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In this study, the high oxygen vacancy-rich ultrathin indium oxide (In2O3) nanosheets are synthesized by low-cost and environmental-friendly solvothermal method. The gas sensing properties of In2O3 nanosheets to low concentration of nitrogen dioxide (NO2) (concentration in 5 ppb to 5 ppm) at 50 °C are investigated. All In2O3 samples are successfully characterized using various techniques to obtain the information related to phase, morphological, oxygen vacancies, and surface area, etc. It is observed that among all the samples, the In2O3-350 exhibited benchmarked response of around 3223 at 2 ppm NO2 gas, with theoretical detection limit down to ppb level. The sensor has shown superior sensing characteristics, such as wide sensing bandwidth, excellent selectivity, high long-term stability, and good repeatability. It is considered that the high oxygen deficiency present on In2O3 nanosheets acts as favorable reaction sites for such remarkable sensing performance, and therefore, these improved gas-sensing properties make the In2O3 nanosheets suitable to detect NO2 at low-temperature.

The photocatalytic water splitting has a stupendous role to generate renewable hydrogen. However, the overall water splitting reaction is limited by the sluggish oxidation step. Bismuth vanadate (BiVO4) has been identified as one of the most promising n-type semiconductors for photocatalytic water oxidation due to its small energy gap and favorable band alignment. Thus, it is necessary to summarize the recent progress done on BiVO4 for the guidance of future research. In this review, we have discussed recent strategies that have been adopted to boost its photoconversion efficiency at three different levels: (1) facet control, (2) morphological control and, (3) interfacial control. The roles of high indexed facets, anisotropic morphologies, and mediator-based Z schemes are comprehensively discussed and the emphasis is given to find the suitable structural, morphological, and interfacial combination of BiVO4 for efficient water oxidation.

Amorphous gallium tin oxide (GTO) thin films were prepared by a facile, and eco-friendly, aqueous solution process and their applications in thin-film transistors (TFTs) were investigated. The success of the aqueous route was realized by introducing tin fluoride (SnF2) instead of the traditional tin chloride (SnCl2) solute. The roles of adding Ga on the GTO’s microstructural, optical, chemical, and electrical performance were comprehensively studied. It was found that Ga can frustrate the crystallization while it augments the optical bandgap (Eg) value of pristine SnO2. More importantly, using Ga could effectively inhibit the formation of oxygen vacancies, thus greatly improving the electrical performance of the GTO TFTs. The amorphous GTO TFTs with a Ga content of 45% exhibited optimum performance, with a saturation mobility (μsat) of 4.26 cm2/V s, an on/off current ratio (Ion/Ioff) >107, and a decent bias stress durability.

In this paper, we report aqueous solution-processed boron-doped gallium oxide dielectric thin films for high-performance oxide thin-film transistors. The role of B incorporation on the microstructu...

MoS2, as a typical representative of two-dimensional semiconductors, has been explored extensively in applications of optoelectronic devices because of its adjustable bandgap. However, to date, the performance of the fabricated photodetectors has been very sensitive to the surrounding environment owing to the large surface-to-volume ratio. In this work, we report on large-scale, high-performance monolayer MoS2 photodetectors covered with a 3-nm Al2O3 layer grown by atomic layer deposition. In comparison with the device without the Al2O3 stress liner, both the photocurrent and responsivity are improved by over 10 times under 460-nm light illumination, which is due to the tensile strain induced by the Al2O3 layer. Further characterization demonstrated state-of-the-art performance of the device with a responsivity of 16.103 A W−1, gain of 191.80, NEP of 7.96 × 10−15 W Hz−1/2, and detectivity of 2.73 × 1010 Jones. Meanwhile, the response rise time of the photodetector also reduced greatly because of the increased electron mobility and reduced surface defects due to the Al2O3 stress liner. Our results demonstrate the potential application of large-scale strained monolayer MoS2 photodetectors in next-generation imaging systems.

Transparent amorphous oxide semiconductor (TAOS) represented by a-InGaZnO (IGZO) has achieved their commercial success in the display industry due to its superior material properties (e.g. high mobility (>10 cm 2 V −1 s −1 ), good transparency and excellent uniformity). However, TAOSs with excellent electrical properties are all n-type due to the particular electronic structures of oxide materials. The absence of high performance p-type TAOS limits the device application such as complimentary circuit and is now the largest drawback for oxide electronics. Here, we propose a low-temperature solution method to fabricate p-type transparent amorphous nickel oxide (NiO). The influence of processing parameters such as annealing temperature, precursor concentration, source/drain electrode, and dielectric layer is systematically investigated to maximum the NiO device performance. The optimized NiO TFT exhibits outstanding p-channel behavior, including a high hole mobility of 6.0 cm 2 V −1 s −1 , remarkable on/off current modulation ratio of ∼10 7 , and good subthreshold swing of 0.13 V/decade. The high performance NiO device is attributed to the synergistic optimization of annealing temperature, channel thickness, source/drain electrodes, and dielectric materials. The properties of our p-type TAOS are comparable with that of traditional n-type TAOS.

