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Clostridioides difficile is endemic in the intestinal tract of healthy people. However, it is responsible for many healthcare-associated infections, such as nosocomial diarrhea following antibiotic treatment. Importantly, there have been cases of unsuccessful treatment and relapse related to the emergence of highly virulent strains of C. difficile and resistance to antimicrobial agents. Fecal microbiota transplantation (FMT) is considered an effective therapy for recurrent C. difficile infection. However, its safety is of concern because deaths caused by antibiotic-resistant bacterial infections after FMT were reported. Therefore, the development of effective C. difficile-specific treatments is urgently needed. In this review, we summarize the importance of phage therapy against C. difficile, and describe a novel next-generation phage therapy developed using metagenomic data.

Bronchoalveolar lavage is commonly performed to assess inflammation and identify responsible pathogens in lung diseases. Findings from bronchoalveolar lavage might be used to evaluate the immune profile of the lung tumor microenvironment (TME). To investigate whether bronchoalveolar lavage fluid (BALF) analysis can help identify patients with non-small cell lung cancer (NSCLC) who respond to immune checkpoint inhibitors (ICIs), BALF and blood were prospectively collected before initiating nivolumab. The secreted molecules, microbiome, and cellular profiles based on BALF and blood analysis of 12 patients were compared with regard to therapeutic effect. Compared with ICI nonresponders, responders showed significantly higher CXCL9 levels and a greater diversity of the lung microbiome profile in BALF, along with a greater frequency of the CD56+ subset in blood T cells, whereas no significant difference in PD-L1 expression was found in tumor cells. Antibiotic treatment in a preclinical lung cancer model significantly decreased CXCL9 in the lung TME, resulting in reduced sensitivity to anti-PD-1 antibody, which was reversed by CXCL9 induction in tumor cells. Thus, CXCL9 might be associated with the lung TME microbiome, and the balance of CXCL9 and lung TME microbiome could contribute to nivolumab sensitivity in patients with NSCLC. BALF analysis can help predict the efficacy of ICIs when performed along with currently approved examinations.

Progress in genomic analysis has resulted in the proposal that the intestinal microbiota is a crucial environmental factor in the development of multifactorial diseases, such as obesity, diabetes, rheumatoid arthritis, and inflammatory bowel diseases represented by Crohn’s disease and ulcerative colitis. Dysregulated gut microbiome contributes to the pathogenesis of such disorders; however, there are few effective treatments for controlling only disease-mediating bacteria. Here, we review current knowledge about the intestinal microbiome in health and disease, and discuss a regulatory strategy using a parenteral vaccine with emulsified curdlan and CpG oligodeoxynucleotides, which we have recently developed. Unlike other conventional injectable immunizations, our vaccine contributes to the induction of antigen-specific systemic and mucosal immunity. This vaccine strategy can prevent infectious diseases such as Streptococcus pneumoniae infection, and control metabolic symptoms mediated by intestinal bacteria (e.g. Clostridium ramosum) by induction of high titers of antigen-specific IgA at target mucosal sites. In the future, our vaccination approach could be an effective therapy for common infectious diseases and dysbiosis-related disorders that have been difficult to control so far.

The intestinal microbiome is dominated by bacteria and plays a pivotal role in the occurrence and development of disease, including several metabolic and autoimmune disorders. While intestinal viral communities, primarily made up of bacteriophages, are also thought to play a role in disease pathogenesis in the gastrointestinal tract, they have received much less attention than intestinal bacteria. Thus, there is limited information about the relationship between bacteriophages and disease. This review explores a potential role for the intestinal viral microbiome in various metabolic and autoimmune diseases.

MotivationBacteriophages/Phages are the viruses that infect and replicate within bacteria and archaea, and rich in human body. To investigate the relationship between phages and microbial communities, the identification of phages from metagenome sequences is the first step. Currently, there are two main methods for identifying phages: database-based (alignment-based) methods and alignment-free methods. Database-based methods typically use a large number of sequences as references; alignment-free methods usually learn the features of the sequences with machine learning and deep learning models.ResultsWe propose INHERIT which uses a deep representation learning model to integrate both database-based and alignment-free methods, combining the strengths of both. Pre-training is used as an alternative way of acquiring knowledge representations from existing databases, while the BERT-style deep learning framework retains the advantage of alignment-free methods. We compare INHERIT with four existing methods on a third-party benchmark dataset. Our experiments show that INHERIT achieves a better performance with the F1-score of 0.9932. In addition, we find that pre-training two species separately helps the non-alignment deep learning model make more accurate predictions.AvailabilityThe codes of INHERIT are now available in: https://github.com/Celestial-Bai/INHERIT.Contactyaozhong@ims.u-tokyo.ac.jp and imoto@hgc.jpSupplementary informationSupplementary data are available at BioRxiv online.

