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Globally, urbanization constitutes one of the major underlying drivers of global ecological degradation. Hence, deurbanization, i.e., demographic shift from urban to distant rural areas in a way that increases quality of life (QoL), can be one of the key pathways to address this global challenge. In this study, we investigated the contribution of nature and other types of rural capital to QoL and to people’s decision to migrate from urban to rural areas by studying residents in Hokuto City, a popular urban-to-rural migration destination in Japan. An integrated analysis of the 414 responses to a questionnaire survey and open and commercial geospatial datasets representing natural, built, human, cultural, and financial capital revealed the contributions of specific elements of rural capital to people’s QoL. These included natural capital (farmland, symbolic natural sites, mountain peak view, lower temperature, and tranquility), built capital (highways, railway stations, shops, and restaurants), and financial capital (employment). Many of these are related to the reasons that migrants, including return and one-way migrants, chose their present home location in Hokuto City, indicating their intention to increase QoL by migration. Particularly, one-way migrant homes were located predominantly on higher up mountain slopes with lower temperatures, higher forest cover, near natural parks, and symbolic natural sites, and yet with easier access to railway stations and employment. These results provide a valuable evidence base for rural spatial planning for increased QoL and attracting migrants that considers ecological–social feedbacks, and hence supports deurbanization.

Alternating cyclocopolymers having a condensed ring structure were synthesized via radical copolymerization of the divinyl ether (DVE) carrying a gem-dimethyl group on the spacer with N-substituted maleimides (MIs). The consumption behaviors of the C=C bonds in both monomers and the values of the pseudo-monomer reactivity ratios close to zero supported the alternating propagation in the order of one of the DVE double bonds, MI, another double bond of DVE, and MI, to afford the topologically unique copolymers. The cyclocopolymerization was controlled via the RAFT process, and thus, one-pot synthesis of the multiblock alternating cyclocopolymer carrying different pendant groups on the MI units was achieved via sequential addition of MIs. The series of alternating cyclocopolymers exhibited high thermal stabilities and high glass temperatures (Tgs). In particular, Tgof the N-ethyl MI-based cyclocopolymer was much higher than the predicted value by the Fox equation, which was presumably derived from the rigid backbone including the condensed ring structure.

Leukocyte cell-derived chemotaxin 2 (LECT2) is a secreted pleiotropic protein that is mainly produced by the liver. We have previously shown that LECT2 plays an important role in the pathogenesis of inflammatory liver diseases. Lipopolysaccharide/d-galactosamine (LPS/d-GalN)-induced acute liver injury is a known animal model of fulminant hepatic failure. Here we found that this hepatic injury was alleviated in LECT2-deficient mice. The levels of TNF-α and IFN-γ, which mediate this hepatitis, had significantly decreased in these mice, with the decrease in IFN-γ production notably greater than that in TNF-α. We therefore analyzed IFN-γ-producing cells in liver mononuclear cells. Flow cytometric analysis showed significantly reduced IFN-γ production in hepatic NK and NKT cells in LECT2-deficient mice compared with in wild-type mice. We also demonstrated a decrease in IFN-γ production in LECT2-deficient mice after systemic administration of recombinant IL-12, which is known to induce IFN-γ in NK and NKT cells. These results indicate that a decrease of IFN-γ production in NK and NKT cells was involved in the alleviation of LPS/d-GalN-induced liver injury in LECT2-deficient mice.

Hole-doping into K–TCNQ (TCNQ = 7,7,8,8-tetracyanoquinodimethane) crystals with segregated TCNQ anion radical columns with dimeric deformation (Peierls state) has been performed by a contact doping method using F4TCNQ (F4TCNQ = 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane) crystals or powder. The sheet resistance of the K–TCNQ surface has been found to decrease by the F4TCNQ contact. Formation of K–F4TCNQ nanocrystals at the contact interface has been observed, but conductive AFM images indicate that current paths form along the hole-doped K–TCNQ surface. Interestingly, hole-doping into K–TCNQ suppresses the phase transition to the high-temperature phase (Mott insulator). This is considered to result from the energy gain by the delocalization of the doped carriers.

Cellular homeostasis is regulated by signals through multiple molecular networks that include protein phosphorylation and metabolites. However, where and when the signal flows through a network and regulates homeostasis has not been explored. We have developed a reconstruction method for the signal flow based on time-course phosphoproteome and metabolome data, using multiple databases, and have applied it to acute action of insulin, an important hormone for metabolic homeostasis. An insulin signal flows through a network, through signaling pathways that involve 13 protein kinases, 26 phosphorylated metabolic enzymes, and 35 allosteric effectors, resulting in quantitative changes in 44 metabolites. Analysis of the network reveals that insulin induces phosphorylation and activation of liver-type phosphofructokinase 1, thereby controlling a key reaction in glycolysis. We thus provide a versatile method of reconstruction of signal flow through the network using phosphoproteome and metabolome data.