Background Annexin A1 (ANXA1) exerts anti-nociceptive effect through ANXA1 receptor formyl peptide receptor 2 (FPR2/ALX (receptor for lipoxin A4), FPR2) at the dorsal root ganglia (DRG) level. However, the mechanisms remain elucidated. By using radiant heat, hot/cold plate, tail flick, von Frey, and Randall-Selitto tests to detect nociception in intact and chemical (capsaicin, menthol, mustard oil, formalin or CFA) injected AnxA1 conditional knockout (AnxA1−/−) mice, applying calcium imaging and patch clamp recordings in cultured DRG neurons to measure neuronal excitability, conducting immunofluorescence and western blotting to detect the protein levels of TRPV1, FPR2 and its downstream molecules, and performing double immunofluorescence and co-immunoprecipitation to investigate the interaction between Calmodulin (CaM) and TRPV1; we aim to uncover the molecular and cellular mechanisms of ANXA1’s role in antinociception. Results AnxA1−/− mice exhibited significant sensitivity to noxious heat (mean ± SD, 6.2 ± 1.0 s vs. 9.9 ± 1.6 s in Hargreaves test; 13.6 ± 1.5 s vs. 19.0 ± 1.9 s in hot plate test; n = 8; P vs. 76.2 ± 10.9; n = 8; P vs. 76.0 ± 21.9 s; n = 8; P vs. 320.4 ± 33.6 s; n = 8; P vs. 5.9 ± 1.4 s; n = 8; P 2+ response, TRPV1 currents and neuronal firing in AnxA1 deficient DRG neurons. Furthermore, ANXA1 mimic peptide Ac2-26 robustly increased intracellular Ca2+, inhibited TRPV1 current, activated PLCβ and promoted CaM-TRPV1 interaction. And these effects of Ac2-26 could be attenuated by FPR2 antagonist Boc2. Conclusions Selective deletion of AnxA1 in DRG neurons enhances TRPV1 sensitivity and deteriorates noxious heat or capsaicin induced nociception, while ANXA1 mimic peptide Ac2-26 desensitizes TRPV1 via FPR2 and the downstream PLCβ-Ca2+-CaM signal. This study may provide possible target for developing new analgesic drugs in inflammatory pain.

We report the aqueous-solution-processed Ni-doped In2O3 (NixIn2–xO3, NiInO) thin-film transistors (TFTs) for the first time. The effect of Ni doping on In2O3 microstructure, oxygen defects, and the electron transport properties are investigated by extensive characterization techniques. Analyses indicate that the oxygen vacancies in NiInO are suppressed as the Ni-doping concentration increases, leading to a lower off-state current and a positive shift in threshold voltage. The optimized NiInO TFTs exhibit a high mobility of 17.71 cm2/(V s), on/off current ratio > 106, threshold voltage of 4.21 V, and superior bias stress stability. The success of Ni doping could be attributed to the small ion radius of Ni, large Lewis acid value, and strong Ni–O bond strength. Therefore, the fabricated NiInO TFT provides a bright path for the development of high-performance oxide TFTs.

Perovskite metal oxide (LiNbO3) nanomaterial is explored as a magneto-optic sensor. The electromagnetic interaction is described by magneto-optic modulation associated with vacancy-induced room temperature ferromagnetism. The guiding and propagation through single mode fiber (SMF) is via the excitation of core modes through the material-mediated cavity and further modulated by external magnetic field. The sensitivity and resolution of the sensor are found to be 186 p.m./mT and 0.51 Oe, respectively. The structure with material integrated optical design resulting in a Fabry-Perrot interferometer (FPI), is implemented as an extrinsic sensor, and sensing mechanism is elaborated.

Background Death-associated protein kinase 1 (DAPK1) is a widely distributed serine/threonine kinase that is critical for cell death in multiple neurological disorders, including Alzheimer’s disease and stroke. However, little is known about the role of DAPK1 in the pathogenesis of Parkinson’s disease (PD), the second most common neurodegenerative disorder. Methods We used Western blot and immunohistochemistry to evaluate the alteration of DAPK1. Quantitative polymerase chain reaction and fluorescence in situ hybridization were used to analyze the expression of microRNAs in PD mice and patients with PD. Rotarod, open field, and pole tests were used to evaluate the locomotor ability. Immunofluorescence, Western blot, and filter traps were used to evaluate synucleinopathy in PD mice. Results We found that DAPK1 is posttranscriptionally upregulated by a reduction in microRNA-26a (miR-26a) caused by a loss of the transcription factor CCAAT enhancer-binding protein alpha. The overexpression of DAPK1 in PD mice is positively correlated with neuronal synucleinopathy. Suppressing miR-26a or upregulating DAPK1 results in synucleinopathy, dopaminergic neuron cell death, and motor disabilities in wild-type mice. In contrast, genetic deletion of DAPK1 in dopaminergic neurons by crossing DAT-Cre mice with DAPK1 floxed mice effectively rescues the abnormalities in mice with chronic MPTP treatment. We further showed that DAPK1 overexpression promotes PD-like phenotypes by direct phosphorylation of α-synuclein at the serine 129 site. Correspondingly, a cell-permeable competing peptide that blocks the phosphorylation of α-synuclein prevents motor disorders, synucleinopathy, and dopaminergic neuron loss in the MPTP mice. Conclusions miR-26a/DAPK1 signaling cascades are essential in the formation of the molecular and cellular pathologies in PD.

Background and objectives Vicagrel, a novel thienopyridine antiplatelet agent, is an analogue of clopidogrel in development for the treatment of acute coronary syndromes. This study investigated the pharmacokinetic properties of vicagrel after single oral dosing with a direct comparison with clopidogrel in healthy Chinese subjects in the first two phase I clinical studies. The relationship between the exposure to the active metabolite and the platelet reactivity was also assessed for vicagrel. Methods Study A was a single-ascending-dose study of vicagrel (5–75 mg) compared with clopidogrel (75 mg) in 67 healthy volunteers. Study B was a randomized, two-period, crossover, loading-dose study of vicagrel 20 mg compared with clopidogrel 300 mg in 12 healthy subjects. Plasma concentrations of three common metabolites of vicagrel and clopidogrel, the active thiol metabolite H4, the inactive thiol metabolite H3, and the S-methylated form of H3 (SM3, the major metabolite of vicagrel), were determined using a validated UHPLC–MS/MS method. The relationship between the AUC0−t of active H4 and the P2Y12 reaction units at 4 h after administration of vicagrel was investigated. Blood concentrations of vicagrel were determined after a single oral administration of vicagrel 25 mg to two healthy Chinese subjects. Results In the single-ascending-dose study, vicagrel was metabolized rapidly with the median tmax for the three metabolites, namely, H4, H3, and SM3, ranging from 0.25–1.75 h. The pharmacokinetics of the three metabolites for vicagrel were linear across the dose range of 5–75 mg, with the mean Cmax and AUCs for H4 and H3 increasing in an approximately 1:1 dose-proportional manner and for SM3 increasing in a Conclusions Vicagrel was rapidly and extensively metabolized, and the levels of the parent drug in circulation were very low. The pharmacokinetics of the three metabolites of vicagrel were linear and predictable across the dose range of 5–75 mg. The AUC of active H4 was apparently associated with the P2Y12 reaction units for vicagrel. For active H4, vicagrel 5 mg produced similar exposure (AUC) with more rapid appearance compared with clopidogrel 75 mg, and vicagrel 20 mg produced even slightly higher exposure (AUC) with more rapid appearance compared with clopidogrel 300 mg in humans. Trial Registration: CTR20150346, CTR20160379.

