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Mellpaladines A-C (1-3) and dopargimine (4) are dopamine-derived guanidine alkaloids isolated from a specimen of Palauan Didemnidae tunicate as possible modulators of neuronal receptors. In this study, we isolated the dopargimine derivative 1-carboxydopargimine (5), three additional mellpaladines D-F (6-8), and serotodopalgimine (9), along with a dimer of serotonin, 5,5'-dihydroxy-4,4'-bistryptamine (10). The structures of these compounds were determined based on spectrometric and spectroscopic analyses. Compound 4 and its congeners dopargine (11), nordopargimine (15), and 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)ethan-1-amine (16) were synthetically prepared for biological evaluations. The biological activities of all isolated compounds were evaluated in comparison with those of 1-4 using a mouse behavioral assay upon intracerebroventricular injection, revealing key functional groups in the dopargimines and mellpaladines for in vivo behavioral toxicity. Interestingly, these alkaloids also emerged during a screen of our marine natural product library aimed at identifying antiviral activities against dengue virus, SARS-CoV-2, and vesicular stomatitis Indiana virus (VSV) pseudotyped with Ebola virus glycoprotein (VSV-ZGP).

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Peroxisome proliferator-activated receptor δ (PPARδ) is considered to be a pharmaceutical target to treat metabolic diseases including atherosclerosis, but there is no PPARδ agonist available for clinical use. We have previously reported the discovery of piperidinyl/piperazinyl benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening methods. In the present study, we found that introduction of a pyrrolidine group into the 4-position of their central piperidine rings enhances hPPARδ activity and subtype selectivity. This led to the discovery of 21 having strong PPARδ agonist activity (EC50 = 3.6 nM) with excellent ADME properties. Furthermore, 21 significantly suppressed atherosclerosis progression by 50-60% with reduction of the serum level of MCP-1 in LDLr-KO mice.

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Ataxia and impaired motor learning are both fundamental features in diseases affecting the cerebellum. However, it remains unclarified whether motor learning is impaired only when ataxia clearly manifests, nor it is known whether the progression of ataxia, the speed of which often varies among patients with the same disease, can be monitored by examining motor learning. We evaluated motor learning and ataxia at intervals of several months in 40 patients with degenerative conditions [i.e., multiple system atrophy (MSA), Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3), SCA6, and SCA31]. Motor learning was quantified as the adaptability index (AI) in the prism adaptation task and ataxia was scored using the Scale for the Assessment and Rating of Ataxia (SARA). We found that AI decreased most markedly in both MSA-C and MSA-P, moderately in MJD, and mildly in SCA6 and SCA31. Overall, the AI decrease occurred more rapidly than the SARA score increase. Interestingly, AIs remained normal in purely parkinsonian MSA-P patients (n = 4), but they dropped into the ataxia range when these patients started to show ataxia. The decrease in AI during follow-up (dAI/dt) was significant in patients with SARA scores < 10.5 compared with patients with SARA scores ≥ 10.5, indicating that AI is particularly useful for diagnosing the earlier phase of cerebellar degeneration. We conclude that AI is a useful marker for progressions of cerebellar diseases, and that evaluating the motor learning of patients can be particularly valuable for detecting cerebellar impairment, which is often masked by parkinsonisms and other signs.

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Peroxisome proliferator-activated receptor δ (PPARδ) is considered to be a target for treating metabolic syndrome, whereas there is no PPARδ agonist in clinical use. Previously, we have reported the discovery of 2-(1-piperidinyl)-1,3-benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening techniques. In this study, we performed the further optimization study of the lead compound 1 focusing on improvement of hydrophobic interactions in the binding site to enhance agonist efficacy for PPARδ and subtype selectivity, thereby discovering a novel PPARδ agonist 5g which exhibited high in vitro agonist activity (hPPARδ, EC50 = 4.1 nM) and sufficiently high selectivity ratio over PPARα and PPARγ. Moreover, 5g revealed a significant upregulation of high-density lipoprotein cholesterol level in vivo.

