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Phosphodiesterase (PDE) inhibitors have been safely and effectively used in the clinic and increase the concentration of intracellular cyclic nucleotides (cAMP/cGMP). These molecules activate downstream mediators, including the cAMP response element-binding protein (CREB), which controls neuronal excitability and growth responses. CREB gain of function enhances learning and allocates neurons into memory engrams. CREB also controls recovery after stroke. PDE inhibitors are linked to recovery from neural damage and to stroke recovery in specific sites within the brain. PDE2A is enriched in cortex. In the present study, we use a mouse cortical stroke model in young adult and aged male mice to test the effect of PDE2A inhibition on functional recovery, and on downstream mechanisms of axonal sprouting, tissue repair, and the functional connectivity of neurons in recovering cortex. Stroke causes deficits in use of the contralateral forelimb, loss of axonal projections in cortex adjacent to the infarct, and functional disconnection of neuronal networks. PDE2A inhibition enhances functional recovery, increases axonal projections in peri-infarct cortex, and, through two-photonin vivoimaging, enhances the functional connectivity of motor system excitatory neurons. PDE2A inhibition after stroke does not have an effect on other aspects of tissue repair, such as angiogenesis, gliogenesis, neurogenesis, and inflammatory responses. These data suggest that PDE2A inhibition is an effective therapeutic approach for stroke recovery in the rodent and that it simultaneously enhances connectivity in peri-infarct neuronal populations.SIGNIFICANCE STATEMENTInhibition of PDE2A enhances motor recovery, axonal projections, and functional connectivity of neurons in peri-infarct tissue. This represents an avenue for a pharmacological therapy for stroke recovery.

Emergent surgery is necessary in patients with strangulation ileus. However, such procedures are associated with high morbidity and mortality. A retrospective analysis was performed to determine whether the preoperative C-reactive protein/albumin ratio (CAR); neutrophil/lymphocyte ratio (NLR); and prognostic nutritional index (PNI) are good indicators of mortality or morbidity in patients undergoing emergent operations for treatment of strangulation ileus. Emergent surgery was performed for 1698 patients at Tottori Prefectural Central Hospital from 2012 and 2015. Among them, 45 patients (2.7%) were preoperatively diagnosed with strangulation ileus. We evaluated the clinical importance of the preoperative CAR, NLR, and PNI in these patients. We excluded pediatric patients from this study. Postoperative complications developed in 14 of 45 (31.1%) patients. The mean postoperative hospital stay among the 14 patients with postoperative complications was significantly longer than that of the 31 patients without postoperative complications (44.0 versus 11.3 days, respectively; P = 0.006). Three patients died of postoperative complications. The overall operative mortality and morbidity rates were 6.7% and 31.1%, respectively. We found strong correlations of postoperative complications with older age, a longer operation time, and an abnormal preoperative CAR, NLR, and PNI. Not only inflammation, but also a patients' nutritional and immune status appear to be strongly correlated with mortality or morbidity after emergent operations for strangulation ileus. Patients with a high CAR and NLR and low PNI preoperatively must be closely monitored for the occurrence of postoperative complications such as surgical site infections or pulmonary complications.

NO2 and NO generated during a boiling and drying accident, which affects the release of volatilized radioactive Ru into the atmosphere, were examined using various samples including simulated high-...

Stroke is the leading cause of adult disability. Recovery of function after stroke involves signaling events that are mediated by cAMP and cGMP pathways, such as axonal sprouting, neurogenesis, and synaptic plasticity. cAMP and cGMP are degraded by phosphodiesterases (PDEs), which are differentially expressed in brain regions. PDE10A is highly expressed in the basal ganglia/striatum. We tested a novel PDE10A inhibitor (TAK-063) for its effects on functional recovery. Stroke was produced in mice in the cortex or the striatum. Behavioral recovery was measured to 9 weeks. Tissue outcome measures included analysis of growth factor levels, angiogenesis, neurogenesis, gliogenesis, and inflammation. TAK-063 improved motor recovery after striatal stroke in a dose-related manner, but not in cortical stroke. Recovery of motor function correlated with increases in striatal brain-derived neurotrophic factor. TAK-063 treatment also increased motor system axonal connections. Stroke affects distinct brain regions, with each comprising different cellular and molecular elements. Inhibition of PDE10A improved recovery of function after striatal but not cortical stroke, consistent with its brain localization. This experiment is the first demonstration of brain region-specific enhanced functional recovery after stroke, and indicates that differential molecular signaling between brain regions can be exploited to improve recovery based on stroke subtype. Electronic supplementary material The online version of this article (10.1007/s12975-020-00819-8) contains supplementary material, which is available to authorized users.

