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Abstinence from prolonged psychostimulant use prompts stimulant withdrawal syndrome. Molecular adaptations within the dorsal striatum have been considered the main hallmark of stimulant abstinence. Here we explored striatal miRNA-target interaction and its impact on circulating miRNA marker as well as behavioral dysfunctions in methamphetamine (MA) abstinence. We conducted miRNA sequencing and profiling in the nonhuman primate model of MA abstinence, followed by miRNA qPCR, LC-MS/MS proteomics, immunoassays, and behavior tests in mice. In nonhuman primates, MA abstinence triggered a lasting upregulation of miR-137 in the dorsal striatum but a simultaneous downregulation of circulating miR-137. In mice, aberrant increase in striatal miR-137-dependent inhibition of SYNCRIP essentially mediated the MA abstinence-induced reduction of circulating miR-137. Pathway modeling through experimental deduction illustrated that the MA abstinence-mediated downregulation of circulating miR-137 was caused by reduction of SYNCRIP-dependent miRNA sorting into the exosomes in the dorsal striatum. Furthermore, diminished SYNCRIP in the dorsal striatum was necessary for MA abstinence-induced behavioral bias towards egocentric spatial learning. Taken together, our data revealed circulating miR-137 as a potential blood-based marker that could reflect MA abstinence-dependent changes in striatal miR-137/SYNCRIP axis, and striatal SYNCRIP as a potential therapeutic target for striatum-associated cognitive dysfunction by MA withdrawal syndrome.

Highlights • Four-week repeated-dose toxicity of intramuscular DSS was studied in minipigs. • DSS administration at ≥10 mg/kg/day causes toxicity and injection-site reaction. • The NOAEL of DSS after 4-week administration was 2 mg/kg/day in minipigs., Diclofenac sodium salt (DSS) is a widely used nonsteroidal anti-inflammatory drug. The present study was performed under good laboratory practice (GLP) regulations to investigate the toxicity of DSS after 4 weeks of repeated intramuscular administration at doses of 0, 2, 10, or 20 mg/kg/day in 32 minipigs and to evaluate the DSS effect following a 2-week recovery period. Dose-related clinical signs and alterations of hematological or clinical chemistry parameters, organ weight, and macroscopic as well as histopathological findings in hepatic, renal, gastrointestinal, skin and injection sites were observed in both sexes’ animals of the 10 or 20 mg/kg/day group. With the exception of the skin-related findings, most symptoms showed a tendency to resolve after the 2-week recovery period. The systemic exposure (AUClast) of DSS in plasma showed similar pattern to the increase rate of the dose and similar values between males and females except for the female 20 mg/kg dose group (56 %) on Day1. The systemic exposure showed a decreasing trend in the 10 or 20 mg/kg group after 4-week of repeated administration compared to Day1. The no-observed-adverse-effect level of DSS in this study was considered to be 2 mg/kg/day in both male and female minipigs.

Sodium dichloroisocyanurate-96% (NaDCC) is commonly used to treat drinking water, industrial water, and wastewater. However, exposure to NaDCC by inhalation can have toxic pulmonary effects in humans. In the present study, we evaluated the potential toxicity of NaDCC following a 90-day inhalation toxicity study in Sprague-Dawley/Crl:CD (SD) rats. The animals were exposed to 0.4, 2.0, or 10.0 mg/m