There is a growing body of evidence that the formation and accumulation of advanced glycation end products (AGE) have been known to progress under diabetic conditions, thereby being involved in diabetic vascular complications. Further, we, along with others, have recently found AGE could disturb insulin actions in cultured adipocytes and skeletal muscles. However, the pathological role of AGE in insulin resistance in vivo is not fully understood. Therefore, in this study, we examined whether pyridoxamine, an inhibitor of AGE formation could ameliorate insulin resistance in KK-Ay mice, a model animal of obese, type 2 diabetes. Fasting blood glucose, serum levels of insulin and AGE in KK-Ay mice were elevated as the mice got older (from 5 weeks old to 15 weeks old). Serum levels of AGE were positively correlated with insulin (R20.3956, P0.002) in KK-Ay mice. Administration of pyridoxamine dose-dependently decreased fasting insulin levels and improved insulin sensitivity in KK-Ay mice of 10 weeks old, although it did not affect fasting blood glucose levels. Our present study suggests the involvement of AGE in insulin resistance in KK-Ay mice. Inhibition of AGE formation may be a novel therapeutic target for improving insulin resistance in diabetes with obesity.

Mulberry 1-deoxynojirimycin (DNJ) is a potent α-glucosidase inhibitor. Although it is useful for the treatment of diabetes, the human absorption and metabolism of DNJ have never been characterized. We developed a method using hydrophilic interaction chromatography coupled with ion trap tandem mass spectrometry, and found that orally administered DNJ was absorbed into the blood and then excreted into the urine.

When starved for a single amino acid, the budding yeast Saccharomyces cerevisiaeactivates the eukaryotic initiation factor 2α (eIF2α) kinase GCN2 in a GCN1-dependent manner. Phosphorylated eIF2α inhibits general translation but selectively derepresses the synthesis of the transcription factor GCN4, which leads to coordinated induction of genes involved in biosynthesis of various amino acids, a phenomenon called general control response. We recently demonstrated that this response requires binding of GCN1 to the GI domain occurring at the N terminus of GCN2 (Kubota, H., Sakaki, Y., and Ito, T. (2000)J. Biol. Chem.275, 20243–20246). Here we provide the first evidence for the involvement of GCN1-GCN2 interaction in activation of GCN2 per se. We identified a C-terminal segment of GCN1 sufficient to bind the GI domain and used a novel dual bait two-hybrid method to identify mutations rendering GCN1 incapable of interacting with GCN2. The yeast bearing such an allele,gcn1-F2291L, fails to display derepression of GCN4translation and hence general control response, as does a GI domain mutant, gcn2-Y74A, defective in association with GCN1. Furthermore, we demonstrated that phosphorylation of eIF2α is impaired in both mutants. Since GCN2 is the sole eIF2α kinase in yeast, these findings indicate a critical role of GCN1-GCN2 interaction in activation of the kinase in vivo.

In response to the starvation of a single amino acid, the budding yeast Saccharomyces cerevisiaeactivates numerous genes involved in various amino acid biosynthetic pathways, all of which are under the control of transcription factor GCN4. This general amino acid control response is based on de-repressed translation of GCN4mRNA, which is induced by the activation of the eIF2α kinase, GCN2. Although it is known thatin vivoactivation of GCN2 requires GCN1, the mode of GCN1 action remains to be elucidated at the molecular level. Here, we show that GCN2 interacts with GCN1 via the GI domain, a novel protein-binding module that occurs at the N terminus; mutations to conserved residues of this domain abolish its binding to GCN1. Furthermore, the yeast cells with GCN2 defective in interaction with GCN1 fail to display general control response. A similar phenotype is observed in cells overexpressing the GI domain of GCN2 or its target region on GCN1. Thus, GI domain-mediated association of GCN2 to GCN1 is required for general amino acid control. This finding provides the first insight into the molecular mechanism for the activation of GCN2 by GCN1.

An effective combination of multi-omic datasets can enhance our understanding of complex biological phenomena. To build a context-dependent network with multiple omic layers, i.e., a trans-omic network, we perform phosphoproteomics, transcriptomics, proteomics, and metabolomics of murine liver for 4 h after insulin administration and integrate the resulting time series. Structural characteristics and dynamic nature of the network are analyzed to elucidate the impact of insulin. Early and prominent changes in protein phosphorylation and persistent and asynchronous changes in mRNA and protein levels through non-transcriptional mechanisms indicate enhanced crosstalk between phosphorylation-mediated signaling and protein expression regulation. Metabolic response shows different temporal regulation with transient increases at early time points across categories and enhanced response in the amino acid and nucleotide categories at later time points as a result of process convergence. This extensive and dynamic view of the trans-omic network elucidates prominent regulatory mechanisms that drive insulin responses through intricate interlayer coordination.

Abstract: A census of wild Yakushima macaques (Macaca fuscata yakui) was carried out in a 23-km2 area of the western coast of Yakushima Island, Japan. We analyzed the census data to investigate changes in monkey distribution associated with the vertical distribution of vegetation. In the lowland coastal zone of 0–300 m above sea level (a.s.l.), 4.8 troops and 62.4–99.8 monkeys are estimated to have existed per km2. In the mountainside zones of 300–900 m a.s.l., the troop density decreased to 1.3–1.6 troops/km2. Since there was no difference in size between the coastal and mountainside troops, population density should decrease with altitude to about 30–36 monkeys per km2. On the other hand, 2.4 troops and about 36 monkeys were estimated to have inhabited per km2 in the mountain summit zone of 900–1,323 m a.s.l.