Background Faster off-rate competitive enzyme inhibitors are generally more sensitive than slower off-rate ones to binding inhibition by enzyme substrates. We previously reported that the cyclic adenosine monophosphate concentration in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) may be higher than that in D2-MSNs. Consequently, compared with slower off-rate phosphodiesterase 10A inhibitors, faster off-rate ones comparably activated D2-MSNs but partially activated D1-MSNs. We further investigated the pharmacological profiles of phosphodiesterase 10A inhibitors with different off-rates. Methods Phosphodiesterase 10A inhibitors with slower (T-609) and faster (T-773) off-rates were used. D1- and D2-MSN activation was assessed by substance P and enkephalin mRNA induction, respectively, in rodents. Antipsychotic-like effects were evaluated by MK-801- and methamphetamine-induced hyperactivity and prepulse inhibition in rodents. Cognition was assessed by novel object recognition task and radial arm maze in rats. Prefrontal cortex activation was evaluated by c-Fos immunohistochemistry in rats. Gene translations in D1- and D2-MSNs were evaluated by translating ribosome affinity purification and RNA sequencing in mice. Results Compared with T-609, T-773 comparably activated D2-MSNs but partially activated D1-MSNs. Haloperidol (a D2 antagonist) and T-773, but not T-609, produced antipsychotic-like effects in all paradigms. T-773, but not T-609 or haloperidol, activated the prefrontal cortex and improved cognition. Overall gene translation patterns in D2-MSNs by all drugs and those in D1-MSNs by T-773 and T-609 were qualitatively similar. Conclusions Differential pharmacological profiles among those drugs could be attributable to activation balance of D1- and D2-MSNs. The “balanced activation” of MSNs by faster off-rate phosphodiesterase 10A inhibitors may be favorable to treat schizophrenia.

Depressive disorders are partly caused by chronic inflammation through the kynurenine (KYN) pathway. Preventive intervention using anti-inflammatory reagents may be beneficial for alleviating the risk of depression. In this study, we focused on the Japanese local citrus plant, Citrus tumida hort. ex Tanaka (C. tumida; CT), which contains flavonoids such as hesperidin that have anti-inflammatory actions. The dietary intake of 5% immature peels of CT fruits slightly increased stress resilience in a subchronic and mild social defeat (sCSDS) model in mice. Moreover, the dietary intake of 0.1% hesperidin significantly increased stress resilience and suppressed KYN levels in the hippocampus and prefrontal cortex in these mice. In addition, KYN levels in the hippocampus and prefrontal cortex were significantly correlated with the susceptibility to stress. In conclusion, these results suggest that dietary hesperidin increases stress resilience by suppressing the augmentation of KYN signaling under sCSDS.

Background TAK-063 is an inhibitor of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the striatum. PDE10A hydrolyzes both cyclic adenosine monophosphate and cyclic guanosine monophosphate and modulates dopamine signaling downstream of receptor activation in both direct and indirect pathways of the striatum. TAK-063 exhibited antipsychotic-like effects in animal models; however, the translatability of these models to the clinical manifestations of schizophrenia and the meaningfulness for new targets such as PDE10A has not been established. Methods The TAK-063 phase 1 program included a comprehensive translational development strategy with the main objective of determining whether the antipsychotic-like pharmacodynamic effects seen in nonclinical models would translate to human subjects. To evaluate this objective, we conducted a single-rising dose study (84 healthy subjects), a positron emission tomography (PET) study (12 healthy subjects), a functional magnetic resonance imaging blood oxygen level-dependent (BOLD) study (27 healthy subjects), and a multiple-rising dose study that included people with schizophrenia (30 healthy Japanese subjects and 47 subjects with stable schizophrenia). In addition, assessments of cognition and electroencephalography (27 healthy subjects and 47 subjects with stable schizophrenia) were included. Results PDE10A engagement by TAK-063 was verified with a novel PET radiotracer for use in primates and humans. TAK-063 showed favorable pharmacokinetic and safety profiles in humans, and TAK-063 reduced ketamine-induced changes in electroencephalography and BOLD signaling in animal models and healthy human subjects. In addition, analogous effects on cognition were observed in animal models and human subjects. Conclusions Overall, the phase 1 results showed some consistent evidence of antipsychotic activity. This translational strategy may be valuable for the future development of novel therapeutic approaches, even when relevant nonclinical models are not available.

Transcranial magnetic stimulation (TMS) is a neurophysiological technique that enables noninvasive evaluation of neuronal excitability in the brain. In the past, a large number of antiepileptic drugs were shown to increase the motor threshold (MT) in clinical TMS studies, suggesting the inhibition of excessive neuronal excitability. To facilitate drug development, the confirmation of similar changes in neurophysiological biomarkers in both preclinical and clinical studies is crucial; however, until now, there have been no data showing the drug efficacies on neuronal excitabilities as measured using TMS in rodents. In this study, we found that the antiepileptic drugs, lamotrigine (10 mg/kg) and retigabine (5 mg/kg), significantly increased the MT in rats using TMS, which is similar to clinical study findings. In addition, we demonstrated that these drugs could inhibit maximal electroshock (MES)-induced seizures in rats when given at the same dose required to be effective in the TMS experiment. These findings suggest that the effects of antiepileptic drugs in our rat TMS system have a similar sensitivity to that of the antiepileptic effects in rats with MES-induced seizures. The measurement of MT in a TMS study may be a noninvasive translational approach for predicting antiepileptic efficacy in drug development.