Background Hyperhomocysteinemia is an independent risk factor for dementia, including Alzheimer’s disease. Lowering homocysteine levels with folic acid treatment with or without vitamin B12 has shown few clinical benefits on cognition. Methods To verify the effect of emodin, a naturally active compound from Rheum officinale, on hyperhomocysteinemia-induced dementia, rats were treated with homocysteine injection (HCY, 400 μg/kg/d, 2 weeks) via vena caudalis. Afterwards, HCY rats with cognitive deficits were administered intragastric emodin at different concentrations for 2 weeks: 0 (HCY-E0), 20 (HCY-E20), 40 (HCY-E40), and 80 mg/kg/d (HCY-E80). Results β-Amyloid overproduction, tau hyperphosphorylation, and losses of neuron and synaptic proteins were detected in the hippocampi of HCY-E0 rats with cognitive deficits. HCY-E40 and HCY-E80 rats had better behavioral performance. Although it did not reduce the plasma homocysteine level, emodin (especially 80 mg/kg/d) reduced the levels of β-amyloid and tau phosphorylation, decreased the levels of β-site amyloid precursor protein-cleaving enzyme 1, and improved the activity of protein phosphatase 2A. In the hippocampi of HCY-E40 and HCY-E80 rats, the neuron numbers, levels of synaptic proteins, and phosphorylation of the cAMP responsive element-binding protein at Ser133 were increased. In addition, depressed microglial activation and reduced levels of 5-lipoxygenase, interleukin-6, and tumor necrosis factor α were also observed. Lastly, hyperhomocysteinemia-induced microangiopathic alterations, oxidative stress, and elevated DNA methyltransferases 1 and 3β were rescued by emodin. Conclusions Emodin represents a novel potential candidate agent for hyperhomocysteinemia-induced dementia and Alzheimer’s disease-like features.

Objective. Inactivation of NLRP3 inflammasome plays a role in reducing the permeability of endothelial cells and improving blood-brain barrier (BBB) dysfunction following traumatic brain injury (TBI). However, the mechanism controlling NLRP3 inflammasome activation remains unclear. This study is aimed at defining the role of miR-29a-5p in NLRP3 inflammasome activation and permeability of endothelial cells under TBI. Methods. The scratch injury model on brain bEnd.3 microvascular endothelial cells was used as in vitro TBI model cells. Effects of miR-29a mimics and inhibitors on TBI model cells were observed by examining their action on FITC, TEER, and protein contents of ZO-1 and occludin, and cell permeability-associated protein. Luciferase reporter assay evaluated miR-29a-5p targeting to NLRP3. ELISA examined of IL-1β and IL-18 levels. miR-29a-5p mimic was injected into TBI mouse and its effect on BBB, indicated by Evans blue (EB) staining assay and cerebral water content, and NLRP3 activation was examined. Results. miR-29a-3p and miR-29a-5p mimics decrease the concentration of FITC, and increase TEER and the protein contents of ZO-1 and occludin in TBI model cells. miR-29a-5p silencing disrupted the permeability of mouse bEnd.3 cells. miR-29a-5p targets to NLRP3 through the binding on its 3 ′ UTR and negatively regulates its expression in TBI model cells. NLRP3 inhibition and miR-29a-5p silencing together caused significantly decreased FITC concentration and increased TEER value and release of IL-1β and IL-18. miR-29a-5p mimic alleviated the BBB and cerebral water content and inactivates NLRP3 in the mouse TBI model. Conclusions. miR-29a-5p mimics protect TBI-induced increased endothelial cell permeability and BBB dysfunction via suppressing NLRP3 expression and activation.

Appropriate migration of cytotoxic T effector cells into the tumors is crucial for their antitumor function. Despite the controversial role of PI3K-Akt in CD8+ T cell mTORC1 activation, a link between Akt-mTORC1 signaling and CD8+ trafficking has been demonstrated. We have recently discovered that TCR-induced calcineurin activates DAPK1, which interacts with TSC2 via its death domain and phosphorylates TSC2 via its kinase domain to mediate mTORC1 activation in CD8+ T cells. However, whether DAPK1 regulates CD8+ trafficking into tumors remains unclear. Here, using pharmacological inhibitor and genetic approaches, we found that like rapamycin, inhibition of DAPK1 activity led to enhanced expression of the homing receptors CD62L and CCR7. Deletion of either kinase domain or death domain in the T cell compartment reduced the T cell activation and maintained the expression of CD62L and CCR7. DAPK1-DD-deficient mice were more susceptible to tumor growth and deficiency of DAPK1 activity significantly reduced the migratory ability of CD8+ into the tumors. These data revealed a crucial role of DAPK1-mTORC1 in mediating CD8+ trafficking and antitumor function.

