Radical Stitching Polymerization and Its Alternating Copolymerization.

Polymers possessing saturated fused polycycles in the main chain repeating unit have been underexplored despite their potential utility based on their expected properties such as high rigidity, chemical resistance, transparency, and thermal stability. In this regard, herein, we developed a radical stitching polymerization of styryl vinyl ketones for the synthesis of polyketones possessing saturated fused bicyclic repeating units. The polymerization proceeded smoothly with a high degree of stitching efficiency in a chain-growth manner under free radical conditions. This method was further extended to the alternating copolymerization of styryl vinyl ketones and 1-styryl-2-vinylbenzenes, representing the first alternating stitching copolymerization of two different monomers. The obtained polymers were found to show promising thermal properties and high transparency in the visible light region.

Radiation dose analysis in interventional neuroradiology of unruptured aneurysm cases.

This study aimed to evaluate the radiation doses (peak skin dose (PSD) and bilateral lens dose) for each interventional neuroradiology procedure. A direct measurement system consisting of small radiophotoluminescence glass dosimeter chips and a dosimetry cap made of thin stretchable polyester was used for radiation dosimetry. The mean PSDs for each procedure were 1565 ± 590 mGy (simple technique coil embolization (STCE) cases), 1851 ± 825 mGy (balloon-assisted coil embolization (BACE) cases), 2583 ± 967 mGy (stent-assisted coil embolization (SACE) cases), 1690 ± 597 mGy (simple flow-diverter stenting (FDS) cases), and 2214 ± 726 mGy (FDS + coiling cases). The mean PSD was higher in SACE cases than in STCE, BACE, and simple FDS cases. Moreover, the PSD exceeded 2000 mGy and 3000 mGy in 46 (67.6%) and 19 (27.9%) SACE cases, respectively. The left lens doses for each procedure were 126 ± 111 mGy (STCE cases), 163 ± 152 mGy (BACE cases), 184 ± 148 mGy (SACE cases), 144 ± 60 mGy (simple FDS cases), and 242 ± 178 mGy (FDS + coiling cases). The left lens dose in SACE cases was higher than that in STCE cases and exceeded 500 mGy in 3 (4.4%) patients. In FDS + coiling cases, the mean PSD and left lens dose were 2214 ± 726 mGy and 242 ± 178 mGy, respectively. The left lens dose was higher than that in the STCE and BACE cases, with two (15.4%) patients receiving doses >500 mGy in FDS + coiling cases. The detailed data obtained in this study are expected to contribute to the promotion of radiation dose optimization.

Repeated activation of Trpv1-positive sensory neurons facilitates tumor growth associated with changes in tumor-infiltrating immune cells.

It is considered that sensory neurons extend into the tumor microenvironment (TME), which could be associated with tumor growth. However, little is known about how sensory signaling could promote tumor progression. In this study, chemogenetic activation of transient receptor potential vanilloid 1 (Trpv1)-positive sensory neurons (C-fibers) by the microinjection of AAV-hSyn-FLEX-hM3Dq-mCherry into the sciatic nerve dramatically increased tumor volume in tumor-bearing Trpv1-Cre mice. This activation in Trpv1::hM3Dq mice that had undergone tumor transplantation significantly reduced the population of tumor-infiltrating CD4+ T cells and increased the mRNA level of the M2-macrophage marker, CX3C motif chemokine receptor 1 (Cx3cr1) in immunosuppressive cells, such as tumor-associated macrophages (TAMs) and tumor-infiltrating monocytic myeloid-derived suppressor cells (M-MDSCs). Under these conditions, we found a significant correlation between the decreased expression of the M1-macrophage marker Tnf and tumor volume. These findings suggest that repeated activation of Trpv1-positive sensory neurons may facilitate tumor growth along with changes in tumor-infiltrating immune cells.

Evaluation of the accuracy of buccal bone thickness measurement from cone beam computed tomography compared with histologic analysis.

