Enhancement of Inhibitory Activity by Combining Allosteric Inhibitors Putatively Binding to Different Allosteric Sites on Cathepsin K.

BACKGROUND: Cathepsin K, which is involved in bone resorption, is a good target for treating osteoporosis, but no clinically approved medicine has been developed. Recently, allosteric inhibitors with high specificity and few side effects have been attracting attention for use in new medicines. METHODS: Cathepsin K inhibitors were isolated from the methanol extract of Chamaecrista nomame (Leguminosae) using cathepsin K inhibition activity-assisted multi-step chromatography. Standard kinetic analysis was employed to examine the mechanism of cathepsin K inhibition when an isolated inhibitor and its derivative were used. The allosteric binding of these cathepsin K inhibitors was supported by a docking study using AutoDock vina. Combinations of allosteric cathepsin K inhibitors expected to bind to different allosteric sites were examined by means of cathepsin K inhibition assay. RESULTS: Two types of cathepsin K inhibitors were identified in the methanol extract of Chamaecrista nomame. One type consisted of cassiaoccidentalin B and torachrysone 8-ß-gentiobioside, and inhibited both cathepsin K and B with similar inhibitory potential, while the other type of inhibitor consisted of pheophytin a, and inhibited cathepsin K but not cathepsin B, suggesting that pheophytin a binds to an allosteric site of cathepsin K. Kinetic analysis of inhibitory activity suggested that pheophytin a and its derivative, pheophorbide b, bind allosterically to cathepsin K. This possibility was supported by a docking study on cathepsin K. The cathepsin K inhibitory activity of pheophytin a and pheophorbide b was enhanced by combining them with the allosteric inhibitors NSC 13345 and NSC94914, which bind to other allosteric sites on cathepsin K. CONCLUSIONS: Different allosteric inhibitors that bind to different sites in combination, as shown in this study, may be useful for designing new allosteric inhibitory drugs with high specificity and few side effects.

Liquid Enteral Nutrients Alter the Pharmacokinetics of Orally Administered Carbamazepine in Rats.

The interaction between enteral nutrients (ENs) and drugs co-administered through a nasogastric (NG) tube reportedly affects the absorption and resultant plasma concentrations of the respective drugs. However, the gastrointestinal absorption of carbamazepine (CBZ), an antiepileptic drug, co-administered with liquid ENs through an NG tube has not been clarified. In this study, we measured the recovery rate (%) of CBZ (Tegretol® powder) passed through an NG tube when co-administered with distilled water or ENs (F2α®, Racol® NF, Ensure Liquid®, and Renalen® LP) of different compositions, frequently used in Japan. We also measured the plasma CBZ level in 26 rats after oral co-administration of CBZ with liquid ENs. The CBZ recovery rate was close to 100% in rats of all EN groups after passage through the NG tube. Furthermore, CBZ area under the plasma concentration-time curve from time zero to 9 h (AUC0→9h) of the Ensure liquid® group decreased compared with that of control group (P < 0.05) and Renalen® LP group (P < 0.01). However, the AUC0→9h of CBZ remained unchanged when co-administered with Ensure liquid® 2 h after initial CBZ administration. In conclusion, the co-administration of CBZ with Ensure Liquid® caused a reduction in the absorption of CBZ from the gastrointestinal tract, without adsorption on the NG tube. The administration of Ensure Liquid® 2 h after CBZ is a way to prevent a decrease in plasma CBZ concentration. Our findings suggest that carefully monitoring the plasma levels of CBZ is necessary in co-administation with Ensure liquid® to prevent the unintended effects of the interaction between CBZ and liquid EN.

Financial conflicts of interest between pharmaceutical companies and the authors of urology clinical practice guidelines in Japan.