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Novel PPARδ agonists, 2-(1-piperidinyl)-1,3-benzothiazole derivatives were discovered by our proprietary docking-based virtual screening technique. Compound 1 as the initial hit was effectively modified to acquire PPARδ agonist activity, resulting in the discovery of compound 12 with high agonistic potency for PPARδ and selectivity over PPARα and PPARγ. Compound 12 also had good ADME profiles and showed in vivo efficacy as a lead.

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Predicting the growth rate of meningiomas is important in treatment planning. Although calcification may be an important sign of slow growth in meningiomas, the developmental process and its relation to the tumor growth pattern have not been elucidated. We retrospectively examined the location and degree of calcification in 150 meningiomas (131 asymptomatic tumors) using computed tomography (CT) scans and mean Hounsfield units (mHU). Tumor growth was evaluated using serial imaging studies wherein we calculated tumor doubling time (Td) and identified the growth curve pattern as exponential, intermediate, or decelerating. Tumors in women more frequently had calcification and showed higher mHU than those in men. The mHU was measured at least twice in 57 tumors. Tumors in women showed greater mHU increases than those in men. We found a significant correlation between Td and mHU (R = 0.49). Tumors in men and those in patients in the younger age group grew significantly faster. Multivariate analysis revealed that mHU was the only significant factor affecting Td (P <0.0001). The growth pattern was significantly related to calcification (n = 61, P = 0.0042). Tumors with decelerating growth more frequently showed calcification and had higher mHU than those with exponential growth. Receiver operating characteristic curve analysis revealed that mHU was a better predictor of growth pattern change compared with calcification on CT scan. Meningiomas with high mHU, even without calcification, were likely to show growth deceleration. Mean Hounsfield unit correlated with Td and may be a good quantitative indicator of the growth rate and pattern.

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A new tris-guanidine alkaloid, KB343 (1), was isolated from the aqueous extract of a Palauan zoantharian, Epizoanthus illoricatus. The structure of 1 was determined on the basis of spectral analyses of 1 and its derivatives. The absolute configuration for 1 was determined upon comparison of the CD spectrum of 1 to those obtained from density functional theory calculations. The structure of 1 is highly unusual, as three guanidine groups are present in one ring system.

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The use of positron emission tomography (PET) imaging in progressive multifocal leukoencephalopathy (PML) has rarely been reported. We herein report a set of PET images in a 63-year-old patient with PML. In PML lesions, the uptake of 18F-fluorodeoxyglucose, 11C-methionine, 11C-flumazenil, and [methyl-11C]4'-thiothymidine was decreased, increased, decreased, and unchanged, respectively. These results suggest that glucose metabolism decreased, protein synthesis increased, neuronal integrity decreased, and the DNA synthesis and cellular proliferation of host cells were not activated in PML lesions. These results may reflect very little infiltration by inflammatory cells and active infection with JC virus in this case.

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The cerebellum plays important roles in motor coordination and learning. However, motor learning has not been quantitatively evaluated clinically. It thus remains unclear how motor learning is influenced by cerebellar diseases or aging, and is related with incoordination. Here, we present a new application for testing human cerebellum-dependent motor learning using prism adaptation. In our paradigm, the participant wearing prism-equipped goggles touches their index finger to the target presented on a touchscreen in every trial. The whole test consisted of three consecutive sessions: (1) 50 trials with normal vision (BASELINE), (2) 100 trials wearing the prism that shifts the visual field 25° rightward (PRISM), and (3) 50 trials without the prism (REMOVAL). In healthy subjects, the prism-induced finger-touch error, i.e., the distance between touch and target positions, was decreased gradually by motor learning through repetition of trials. We found that such motor learning could be quantified using the "adaptability index (AI)", which was calculated by multiplying each probability of [acquisition in the last 10 trials of PRISM], [retention in the initial five trials of REMOVAL], and [extinction in the last 10 trials of REMOVAL]. The AI of cerebellar patients less than 70 years old (mean, 0.227; n = 62) was lower than that of age-matched healthy subjects (0.867, n = 21; p < 0.0001). While AI did not correlate with the magnitude of dysmetria in ataxic patients, it declined in parallel with disease progression, suggesting a close correlation between the impaired cerebellar motor leaning and the dysmetria. Furthermore, AI decreased with aging in the healthy subjects over 70 years old compared with that in the healthy subjects less than 70 years old. We suggest that our paradigm of prism adaptation may allow us to quantitatively assess cerebellar motor learning in both normal and diseased conditions.