STATEMENT OF PROBLEM: Three-dimensional radiographic assessment of buccal bone thickness and its integrity from cone beam computed tomography (CBCT) plays an essential role in immediate implant placement. However, the accuracy of CBCT measurements for the assessment of buccal bone thickness adjacent to maxillary anterior teeth is not well understood. PURPOSE: The purpose of this observational study was to evaluate the accuracy of measuring the buccal bone thickness of maxillary anterior teeth from CBCT compared with direct measurement from histologic sections. A secondary objective was to analyze whether a minimal level of buccal bone thickness of maxillary anterior teeth can be detected from the CBCT scan. MATERIAL AND METHODS: Five embalmed human cadavers with a complete anterior dentition were included in this study, providing 30 teeth for evaluation. After preparing reference notches at the gingival margin of each tooth, the anterior segments were scanned. The buccal bone thickness at 3, 5, and 7 mm from the notches was measured on the cross-sections obtained from the CBCT and histomorphometric images for a total of 90 sites. The CBCT measurements were compared with the histomorphometric measurements, and their agreement was assessed by using the Bland-Altman plots and intraclass correlation coefficients. The sensitivity and specificity of buccal bone detection were calculated from the CBCT scan. RESULTS: Histologic examination showed absence of the buccal bone in 29 sites (32%). The mean ±standard deviation thickness of the buccal bone was 0.52 ±0.05 mm (range: 0 to 1.97 mm) from the CBCT analysis and 0.40 ±0.05 mm (range: 0 to 1.67 mm) from histology. Measurements obtained from the CBCT sections significantly overestimated the buccal bone thickness when compared with the histologic evaluation (P=.001). The intraclass correlation coefficient of buccal bone thickness between the CBCT and histology was ≤0.53, an agreement considered as poor. The sensitivity of the CBCT as a diagnostic tool to detect the presence or absence of the buccal bone was 75.4%, and the specificity was 65.5%. CONCLUSIONS: The buccal bone thickness of maxillary anterior teeth was less than 2 mm at all sites as measured with both CBCT and histology evaluations. CBCT measurements had relatively low accuracy and reliability for the measurement of buccal bone thickness. These findings should be considered when using CBCT as a measuring tool for thin bone structures.

Possible mechanism for improving the endogenous immune system through the blockade of peripheral µ-opioid receptors by treatment with naldemedine.

BACKGROUND: It has been considered that activation of peripheral µ-opioid receptors (MORs) induces side effects of opioids. In this study, we investigated the possible improvement of the immune system in tumour-bearing mice by systemic administration of the peripheral MOR antagonist naldemedine. METHODS: The inhibitory effect of naldemedine on MOR-mediated signalling was tested by cAMP inhibition and ß-arrestin recruitment assays using cultured cells. We assessed possible changes in tumour progression and the number of splenic lymphocytes in tumour-bearing mice under the repeated oral administration of naldemedine. RESULTS: Treatment with naldemedine produced a dose-dependent inhibition of both the decrease in the cAMP level and the increase in ß-arrestin recruitment induced by the MOR agonists. Repeated treatment with naldemedine at a dose that reversed the morphine-induced inhibition of gastrointestinal transport, but not antinociception, significantly decreased tumour volume and prolonged survival in tumour-transplanted mice. Naldemedine administration significantly decreased the increased expression of immune checkpoint-related genes and recovered the decreased level of toll-like receptor 4 in splenic lymphocytes in tumour-bearing mice. CONCLUSIONS: The blockade of peripheral MOR may induce an anti-tumour effect through the recovery of T-cell exhaustion and promotion of the tumour-killing system.

Successful trans-femoral retrieval of a stuck axillary Impella 5.0 device.

We describe a case in which an axillary Impella 5.0, stuck in an area of calcification in the right subclavian artery, could not be retrieved in the usual manner. However, it was successfully removed using a long 22-Fr sheath and snaring catheter by means of the trans-femoral artery. Device retrieval using the trans-femoral artery snare technique is considered a valid option for removing the Impella device in patients who exhibit this complication.

Normal aging induces PD-1-enriched exhausted microglia and A1-like reactive astrocytes in the hypothalamus.

