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Computation of expected values (i.e., probability x magnitude) seems to be a dynamic integrative process performed by the brain for efficient economic behavior. However, neural dynamics underlying this computation is largely unknown. Using lottery tasks in monkeys (Macaca mulatta, male; Macaca fuscata, female), we examined (1) whether four core reward-related brain regions detect and integrate probability and magnitude cued by numerical symbols and (2) whether these brain regions have distinct dynamics in the integrative process. Extraction of the mechanistic structure of neural population signals demonstrated that expected value signals simultaneously arose in the central orbitofrontal cortex (cOFC; medial part of area 13) and ventral striatum (VS). Moreover, these signals were incredibly stable compared with weak and/or fluctuating signals in the dorsal striatum and medial OFC. Temporal dynamics of these stable expected value signals were unambiguously distinct: sharp and gradual signal evolutions in the cOFC and VS, respectively. These intimate dynamics suggest that the cOFC and VS compute the expected values with unique time constants, as distinct, partially overlapping processes. [ABSTRACT FROM AUTHOR]

For the safety assessment of pharmaceuticals, initial data management requires accurate toxicological data acquisition, which is based on regulatory safety studies according to guidelines, and computational systems have been developed under the application of Good Laboratory Practice (GLP). In addition to these regulatory toxicology studies, investigative toxicological study data for the selection of lead compound and candidate compound for clinical trials are directed to estimation by computational systems such as Quantitative Structure-Activity Relationship (QSAR) and related expert systems. Furthermore, in the "Go" or "No-Go" decision of drug development, supportive utilization of a scientifically interpretable computational toxicology system is required for human safety evaluation. A pharmaceutical safety evaluator as a related toxicologist who is facing practical decision needs not only a data-driven Artificial Intelligence (AI) system that calls for the final consequence but also an explainable AI that can provide comprehensive information necessary for evaluation and can help with decision making. Through the explication and suggestion of information on the mechanism of toxic effects to safety assessment scientists, a subsidiary partnership system for risk assessment is ultimately to be a powerful tool that can indicate project-vector with data weight for the corresponding counterparts. To bridge the gaps between big data and knowledge, multi-dimensional thinking based on philosophical ontology theory is necessary for handling heterogeneous data for integration. In this review, we will explain the current state and future perspective of computational toxicology related to drug safety assessment from the viewpoint of ontology thinking. [ABSTRACT FROM AUTHOR]

Background: Diffuse idiopathic skeletal hyperostosis has long been regarded as a benign asymptomatic clinical entity with an innocuous clinical course. Neurological complications are rare in diffuse idiopathic skeletal hyperostosis. However, if they do occur, the consequences are often significant enough to warrant major neurosurgical intervention. Neurological complications occur when the pathological process of ossification in diffuse idiopathic skeletal hyperostosis extends to other vertebral ligaments, causing ossification of the posterior longitudinal ligaments and/or ossification of the ligamentum flavum. Thoracic spondylolisthesis with spinal cord compression in diffuse idiopathic skeletal hyperostosis has not previously been reported in the literature.Case Presentation: A 78-year-old Japanese man presented with a 6-month history of gait disturbance. A magnetic resonance imaging scan of his cervical and thoracic spine revealed anterior spondylolisthesis and severe cord compression at T3 to T4 and T10 to T11, as well as high signal intensity in a T2-weighted image at T10/11. Computed tomography revealed diffuse idiopathic skeletal hyperostosis at T4 to T10. He underwent partial laminectomy of T10 and posterior fusion of T9 to T12. The postoperative magnetic resonance imaging revealed resolution of the spinal cord compression and an improvement in the high signal intensity on the T2-weighted image.Conclusions: We report the first case of thoracic spondylolisthesis and spinal cord compression in diffuse idiopathic skeletal hyperostosis. Neurosurgical intervention resulted in a significant improvement of our patient's neurological symptoms. [ABSTRACT FROM AUTHOR]

Background: Dietary supplements are used by >50% of the adult population in Japan, and adverse events related to these products have been reported with their increased use. Thus, an efficient system to gather and report data on these adverse events is essential. To date, however, reporting has been limited. The aim of this study was to address this deficiency by exploring the routine reporting practices of the medical staff employed at clinics or pharmacies in Japan.Methods: We conducted a survey of the procedures used by the medical staff to report adverse events related to dietary supplement intake to public health centers in Japan. The survey was conducted in Japan between November 2015 and January 2016. Based on a sample size calculation, questionnaires were administered to 1,700 potential respondents (850 pharmacists and 850 physicians). The questionnaire inquired about the sociodemographic characteristics and dietary supplement-related adverse event-reporting practices.Results: The response rate was 34.7%, including 286 pharmacists and 304 physicians. Although >30% of the pharmacists and physicians had prior experience dealing with such adverse events, <5% had reported these to a public health center. The survey identified several barriers to reporting, such as "difficulty judging the relationship between an adverse event and the dietary supplement" and "lack of clarity regarding the severity of an adverse event".Conclusion: This is the first study to explore the routine reporting practices of physicians and pharmacists in terms of adverse events related to dietary supplements. Further studies are required to elucidate the severity of these adverse events. Moreover, standard reporting criteria ought to be introduced to improve public health. [ABSTRACT FROM AUTHOR]

Background: Influenza viruses can spread easily from person to person, and annual influenza epidemics are serious public health issues worldwide. Non-pharmaceutical public health interventions could potentially be effective for combatting influenza epidemics, but combined interventions and/or interventions with greater effectiveness are needed. Experimental studies have reported that tea and its ingredients (especially catechins) have antiviral activities. Although several clinical studies have investigated the use of tea or its ingredients to prevent influenza infections, the effect of gargling these substances has remained uncertain.Methods: We conducted a meta-analysis of randomized controlled studies and prospective cohort studies to assess the effect of gargling with tea and its ingredients on the prevention of influenza infection. The published literature was searched using the Cochrane Library, PubMed/MEDLINE (1966 to September 2015), Web of Science (1981 to September 2015), and Ichu-shi Web (1983 to September 2015). The extracted studies were read by two reviewers independently, and their overall scientific quality was evaluated. Studies meeting our inclusion criteria were pooled using the Mantel-Haenszel method in a fixed effects model and were also analyzed in a random effects model. The qualities of the model fits were assessed using the Akaike information criterion (AIC) and Bayesian information criterion (BIC).Results: The literature search and review identified 5 studies that met the inclusion criteria for the meta-analysis (total number of participants, 1890; mean age range, 16-83 years). The participants who gargled with tea or its ingredients showed a lower risk of influenza infection than did participants who gargled with placebo/water or who did not gargle (fixed effects model, Mantel-Haenszel method: relative risk [RR] = 0.70, 95 % confidence interval [CI] = 0.54-0.89; random effects model: RR = 0.71, 95 % CI = 0.56-0.91). The fixed effects model had a better quality of fit than the random effects model (fixed effects model: AIC = 6.04, BIC = 5.65; random effects model: AIC = 8.74, BIC = 7.52).Conclusions: Gargling with tea and its ingredients may have a preventative effect for influenza infection. However, additional large-scale studies in different populations and a pooled analysis of these studies are needed to confirm the effect. [ABSTRACT FROM AUTHOR]