Thin-film transistors (TFTs) made of metal oxide semiconductors are now increasingly used in flat-panel displays. Metal oxides are mainly fabricated via vacuum-based technologies, but solution approaches are of great interest due to the advantages of low-cost and high-throughput manufacturing. Unfortunately, solution-processed oxide TFTs suffer from relatively poor electrical performance, hindering further development. Recent studies suggest that this issue could be solved by introducing a novel heterojunction strategy. This article reviews the recent advances in solution-processed heterojunction oxide TFTs, with a specific focus on the latest developments over the past five years. Two of the most prominent advantages of heterostructure oxide TFTs are discussed, namely electrical-property modulation and mobility enhancement by forming 2D electron gas. It is expected that this review will manifest the strong potential of solution-based heterojunction oxide TFTs towards high performance and large-scale electronics.

Anorethidrani disuccinate (ACP) is a domestically designed A-decarbonized steroid that is currently being investigated in Phase I clinical trials for the treatment of solid tumors. Only the parent drug exhibited antitumor activity; its sterol metabolite M2 showed obvious antiestrogenic effects. We have developed a rapid, sensitive, and robust liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for the direct quantification of ACP and a chemical derivatization method that can be used to quantify M2 derivatized with glycidyl trimethyl ammonium chloride (GTMA). A simple protein precipitation procedure was performed to quantify ACP. Injections were obtained within 3.5 min on an Eclipse Plus Phenyl-Hexyl column (50 mm × 2.1 mm i.d., 1.8 μm) with gradient elution; the calibration curve was linear over the range of 2.00–8000 ng/mL. For quantification of M2 in plasma, analytes were extracted by protein precipitation and converted to their GTMA derivatives at 60 °C for 2 h at pH 12; the analytes and coelutants were separated on a Luna C8(2) column (50 mm × 2.0 mm i.d., 5.0 μm). The precision (RSD) and accuracy (RE) of the intra- and interday determinations were within 10%. The derivatization procedure is a novel method for sterol determination by LC-MS/MS. The results confirmed the usefulness of this method for characterizing the pharmacokinetic profiles of ACP and its major metabolite M2 in a Phase I pharmacokinetic study.

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease for which there are limited therapeutic strategies. Protein phosphatase 2A (PP2A) activity is decreased in AD brains, which promotes the hyperphosphorylation of Tau and APP, thus participate in the formation of neurofibrillary tangles (NFTs) and β-amyloid (Aβ) overproduction. In this study, the effect of synthetic tricyclic sulfonamide PP2A activators (aka SMAPs) on reducing AD-like pathogenesis was evaluated in AD cell models and AD-like hyperhomocysteinemia (HHcy) rat models. SMAPs effectively increased PP2A activity, and decreased tau phosphorylation and Aβ(40/42) levels in AD cell models. In HHcy-AD rat models, cognitive impairments induced by HHcy were rescued by SMAP administration. HHcy-induced tau hyperphosphorylation and Aβ overproduction were ameliorated through increasing PP2A activity on compound treatment. Importantly, SMAP therapy also prevented neuronal cell spine loss and neuronal synapse impairment in the hippocampus of HHcy-AD rats. In summary, our data reveal that pharmacological PP2A reactivation may be a novel therapeutic strategy for AD treatment, and that the tricyclic sulfonamides constitute a novel candidate class of AD therapeutic. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00841-6) contains supplementary material, which is available to authorized users.

Neurotoxicity is one of the major pathological changes in multiple neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), the second popular neurodegenerative disease in aged people. It is known that the AD and PD share the similar neuropathological hallmarks, such as the oxidative stress, loss of specific neurons, and aggregation of specific proteins. However, there are no effective therapeutic drugs for both AD and PD yet. Oxytocin (OXT) is a small peptide with 9 amino acids that is neuroprotective to many neurological disorders. Whether OXT administration confers neuroprotection to 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP)-induced neurotoxicity in mice are still not known. In this study, we first found that the OXT levels are decreased in MPTP mice. Supplementation with OXT effectively rescues the locomotor disabilities and anxiety-like behaviors in MPTP mice. OXT also alleviates the hyperphosphorylation of α-synuclein at S129 site and the loss of dopaminergic neurons in the substantia nigra pars compacta, as well as the oxidative stress in the MPTP mice, and alleviates both oxidative stress and cell cytotoxicity in vitro. Furthermore, we found that OXT could inhibit the miR-26a/DAPK1 signal pathway in MPTP mice. In summary, our study demonstrates protective effects of OXT in MPTP mice and that miR-26a/DAPK1 signaling pathway may play an important role in mediating the protection of OXT.

Loss of memory is an inevitable clinic sign in aging, but its underlying mechanisms remain unclear. Here we show that death-associated protein kinase (DAPK1) is involved in the decays of learning and memory in aging via degradation of Caytaxin, a brain-specific member of BNIP-2. DAPK1 becomes activated in the hippocampus of mice during aging. Activation of DAPK1 is closely associated with degradation of Caytaxin protein. Silencing Caytaxin by the expression of small interfering RNA (siRNA) that targets specifically to Caytaxin in the hippocampus of adult mice impairs the learning and memory. Genetic inactivation of DAPK1 by deletion of DAPK1 kinase domain prevents the degradation of Caytaxin and protects against learning and memory declines. Thus, activation of DAPK1 impairs learning and memory by degrading Caytaxin during aging.