Hypothalamic aging is considered to be critical for systemic aging, and the accumulation of "exhausted glial cells" in the hypothalamus may contribute to brain dysfunction. In this study, we used normal aging mice and investigated aging-specific transcriptional identities of microglia and astrocytes in the hypothalamus. We confirmed that normal aging promoted anxiety, induced impairment of motor coordination and reduced physical strength of muscle in mice. To investigate the senescence of hypothalamic glial cells, we isolated CD11b-positive microglia and ACSA-2-positive astrocytes from the hypothalamus of aged mice using magnetic-activated cell sorting (MACS). The mRNA level of p16INK4A was dramatically increased in the hypothalamic microglia of aged mice compared to young mice. Furthermore, the expression of programmed cell death 1 (PD-1) as well as A1-like astrocyte mediators in the hypothalamic microglia was dramatically induced by aging, indicating that normal aging may produce PD-1-enriched "exhausted microglia" in the hypothalamus. Furthermore, neuroinflammatory A1-like reactive astrocytes with a p16INK4A-positive senescent state were predominantly detected in the hypothalamus of aged mice. Exhausted microglia were also detected in the prefrontal cortex of aged mice, whereas astrocytic neuroinflammation was milder than that observed in the hypothalamus, even with p16INK4A-positive senescence. These results suggest that the production of PD-1-enriched exhausted and senescent microglia and neuroinflammatory A1-like reactive astrocytes in the hypothalamus may partly contribute to aging-related emotional and physical dyscoordination.

Further investigation of the rapid-onset and short-duration action of the G protein-biased µ-ligand oliceridine.

TRV130 (oliceridine), a G protein-biased ligand for µ-opioid receptor, has recently been synthesized. It is considered to have strong antinociceptive effects and only minor adverse effects. However, whether or not oliceridine actually exhibits an ideal pharmacological profile as an analgesic has not yet been fully clarified in animal studies. This study examined the pharmacological profile of oliceridine in cells and animals. Oliceridine (10 µM) did not produce any µ-opioid receptor internalization in cells even though it increased impedance, which reflects the activation of Gi protein using the CellKey™ system, and inhibited the formation of cAMP. In mice, oliceridine (0.3-10 mg/kg) produced a dose-dependent antinociceptive effect with a rapid-onset and short-duration action in the hot-plate test, as well as antihyperalgesia after sciatic nerve ligation without the development of antinociceptive tolerance using the thermal hyperalgesia test. On the other hand, oliceridine inhibited gastrointestinal transit. Furthermore, oliceridine produced rapid-onset hyperlocomotion at antinociceptive doses; sensitization developed in mice and an emetic effect was observed in ferrets. These results indicate that, although oliceridine may produce dopamine-related behaviors even through selective stimulation of the G-protein-biased µ-opioid receptor pathway, it still offers advantages for breakthrough pain without antinociceptive tolerance with adequate doses.

Direct evidence that the brain reward system is involved in the control of scratching behaviors induced by acute and chronic itch.

In the present study, we demonstrated that there is a direct relationship between scratching behaviors induced by itch and functional changes in the brain reward system. Using a conditional place preference test, the rewarding effect was clearly evoked by scratching under both acute and chronic itch stimuli. The induction of ΔFosB, a member of the Fos family of transcription factors, was observed in dopamine transporter (DAT)-positive dopamine neurons in the ventral tegmental area (VTA) of mice suffering from a chronic itch sensation. Based on a cellular analysis of scratching-activated neurons, these neurons highly expressed tyrosine hydroxylase (TH) and DAT genes in the VTA. Furthermore, in an in vivo microdialysis study, the levels of extracellular dopamine in the nucleus accumbens (NAcc) were significantly increased by transient scratching behaviors. To specifically suppress the mesolimbic dopaminergic pathway using pharmacogenetics, we used the TH-cre/hM4Di mice. Pharmacogenetic suppression of mesolimbic dopaminergic neurons significantly decreased scratching behaviors. Under the itch condition with scratching behaviors restricted by an Elizabethan collar, the induction of ΔFosB was found mostly in corticotropin-releasing hormone (CRH)-containing neurons of the hypothalamic paraventricular nucleus (PVN). These findings suggest that repetitive abnormal scratching behaviors under acute and chronic itch stimuli may activate mesolimbic dopamine neurons along with pleasant emotions, while the restriction of such scratching behaviors may initially induce the activation of PVN-CRH neurons associated with stress.

Effect of Medical-Grade Polyurethane Sponges on Sinus Membrane Perforation With a Lateral Window Approach.