Our bodies are constantly exposed to a wide variety of pathogenic micro-organisms through mucosal sites. Therefore, effective vaccines that can protect at the mucosa are vital; however, only a few clinically established mucosal vaccines are available. Although conventional injectable vaccines can induce antigen-specific serum immunoglobulin G (IgG) and prevent severe infection, it is difficult to efficiently inhibit the invasion of pathogens at mucosal surfaces because of the inadequate ability to induce antigen-specific IgA. Recently, we have developed a parenteral vaccine with emulsified curdlan and CpG oligodeoxynucleotides and reported its application. Unlike other conventional injectable vaccines, this immunization contributes to the induction of antigen-specific mucosal and systemic immune responses. Even if antigen-specific IgA at the mucosa disappears, this immunization can induce high-titer IgA after boosting with a small amount of antigen on the target mucosal surface. Indeed, vaccination with Streptococcus pneumoniae antigen effectively prevented lung infection induced by this bacterium. In addition, vaccination with Clostridium ramosum, which is a representative pathobiont associated with obesity and diabetes in humans, reduced obesity in mice colonized with this microorganism. This immunization approach might be an effective treatment for intestinal bacteria-mediated diseases that have been difficult to regulate so far, as well as common infectious diseases.

The receptor activator of nuclear factor κB ligand (RANKL) is an important factor for osteoclastogenesis and contributes to the pathology of rheumatoid arthritis (RA); thus, the anti-RANKL antibody (Ab) has been expected to protect joint destruction in RA patients. IL-8 also has osteoclastogenic activity; however, the role of IL-8 in the bone pathology of RA as well as the relation between IL-8 and RANKL remain unclear. In the present study, clinical observation revealed serum IL-8 levels of 611 pg ml−1 in RA patients with anti-RANKL Ab and 266 pg ml−1 in the same patients without anti-RANKL Ab. In vitro assay showed that anti-RANKL Ab induced production of IL-8 from pre-osteoclast-like cells (OCLs), and IL-8 promoted the formation of OCLs from peripheral monocytes even without RANKL activity. We further showed that treatment with FK506 (tacrolimus) possibly inhibits the increase in IL-8 levels in RA patients with anti-RANKL Ab, and in vitro assay confirmed that FK506 suppressed IL-8 production in pre-OCLs. These results suggest that inhibition of RANKL induces the change in osteoclastogenesis-promoting factor from RANKL to IL-8, and FK506 may be a valuable combination drug to support the use of anti-RANKL Ab in treatment of RA., A therapeutic anti-RANKL Ab increases IL-8 production in RA

The aim of this study was to investigate the prognostic impact of postoperative systemic inflammation in patients with colorectal cancer(CRC).This study reviewed the medical records of 382 patients with CRC who underwent curative surgery. We evaluated the postoperative serum C-reactive protein(CRP)level on postoperative day 1 (CRP1)and its peak value(CRPmax)as prognostic factors.CRP1(p=0.001)and CRPmax(p=0.023)were significantly associated with the overall survival(OS)rate. In the multivariate analysis, a high-CRP1, age of≥75 years, and high serum carcinoembryonic antigen level were identified as independent predictors for the poor OS. Death from relapse of CRC was more frequent in the high-CRP1 group than in the low-CRP1 group(18.0% vs 5.6%, p=0.001).The serum CRP level during the early postoperative period predicts the long-term outcomes in CRC.

Worldwide prevalence of obesity is associated with the increase of lifestyle-related diseases. The accumulation of intermuscular adipose tissue (IMAT) is considered a major problem whereby obesity leads to sarcopenia and metabolic disorders and thus is a promising target for treating these pathological conditions. However, whereas obesity-associated IMAT is suggested to originate from PDGFRα+ mesenchymal progenitors, the processes underlying this adipogenesis remain largely unexplored. Here, we comprehensively investigated intra- and extracellular changes associated with these processes using single-cell RNA sequencing and mass spectrometry. Our single-cell RNA sequencing analysis identified a small PDGFRα+ cell population in obese mice directed strongly toward adipogenesis. Proteomic analysis showed that the appearance of this cell population is accompanied by an increase in galectin-3 in interstitial environments, which was found to activate adipogenic PPARγ signals in PDGFRα+ cells. Moreover, IMAT formation during muscle regeneration was significantly suppressed in galectin-3 knockout mice. Our findings, together with these multi-omics datasets, could unravel microenvironmental networks during muscle regeneration highlighting possible therapeutic targets against IMAT formation in obesity.

