Search

Multiparameter screening of reductive carboxylation in an electrochemical flow microreactor was performed using a Bayesian optimization (BO) strategy. The developed algorithm features a constraint on passed charge for the electrochemical reaction, which led to suitable conditions being instantaneously found for the desired reaction. Analysis of the BO-suggested conditions underscored the physicochemical validity.

The synthesis of α-amino acids was carried out in a continuous flow system. In this system, aldimines were efficiently generated in situ via the dehydration-condensation of aldehydes with anilines in a desiccant bed column filled with 4 A molecular sieves desiccant, followed by reaction with CO2 in an electrochemical flow microreactor to afford the α-amino acids in high to moderate yields. The present system can provide α-amino acids without using stoichiometric amounts of metal reagents or highly toxic cyanide reagents.

Motivation Understanding life cannot be accomplished without making full use of biological data, which are scattered across databases of diverse categories in life sciences. To connect such data seamlessly, identifier (ID) conversion plays a key role. However, existing ID conversion services have disadvantages, such as covering only a limited range of biological categories of databases, not keeping up with the updates of the original databases and outputs being hard to interpret in the context of biological relations, especially when converting IDs in multiple steps. Results TogoID is an ID conversion service implementing unique features with an intuitive web interface and an application programming interface (API) for programmatic access. TogoID currently supports 65 datasets covering various biological categories. TogoID users can perform exploratory multistep conversions to find a path among IDs. To guide the interpretation of biological meanings in the conversions, we crafted an ontology that defines the semantics of the dataset relations. Availability and implementation The TogoID service is freely available on the TogoID website (https://togoid.dbcls.jp/) and the API is also provided to allow programmatic access. To encourage developers to add new dataset pairs, the system stores the configurations of pairs at the GitHub repository (https://github.com/togoid/togoid-config) and accepts the request of additional pairs. Supplementary information Supplementary data are available at Bioinformatics online.

Hypercapnia occurs in ventilated infants even if tidal volume (VT) and minute ventilation (VE) are maintained. We hypothesised that increased physiological dead space (Vd,phys) caused decreased minute alveolar ventilation (VA; alveolar ventilation (VA) × respiratory rate) in well-ventilated infants with hypercapnia. We investigated the relationship between dead space and partial pressure of carbon dioxide (PaCO2) and assessed VA. Intubated infants (n = 33; mean birth weight, 2257 ± 641 g; mean gestational age, 35.0 ± 3.3 weeks) were enrolled. We performed volumetric capnography (Vcap), and calculated Vd,phys and VA when arterial blood sampling was necessary. PaCO2 was positively correlated with alveolar dead space (Vd,alv) (r = 0.54, p < 0.001) and Vd,phys (r = 0.48, p < 0.001), but not Fowler dead space (r = 0.14, p = 0.12). Normocapnia (82 measurements; 35 mmHg ≤ PaCO2 < 45 mmHg) and hypercapnia groups (57 measurements; 45 mmHg ≤ PaCO2) were classified. The hypercapnia group had higher Vd,phys (median 0.57 (IQR, 0.44-0.67)) than the normocapnia group (median Vd,phys/VT = 0.46 (IQR, 0.37-0.58)], with no difference in VT. The hypercapnia group had lower VA (123 (IQR, 87-166) ml/kg/min) than the normocapnia group (151 (IQR, 115-180) ml/kg/min), with no difference in VE.Conclusion: Reduction of VA in well-ventilated neonates induces hypercapnia, caused by an increase in Vd,phys. What is Known: • Volumetric capnography based on ventilator graphics and capnograms is a useful tool in determining physiological dead space of ventilated infants and investigating the cause of hypercapnia. What is New: • This study adds evidence that reduction in minute alveolar ventilation causes hypercapnia in ventilated neonates.

The recent development of ecological studies has been fueled by the introduction of massive information based on chromosome-scale genome sequences, even for species for which genetic linkage is not accessible. This was enabled mainly by the application of Hi-C, a method for genome-wide chromosome conformation capture that was originally developed for investigating the long-range interaction of chromatins. Performing genomic scaffolding using Hi-C data is highly resource-demanding and employs elaborate laboratory steps for sample preparation. It starts with building a primary genome sequence assembly as an input, which is followed by computation for genome scaffolding using Hi-C data, requiring careful validation. This article presents technical considerations for obtaining optimal Hi-C scaffolding results and provides a test case of its application to a reptile species, the Madagascar ground gecko (Paroedura picta). Among the metrics that are frequently used for evaluating scaffolding results, we investigate the validity of the completeness assessment of chromosome-scale genome assemblies using single-copy reference orthologs, and report problems of the widely used program pipeline BUSCO.