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This study aimed to create a thick hydroxyapatite (HA) film on the surface of a human tooth via a powder jet deposition (PJD) device for dental handpieces, and to examine the microstructural and mechanical properties of the HA film. In particular, the effects of thermal stress on this film were evaluated. The HA film was created by blasting 3.18-µm HA particles, calcinated at 1,200°C, onto the enamel substrate at room temperature and atmospheric pressure. An HA film with an area of 3 mm × 3 mm was prepared and polished. The following HA film parameters were evaluated from the three-dimensional surface profile: surface roughness, Vickers hardness, and bonding strength before and after artificial aging induced by 500 cycles of thermal cycling (5-55°C). The HA particles in the deposited film were densely packed, and the surface of the HA film was unchanged after thermal cycling. There were also no significant differences in the hardness and the bonding strength of the HA film before and after thermal cycling. The HA film created in this study demonstrated excellent microstructural and mechanical properties, even after the application of thermal stress.

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A powder jet deposition (PJD) process can be used to create a thick hydroxyapatite (HA) film on the surface of a human tooth. This study aimed to investigate in vitro the ability of an HA film, applied using PJD, to diminish dentin permeability. Discs of human coronal dentin were cut perpendicular to the tooth axis and the smear layer was removed by EDTA treatment. The HA film was created by accelerating HA particles, calcinated at 1200°C, onto the dentin discs at room temperature and atmospheric pressure. The surfaces and cross-sections of the HA PJD-treated samples were observed using scanning electron microscopy. Their permeability was indirectly recorded with a split-chamber device utilizing a chemiluminescence technique. MS-coat, a commercial dentin-desensitizing agent, was also evaluated for its effect on reducing liquid flow through the dentin. The scanning electron microscopy images showed that the HA particles were successfully deposited onto the dentin and solidly into the dentin tubules. The permeability of dentin after application of the HA films was significantly lower than that following application of MS-coat. This study showed the potential clinical application of PJD techniques in desensitizing dentin hypersensitivity.

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We examined the effects of cadmium chloride (CdCl(2)) exposure on the phosphorylation and functionality of extracellular signal-regulated kinase 5 (ERK5), a recently identified member of the mitogen-activated protein kinase (MAPK) family, in HK-2 human renal proximal tubular cells. Following exposure to CdCl(2), ERK5 phosphorylation increased markedly, but the level of total ERK5 was unchanged. ERK5 phosphorylation following CdCl(2) exposure was rapid and transient, similar to the time course of ERK1/2 phosphorylation. Treatment of HK-2 cells with the MAPK/ERK kinase 5 inhibitor, BIX02189, suppressed CdCl(2)-induced ERK5 but not ERK1/2 phosphorylation. The CdCl(2)-induced increase of phosphorylated cAMP response element-binding protein (CREB) and activating transcription factor-1 (ATF-1), as well as the accumulation of mobility-shifted c-Fos protein, were suppressed by BIX02189 treatment. Furthermore, BIX02189 treatment enhanced cleavage of poly(ADP-ribose) polymerase and increased the level of cytoplasmic nucleosomes in HK-2 cells exposed to CdCl(2). These findings suggest that ERK5 pathway activation by CdCl(2) exposure might induce the phosphorylation of cell survival-transcription factors, such as CREB, ATF-1, and c-Fos, and may exert a partial anti-apoptotic role in HK-2 cells.

