Institute of Science Tokyo

The nucleotide sequence of a 25.7 kilobase Drosophila melanogaster genomic DNA segment containing a gene for a ryanodine receptor/calcium release channel homologue has been determined. Computer analysis and partial cDNA cloning revealed 26 exons comprising the protein-coding sequence in this gene. The predicted protein is homologous in amino acid sequence and shares characteristic structural features with the mammalian ryanodine receptors. In blot hybridization analysis, a approximately 16 kilobase RNA species was identified abundantly in a 6-12 h embryo as the transcript from this gene. In situ hybridization to polytene chromosomes indicated that this gene locates at band position 44F on the second chromosome.

Our analysis of chromosomal aberrations in primary gastric cancers using comparative genomic hybridization has revealed novel, high and frequent copy number increases in the long arm of chromosome 20, indicating that this region contains novel amplified genes involved in gastric cancer progression. AIB1, a member of the steroid receptor co-activator-1 family, has been cloned on 20q12 as a candidate target gene for this amplification in human breast cancers. In this study, we examined the numbers of AIB1 copies as well as their expression and relation to clinico-pathological features in 72 primary gastric cancers. AIB1 amplification was observed in 7% and over-expression in 40% of the specimens. AIB1 amplification always coincided with its over-expression, but several cases showed AIB1 over-expression without amplification, suggesting that expression of AIB1 is regulated not only by gene amplification but also by other mechanisms, such as transcriptional activation, in human gastric cancer. Gastric cancers with AIB1 amplification showed extensive lymph node metastases, liver metastases and poorer prognosis compared to those without amplification. Our results suggest that amplification and over-expression of AIB1 are likely to increase the number of malignant phenotypes of gastric cancers and that it can be expected to be useful as a marker of poor prognosis.

We investigated the action of a synthetic rat atrial natriuretic factor (ANF) with 28 amino acids on renin secretion in rats. Renin release by kidney cortex slices was determined after 90 min of incubation at 37C. ANF inhibited basal renin release in a dose-related fashion. ANF also decreased cAMP release and increased cGMP release in a dose-dependent manner. Renin release stimulated by 10(-7) M isoproterenol was inhibited by ANF with an ID50 of 5.8 x 10(-8) M. The renin-inhibitory effect was not calcium-dependent. In anesthetized rats, a bolus IV dose of ANF decreased plasma renin activity and cAMP concentration, but increased cGMP concentration. These data suggest that ANF inhibits renin secretion via the direct action on juxtaglomerular cells and that this effect may be partly mediated by the changes in cyclic nucleotide production.

Owing to the Japanese language's unique writing system, which consists of phonograms and ideograms, reading impairments of Japanese brain-damaged patients have attracted the interest of many researchers. Past case reports as well as some widely accepted handbooks and textbooks have concluded that a specific aphasia type or lesion site is associated with a particular impairment pattern of phonograms and ideograms in reading. However, the methodology and analytical procedures in previous studies were inadequate for reliable generalizations to be made. First, the test materials were unspecified or inappropriate, or the number of test items was small. Secondly, the conclusions were presented without providing individual performance data to support them. Thirdly, in associating patterns of reading impairment with lesion sites, only single cases were reported. The present investigation was designed to overcome the omissions of previous studies, and examined the ability to read 46 single phonograms and 46 single ideograms aloud in four groups of sufficiently large numbers of patients; namely, seven pure alexics, 23 Broca aphasics, 13 Wernicke aphasics, and seven patients with alexia and agraphia. Ours are the first data to demonstrate unequivocally no consistent linkage between aphasia type and the patterns of impairment of phonogram and ideogram reading. The impairment patterns were not uniform across patients even in the same aphasia group. A majority of the cases in each group showed that phonograms and ideograms were unselectively impaired. However, ideogram reading was more difficult in three cases in the pure alexia and Broca aphasia groups, respectively, and in one case in the Wernicke aphasia group. Phonogram reading was more severely disturbed in four cases among the Broca aphasics and in one case among the patients with alexia with agraphia. An apparent variability of impairment patterns characterized the Broca aphasic group. These dyslexic patterns did not appear to correlate with the site and extent of lesions identified by computerized tomography scans. Past reports linking a particular impairment pattern of phonogram and ideogram reading and a specific lesion site were studies of single cases, and their conclusions seem oversimplified. While sensory and motor dysfunctions can usually be neuroanatomically localized in individuals, impairments of certain high cortical functions, such as the reading of phonograms and ideograms, may not be correlated with damage to definite neuroanatomical structures.

