The phytohormone 7-iso-(+)-jasmonoyl-L-isoleucine (JA-Ile) mediates plant defense responses against herbivore and pathogen attack, and thus increases plant resistance against foreign invaders. However, JA-Ile also causes growth inhibition; and therefore JA-Ile is not a practical chemical regulator of plant defense responses. Here, we describe the rational design and synthesis of a small molecule agonist that can upregulate defense-related gene expression and promote pathogen resistance at concentrations that do not cause growth inhibition in Arabidopsis. By stabilizing interactions between COI1 and JAZ9 and JAZ10 but no other JAZ isoforms, the agonist leads to formation of JA-Ile co-receptors that selectively activate the JAZ9-EIN3/EIL1-ORA59 signaling pathway. The design of a JA-Ile agonist with high selectivity for specific protein subtypes may help promote the development of chemical regulators that do not cause a tradeoff between growth and defense.

Bone homeostasis is maintained by the coupled actions of hematopoietic bone-resorbing osteoclasts (OCs) and mesenchymal bone-forming osteoblasts (OBs). Here we identify early B cell factor 1 (Ebf1) and the transcriptional coregulator Zfp521 as components of the machinery that regulates bone homeostasis through coordinated effects in both lineages. Deletion of Zfp521 in OBs led to impaired bone formation and increased OB-dependent osteoclastogenesis (OC-genesis), and deletion in hematopoietic cells revealed a strong cell-autonomous role for Zfp521 in OC progenitors. In adult mice, the effects of Zfp521 were largely caused by repression of Ebf1, and the bone phenotype of Zfp521(+/-) mice was rescued in Zfp521(+/-):Ebf1(+/-) mice. Zfp521 interacted with Ebf1 and repressed its transcriptional activity. Accordingly, deletion of Zfp521 led to increased Ebf1 activity in OBs and OCs. In vivo, Ebf1 overexpression in OBs resulted in suppressed bone formation, similar to the phenotype seen after OB-targeted deletion of Zfp521. Conversely, Ebf1 deletion led to cell-autonomous defects in both OB-dependent and cell-intrinsic OC-genesis, a phenotype opposite to that of the Zfp521 knockout. Thus, we have identified the interplay between Zfp521 and Ebf1 as a novel rheostat for bone homeostasis.

Severe genetic redundancy is particularly clear in gene families encoding plant hormone receptors, each subtype sharing redundant and specific functions. Genetic redundancy of receptor family members represents a major challenge for the functional dissection of each receptor subtype. A paradigmatic example is the perception of the hormone (+)-7-iso-jasmonoyl-L-isoleucine, perceived by several COI1-JAZ complexes; the specific role of each receptor subtype still remains elusive. Subtype-selective agonists of the receptor are valuable tools for analyzing the responses regulated by individual receptor subtypes. We constructed a stereoisomer library consisting of all stereochemical isomers of coronatine (COR), a mimic of the plant hormone (+)-7-iso-jasmonoyl-L-isoleucine, to identify subtype-selective agonists for COI1-JAZ co-receptors in Arabidopsis thaliana and Solanum lycopersicum. An agonist selective for the Arabidopsis COI1-JAZ9 co-receptor efficiently revealed that JAZ9 is not involved in most of the gene downregulation caused by COR, and the degradation of JAZ9-induced defense without inhibiting growth.

The medical situation during disasters often differs from that at usual times. Disasters can lead to significant mortality that can be difficult to monitor. The types of disaster-related deaths are largely unknown. In this study, we conducted a survey to categorize the disaster-related deaths caused by a radiation disaster. A total of 520 people living in Minamisoma City, Fukushima Prefecture, at the time of the Fukushima Daiichi Nuclear Power Plant accident, who were certified to have died due to disaster-related causes were surveyed. We divided the participants into those who were at home at the time of the earthquake and those who were in hospitals or facilities when the disaster struck and conducted a hierarchical cluster analysis of the two groups. Disaster-related deaths could be divided into seven groups for those who were at home at the time of the disaster and five groups for those who were in hospitals or facilities at the time of the disaster. Each group showed different characteristics, such as "the group with disabilities," "the group receiving care," and "the group with depression," and it became evident that not only uniform post-disaster support, but support tailored to the characteristics of each group is necessary.