Key Clinical Massage Here, we report a case with successful treatment of inferior pancreaticoduodenal artery aneurysm rupture due to celiac artery trunk compression caused by the median arcuate ligament. When clinicians see visceral aneurysms, the possibility of arcuate midline ligament compression syndrome (MALS) and ligamentectomy for MALS should be considered.

The catalytic conversion of CO2 to useful compounds is of great importance from the viewpoint of global warming and development of alternatives to fossil fuels. Electrochemical reduction of CO2 using aromatic N-heterocylic molecules is a promising research area. We describe a high performance electrochemical system for reducing CO2 to formate, methanol, and CO using imidazole incorporated into a phosphonium-type ionic liquid-modified Au electrode, imidazole@IL/Au, at a low onset-potential of −0.32 V versus Ag/AgCl. This represents a significant improvement relative to the onset-potential obtained using a conventional Au electrode (−0.56 V). In the reduction carried out at −0.4 V, formate is mainly generated and methanol and CO are also generated with high efficiency at −0.6 ∼ −0.8 V. The generation of methanol is confirmed by experiments using 13CO2 to generate 13CH3OH. To understand the reaction behavior of CO2 reduction, we characterized the reactions by conducting potential- and time-dependent in situ ...

The basal ganglia regulates motor, cognitive, and emotional behaviors. Dysfunction of dopamine system in this area is implicated in the pathophysiology of schizophrenia characterized by positive symptoms, negative symptoms, and cognitive deficits. Medium spiny neurons (MSNs) are principal output neurons of striatum in the basal ganglia. Similar to current antipsychotics with dopamine D(2) receptor antagonism or partial agonism, phosphodiesterase 10A (PDE10A) inhibitors activate indirect pathway MSNs, leading to the expectation of therapeutic potential for the treatment of psychosis. PDE10A inhibitors also activate direct pathway MSNs which may be associated with cognitive functions. These pathways have competing effects on antipsychotic‐like activities and extrapyramidal symptoms in rodents. Therefore, careful consideration of activation pattern of these pathways by a PDE10A inhibitor is critical to produce potent efficacy and superior safety profiles. In this review, we outline the pharmacological profile of TAK‐063, a novel PDE10A selective inhibitor. Our study revealed that off‐rates of PDE10A inhibitors may characterize their pharmacological profiles via regulation of each MSN pathway. TAK‐063, with a faster off‐rate property, could provide a unique opportunity as a novel therapeutic approach to treatment of psychosis and cognitive deficits in schizophrenia. TAK‐063 also has a therapeutic potential in other basal ganglia disorders.

Purpose: We evaluated the clinical importance, such as the occurrence of postoperative pancreatic fistula (POPF) or prognosis, of preoperative serum markers of chronic inflammation, nutrition, and immunity, as well as that of serum tumor markers after curative resection of pancreatic ductal adenocarcinomas (PDACs). Methods: Between 2006 and 2015, 43 patients with PDACs underwent curative resection at Tottori Prefectural Central Hospital. We analyzed which preoperative indicators (i.e., C-reactive protein/albumin ratio [CAR], neutrophil/lymphocyte ratio [NLR], prognostic nutritional index [PNI], carcinoembryonic antigen [CEA], and carbohydrate antigen 19-9 [CA 19-9]) were the most relevant risk factors for occurrence of POPF and poor patient survival. Results: POPF was detected in 8/43 (18.6%) patients. One patient died of pancreatic fistula at 2 months postoperatively. Among nine candidate factors (operative procedure, operation time, tumor stage, preoperative serum amylase, preoperative CAR, NLR, PNI, CEA, and CA 19-9), we did not identify any significant risk factor for the occurrence of POPF. The 5-year overall survival (OS) rate of the 43 patients was 22.4%, and the overall median survival time was 21 months. The multivariate OS analysis demonstrated that high CAR and low PNI were strong preoperative markers of poor prognosis independently of tumor stage. Conclusions: Preoperative CAR and PNI are useful prognostic markers for patients with operable PDACs.