Let $P_{n}(C)$ be a complex projective space of complex dimension $n(\geqq 2)$ with the metric of constant holomorphic sectional curvature. We proved in The purpose of this paper is to determine all real hypersurfaces in $P_{n}(C)(n\geqq 3)$ with three constant principal curvatures.

Abstract Background Environmental DNA (eDNA) analysis has been recently applied to the surveillance of species distribution and composition in aquatic ecosystems. However, most eDNA studies have used mitochondrial DNA markers, and those using nuclear DNA markers are quite scarce. Moreover, although some studies reported the availability of nuclear DNA markers for eDNA analyses, the characteristics and dynamics of nuclear environmental DNA (nu‐eDNA) of macro‐organisms remain unknown. Herein, we re‐analyzed eDNA samples described in a previously published paper to investigate the shedding and decay rates of nu‐eDNA from Japanese Jack Mackerel ( Trachurus japonicus ) and compared them to those of mt‐eDNA (mitochondrial environmental DNA). Materials & Methods Tank experiments consisting of 12 combinations of four temperatures and three fish biomass levels were performed, and four tank replicates were prepared for each treatment level. Before and after removing the fish from the tanks, we sampled rearing water over time to quantify nu‐eDNA copy numbers. Results & Discussion Model fitting to eDNA decay curves demonstrated that nu‐eDNA decay rates increased in higher water temperature and with larger fish biomass. The estimated shedding rates of nu‐eDNA also increased with higher temperature and larger biomass. These results were generally consistent with those of mt‐eDNA. Moreover, the ratio of mt‐eDNA to nu‐eDNA shedding and concentration decreased with larger fish biomass levels, which implied that these values may be among the potential indices for estimating the age and body size of organisms from environmental samples. Our findings contribute to the understanding of eDNA characteristics and dynamics between different DNA markers and may help us to interpret future results of eDNA surveillance.

The effect of cabbage extract on cholesterol metabolism was studied in Donryu rats subcutaneously implanted with an ascites hepatoma cell line (AH109A). The hepatoma-bearing rats exhibited hypercholesterolemia induced by increasing cholesterogenesis in the host liver and decreasing steroid excretion into feces. The cabbage extract intake or administration reduced serum cholesterol level and enhanced fecal bile acid excretion and cholesterol 7alpha-hydroxylase activity, the rate-limiting enzyme of bile acid biosynthesis, in the microsomal fraction of the liver. Furthermore, S-methyl-L-cysteine sulfoxide, a component of cabbage, could mimic the effect of cabbage extract when orally administered. These results suggest that cabbage suppresses hypercholesterolemia responding to hepatoma growth by upregulating cholesterol catabolism and that S-methyl-L-cysteine sulfoxide in cabbage is one of the factors suppressing hypercholesterolemia in the hepatoma-bearing rats.

AIMS: To elucidate the diagnostic value of sarcoplasmic expression of myxovirus resistance protein A (MxA) for dermatomyositis (DM) specifically analysing different DM subforms, and to test the superiority of MxA to other markers. METHODS: Immunohistochemistry for MxA and retinoic acid-inducible gene I (RIG-I) was performed on skeletal muscle samples and compared with the item presence of perifascicular atrophy (PFA) in 57 DM patients with anti-Mi-2 (n = 6), -transcription intermediary factor 1 gamma (n = 10), -nuclear matrix protein 2 (n = 13), -melanoma differentiation-associated gene 5 (MDA5) (n = 10) or -small ubiquitin-like modifier activating enzyme (n = 1) autoantibodies and with no detectable autoantibody (n = 17). Among the patients, nine suffered from cancer and 22 were juvenile-onset type. Disease controls included antisynthetase syndrome (ASS)-associated myositis (n = 30), immune-mediated necrotizing myopathy (n = 9) and inclusion body myositis (n = 5). RESULTS: Sarcoplasmic MxA expression featured 77% sensitivity and 100% specificity for overall DM patients, while RIG-I staining and PFA reached respectively 14% and 59% sensitivity and 100% and 86% specificity. In any subset of DM, sarcoplasmic MxA expression showed higher sensitivity than RIG-I and PFA. Some anti-MDA5 antibody-positive DM samples distinctively showed a scattered staining pattern of MxA. No ASS samples had sarcoplasmic MxA expression even though six patients had DM skin rash. CONCLUSIONS: Sarcoplasmic MxA expression is more sensitive than PFA and RIG-I expression for a pathological diagnosis of DM, regardless of the autoantibody-related subgroup. In light of its high sensitivity and specificity, it may be considered a pathological hallmark of DM per se. Also, lack of MxA expression in ASS supports the idea that ASS is a distinct entity from DM.