Background: Green tea is a beverage with potential effects on cognitive dysfunction, as indicated by results of experimental studies. However, its effects in humans, especially at real-world (typical) consumption levels, are unclear.Methods: A double-blind, randomized controlled study was conducted to assess the effects of green tea consumption on cognitive dysfunction (Mini-Mental State Examination Japanese version (MMSE-J) score <28) in Japan. Participants were randomly allocated to the green tea or placebo group, and consumed either 2 g/day of green tea powder (containing 220.2 mg of catechins) or placebo powder (containing 0.0 mg of catechins), respectively, for 12 months. Cognitive function assessments were performed every 3 months using the MMSE-J and laboratory tests.Results: Thirty-three nursing home residents with cognitive dysfunction were enrolled (four men, 29 women; mean age ± SD, 84.8 ± 9.3; mean MMSE-J score ± SD, 15.8 ± 5.4), of whom 27 completed the study. Changes of MMSE-J score after 1 year of green tea consumption were not significantly different compared with that of the placebo group (-0.61 [-2.97, 1.74], least square mean (LSM) difference [95 % CI]; P = 0.59). However, levels of malondialdehyde-modified low-density lipoprotein (U/L), a marker of oxidative stress, was significantly lower in the green tea group (-22.93 [-44.13, -1.73], LSM difference [95 % CI]; P = 0.04).Conclusions: Our results suggest that 12 months green tea consumption may not significantly affect cognitive function assessed by MMSE-J, but prevent an increase of oxidative stress in the elderly population. Additional long-term controlled studies are needed to clarify the effects.Trial Registration: UMIN000011668. [ABSTRACT FROM AUTHOR]

The Hodrick-Prescott (HP) filter is a popular econometric tool for estimating the trend component of a given time series. Paige and Trindade (2010) present a ridge regression representation of the HP filter, which enhances our understanding of the filter. Schlicht (2005) presents another ridge regression representation of the HP filter. In this paper, we aim to generalize their results. In addition, we present an orthogonal decomposition of the generalized HP trend and newly introduce the pure generalized HP filter. [ABSTRACT FROM AUTHOR]

PURPOSE: To determine if asymmetry in thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer, ganglion cell complex, and total retina between upper and lower macula halves can predict glaucoma. DESIGN: Retrospective case-control series. METHODS: One hundred twenty-two eyes of 122 patients (30 normal eyes and 30 preperimetric, 31 early, and 31 advanced glaucoma eyes) were studied. The RNFL, ganglion cell layer, ganglion cell complex, and total retina were segmented and measured on 10 vertical B-scans over a 30 X 15 degree macular area. The equation asymmetry index = |logio (lower hemiretinal thickness/ upper hemiretinal thickness) | was used to calculate asymmetry indices for 8 pairs of upper and lower 0.5-mm segments equidistant from the fovea on each scan. Areas under the receiver operating characteristic curve (AROCs) for mean thickness and mean asymmetry index of 10 B-scans were compared. RESULTS: The overlap in values for normal and glaucomatous eyes was minimal for the ganglion cell layer asymmetry index. Thickness parameters decreased with the severity of glaucoma, whereas asymmetry indices did not. AROCs for thickness measurements tended to increase with increasing glaucoma severity (preperimetric, 0.746-0.808; early, 0.842-0.940; advanced, 0.943-0.995), whereas AROCs for asymmetry indices did not have distinct ranges according to glaucoma severity (advanced, 0.819-0.996; early, 0.861-0.998; preperimetric, 0.773-0.994). The AROC for the ganglion cell layer asymmetry index remained almost perfect regardless of glaucoma severity (0.994-0.998). CONCLUSIONS: Macular retinal layer thickness asymmetry indices, particularly for the ganglion cell layer, show promise as early indicators of glaucomatous retinal damage. [ABSTRACT FROM AUTHOR]

A nanopipette containing a solution of bis(benzo-15-crown-5) dissolved in 1,6-dichlorohexane was used as an ion-selective electrode (ISE) to probe K+ for shear force-based constant-distance scanning electrochemical microscopy (SECM). In a previous study, the ISE responded only at low K+ concentrations ([K+] < 1 mM), due to the depletion of the bis(benzo-15-crown-5) at the oil/water interface at high K+ concentrations and the unstable response of the tip at the oil/water interface for shear force and current detection. In the present study, a nanopipette reshaped by heating and with the hydrophobic layer removed was used as the ISE. This modified ISE enabled a rapid response to changes in K+ flux at a physiological concentration of K+ and allowed SECM imaging on a nanometer scale. The fabricated nano-ISE was used as a probe for shear force-based SECM. Topography and K+ flux images were obtained simultaneously at a polycarbonate membrane filter with 5 μm pores and human embryonic kidney 293 cells (HEK293). Several areas containing a K+ flux larger than the surrounding areas were found in the SECM images of the HEK293 cells, which indicated the existence of K+ channels. [ABSTRACT FROM AUTHOR]

A single living cell (PC12), cultured on a polystyrene dish and an albumin island immobilized on glass, were successfully imaged utilizing the differential standing approach (d-SA) mode of a scanning ion conductance microscope (SICM). In the d-SA mode, the differential of the output voltage of a tuning fork (rather than its absolute value) is used as the signal for maintaining a constant distance between the probe of a scanning ion conductance microscope (SICM) and the sample. The topography and SICM images were obtained simultaneously, and approach curves, when the tip approached the immobilized albumin or the PC12 cell membrane, were also obtained. The settings for the d-SA mode were carefully determined from the PC12 cell approach curve. Furthermore, differences in the topographies of the immobilized albumin and living PC12 cell images obtained using the standing approach (SA) versus d-SA mode are discussed. It is shown that SICM in d-SA mode is capable of imaging soft samples such as living cells without damaging them. [ABSTRACT FROM AUTHOR]

Experimental economic techniques have been widely used to evaluate human risk attitudes, but how these measured attitudes relate to overall individual wealth levels is unclear. Previous noneconomic work has addressed this uncertainty in animals by asking the following: (i) Do our close evolutionary relatives share both our risk attitudes and our degree of economic rationality? And (ii) how does the amount of food or water one holds (a non-pecuniary form of "wealth") alter risk attitudes in these choosers? Unfortunately, existing noneconomic studies have provided conflicting insights from an economic point of view. We therefore used standard techniques from human experimental economics to measure monkey risk attitudes for water rewards as a function of blood osmolality (an objective measure of how much water the subjects possess). Early in training, monkeys behaved randomly, consistently violating first-order stochastic dominance and mono-tonicity. After training, they behaved like human choosers--technically consistent in their choices and weakly risk averse (i.e., risk averse or risk neutral on average)--suggesting that well-trained monkeys can serve as a model for human choice behavior. As with attitudes about money in humans, these risk attitudes were strongly wealth dependent; as the animals became "poorer," risk aversion increased, a finding incompatible with some models of wealth and risk in human decision making. [ABSTRACT FROM AUTHOR]

The objective of this study is to measure vapor–liquid equilibria (VLE) data for an ethanol fatty acid ethyl ester (FAEE) system. VLE data for the binary system ethanol ethyl hexanoate were determined at pressures of (40.00 to 101.3) kPa using an ebulliometer, which could compensate for vapor hold-up. The hold-up compensable ebulliometer was designed for this study, and the experimental apparatus and procedure were verified by measuring the VLE data for ethanol p-xylene at pressures of (40.00 to 101.3) kPa. The densities at 298.15 K for pure components investigated in this study were also measured by a densimeter. The experimental VLE data of the two binary mixtures, ethanol p-xylene and ethanol ethyl hexanoate, were represented by the Wilson and nonrandom two-liquid (NRTL) models. The analytical solutions of groups (ASOG) and modified universal functional activity coefficient (UNIFAC, Dortmund) group contribution models were also used to predict the VLE behavior of these binary mixtures. The VLE data could be applied for the production of a biodiesel fuel synthesized from fatty acid ethyl esters using supercritical ethanol without a catalyst. [ABSTRACT FROM AUTHOR]

