorder, with characteristics that differ from traditional medications that are in clinical use. [ABSTRACT FROM AUTHOR]

Chronic pain is reportedly associated with the transient receptor potential canonical 3 (TRPC3) gene. The present study examined the genetic associations between the single-nucleotide polymorphisms (SNPs) of the TRPC3 gene and chronic pain. The genomic samples from 194 patients underwent linkage disequilibrium (LD) analyses of 29 SNPs within and around the vicinity of the TRPC3 gene. We examined the associations between the SNPs and the susceptibility to chronic pain by comparing the genotype distribution of 194 patients with 282 control subjects. All SNP genotype data were extracted from our previous whole-genome genotyping results. Twenty-nine SNPs were extracted, and a total of four LD blocks with 15 tag SNPs were observed within and around the TRPC3 gene. We further analyzed the associations between these tag SNPs and chronic pain. The rs11726196 SNP genotype distribution of patients was significantly different from the control subjects even after multiple-testing correction with the number of SNPs. The TT + TG genotype of rs11726196 is often carried by chronic pain patients, suggesting a causal role for the T allele. These results contribute to our understanding of the genetic risk factors for chronic pain. [ABSTRACT FROM AUTHOR]

K2NiF4‐type Ba–Li oxyhydride (BLHO) transitions to a so‐called hydride superionic conductor, exhibiting a high and essentially temperature‐independent hydride ion (H−) conductivity over 0.01 S cm−1 through the disordering of H− vacancies above 300 °C. In this study, a Ba–Li–Na–H–O oxyhydride system synthesized in which lithium is partially substituted with sodium in BLHO and investigated the effects of Na content on the phase transition behavior and the conductivity. Structural refinements and differential scanning calorimetry experiments confirmed a lowering trend in the phase transition temperatures and decreasing enthalpy changes for the transition with increasing Na content. Substitution of not <40% of Li with Na lowered the degree of ordered vacancies at the H− sites at room temperature and improved conductivities by more than two orders of magnitude in the low‐temperature region (T < 300 °C) before the phase transition. These findings clearly show that introducing Na into the lattice effectively stabilizes the high‐conductive phase of BLHO. [ABSTRACT FROM AUTHOR]

A 22.5‐kg, 8.4‐year‐old female mixed breed dog was presented for an emergency ovariohysterectomy for pyometra. No neurological abnormalities were observed on preoperative physical examination. Surgery was completed uneventfully under fentanyl‐ and sevoflurane‐based anaesthesia. Cardiorespiratory indices remained stable under mechanical ventilation throughout the procedure. Approximately 23 min after the discontinuation of fentanyl infusion, the investigator noticed jaw closure and stiffness and thoraco‐abdominal muscle rigidity. To rule out fentanyl‐induced muscle rigidity, naloxone was administered. Following administration of naloxone, there was a return of spontaneous respiratory effort, indicated by capnogram and visible chest wall excursion. Based on the clinical signs and response to naloxone administration, the dog was diagnosed with suspected fentanyl‐induced muscle rigidity. Six minutes after the return of spontaneous respiration, the dog was extubated uneventfully without additional naloxone administration. During 4 days of postoperative hospitalization, no recurrent muscle rigidity was observed, and the patient was discharged safely. The total dose of fentanyl administered was 0.61 mg (27 μg kg−1). [ABSTRACT FROM AUTHOR]

Dopamine-deficient (DD) mice exhibit psychomotor hyperactivity that might be related to a decrease in muscarinic signaling. In the present study, muscarinic acetylcholine receptor M2 (CHRM2) density decreased in the cortex in DD mice. This is significant because cortical CHRM2 acts as an autoreceptor; therefore, changes in CHRM2 levels could alter acetylcholine in DD mice. We also found that the CHRM1/CHRM4 agonist xanomeline and CHRM2 agonist arecaidine propargyl ester tosylate inhibited hyperactivity in DD mice, suggesting that postsynaptic CHRM1 and CHRM2 and presynaptic CHRM2 may be involved in hyperactivity in DD mice. [ABSTRACT FROM AUTHOR]

Due to their accessible lattice oxygen redox (l‐OR) at high voltages, Li‐rich layered transition metal (TM) oxides have shown promising potential as candidate cathodes for high‐energy‐density Li‐ion batteries. However, this l‐OR process is also associated with unusual electrochemical issues such as voltage hysteresis and long‐term voltage decay. The structure response mechanism to the l‐OR behavior also remains unclear, hindering rational structure optimizations that would enable practical Li‐rich cathodes. Here, this study reveals a strong coupling between l‐OR and structure dynamic evolutions, as well as their effects on the electrochemical properties. Using the technique of neutron total scattering with pair distribution function analysis and small‐angle neutron scattering, this study quantifies the local TM migration and formation of nanopores that accompany the l‐OR. These experiments demonstrate the causal relationships among l‐OR, the local/nanostructure evolutions, and the unusual electrochemistry. The TM migration triggered by the l‐OR can change local oxygen coordination environments, which results in voltage hysteresis. Coupled with formed oxygen vacancies, it will accelerate the formation of nanopores, inducing a phase transition, and leading to irreversible capacity and long‐cycling voltage fade. [ABSTRACT FROM AUTHOR]