The most commonly reported complication during the sinus elevation surgical procedure is the perforation of the Schneiderian membrane. The aim of this retrospective study was to compare the rate of sinus membrane perforation during lateral window augmentation using either conventional sinus curettes or medical-grade polyurethane sponges. This retrospective study included patients who received a lateral window approach for sinus floor elevation. The sinus elevation procedures using medical-grade polyurethane sponges (test) or conventional curettes (control) were recorded and analyzed. All subjects' demographic data and preexisting conditions were evaluated. A total of 38 procedures met inclusion criteria, and those data were evaluated for analysis. There were no statistically significant differences in demographic data or preexisting conditions including age, sex, treatment location, presence and absence of septum, Schneiderian membrane thickness, and residual bone height between test and control groups. The membrane perforation rate was 7% in the test group and 43% in the control group; however, this difference did not reach statistical significance (P = .064). Within the limitations of this study, although there was no statistically significant reduction of sinus membrane perforation with the use of medical-grade polyurethane sponges, the decreased incidence of perforation might be of clinical significance.

Levels of growth factors from platelet-rich fibrin from chronic periodontitis versus periodontally healthy subjects: a pilot study.

OBJECTIVES: This study aimed to (1) compare the amounts of growth factors from platelet-rich fibrin (PRF) between chronic periodontitis and periodontally healthy subjects and (2) evaluate the relationships between the amounts of growth factors from PRF with complete blood counts (white blood cell (WBC) and platelet counts) and the serum concentrations of IL-1ß, IL-6, and tumor necrosis factor-α (TNF-α). MATERIALS AND METHODS: Venous blood was collected from chronic periodontitis (test) and periodontally healthy subjects (control). PRF and serum were collected from the centrifuged blood. Liquid exudates from the compression of PRF were collected. The compressed PRF membranes were incubated in saline, and eluted aliquots were collected at 1, 24, and 72 h, and the membranes were then digested with trypsin. Epidermal growth factor, insulin-like growth factor-1, platelet-derived growth factor-BB, transforming growth factor-ß1, and vascular endothelial growth factor in the exudates and eluents were quantified by ELISA. Serum was used for IL-1ß, IL-6, and TNF-α quantifications. Complete blood counts were measured. RESULTS: There were no significant differences in the amounts of growth factors from PRF exudates and membranes measured between groups (all p > 0.05). The test group had significantly higher WBC (p < 0.05). However, there was no significant correlation between the WBC and the amounts of the growth factors from PRF (all p > 0.05). CONCLUSIONS: PRF can be utilized as an autologous source of growth factors not affected by periodontal condition and WBC level. CLINICAL RELEVANCE: The amounts of growth factors from PRF were not affected by the periodontal condition of the patient.

Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms.

Mucopolysaccharidoses (MPS) are a group of genetic deficiencies of lysosomal enzymes that catabolize glycosaminoglycans (GAG). Here we describe a novel MPS-like disease caused by a specific mutation in the VPS33A gene. We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG. However, these patients could not be diagnosed enzymatically as MPS. They showed extremely high levels of plasma heparan sulphate (HS, one of GAG); 60 times the normal reference range and 6 times that of MPS patients. Additionally, most patients developed heart, kidney, and hematopoietic disorders, which are not typical symptoms for conventional MPS, leading to a fatal outcome between 1 and 2-years old. Using whole exome and Sanger sequencing, we identified homozygous c.1492C > T (p.Arg498Trp) mutations in the VPS33A gene of 13 patients. VPS33A is involved in endocytic and autophagic pathways, but the identified mutation did not affect either of these pathways. Lysosomal over-acidification and HS accumulation were detected in patient-derived and VPS33A-depleted cells, suggesting a novel role of this gene in lysosomal functions. We hence propose a new type of MPS that is not caused by an enzymatic deficiency.

Activation of ventral tegmental area dopaminergic neurons reverses pathological allodynia resulting from nerve injury or bone cancer.

Chronic pain induced by nerve damage due to trauma or invasion of cancer to the bone elicits severe ongoing pain as well as hyperalgesia and allodynia likely reflecting adaptive changes within central circuits that amplify nociceptive signals. The present study explored the possible contribution of the mesolimbic dopaminergic circuit in promoting allodynia related to neuropathic and cancer pain. Mice with ligation of the sciatic nerve or treated with intrafemoral osteosarcoma cells showed allodynia to a thermal stimulus applied to the paw on the injured side. Patch clamp electrophysiology revealed that the intrinsic neuronal excitability of ventral tegmental area (VTA) dopamine neurons projecting to the nucleus accumbens (N.Acc.) was significantly reduced in those mice. We used tyrosine hydroxylase (TH)-cre mice that were microinjected with adeno-associated virus (AAV) to express channelrhodopsin-2 (ChR2) to allow optogenetic stimulation of VTA dopaminergic neurons in the VTA or in their N.Acc. terminals. Optogenetic activation of these cells produced a significant but transient anti-allodynic effect in nerve injured or tumor-bearing mice without increasing response thresholds to thermal stimulation in sham-operated animals. Suppressed activity of mesolimbic dopaminergic neurons is likely to contribute to decreased inhibition of N.Acc. output neurons and to neuropathic or cancer pain-induced allodynia suggesting strategies for modulation of pathological pain states.