Mechanisms of carbohydrate-induced secretion of the two incretins namely glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are considered to be mostly similar. However, we found that mice exhibit opposite secretory responses in response to co-administration of maltose plus an α-glucosidase inhibitor miglitol (maltose/miglitol), stimulatory for GLP-1, as reported previously, but inhibitory for GIP. Gut microbiota was shown to be involved in maltose/miglitol-induced GIP suppression, as the suppression was attenuated in antibiotics (Abs)-treated mice and abolished in germ-free mice. In addition, maltose/miglitol administration increased plasma levels of short-chain fatty acids (SCFAs), carbohydrate-derived metabolites, in the portal vein. GIP suppression by maltose/miglitol was not observed in mice lacking a SCFA receptor Ffar3, but it was normally seen in Ffar2-deficient mice. Similar to maltose/miglitol administration, co-administration of glucose plus a sodium glucose transporter inhibitor phloridzin (glucose/phloridzin) induced GIP suppression, which was again cancelled by Abs treatment. In conclusion, oral administration of carbohydrates with α-glucosidase inhibitors suppresses GIP secretion through a microbiota/SCFA/FFAR3 pathway.

The gut is an extremely complicated ecosystem where micro-organisms, nutrients and host cells interact vigorously. Although the function of the intestine and its barrier system weakens with age, some probiotics can potentially prevent age-related intestinal dysfunction. Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131, which are the constituents of LB81 yogurt, are representative probiotics. However, it is unclear whether their long-term intake has a beneficial influence on systemic function. Here, we examined the gut microbiome, fecal metabolites and gene expression profiles of various organs in mice. Although age-related alterations were apparent in them, long-term LB81 yogurt intake led to an increased Bacteroidetes to Firmicutes ratio and elevated abundance of the bacterial family S24-7 (Bacteroidetes), which is known to be associated with butyrate and propanoate production. According to our fecal metabolite analysis to detect enrichment, long-term LB81 yogurt intake altered the intestinal metabolic pathways associated with propanoate and butanoate in the mice. Gene ontology analysis also revealed that long-term LB81 yogurt intake influenced many physiological functions related to the defense response. The profiles of various genes associated with antimicrobial peptides-, tight junctions-, adherens junctions- and mucus-associated intestinal barrier functions were also drastically altered in the LB81 yogurt-fed mice. Thus, long-term intake of LB81 yogurt has the potential to maintain systemic homeostasis, such as the gut barrier function, by controlling the intestinal microbiome and its metabolites.

Genome-wide association studies and subsequent deep sequencing analysis have identified susceptible loci for inflammatory bowel diseases (IBDs) including ulcerative colitis (UC). A gene encoding RING finger protein 186 (RNF186) is located within UC-susceptible loci. However, it is unclear whether RNF186 is involved in IBD pathogenesis. Here, we show that RNF186 controls protein homeostasis in colonic epithelia and regulates intestinal inflammation. RNF186, which was highly expressed in colonic epithelia, acted as an E3 ligase mediating polyubiquitination of its substrates. Permeability of small organic molecules was augmented in the intestine of Rnf186-/- mice. Increased expression of several RNF186 substrates, such as occludin, was found in Rnf186-/- colonic epithelia. The disturbed protein homeostasis in Rnf186-/- mice correlated with enhanced endoplasmic reticulum (ER) stress in colonic epithelia and increased sensitivity to intestinal inflammation after dextran sulfate sodium (DSS) treatment. Introduction of an UC-associated Rnf186 mutation led to impaired E3 ligase activity and increased sensitivity to DSS-induced intestinal inflammation in mice. Thus, RNF186 maintains gut homeostasis by controlling ER stress in colonic epithelia.

Summary The application of bacteriophages (phages) is proposed as a highly specific therapy for intestinal pathobiont elimination. However, the infectious associations between phages and bacteria in the human intestine, which is essential information for the development of phage therapies, have yet to be fully elucidated. Here, we report the intestinal viral microbiomes (viromes), together with bacterial microbiomes (bacteriomes), in 101 healthy Japanese individuals. Based on the genomic sequences of bacteriomes and viromes from the same fecal samples, the host bacteria-phage associations are illustrated for both temperate and virulent phages. To verify the usefulness of the comprehensive host bacteria-phage information, we screened Clostridioides difficile-specific phages and identified antibacterial enzymes whose activity is confirmed both in vitro and in vivo. These comprehensive metagenome analyses reveal not only host bacteria-phage associations in the human intestine but also provide vital information for the development of phage therapies against intestinal pathobionts.