The synthesis of α-amino acids was carried out in a continuous flow system. In this system, aldimines were efficiently generated

Antisense oligonucleotide (ASO) has the potential to induce off‐target effects due to complementary binding between the ASO and unintended RNA with a sequence similar to the target RNA. Conventional animal studies cannot be used to assess toxicity induced by off‐target effects because of differences in the genome sequence between humans and other animals. Consequently, the assessment of off‐target effects with in silico analysis using a human RNA database and/or in vitro expression analysis using human cells has been proposed. Our previous study showed that the number of complementary regions of ASOs with mismatches in the human RNA sequences increases dramatically as the number of tolerated mismatches increases. However, to what extent the expression of genes with mismatches is affected by off‐target effects at the cellular level is not clear. In this study, we evaluated off‐target effects of gapmer ASOs, which cleave the target RNA in an RNase H‐dependent manner, by introducing the ASO into human cells and performing microarray analysis. Our data indicate that gapmer ASOs induce off‐target effects depending on the degree of complementarity between the ASO and off‐target candidate genes. Based on our results, we also propose a scheme for the assessment of off‐target effects of gapmer ASOs., We showed that gapmer oligonucleotide (ASO) induce off‐target effects depending on the degree of complementarity between the ASO and off‐target candidate genes. Based on our results, we also proposed a scheme for the assessment of off‐target effects of gapmer ASOs.

Background: We conducted active surveillance to elucidate the distribution of Streptococcus pneumoniae serotypes causing invasive pneumococcal disease (IPD) and clarified the genetic relatedness among the isolates in Kobe City, Japan. Methods: Forty-five IPD-causing S. pneumoniae strains were analyzed from March 2016 to May 2018 through active surveillance in Kobe City, Hyogo, Japan. Serotypes were determined by multiplex serotyping PCR and the Quellung reaction with pneumococcal antisera. Fourteen Sp12F strains were subjected to whole-genome sequencing (WGS). Results: Among 45 isolates, the most frequent serotypes were 12F (n = 14, 31%), 24F (n = 5, 11%), and 10A (n = 4, 9%). Multilocus sequence typing (MLST) analysis of 14 isolates of Sp12F divided them into ST4846 (n = 4) and ST6495 (n = 10). WGS showed clonality of the 10 isolates of ST6495, with only 13 single nucleotide polymorphisms in the genomes. Meanwhile, ST4846 strains in Kobe differed from only the outbreak strains of Sp12F ST4846 in Tsuruoka, Japan, reported on 2018. Conclusions: Serotype monitoring showed Sp12F to be the predominant serotype in Kobe, and WGS revealed the clonal spread of Sp12F ST6495 in this city. Thus, the spread of Sp12F could become a serious public health problem in Japan, warranting thorough monitoring in future. Keywords: Streptococcus pneumoniae, Serotype, Sp12F, Whole-genome sequencing, Single nucleotide polymorphism

Aim Intentional or unintentional acute drug poisoning occurs even in elderly people, but little is known about the factors influencing the intention to poisoning. A retrospective study was undertaken to describe the characteristics of acute drug poisoning in elderly people according to whether the poisoning was intentional or unintentional and the responsible agents. Methods The study was carried out in a single tertiary hospital in Japan. A total of 145 patients aged ≥65 years who were transferred by an ambulance service and were diagnosed with acute drug poisoning were included. Medical records were used to collect information on the intention behind poisoning and the responsible agents. Patients were divided into two groups according to whether they experienced intentional or unintentional poisoning and were further classified according to the responsible agent. Multivariable logistic regression models were used to estimate the association between hospitalization for acute drug poisoning and the use of benzodiazepine receptor agonists (BzRAs). Results Poisoning was unintentional in 102 (70.3%) patients and intentional in 43 (29.7%) patients. In total, 65 (44.8%) patients required hospitalization. Among patients in the unintentional poisoning group, those using non-BzRAs were more likely to be hospitalized than those using BzRAs (odds ratio, 6.64; 95% confidence interval, 2.56-17.22). The length of hospital stay was significantly longer in the unintentional poisoning group than in the intentional poisoning group (13.9 vs. 6.2 days; P = 0.013). Conclusions The proportion of unintentional poisoning in the elderly is high, and particularly with respect to poisoning with non-BzRAs, the hospitalization rates are high.