Animals optimize behaviors by predicting future critical events based on histories of actions and their outcomes. When behavioral outcomes like reward and aversion are signaled by current external cues, actions are directed to acquire the reward and avoid the aversion. The basal ganglia are thought to be the brain locus for reward-based adaptive action planning and learning. To understand the role of striatum in coding outcomes of forthcoming behavioral responses, we addressed two specific questions. First, how are the histories of reward and aversion used for encoding forthcoming outcomes in the striatum during a series of instructed behavioral responses? Second, how are the behavioral responses and their instructed outcomes represented in the striatum? We recorded discharges of 163 presumed projection neurons in the striatum while monkeys performed a visually instructed lever-release task for reward, aversion, and sound outcomes, whose occurrences could be estimated by their histories. Before outcome instruction, discharge rates of a subset of neurons activated in this epoch showed positive or negative regression slopes with reward history (24/44), that is, to the number of trials since the last reward trial, which changed in parallel with reward probability of current trials. The history effect was also observed for the aversion outcome but in far fewer neurons (3/44). Once outcomes were instructed in the same task, neurons selectively encoded the outcomes before and after behavioral responses (reward, 46/70; aversion, 6/70; sound, 6/70). The history- and current instruction–based coding of forthcoming behavioral outcomes in the striatum might underlie outcome-oriented behavioral modulation. [ABSTRACT FROM AUTHOR]

Dilute aqueous dispersions of charged colloidal silica (particle volume fraction ∼0.03−0.04, particle diameter 110 nm) exhibit unidirectional crystal growth due to the diffusion of a weak base, pyridine (Py). Similar diffusion−crystallization is enabled by a salt of a weak acid and a strong base, sodium hydrogen carbonate (NaHCO3). The resulting crystals consist of columnar (or cubic) crystal grains with a maximum height of a few centimeters and a maximum width of 1 cm. The crystal growth process is attributed to a combination of (i) the diffusion of Py or NaHCO3accompanied by a charging reaction of the silica particles and (ii) the charge-induced crystallization of the silica colloids. Theoretical growth curves based on the reaction−diffusion model for the case of Py were in good agreement with the observed curves. We also report the immobilization of the resulting large crystals by using a polymer hydrogel matrix. [ABSTRACT FROM AUTHOR]

OBJECTIVE:: To examine the effect of suppressive oligodeoxynucleotides (ODNs) on the pulmonary inflammation induced by immunostimulatory CpG DNA.DESIGN:: Prospective, randomized, controlled study.SETTING:: Research laboratories.SUBJECTS:: RAW 264.7 murine macrophage-like cell line and BALB/c mice.INTERVENTIONS:: RAW 264.7 cells were incubated with bacterial DNA or CpG ODN, alone or combined with suppressive ODN. The in vivo effect of suppressive ODN was determined using an acute lung injury model. CpG ODN alone or combined with suppressive ODN was instilled into the mouse lung.MEASUREMENTS AND MAIN RESULTS:: Production of tumor necrosis factor (TNF)-? and macrophage inflammatory protein (MIP)-2 by RAW 264.7 cells were measured by enzyme-linked immunosorbent assay (ELISA), whereas their messenger RNA levels were determined by reverse transcriptase-polymerase chain reaction. Synthetic ODN containing CpG motifs (CpG ODN) mimicked the ability of bacterial DNA to stimulate the production of TNF-? and MIP-2. Suppressive ODN significantly inhibited the activation of RAW 264.7 cells by both bacterial DNA and CpG ODN. In the lung injury model, production of proinflammatory cytokines (TNF-? and IL-6) and chemokines (MIP-2 and KC) in bronchoalveolar lavage (BAL) fluids was measured by ELISA. Neutrophil accumulation in the alveolar spaces was also evaluated. Instillation of CpG ODN into the lungs of normal mice triggered the synthesis of TNF-?, IL-6, MIP-2, and KC. Suppressive ODN significantly blocked the production of these proinflammatory cytokines and chemokines and also reduced neutrophil mobilization into the alveolar spaces by CpG DNA.CONCLUSIONS:: Proinflammatory cytokines and chemokines are up-regulated by CpG motifs in bacterial DNA. Suppressive ODN significantly inhibits the inflammatory response induced by CpG DNA in murine macrophages and the lung. This study supports the use of suppressive ODN to reduce the deleterious inflammatory responses induced by bacterial DNA. [ABSTRACT FROM AUTHOR]

Objectives: Vitamin C is a major antioxidant and also is known as a neuromodulator in dopaminergic neurons. The aim of this study was to investigate the association between lymphocyte and plasma vitamin C levels in various stages of Parkinson's disease (PD). Methods: Sixty-two individuals with PD (age 71 ± 8.8 y [mean ± SD]) being treated at Shizuoka General Hospital from December 2007 to August 2013 were consecutively recruited. PD severity was classified using the Hoehn-Yahr scale for staging PD. Fasting blood samples were collected, and plasma and lymphocyte vitamin C levels were measured. The association between PD severity and vitamin C levels was estimated by ordinal logistic regression with confounding variables. Results: The distribution of Hoehn-Yahr stages in patients was as follows: stage I, 7; II, 28; III, 16; and IV, 11. Lymphocyte vitamin C levels in patients with severe PD were significantly lower (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.80-0.97; P < 0.01) compared with those at less severe stages. Plasma vitamin C levels also tended to be lower in patients with severe PD; however, this was not significant (OR, 0.98; 95% CI, 0.96-1.00; P = 0.09). Conclusions: Our findings suggest that lymphocyte vitamin C levels in the peripheral blood may be a potentially useful biomarker for the progression of PD. [ABSTRACT FROM AUTHOR]

Mitochondrial toxicity has been implicated in the development of various toxicities, including hepatotoxicity. Therefore, mitochondrial toxicity has become a major screening factor in the early discovery phase of drug development. Several models have been developed to predict mitochondrial toxicity based on chemical structures. However, they only provide a binary classification of positive or negative results and do not provide the substructures that contribute to a positive decision. Therefore, we developed an artificial intelligence (AI) model to predict mitochondrial toxicity and visualize structural alerts. To construct the model, we used the open-source software library kMoL, which employs a graph neural network approach that allows learning from chemical structure data. We also utilized the integrated gradient method, which enables the visualization of substructures that contribute to positive results. The dataset used to construct the AI model exhibited a significant imbalance, with significantly more negative than positive data. To address this, we employed the bagging method, which resulted in a model with high predictive performance, as evidenced by an F1 score of 0.839. This model can also be used to visualize substructures that contribute to mitochondrial toxicity using the integrated gradient method. Our AI model predicts mitochondrial toxicity based on chemical structures and may contribute to screening mitochondrial toxicity in the early stages of drug discovery. [ABSTRACT FROM AUTHOR]