Effect of ghrelin on the motor deficit caused by the ablation of nigrostriatal dopaminergic cells or the inhibition of striatal dopamine receptors.

Ghrelin plays roles in a wide range of central functions by activating the growth hormone secretagogue receptor (GHSR). This receptor has recently been found in the substantia nigra (SN) to control dopamine (DA)-related physiological functions. The dysregulation of DA neurons in the SN pars compacta (SNc) and the consequent depletion of striatal DA are known to underlie the motor deficits observed in Parkinson's disease (PD). In the present study, we further investigated the role of the SN-ghrelin system in motor function under the stereotaxic injection of AAV-CMV-FLEX-diphtheria toxin A (DTA) into the SN of dopamine transporter (DAT)-Cre (DATSN::DTA) mice to expunge DA neurons of the SNc. First, we confirmed the dominant expression of GHSR1a, which is a functional GHSR, in tyrosine hydroxylase (TH)-positive DA neurons in the SNc of control mice. In DATSN::DTA mice, we clearly observed motor dysfunction using several behavioral tests. An immunohistochemical study revealed a dramatic loss of TH-positive DA neurons in the SNc and DAT-labeled axon terminals in the striatum, and an absence of mRNAs for TH and DAT in the SN of DATSN::DTA mice. The mRNA level of GHSR1a was drastically decreased in the SN of these mice. In normal mice, we also found the mRNA expression of GHSR1a within GABAergic neurons in the SN pars reticulata (SNr). Under these conditions, a single injection of ghrelin into the SN failed to improve the motor deficits caused by ablation of the nigrostriatal DA network using DATSN::DTA mice, whereas intra-SN injection of ghrelin suppressed the motor dysfunction caused by the administration of haloperidol, which is associated with the transient inhibition of DA transmission. These findings suggest that phasic activation of the SNc-ghrelin system could improve the dysregulation of nigrostriatal DA transmission related to the initial stage of PD, but not the motor deficits under the depletion of nigrostriatal DA. Although GHSRs are found in non-DA cells of the SNr, GHSRs on DA neurons in the SNc may play a crucial role in motor function.

Usefulness for the combination of G-protein- and ß-arrestin-biased ligands of µ-opioid receptors: Prevention of antinociceptive tolerance.

Background: µ-Opioid receptor internalization is considered to be critically linked to antinociceptive tolerance. Although µ-opioid receptor agonists have been administered simultaneously with other drugs to control pain, little information is available regarding opioid­opioid interactions. Therefore, the present study was designed to further investigate the utility of a new G protein-biased ligand for µ-opioid receptors, TRV130, which has an antinociceptive effect without ß-arrestin-dependent µ-opioid receptor internalization, and its combination with fentanyl using µ-opioid receptor-expressing cells and mice. Results: In the present study, we confirmed that fentanyl produced a profound increase in ß-arrestin-2 recruitment accompanied by µ-opioid receptor internalization, whereas TRV130 did not induce either the recruitment of ß-arrestin-2 or µ-opioid receptor internalization in µ-opioid receptor-expressing cells. Under these conditions, ß-arrestin-2 recruitment accompanied by µ-opioid receptor internalization induced by fentanyl was abolished by TRV130, whereas TRV130 did not alter the reduction of cyclic adenosine monophosphate formation by fentanyl in µ-opioid receptor-expressing cells. In a behavioral assay, TRV130 exerted an antinociceptive effect in a hot-plate test in mice. In a combination test, the antinociceptive effect of TRV130 was synergistically increased by fentanyl. Fentanyl induced antihyperalgesia and development of its tolerance under a neuropathic pain-like state following sciatic nerve ligation. However, treatment of mice with an antinociceptive dose of TRV130 did not induce the rapid development of tolerance to its antihyperalgesic effect under a neuropathic pain-like state. Furthermore, the rapid development of tolerance to the antihyperalgesic effect induced by fentanyl plus TRV130 in mice with sciatic nerve ligation was not observed, unlike in the case of fentanyl alone. Conclusions: These findings provide evidence that activation of the G protein-biased pathway through µ-opioid receptors can alter signaling in the ß-arrestin-2 pathway linked to the stimulation of µ-opioid receptors. Furthermore, the combination of G protein-biased and ß-arrestin-biased ligands of µ-opioid receptors exerts an ideal antinociceptive effect without the rapid development of antinociceptive tolerance.