The risk of serious complication gradually increases as diabetes mellitus (DM) progresses. Thus, strategies for the prevention and delay of symptom progression are urgently needed. Previously, we synthesized zinc (Zn) complexes estimated to have a high bioavailability and evaluated their insulin-like anti-DM effects. However, in vivo studies of the effects of Zn compounds on the insulin signaling pathway and the molecular mechanisms underlying the anti-diabetic activities of Zn complexes were unresolved. In this study, we evaluated the effect of bis(maltolato)zinc(II) complex [Zn(mal)2] on male ICR mice (6-week-old) that received intraperitoneal (i.p.) injection of [Zn(mal)2]. The liver, skeletal muscle, and adipose tissues were collected from mice under anesthesia with isoflurane 40 or 90 min after i.p. injection. The [Zn(mal)2]-treatment did not affect Akt phosphorylation in the liver or skeletal muscle. In contrast, in adipose tissues, [Zn(mal)2]-treatment showed increased Akt phosphorylation at 40 min and 90 min after injection (p

Recent development of ecological studies has been fueled by the introduction of massive information based on chromosome-scale genome sequences, even for species whose genetic linkage was previously not accessible. This was enabled mainly by the application of Hi-C, a method for genome-wide chromosome conformation capture which was originally developed for investigating long-range interaction of chromatins. Performing genomic scaffolding using Hi-C data is highly resource-demanding in elaborate laboratory steps for sequencing sample preparation, building primary genome sequence assembly as an input, and computation for genome scaffolding using Hi-C data, followed by careful validation. This article summarizes existing solutions for these steps and provides a test case of its application to a reptile species, the Madagascar ground gecko (Paroedura picta). Among frequently exerted metrics for evaluating scaffolding results, we investigate the validity of completeness assessment using single-copy reference orthologs and report problems with the widely used program pipeline BUSCO.

We report on the activities of the 2015 edition of the BioHackathon, an annual event that brings together researchers and developers from around the world to develop tools and technologies that promote the reusability of biological data. We discuss issues surrounding the representation, publication, integration, mining and reuse of biological data and metadata across a wide range of biomedical data types of relevance for the life sciences, including chemistry, genotypes and phenotypes, orthology and phylogeny, proteomics, genomics, glycomics, and metabolomics. We describe our progress to address ongoing challenges to the reusability and reproducibility of research results, and identify outstanding issues that continue to impede the progress of bioinformatics research. We share our perspective on the state of the art, continued challenges, and goals for future research and development for the life sciences Semantic Web.

Sunitinib has been shown to offer clinical benefits during the treatment of advanced renal cell carcinoma. However, molecular targeting drugs are expensive and can have a significant impact on medical expenses. The purpose of this study was to assess the cost-effectiveness of sunitinib as a first-line therapy compared with interferon-alpha (IFN-α) in metastatic renal cell carcinoma patients. A Markov model was used to show the clinical courses of patients with metastatic renal cell carcinoma who received sunitinib or IFN-α. The transition probabilities and utilities employed in this Markov model were derived from two sources. This study focused on the perspective of public healthcare payer, as only direct medical costs were estimated from the treatment schedule for metastatic renal cell cancer. In the cost-effectiveness analysis, outcomes were valued in terms of life years (LYs) and quality-adjusted life years (QALYs). We calculated the incremental cost-effectiveness ratio (ICER) during the cost-effectiveness analysis. The results were tested using Monte Carlo simulations. Sunitinib and IFN-α treatment resulted in LYs of 2.40 years and 2.03 years, QALYs of 1.58 and 1.25, and expected costs of 13,572,629 yen and 6,083,002 yen, respectively. As a result, the ICER associated with replacing IFN-α with sunitinib was 22,695,839 yen/QALYs. Our results suggest that compared with IFN-α, sunitinib prolongs LYs and QALYs, but the increases in quality achieved by sunitinib are more expensive than those produced by IFN-α.

Although single-component Class 2 CRISPR systems, such as type II Cas9 or type V Cas12a (Cpf1), are widely used for genome editing in eukaryotic cells, the application of multi-component Class 1 CRISPR has been less developed. Here we demonstrate that type I-E CRISPR mediates distinct DNA cleavage activity in human cells. Notably, Cas3, which possesses helicase and nuclease activity, predominantly triggered several thousand base pair deletions upstream of the 5′-ARG protospacer adjacent motif (PAM), without prominent off-target activity. This Cas3-mediated directional and broad DNA degradation can be used to introduce functional gene knockouts and knock-ins. As an example of potential therapeutic applications, we show Cas3-mediated exon-skipping of the Duchenne muscular dystrophy (DMD) gene in patient-induced pluripotent stem cells (iPSCs). These findings broaden our understanding of the Class 1 CRISPR system, which may serve as a unique genome editing tool in eukaryotic cells distinct from the Class 2 CRISPR system., Class 1 CRISPR systems are not as developed for genome editing as Class 2 systems are. Here the authors show that Cas3 can be used to generate functional knockouts and knock-ins, as well as Cas3-mediated exon-skipping in DMD cells.