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We report a patient with Villaret's syndrome (left hypoglossopharyngeal nerve, vagus nerve, accessory nerve, and hypoglossal nerve palsies and left Horner's sign) caused by internal carotid artery dissection. He had neck pain on the left side, Horner's sign on the left side and paralysis of the left hypoglossopharyngeal nerve, vagus nerve, accessory nerve, and hypoglossal nerve. Brain MRI revealed no signal from the left internal carotid artery and no brain infarction, although a tumor-like lesion was observed in the left internal carotid artery. Subsequent MRI studies revealed intramural hematoma in the left internal carotid artery, and on the basis of this finding, he was diagnosed with internal carotid artery dissection. He received anticoagulant and antiplatelet therapy. His symptoms improved gradually. The symptoms of internal carotid artery dissection are neck pain, Horner's sign, brain infarction, and lower cranial nerve palsy. A characteristic feature in this case was that brain infarction was not observed. Only 3 similar cases have been reported in the past In all these cases, the patients had a good clinical course and showed complete recovery from the symptoms. Compared with western countries, in Japan, carotid artery dissection is rare. Carotid artery dissection should be considered as a differential diagnosis of lower cranial nerve palsy.

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Medical records of 513 patients with aneurysmal subarachnoid hemorrhage were reviewed to analyze the factors precipitating aneurysmal rupture. There was no seasonal difference in incidence. A significantly higher incidence was observed during 6:00 AM to 9:00 AM and 6:00 PM to 9:00 PM when engaging in daily routines such as defecation/micturition, brushing teeth/washing face/dressing, eating/drinking, and taking a bath. These activities are associated with a Valsalva maneuver that results in sudden pressure changes across the aneurysmal wall precipitating aneurysmal rupture. Aneurysmal rupture occurred most frequently during talking, chatting, watching television, or staying home without any strenuous physical activity. Considering the time spent, the highest incidence rate was found during defecation/micturition. There was no significant difference between men and women or between younger and older age groups regarding activities or events preceding aneurysmal rupture. Hypertension was the most common pre-existing medical problem. The main results are the same as those of the previous study except for aging of the patients.

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BACKGROUND: In cardiac muscle, the gap junction plays a pivotal role in electrical cell-to-cell coupling and impulse propagation between cells. The function of the gap junction depends on the regulation of connexin in the gap junction channel. A dysfunction of the gap junction is possibly caused by the downregulation of connexin or one of arrhythmogenic factors. The mechanisms of ventricular fibrillation, a lethal tachyarrhythmia, have been studied in relation to the remodelling of connexin. OBJECTIVES: To determine what type of connexin 43 (Cx43) remodelling contributes to the generation of ventricular fibrillation and what factors induce the modelling of Cx43. METHODS: Aconitine-induced ventricular fibrillation was induced in hearts isolated from adult rats. Alterations in the electrical activity, the phosphorylation of Cx43 and the expression of Cx43 were evaluated by both intracellular and extracellular recording of the action potentials, Western blotting and immunohistochemistry, respectively. Flutter activity after the application of aconitine shifted spontaneously to fibrillation, showing an electrical interaction between neighbouring cells in close proximity to one another. The facility of the shift from flutter to fibrillation was evaluated as a susceptibility of the heart to fibrillation in relation to gap junction function. The effects of phorbol 12-myristate 13-acetate, angiotensin II (AII) analogues, AII antagonists, the diabetic state, protein kinase A (PKA) activator, cyclic AMP analogues, d-sotalol (class III antiarrhythmic drug) and PKA inhibitors on the susceptibility of the heart to fibrillation were examined. RESULTS: Pathological hearts with heterogeneous expression of Cx43 at the gap junction, such as phorbol 12-myristate 13-acetate-and AII analogue-treated hearts, as well as diabetic hearts, showed a significantly higher susceptibility to fibrillation. On the other hand, hearts with augmentative expression of Cx43 at the gap junction, such as hearts pretreated with a PKA activator, a cyclic AMP analogue (8-bromo-cyclic AMP) or d-sotalol, showed a significantly lower susceptibility to fibrillation. At the beginning of fibrillation, an increase in the cardiac tissue AII level, an augmentation of the protein kinase C (PKC)-epsilon activity, the presence of PKC-mediated hyperphosphorylation, a suppression of the PKA-mediated phosphorylation of Cx43 and a reduction in the expression of Cx43 at the gap junction were observed. These alterations in Cx43 expression were also observed to increase as the fibrillation advanced. CONCLUSIONS: Augmentation of PKC-mediated phosphorylation and suppression of PKA-mediated phosphorylation induces the downward remodelling of Cx43. Such remodelling of Cx43 induces asynchronous electrical activities and makes the ventricular tissue susceptible to fibrillation. PKC is activated by AII. The fibrillation itself remodels Cx43, thereby causing a vicious cycle. As a result, PKC inhibitors, AII antagonists and PKA activators are considered to possibly have a protective effect against the initiation or advancement of ventricular fibrillation.