Mammalian mucosal surfaces form critical interfaces between the bodily tissues and foreign antigens such as commensal flora and ingested food. Innate mucosal immunity in the gut, as represented by intestinal barrier functions and germline-encoded pattern recognition receptor (PRR)-mediated immune responses, plays an important role in regulating intestinal health and in disease prevention. Intestinal epithelial cells not only function as physical barriers, but also participate in innate immune responses. Disrupted epithelial cell function in the gut can lead to intestinal disorders. Additionally, PRR gene defects, including those relating to toll-like receptors, C-type lectin receptors, retinoic-acid-inducible gene-I-like receptors, and NOD-like receptors, lead to mucosal dysfunction and the subsequent induction of intestinal inflammation. In this chapter, we focus primarily on the current understanding of the role played by innate immunity at mucosal surfaces as an intestinal barrier system and how PRRs relate to such immunity.

Non-steroidal anti-inflammatory drugs (NSAIDs) cause damage in the small intestine in a bacteria-dependent manner. As high-fat diet (HFD) is a potent inducer of gut dysbiosis, we investigated the effects of HFD on bacterial flora in the small intestine and NSAID-induced enteropathy. 16S rRNA gene analysis revealed that the population of Bifidobacterium spp. significantly decreased by fold change of individual operational taxonomic units in the small intestine of mice fed HFD for 8 weeks. HFD increased intestinal permeability, as indicated by fluorescein isothiocyanate-dextran absorption and serum lipopolysaccharide levels, accompanied by a decrease in the protein expressions of ZO-1 and occludin and elevated mRNA expression of interleukin (IL)-17A in the small intestine. HFD-fed mice exhibited increased susceptibility to indomethacin-induced damage in the small intestine; this phenotype was observed in normal diet-fed mice that received small intestinal microbiota from HFD-fed mice. Administration of neutralizing antibodies against IL-17A to HFD-fed mice reduced intestinal permeability and prevented exacerbation of indomethacin-induced damage. Thus, HFD-induced microbial dysbiosis in small intestine caused microinflammation through the induction of IL-17A and increase in intestinal permeability, resulting in the aggravation of NSAID-induced small intestinal damage.

Background & Aims Fecal microbiota transplantation (FMT) is an effective therapy for recurrent Clostridioides difficile infection (rCDI). However, the overall mechanisms underlying FMT success await comprehensive elucidation, and the safety of FMT has recently become a serious concern because of the occurrence of drug-resistant bacteremia transmitted by FMT. We investigated whether functional restoration of the bacteriomes and viromes by FMT could be an indicator of successful FMT. Methods The human intestinal bacteriomes and viromes from 9 patients with rCDI who had undergone successful FMT and their donors were analyzed. Prophage-based and CRISPR spacer-based host bacteria–phage associations in samples from recipients before and after FMT and in donor samples were examined. The gene functions of intestinal microorganisms affected by FMT were evaluated. Results Metagenomic sequencing of both the viromes and bacteriomes revealed that FMT does change the characteristics of intestinal bacteriomes and viromes in recipients after FMT compared with those before FMT. In particular, many Proteobacteria, the fecal abundance of which was high before FMT, were eliminated, and the proportion of Microviridae increased in recipients. Most temperate phages also behaved in parallel with the host bacteria that were altered by FMT. Furthermore, the identification of bacterial and viral gene functions before and after FMT revealed that some distinctive pathways, including fluorobenzoate degradation and secondary bile acid biosynthesis, were significantly represented. Conclusions The coordinated action of phages and their host bacteria restored the recipients' intestinal flora. These findings show that the restoration of intestinal microflora functions reflects the success of FMT.