INTRODUCTION AND HYPOTHESIS: In Japan, the authors of urology clinical practice guidelines (UCPG) used in patient-centered care are often targeted by pharmaceutical companies with financial payments. However, the financial relationship between UCPG authors and pharmaceutical companies remains unclear. This study aimed to determine the characteristics of industry payments to physicians that may influence recommendations in UCPG and to assess the transparency of payment disclosure. METHODS: We considered 193 UCPG authors receiving payments from 79 companies between 2016 and 2017 and the 13 UCPG published by the Japanese Urological Association between 2015 and 2018. We determined 2-year combined mean and median payments to authors, total company payments, and associations between author attributes and payment values using multivariate negative binomial regression. Also, we assessed the extent of the financial disclosure policies among the 13 UCPG. RESULTS: Overall, 171 (88.6%) authors received payments with a combined value of $6,169,333. Median and mean payments were $7147 (interquartile range, $1512-$44,807) and $31,965 (standard deviation, $51,684), respectively. University professors working on multiple UCPG with new drug approvals were associated with higher payments. Twelve (92.3%) UCPG failed to disclose financial conflicts. CONCLUSIONS: While it remains unclear whether financial entanglements improperly influence the contents of UCPG, most Japanese authors received substantial payments from pharmaceutical companies with little or no disclosure. Because insufficient transparency in disclosure of these financial entanglements may compromise the integrity of UCPG, more rigorous regulation and greater disclosure of financial conflicts of interest are needed.

Brassica rapa L. activates macrophages via Toll-like receptors.

Macrophages can initiate innate immune responses against microbes and cancer. The aim of this study was to elucidate the effects of Brassica rapa L. on macrophages. The production of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and interferon-γ induced by the insoluble fraction of B. rapa L. was decreased in macrophage-depleted spleen cells compared with controls. The insoluble fraction of B. rapa L. induced expression of H-2Kb, I-Ab, CD40, and CD86, production of cytokines and nitric oxide, and phagocytic activity in RAW264 cells. After treatment with the insoluble fraction, IL-6 and TNF-α production was significantly decreased by anti-Toll-like receptor (TLR)2 mAb or polymyxin B compared with the control. Furthermore, insoluble fraction-mediated cytokine production was significantly lower in peritoneal macrophages from TLR2-/- and TLR4-/- mice compared with wild-type mice. These results suggest that B. rapa L. is a potentially effective immunomodulator for activating macrophages to prevent infections.

Visualization of mandibular movement relative to the maxilla during mastication in mice: integration of kinematic analysis and reconstruction of a three-dimensional model of the maxillofacial structure.

BACKGROUND: Mastication is one of the most fundamental functions for the conservation of human life. To clarify the pathogenetic mechanism of various oral dysfunctions, the demand for devices for evaluating stomatognathic function has been increasing. The aim of the present study was to develop a system to reconstruct and visualize 3-dimensional (3D) mandibular movements relative to the maxilla, including dynamic transition of occlusal contacts between the upper and lower dentitions during mastication in mice. METHODS: First, mandibular movements with six degrees of freedom were measured using a motion capture system comprising two high-speed cameras and four reflective markers. Second, 3D models of maxillofacial structure were reconstructed from micro-computed tomography images. Movement trajectories of anatomical landmark points on the mandible were then reproduced by integrating the kinematic data of mandibular movements with the anatomical data of maxillofacial structures. Lastly, 3D surface images of the upper dentition with the surrounding maxillofacial structures were transferred to each of the motion capture images to reproduce mandibular movements relative to the maxilla. We also performed electromyography (EMG) of masticatory muscles associated with mandibular movements. RESULTS: The developed system could reproduce the 3D movement trajectories of arbitrary points on the mandible, such as incisor, molars and condylar points with high accuracy and could visualize dynamic transitions of occlusal contacts between upper and lower teeth associated with mandibular movements. CONCLUSIONS: The proposed system has potential to elucidate the mechanisms underlying motor coordination of masticatory muscles and to clarify their roles during mastication by taking advantage of the capability to record EMG data synchronously with mandibular movements. Such insights will enhance our understanding of the pathogenesis and diagnosis of oral motor disorders by allowing comparisons between normal mice and genetically modified mice with oral behavioral dysfunctions.

Collaborative Study to Validate Purity Determination by 1H Quantitative NMR Spectroscopy by Using Internal Calibration Methodology.