Purpose This paper aims to clarify how to start up and establish a new business by developing, combining and utilizing strategic resources and capabilities. Design/methodology/approach The paper studies the case of Park24 by examining how it created a market, changed the way to compete in the market and utilized its business model effectively to enter a new business. Findings The paper finds that Park24 has become a leading company in its core business by developing its new development staff, its parking sites nationwide, its brand and its IT system, and that it has built a profitable business model and successfully entered the car sharing business by making good use of that business model. Originality/value The case study suggests that Park24 started and developed its core business by accumulating strategic resources and capabilities and establishing a profitable business model, and that it utilized this business model effectively to dominate the market shortly after entering.

This research explores the impact of national culture on cross-border acquisitions. National culture can influence the ways managers cope with uncertainty, and their subsequent business decisions, as was described in seminal research by Hofstede (1991). By their very nature, cross-border acquisitions require that managers deal with different cultures and higher levels of uncertainty. We seek to understand how national culture affects value in cross-border acquisitions using data from the Asia-Pacific Rim region over the period between 2000 and 2009. The countries of this region have large cultural differences and the potential gains from acquisitions are very substantial, so these data are an excellent population for analysis. Our results show that different national cultures have an important influence on financial decisions by firms in ways consistent with classic research by Knight (2006), and also that different national cultures cope with uncertainty in different ways. We find that acquirers from countries with a high aversion to uncertainty conduct fewer cross-border acquisitions. Further, these high uncertainty aversion firms pay a higher price for control in cross-border deals.

TAK-063 is a selective phosphodiesterase 10A (PDE10A) inhibitor that produces potent antipsychotic-like and pro-cognitive effects at 0.3 mg/kg (26% PDE10A occupancy in rats) or higher in rodents through the balanced activation of the direct and indirect pathways of striatal medium spiny neurons (MSNs). In this study, we evaluated the specific binding of TAK-063 using in vitro autoradiography (ARG) and the modulation of brain activity using pharmacological magnetic resonance imaging (phMRI) and electroencephalography (EEG). [3H]TAK-063 significantly accumulated in the caudate—putamen (CPu), ventral pallidum (VP), substantia nigra (SN), hippocampus (Hipp), and amygdala (Amy), but not in the frontal cortex (Fcx), brainstem (Bs), or cerebellum (Cb) in an ARG study using rat brain sections. [3H]TAK-063 accumulation in the CPu was more than eighteen-fold higher than that in the Hipp and Amy. TAK-063 at 0.3 mg/kg increased the blood oxygenation level-dependent (BOLD) signal in the striatum and Amy, and decreased it in the Fcx in a phMRI study with anesthetized rats. TAK-063 at 0.3 mg/kg significantly reduced the ketamine-induced increase in EEG gamma power both in awake and anesthetized rats. TAK-063 at 0.2 mg/kg (35% PDE10A occupancy in monkeys) also reduced the ketamine-induced increase in EEG gamma power in awake monkeys. In line with the EEG data, TAK-063 at 0.3 mg/kg reversed the ketamine-induced BOLD signal changes in the cortex, Bs, and Cb in a phMRI study with anesthetized rats. These data suggest that TAK-063 at about 30% PDE10A occupancy modulates activities of multiple brain regions through activation of neuronal circuits in rats and monkeys.

Huntington's disease (HD) is characterized by progressive loss of striatal medium spiny neurons (MSNs) that constitute direct and indirect pathways: the indirect pathway MSNs is more vulnerable than the direct pathway MSNs. Impairment of cAMP/cGMP signaling by mutant huntingtin is hypothesized as the molecular mechanism underlying degeneration of MSNs. Phosphodiesterase 10A (PDE10A) is selectively expressed in MSNs and degrades both cAMP and cGMP; thus, PDE10A inhibition can restore impaired cAMP/cGMP signaling. Compared with other PDE10A inhibitors, a novel PDE10A inhibitor 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063) showed comparable activation of the indirect pathway MSNs, whereas it produced partial activation of the direct pathway MSNs by its faster off-rate property. In this study, we report the effects of TAK-063 on striatal neurodegeneration and behavioral deficits in the R6/2 mouse model of HD. TAK-063 at 0.5 or 5 mg/kg/day was orally administrated from 4.5-5 to 12 weeks of age, and the effects of TAK-063 were characterized over this period. Repeated treatment with TAK-063 suppressed the reduction of brain-derived neurotrophic factor levels, prevented striatal neurodegeneration, and suppressed increase in seizure frequency, but did not prevent the suppression of body weight gain. As for motor deficits, TAK-063 suppressed the development of clasping behavior and motor dysfunctions, including decreased motor activity in the open field, but did not improve the impairment in motor coordination on the rotarod. Regarding cognitive functions, TAK-063 improved deficits in procedural learning, but was ineffective for deficits in contextual memory. These results suggest that TAK-063 reduces striatal neurodegeneration and ameliorates behavioral deficits in R6/2 mice.