O3–KCrO2 is the only known stoichiometric layered transition metal oxide with a layered structure, which enables efficient coupling with a graphite anode for K+-shuttling batteries. O3–KCrO2, however, shows low Coulombic efficiency during 1st charge/discharge cycle and continuous capacity fading during subsequent cycles. Here, we present a slightly K+-deficient compound P′3-K0.8CrO2, synthesized from a commercially available K2CrO4, as a stable cathode in potassium ion batteries. During the 1st charge, K0·8CrO2 mostly retains its P′3-phase with a short P3 region and finally returns to a P′3-phase (K0·48CrO2). Subsequent discharge shows reversible phase transitions, but ultimately yielded a new O′3-K0.9CrO2 phase. Absence of an O3-phase and persistence of a P′3-phase during charge/discharge, result in negligible volume changes (1.08%) and facile K+-diffusion through the spacious-prismatic sites (D = 10−11 - 10−10 cm2 s−1). This eventually contributes to a significant improvement in cyclic stability (99% retention after 300 cycles at 1 C) and rate capability (52 mAh·g−1 at 2 C), respectively. We believe that the use of slightly K+-deficient chromium oxides synthesized via a simple protocol should enhance the commercial viability of KxCrO2 in potassium ion batteries.

Herein is the first use of a CoSn(OH)6/graphene composites as a high-performance anode in lithium ion batteries (LIBs). CoSn(OH)6 alone is found to be electrochemically active and to possess electrochemical properties that are superior to those displayed in its dehydrated form (CoSnO3). In contrast to the formation of 3Li2O in CoSnO3 during the first discharge (CoSnO3 + 6Li+ + 6e− → Co + Sn + 3Li2O), the production of 6 mol of LiOH in CoSn(OH)6 (CoSn(OH)6 + 6Li+ + 6e− → Co + Sn + 6LiOH) seems to provide nanometric Co/Sn particles with more efficient reversibility for the subsequent Li+-insertion/de-insertion via conversion/alloy reactions. The electrochemical performance of CoSn(OH)6 is further improved when composited with graphenes. This is accomplished by electrostatically combining negatively charged Co2+/Sn2+-anchored graphene oxide (GO) with positively charged amine-functionalized graphene (GN) in a solution. The subsequent hydrothermal reaction produces CoSn(OH)6 nanocubes that are tightly held by graphene sheets (GO/CS/GN). The GO/CS/GN delivers unprecedentedly high capacity and excellent cyclability (discharge capacities of 1475 mAh·g−1 for the 100th charge/discharge (C/D) cycles at a 0.1 A·g−1). In contrast to the comparison materials (CoSnO3/graphene composites) the rate performance is also remarkable, delivering a capacity of 650 mAh·g−1 at 2.0 A·g−1. Keywords: CoSn(OH)6, Graphene, Lithium ion battery, Anode, Self-assembly

Despite extensive effort during the past few decades, a comprehensive understanding of the key variables governing the electrochemical properties of cathode materials in Li-ion batteries is still far from complete. To elucidate the critical parameters affecting energy density (ED) and capacity (Q) retention in layer and spinel cathodes, we data-mine the existing experimental data via confirmatory factor analysis (CFA) based on a structural equation model (SEM), which is a proven, versatile tool in understanding complex problems in the social science. The data sets are composed of 18 and 15 parameters extracted from 38 layer and 33 spinel compounds, respectively. CFA reveals the irrelevance of Q retention to all the parameters we adopt, but it also reveals the sensitive variations of ED with specific parameters. We validate the usefulness of CFA in material science and pinpointed critical parameters for high-ED cathodes, hoping to suggest a new insight in materials design.

Repeated dose oral toxicity and toxicokinetic of KDS2010, a new drug for Parkinson's disease, was investigated after 4-week repeated oral administration at 30, 50, 75, or 100 mg/kg/day in rats. Body weight and body weight gain decreased in rats of both sexes in the 75 and 100 mg/kg groups, and food consumption was reduced in male rats of the 75 and 100 mg/kg male groups. Histological alterations were observed in the kidney (urothelial hyperplasia, inflammatory cell infiltration in the renal pelvis, tubular vacuolation/degeneration, basophilic tubules, and hyaline droplets in the proximal tubules) of the 75 and 100 mg/kg male groups and the 50 and 100 mg/kg female groups. The 75 and 100 mg/kg male groups showed adverse effect in the testes (degeneration/exfoliation of germ cells, seminiferous tubules atrophy) and epididymis (cellular debris, oligospermia). These changes were partially recovered after a 2-week recovery period. However, basophilic tubules and hyaline droplets in the proximal tubules in the kidney and germ cell degeneration/exfoliation in the testis were not recovered. In toxicokinetics study, systemic exposure to KDS2010 increased proportionally in both sexes by in a dose -dependent manner. In addition, repeated administration for 4 weeks led to increased tendency of systemic exposure in both sexes compared with that in Day 1. In conclusion, KDS2010 was shown to target the kidney and testis with a no-observed-adverse-effect level of 50 and 30 mg/kg/day for males and females, respectively.