NMR spectroscopy has recently been utilized to determine the absolute amounts of organic molecules with metrological traceability since signal intensity is directly proportional to the number of each nucleus in a molecule. The NMR methodology that uses hydrogen nucleus (1H) to quantify chemicals is called quantitative 1H-NMR (1H qNMR). The quantitative method using 1H qNMR for determining the purity or content of chemicals has been adopted into some compendial guidelines and official standards. However, there are still few reports in the literature regarding validation of 1H qNMR methodology. Here, we coordinated an international collaborative study to validate a 1H qNMR based on the use of an internal calibration methodology. Thirteen laboratories participated in this study, and the purities of three samples were individually measured using 1H qNMR method. The three samples were all certified via conventional primary methods of measurement, such as butyl p-hydroxybenzoate Japanese Pharmacopeia (JP) reference standard certified by mass balance; benzoic acid certified reference material (CRM) certified by coulometric titration; fludioxonil CRM certified by a combination of freezing point depression method and 1H qNMR. For each sample, 1H qNMR experiments were optimized before quantitative analysis. The results showed that the measured values of each sample were equivalent to the corresponding reference labeled value. Furthermore, assessment of these 1H qNMR data using the normalized error, En-value, concluded that statistically 1H qNMR has the competence to obtain the same quantification performance and accuracy as the conventional primary methods of measurement.

[A case of mucosa-associated lymphoid tissue lymphoma of the bile duct diagnosed using intraductal ultrasonography and transpapillary investigation of the bile duct].

A 78-year-old woman with a chief complaint of mammary tumor was referred to our hospital and was diagnosed with mucosa-associated lymphoid tissue (MALT) lymphoma using needle biopsies. She presented with MALT lymphoma lesions in the stomach, duodenum, and intraperitoneal lymph nodes. Abdominal ultrasonography revealed thickened internal layer of the bile duct. Cholangiocarcinoma, immunoglobulin G4-related sclerosing cholangitis, and MALT lymphoma were suspected. She did not report any abdominal pain, and did not have jaundice. Endoscopic retrograde cholangiopancreatography and intraductal ultrasonography indicated diffuse, irregular wall thickening with the formation of nodule lesions in the extrahepatic bile duct. Transpapillary cytology indicated CD20-positive atypical lymphocytes. MALT lymphoma of the bile duct was diagnosed. CVP with rituximab therapy was performed. After treatment, computed tomography, gastrointestinal endoscopy, endoscopic retrograde cholangiopancreatography, intraductal ultrasonography, and transpapillary cytology revealed that the tumor and the biliary wall thickening had disappeared. It is difficult to diagnose MALT lymphoma of the bile duct. We report a case in which intraductal ultrasound and transpapillary cytology were useful for establishing a diagnosis and evaluating the therapy for MALT lymphoma of the bile duct.

Autism-associated protein kinase D2 regulates embryonic cortical neuron development.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder, characterized by impaired social interaction, repetitive behavior and restricted interests. Although the molecular etiology of ASD remains largely unknown, recent studies have suggested that de novo mutations are significantly involved in the risk of ASD. We and others recently identified spontaneous de novo mutations in PKD2, a protein kinase D family member, in sporadic ASD cases. However, the biological significance of the de novo PKD2 mutations and the role of PKD2 in brain development remain unclear. Here, we performed functional analysis of PKD2 in cortical neuron development using in utero electroporation. PKD2 is highly expressed in cortical neural stem cells in the developing cortex and regulates cortical neuron development, including the neuronal differentiation of neural stem cells and migration of newborn neurons. Importantly, we determined that the ASD-associated de novo mutations impair the kinase activity of PKD2, suggesting that the de novo PKD2 mutations can be a risk factor for the disease by loss of function of PKD2. Our current findings provide novel insight into the molecular and cellular pathogenesis of ASD.

Conserved Pyridoxal 5'-Phosphate-Binding Protein YggS Impacts Amino Acid Metabolism through Pyridoxine 5'-Phosphate in Escherichia coli.