Newborn screening for carnitine palmitoyltransferase II deficiency using (C16+C18:1)/C2: Evaluation of additional indices for adequate sensitivity and lower false-positivity.

BACKGROUND: Carnitine palmitoyltransferase (CPT) II deficiency is one of the most common forms of mitochondrial fatty acid oxidation disorder (FAOD). However, newborn screening (NBS) for this potentially fatal disease has not been established partly because reliable indices are not available. METHODS: We diagnosed CPT II deficiency in a 7-month-old boy presenting with hypoglycemic encephalopathy, which apparently had been missed in the NBS using C16 and C18:1 concentrations as indices. By referring to his acylcarnitine profile from the NBS, we adopted the (C16+C18:1)/C2 ratio (cutoff 0.62) and C16 concentration (cutoff 3.0nmol/mL) as alternative indices for CPT II deficiency such that an analysis of a dried blood specimen collected at postnatal day five retroactively yielded the correct diagnosis. Thereafter, positive cases were assessed by measuring (1) the fatty acid oxidation ability of intact lymphocytes and/or (2) CPT II activity in the lysates of lymphocytes. The diagnoses were then further confirmed by genetic analysis. RESULTS: The disease was diagnosed in seven of 21 newborns suspected of having CPT II deficiency based on NBS. We also analyzed the false-negative patient and five symptomatic patients for comparison. Values for the NBS indices of the false-negative, symptomatic patient were lower than those of the seven affected newborns. Although it was difficult to differentiate the false-negative patient from heterozygous carriers and false-positive subjects, the fatty acid oxidation ability of the lymphocytes and CPT II activity clearly confirmed the diagnosis. Among several other indices proposed previously, C14/C3 completely differentiated the seven NBS-positive patients and the false-negative patient from the heterozygous carriers and the false-positive subjects. Genetic analysis revealed 16 kinds of variant alleles. The most prevalent, detected in ten alleles in nine patients from eight families, was c.1148T>A (p.F383Y), a finding in line with those of several previous reports on Japanese patients. CONCLUSIONS: These findings suggested that CPT II deficiency can be screened by using (C16+C18:1)/C2 and C16 as indices. An appropriate cutoff level is required to achieve adequate sensitivity albeit at the cost of a considerable increase in the false-positive rate, which might be reduced by using additional indices such as C14/C3.

Involvement of mesolimbic dopaminergic network in neuropathic pain relief by treadmill exercise: A study for specific neural control with Gi-DREADD in mice.

BACKGROUND: Exercise alleviates pain and it is a central component of treatment strategy for chronic pain in clinical setting. However, little is known about mechanism of this exercise-induced hypoalgesia. The mesolimbic dopaminergic network plays a role in positive emotions to rewards including motivation and pleasure. Pain negatively modulates these emotions, but appropriate exercise is considered to activate the dopaminergic network. We investigated possible involvement of this network as a mechanism of exercise-induced hypoalgesia. METHODS: In the present study, we developed a protocol of treadmill exercise, which was able to recover pain threshold under partial sciatic nerve ligation in mice, and investigated involvement of the dopaminergic reward network in exercise-induced hypoalgesia. To temporally suppress a neural activation during exercise, a genetically modified inhibitory G-protein-coupled receptor, hM4Di, was specifically expressed on dopaminergic pathway from the ventral tegmental area to the nucleus accumbens. RESULTS: The chemogenetic-specific neural suppression by Gi-DREADD system dramatically offset the effect of exercise-induced hypoalgesia in transgenic mice with hM4Di expressed on the ventral tegmental area dopamine neurons. Additionally, anti-exercise-induced hypoalgesia effect was significantly observed under the suppression of neurons projecting out of the ventral tegmental area to the nucleus accumbens as well. CONCLUSION: Our findings suggest that the dopaminergic pathway from the ventral tegmental area to the nucleus accumbens is involved in the anti-nociception under low-intensity exercise under a neuropathic pain-like state.