Study Design. This study compared hip stress among different types of lumbopelvic fusion based on finite element (FE) analysis. Objective. We believe that the number and placement of S2 alar iliac (AI) screws and whether the screws loosen likely influence hip joint stress in the FE model. Summary of Background Data. Spinopelvic fixation has been shown to increase the risk of progression for hip joint osteoarthritis. The biomechanical mechanism is not well understood. We hypothesize that the rigid pelvic fixation may induce stress at adjacent joints. Materials and Methods. A three-dimensional nonlinear FE model was constructed from the L4 vertebra to the femoral bone. From the intact model, we made four fusion models, each with different lower vertebrae instrumentation: (1) intact, (2) L4-S1 fusion, (3) L4-S2 AI screw fixation, (4) L4-S2 AI screw fixation with S2 AI screw loosening, and (5) L4-S1 and dual sacral AI screw fixation. A compressive load of 400 N was applied vertically to the L4 vertebra, followed by an additional 10 Nm bending moment about different axes to simulate either flexion, extension, left lateral bending, or right axial rotation. The distal femoral bone was completely restrained. The von Mises stress and angular motion were analyzed across the hip joints within each fusion construct model. Results. Hip joint cartilage stress and range of motion increased for all postures as pelvic fixation became more rigid. The dual sacral AI screw fixation model increased stress and angular motion at the hip joint more than intact model. Our results suggest that more rigid fixation of the pelvis induces additional stress on the hip joint, which may precipitate or accelerate adjacent joint disease. Conclusions. Dual sacral AI fixation led to the highest stress while loosening of S2 AI decreased stress on the hip joint. This study illustrates that more rigid fixation among lumbosacral fusion constructs increases biomechanical stress on the hip joints. [ABSTRACT FROM AUTHOR]

Focuses on an electronic compliance monitoring device for use with press-through-packaging sheets designed by Hamamatsu, Japan-based Ohm Electric Co. Configuration of the device; Benefits of the device in measuring drug compliance.

The article investigates the distinct roles of the orbitofrontal cortex, ventral striatum, and dopamine neurons in processing counterfactual outcomes in decision-making. It highlights the differentiated contributions of these brain regions in processing and integrating actual and counterfactual outcome signals, shedding light on the cooperation between the prefrontal cortex and subcortical regions in decision-making using counterfactual information.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders worldwide. Its incidence is gradually increasing because of an aging demographic. Therefore, AD prevention and modification is important to improve the health status of older adults. Oxidative stress is a component of the pathological mechanisms underlying AD. It is caused by a disruption of the balance between reactive oxygen species and antioxidant molecules. This imbalance also causes neuroinflammation. Catechins, which are bioactive components of tea, have antioxidative and anti-inflammatory effects. Moreover, other potential properties related to AD prevention and modification have been reported in in vitro and in vivo studies. Several clinical studies have also been conducted to date. The current review summarizes recent updates and perspectives of the effects of catechins on AD based on the molecular mechanisms and related clinical studies. [ABSTRACT FROM AUTHOR]

Collective cell migration is the coordinated movement of multiple cells connected by cadherin-based adherens junctions and is essential for physiological and pathological processes. Cadherins undergo dynamic intracellular trafficking, and their surface level is determined by a balance between endocytosis, recycling and degradation.However, the regulatory mechanism of cadherin turnover in collective cell migration remains elusive. In this study, we show that the Bin/amphiphysin/Rvs (BAR) domain protein pacsin 2 (protein kinase C and casein kinase substrate in neurons protein 2) plays an essential role in collective cell migration by regulating N-cadherin (also known as CDH2) endocytosis in human cancer cells.Pacsin 2-depleted cells formed cell--cell contacts enriched with N-cadherin and migrated in a directed manner. Furthermore, pacsin 2-depleted cells showed attenuated internalization of N-cadherin from the cell surface. Interestingly, GST pull-down assays demonstrated that the pacsin 2 SH3 domain binds to the cytoplasmic region of N-cadherin, and expression of an N-cadherin mutant defective in binding to pacsin 2 phenocopied pacsin 2 RNAi cells both in cell contact formation and N-cadherin endocytosis. These data support new insights into a novel endocytic route of N-cadherin in collective cell migration, highlighting pacsin 2 as a possible therapeutic target for cancer metastasis. [ABSTRACT FROM AUTHOR]

The interaction between sunlight and drugs can lead to phototoxicity in patients who have received such drugs. Phototoxicity assessment is a regulatory requirement globally and one of the main toxicity screening steps in the early stages of drug discovery. An in silica-in vitro approach has been utilized mainly for toxicology assessments at these stages. Although several quantitative structure-activity relationship (QSAR) models for phototoxicity have been developed, in silica technology to evaluate phototoxicity has not been well established. In this study, we attempted to develop an artificial intelligence (Al) model to predict the in vitro Neutral Red Uptake Phototoxicity Test results from a chemical structure and its derived information. To accomplish this, we utilized an open-source software library, kMoL. kMoL employs a graph convolutional neural networks (GCN) approach, which allows it to learn the data for the specified chemical structure. kMoL also utilizes the integrated gradient (IG) method, enabling it to visually display the substructures contributing to any positive results. To construct this AI model, we used only the chemical structure as a basis, then added the descriptors and the HOMO-LUMO gap, which was obtained from quantum chemical calculations. As a result, the assortment of chemical structures and the HOMO-LUMO gap produced an AI model with high discrimination performance, and an Fl score of 0.857. Additionally, our AI model could visualize the substructures involved in phototoxicity using the IG method. Our AI model can be applied as a toxicity screening method and could enhance productivity in drug development. [ABSTRACT FROM AUTHOR]

An ultraviolet visible (UV-Vis) microspectroscopic system was designed for the in situ characterization of the activity of the silica supported platinum (Pt) catalyst toward the dehydrogenation of 1-methyl-1,4-cyclohexadiene carried out in a custom-designed catalytic microreactor cell. The in situ catalytic microreactor cell (ICMC) with inlet/outlet ports was prepared using quartz cover as the optical window to facilitate UV-Vis observation. A fabricated thermometric stage was adapted to the UV-Vis microspectrophotometer to control the reaction temperature inside the ICMC. The spectra were collected by focusing the UV-Vis beam on a 30 × 30 mm area at the center of ICMC. At 393 K, the sequential measurement of the spectra recorded during the reaction exhibited a broad absorption peak with maximum absorbance at 260 nm that is characteristic for gaseous toluene. This result indicates that the silica supported Pt catalyst is active towards the dehydrogenation of 1-methyl-1,4-cyclohexadiene at the given experimental conditions. The onset of coke formation was also detected based on the appearance of absorption bands at 300 nm. The UV-Vis microspectroscopic system developed can be used further in studying the mechanism of the dehydrogenation reaction. [ABSTRACT FROM AUTHOR]

Elevation of soluble wild-type (WT) tau occurs in synaptic compartments in Alzheimer's disease. We addressed whether tau elevation affects synaptic transmission at the calyx of Held in slices from mice brainstem. Whole-cell loading of WT human tau (h-tau) in presynaptic terminals at 10-20 µM caused microtubule (MT) assembly and activity-dependent rundown of excitatory neurotransmission. Capacitance measurements revealed that the primary target of WT h-tau is vesicle endocytosis. Blocking MT assembly using nocodazole prevented tau-induced impairments of endocytosis and neurotransmission. Immunofluorescence imaging analyses revealed that MT assembly by WT h-tau loading was associated with an increased MT-bound fraction of the endocytic protein dynamin. A synthetic dodecapeptide corresponding to dynamin 1-pleckstrin-homology domain inhibited MT-dynamin interaction and rescued tau-induced impairments of endocytosis and neurotransmission. We conclude that elevation of presynaptic WT tau induces de novo assembly of MTs, thereby sequestering free dynamins. As a result, endocytosis and subsequent vesicle replenishment are impaired, causing activity-dependent rundown of neurotransmission. [ABSTRACT FROM AUTHOR]