Escherichia coli YggS (COG0325) is a member of the highly conserved pyridoxal 5'-phosphate (PLP)-binding protein (PLPBP) family. Recent studies suggested a role for this protein family in the homeostasis of vitamin B6 and amino acids. The deletion or mutation of a member of this protein family causes pleiotropic effects in many organisms and is causative of vitamin B6-dependent epilepsy in humans. To date, little has been known about the mechanism by which lack of YggS results in these diverse phenotypes. In this study, we determined that the pyridoxine (PN) sensitivity observed in yggS-deficient E. coli was caused by the pyridoxine 5'-phosphate (PNP)-dependent overproduction of Val, which is toxic to E. coli The data suggest that the yggS mutation impacts Val accumulation by perturbing the biosynthetic of Thr from homoserine (Hse). Exogenous Hse inhibited the growth of the yggS mutant, caused further accumulation of PNP, and increased the levels of some intermediates in the Thr-Ile-Val metabolic pathways. Blocking the Thr biosynthetic pathway or decreasing the intracellular PNP levels abolished the perturbations of amino acid metabolism caused by the exogenous PN and Hse. Our data showed that a high concentration of intracellular PNP is the root cause of at least some of the pleiotropic phenotypes described for a yggS mutant of E. coliIMPORTANCE Recent studies showed that deletion or mutation of members of the YggS protein family causes pleiotropic effects in many organisms. Little is known about the causes, mechanisms, and consequences of these diverse phenotypes. It was previously shown that yggS mutations in E. coli result in the accumulation of PNP and some metabolites in the Ile/Val biosynthetic pathway. This work revealed that some exogenous stresses increase the aberrant accumulation of PNP in the yggS mutant. In addition, the current report provides evidence indicating that some, but not all, of the phenotypes of the yggS mutant in E. coli are due to the elevated PNP level. These results will contribute to continuing efforts to determine the molecular functions of the members of the YggS protein family.

Factors affecting the provision of analgesia during childbirth, Japan.

Japan's universal health-care system means that it is a very safe country in which to give birth. Perinatal outcomes in Japan are excellent, with low infant mortality and neonatal mortality. However, childbirth remains a challenge for many Japanese women, who are faced with a scarcity of places to give birth, limited availability of analgesia and social norms that favour natural birth. The number of birth facilities in Japan continues to decrease as fewer children are born. The numbers of qualified medical staff remain inadequate, with a continuing lack of female physicians, perpetuated by a pervasive negative gender bias. Recruitment efforts are underway, but few doctors want to specialize in obstetrics or gynaecology. Furthermore, around half of female obstetricians and gynaecologists in Japan's male-dominated medical system stop practising when they have their own children. The difficulty of obtaining analgesia during labour is another problem. Although low uptake of labour pain relief in Japan is said to be due to cultural influences, the root of the problem is a lack of qualified anaesthesiologists and the inflexibility of a system that will not allow other staff to be trained to administer labour analgesia. Problems with labour anaesthesia have been linked to 14 maternal deaths since 2010. Japanese policy-makers need to act to renovate the nation's obstetric facilities, reorganize regional perinatal care systems, train more obstetricians and anaesthesiologists, promote task-shifting and better integrate biomedical and traditional, non-medical care for pregnant women.

Le système de soins de santé universel du Japon en fait un pays très sûr pour les accouchements. Les résultats en matière de santé périnatale au Japon sont excellents, avec une mortalité infantile et une mortalité néonatale faibles. Néanmoins, l'accouchement reste problématique pour de nombreuses Japonaises, qui doivent faire face à un manque d'établissements adaptés pour les accouchements, à une disponibilité limitée de l'analgésie et à des normes sociales qui favorisent les accouchements naturels. Le nombre de maternités au Japon ne cesse de baisser, à mesure de la diminution du nombre de naissances. Les effectifs en personnel médical qualifié restent inappropriés, avec une pénurie persistante de femmes médecins, perpétuée par des préjugés négatifs généralisés liés au genre. Des efforts de recrutement sont en cours, mais peu de médecins souhaitent se spécialiser en obstétrique ou en gynécologie. Par ailleurs, dans le système médical japonais dominé par les hommes, près de la moitié des femmes obstétriciennes et gynécologues cessent de pratiquer dès qu'elles ont elles-mêmes des enfants. La difficulté à bénéficier d'une analgésie obstétricale pendant l'accouchement constitue un autre problème. Même si, au Japon, le faible recours au soulagement de la douleur pendant le travail est généralement imputé à des influences culturelles, le fond du problème est une pénurie d'anesthésistes qualifiés et le manque de souplesse d'un système qui ne permet pas de former d'autres professionnels de santé pour pouvoir pratiquer l'analgésie obstétricale. Les problèmes liés à la réalisation d'une analgésie obstétricale ont donné lieu à 14 décès maternels depuis 2010. Au Japon, les décideurs politiques doivent agir pour rénover les installations obstétricales du pays, réorganiser les systèmes régionaux de santé périnatale, former davantage d'obstétriciens et d'anesthésistes, promouvoir le transfert des tâches et mieux intégrer les soins biomédicaux et les soins traditionnels, non médicaux, pour les femmes enceintes.