Pathway complexity in supramolecular polymerization has recently sparked interest as a method to generate complex material behavior. The response of these systems relies on the existence of a metastable, kinetically trapped state. In this work, we show that strong switch-like behavior in supramolecular polymers can also be achieved through the introduction of competing aggregation pathways. This behavior is illustrated with the supramolecular polymerization of a porphyrin-based monomer at various concentrations, solvent compositions, and temperatures. It is found that the monomers aggregate via an isodesmic mechanism in weakly coupled J-type aggregates at intermediate solvent quality and temperature, followed by nucleated H-aggregates at lower solvent qualities and temperatures. At further increased thermodynamic driving forces, such as high concentration and low temperature, the H-aggregates can form hierarchical superhelices. Our mathematical models show that, contrary to a single-pathway polymerization, the existence of the isodesmic aggregation pathway buffers the free monomer pool and renders the nucleation of the H-aggregates insensitive to concentration changes in the limit of high concentrations. We also show that, at a given temperature or solvent quality, the thermodynamically stable aggregate morphology can be selected by controlling the remaining free external parameter. As a result, the judicious application of pathway complexity allows us to synthesize a diverse set of materials from only a single monomer. We envision that the engineering of competing pathways can increase the robustness in a wide variety of supramolecular polymer materials and lead to increasingly versatile applications.

Nitrogen (N) is a major macronutrient that is essential for plant growth. It is important for us to understand the key genes that are involved in the regulation of N utilization. In this study, we focused on a GARP-type transcription factor known as NSR1/MYR2, which has been reported to be induced under N-deficient conditions. Our results demonstrated that NSR1/MYR2 has a transcriptional repression activity and is specifically expressed in vascular tissues, especially in phloem throughout the plant under daily light-dark cycle regulation. The overexpression of NSR1/MYR2 delays nutrient starvation- and dark-triggered senescence in the mature leaves of excised whole aerial parts of Arabidopsis plants. Furthermore, the expression of asparagine synthetase 1 (ASN1), which plays an important role in N remobilization and reallocation, i.e. N reutilization, in Arabidopsis, is negatively regulated by NSR1/MYR2, since the expressions of NSR1/MYR2 and ASN1 were reciprocally regulated during the light-dark cycle and ASN1 expression was down-regulated in overexpressors of NSR1/MYR2 and up-regulated in T-DNA insertion mutants of NSR1/MYR2. Therefore, the present results suggest that NSR1/MYR2 plays a role in N reutilization as a negative regulator through controlling ASN1 expression.

Zinc (Zn) is a trace element with anti-diabetes mellitus (anti-DM) effects. Zn complexes exhibit stronger insulin-like activity than Zn ions. Bis(hinokitiolato)zinc complex ([Zn(hkt)2]) was recently reported to be a potent anti-DM candidate. We examined the effects of [Zn(hkt)2] on insulin resistance and pancreatic islet cells through in vivo long-term ingestion studies. In an in vivo study, we performed 4-month long-term [Zn(hkt)2] administration experiments in KK-Ay mice as a type 2 DM animal model. Ingestion of [Zn(hkt)2] resulted in lower blood glucose levels compared with the non-treated KK-Ay mice (control group). Additionally, [Zn(hkt)2] treatment decreased plasma insulin concentration compared with that of the non-treated KK-Ay group. [Zn(hkt)2] treatment resulted in a significant suppression of islet cell enlargement and a significantly decreased number of insulin-positive cells compared with the non-treated KK-Ay control group. The [Zn(hkt)2] treatment group showed the increasing tendency in the amount of Zn levels in peripheral organs; liver, muscle, adipose, and pancreas, compared with the non-treated KK-Ay control group. However, the Zn level in the pancreas of the [Zn(hkt)2] treatment group did not show the significant increase compared with the non-treated KK-Ay control group. This accumulation of Zn in pancreas suggested that [Zn(hkt)2] mainly effects on the peripheral tissue, and [Zn(hkt)2] has the less effect on the pancreas directly. Thus, we concluded that [Zn(hkt)2] exerted the main effect on peripheral organs by ameliorating insulin resistance.

In the present study, we investigated the effects of exercise intended to prevent or treat lifestyle-related diseases on the glucose tolerance, insulin level, lactic acid utilization, muscle glycogen synthesis, hepatic and renal oxidative stress, hepatic selenoprotein P and biological trace element levels in organs of obese, glucose-intolerant rats. We fed normal, healthy rats a 20% casein diet while the glucose-intolerant, obese rats received a high-fructose diet. They were forced to run for one hour per day, six days per week, for ten weeks. Exercise reduced visceral fat and ameliorated glucose tolerance in the high-fructose group, lowered blood lactic acid levels, improved lactic acid usage efficiency, and increased oxidative stress and hepatic levels of Mn, Fe, Cu, and Zn in the normal and high-fructose groups. Additionally, exercise significantly upregulated hepatic selenoprotein P expression in both groups, however, its effect was remarkable in healthy group. On the other hand, muscle glycogen synthesis was not markedly enhanced in high-fructose-diet rats but in normal-diet rats in response to exercise. It is concluded that exercise conditions rather than exercise load must be customized and optimized for each health and disease states in advance before starting exercise training intended to prevent or treat lifestyle-related diseases.