Changes in the expression of IL-6-Mediated MicroRNAs in the dorsal root ganglion under neuropathic pain in mice.

A multiplex analysis for profiling the expression of candidate microRNAs (miRNAs), which are small noncoding RNAs that function as key post-transcriptional regulators, may lead to a better understanding of the complex machinery of neuropathic pain. In the present study, we performed a miRNA array analysis using tissues of the dorsal root ganglion (DRG), a primary site for pain processing, obtained from mice with partial sciatic nerve ligation. Among 1135 total miRNAs, 26 miRNAs showed up-regulation (more than 2-fold change) and only 4 miRNAs showed down-regulation (less than 0.5-fold change) in the DRG of nerve-ligated mice. In a RT-qPCR assay, the levels of miR-21, miR-431, and miR-511-3p were significantly increased on the ipsilateral side of the DRG from 3 to 7 days after sciatic nerve ligation. These elevations were almost absent in IL-6 knockout mice. Furthermore, the expression level of miR-21, but not those of miR-431 or miR511-3p, was significantly increased in exosomes extracted from blood of nerve-ligated mice. These findings suggest that the increased expression of IL-6-regulated miR-21, miR-431, and miR-511-3p in the DRG and increased exosomal miR-21 extracted from blood after sciatic nerve ligation may play at least a partial role in neuropathic pain. Synapse 70:317-324, 2016. © 2016 Wiley Periodicals, Inc.

Electroreductive Intermolecular Coupling of Uracils with Aromatic Ketones: Synthesis of 6-Substituted and cis-5,6-Disubstituted 5,6-Dihydro-1,3-dimethyluracils and Their Transformation to 6-Substituted 1,3-Dimethyluracils, trans-5,6-Disubstituted 5,6-Dihydro-1,3-dimethyluracils, and 4,5,5-Trisubstituted 3-Methyloxazolizin-2-ones.

The electroreductive coupling of 1,3-dimethyluracil, thymine, and 5-fluorouracil with aromatic ketones in the presence of TMSCl gave 6-substituted and cis-5,6-disubstituted 5,6-dihydro-1,3-dimethyluracils. The dehydrotrimethylsiloxylation of the adducts afforded 6-substituted and 5,6-fused 1,3-dimethyluracils. The detrimethylsilylation of the adducts with TBAF or 1 M HCl-MeOH gave 4,5,5-trisubstituted 3-methyloxazolizin-2-ones or 3-methyloxazolizin-2-imines in addition to simply desilylated alcohols. The cis-5,6-disubstituted 5,6-dihydro-1,3-dimethyluracils were isomerized to the corresponding trans-isomers by heating in the presence of cat. DMAP. The cis- and trans-5,6-disubstituted 5,6-dihydro-1,3-dimethyluracils were assigned by the coupling constants J5,6 of their (1)H NMR spectra.

Electroreductive Intermolecular Coupling of Coumarins with Benzophenones: Synthesis of 4-(2-Hydroxyphenyl)-5,5-diaryl-γ-butyrolactones, 2-(2,2-Diaryl-2,3-dihydrobenzofuran-3-yl)acetic Acids, and 4-(Diarylmethyl)coumarins.

The electroreductive coupling of coumarins with benzophenones in the presence of TMSCl gave adducts reacted at the 4-position of coumarins as trimethylsilyl ethers. From 3-methylcoumarin, 3,4-cis-adducts were formed stereoselectively. The de-trimethylsilylation of the adducts with 1 M HCl aq or TBAF in THF at 25 °C produced 4-(2-hydroxyphenyl)-5,5-diaryl-γ-butyrolactones. The γ-butyrolactones were further transformed to 2-(2,2-diaryl-2,3-dihydrobenzofuran-3-yl)acetic acids by treatment with 1 M HCl aq at reflux temperature. The de-trimethylsilylation of the adducts with 1 M HCl in MeOH afforded 2-(2,2-diaryl-2,3-dihydrobenzofuran-3-yl)acetic acid methyl esters. The de-trimethylsiloxylation of the adducts or dehydration of the γ-butyrolactones brought about 4-(diarylmethyl)coumarins.