Abstract Black carbon (BC) aerosols, which are strong contributors to positive radiative forcing, are found in the atmosphere as bare BC or as internal mixtures of BC with non‐BC compounds (mixed BC‐containing particles). Mixed BC‐containing particles can be broadly classified into two morphological types: bare BC on the surface of non‐BC particles (attached type) or BC embedded within or coated by non‐BC compounds (coated type). For the same amount of mixed non‐BC compounds, enhancements of the mass absorption cross section of BC by the coated type are much larger than those of the attached type. Consequently, identification of the two morphological types in mixed BC‐containing particles is important for understanding the impact of BC on climate. We develop a new algorithm to classify mixed BC‐containing particles into attached and coated types by using the single‐particle soot photometer (SP2), based on laboratory experiments generating and detecting mixed BC‐containing particles of known morphological types. Our algorithm allows users to choose an optimal set of operational parameters, depending on their purpose and instrumental conditions. We used the algorithm to identify the morphology of mixed BC‐containing particles with a BC mass of ~8.0 fg in ambient air in Tokyo. The observed number fractions of attached type particles among morphologically identified BC‐containing particles were generally less than 0.1 but occasionally reached ~0.4 during short events. This finding will motivate further observations, including in known outflow regions, to investigate the regional and global abundance of the attached type among mixed BC‐containing particles.

Recent advances in RNA analysis have deepened our understanding of cellular states in biological tissues. However, a substantial gap remains in integrating RNA expression data with spatial context across organs, primarily owing to the challenges associated with RNA detection within intact tissue volumes. Here, we developed Tris buffer-mediated retention of in situ hybridization chain reaction signal in cleared organs (TRISCO), an effective tissue-clearing method designed for whole-brain spatial three-dimensional (3D) RNA imaging. TRISCO resolved several crucial issues, including the preservation of RNA integrity, achieving uniform RNA labeling, and enhancing tissue transparency. We tested TRISCO using a broad range of cell-identity markers, noncoding and activity-dependent RNAs, within diverse organs of varying sizes and species. TRISCO thus emerges as a powerful tool for single-cell, whole-brain, 3D imaging that enables comprehensive transcriptional spatial analysis across the entire brain.

The electron density determines all properties of a system of nuclei and electrons. It is both computable and observable. Its topology allows gaining insight into the mechanisms of bonding and other phenomena in a way that is complementary to and beyond that available from the molecular orbital picture and the formal oxidation state (FOS) formalism. The ability to derive mechanistic insight from electron density is also important with methods where orbitals are not available, such as orbital-free density functional theory (OF-DFT). While density topology-based analyses such as QTAIM (quantum theory of atoms-in-molecules) have been widely used, novel, vector-based techniques recently emerged such as next-generation (NG) QTAIM. Density-dependent quantities are also actively used in machine learning (ML)-based methods, in particular, for ML DFT functional development, including machine-learnt kinetic energy functionals. We review QTAIM and its recent extensions such as NG-QTAIM and localization-delocalization matrices (LDM) and their uses in the analysis of bonding, conformations, mechanisms of redox reactions excitations, as well as ultrafast phenomena. We review recent research showing that direct density analysis can circumvent certain pitfalls of the FOS formalism, in particular in the description of anionic redox, and of the widely used (spherically) projected density of states analysis. We discuss uses of density-based quantities for the construction of DFT functionals and prospects of applications of analyses of density topology to get mechanistic insight with OF-DFT and recently developed time-dependent OF-DFT.

The gravitational-wave signal GW250114 was observed by the two LIGO detectors with a network matched-filter signal-to-noise ratio of 80. The signal was emitted by the coalescence of two black holes with near-equal masses m_{1}=33.6_{-0.8}^{+1.2}M_{⊙} and m_{2}=32.2_{-1.3}^{+0.8}M_{⊙}, and small spins χ_{1,2}≤0.26 (90% credibility) and negligible eccentricity e≤0.03. Postmerger data excluding the peak region are consistent with the dominant quadrupolar (ℓ=|m|=2) mode of a Kerr black hole and its first overtone. We constrain the modes' frequencies to ±30% of the Kerr spectrum, providing a test of the remnant's Kerr nature. We also examine Hawking's area law, also known as the second law of black hole mechanics, which states that the total area of the black hole event horizons cannot decrease with time. A range of analyses that exclude up to five of the strongest merger cycles confirm that the remnant area is larger than the sum of the initial areas to high credibility.