A 14-year-old girl was referred to our department because of headache and visual impairment following the resection of recurrent cardiac myxoma. Head magnetic resonance imaging (MRI) scan detected an intra- and supra-sellar tumor. Moreover, the patient showed the presence of spotty skin pigmentations on her cheeks and lower lip. Blood examination revealed hypothyrotropinemia, and ultrasonography results revealed multiple thyroid nodules. She was diagnosed with Carney complex (CNC). Her pituitary tumor was suspected as growth hormone (GH)-secreting adenoma, because overgrowth was observed in the patient. However, biochemical examinations, including oral glucose tolerance test, failed to show the characteristic findings of GH-secreting adenoma. In contrast, insulin tolerance test showed GH deficiency. Her visual impairment improved without performing decompression surgery, and the tumor size decreased, as per the MRI findings. Based on clinical course, the patient was diagnosed with pituitary apoplexy in pituitary adenoma, following which she was discharged. At 3 months after discharge, thyrotropin-releasing hormone loading test performed revealed low thyrotropin-stimulating hormone and thyroid hormone levels, and the patient was in a depressed mood. Therefore, l-T4 replacement was initiated, following which her GH secretory capacity gradually improved. Here, we report, to the best of our knowledge, the first case of a patient with pituitary apoplexy in CNC. Such condition must be identified in young patients with recurrent cardiac myxoma, and examinations, such as head MRI, must be performed.

TogoGenome is a genome database that is purely based on the Semantic Web technology, which enables the integration of heterogeneous data and flexible semantic searches. All the information is stored as Resource Description Framework (RDF) data, and the reporting web pages are generated on the fly using SPARQL Protocol and RDF Query Language (SPARQL) queries. TogoGenome provides a semantic-faceted search system by gene functional annotation, taxonomy, phenotypes and environment based on the relevant ontologies. TogoGenome also serves as an interface to conduct semantic comparative genomics by which a user can observe pan-organism or organism-specific genes based on the functional aspect of gene annotations and the combinations of organisms from different taxa. The TogoGenome database exhibits a modularized structure, and each module in the report pages is separately served as TogoStanza, which is a generic framework for rendering an information block as IFRAME/Web Components, which can, unlike several other monolithic databases, also be reused to construct other databases. TogoGenome and TogoStanza have been under development since 2012 and are freely available along with their source codes on the GitHub repositories at https://github.com/togogenome/ and https://github.com/togostanza/, respectively, under the MIT license.

Objective Constipation negatively affects the quality of life by causing abdominal pain and distention. It is common among women and older individuals and frequently encountered in Japan. Coffee and soda ingestion promote gastrointestinal motility; therefore, both liquids are considered effective for alleviating constipation. While invasive approaches or large-scale equipment, such as magnetic resonance imaging and radiography, are needed to confirm their effect on gastrointestinal motility, bowel sound (BS) assessment can be easily and non-invasively performed using low-cost equipment. Differently to coffee, soda contains carbon dioxide and its ingestion may therefore increase gastrointestinal gas and in turn affect the BS generation process. However, the relationship between gastrointestinal gas and acoustic BS features has not yet been investigated. This study aimed to investigate the effect of increased gastrointestinal gas resulting from soda ingestion on the acoustic BS features extracted using a newly improved BS detection technique. Methods We used BS-based acoustic features, including number of BSs detected/min, BS length, and BS power, extracted via an artificial neural network-based BS detection approach, which was developed in a previous study and here improved. Results BSs detected/min and BS length significantly increased after, compared with before, coffee and soda intake. Furthermore, we found that longer BSs (>128 ms) were more significantly associated with soda (200 mL) intake than with coffee (200 mL) intake. Conclusions BS length and BSs detected/min can sensitively evaluate gastrointestinal motility, and BS length may reflect information on gastrointestinal gas in addition to gastrointestinal motility. Recording of BS-based acoustic features is a non-invasive and convenient means to evaluate the effects of liquid intake on gastrointestinal motility in patients with functional gastrointestinal disorders.

Identification of the factors involved in the regulation of senescence and the analysis of their function are important for both a biological understanding of the senescence mechanism and the improvement of agricultural productivity. In this study, we identified an ERF gene termed "ERF gene conferring Postharvest longevity Improvement 1" (EPI1) as a possible regulator of senescence in Arabidopsis. We found that EPI1 possesses transcriptional repression activity and that the transgenic plants overexpressing EPI1 and expressing its chimeric repressor, EPI1-SRDX, commonly suppressed the darkness-induced senescence in their excised aerial parts. These transgenic plants additionally maintained a high level of chlorophyll, even after the methyl jasmonate (MeJA) treatment, which stimulated senescence in the dark. In addition, we found that senescence-induced and -reduced genes are down- and upregulated, respectively, in the MeJA-treated transgenic plants under darkness. Our results suggest that EPI1 functions as a negative regulator of the dark-induced and JA-stimulated senescence.