Background & Aims Dysregulation of the microbiome has been associated with development of complex diseases, such as obesity and diabetes. However, no method has been developed to control disease-associated commensal microbes. We investigated whether immunization with microbial antigens, using CpG oligodeoxynucleotides and/or curdlan as adjuvants, induces systemic antigen-specific IgA and IgG production and affects development of diseases in mice. Methods C57BL/6 mice were given intramuscular injections of antigens (ovalbumin, cholera toxin B-subunit, or pneumococcal surface protein A) combined with CpG oligodeoxynucleotides and/or curdlan. Blood and fecal samples were collected weekly and antigen-specific IgG and IgA titers were measured. Lymph nodes and spleens were collected and analyzed by enzyme-linked immunosorbent assay for antigen-specific splenic T-helper 1 cells, T-helper 17 cells, and memory B cells. Six weeks after primary immunization, mice were given a oral, nasal, or vaginal boost of ovalbumin; intestinal lamina propria, bronchial lavage, and vaginal swab samples were collected and antibodies and cytokines were measured. Some mice were also given oral cholera toxin or intranasal Streptococcus pneumoniae and the severity of diarrhea or pneumonia was analyzed. Gnotobiotic mice were gavaged with fecal material from obese individuals, which had a high abundance of Clostridium ramosum (a commensal microbe associated with obesity and diabetes), and were placed on a high-fat diet 2 weeks after immunization with C ramosum. Intestinal tissues were collected and analyzed by quantitative real-time polymerase chain reaction. Results Serum and fecal samples from mice given injections of antigens in combination with CpG oligodeoxynucleotides and curdlan for 3 weeks contained antigen-specific IgA and IgG, and splenocytes produced interferon-gamma and interleukin 17A. Lamina propria, bronchial, and vaginal samples contained antigen-specific IgA after the ovalbumin boost. This immunization regimen prevented development of diarrhea after injection of cholera toxin, and inhibited lung colonization by S pneumoniae. In gnotobiotic mice colonized with C ramosum and placed on a high-fat diet, the mice that had been immunized with C ramosum became less obese than the nonimmunized mice. Conclusions Injection of mice with microbial antigens and adjuvant induces antigen-specific mucosal and systemic immune responses. Immunization with S pneumoniae antigen prevented lung infection by this bacteria, and immunization with C ramosum reduced obesity in mice colonized with this microbe and placed on a high-fat diet. This immunization approach might be used to protect against microbe-associated disorders of intestine.

Purpose: Image-guided cryotherapy of renal cancer is an emerging alternative to surgical nephrectomy, particularly for those who cannot sustain the physical burden of surgery. It is well known that the outcome of this therapy depends on the accurate placement of the cryotherapy probe. Therefore, a robotic instrument guide may help physicians aim the cryotherapy probe precisely to maximize the efficacy of the treatment and avoid damage to critical surrounding structures. The objective of this paper was to propose a robotic instrument guide for orienting cryotherapy probes in image-guided cryotherapy of renal cancers. The authors propose a body-mounted robotic guide that is expected to be less susceptible to guidance errors caused by the patient’s whole body motion. Methods: Keeping the device’s minimal footprint in mind, the authors developed and validated a body-mounted, robotic instrument guide that can maintain the geometrical relationship between the device and the patient’s body, even in the presence of the patient’s frequent body motions. The guide can orient the cryotherapy probe with the skin incision point as the remote-center-of-motion. The authors’ validation studies included an evaluation of the mechanical accuracy and position repeatability of the robotic instrument guide. The authors also performed a mock MRI-guided cryotherapy procedure with a phantom to compare the advantage of robotically assisted probe replacements over a free-hand approach, by introducing organmotions to investigate their effects on the accurate placement of the cryotherapy probe. Measurements collected for performance analysis included accuracy and time taken for probe placements. Multivariate analysis was performed to assess if either or both organmotion and the robotic guide impacted these measurements. Results: The mechanical accuracy and position repeatability of the probe placement using the robotic instrument guide were 0.3 and 0.1 mm, respectively, at a depth of 80 mm. The phantom test indicated that the accuracy of probe placement was significantly better with the robotic instrument guide (4.1 mm) than without the guide (6.3 mm, p

The purpose of this study is to determine whether or not opioid administration influenced the survival time of patients with advanced lung cancer in an acute care hospital setting. This was a single institutional and retrospective study. We reviewed patients with advanced lung cancer who had died from January 2008 to December 2013 at the Osaka Police Hospital. We compared survival times, calculated from the time of the last hospitalization or the last chemotherapy, between patients who had not used any opioids, those who had used a low dose of opioids (

In this report, we report on the features of the structure and construction, of an RC viaduct on JR Joban Line that suffered damage from The Tohoku-pacific Ocean Earthquake. The Tohoku-pacific Ocean Earthquake, occurring on March 11, 2011, caused widespread tsunami damage along the coast of the Tohoku region in Japan. The Joban Line of The East Japan Railway Company, running near the shoreline, suffered serious damage. We planned to shift the service route of the Joban Line as part of a city restoration and construction plan. The RC viaduct length is about 6.3 km, while the total length of the restored section is 14.6 km. Basic viaduct type is rigid-frame RC viaduct of reinforced concrete beam-slab type without the underground girders and a clear span of 20 m. We optimized clear spans, use of underground girders, etc., according to geotechnical conditions.