Fluorescence thermometry has emerged as a significant area of research in the field of remote temperature sensing with high accuracy. However, the development of noninvasive and reliable small organic fluorescence thermometers (FTs) remains challenging. In this study, we developed a high-sensitivity, high-resolution small organic ratiometric FT with a solvatochromic dye and analyzed its temperature response mechanism. π-Extended fluorene-based D−π–A-type small solvatochromic dyes (FπAc, FπF, and FπVC) were synthesized and characterized. A significant solvatochromic shift of >200 nm was observed between n-hexane and tetrahydrofuran (THF) for both FπF and FπVC, with emission in THF reaching the red region (701 nm, 828 nm). This substantial solvatochromic shift was accompanied by a concurrent decrease in the fluorescence quantum yield and is attributable to accelerated internal conversion. The fluorescence spectra of FπF in THF and FπVC in diethyl ether exhibited blue shifts and increased fluorescence intensities with a decrease in polarity at increased temperatures. Our observations revealed an absolute sensitivity of 21%/°C and a relative sensitivity of 3.0%/°C at the maximum. These results represent the highest sensitivity and resolution reported for single fluorophore small organic ratiometric FTs dispersed in solution. The positive temperature coefficient of the fluorescence intensity was attributed to control of the nonradiative decay pathway by solvatochromism. The temperature responsiveness of FπF could be detected in living HeLa cells by ratiometric confocal microscopy. Using the proposed strategy to develop FTs, we plan to build a library of FTs that will cover various environments of interest in both simple and complex systems.

BACKGROUND: Exercise alleviates pain and it is a central component of treatment strategy for chronic pain in clinical setting. However, little is known about mechanism of this exercise-induced hypoalgesia. The mesolimbic dopaminergic network plays a role in positive emotions to rewards including motivation and pleasure. Pain negatively modulates these emotions, but appropriate exercise is considered to activate the dopaminergic network. We investigated possible involvement of this network as a mechanism of exercise-induced hypoalgesia. METHODS: In the present study, we developed a protocol of treadmill exercise, which was able to recover pain threshold under partial sciatic nerve ligation in mice, and investigated involvement of the dopaminergic reward network in exercise-induced hypoalgesia. To temporally suppress a neural activation during exercise, a genetically modified inhibitory G-protein-coupled receptor, hM4Di, was specifically expressed on dopaminergic pathway from the ventral tegmental area to the nucleus accumbens. RESULTS: The chemogenetic-specific neural suppression by Gi-DREADD system dramatically offset the effect of exercise-induced hypoalgesia in transgenic mice with hM4Di expressed on the ventral tegmental area dopamine neurons. Additionally, anti-exercise-induced hypoalgesia effect was significantly observed under the suppression of neurons projecting out of the ventral tegmental area to the nucleus accumbens as well. CONCLUSION: Our findings suggest that the dopaminergic pathway from the ventral tegmental area to the nucleus accumbens is involved in the anti-nociception under low-intensity exercise under a neuropathic pain-like state.

The RFamide neuropeptide 26RFa was first isolated from the brain of the European green frog on the basis of cross-reactivity with antibodies raised against bovine neuropeptide FF (NPFF). 26RFa and its N-terminally extended form glutamine RF-amide peptide (QRFP) have been identified as cognate ligands of the former orphan receptor GPR103, now renamed glutamine RF-amide peptide receptor (QRFP receptor). The 26RFa/QRFP precursor has been characterized in various mammalian and non-mammalian species. In the brain of mammals, including humans, 26RFa/QRFP mRNA is almost exclusively expressed in hypothalamic nuclei. The 26RFa/QRFP transcript is also present in various organs especially in endocrine glands. While humans express only one QRFP receptor, two isoforms are present in rodents. The QRFP receptor genes are widely expressed in the CNS and in peripheral tissues, notably in bone, heart, kidney, pancreas and testis. Structure-activity relationship studies have led to the identification of low MW peptidergic agonists and antagonists of QRFP receptor. Concurrently, several selective non-peptidic antagonists have been designed from high-throughput screening hit optimization. Consistent with the widespread distribution of QRFP receptor mRNA and 26RFa binding sites, 26RFa/QRFP exerts a large range of biological activities, notably in the control of energy homeostasis, bone formation and nociception that are mediated by QRFP receptor or NPFF2. The present report reviews the current knowledge concerning the 26RFa/QRFP-QRFP receptor system and discusses the potential use of selective QRFP receptor ligands for therapeutic applications.

Discoveries and technological innovations over the past decade are transforming our understanding of the properties of ceramics, such as 'hard', 'brittle', and 'homogeneous'. For example, inorganic crystals containing molecular anions exhibit excellent secondary battery characteristics, and the fusion of inorganic solids and molecules results in innovative catalytic functions and physical properties. Different from the conventional ceramics such as metal oxides that are formed by monatomic cations and anions, unique properties and functions can be expected in molecular-incorporated inorganic solids, due to the asymmetric and dynamic properties brought about by the constituent molecular units. We name the molecular-incorporated inorganic materials that produce innovative properties and functions as supra-ceramics. In this article, we describe various kinds of supra-ceramics from the viewpoint of synthesis, analysis and physical properties/functions for a wide range of applications.