Vicagrel, an analog of clopidogrel, is a novel thienopyridine P2Y12 antagonist in clinical development in China for the treatment of acute coronary syndromes. Vicagrel and clopidogrel are prodrugs requiring metabolic activation to produce a pharmacologically active thiol metabolite (H4) in vivo. The formation of H4 from vicagrel in humans is promising more efficient and consistent than that from clopidogrel. After oral dosing of vicagrel or clopidogrel to humans, the active thiol metabolite H4 and two inactive metabolites closely related to H4 formation (the thiol metabolite H3 and the S-methylated metabolite SM3) were observed in plasma; SM3 was the most abundant drug-related component of vicagrel in circulation. In this study, a sensitive, rapid, and reliable UHPLC-MS/MS method was developed for the simultaneous determination of derivatized H3 (MP-H3), derivatized H4 (MP-H4), and SM3 in human plasma to investigate the pharmacokinetics of vicagrel in healthy subjects compared with clopidogrel. After extracted from 50μL of plasma by simple protein precipitation, the analytes and stable isotope-labeled internal standards were separated on an Acquity UPLC BEH C18 column (100mm×2.1mm, 1.7μm). The mobile phase was acetonitrile-water-formic acid (45:55:0.0275, v/v/v) delivered at a flow rate of 0.45mL/min under isocratic elution. The total chromatographic run time was 6min. MP-H3, MP-H4, and SM3 were separated from their corresponding isomers under the chromatographic conditions. Mass spectrometric detection was conducted in multiple reaction monitoring mode on an AB Sciex Qtrap 5500 System using a positive electrospray ionization interface. The calibration curves were linear in the following ranges: 0.100-200ng/mL for MP-H3 and MP-H4 and 1.00-1000ng/mL for SM3. The intra- and inter-day accuracy and precision for each analyte at all concentrations were within acceptable limits (±15%). The validated method was successfully applied to compare the pharmacokinetics of vicagrel and clopidogrel after a single oral administration to healthy subjects in the first-in-human study of vicagrel.

Two-dimensional thin layers of indium selenide (InSe) have attracted much attention due to their potential applications in optoelectronics as highly responsive photo-detectors and field-effect transistors. In the present work, we explore thermal properties of InSe thin layers on a high-k substrate with a thin SiO2 passivation layer using temperature and power dependent Raman spectroscopy. The first order temperature coefficients for in-plane (E12g) and out-of-plane (A21g) modes of InSe few-layers on a Al2O3 substrate were found to be −0.00507 and −0.00310 cm−1/K, respectively, which are much smaller than the corresponding values −0.00612 and −0.00528 cm−1/K of similarly prepared sample on SiO2 substrate. The difference in temperature coefficients is attributed to compressive strain introduced by the Al2O3. Further, the average thermal conductivity of a 4 nm thin InSe layer on the Al2O3 substrate at room temperature was found to be ∼53.4 W/m-K, which is significantly larger than those of InSe layers prepared on SiO2 substrate (∼28.7 W/m-K). The existed interface charges between the Al2O3 and InSe layers cause the observed improvement of thermal conductivity by electron-phonon interactions.

The PSD-95/SAPAP/Shank complex functions as the major scaffold in orchestrating the formation and plasticity of the post-synaptic densities (PSDs). We previously demonstrated that the exquisitely specific SAPAP/Shank interaction is critical for Shank synaptic targeting and Shank-mediated synaptogenesis. Here, we show that the PSD-95/SAPAP interaction, SAPAP synaptic targeting, and SAPAP-mediated synaptogenesis require phosphorylation of the N-terminal repeat sequences of SAPAPs. The atomic structure of the PSD-95 guanylate kinase (GK) in complex with a phosphor-SAPAP repeat peptide, together with biochemical studies, reveals the molecular mechanism underlying the phosphorylation-dependent PSD-95/SAPAP interaction, and it also provides an explanation of a PSD-95 mutation found in patients with intellectual disabilities. Guided by the structural data, we developed potent non-phosphorylated GK inhibitory peptides capable of blocking the PSD-95/SAPAP interaction and interfering with PSD-95/SAPAP-mediated synaptic maturation and strength. These peptides are genetically encodable for investigating the functions of the PSD-95/SAPAP interaction in vivo.

Urea electrolysis enables simultaneous energy-saving hydrogen production and wastewater purification at a small thermodynamic potential of 0.37 V; however, the total energy-utilization efficiency is still substantially restricted by the sluggish kinetics of the urea oxidization reaction (UOR) at the anode. In this work, an electrochemical tuning strategy has been employed to obtain a Ni (III)-enriched catalyst by starting from NiMoO4∙xH2O nanorod arrays. It has been found that the electrochemical tuning not only modifies the valency state of Ni but also causes a dramatic change in stoichiometry and microstructure of the material, leading to significantly improved activities for UOR under alkaline conditions. Notably, the obtained catalyst delivers a current density of 100 mA cm−2 for UOR at the potential of only 1.36 V vs RHE, which surpasses the best-reported values for UOR catalysis at the same applied potential, demonstrating the great promise of the electrochemical tuning strategy in rational modifications of material towards promoted electrocatalysis.

Caffeine, an antagonist of the adenosine receptor A1R, is used as a dietary supplement to reduce body weight, although the underlying mechanism is unclear. Here, we report that adenosine level in the cerebrospinal fluid, and hypothalamic expression of A1R, are increased in the diet-induced obesity (DIO) mouse. We find that mice with overexpression of A1R in the neurons of paraventricular nucleus (PVN) of the hypothalamus are hyperphagic, have glucose intolerance and high body weight. Central or peripheral administration of caffeine reduces the body weight of DIO mice by the suppression of appetite and increasing of energy expenditure. We also show that caffeine excites oxytocin expressing neurons, and blockade of the action of oxytocin significantly attenuates the effect of caffeine on energy balance. These data suggest that caffeine inhibits A1Rs expressed on PVN oxytocin neurons to negatively regulate energy balance in DIO mice.