El sistema universal de atención sanitaria de Japón hace que sea un país muy seguro para dar a luz. Los resultados perinatales en Japón son excelentes, con baja mortalidad infantil y mortalidad neonatal. Sin embargo, el parto sigue siendo un problema para muchas mujeres japonesas, que se enfrentan a la escasez de lugares para dar a luz, la limitada disponibilidad de analgesia y las normas sociales que favorecen el parto natural. El número de centros de maternidad en Japón sigue disminuyendo a medida que nacen menos niños. El número de personal médico cualificado sigue siendo insuficiente, con una continua falta de mujeres médicas, perpetuada por un prejuicio de género negativo generalizado. Los esfuerzos de reclutamiento están en marcha, pero pocos médicos quieren especializarse en obstetricia o ginecología. Además, alrededor de la mitad de las obstetras y ginecólogas del sistema médico japonés dominado por los hombres dejan de ejercer cuando tienen sus propios hijos. La dificultad para obtener analgesia durante el trabajo de parto es otro problema. Aunque se dice que la baja aceptación del alivio del dolor del trabajo de parto en Japón se debe a influencias culturales, la raíz del problema es la falta de anestesiólogos calificados y la inflexibilidad de un sistema que no permitirá que otro personal esté capacitado para administrar la analgesia del trabajo de parto. Los problemas con la anestesia del trabajo de parto se han relacionado con 14 muertes maternas desde 2010. Los responsables de formular políticas en Japón deben actuar para renovar las instalaciones obstétricas del país, reorganizar los sistemas regionales de atención perinatal, capacitar a más obstetras y anestesiólogos, promover el cambio de tareas e integrar mejor la atención biomédica y la atención no médica tradicional para las mujeres embarazadas.

Radiation doses and decontamination effects in Minamisoma city: airborne and individual monitoring after the Fukushima nuclear accident.

After the Fukushima accident, airborne monitoring was implemented to measure airborne radiation. We examined the relationships between airborne and individual radiation monitoring and clarified the use of airborne monitoring to evaluate the effects of decontamination on residents' received doses. We used the air dose rate data from four airborne monitors conducted between 2013 and 2016, and the dose data from four individual monitors (in which a total of 18 392 adults and 3650 children participated), conducted in Minamisoma City during the same period. We examined the Pearson correlation coefficients between the airborne and individual monitoring data and estimated exposure ratios (ERs; ratios of individual dose to air dose rates) among adults and children. We also estimated the effects of decontamination on residents' doses based on airborne monitoring data, adjusting this for timing and dosing through propensity score matching, which were then compared to individual monitoring data. There were significant correlations between airborne and individual monitoring doses among adults and children, and more than 80% of residents showed a good estimation-observation agreement within a factor of two. The median of ERs was 0.304 and 0.250 among adults and children, respectively. There was a significant difference between the two. Effects of decontamination on residents' doses estimated from airborne monitoring were significantly lower than those estimated from individual monitoring. These findings suggest that airborne monitoring can be used to estimate representative radiation doses within residential areas. It may be a useful tool for enhancing communication among stakeholders and supporting individual and policy decisions; however, it is less sensitive for evaluating individual effects of decontamination than individual monitoring. Combined use of airborne and individual monitoring also showed a lower median of ERs in children than in adults and in a Japanese government's model, possibly due to prioritised decontamination for children and differences between their behavioral patterns.

Enhancement of natural killer activity and IFN-γ production in an IL-12-dependent manner by a Brassica rapa L.

Certain food components possess immunomodulatory effects. The aim of this study was to elucidate the mechanism of the immunostimulatory activity of Brassica rapa L. We demonstrated an enhancement of natural killer (NK) activity and interferon (IFN)-γ production in mice that were orally administered an insoluble fraction of B. rapa L. The insoluble fraction of B. rapa L. significantly induced IFN-γ production in mouse spleen cells in an interleukin (IL)-12-dependent manner, and NK1.1+ cells were the main cells responsible for producing IFN-γ. Additionally, the results suggested that the active compounds in the insoluble fraction were recognized by Toll-like receptor (TLR) 2, TLR4, and C-type lectin receptors on dendritic cells, and they activated signaling cascades such as MAPK, NF-κB, and Syk. These findings suggest that B. rapa L. is a potentially promising immuno-improving material, and it might be useful for preventing immunological disorders such as infections and cancers by activating innate immunity.