We invert seismic body‐wave waveform data for the vertical dependence of (isotropic) shear‐velocity in the D″ layer beneath Central America, using the transverse components of relatively long period broadband waveforms (20–200 s) as data. Our models suggest that the S‐velocity increase in D″ may be localized in the zone from 100–200 km above the core‐mantle boundary (CMB), while the S‐velocity does not significantly deviate from PREM in the zone from 0–100 km above the CMB. This suggests the possible existence of a double crossing (a reverse phase transition from post‐perovskite back to perovskite) at a depth of 100 km above the CMB. Resolution tests indicate that our methods and data can resolve the vertical velocity profile within D″, and that the lower half of D″ is especially well resolved.

The complement 3a receptor (C3aR1) participates in microglial signaling under pathological conditions and was recently shown to be activated by the neuropeptide TLQP-21. We previously demonstrated that TLQP-21 elicits hyperalgesia and contributes to nerve injury-induced hypersensitivity through an unknown mechanism in the spinal cord. Here we determined that this mechanism requires C3aR1 and that microglia are the cellular target for TLQP-21. We propose a novel neuroimmune signaling pathway involving TLQP-21-induced activation of microglial C3aR1 that then contributes to spinal neuroplasticity and neuropathic pain. This unique dual-ligand activation of C3aR1 by a neuropeptide (TLQP-21) and an immune mediator (C3a) represents a potential broad-spectrum mechanism throughout the CNS for integration of neuroimmune crosstalk at the molecular level.

BACKGROUND: Three Janus kinase (JAK) inhibitors are approved for ulcerative colitis (UC) in Japan. AIM: To compare the real-world efficacy and safety of these three JAK inhibitors in UC. METHODS: This was a multicentre, retrospective study of patients with UC started on JAK inhibitors. The primary outcome was clinical remission at 10, 26 and 58 weeks, and at the most recent follow-up. To compare the efficacy and safety among the JAK inhibitors, we created three matched cohorts (upadacitinib vs. filgotinib, tofacitinib vs. filgotinib and upadacitinib vs. tofacitinib) using propensity score matching. RESULTS: We identified 228 upadacitinib-treated patients (median follow-up 49 weeks; IQR 25-72), 215 filgotinib-treated patients (follow-up 56 weeks; IQR 17-82) and 159 tofacitinib-treated patients (follow-up 112 weeks; IQR 10-258). Clinical remission rates for upadacitinib, filgotinib and tofacitinib at the most recent follow-up were 72.8%, 50.6% and 45.8%, respectively. Over 70% of the patients previously treated with other biologics or JAK inhibitors achieved clinical remission with upadacitinib. On multivariate analysis, the number of previous advanced therapies was inversely associated with the efficacy of filgotinib and tofacitinib. Comparative analysis showed that upadacitinib-treated patients had higher efficacy and lower risk of discontinuation than patients treated with other JAK inhibitors. However, upadacitinib had a significant risk of acne. CONCLUSIONS: Considering the particularly high efficacy of upadacitinib, even in patients with refractory UC, filgotinib or tofacitinib may be considered as an upfront JAK inhibitor before using upadacitinib.

Abstract Large language models (LLMs) have become increasingly capable, but their development often requires substantial computational resources. Although model merging has emerged as a cost-effective promising approach for creating new models by combining existing ones, it currently relies on human intuition and domain knowledge, limiting its potential. Here we propose an evolutionary approach that overcomes this limitation by automatically discovering effective combinations of diverse open-source models, harnessing their collective intelligence without requiring extensive additional training data or compute. Our approach operates in both parameter space and data flow space, allowing optimization beyond just the weights of the individual models. This approach even facilitates cross-domain merging, generating models such as a Japanese LLM with math reasoning capabilities. Surprisingly, our Japanese math LLM achieved state-of-the-art performance on a variety of established Japanese LLM benchmarks, even surpassing models with substantially more parameters, despite not being explicitly trained for such tasks. Furthermore, a culturally aware Japanese vision–language model generated through our approach demonstrates its effectiveness in describing Japanese culture-specific content, outperforming previous Japanese vision–language models. This work not only contributes new state-of-the-art models back to the open-source community but also introduces a new paradigm for automated model composition, paving the way for exploring alternative, efficient approaches to foundation model development.