The Glasgow Prognostic Score (GPS), neutrophil/lymphocyte ratio (NLR) and prognostic nutritional index (PNI) are prognostic parameters for malignancies. Additionally, serum squamous cell carcinoma antigen (SCC-Ag) and cytokeratin 19 fragments (CYFRA 21-1) are tumor markers for squamous cell carcinoma. In the present study, the prognostic importance of these markers in patients with resectable thoracic esophageal cancer was investigated. In this retrospective study, 84 enrolled patients diagnosed with resectable clinical stage I-III thoracic esophageal squamous cell carcinomas (ESCCs) underwent thoracic esophageal resection and three-field lymph node dissection at Tottori University Hospital between January 2007 and December 2013. The correlations among preoperative patient markers (GPS, NLR, PNI, SCC-Ag and CYFRA 21-1) and the occurrence of postoperative complications and patient survival were analyzed. The operative mortality was 2.4%, and morbidity was 42.9%. Strong correlations between occurrence of postoperative complications and open thoracotomy (P=0.083) and high-serum CYFRA 21-1 (P=0.007) were observed. In 15 patients with high-serum CYFRA 21-1, postoperative complications were detected in 11 of them (73.3%); on the other hand, complications occurred in 25 of 69 (36.2%) with low-serum CYFRA 21-1. The 5-year disease-free survival rate and 5-year overall survival rate of all the patients were 52.2 and 50.8%, respectively. Among the prognostic parameters, preoperative high NLR was determined to be a poor prognostic factor, independent of the tumor stage in the multivariate analysis. These results may indicate that, in patients with preoperative high-serum CYFRA 21-1, more attention should be paid to the occurrence of postoperative complications. Therefore, in such cases, anastomosis between blood vessels of the substitute esophagus and cervical vessels would be recommended. Furthermore, in patients with high preoperative NLR, effective adjuvant chemoradiotherapy should be considered to prolong the patients' survival, even of stage I or II patients.

Phosphodiesterase 10A (PDE10A) inhibitors are expected to be novel drugs for schizophrenia through activation of both direct and indirect pathway medium spiny neurons. However, excess activation of the direct pathway by a dopamine D1 receptor agonist SKF82958 canceled antipsychotic-like effects of a dopamine D2 receptor antagonist haloperidol in methamphetamine (METH)-induced hyperactivity in rats. Thus, balanced activation of these pathways may be critical for PDE10A inhibitors. Current antipsychotics and the novel PDE10A inhibitor TAK-063, but not the selective PDE10A inhibitor MP-10, produced dose-dependent antipsychotic-like effects in METH-induced hyperactivity and prepulse inhibition in rodents. TAK-063 and MP-10 activated the indirect pathway to a similar extent; however, MP-10 caused greater activation of the direct pathway than did TAK-063. Interestingly, the off-rate of TAK-063 from PDE10A in rat brain sections was faster than that of MP-10, and a slower off-rate PDE10A inhibitor with TAK-063-like chemical structure showed an MP-10-like pharmacological profile. In general, faster off-rate enzyme inhibitors are more sensitive than slower off-rate inhibitors to binding inhibition by enzyme substrates. As expected, TAK-063 was more sensitive than MP-10 to binding inhibition by cyclic nucleotides. Moreover, an immunohistochemistry study suggested that cyclic adenosine monophosphate levels in the direct pathway were higher than those in the indirect pathway. These data can explain why TAK-063 showed partial activation of the direct pathway compared with MP-10. The findings presented here suggest that TAK-063's antipsychotic-like efficacy may be attributable to its unique pharmacological properties, resulting in balanced activation of the direct and indirect striatal pathways.

Stroke is the leading cause of adult disability. Recovery of function after stroke involves signaling events that are mediated by cAMP and cGMP pathways, such as axonal sprouting, neurogenesis, and synaptic plasticity. cAMP and cGMP are degraded by phosphodiesterases (PDEs), which are differentially expressed in brain regions. PDE10A is highly expressed in the basal ganglia/striatum. We tested a novel PDE10A inhibitor (TAK-063) for its effects on functional recovery. Stroke was produced in mice in the cortex or the striatum. Behavioral recovery was measured to 9 weeks. Tissue outcome measures included analysis of growth factor levels, angiogenesis, neurogenesis, gliogenesis, and inflammation. TAK-063 improved motor recovery after striatal stroke in a dose-related manner, but not in cortical stroke. Recovery of motor function correlated with increases in striatal brain-derived neurotrophic factor. TAK-063 treatment also increased motor system axonal connections. Stroke affects distinct brain regions, with each comprising different cellular and molecular elements. Inhibition of PDE10A improved recovery of function after striatal but not cortical stroke, consistent with its brain localization. This experiment is the first demonstration of brain region-specific enhanced functional recovery after stroke, and indicates that differential molecular signaling between brain regions can be exploited to improve recovery based on stroke subtype.