Runx2 is indispensable for osteoblast lineage commitment and early differentiation but also blocks osteoblast maturation, thereby causing bone loss in Runx2 transgenic mice. Zinc finger protein 521 (Zfp521) antagonizes Runx2 in vivo. Eliminating one Zfp521 allele mitigates the cleidocranial dysplasia-like phenotype of newborn Runx2(+/-) mice, whereas overexpressing Zfp521 exacerbates it. Overexpressing Zfp521 also reverses the severe osteopenia of adult Runx2 transgenic mice. Zfp521 binds to both Runx2 and histone deacetylase 3 (HDAC3), promotes their association, and antagonizes Runx2 transcriptional activity in an HDAC3-dependent manner. Mutating the Zfp521 zinc finger domains 6 and 26 reduces the binding of Zfp521 to Runx2 and inhibition of Runx2 activity. These data provide evidence that Zfp521 antagonizes Runx2 in vivo and thereby regulates two stages of osteoblast development, early during mesenchymal cell lineage commitment and later during osteoblast maturation. Thus, the balance and molecular interplay between Zfp521 and Runx2 contribute to the control of osteoblast differentiation, skeletal development, and bone homeostasis.

In the growth plate, the interplay between parathyroid hormone-related peptide (PTHrP) and Indian hedgehog (Ihh) signaling tightly regulates chondrocyte proliferation and differentiation during longitudinal bone growth. We found that PTHrP increases the expression of Zfp521, a zinc finger transcriptional coregulator, in prehypertrophic chondrocytes. Mice with chondrocyte-targeted deletion of Zfp521 resembled PTHrP(-/-) and chondrocyte-specific PTHR1(-/-) mice, with decreased chondrocyte proliferation, early hypertrophic transition, and reduced growth plate thickness. Deleting Zfp521 increased expression of Runx2 and Runx2 target genes, and decreased Cyclin D1 and Bcl-2 expression while increasing Caspase-3 activation and apoptosis. Zfp521 associated with Runx2 in chondrocytes, antagonizing its activity via an HDAC4-dependent mechanism. PTHrP failed to upregulate Cyclin D1 and to antagonize Runx2, Ihh, and collagen X expression when Zfp521 was absent. Thus, Zfp521 is an important PTHrP target gene that regulates growth plate chondrocyte proliferation and differentiation.

The recent emergence of antibiotic-resistant bacteria requires the development of new antibiotics or new agents capable of enhancing antibiotic activity. This study evaluated the antibacterial activity of lysozyme-chitosan oligosaccharide conjugates (LYZOX) against Pseudomonas aeruginosa, Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA), which should resolve the problem of antibiotic-resistant bacteria. Bactericidal tests showed that LYZOX killed 50% more P. aeruginosa (NBRC 13275), A. baumannii and MRSA than the control treatment after 60 min. In addition, LYZOX was shown to inhibit the growth of P. aeruginosa (NBRC 13275 and PAO1), A. baumannii and MRSA better than its components. To elucidate the antibacterial mechanism of LYZOX, we performed cell membrane integrity assays, N-phenyl-1-naphthylamine assays, 2-nitrophenyl β-D-galactopyranoside assays and confocal laser scanning microscopy. These results showed that LYZOX affected bacterial cell walls and increased the permeability of the outer membrane and the plasma membrane. Furthermore, each type of bacteria treated with LYZOX was observed by electron microscopy. Electron micrographs revealed that these bacteria had the morphological features of both lysozyme-treated and chitosan oligosaccharide-treated bacteria and that LYZOX destroyed bacterial cell walls, which caused the release of intracellular contents from cells. An acquired drug resistance test revealed that these bacteria were not able to acquire resistance to LYZOX. The hemolytic toxicity test demonstrated the low hemolytic activity of LYZOX. In conclusion, LYZOX exhibited antibacterial activity and low drug resistance in the presence of P. aeruginosa, A. baumannii and MRSA and showed low hemolytic toxicity. LYZOX affected bacterial membranes, leading to membrane disruption and the release of intracellular contents and consequent bacterial cell death. LYZOX may serve as a novel candidate drug that could be used for the control of refractory infections.