The study of mycobiota remains relatively unexplored due to the lack of sufficient available reference strains and databases compared to those for bacterial microbiome studies. Deep sequencing of Internal Transcribed Spacer (ITS) regions is the de facto standard for fungal diversity analysis. However, results are often biased because of the wide variety of sequence lengths in the ITS regions and the complexity of high-throughput sequencing (HTS) technologies. In this study, a curated ITS database, ntF-ITS1, was constructed. This database can be utilized for the taxonomic assignment of fungal community members. We evaluated the efficacy of strategies for mycobiome analysis by using this database and characterizing a mock fungal community consisting of 26 species representing 15 genera using ITS1 sequencing with three HTS platforms: Illumina MiSeq (MiSeq), Ion Torrent Personal Genome Machine (IonPGM), and Pacific Biosciences (PacBio). Our evaluation demonstrated that PacBio’s circular consensus sequencing with greater than 8 full-passes most accurately reconstructed the composition of the mock community. Using this strategy for deep-sequencing analysis of the gut mycobiota in healthy Japanese individuals revealed two major mycobiota types: a single-species type composed of Candida albicans or Saccharomyces cerevisiae and a multi-species type. In this study, we proposed the best possible processing strategies for the three sequencing platforms, of which, the PacBio platform allowed for the most accurate estimation of the fungal community. The database and methodology described here provide critical tools for the emerging field of mycobiome studies.

As glucose-dependent insulinotropic polypeptide (GIP) possesses pro-adipogenic action, the suppression of the GIP hypersecretion seen in obesity might represent a novel therapeutic approach to the treatment of obesity. However, the mechanism of GIP hypersecretion remains largely unknown. In the present study, we investigated GIP secretion in two mouse models of obesity: High-fat diet-induced obese (DIO) mice and leptin-deficient Lepob/ob mice. In DIO mice, plasma GIP was increased along with an increase in GIP mRNA expression in the lower small intestine. Despite the robust alteration in the gut microbiome in DIO mice, co-administration of maltose and the &alpha, glucosidase inhibitor (&alpha, GI) miglitol induced the microbiome-mediated suppression of GIP secretion. The plasma GIP levels of Lepob/ob mice were also elevated and were suppressed by fat transplantation. The GIP mRNA expression in fat tissue was not increased in Lepob/ob mice, while the expression of an interleukin-1 receptor antagonist (IL-1Ra) was increased. Fat transplantation suppressed the expression of IL-1Ra. The plasma IL-1Ra levels were positively correlated with the plasma GIP levels. Accordingly, although circulating GIP levels are increased in both DIO and Lepob/ob mice, the underlying mechanisms differ, and the anti-obesity actions of &alpha, GIs and leptin sensitizers may be mediated partly by the suppression of GIP secretion.

The aim of the study was to compare timing and decision-makers of do-not-resuscitate (DNR) orders between patients with end-stage thoracic cancer and non-cancer respiratory diseases in a Japanese acute care hospital. This study retrospectively reviewed the medical records of patients who died between January 2008 and March 2013 in the Department of Respiratory Medicine of Osaka Police Hospital, a teaching and acute care hospital. We compared the decision-making process, especially timing and decision-maker, of DNR orders between patients with thoracic cancer and patients with non-cancer respiratory diseases. There were 300 cancer patients and 147 non-cancer patients. Cancer patients were significantly younger, were hospitalized more frequently and for longer, were more likely to have a DNR order placed earlier and decided in advance of last admission, and were more likely to have normal cognitive function at the time of the DNR order than non-cancer patients. Spouses of cancer patients were more likely to participate in DNR discussion. Only approximately 6 % of patients participated in DNR discussion in both groups. Cancer patients less frequently received aggressive treatment at the end of life (EOL) and were more likely to die in general wards than in intensive care units. Our study found that most Japanese patients, with or without cancer, who died in an acute care respiratory department, were not included in DNR discussions and that familial surrogates usually made the DNR decision at the EOL.

Extracellular adenosine 5'-triphosphate (ATP) performs multiple functions including activation and induction of apoptosis of many cell types. The ATP-hydrolyzing ectoenzyme ecto-nucleotide pyrophosphatase/phosphodiesterase 3 (E-NPP3) regulates ATP-dependent chronic allergic responses by mast cells and basophils. However, E-NPP3 is also highly expressed on epithelial cells of the small intestine. In this study, we showed that E-NPP3 controls plasmacytoid dendritic cell (pDC) numbers in the intestine through regulation of intestinal extracellular ATP. In Enpp3-/- mice, ATP concentrations were increased in the intestinal lumen. pDC numbers were remarkably decreased in the small intestinal lamina propria and Peyer's patches. Intestinal pDCs of Enpp3-/- mice showed enhanced cell death as characterized by increases in annexin V binding and expression of cleaved caspase-3. pDCs were highly sensitive to ATP-induced cell death compared with conventional DCs. ATP-induced cell death was abrogated in P2rx7-/- pDCs. Accordingly, the number of intestinal pDCs was restored in Enpp3-/- P2rx7-/- mice. These findings demonstrate that E-NPP3 regulates ATP concentration and thereby prevents the decrease of pDCs in the small intestine.