Activation of indirect pathway medium spiny neurons (MSNs) via promotion of cAMP production is the principal mechanism of action of current antipsychotics with dopamine D2 receptor antagonism. TAK‐063 [1‐[2‐fluoro‐4‐(1H‐pyrazol‐1‐yl)phenyl]‐5‐methoxy‐3‐(1‐phenyl‐1H‐pyrazol‐5‐yl)pyridazin‐4(1H)‐one] is a novel phosphodiesterase 10A inhibitor that activates both direct and indirect pathway MSNs through increasing both cAMP and cGMP levels by inhibition of their degradation. The activation of indirect pathway MSNs through the distinct mechanism of action of these drugs raises the possibility of augmented pharmacological effects by combination therapy. In this study, we evaluated the potential of combination therapy with TAK‐063 and current antipsychotics, such as haloperidol or olanzapine after oral administration. Combined treatment with TAK‐063 and either haloperidol or olanzapine produced a significant increase in phosphorylation of glutamate receptor subunit 1 in the rat striatum. An electrophysiological study using rat corticostriatal slices showed that TAK‐063 enhanced N‐methyl‐D‐aspartic acid receptor‐mediated synaptic responses in both direct and indirect pathway MSNs to a similar extent. Further evaluation using pathway‐specific markers revealed that coadministration of TAK‐063 with haloperidol or olanzapine additively activated the indirect pathway, but not the direct pathway. Combined treatment with TAK‐063 and either haloperidol or olanzapine at subeffective doses produced significant effects on methamphetamine‐ or MK‐801‐induced hyperactivity in rats and MK‐801‐induced deficits in prepulse inhibition in mice. TAK‐063 at 0.1 mg/kg did not affect plasma prolactin levels and cataleptic response from antipsychotics in rats. Thus, TAK‐063 may produce augmented antipsychotic‐like activities in combination with antipsychotics without effects on plasma prolactin levels and cataleptic responses in rodents.

Purpose – This paper aims to clarify how to develop characters business models by utilizing new business concepts. Design/methodology/approach – The paper examines three cases in Japan to innovate characters business models: Duffy, Hello Kitty and Kumamon. Findings – The paper suggests that utilizing experience-based promotions, open innovation and a royalty-free strategy enhances customer loyalty to characters, expands customer targets and encourages autonomous collaboration of stakeholders. Originality/value – These case studies clarify how new business models aim to increase customer loyalty to characters and widen customer targets beyond generation, industry and country.

Introduction Phosphodiesterase 10A (PDE10A) is a dual-substrate PDE that hydrolyzes both cAMP and cGMP and is selectively expressed in striatal medium spiny neurons. Recent studies have suggested that PDE10A inhibition is a novel approach for the treatment of disorders such as schizophrenia and Huntington's disease. A positron emission tomography (PET) occupancy study can provide useful information for the development of PDE10A inhibitors. We discovered T-773 as a candidate PET radioligand for PDE10A and investigated its properties by in vitro autoradiography and a PET study in a monkey. Methods Profiling of T-773 as a PET radioligand for PDE10A was conducted by in vitro enzyme inhibitory assay, in vitro autoradiography, and PET study in a monkey. Results T-773 showed a high binding affinity and selectivity for human recombinant PDE10A2 in vitro ; the IC 50 value in an enzyme inhibitory assay was 0.77nmol/L, and selectivity over other PDEs was more than 2500-fold. In autoradiography studies using mouse, rat, monkey, or human brain sections, radiolabeled T-773 selectively accumulated in the striatum. This selective accumulation was not observed in the brain sections of Pde10a -KO mice. The binding of [ 3 H]T-773 to PDE10A in rat brain sections was competitively inhibited by MP-10, a selective PDE10A inhibitor. In rat brain sections, [ 3 H]T-773 bound to a single high affinity site of PDE10A with K d values of 12.2±2.2 and 4.7±1.2nmol/L in the caudate-putamen and nucleus accumbens, respectively. In a monkey PET study, [ 11 C]T-773 showed good brain penetration and striatum-selective accumulation. Conclusion These results suggest that [ 11 C]T-773 is a potential PET radioligand for PDE10A.

Port-site metastasis of hepatocellular carcinoma (HCC) is extremely rare, and only one case has been reported in the English-language literature. Contamination with malignant cells along the needle tract during percutaneous biopsy or radiofrequency ablation is a well-recognized cause of HCC recurrence. Here, we describe a case of port-site metastasis after laparoscopic liver resection of HCC. The patient, who had undergone laparoscopic partial resection of the left lateral segment of the liver 18 months earlier, was diagnosed with HCC. CT showed a nodule in the abdominal wall where the laparoscopic port had been inserted during resection. Local excision was performed, and histological examination revealed HCC consistent with recurrence after laparoscopic resection. The experience described in this report highlights the risk of port-site metastasis of HCC. Imaging for oncologic surveillance after laparoscopic resection must include all port sites.