Study Design: A retrospective study. Purpose: To examine the effectiveness of using an electrodiagnostic technique as a new approach in the clinical diagnosis of extraforaminal stenosis at L5-S1. Overview of Literature: We introduced a new effective approach to the diagnosis of extraforaminal stenosis at the lumbosacral junction using the existing electrophysiological evaluation technique. Methods: A consecutive series of 124 patients with fifth lumbar radiculopathy were enrolled, comprising a group of 74 patients with spinal canal stenosis and a second group of 50 patients with extraforaminal stenosis at L5-S1. The technique involved inserting a pair of needle electrodes into the foraminal exit zone of the fifth lumbar spinal nerves, which were used to provide electrical stimulation. The compound muscle action potentials from each of the tibialis anterior muscles were recorded. Results: The distal motor latency (DML) of the potentials ranged from 11.2 to 24.6 milliseconds in patients with extraforaminal stenosis. In contrast, the DML in patients with spinal canal stenosis ranged from 10.0 to 17.2 milliseconds. After comparing the DML of each of the 2 groups and at the same time comparing the differences in DML between the affected and unaffected side of each patient, we concluded there were statistically significant differences (p <0.01) between the 2 groups. Using receiver operating characteristic curve analysis, the cutoff values were calculated to be 15.2 milliseconds and 1.1 milliseconds, respectively. Conclusions: This approach using a means of DML measurement enables us to identify and localize lesions, which offers an advantage in diagnosing extraforaminal stenosis at L5-S1. [ABSTRACT FROM AUTHOR]

Upon the treatment of bis(arylcarbonyl)diphenylacetylenes with lithium naphthalenide, the carbonyl reduction dominantly occurs over the acetylene reduction. The produced bis(radical anion) intermediate undergoes a synchronous double-radical 5-endo-digcyclization. This simple reduction procedure produces two intriguing classes of ladder π-conjugated skeletons, i.e., emissive methylene-bridged stilbenes and dibenzo[a,e]pentalenes regarded as a cyclic 1,4-diphenylbutadiene. [ABSTRACT FROM AUTHOR]

A cascade-type anionic double cyclization of (o-silylphenyl)(o-halophenyl)acetylenes via lithiation followed by treatment with elemental chalcogen produces silicon and chalcogen-bridged stilbenes. Based on this reaction, a series of silicon and sulfur- or silicon and selenium-bridged ladder distyrylbenzenes have been synthesized. Their chemical modification by oxidation, crystal structures, and photophysical properties are described. [ABSTRACT FROM AUTHOR]

Several in vivo studies report that the fungus Isaria japonica grown on silkworm pupae, classified as a Cordycipitaceae, plays a role in preventing memory deficits and may have a protective role against cognitive impairment. The present study investigated the cognitive effects and safety of I. japonica in older adults with mild cognitive decline. Intervention trial was conducted in subjects over 60 years of age with mild cognitive decline (Mini-Mental State Examination [MMSE] score: 20-27). The subjects consumed the I. japonica supplements twice per day for 12 weeks. The outcome measures included the MMSE score and blood test values before and after the intervention. A total of 25 subjects (aged 64-94 years) were eligible for the study. After the intervention, the MMSE score (mean ± standard deviation) significantly increased from 25.5 ± 1.6 to 27.1 ± 2.4 (P < 0.0001). The blood test revealed no change in any of the hematological and biochemical parameters evaluated. Also, no serious adverse events were reported. Despite several limitations in the study design, the findings of the present study suggest that the fungus I. japonica is safe to consume and it may improve cognitive function in older adults with mild cognitive decline. [ABSTRACT FROM AUTHOR]

Animal behavior is regulated based on the values of future rewards. The phasic activity of midbrain dopamine neurons signals these values. Because reward values often change over time, even on a subsecond-by-subsecond basis, appropriate behavioral regulation requires continuous value monitoring. However, the phasic dopamine activity, which is sporadic and has a short duration, likely fails continuous monitoring. Here, we demonstrate a tonic firing mode of dopamine neurons that effectively tracks changing reward values. We recorded dopamine neuron activity in monkeys during a Pavlovian procedure in which the value of a cued reward gradually increased or decreased. Dopamine neurons tonically increased and decreased their activity as the reward value changed. This tonic activity was evoked more strongly by non-burst spikes than burst spikes producing a conventional phasic activity. Our findings suggest that dopamine neurons change their firing mode to effectively signal reward values in a given situation. [ABSTRACT FROM AUTHOR]

Membrane remodeling is required for dynamic cellular processes such as cell division, polarization, and motility. BAR domain proteins and dynamins are key molecules in membrane remodeling that work together for membrane deformation and fission. In striated muscles, sarcolemmal invaginations termed T-tubules are required for excitation-contraction coupling. BIN1 and DNM2, which encode a BAR domain protein BIN1 and dynamin 2, respectively, have been reported to be causative genes of centronuclear myopathy (CNM), a hereditary degenerative disease of skeletal muscle, and deformation of T-tubules is often observed in the CNM patients. However, it remains unclear how BIN1 and dynamin 2 are implicated in T-tubule biogenesis and how mutations in these molecules cause CNM to develop. Here, using an in cellulo reconstitution assay, we demonstrate that dynamin 2 is required for stabilization of membranous structures equivalent to T-tubules. GTPase activity of wild-type dynamin 2 is suppressed through interaction with BIN1, whereas that of the disease-associated mutant dynamin 2 remains active due to lack of the BIN1-mediated regulation, thus causing aberrant membrane remodeling. Finally, we show that in cellulo aberrant membrane remodeling by mutant dynamin 2 variants is correlated with their enhanced membrane fission activities, and the results can explain severity of the symptoms in patients. Thus, this study provides molecular insights into dysregulated membrane remodeling triggering the pathogenesis of DNM2-related CNM. [ABSTRACT FROM AUTHOR]

The article explores the findings which suggest that dopamine neurons as a key component of the neural network that makes choices from values during ongoing decision-making processes. It mentions the understanding the neural mechanism underlying the decision-making process, along with neurons in the orbitofrontal cortex (OFC) encode multiple decision variables associated with internal processing.