Exchange protein directly activated by cAMP (Epac) is a direct effector for the ubiquitous second messenger cAMP. Epac activates the phospholipase Cε (PLCε) pathway. PLCβ has been linked to the synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Here, we report that Epac facilitates endocannabinoid-mediated retrograde synaptic depression through activation of PLCε. Intracellular loading of a selective Epac agonist 8-CPT-2Me-cAMP into ventral tegmental area (VTA) dopamine neurons enabled previously ineffective stimuli to induce depolarization-induced suppression of inhibition (DSI) and long-term depression of IPSCs (I-LTD) in the VTA. DSI and I-LTD are mediated by 2-AG since they were blocked by a diacylglycerol lipase inhibitor. The effects of 8-CPT-2Me-cAMP on DSI and I-LTD were absent in Epac2 and PLCε knock-out mice, but remained intact in Epac1 knock-out mice. These results identify a novel mechanism for on-demand synthesis of retrograde signaling 2-AG by the Epac2-PLCε pathway. We investigated the functional significance of Epac2-PLCε-2-AG signaling in regulating inhibitory synaptic plasticity in VTA dopamine neurons induced byin vivococaine exposure. We showed that cocaine place conditioning led to a decrease in the frequency and amplitude of spontaneous IPSCs and an increase in action potential firing in wild-type mice, but not in Epac2 or PLCε knock-out mice. Together, these results indicate that the Epac2-PLCε-2-AG signaling cascade contributes to cocaine-induced disinhibition of VTA dopamine neurons.SIGNIFICANCE STATEMENT2-arachidonoylglycerol (2-AG) is an endogenous cannabinoid that depresses synaptic transmission through stimulation of CB1receptors. Among the six isoforms of phospholipase C (PLC; PLCβ, PLCγ, PLCδ, PLCε, PLCζ, PLCη), only PLCβ has been linked to 2-AG synthesis. Here we demonstrate that 8-CPT-2Me-cAMP, a selective agonist of the cAMP sensor protein Epac, enhances 2-AG-mediated synaptic depression in ventral tegmental area (VTA) dopamine neurons via activation of PLCε. These results identify a novel mechanism for 2-AG synthesis via activation of the Epac-PLCε pathway. Furthermore, we show that cocaine-induced conditioned place preference and disinhibition of VTA dopamine neurons were impaired in mice lacking Epac or PLCε. Thus, the Epac-PLCε signaling pathway contributes to cocaine-induced disinhibition of VTA dopamine neurons and formation of drug-associated memories.

Mechanistic target of rapamycin complex 1 (mTORC1) regulates CD8(+) T-cell differentiation and function. Despite the links between PI3K-AKT and mTORC1 activation in CD8(+) T cells, the molecular mechanism underlying mTORC1 activation remains unclear. Here, we show that both the kinase activity and the death domain of DAPK1 are required for maximal mTOR activation and CD8(+) T-cell function. We found that TCR-induced activation of calcineurin activates DAPK1, which subsequently interacts with TSC2 via its death domain and phosphorylates TSC2 to mediate mTORC1 activation. Furthermore, both the kinase domain and death domain of DAPK1 are required for CD8(+) T-cell antiviral responses in an LCMV infection model. Together, our data reveal a novel mechanism of mTORC1 activation that mediates optimal CD8(+) T-cell function and antiviral activity.

Precisely controlled dimensions of heterostructured ZnO nanorod arrays were grown on micropatterned Au films supported by Si substrate using chemical vapor deposition (CVD). The field emission properties were attributed to pointed nanorods, thickness of catalyst, preferential growth, density, morphology of ZnO and Molybdenum (Mo) decorated ZnO nanorod arrays (Mo/ZnO). The selective restrained heterostructure approach resulted in excellent control over periodicity, location and density of ZnO nanorod arrays. Overall, field emission properties of bare ZnO nanorod arrays showed a low turn-on field of ~4.7 V/μm and a high field enhancement factor (β) ~1686 to 7.3 V/μm and (β) ~807 for Mo/ZnO. It was also found that the field emission properties were significantly influenced by densely decorated Mo nanoparticles on as-grown ZnO nanorod arrays.

We prepared ZnO:H thin films in Ar + H2 atmosphere with substrate at room temperature by magnetron sputtering, the effect of H2 flow ratio on the properties of thin films and the performance of ZnO:H thin-film transistors (ZnO:H-TFTs) were investigated. Hydrogen could act as a defect passivator and a shallow donor in ZnO films, which not only increases the carrier concentration but also reduces the interface trap density, therefore improving the TFT performance. Compared with pristine ZnO-TFT, the optimal ZnO:H-TFT exhibits great enhancement, with the saturation mobility increasing from 2.17 cm2/V⋅s to 5.17 cm2/V⋅s, the on/off ratio increasing from 3.47 × 105 to 4.98 × 106, the threshold voltage reducing from 15.12 V to 6.03 V. Meanwhile, the positive and negative bias stability is also improved from ΔVth = 3.89 V and −6.35 V to 1.74 V and −3.72 V, respectively. Our results show that introducing hydrogen into the sputtering atmosphere to achieve hydrogen doping is a simple and effective method to improve the performance of ZnO-TFTs. Furthermore, the high-performance ZnO:H-TFTs fabricated at room temperature have great potential in the field of flexible electronics.

This work reports a simple, time efficient, template-free solvothermal and environmentally friendly method for the synthesis of V2O5 nanospheres (NSs) for xylene gas detection. The four types of V2O5-5, V2O5-7, V2O5-9 and V2O5-11 NSs have been synthesized and tested toward xylene in concentration ranging from 1 ppm to 300 ppm. The V2O5-7 sensor exhibits excellent sensing response of 2.75 toward 100 ppm xylene gas within fast response time of 21 s with obtained limit of detection (LOD) of 1 ppm at optimal operating temperature 290 °C. The sensing mechanism is based on an interaction of V2O5 NSs towards xylene through chemical reaction with adsorbed oxygen species present on V2O5 NSs, resulting in a thinner depletion layer and a lower potential barrier which further leads to decrease in sensor resistance. These experimental results suggest that the V2O5 NSs based sensors have potential to fulfill the demands in the gas sensing field.