α-Amino acids and their derivatives are important and essential resources for human life such as foods, medical drugs, cosmetics and so on. The classical Strecker α-amino acids synthesis is a longstanding method although this classical method requires highly toxic cyanide reagents as the carbon source and these regents are unfavorable from the viewpoint of green chemistry. Carbon dioxide, on the other hand, would also be an abundant and favorable carbon source. There are several examples of synthesis of α-amino acids by direct carboxylation of imines with carbon dioxide. Because of chemical stability of carbon dioxide, this direct carboxylation requires stoichiometric quantities of hard to handle reagents such as magnesium metal and organotins under severe or harsh reaction conditions. In this context, electrochemical carboxylation represents an attractive alternative to conventional chemical carboxylation methods because it is possible to readily generate highly reactive carbon nucleophiles that immediately react with carbon dioxide without handling sensitive, expensive, and toxic reagent. However, metal ions derived from sacrificial anode such as magnesium and aluminium anodes are generally required to stabilize the unstable carboxylate ions. A flow microreactor enables fast generation and consumption of the unstable species. Therefore, it is attractive reaction system for electrochemical carboxylation involving unstable carboxylate ions without sacrificial anodes. Moreover, the electrochemical synthesis with a flow microreactor offers operational advantages over batch processes. Under these backgrounds, we have demonstrated the electrochemical carboxylation of in situ generated imines in a continuous flow system. The present method enables an efficient synthesis for N-phenylphenylglycine derivatives using easily available aldehydes, amines, and CO2 without the use of toxic metal reagents and sacrificial anode. As shown in Figure 1, the imine was smoothly generated from aldehyde and amine by dehydration using MS4A desiccant in a flow operation, and then reacted with carbon dioxide in the electrochemical flow microreactor to afford N-phenylphenylglycine derivatives with high to moderate yields. Figure 1

Gridded ion thrusters are one of the most commonly used types of electric propulsion, and alternative propellants have been studied for miniature ion thrusters to meet the demand of propulsion systems for micro-/nano-satellites. Water is a candidate as an alternative non-pressurized propellant for a CubeSat thruster. It is consistent with the CubeSat concept of short-term and low-cost development. In this paper, the characteristics of a miniature water ion thruster were compared with those of a xenon one using a global model and experiments. The dependence of the performance on the mass flow rate and the input microwave power was examined, and the effects of dissociation and doubly charged ions were directly measured by a quadrupole mass spectrometer. The estimates on the model were compared against experimental results for both propellants, and the performance of the thruster operating on xenon propellant was compared to the performance operating on water propellant. In the comparison between the estimates and the experimental results, the two differences were discussed: the one between water and xenon and the other from the experimental result in both cases. A performance decrease in the propellant utilization efficiency and the specific impulse cannot be avoided when using water as a propellant in an ion thruster. However, the ion production cost did not increase, and it showed the capability of water ion thruster for CubeSat application taking advantage of safety, low cost, non-pressurized system, and human-friendliness of water when used as a propellant.

Sunitinib has been shown to offer clinical benefits during the treatment of advanced renal cell carcinoma. However, molecular targeting drugs are expensive and can have a significant impact on medical expenses. The purpose of this study was to assess the cost-effectiveness of sunitinib as a first-line therapy compared with interferon-alpha (IFN-α) in metastatic renal cell carcinoma patients. A Markov model was used to show the clinical courses of patients with metastatic renal cell carcinoma who received sunitinib or IFN-α. The transition probabilities and utilities employed in this Markov model were derived from two sources. This study focused on the perspective of public healthcare payer, as only direct medical costs were estimated from the treatment schedule for metastatic renal cell cancer. In the cost-effectiveness analysis, outcomes were valued in terms of life years (LYs) and quality-adjusted life years (QALYs). We calculated the incremental cost-effectiveness ratio (ICER) during the cost-effectiveness analysis. The results were tested using Monte Carlo simulations. Sunitinib and IFN-α treatment resulted in LYs of 2.40 years and 2.03 years, QALYs of 1.58 and 1.25, and expected costs of 13,572,629 yen and 6,083,002 yen, respectively. As a result, the ICER associated with replacing IFN-α with sunitinib was 22,695,839 yen/QALYs. Our results suggest that compared with IFN-α, sunitinib prolongs LYs and QALYs, but the increases in quality achieved by sunitinib are more expensive than those produced by IFN-α.

We study a geometric kind of asymptotic behaviour of every C 1 solution of a class of nonautonomous systems of half-linear differential equations with continuous coefficients. We give necessary and sufficient conditions such that the image of every solution (solution curve) has finite length (rectifiable curve) and infinite length (nonrectifiable, possible fractal curve). A particular attention is paid to systems having attractive zero solution. The main results are proved by using a new result for the nonrectifiable plane curves.