Na x Ca y CoO 2 (0.45 ≤ x ≤ 0.64, 0.02 ≤ y ≤ 0.10) is synthesized via a solid-state method and examined as a cathode material to improve the cyclability of sodium ion batteries (SIBs). The substitution of one Ca 2+ for two Na + does not alter the P2-phase of undoped Na 0.73 CoO 2 , accompanying the continuous contraction of the unit cell volume with Ca-doping. The existence of Ca 2+ in the prismatic sites between CoO 6 slabs also affects the phase transition behaviors during charge–discharge (C–D). The suppression of Na + -vacancy ordering, ascribed to the immobility of Ca 2+ in Na x Ca y CoO 2 , leads to continuous changes of the cell voltages with no abrupt voltage drops during C–D. The reduced cell dimension and the mitigation of distinctiveness between biphasic and solid-solution domains during C-D improve the cyclability of Na x Ca y CoO 2 in SIBs. As an example, the negligible capacity fading in Na 0.60 Ca 0.07 CoO 2 during 60 cycles (0.07 mAh g −1 cycle −1 ) is contrasted with a substantial decrease in the reversible capacity of Na 0.73 CoO 2 (0.56 mAh g −1 cycle −1 ). Furthermore, a slower Na + diffusion of Na x Ca y CoO 2 in Na + -vacancy ordering regions, is sufficiently offset by a more rapid diffusion in all the other regions, which results in an improved rate performance. The platform presented here (multi-valent cation substitution for Na + ) could be utilized in other layered cathode materials to improve the electrochemical performance of SIBs.

Here, we propose a novel strategy to prepare dense stacks composed of alternating CoO and graphene layers for an anode in lithium ion batteries (LIBs), which contributes to enhanced stability and relatively large reversible capacity. This is accomplished by spontaneously pre-aligning negatively charged CoO-anchored graphene oxide (CG) and positively charged amine-functionalized graphene (GN) in an acidic medium, followed by thermal reduction. The performance of this product is contrasted with that of CG prepared under the identical conditions without the addition of GN, in which CoO nanoparticles are sandwiched between relatively loose and randomly oriented graphene stacks. For example, the composite delivers a capacity greater than 800 mAh g −1 with a fading rate of 0.04 mAh g −1 cycle −1 during 1000 charge/discharge (C/D) cycles at 1.0 A g −1 , in contrast to ca. 400 mAh g −1 and 0.24 mAh g −1 cycle −1 for thermally reduced CG without the addition of GN. The origin of the superior electrochemical performance in the dense stacks is ascribed to the enhanced reversibility of a conversion reaction, which in turn contributes to a persistent formation/dissolution of gel-like polymer films (i.e., stable pseudo-capacitance). Experimental evidences that substantiate the aforementioned behaviors (improved reversibility for both processes) are presented.