Real-time demonstration of 30 Gbit/s hierarchical star 8-quadrature amplitude modulation optical access system is presented. By incorporating a novel signed-error radius directed equalisation algorithm with a fractionally-spaced filter structure, the receiver supports high-speed hierarchically-modulated signals. The feasibility of the proposal is confirmed by demonstrating downlink coexistence in a 10 gigabit Ethernet passive optical network that conforms to IEEE 802.3av standards.

We encountered a patient with an adult Bochdalek hernia discovered asymptomatically. A 77-year-old Japanese woman visited a local clinic with chief complaints of melena and difficulty in defecation. Based on the results of the detailed examination in our hospital, she was diagnosed with a rectal gastrointestinal stromal tumor (GIST) with a concurrent asymptomatic adult right-sided Bochdalek hernia. Because the tumor was large, laparoscopic abdominoperineal rectal amputation was performed after systemic imatinib therapy. During the surgery, we found a right diaphragmatic defect more than 13cm in long dia., through which the right hepatic lobe, colon, and greater omentum had prolapsed into the right thoracic cavity. No visceral adhesions were noted. No hernia sac was observed. Adult Bochdalek hernia is a relatively rare condition, and only three (incidentally discovered) cases of asymptomatic Bochdalek hernia, including the present case, have been reported in Japan. Here we provide a case report for the patient, who was followed-up without hernia surgery, plus a review of the literature.

Background Activation of indirect pathway medium spiny neurons (MSNs) via promotion of cAMP production is the principal mechanism of action (MOA) of current antipsychotics with dopamine D2 receptor antagonism. Phosphodiesterase 10A (PDE10A) inhibitors activate both direct and indirect pathway MSNs by increasing both cAMP and cGMP levels by inhibiting their degradation, which might be expected to promote activation of intracellular signaling similar to that of D2 antagonists in the indirect pathway MSNs. Thus, the activation of the indirect MSN pathway through the distinct MOA of these compounds raises the possibility of augmented pharmacologic effects with combined treatment. In this study, we compared gene-regulation patterns in the indirect pathway MSNs induced by the PDE10A inhibitors T-773 and T-609, and the D2 antagonist haloperidol, using a cell-type-specific comprehensive gene expression analysis in Drd2-bacTRAP (translating ribosome affinity purification) mice. The pharmacologic effects of combined treatment with another PDE10A inhibitor, TAK-063, and clinically used antipsychotics, haloperidol (HAL) and olanzapine (OLA), were evaluated in multiple rodent models. Methods Male ICR mice, Drd2-bacTRAP mice, and Sprague-Dawley rats were used. The indirect pathway MSN-specific gene expression changes by T-773, T-609, and HAL were investigated using RNA sequencing of striatal samples of Drd2-bacTRAP mice. The activation of MSNs in rats was evaluated by measuring glutamate receptor subunit 1 phosphorylation (pGluR1) levels. An in vitro electrophysiological study on the corticostrial pathway in rats was conducted in a slice preparation. The activation of each MSN pathway was assessed by inducing genes as pathway-specific markers: enkephalin for the indirect pathway and substance P for the direct pathway. Suppression of MK-801- or methamphetamine (METH)-induced hyperactivity was assessed by measuring locomotor activity for 2 hours after administration of these stimulants to rats. Improvement of prepulse inhibition (PPI) was investigated in a MK-801-induced PPI deficit mouse model. Results Translational profiling in Drd2-bacTRAP mice treated with the PDE10A selective inhibitors, T-773 and T-609, and with HAL suggested regulatory of a largely overlapping signaling pathway by these compounds in the indirect pathway MSNs: 87% of the genes regulated by HAL were also regulated by both T-773 and T-609. Combined treatment with TAK-063 and either HAL or OLA produced an augmented effect on pGluR1 in the rat striatum. An electrophysiological study in rat brain slices indicated that TAK-063 enhanced synaptic responses to a similar extent in both direct and indirect pathway MSNs. Additional evaluation using MSN pathway-specific markers revealed that coadministration of TAK-063 with HAL or OLA additively activated the indirect pathway, but not the direct pathway. Combined treatment with TAK-063 (0.1 mg/kg p.o.) and either HAL (0.3 mg/kg p.o.) or OLA (3 mg/kg p.o.) at subeffective doses produced augmented effects on METH- or MK-801–induced hyperactivity in rats and MK-801–induced PPI deficits in mice. TAK-063 at 0.1 mg/kg did not affect plasma prolactin levels and cataleptic response induced by HAL or OLA in rats. Discussion PDE10A inhibitors and HAL showed similar patterns of gene regulation in indirect pathway MSNs in mice. Combined treatment with TAK-063 and either HAL or OLA at subeffective doses produced significant antipsychotic-like effects but no augmentation of the plasma prolactin level and cataleptic response. Although further preclinical and clinical studies will be needed, TAK-063 may provide a novel mechanism as a PDE10A inhibitor for use as combination therapy in schizophrenia.