Obesity shifts glucose-responsive hepatic metabolism from rapid regulation by metabolites to slower changes in gene expression.

Cell-to-cell variability in signal transduction in biological systems is often considered noise. However, intercellular variation (i.e., cell-to-cell variability) has the potential to enable individual cells to encode different information. Here, we show that intercellular variation increases information transmission of skeletal muscle. We analyze the responses of multiple cultured myotubes or isolated skeletal muscle fibers as a multiple-cell channel composed of single-cell channels. We find that the multiple-cell channel, which incorporates intercellular variation as information, not noise, transmitted more information in the presence of intercellular variation than in the absence according to the “response diversity effect,” increasing in the gradualness of dose response by summing the cell-to-cell variable dose responses. We quantify the information transmission of human facial muscle contraction during intraoperative neurophysiological monitoring and find that information transmission of muscle contraction is comparable to that of a multiple-cell channel. Thus, our data indicate that intercellular variation can increase the information capacity of tissues.

The thymic function to produce self-protective and self-tolerant T cells is chiefly mediated by cortical thymic epithelial cells (cTECs) and medullary TECs (mTECs). Recent studies including single-cell transcriptomic analyses have highlighted a rich diversity in functional mTEC subpopulations. Because of their limited cellularity, however, the biochemical characterization of TECs, including the proteomic profiling of cTECs and mTECs, has remained unestablished. Utilizing genetically modified mice that carry enlarged but functional thymuses, here we show a combination of proteomic and transcriptomic profiles for cTECs and mTECs, which identified signature molecules that characterize a developmental and functional contrast between cTECs and mTECs. Our results reveal a highly specific impact of the thymoproteasome on proteasome subunit composition in cTECs and provide an integrated trans-omics platform for further exploration of thymus biology.

The occurrence of tumor in the small intestine is relatively rare. It has been demonstrated that lipoma of the ileum is a cause of intussusception. We report a 59-year-old man admitted to our hospital for lower abdominal pain. Diagnosis of intussusception was made by abdominal x-ray and ultrasonography. Enema contrast studies revealed ileocolic intussusception. Colonoscopy revealed a tumor with an submucosal tumor (SMT)-like head and coil-spring appearance in the ascending colon. Endoscopic ultrasonography (EUS) revealed a hyperechoic submucosal lesion with features compatible with lipoma. Subsequently, this was confirmed histopathologically after resection. To our knowledge, this is the first report of preoperative diagnosis of ileal lipoma by EUS.

Cells respond to various extracellular stimuli through a limited number of signaling pathways. One strategy to process such stimuli is to code the information into the temporal patterns of molecules. Although we showed that insulin selectively regulated molecules depending on its temporal patterns using Fao cells, the in vivomechanism remains unknown. Here, we show how the insulin-AKT pathway processes the information encoded into the temporal patterns of blood insulin. We performed hyperinsulinemic-euglycemic clamp experiments and found that, in the liver, all temporal patterns of insulin are encoded into the insulin receptor, and downstream molecules selectively decode them through AKT. S6K selectively decodes the additional secretion information. G6Paseinterprets the basal secretion information through FoxO1, while GSK3β decodes all secretion pattern information. Mathematical modeling revealed the mechanism via differences in network structures and from sensitivity and time constants. Given that almost all hormones exhibit distinct temporal patterns, temporal coding may be a general principle of system homeostasis by hormones.

Transcriptomic analysis and mathematical modeling reveal selective gene regulation by insulin.

The Akt pathway can serve as a signal decoupler, converting a weak receptor signal into a strong effector signal.

A fast and simple method of simulating developed resist pattern contours obtained with optical lithography has been developed. This simulation method consists of calculating the aerial image intensity, the inhibitor concentration in the resist film, and the mean inhibitor concentration obtained by averaging the inhibitor concentration along the axis normal to the resist layer. The contours of a resist pattern formed with optical lithography are determined from contours related to the threshold value of the mean inhibitor concentration. Although the calculation of post-exposure baking (PEB) diffusion and development is eliminated, the influences of the resist thickness and a multiple-layer substrate structure on the resist pattern width and contours due to interference in the resist film are taken into account. The validity of this method was tested by comparing the calculation results with experimental data. The computing time was between one-sixth and one-twelfth of that needed for a conventional three-dimensional simulation which includes calculation of the aerial image intensity, inhibitor concentration in the resist layer, PEB diffusion, and development. Moreover, the new method requires much less memory than the conventional three-dimensional simulation since only a two-dimensional array representing the resist plane is necessary. When the new method was applied to model patterns, we found that the pattern dimensions and contours varied as the thickness of the resist film and the thin layer between the resist film and substrate changed, which demonstrates the effectiveness of this method.