Study Design: Prospective cohort imaging study. Purpose: This study aimed to evaluate lumbar sagittal alignment and range of motion (ROM) using radiographs in a large asymptomatic cohort and identify sex-based differences and age-related changes in the subjects. Overview of Literature: Several researchers have tried to establish normal alignment and kinematic behavior of the lumbar spine, using plain radiographs. Few studies have employed a large and sex-and age-balanced cohort. Methods: Total 627 healthy volunteers (at least 50 males and 50 females in each age decade, from the 3rd to the 8th decade) underwent whole spine radiography in the standing position; lumbar spine radiography was performed for all subjects in the recumbent position. Lumbar lordosis (LL, T12-S1) and ROM during flexion and extension were measured using a computer digitizer. Results: The mean LL was 36.8°±13.2° in the recumbent position and 49.8°±11.2° in the standing position. The LL was greater in the standing position than in the recumbent position; further, LL was higher in females as compared to that in males. Local lordosis at each disk level increased incrementally with distal progression through the lumbar spine in both the positions. Local lordosis at L4-S1 was 29.8°±8.0° in the recumbent position and 34.2°±8.3° in the standing position and occupied 85.1% and 70.8% of the total LL, respectively. However, local lordosis in the standing position decreased with age at L2-3, L3-4, and L4-5 levels. Total lumbar ROM (T12-S1) decreased with age. The ROM in females was higher than that in males. Conclusions: We established the standard value and age-related changes in the lumbar alignment and ROM in each age decade in asymptomatic subjects. These data will be useful and provide the normal values for comparison in clinical practice to identify sexbased differences and age-related changes. [ABSTRACT FROM AUTHOR]

Dynamin is a mechanochemical GTPase essential for membrane fission during clathrimmediated endocytosis. Dynamin forms helical complexes at the neck of clathrin-coated pits and their structural changes coupled with GTP hydrolysis drive membrane fission. Dynamin and its binding protein amphiphysin cooperatively regulate membrane remodeling during the fission, but its precise mechanism remains elusive. In this study, we analyzed structural changes of dynaminamphiphysin complexes during the membrane fission using electron microscopy (EM) and highspeed atomic force microscopy (HS-AFM). Interestingly, HS-AFM analyses show that the dynaminamphiphysin helices are rearranged to form clusters upon GTP hydrolysis and membrane constriction occurs at protein-uncoated regions flanking the clusters. We also show a novel function of amphiphysin in size control of the clusters to enhance biogenesis of endocytic vesicles. Our approaches using combination of EM and HS-AFM clearly demonstrate new mechanistic insights into the dynamics of dynamin-amphiphysin complexes during membrane fission. [ABSTRACT FROM AUTHOR]

Objectives: Total depressive symptom scores in the general population have been reported to follow an exponential distribution except at the lowest end of the range of scores. To verify the hypothesis that total depressive symptom scores follow the distribution of the latent trait, we performed a simulation study of depressive symptom scoring modeled after the Revised Clinical Interview Schedule (CIS-R). To simulate the scoring of ordinal scale items in CIS-R, two sets of random numbers were generated, one expressing the degree of the latent trait of depressive symptoms and another expressing the threshold for each item. Random latent trait numbers greater than those of item thresholds indicated the presence of specific symptoms. Results: When exponential distribution was set to the latent trait's random numbers and each item's threshold had a certain degree of standard deviation, simulated total depressive symptom scores showed a linear pattern except at the lowest end of scores with a log-normal scale. Our results suggest that total depressive symptom scores follow the distribution of the latent trait of depressive symptoms due to the property of ordinal scales, which is characterized by individual differences in the threshold of each item. [ABSTRACT FROM AUTHOR]

Intravenous immunoglobulin (IVIG) is used to treat or prevent severe viral infection, especially cytomegalovirus (CMV) infections. IVIG was characterized to understand its interaction with CMV-infected cells. IVIG retarded CMV spread and reduced virus yields depending on the neutralizing (NT) antibody titer. Immediate early protein synthesis was reduced by IVIG in 3 to 15 h, and IVIG specifically reduced the ratio of 66/68k protein synthesis among immediate early proteins in an NT antibody-dependent manner between 4 and 8 h after infection, indicating that antigenic modulation of CMV-infected cells by IVIG reduced viral protein synthesis and virus production. The half-life of antibody bound to CMV-infected cells was 3.8 h. NT antibody titers to varicella-zoster virus (VZV) and CMV in IVIG were dose dependently absorbed by cells infected with VZV and CMV, respectively, but the antibody titers to CMV and VZV, respectively, were not affected. NT antibody in 0.3 mL of IVIG (15 mg) was specifically absorbed by 108 CMV-infected cells and 107 VZV-infected cells, suggesting that the NT antibody in IVIG might be inactivated by one-tenth of a similar volume of CMV-infected or VZV-infected cells. Various antiviral activities of IVIG may contribute to control and alleviation of CMV infection. [ABSTRACT FROM AUTHOR]

Background: The distributional pattern of total scores on depression screening scales in the general population has not been well studied. Recent studies suggest that the total scores on depression screening scales follow an exponential pattern, with the exception of the lower end of the distribution. To further investigate the findings, we determined the distributions of the total and individual item scores on the Kessler Screening Scale for Psychological Distress (K6). Methods: Data were obtained from the National Survey of Midlife Development in the United States. Participants comprised 6,223 individuals between the ages of 25 and 74. The distributions of the total and individual item scores in various combinations were investigated with histograms and regression analysis. Results: Irrespective of the combination of items, the total and individual item scores followed an exponential pattern except at the lower scores. The estimated rate parameters of regression analysis were similar among distributions with the same number of chosen items. At the lower scores, the distributional patterns of total scores varied according to the ratio of "a little" to "none" for each item response. Conclusions: The present results have the potential to estimate the distribution of depressive symptoms in the general population. While the degree of depressive symptoms varies from individual to individual, an entire population may show a certain mathematical distribution. [ABSTRACT FROM AUTHOR]

Diethyl ether (ether) had been widely used in Japan for anesthesia, despite its explosive properties and toxicity to both humans and animals. We also had used ether as an anesthetic for euthanizing rats for research in the Toxicogenomics Project (TGP). Because the use of ether for these purposes will likely cease, it is required to select an alternative anesthetic which is validated for consistency with existing TGP data acquired under ether anesthesia. We therefore compared two alternative anesthetic candidates, isoflurane and pentobarbital, with ether in terms of hematological findings, serum biochemical parameters, and gene expressions. As a result, few differences among the three agents were observed. In hematological and serum biochemistry analysis, no significant changes were found. In gene expression analysis, four known genes were extracted as differentially expressed genes in the liver of rats anesthetized with ether, isoflurane, or pentobarbital. However, no significant relationships were detected using gene ontology, pathway, or gene enrichment analyses by DAVID and TargetMine. Surprisingly, although it was expected that the lung would be affected by administration via inhalation, only one differentially expressed gene was extracted in the lung. Taken together, our data indicate that there are no significant differences among ether, isoflurane, and pentobarbital with respect to effects on hematological parameters, serum biochemistry parameters, and gene expression. Based on its smallest affect to existing data and its safety profile for humans and animals, we suggest isoflurane as a suitable alternative anesthetic for use in rat euthanasia in toxicogenomics analysis. [ABSTRACT FROM AUTHOR]

Study Design: Cross-sectional study.Objective: To determine the association between lumbar spondylolisthesis and low back pain and symptomatic lumbar spinal stenosis (LSS) in a population-based cohort.Summary Of Background Data: The basic epidemiology of lumbar spondylolisthesis is not well known. There is little information regarding the association between lumbar spondylolisthesis and clinical symptoms such as low back pain and LSS symptoms.Methods: This cross-sectional study included data from 938 participants (308 males, 630 females; mean age, 67.3 years; range, 40-93 years). Lumbar spondylolisthesis was defined as a slip of ≥5%. Diagnostic criteria for symptomatic LSS required the presence of both leg symptoms and radiographic LSS findings on magnetic resonance imaging. The prevalence of low back pain and symptomatic LSS was compared between those with or without spondylolisthesis. Furthermore, we determined the association between the amount of slippage and presence of symptomatic LSS.Results: The prevalence of spondylolisthesis at any level was 15.8% in the total sample, 13.0% in males, and 17.1% in females; the prevalence was not significantly different between males and females (P = 0.09). In both, males and females, symptomatic LSS was related to spondylolisthesis [odds ratio (OR): 2.07; 95% CI: 1.20-3.44]; however, no such association was found for spondylolisthesis and presence of low back pain. The amount of slippage was not related to the presence of symptomatic LSS (P = 0.93).Conclusion: This population-based cohort study revealed that lumbar spondylolisthesis had a closer association with leg symptoms than with low back pain. There was a significant difference in the presence of symptomatic LSS between participants with and without spondylolisthesis. However, the amount of slippage was not related to the presence of symptomatic LSS.Level Of Evidence: 3. [ABSTRACT FROM AUTHOR]