In this work, we report parts per billion (ppb) NO2 gas detection by utilizing zinc oxide/reduced graphene oxide (ZnO/rGO) heterostructure through a chemiresistive approach. The sensing material is carefully investigated through numerous characterization techniques. The experimental results indicated that the designed sensor shown good linearity in low ppb range of nitrogen dioxide (NO2) gas. The sensor exhibited very high response of 33.11 at 2.5 ppm in 182 s with obtained detection limit down to ppb at relatively low optimal operating temperature of 110 °C. The remarkable performance of ZnO/rGO heterostructure towards NO2 and negligible cross-response to other interfering gases along with high repeatability and long-term stability of the sensor is investigated. Due to many reactive sites and high transport capability of rGO along with high gas adsorption of ZnO nanospheres which attributes to the favorable charge transfer at ZnO/rGO interface under exposure of NO2 gas which leads to modulate the energy band structure. This study shows that the simple, cost-effective synthesis method along with easy-fabricated and deployable sensor can be applied in many industrial and environmental applications.

The electro-optic effect in two-dimensional (2D) MgO nanoflakes synthesized by a microwave-assisted process is demonstrated using a designed optical fiber modulator. The guiding properties of intense core modes excited by the material cavity are modulated by the external electric field. The feasibility of 2D MgO nanoflakes as an effective electro-optic modulator and switching are experimentally verified for the first time, to the best of our knowledge. The proposed optical-fiber-based electro-optic modulator achieves a linear wavelength shift with a high sensitivity of 12.87 pm/V(77.22 nm/kV/mm, in the electric field). The results show that MgO, as a metal oxide 2D material, is a very promising material for electro-optic modulators and switching.

Indium dysprosium oxide (InDyO) thin-film transistors (TFTs) are demonstrated by aqueous solution processing. The structure, morphology, chemical, oxygen defects, optical, and electrical properties of InDyO films with the change of Dy doping contents are systematically studied. It is observed that Dy doping could effectively improve the off current and the bias stress stability of the In2O3 devices due to the suppression of oxygen vacancies (VO). The optimized InDyO TFTs with 10 mol% Dy doping exhibit excellent electrical characteristics, including a μ of 7.60 cm2 V−1 s−1, high Ion/Ioff >108, small SS of 0.77 V/dec, Vth of 1.78 V, and excellent bias stress stability. Therefore, the InDyO TFTs grown from aqueous solution enable the development of environmentally friendly and large area electronics.

Present work proposes the insight towards synthesis of flower-like vanadium oxide hierarchical nanostructures (V2O5 HNs) through a simple and template-free hydrothermal method and their utilization as a potential xylene gas sensing materials. XRD and XPS analysis supports to the configuration of highly crystalline orthorhombic phase of V2O5. Surface morphologies of V2O5 were controlled through varying the reaction times during hydrothermal synthesis. SEM and TEM studies undoubtedly corroborates that the flower-like V2O5 HNs (3–5 μm in diameters) are composed of large number of nanosheet- and nanoneedle-type structures. BET and BJH analysis supports to the mesoporous character of V2O5 HNs with specific surface area of 19.5291 m2/g. Gas sensing studies on as-fabricated V2O5 HNs sensors were performed towards a various target gases, temperatures, and varying concentrations thoroughly and described. Gas sensing studies demonstrate that the flower-like V2O5 HNs sensors are selective and effective towards xylene @300 °C. Among various V2O5 HNs sensors, the sensor based on V2O5-3 exhibits maximum response of 3.03 to 500 ppm xylene together with good response repeatability and long term stability (towards 100 ppm, Ra/Rg = 2.20) @300 °C. Finally, the selective detection of xylene using as-grown flower-like V2O5 HNs can cover the road in the direction of the development of sensing systems for the acute detection and monitoring of toxic xylene.

Summary: Kibra is a synaptic scaffold protein regulating learning and memory. Alterations of Kibra-encoding gene WWC1 cause various neuronal disorders, including Alzheimer’s disease and Tourette syndrome. However, the molecular mechanism underlying Kibra’s function in neurons is poorly understood. Here we discover that Kibra, via its N-terminal WW12 tandem domains, binds to a postsynaptic density enriched protein, Dendrin, with a nanomolar dissociation constant. On the basis of the structure of Kibra WW12 in complex with Dendrin PY motifs, we developed a potent peptide inhibitor capable of specifically blocking the binding between Kibra and Dendrin in neurons. Systematic administration of the inhibitory peptide attenuated excitatory synaptic transmission, completely blocked long-term potentiation induction, and impaired spatial learning and memory. A Kibra mutation found in Tourette syndrome patients causes defects in binding to Dendrin. Thus, Kibra can modulate spatial learning and memory via binding to Dendrin. : Ji et al. report that the memory-related molecule Kibra, via its WW tandem domains, specifically binds to the synaptic protein Dendrin with a low-nanomolar dissociation constant to modulate spatial learning and memory. Keywords: Kibra, Dendrin, WW domains, tandem repeats, scaffold protein, synaptic complex, synaptic transmission, learning and memory, psychiatric disorder, Tourette syndrome

The development of defined hierarchical transition metal oxide nanostructures has attracted remarkable attention due to their superior chemiresistive gas sensing performances. In the present study, vertically aligned zinc oxide nanorods (ZnO-NRs) were grown by chemical vapor deposition (CVD) and precise decoration with palladium nanoparticles (Pd-NPs) on their surfaces, at different deposition times, was done through unique RF magnetic sputtering followed by annealing. The effect of different Pd-NPs loadings on structure, surface morphology, elemental composition, and chemiresistive C2H5OH gas sensing properties of CVD-mediated pristine ZnO-NRs was elucidated thoroughly and accounted. As-fabricated pristine and Pd-loaded ZnO-NRs sensors are sensitive towards ethanol (C2H5OH) at 260 °C. Moreover, gas sensing investigations revealed that the C2H5OH response of pristine ZnO NRs was enhanced strongly due to Pd-decoration. Such a response enhancement is mainly attributed to the catalytic activity of Pd-NPs. It is confirmed that the influence of Pd-NPs on ZnO-NRs sensor is normally to strengthen the amount of chemisorbed oxygen on ZnO-NRs surface and enhance the C2H5OH response. Present work can motivate research advancement on precise designing of innovative one dimensional and related nanostructures for the application of selective chemiresistive gas sensors.