The innate immune system provides the first line of host defense against invading pathogens. Innate immune responses are initiated by germline-encoded PRR, which recognize specific structures expressed by microorganisms. TLR are a family of PRR which sense a wide range of microorganisms, including bacteria, fungi, protozoa and viruses. TLR are also expressed in the intestine and are critical for intestinal homeostasis. Recently, cytoplasmic PRR, such as NLR and RLR, have been shown to detect pathogens that have invaded the cytosol. One of the NLR, NOD2, is thought to be involved in the pathogenesis of Crohn's disease. This review focuses on the innate immune responses triggered by PRR in the intestine.

Pyrolysis of Douglas fir with metal compounds has been carried out to examine the effect of metal compounds on the pyrolysis profiles. The profiles dramatically shifted into lower or higher temperatures by adding some metal compounds. On the other hand, the presence of metal chlorides promoted the decomposition of Douglas fir at low temperature. The metal compounds having high hydrophilicity, by which Douglas fir decomposition was shifted toward lower temperatures, caused an increase in char and a decrease in tar through promoting the cross-linking reaction at low temperature. From these results, it can be said that the control of dehydration at low temperature is an essential factor to achieve high char yield with minimizing tar formation.

Pyrolysis of NaOH-loaded Douglas fir and cellulose has been carried out to determine the effect of sodium hydroxide on the pyrolysis profile. A tar yield of 0 wt% and the char yield of 32 wt% were obtained at a final pyrolysis temperature of 500°C. It was revealed that the amount of hydroxyl groups in the residue significantly decreased at 200°C and that the structure of cellulose was distorted via cross-linking at the same temperature through spectroscopic analyses and diffraction patterns. The cross-linking led to the increase in char yield at 500°C. A detailed analysis showed that char yield from cellulose at 500°C correlated linearly with the degree of cross-linking calculated from the amount of dehydration at 200°C. These results showed a possibility that the pyrolysis profile of biomass may be controlled through an appropriate pretreatment to change the structure of the intermediate.

Clowse et al 1 have reported minimal to no transfer of certolizumab pegol (CZP) into breast milk, and their findings have supported the continuation of CZP treatment during breast milk feeding. Rheumatoid arthritis (RA) often develops in women of childbearing age. It is generally difficult to treat these patients with methotrexate, which is the anchor drug for RA. Therefore, biologics, such as tumour necrosis factor (TNF) inhibitors, are often considered for active RA during pregnancy. However, the biologics cross the placenta from mother to fetus and transfer into breast milk during lactation. Although a meta-analysis report indicated that anti-TNF-α therapy did not increase the risks, such as congenital malformation or abortion during pregnancy, in patients with inflammatory …

Pedestrians have difficulty noticing hybrid vehicles (HVs) and electrical vehicles (EVs) quietly approaching from behind. We propose a vehicle detection scheme using a smartphone carried by a pedestrian. A notification of a vehicle approaching can be delivered to wearable devices such as Google Glass. We exploit the high-frequency switching noise generated by the motor unit in HVs and EVs. Although people are less sensitive to these high-frequency ranges, these sounds are prominent even on a busy street, and it is possible for a smartphone to detect these signals. The ambient sound captured at 48 kHz is converted to a feature vector in the frequency domain. A J48 classifier implemented on a smartphone can determine whether an EV or HV is approaching. We have collected a large amount of vehicle data at various locations. The false-positive and false-negative rates of our detection scheme are 1.2% and 4.95%, respectively. The first alarm was detected as early as 11.6 s before the vehicle approached the observer. The scheme can also determine the vehicle speed and vehicle type.

Carrier injection rate in tunnel injection quantum well structures used in semiconductor lasers was investigated through theoretical analysis. Carrier capture time from 3D-state to 2D-state in a conventional quantum well was several ten picoseconds and it is almost uncontrollable characteristics. The tunnel injection structure can be designed to control the carrier injection rate. The carrier transition time from carrier reservoir-region of the tunnel injection structure to the active well was a few picoseconds when the structure was designed for high speed transition. As results, carrier injection to ground state of the active well takes less than 10 picoseconds. The change of the radiative recombination rate in the active well also defines the optimal design of the tunnel injection structure. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

The innate immune system provides the first line of host defense against invading pathogens. Innate immune responses are initiated by germline-encoded PRR, which recognize specific structures expressed by microorganisms. TLR are a family of PRR which sense a wide range of microorganisms, including bacteria, fungi, protozoa and viruses. TLR are also expressed in the intestine and are critical for intestinal homeostasis. Recently, cytoplasmic PRR, such as NLR and RLR, have been shown to detect pathogens that have invaded the cytosol. One of the NLR, NOD2, is thought to be involved in the pathogenesis of Crohn's disease. This review focuses on the innate immune responses triggered by PRR in the intestine.