The peel of Citrus kawachiensis (kawachi bankan) ameliorates microglial activation, tau hyper-phosphorylation, and suppression of neurogenesis in the hippocampus of senescence-accelerated mice.

We previously reported that the dried peel powder of Citrus kawachiensis, one of the citrus products of Ehime, Japan, exerted anti-inflammatory effects in the brain of a lipopolysaccharide-injected systemic inflammation animal model. Inflammation is one of the main mechanisms underlying aging in the brain; therefore, we herein evaluated the anti-inflammatory and other effects of the dried peel powder of C. kawachiensis in the senescence-accelerated mouse-prone 8 (SAMP8) model. The C. kawachiensis treatment inhibited microglial activation in the hippocampus, the hyper-phosphorylation of tau at 231 of threonine in hippocampal neurons, and ameliorated the suppression of neurogenesis in the dentate gyrus of the hippocampus. These results suggest that the dried peel powder of C. kawachiensis exert anti-inflammatory and neuroprotective effects.

Neuroprotective effect of Citrus kawachiensis (Kawachi Bankan) peels, a rich source of naringin, against global cerebral ischemia/reperfusion injury in mice.

Cerebral ischemia/reperfusion is known to induce the generation of reactive oxygen species and inflammatory responses. Numerous studies have demonstrated that naringin (NGIN) has anti-oxidant and anti-inflammatory properties. We previously reported that Citrus kawachiensis contains a large quantity of NGIN in its peel. In the present study, we orally (p.o.) administered dried peel powder of C. kawachiensis to mice of a transient global ischemia model and found in the hippocampus region that it 1) suppressed neuronal cell death, 2) reversed the reduction in the level of phosphorylated calcium-calmodulin-dependent protein kinase II, 3) had the tendency to reverse the reduction in the level of glutathione, and 4) blocked excessive activation of microglia and astrocytes. These results suggested that the dried peel powder of C. kawachiensis had a neuroprotective effect against ischemic brain via anti-oxidative and anti-inflammatory effects. We also showed that these effects of the dried peel powder were more powerful than those obtained with a comparable amount of NGIN alone.

[A Case of Arteritis That Developed after Pegfilgrastim Administration during Chemotherapy for Breast Cancer].

A 61-year-old woman presented with metastatic breast cancer in her right lung 4 years and 11 months after the operation for her right breast cancer(HER2 enriched type). Chemotherapy(pertuzumab plus trastuzumab plus docetaxel)were ad- ministered. On day 2 of cycle 2, pegfilgrastim was administered because her neutrophils decreased to 54 cells/mL on day 8 of cycle 1. On day 9 of cycle 2, she developed left neck and chest pain. Moreover, she developed a fever of 39°C on day 14 and visited our hospital. Her WBC and CRP increased to 18,300 cells/mL and 25.48mg/dL, respectively. Computed tomography revealed an increased CT value of the panniculus, around the aorta and left pleural effusion. Ultrasonography of the neck showed a marginal hypoechoic area around the left carotid artery, which corresponded with the pain. Arteritis induced by PFG was suspected. The neck pain and fever almost completely improved 19 days later, and cycle 3 was performed 28 days after cycle 2. To our knowledge, the present case is the second report of arteritis that was suspected to be associated with PFG.

Chiral Self-Recognition between Stereogenic Tetrapalladium Units Affording Pd8 Chains Supported by Homochiral Tetraphosphines.

By using a chiral tetraphosphine, rac-bis[(diphenylphosphinomethyl)phenylphosphino]methane (rac-dpmppm), linear octapalladium chains were synthesized as discrete molecules of [Pd8 (µ-rac-dpmppm)4 L2 ](BF4 )4 (L=CH3 CN, dmf, XylNC), [Pd8 (µ-rac-dpmppm)4 ](BF4 )4 , and [Pd8 (µ-rac-dpmppm)4 (Cl)2 ](BF4 )2 , which are stable in the solution states and characterized by spectroscopic and crystallographic methods to reveal the octapalladium chains supported by homochiral four tetraphosphines. Variable-temperature NMR studies for a 1:1 mixture of [Pd8 (µ-rac-dpmppm)4 (dmf)2 ](BF4 )4 and [Pd8 (µ-meso-dpmppm)4 (dmf)2 ]-(BF4 )4 in [D7 ]DMF revealed that the Pd8 chains were dissociated at higher temperature (T≈140 °C) into the Pd4 units of {Pd4 (µ-rac-dpmppm)2 }2+ and {Pd4 (µ-meso-dpmppm)2 }2+ , and they were thermodynamically self-aligned to restore the Pd8 chains at lower temperature (T<60 °C), through perfect chiral self-recognition between the stereogenic tetrapalladium units.