Background: The prevalence of dietary supplements has increased in Japan, and, as a consequence, the adverse events associated with dietary supplement use have become more prominent. Severe adverse events must be reported to the Japanese government via public health centers. However, the number of cases reported to the Japanese government is limited. To clarify this discrepancy, we conducted an internet questionnaire, and surveyed how consumers, physicians and pharmacists acted when they or their patients developed adverse events due to dietary supplement use.Methods: This study was completed by 2732 consumers, 515 physicians, and 515 pharmacist via internet surveillance on November 2015.Results: Although 8.8% of consumers developed adverse events including diarrhea, constipation, stomachache, headache, and nausea and vomiting, most of them did not report their adverse events to public health centers. However, some consumers went to hospitals because of adverse events. We also surveyed how physicians and pharmacists acted when their patients developed adverse events due to dietary supplement use. Most physicians and pharmacists did not report these cases to public health centers because they were unable to definitively prove the cause-and-effect relationship of these adverse events. Furthermore, some physicians and pharmacists did not know how or where to report these adverse events.Conclusions: We clarified the reasons for the limited number of reports of adverse events to the Japanese government in this survey. It is important to encourage not only consumers, but also physicians and pharmacists to report adverse events to public health centers. In addition, an analyzing tool of cause-and-effect relationships might be helpful for physicians and pharmacists. [ABSTRACT FROM AUTHOR]

Background: Glia-neuron interactions play an important role in the development of neuropathic pain. Expression of the pro-inflammatory cytokne → cytokine Interferon-gamma (IFNγ) is upregulated in the dorsal horn after peripheral nerve injury, and intrathecal IFNγ administration induces mechanical allodynia in rats. A growing body of evidence suggests that IFNγ might be involved in the mechanisms of neuropathic pain, but its effects on the spinal dorsal horn are unclear. We performed blind whole-cell patch-clamp recording to investigate the effect of IFNγ on postsynaptic glutamate-induced currents in the substantia gelatinosa neurons of spinal cord slices from adult male rats. Results: IFNγ perfusion significantly enhanced the amplitude of NMDA-induced inward currents in substantia gelatinosa neurons, but did not affect AMPA-induced currents. The facilitation of NMDA-induced current by IFNγ was inhibited by bath application of an IFNγ receptor-selective antagonist. Adding the Janus activated kinase inhibitor tofacitinib to the pipette solution did not affect the IFNγ-induced facilitation of NMDA-induced currents. However, the facilitatory effect of IFNγ on NMDA-induced currents was inhibited by perfusion of the microglial inhibitor minocycline. These results suggest that IFNγ binds the microglial IFNγ receptor and enhances NMDA receptor activity in substantia gelatinosa neurons. Next, to identify the effector of signal transmission from microglia to dorsal horn neurons, we added an inhibitor of G proteins, GDP-b-S, to the pipette solution. In a GDP-b-S-containing pipette solution, IFNγ-induced potentiation of the NMDA current was significantly suppressed after 30 min. In addition, IFNγ-induced potentiation of NMDA currents was blocked by application of a selective antagonist of CCR2, and its ligand CCL2 increased NMDA-induced currents. Conclusion: Our findings suggest that IFNγ enhance the amplitude of NMDA-induced inward currents in substantia gelatinosa neurons via microglial IFNγ receptors and CCL2/CCR2 signaling. This mechanism might be partially responsible for the development of persistent neuropathic pain. [ABSTRACT FROM AUTHOR]

Background: Transient receptor potential (TRP) channels are nonselective cation channels expressed in a variety of sensory structures, and are important molecular mediators of thermal, mechanical, cellular and chemical signals. We investigated the function of one key member of the TRP superfamily, TRPA1, in the spinal dorsal horn using in vivo patch-clamp recordings. Results: The application of allyl isothiocyanate (AITC), a TRPA1 agonist, significantly increased the frequency and amplitude of inhibitory postsynaptic currents (IPSCs; holding potential (VH) = 0 mV) as well as excitatory postsynaptic currents (EPSCs; VH= -70 mV) in substantia gelatinosa (SG) neurons. The AITC-induced increases in EPSC frequency and amplitude were resistant to the Na+ channel blocker tetrodotoxin (TTX). In the presence of the glutamate receptor antagonists CNQX and AP5, AITC did not generate any synaptic activity. The AITC-induced increases in IPSC frequency and amplitude were abolished by TTX or glutamate receptor antagonists. Moreover, the duration of IPSCs enhanced by TRPA1 activation were significantly longer than those of EPSCs enhanced by activation of this channel in the spinal dorsal horn. AITC induced hyperpolarization of the membrane potential of SG neurons in the spinal cord but depolarized the membrane potential in the presence of TTX. Furthermore, we examined the effects of mechanical stimuli to the skin during TRPA1 activation in the spinal dorsal horn in normal rats in both voltage-clamp and current-clamp modes. In the peripheral tissue stimuli test, AITC significantly suppressed EPSCs evoked by pinch or air puff stimulation of the skin. In current-clamp mode, AITC significantly suppressed excitatory postsynaptic potentials (EPSPs) evoked by pinch stimuli. Conclusions: TRPA1 appears to be localized not only at presynaptic terminals on SG neurons, enhancing glutamate release, but also in the terminals of primary afferents innervating spinal inhibitory interneurons, which have synaptic interactions with SG neurons. This study offers further insight into the mechanisms underlying the possible antinociceptive actions of TRPA1 activation in the spinal dorsal horn. Our findings suggest that pharmacological activation of spinal TRPA1 channels may have therapeutic potential for the treatment of pain. [ABSTRACT FROM AUTHOR]

Cyclodextrins are commonly used as a safe excipient to enhance the solubility and bioavailability of hydrophobic pharmaceutical agents. Their efficacies and mechanisms as drug-delivery systems have been investigated for decades, but their immunological properties have not been examined. In this study, we reprofiled hydroxypropyl-β-cyclodextrin (HP-β-CD) as a vaccine adjuvant and found that it acts as a potent and unique adjuvant. HP-β-CD triggered the innate immune response at the injection site, was trapped by MARCO+ macrophages, increased Ag uptake by dendritic cells, and facilitated the generation of T follicular helper cells in the draining lymph nodes. It significantly enhanced Ag-specific Th2 and IgG Ab responses as potently as did the conventional adjuvant, aluminum salt (alum), whereas its ability to induce Ag-specific IgE was less than that of alum. At the injection site, HP-β-CD induced the temporary release of host dsDNA, a damage-associated molecular pattern. DNase-treated mice, MyD88-deficient mice, and TBK1-deficient mice showed significantly reduced Ab responses after immunization with this adjuvant. Finally, we demonstrated that HP-β-CD-adjuvanted influenza hemagglutinin split vaccine protected against a lethal challenge with a clinically isolated pandemic H1N1 influenza virus, and the adjuvant effect of HP-β-CD was demonstrated in cynomolgus macaques. Our results suggest that HP-β-CD acts as a potent MyD88- and TBK1-dependent T follicular helper cell adjuvant and is readily applicable to various vaccines. [ABSTRACT FROM AUTHOR]