Aiming at developing a methodology for constructing continuous-time chaotic dynamical systems as flexible pattern generators, this paper discusses a strategy for binding desired unstable periodic orbits into a chaotic attractor. The strategy is comprised of the following two stages: constructing an interim “chaos-generating template”, and deforming the template according to the specifically desired orbits. INTRODUCTION Chaos is a fascinating phenomenon arising from nonlinearities in dynamical systems, and investigations on its applications to intelligent and flexible systems have appeared in many fields. An important aspect of chaos is that chaotic attractors embed or “host” an infinite number of unstable periodic orbits (UPO’s) bifurcated from prechaotic states (Ott, 2002). Among them, some distinctive orbits can be used for characterization or control purposes. For example, a variety of chaos control methods (Ott et al., 1990; Pyragas, 1992; Zhang et al., 2009) can stabilize UPO’s embedded in chaotic attractors, enlarging the operation range and/or enhancing the functionality of the system. In more recent years, the synthesis of chaos from various approaches (Chen and Ueta, 2002; Zelinka et al., 2008; Munoz-Pacheco and Tlelo-Cuautle, 2009) has been an active direction of research along the line of exploiting chaos. Primary concerns of these efforts include statistical and topological characteristics (e.g., invariant measure, Lyapunov spectrum, novel scrolling behaviors) that would be important in designing chaos-based information processing and communication applications. While the present study share some common motivation with the above-mentioned studies, we have put more focus on the geometrical shape and dynamical properties of UPO’s themselves from the viewpoint of the adaptive generation of periodic behaviors. Here our intention lies in extending the functionality of (stable) periodic pattern generators based on function approximation of vector fields, e.g., polynomial approximation (Okada and Nakamura, 2002) and neural network learning (Kuroe and Miura, 2006). In this paper, we consider continuous-time chaotic attractors as a container of UPO’s (patterns) where they can be stabilized, entrained, or targeted by external inputs into the dynamical system. In what follows, we propose a design strategy for binding desired UPO’s into a chaotic attractor governed by a polynomial vector field. The strategy is comprised of the following two stages: constructing an interim “chaos-generating template”, and deforming the template according to the specifically desired orbits. POLYNOMIAL VECTOR FIELDS We consider polynomial dynamical systems of the form ẋ = f(x)(x ∈ R ) where the vector field f(x) is represented as f(x) = [f1(x) · · · fN (x)] T = Φ(a(p1p2···pN ))θ(x), (1) θ(x) = [x1 · · · x ` N x `−1 1 x2 · · · 1] T . (2) Here, ` denotes the maximum degree of the polynomials, and the matrix Φ is comprised of the coefficients a(p1p2···pN ) of the polynomials. For example, with 3rdorder polynomials, the first element of a two-dimensional vector field is represented as f1(x) = a1(30)x 3 1 + a1(21)x 2 1x2 + a1(12)x1x 2 2 + a1(03)x 3 2 + a1(20)x 2 1 + a1(11)x1x2 + a1(02)x 2 2 + a1(10)x1 + a1(01)x2 + a1(00).(3) In our design process of the dynamical system, the coefficients are obtained by least-square fitting. To this end, we set up target vectors f(ηi) (i = 1, 2, · · · , L) at design points ηi on and in the vicinity of the target orbits, and construct matrices F = [f(η1) f(η2) · · · f(ηL)], (4) Θ = [θ(η1) θ(η2) · · · θ(ηL)]. (5) With these matrices, the least-square solution for Φ is given by Φ(a(p1 p2 ··· pN )) = FΘ # (6) where Θ is the Moore-Penrose pseudo inverse of Θ. Proceedings 24th European Conference on Modelling and Simulation ©ECMS Andrzej Bargiela, Sayed Azam Ali David Crowley, Eugene J.H. Kerckhoffs (Editors) ISBN: 978-0-9564944-0-5 / ISBN: 978-0-9564944-1-2 (CD)

We propose a SOA with a tunnel injection structure and analyze the operation properties. High-speed carrier recovery was suggested in the tunnel-injection SOA. The results indicate tunnel-injection SOAs have a potential of high-speed operation.