Antisense oligonucleotide (ASO) therapeutics are single-stranded oligonucleotides which bind to RNA through sequence-specific Watson-Crick base pairings. A unique mechanism of toxicity for ASOs is hybridization-dependent off-target effects that can potentially occur due to the binding of ASOs to complementary regions of unintended RNAs. To reduce the off-target effects of ASOs, it would be useful to know the approximate number of complementary regions of ASOs, or off-target candidate sites of ASOs, of a given oligonucleotide length and complementarity with their target RNAs. However, the theoretical number of complementary regions with mismatches has not been reported to date. In this study, we estimated the general number of complementary regions of ASOs with mismatches in human mRNA sequences by mathematical calculation and in silico analysis using several thousand hypothetical ASOs. By comparing the theoretical number of complementary regions estimated by mathematical calculation to the actual number obtained by in silico analysis, we found that the number of complementary regions of ASOs could be broadly estimated by the theoretical number calculated mathematically. Our analysis showed that the number of complementary regions increases dramatically as the number of tolerated mismatches increases, highlighting the need for expression analysis of such genes to assess the safety of ASOs.

要旨 【目的】外傷患者に対する病院前輸液が生命予後に与える影響は議論が分かれている。今回我々はショックを呈した外傷症例に対し，病院前輸液が来院時のfibrinogen値に与える影響と，ショックに対する改善効果を検討した。【対象】2010年4月から2014年10月までに当院へ搬送された18歳以上の外傷患者で現場にて出血性ショックであったものを対象とし後方視的に診療録調査を行い，病院前輸液施行群と非輸液群に分けて比較検討した。【結果】91例中，非輸液群が50例，輸液群が41例であった。fibrinogen値が200mg/dL未満となる予測因子を求めて多重ロジスティック回帰分析を施行したところ，病院前輸液の調整オッズ比が3.16（95%信頼区間:1.15–8.68）であった。一方，輸液群においては来院時収縮期血圧が有意に高く（非輸液群100.6±26.2mmHg vs 輸液群113.0±27.1mmHg），Base Deficitが有意に低かった（非輸液群4.4 [1.6–9.3] mmol/L vs 輸液群2.6 [0.6–4.7] mmol/L）。院内死亡率に有意差はなかったが，輸液群で低い傾向があった。【結語】病院前輸液はfibrinogen値を低下させる要因であったが，ショックとそれに伴う代謝性アシドーシスを抑制し，少なくとも生命予後を悪化させなかった。 ABSTRACT Background: The survival effect of prehospital intravenous fluid (IVF) administration for severely injured patients remains controversial. This study focuses on the impact of prehospital IVF on the fibrinogen level on admission to the emergency department and also analyzes the beneficial effect of prehospital IVF for fluid resuscitation in shock. Object and Methods: The medical charts of trauma patients aged 18 years or older who presented to the hospital between April 2010 and October 2014 were retrospectively reviewed; patients with hemorrhagic shock at the scene of arrival were identified and classified into two groups depending on whether or not prehospital IVF was administered. Results: Of the 91 patients who met the inclusion criteria, 41 of them received prehospital IVF and 50 did not. Multiple logistic regression analysis showed that the only prognostic factor for a fibrinogen level lower than 200mg/dL included prehospital IVF with an adjusted odds ratio: 3.16 (95% confidence interval: 1.15–8.68). On the other hand, in the IVF group, systolic blood pressure on arrival was significantly higher (no IVF: 100.6±26.2mmHg vs IVF: 113±27.1mmHg), and base deficit was significantly lower (no IVF: 4.4 [1.6–9.3] mmol/L vs IVF: 2.6 [0.6–4.7] mmol/L). In–hospital mortality of the IVF group was 9.8%, which was slightly lower than the no IVF group (14%), but the difference was not significant. Conclusion: Prehospital IVF decreased fibrinogen level in trauma patients, but it also reduced the metabolic acidosis during hemorrhagic shock and did not worsen survival.