Clinical Practice Guidelines (CPGs) play significant roles in most medical fields. However, little is known about the extent of financial Conflicts of Interest (FCOIs) related to pharmaceutical companies (Pharma) selling dermatology prescription products and dermatology CPG authors in Japan. The aims of this study were to elucidate the characteristics and distribution of payments from Pharma to dermatology CPG authors in Japan, and to evaluate the extent of transparency and accuracy in their FCOI disclosures. We analyzed the records of 296 authors from 32 dermatology CPGs published by the Japanese Dermatological Association from the beginning of 2015 to the end of 2018. Using the payment data reported by 79 Pharma between 2016-2017 in Japan, we investigated the characteristics of the CPG authors and the payments from the Pharma to them. Furthermore, we evaluated the transparency and accuracy of the FCOI disclosures of the individual CPG authors. Of the 296 CPGs authors, 269 authors (90.6%) received at least one payment from the Pharma. The total monetary value of payments for the 2-year period was $7,128,762. The median and mean monetary value of payments from the Pharma reporting were $10,281 (interquartile range $2,796 -$34,962) and $26,600 (standard deviation $40,950) for the two years combined. Of the 26 CPG authors who disclosed FCOIs due to the monies received from Pharma, only the atopic dermatitis CPG authors and the acne vulgaris CPG authors published their potential FCOIs. In Japan, most dermatology CPG authors received financial payments from Pharma. The transparency of the CPGs, as reported by the CPG authors, was inadequate, and a more rigorous framework of reporting and monitoring FCOI disclosure is required to improve the accuracy and transparency with relation to possible Conflicts of Interest.

Seasonal drawdown of dissolved inorganic carbon (DIC) in the subtropical upper ocean makes a significant contribution to net community production (NCP) globally. Although NCP requires macronutrient supply, surface macronutrients are chronically depleted, and their supply has been unable to balance the NCP demand. Here, we report nanomolar increases in surface nitrate plus nitrite (N+N, ~20 nM) and phosphate (PO4, ~15 nM) from summer to winter in the western subtropical North Pacific. Molar ratios of upward fluxes of DIC:N+N:PO4 to the euphotic zone (< 100 m) were in near-stoichiometric balance with microbial C:N:P ratios (107~243:16~35:1). Comparison of these upward influxes with other atmospheric and marine sources demonstrated that total supply is largely driven by the other sources for C and N (93~96%), but not for P (10%), suggesting that nanomolar upward supply of P and its preferential recycling play a vital role in sustaining the NCP.

Background: Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) is becoming increasingly popular. However, the risk factors for stent migration into the abdominal cavity remain unknown. Methods: Forty-eight patients undergoing EUS-HGS with placement of a long, partially covered self-expandable metallic stent (LPC-SEMS) were studied retrospectively to identify risk factors of stent migration. We determined the technical and functional success rates, and recorded adverse events, including stent migration. Results: EUS-HGS was technically successful in all patients. However, stent migration was evident in five patients (one actual and four imminent, 10%). Stent migration into the abdominal cavity was observed in one patient (2%), and the other four cases required additional procedures to prevent migration (8%). Logistic regression analysis revealed that the risk of stent migration increased as the initial (pre-procedure) distance between the stomach and liver at the puncture site increased (p = 0.012). Conclusions: A longer distance between the stomach and liver at the puncture site increased the risk of stent migration. However, during EUS-HGS, it is difficult to adjust the puncture position. It is important to ensure that the proportion of the stent in the stomach is large; the use of a self-anchoring stent may be optimal.