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BACKGROUND: In the ischemic or hypoxic heart, an impairment of electrical cell-to-cell coupling and a dephosphorylation of the connexins that comprise the gap junction channel were observed. However, it remains to be elucidated whether the dephosphorylation of the connexin during hypoxia is due to alterations in the ionic strength of Ca(2+) or H(+), and how the activation of protein kinase A (PKA) affects the hypoxia-induced abnormal function of the gap junction. OBJECTIVES: The effects of hypoxia, intracellular Ca(2+) overload and intracellular acidosis on the PKA-mediated phosphorylation of connexin 43 (Cx43) were examined in relation to the function of the cardiac gap junction. METHODS: Hearts isolated from adult, male guinea pigs were used. The intercellular electrical cell-to-cell coupling was evaluated by the longitudinal internal resistance and the conduction velocity observed in in vitro experiments using isolated muscle strip preparations. The phosphorylation of Cx43 was evaluated by an immunoblot (Western blot). The localization of immunoreactive Cx43 at the intercalated disk was detected using confocal laser scan microscopy. RESULTS: Cyclic AMP or the activation of PKA promotes the intercellular electrical coupling that accompanies an augmentation of the PKA-mediated phosphorylation of Cx43. Electrical cell-to-cell decoupling and reduction of the PKA-mediated phosphorylation of Cx43 were dependent on the progression of hypoxia. These results agree with those observed in the progression of intracellular Ca(2+) overload or intracellular acidosis. Cyclic AMP or the activation of PKA alleviated the electrical cellular decoupling and the hypoxia-, intracellular Ca(2+) overload- and intracellular acidosis-induced deteriorated expression of Cx43. These ameliorative effects of cyclic AMP on the function of the gap junction and on the expression of Cx43 weakened as the hypoxia progressed, and as the intracellular ionic strength of Ca(2+) and H(+) increased. CONCLUSIONS: In cardiac ventricular muscle cells, cyclic AMP or the activation of PKA promotes electrical cell-to-cell coupling through the gap junction due to an augmentation of the PKA-mediated phosphorylation of Cx43 in the early stage of hypoxia, as well as in normoxia. The suppression of PKA-mediated phosphorylation of Cx43 during hypoxia may be caused by an increase in the intracellular ionic strength of Ca(2+) and H(+). Thus, the activation of cyclic AMP-dependent PKA may have an antiarrhythmic effect in the early stage of hypoxia.

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A 68-year-old woman presented with generalized clonic seizure following a 2-month history of initiative loss, incoherent speech, headache, and left hemiparesis. No systemic signs or symptoms were seen and laboratory studies were within normal range. Computed tomography and magnetic resonance imaging demonstrated a well-delineated small mass with homogeneous enhancement in the right parietal convexity, associated with unusually extensive perifocal edema compared to the size of the mass. Cerebral angiography showed a faint stain fed by the middle meningeal artery. These imaging features were very similar to those of meningioma. Full recovery from the symptoms was achieved by total removal of the lesion and no recurrence was found after 3 years. Histological examination identified the hyaline-vascular type of angiofollicular lymph node hyperplasia (Castleman's disease). Castleman's disease involving the central nervous system is rare, with only 12 previous cases, but should be considered in the diagnosis of intracranial meningeal tumors. The treatment of choice for localized Castleman's disease is complete surgical resection, which is curative in most of the cases.

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