Recent studies have shown that epigenetic alterations correlate with carcinogenesis in various tissues. Identification of these alterations might help characterize the early stages of carcinogenesis. We comprehensively analyzed DNA methylation and gene expression in livers obtained from rats exposed to nitrosodiethylamine (DEN) followed by a promoter of hepatic carcinogenesis, phenobarbi-tal (PB). The combination of DEN and PB induced marked increases in number and area of glutathione S-transferase-placental form (GST-P)-positive foci in the liver. In the liver of rats that received 30 mg/kg of DEN, pathway analysis revealed alterations of common genes in terms of gene expression and DNA methylation, and that these alterations were related to immune responses. Hierarchical clustering analysis of the expression of common genes from public data obtained through the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system (TG-GATEs) showed that carcinogenic compounds clustered together. MBD-seq and GeneChip analysis indicated that major histocompatibility complex class Ib gene RT1-CE5, which has an important role in antigen presentation, was hypomethylated around the promoter region and specifically induced in the livers of DEN-treated rats. Further, immunohistochemical analysis indicated that the co-localization of GST-P and protein homologous to RT1-CE5 was present at the foci of some regions. These results suggest that common genes were altered in terms of both DNA methylation and expression in livers, with preneoplastic foci indicating carcinogenic potential, and that immune responses are involved in early carcinogenesis. In conclusion, the present study identified a specific profile of DNA methylation and gene expression in livers with preneoplastic foci. Early epigenetic perturbations of immune responses might correlate with the early stages of hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

We previously reported a toxicogenomics-based prediction model for hepatocarcinogens in which the expression patterns of signature genes following repeated doses of either genotoxic or non-genotoxic compounds were similar. Based on the results of our prediction model, we hypothesized that repeated doses of non-genotoxic carcinogens might have initiating potential. Here, we conducted a two-stage hepatocarcinogenesis study in rats exposed to the initiating agent nitrosodiethylamine (DEN), and hepatotoxic compounds thioacetamide (TAA), methapyrilene (MP) and acetaminophen (APAP) for 1-2 weeks followed by the liver tumor promoter phenobarbital (PB). The duration of initial treatment was determined based on positive results from our prediction model. Combined treatment of 3 or 30 mg/kg of genotoxic DEN and PB induced marked increases in altered hepatocellular foci and a DEN dose-dependent increase in the number and area of glutathione S-transferase-placental form (GST-P)-positive foci. A low number of altered hepatocellular foci were also observed in rats treated with TAA at a dose of 45 mg/kg. MP at a dose of 100 mg/kg induced a very low number of foci, but APAP did not. Hierarchical clustering analysis using gene expression data revealed that 2-week treatment with TAA at a dose of 30 mg/kg and MP at 45 mg/kg induced specific expression of DNA damage-related genes, similar to 1-week treatment with DEN at a dose of 30 mg/kg. These results suggest that TAA and MP induce DNA damage, which partially supports our hypothesis. Although this study does not indicate whether tumor growth in response to these compounds can be assessed in this model, our results suggest that cumulative treatment with non-genotoxic TAA might have initiating potential in the liver. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to investigate the efficacy of additional oblique magnetic resonance imaging (MRI) for the diagnosis of anterior cruciate ligament (ACL) tear and evaluation of ACL remnant tissue. Methods: We retrospectively reviewed the records of 54 knees. Three independent readers evaluated the MR images by the use of three methods: orthogonal sagittal images only (method A); orthogonal sagittal and additional oblique sagittal images (method B); and orthogonal sagittal and oblique coronal images (method C). The sensitivity, specificity, and accuracy for the diagnosis of an ACL tear and the detection of the condition of the ACL remnant tissue by the use of each method were calculated in comparison with arthroscopic findings as the reference standard. Results: The arthroscopic records revealed 27 knees with intact ACLs and 27 with torn ACLs. Among the 27 knees with torn ACLs, 9 did not have continuous remnant tissue and 18 had certain remnant tissue attached to the femur or the posterior cruciate ligament. The specificities and accuracies of methods B and C for diagnosing an ACL tear were higher than those for method A. The sensitivity, specificity, and accuracy of method C for the detection of ACL remnant tissue were higher than those for method A and B. Conclusions: Additional use of oblique MRI improved the accuracy of diagnosis of ACL tear and showed a reasonable level of efficacy in detecting ACL remnant tissue. Level of evidence: Level IV (case series). [ABSTRACT FROM AUTHOR]

Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin-induced diabetic mice. Am J Physiol Renal Physiol 306: F105-F115, 2014. First published October 23, 2013; doi:10.1152/ajprenal.00034.2013.--Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an antioxidant in the diabetic kidney; however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT-/-) and MT-/- mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT-/- mice compared with diabetic MT-/- mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT-/- mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy. [ABSTRACT FROM AUTHOR]

An important technology used in toxicogenomic drug discovery research is the microarray, which enables researchers to simultaneously analyze the expression of a large number of genes. To build a database and data analysis system for use in assessing the safety of drugs and drug candidates, in 2002 we conducted a 5-year collaborative study in the Toxicogenomics Project (TGP1) in Japan. Experimental data generated by such studies must be validated by different laboratories for robust and accurate analysis. For this purpose, we conducted intra- and inter-laboratory validation studies with participating companies in the second collaborative study in the Toxicogenomics Project (TGP2). Gene expression in the liver of rats treated with acetaminophen (APAP) was independently examined by the participating companies using Affymetrix GeneChip microarrays. The intra- and inter-laboratory reproducibility of the data was evaluated using hierarchical clustering analysis. The toxicogenomics results were highly reproducible, indicating that the gene expression data generated in our TGP1 project is reliable and compatible with the data generated by the participating laboratories. [ABSTRACT FROM AUTHOR]

The synthesis and properties of the phosphonium- and borate-bridged stilbenes are reported. The zwitterionic ladder stilbenes were synthesized by the intramolecular cascade cyclization from the phosphanyl- and boryl-substituted diphenylacetylenes 1. The study of the substituent effects of the phosphanyl and boryl groups revealed the significant dependence of the reactivity on both the nucleophilicity of the phosphanyl group and the electrophilicity of the boryl group. Theoretical calculations indicated that this reaction is initiated by the nucleophilic attack of the phosphanyl group, irrespective of the degree of the electrophilicity of the boryl group, in contrast to the analogous intermolecular reaction promoted by the frustrated Lewis pairs of R3P and B(C6F5)3. Moreover, even in the case of compound 1c, which does not undergo cascade cyclization under thermal conditions, photoexcitation promoted the cyclization to produce the corresponding zwitterionic stilbene 2c, indicative of the potential use as a photoresponsive material. The photophysical properties of a series of zwitterionic stilbenes, 2a–e, also display dependence on the substituents. The fluorescence quantum yields (ΦF) of the stilbenes 2dand 2e, with electron-withdrawing diarylboryl groups, were an order of magnitude higher than those of 2a–c, with a dimesitylboryl group. Time-resolved fluorescence spectroscopy as well as the measurement of ΦFin the polymer matrices revealed that the electron-withdrawing diarylboryl groups significantly retarded the nonradiative decay process from the singlet excited state, resulting in a higher ΦF. [ABSTRACT FROM AUTHOR]