Chemical Th-U-total Pb isochron method (CHIME) of monazite and xenotime from three leucogranites in far-eastern Nepal revealed the presence of Carboniferous inherited grains of monazite and intense intrusion of leucogranites around 18–16 Ma in the High Himalaya. In garnet-bearing sillimanite-muscovite-biotite leucogranite, most monazite grains have inherited cores with the chemical dates of ~ 504–418 and ~ 342–272 Ma, which were overgrown by Early Miocene mantles and rims of 17.9 ± 1.5 Ma. Early Ordoviciain and Carboniferous ages are rarely found in the same euhedral-subhedral cores. In addition to the previously recognized Early Paleozoic magmatism, monazite cores with Carboniferous ages in Early Miocene leucogranites provide evidence for two periods of magmatism at the base of the High Himalaya prior to the Cenozoic Himalayan orogeny. In muscovite-biotite leucogranite, no inherited domains were observed in monazite and xenotime grains. They yielded the CHIME monazite and xenotime dates of 16.1 ± 2.0 and 19.8 ± 6.5 Ma, respectively. Monazite grains adjacent to xenotime have significantly lower concentrations of UO 2 and Y 2 O 3 compared to those isolated from xenotime. These results imply that xenotime influences Y and U contents in monazite, reflecting local equilibrium system. In aplitic leucogranite, monazite grains yielded the mean of apparent chemical date of 18.0 ± 2.2 Ma. The CHIME monazite ages of ~ 18–16 Ma in three leucogranites reflect the timing of melt crystallization.

To identify the superconducting symmetry of Fe-based superconductors, we studied effects of nonmagnetic-impurities on T c , magnetic excitation spectra x″ and NMR 1/T 1 − T curve, which are sensitive to the relative signs between the order parameters on the disconnected Fermi surfaces in reciprocal space, because the symmetry is closely connected with the pairing mechanism: If the signs are opposite (symmetry S ±), the mechanism is considered to be a magnetic one, but when the signs are the same (symmetry S ++), a novel mechanism is plausible because the ordinary phonon mechanism cannot realize the T c value as high as ∼55 K found in Ln1111 (Ln=lanthanide). Results are as follows: (a) The very small rates of T c -suppression by impurity atoms M of LnFe1−y M y As0.89−x F0.11+x (M=Ni, Co, Ru) can be explained only by S ++. (b) The x″-data for Ba(Fe, Co)2As2 (T c ∼ 23 K) and Ca-Fe-Pt-As crystals seem to be well explained by S ++ rather than by S ±. (c) The nuclear magnetic resonance data can be consistently understood by S ++, too. These results suggest the S ++ symmetry and a novel pairing mechanism, which can be considered to be related to the elastic softening of C66 induced by the orbital fluctuation of the system.

Port-site metastasis of hepatocellular carcinoma (HCC) is extremely rare, and only one case has been reported in the English-language literature. Contamination with malignant cells along the needle tract during percutaneous biopsy or radiofrequency ablation is a well-recognized cause of HCC recurrence. Here, we describe a case of port-site metastasis after laparoscopic liver resection of HCC. The patient, who had undergone laparoscopic partial resection of the left lateral segment of the liver 18 months earlier, was diagnosed with HCC. CT showed a nodule in the abdominal wall where the laparoscopic port had been inserted during resection. Local excision was performed, and histological examination revealed HCC consistent with recurrence after laparoscopic resection. The experience described in this report highlights the risk of port-site metastasis of HCC. Imaging for oncologic surveillance after laparoscopic resection must include all port sites.

Oryzacystatins I and II, cysteine proteinase inhibitors in rice seeds, caused growth retardation of different species of bean insect pests, Callosobruchus chinensis (Coleoptera) and Riptortus clavatus (Hemiptera), when added to their diets at concentrations of 0.3-0.5% (w/w). At concentrations of up to 1%, almost all insects died. Our results suggest the usefulness of cystatin for insect pest control and also the critical role of cysteine proteinase in the digestive events of insects.

We report an integrated pump source for distributed Raman amplification (DRA) in multicore fiber (MCF) where the MCF cores share pump laser diodes (LDs). The DRA requires many LDs and passive components if it is to obtain a flat and polarization-insensitive gain spectrum, especially in MCF transmission. To reduce the number of optical components, we propose a pump configuration where two cores share a pump LD set. The number of LDs is reduced almost by half. We integrate passive components, such as wavelength division multiplexers and polarization beam combiners, in a planar lightwave circuit to realize the LD sharing circuit. With our proposed pump sharing configuration, we obtain a DRA gain of more than 5.7 dB over the entire C-band in an MCF.