Patients who undergo gastrectomy for gastric cancer (GC) are likely to have nutritional difficulty after surgery. Readmission due to nutritional difficulty is common in such patients. Thus, in this study, we aim to identify the predictive indicators for readmission due to nutritional difficulty in patients who underwent gastrectomy for GC.

Aging is accompanied by osteopenia, characterized by reduced bone formation and increased bone resorption. Osteocytes, the terminally differentiated osteoblasts, are regulators of bone homeostasis, and parathyroid hormone (PTH) receptor (PPR) signaling in mature osteoblasts/osteocytes is essential for PTH-driven anabolic and catabolic skeletal responses. However, the role of PPR signaling in those cells during aging has not been investigated. The aim of this study was to analyze the role of PTH signaling in mature osteoblasts/osteocytes during aging. Mice lacking PPR in osteocyte (Dmp1-PPRKO) display an age-dependent osteopenia characterized by a significant decrease in osteoblast activity and increase in osteoclast number and activity. At the molecular level, the absence of PPR signaling in mature osteoblasts/osteocytes is associated with an increase in serum sclerostin and a significant increase in osteocytes expressing 4-hydroxy-2-nonenals, a marker of oxidative stress. In Dmp1-PPRKO mice there was an age-dependent increase in p16Ink4a/Cdkn2a expression, whereas it was unchanged in controls. In vitro studies demonstrated that PTH protects osteocytes from oxidative stress-induced cell death. In summary, we reported that PPR signaling in osteocytes is important for protecting the skeleton from age-induced bone loss by restraining osteoclast's activity and protecting osteocytes from oxidative stresses.

No abstract available

Limited evidence is available regarding the financial relationships between gastroenterologists and pharmaceutical companies in Japan. This study analysed the magnitude, prevalence and trends of personal payments made by major pharmaceutical companies to board-certified gastroenterologists in Japan in recent years.

Postmenopausal bone loss often leads to osteoporosis and fragility fractures. Bone mass can be increased by the first 34 amino acids of human parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), or by a monoclonal antibody against sclerostin (Scl-Ab). Here, we show that PTH and Scl-Ab reduce the expression of microRNA-19a and microRNA-19b (miR-19a/b) in bone. In bones from patients with lower bone mass and from osteoporotic mice, miR-19a/b expression is elevated, suggesting an inhibitory function in bone remodeling. Indeed, antagonizing miR-19a/b in vivo increased bone mass without overt cytotoxic effects. We identified TG-interacting factor 1 (Tgif1) as the target of miR-19a/b in osteoblasts and essential for the increase in bone mass following miR-19a/b inhibition. Furthermore, antagonizing miR-19a/b augments the gain in bone mass by PTH and restores bone loss in mouse models of osteoporosis in a dual mode of action by supporting bone formation and decreasing receptor activator of NF-κB ligand (RANKL)-dependent bone resorption. Thus, this study identifies novel mechanisms regulating bone remodeling, which opens opportunities for new therapeutic concepts to treat bone fragility.

(+)-7-iso-Jasmonoyl-L-isoleucine (JA-Ile) is a lipid-derived phytohormone implicated in plant development, reproduction, and defense in response to pathogens and herbivorous insects. All these effects are instigated by the perception of JA-Ile by the COI1-JAZ co-receptor in the plant body, which in Arabidopsis thaliana is profoundly influenced by the short JAZ degron sequence (V/L)P(Q/I)AR(R/K) of the JAZ protein. Here, we report that SlJAZ-SlCOI1, the COI1-JAZ co-receptor found in the tomato plant, relies on the extended JAZ degron sequence (V/L)P(Q/I)AR(R/K)XSLX instead of the canonical JAZ degron. This finding illuminates our understanding of the mechanism of ligand perception by JA-Ile in this plant, and will inform both efforts to improve it by genetic modification of the SlCOI1-SlJAZ co-receptor, and the development of the synthetic agonists/antagonists.