Oligopyrene (OPr, 3–4 pyrene units) is chemically synthesized and used as a high-voltage organic cathode for sodium ion batteries (SIBs). OPr shows anion-dominant transport behaviors during redox-switching in NaClO4 electrolytes, indicating that, when implemented in SIBs, OPr can reversibly incorporate/release perchlorate anions for charge-balance. A composite film, in which OPr maintains a crystalline phase with a layered structure, shows a sloping charge–discharge (C–D) curve (discharge capacity = 42.5 mAh g−1 and average voltage = 2.9 V vs. Na/Na+ at 20 mA g−1), implying a large overpotential due to slow ClO4− diffusion through the crystalline phase. In contrast, a composite film containing amorphous OPr exhibits substantially reduced overpotential with a plateau potential at 3.5 V during discharge. An initial reversible capacity of 121.0 mAh g−1, which is close to one-electron transfer per pyrene unit, is decreased to 95.8 mAh g−1 during the first 10 C–D cycles, but is subsequently stabilized with a decreasing rate of 0.30 mAh g−1 per C–D cycle. The energy density of amorphous OPr (423 Wh kg−1 for the 1st discharge) is so large that it exceeds those of most inorganic-based cathode materials that have been reported thus far.

Ethnopharmacological relevance Gyejibokryeong-hwan is a traditional herbal medicine and is reported to have various pharmacological actions. Despite many reports of previous studies, there is limited scientific evidence concerning its safety and few drug-metabolism profiles to support the continued therapeutic application of Gyejibokryeong-hwan. Aim of the study The purpose of the present study was to investigate the acute and subacute toxicity profile of a Gyejibokryeong-hwan water extract (GBHW) in vivo, and its effects on the activities of drug-metabolizing enzymes in vitro. Materials and methods Acute and subacute toxicity was evaluated by giving GBHW to rats. In a study of acute toxicity, the rats were given GBHW by single oral gavage administration at 0 and 5000 mg/kg. In a study of subacute toxicity, rats were given GBHW by oral gavage at 0, 1000, 2000, and 5000 mg/kg/day daily for 28 days. The activities of the major human microsomal cytochrome P450 (CYP450) and UDP-glucuronosyltransferase (UGT) isozymes were investigated using fluorescence- and luminescence-based enzyme assays in vitro, respectively. Results GBHW did not cause any mortality in the study of acute toxicity. In the study of subacute toxicity, GBHW at more than 2000 mg/kg/day was observed with minor changes in the absolute and relative organ weight, hematology, serum biochemistry and urinalysis parameters in rats of either sex. However, these changes were not considered to be important toxicologically. GBHW moderately inhibited the activities of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2E1, CYP3A4, and UGT1A1. Conclusions Our present data suggest that GBHW does not cause toxicologically important adverse events at doses up to 2000 mg/kg/day in the 4-week repeated dose toxicity study and provide valuable information concerning its potential to interact with conventional medicine.

W-doped LiW x Ni 0.5 Mn 1.5− x O 4 ( x = 0.00–0.10) are synthesized via a sol–gel method, and their electrochemical properties are investigated. During synthesis, W 4+ is converted to W 6+ , the amount of which significantly affects the charge–discharge behaviors of LiW x Ni 0.5 Mn 1.5− x O 4 . When limited to x ≤ 0.005, W-doping enhances the electrochemical activity of cathodes, leading to a greater discharge capacity and less capacity fading than LiNi 0.5 Mn 1.5 O 4 at high C -rates. This is interesting since lowering the average valence state of Mn ions by incorporating W 6+ can introduce structural instability, extending a 4 V plateau (Mn 3+/4+ ). The reasons for such behavior associated with W-doping are examined by electron microscopy, X-ray photoelectron spectroscopy, X-ray diffraction, and impedance spectroscopy. It is disclosed that the simultaneous increase in Li O bond length and decrease in transition metal-oxide bond length, while the unit cell volume is maintained almost invariant, provides LiW 0.005 Ni 0.5 Mn 1.495 O 4 with optimal high rate performance. When W-doping exceeds x = 0.01, 3 factors (intrinsically low electronic conductivity of W 6+ , the presence of tungsten oxide impurities, and an increase in the inter-metallic distance) aggravates electrochemical performance of LiW x Ni 0.5 Mn 1.5− x O 4 . The last factor also induces structural instability during repeated cycling because of the expansion of a unit cell volume.