Aims Previous studies reported the anti-diabetic effects of α-lipoic acid (αLA) isomers: racemic-αLA, R-αLA, or S-αLA. Previously, we examined the anti-diabetic effects of αLA administered as a food additive, but were unable to demonstrate the differences among different isomers. In this study, αLAs were complexed with γ-cyclodextrin (γCD) for the stability. We then investigated the anti-diabetic effects of racemic-, R-, and S-αLA/γCDs in KKA y mice. Main methods Male type 2 diabetic KKA y mice were divided into 5 groups, and fed either a high-fat-diet (HFD), HFD supplemented with γCD, or HFD supplemented with racemic-αLA/γCD, R-αLA/γCD, or S-αLA/γCD for 4 weeks. At the end of the feeding period, HbA1c and adiponectin levels were measured, PPARγ2 mRNA expression levels were assessed in adipose tissues using real-time PCR, and AMP-activated protein kinase (AMPK) phosphorylation levels were evaluated in the liver by Western blotting. Key findings The anti-diabetic effects of αLA; the isomeric compounds racemic-, R-, and S-αLA/γCD were investigated using a male type 2 diabetic KKA y mouse model. Significant differences were observed in HbA1c and plasma adiponectin levels between R-αLA/γCD-treated mice and control mice. PPARγ2 mRNA expression levels were slightly higher in racemic- and R-αLA/γCD-treated mice. Moreover, AMPK phosphorylation levels were elevated in racemic-αLA/γCD- and R-αLA/γCD-treated mice, but remained unchanged in S-αLA/γCD-treated mice. Significance These results suggested that the stereoisomerism mediates a difference in the anti-diabetic effects of racemic-, R-, and S-αLA/γCDs. Furthermore, the anti-diabetic mechanism of αLA/γCD action may be attributed to the activation of AMPK in the liver.

Botulinum toxin A (BTXA) can disrupt the neuromuscular and autonomic functions. We herein report a case of autonomic system dysfunction that manifested as Takotsubo-like myocardial dysfunction in a patient with botulism. Takotsubo syndrome results in acute cardiac insufficiency, another fatal complication of botulism in addition to respiratory muscle paralysis, particularly in patients with cardiovascular disease.

Background/aim Metabolic syndrome-induced lifestyle-related diseases include diabetes mellitus (DM) and hypertension, and Zn-based compounds have effects on DM. We aimed to investigate the ameliorating effects of bis(hinokitiolato)Zn, [Zn(hkt)2] on lipid metabolism in the liver and kidney, histopathologically. Materials and methods We used a high-fat diet (HFD)-fed C57BL/6J mouse model and administered a diet containing 10-20 mg Zn/kg body weight (BW) or 20 mg pioglitazone/kg BW as the positive control. After the treatments, we collected blood, liver, and kidney samples and morphologically evaluated the mouse organs for fat accumulation. Results After a 4-month HFD administration, ectopic fat deposition was detected in the liver and kidney. Furthermore, Zn accumulation in the liver and kidney increased following [Zn(hkt)2] treatment, that reduced lipid accumulations and lipid toxicity in these tissues. Conclusion The results of this study suggest that [Zn(hkt)2] could be a novel anti-dyslipidaemia compound for treating diet-induced obesity.

Zinc (Zn) is a trace element with anti-diabetes mellitus (anti-DM) effects. Zn complexes exhibit stronger insulin-like activity than Zn ions. Bis(hinokitiolato)zinc complex ([Zn(hkt)

Radiotherapy (RT) and chemoradiotherapy (CRT) is widely accepted as the standard treatment for head and neck cancer (HNC). Oral mucositis (OM) often develops as an adverse reaction in HNC patients that receive RT or CRT involving S-1. However, little is known about the risk factors for OM in HNC patients. We retrospectively evaluated patients' pre-treatment clinical data in order to identify the risk factors for severe OM in HNC patients that are treated with RT or CRT involving S-1. We analyzed the cases of 129 patients who received RT or CRT involving S-1 for HNC. The endpoint of the survey was the occurrence of severe OM (≥grade 2). Risk factors that were significantly related to severe OM were identified using logistic regression analysis. The patients' mean age was 69.3±10.1 years, and 118 (92%) of the patients were male. The primary tumor was located in the oropharynx in 21.7% of cases. Severe OM occurred in 85.0% of cases. In the univariate analysis, the following variables were found to be associated with severe OM: age, the type of radiotherapy, disease stage, and chemotherapy. In the multivariate analysis, the location of the primary tumor and chemotherapy were identified as significant risk factors that contributed independently to the risk of severe OM (p

In recent years, the number of patients suffering from diabetes mellitus has been increasing worldwide. In particular, type 2 diabetes mellitus, a lifestyle-related disease, is recognized as a serious disease with various complications. Many types of pharmaceutics or specific health foods have been used for the management of diabetes mellitus. At the same time, the relationship between diabetes mellitus and α-lipoic acid has been recognized for many years. In this study, we found that the α-lipoic acid γ-cyclodextrin complex exhibited an HbA1c lowering effect for treating type 2 diabetes mellitus in animal models. Moreover, in this study, we investigated the activation of phosphorylation of AMP-activated protein kinase, which plays a role in cellular energy homeostasis, in the liver of KKA(y) mice by using α-lipoic acid and the α-lipoic acid γ-cyclodextrin complex. Our results show that the α-lipoic acid γ-cyclodextrin complex strongly induced the phosphorylation of AMP-activated protein kinase. Thus, we concluded that intake of the α-lipoic acid γ-cyclodextrin complex exerted an antidiabetic effect by suppressing the elevation of postprandial hyperglycemia as well as doing exercise.