Population-based Helicobacter pylori (H. pylori) screening and eradication for adults in areas with a high incidence of gastric cancer have been shown to be effective. The current status of H. pylori screening for young people, however, has not been sufficiently evaluated.

Cell-cell fusion is an evolutionarily conserved process that leads to the formation of multinucleated myofibers, syncytiotrophoblasts and osteoclasts, allowing their respective functions. Although cell-cell fusion requires the presence of fusogenic membrane proteins and actin-dependent cytoskeletal reorganization, the precise machinery allowing cells to fuse is still poorly understood. Using an inducible knockout mouse model to generate dynamin 1- and 2-deficient primary osteoclast precursors and myoblasts, we found that fusion of both cell types requires dynamin. Osteoclast and myoblast cell-cell fusion involves the formation of actin-rich protrusions closely associated with clathrin-mediated endocytosis in the apposed cell. Furthermore, impairing endocytosis independently of dynamin also prevented cell-cell fusion. Since dynamin is involved in both the formation of actin-rich structures and in endocytosis, our results indicate that dynamin function is central to the osteoclast precursors and myoblasts fusion process, and point to an important role of endocytosis in cell-cell fusion.

Stem cell transplantation has been expected to have various applications for regenerative medicine. However, in order to detect and trace the transplanted stem cells in the body, non-invasive and widely clinically available cell imaging technologies are required. In this paper, we focused on magnetic resonance (MR) imaging technology, and investigated whether the trimethylamino dextran-coated magnetic iron oxide nanoparticle -03 (TMADM-03), which was newly developed by our group, could be used for labeling adipose tissue-derived stem cells (ASCs) as a contrast agent. No cytotoxicity was observed in ASCs transduced with less than 100 µg-Fe/mL of TMADM-03 after a one hour transduction time. The transduction efficiency of TMADM-03 into ASCs was about four-fold more efficient than that of the alkali-treated dextran-coated magnetic iron oxide nanoparticle (ATDM), which is a major component of commercially available contrast agents such as ferucarbotran (Resovist), and the level of labeling was maintained for at least two weeks. In addition, the differentiation ability of ASCs labeled with TMADM-03 and their ability to produce cytokines such as hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2), were confirmed to be maintained. The ASCs labeled with TMADM-03 were transplanted into the left kidney capsule of a mouse. The labeled ASCs could be imaged with good contrast using a 1T MR imaging system. These data suggest that TMADM-03 can therefore be utilized as a contrast agent for the MR imaging of stem cells.

Excess consumption of trans-fatty acid could increase the risk of non-alcoholic steatohepatitis (NASH); however, treatment targeting trans-fatty acid-induced NASH has not been examined. Here we focused on the influence of trans-fatty acid intake on endoplasmic reticulum (ER) stress in hepatocytes, so we investigated the effect of the chemical chaperone 4-phenylbutyric acid (PBA), on trans-fatty acid-caused steatohepatitis using diabetic KK-A(y) mice. Elaidic acid (EA, trans-fatty acid) alone did not cause definitive liver injury. In contrast, EA plus low-dose fructose induced extensive apoptosis in hepatocytes with severe fat accumulation. EA plus fructose significantly increased ER stress markers such as glucose-regulated protein 78 (GRP78), eukaryotic initiation factor 2α (eIF2α) and phosphorylated c-jun N-terminal kinase (JNK), while PBA significantly reduced this response. In vitro, EA promoted expression of GRP78 and phosphorylation of eIF2α in primary-cultured hepatocytes. EA also increased hepatocellular susceptibility to low-dose tert-butyl hydroperoxide. Treatment with PBA significantly reduced these responses. In conclusion, EA potentiates susceptibly to non-hazardous dose of fructose, and increases ER and oxidative stress. PBA improved steatohepatitis induced by EA plus fructose through amelioration of ER stress. Therefore, ER stress-targeted therapy using a chemical chaperone is a promising novel strategy for trans-fatty acid-induced steatohepatitis.