Trends of Media Coverage on Human Papillomavirus Vaccination in Japanese Newspapers.

A sensational newspaper article concerning a possible adverse reaction to the human papillomavirus (HPV) vaccine was published in March 2013 in Japan. In June 2013, the Japanese government suspended their proactive recommendation for vaccination, despite the lack of proof for a causal relationship. We searched Nikkei Telecom 21, the largest newspaper database in Japan, for articles published from January 2011 to December 2015 to evaluate the characteristics of newspaper publications about human papillomavirus vaccination. We identified 1138 HPV vaccine-related articles. Compared with those published before March 2013, articles concerning human papillomavirus vaccination after March 2013 were more likely to include adverse reaction-related and authority-related keywords; articles that included efficacy-related keywords decreased significantly. Negative-negative and negative-neutral articles became more frequent, and positive-positive and positive-neutral articles were less frequent. A sensational case report shaped the tone of negative media coverage as a catalyst, regardless of scientific statements from health authorities.

Relationship of Enhanced Butyrate Production by Colonic Butyrate-Producing Bacteria to Immunomodulatory Effects in Normal Mice Fed an Insoluble Fraction of Brassica rapa L.

This study was performed to determine the effects of feeding a fiber-rich fraction of Brassica vegetables on the immune response through changes in enteric bacteria and short-chain fatty acid (SCFA) production in normal mice. The boiled-water-insoluble fraction of Brassica rapa L. (nozawana), which consists mainly of dietary fiber, was chosen as a test material. A total of 31 male C57BL/6J mice were divided into two groups and housed in a specific-pathogen-free facility. The animals were fed either a control diet or the control diet plus the insoluble B. rapa L. fraction for 2 weeks and sacrificed to determine microbiological and SCFA profiles in lower-gut samples and immunological molecules. rRNA-based quantification indicated that the relative population of Bacteroidetes was markedly lower in the colon samples of the insoluble B. rapa L. fraction-fed group than that in the controls. Populations of the Eubacterium rectale group and Faecalibacterium prausnitzii, both of which are representative butyrate-producing bacteria, doubled after 2 weeks of fraction intake, accompanying a marginal increase in the proportion of colonic butyrate. In addition, feeding with the fraction significantly increased levels of the anti-inflammatory cytokine interleukin-10 (IL-10) and tended to increase splenic regulatory T cell numbers but significantly reduced the population of cells expressing activation markers. We demonstrated that inclusion of the boiled-water-insoluble fraction of B. rapa L. can alter the composition of the gut microbiota to decrease the numbers of Bacteroidetes and to increase the numbers of butyrate-producing bacteria, either of which may be involved in the observed shift in the production of splenic IL-10.

3,5,6,7,8,3',4'-Heptamethoxyflavone, a Citrus Flavonoid, Ameliorates Corticosterone-Induced Depression-like Behavior and Restores Brain-Derived Neurotrophic Factor Expression, Neurogenesis, and Neuroplasticity in the Hippocampus.

We previously reported that the citrus flavonoid 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) increased the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of a transient global ischemia mouse model. Since the BDNF hypothesis of depression postulates that a reduction in BDNF is directly involved in the pathophysiology of depression, we evaluated the anti-depressive effects of HMF in mice with subcutaneously administered corticosterone at a dose of 20 mg/kg/day for 25 days. We demonstrated that the HMF treatment ameliorated (1) corticosterone-induced body weight loss, (2) corticosterone-induced depression-like behavior, and (3) corticosterone-induced reductions in BDNF production in the hippocampus. We also showed that the HMF treatment restored (4) corticosterone-induced reductions in neurogenesis in the dentate gyrus subgranular zone and (5) corticosterone-induced reductions in the expression levels of phosphorylated calcium-calmodulin-dependent protein kinase II and extracellular signal-regulated kinase1/2. These results suggest that HMF exerts its effects as an anti-depressant drug by inducing the expression of BDNF.