Endothelin1 (ET1) is a potent vasoconstrictor that is also known to be a neuropeptide that is involved in neural circuits. We examined the role of ET1 that has been implicated in the anxiogenic process. We found that infusing ET1 into the IL cortex increased anxiety-like behaviors. The ET(A) receptor (ET(A)R) antagonist (BQ123) but not the ET(B) receptor (ET(B)R) antagonist (BQ788) alleviated ET1-induced anxiety. ET1 had no effect on GABAergic neurotransmission or NMDA receptor (NMDAR)-mediated neurotransmission, but increased AMPA receptor (AMPAR)-mediated excitatory synaptic transmission. The changes in AMPAR-mediated excitatory postsynaptic currents were due to presynaptic mechanisms. Finally, we found that the AMPAR antagonists (CNQX) and BQ123 reversed ET1's anxiogenic effect, with parallel and corresponding electrophysiological changes. Moreover, infusing CNQX + BQ123 into the IL had no additional anxiolytic effect compared to CNQX treatment alone. Altogether, our findings establish a previously unknown anxiogenic action of ET1 in the IL cortex. AMPAR-mediated glutamatergic neurotransmission may underlie the mechanism of ET1-ET(A)R signaling pathway in the regulation of anxiety.

Cognition in all mammals including human beings declines during aging. The cellular events responsible for this decay involve a reduction of neurogenesis in the dentate gyrus. Here, we show that treatment with a nature product from a traditional Chinese medicine, namely salidroside restores the capacity of the dentate gyrus to generate new neurons and intercepts learning and memory decays in mice during aging. We uncover that new neurons in aging mice have functional features of an adult granule neuron by forming excitatory synapses with their putative targeting neurons. Genetic inhibition of synaptic transmission from new neurons abolishes the therapeutic effects of salidroside in behavioral tests. We also identify that salidroside targets CREB transcription for the survival of new neurons in the dentate gyrus of old mice. Thus, salidroside is therapeutically effective against learning and memory decays via stimulation of CREB-dependent functional neurogenesis in aging.

The aberrant activation of CDK5 has been implicated in neuronal death in stroke. The goal of this study is to determine whether knocking down CDK5 by a peptide-directed lysosomal degradation approach is therapeutically effective against stroke. We synthesized a membrane-permeable peptide that specifically binds to CDK5 with a chaperone-mediated autophagy targeting motif (Tat-CDK5-CTM) and tested its therapeutic effects on a mouse model of ischemic stroke. Our results showed that Tat-CDK5-CTM blocked the CDK5-NR2B interaction, resulting in the degradation of CDK5, which in turn prevented calcium overload and neuronal death in cultured neurons. Tat-CDK5-CTM also reduced the infarction area and neuronal loss and improved the neurological functions in MCAO (Middle cerebral artery occlusion) mice. The peptide-directed lysosomal degradation of CDK5 is a promising therapeutic intervention for stroke.

Exchange protein directly activated by cAMP (Epac) and protein kinase A (PKA) are intracellular receptors for cAMP. Although PKA and its downstream effectors have been studied extensively in the context of drug addiction, whether and how Epac regulates cellular and behavioral effects of drugs of abuse remain essentially unknown. Epac is known to regulate AMPA receptor (AMPAR) trafficking. Previous studies have shown that a single cocaine exposurein vivoleads to an increase in GluA2-lacking AMPARs in dopamine neurons of the ventral tegmental area (VTA). We tested the hypothesis that Epac mediates cocaine-induced changes in AMPAR subunit composition in the VTA. We report that a single cocaine injectionin vivoin wild-type mice leads to inward rectification of EPSCs and renders EPSCs sensitive to a GluA2-lacking AMPAR blocker in VTA dopamine neurons. The cocaine-induced increase in GluA2-lacking AMPARs was absent in Epac2-deficient mice but not in Epac1-deficient mice. In addition, activation of Epac with the selective Epac agonist 8-CPT-2Me-cAMP (8-CPT) recapitulated the cocaine-induced increase in GluA2-lacking AMPARs, and the effects of 8-CPT were mediated by Epac2. We also show that conditioned place preference to cocaine was impaired in Epac2-deficient mice and in mice in which Epac2 was knocked down in the VTA but was not significantly altered in Epac1-deficient mice. Together, these results suggest that Epac2 is critically involved in the cocaine-induced change in AMPAR subunit composition and drug-cue associative learning.SIGNIFICANCE STATEMENTAddictive drugs, such as cocaine, induce long-lasting adaptions in the reward circuits of the brain. A single intraperitoneal injection of cocaine leads to changes in the composition and property of the AMPAR that carries excitatory inputs to dopamine neurons. Here, we provide evidence that exchange protein directly activated by cAMP (Epac), a cAMP sensor protein, is required for the cocaine-induced changes of the AMPAR. We found that the effects of cocaine were mimicked by activation of Epac but were blocked by genetic deletion of Epac. Furthermore, cocaine-cue associative learning was impaired in mice lacking Epac. These findings uncovered a critical role of Epac in regulating the cellular and behavioral actions of cocaine.

Alzheimer’s disease (AD) is a late-onset progressive neurodegenerative disorder that leads to cognitive, memory and behavioural impairments. Substantial evidence indicates that disrupted neuronal calcium homeostasis is an early event in AD that could mediate synaptic dysfunction and neuronal toxicity. Sodium calcium exchangers (NCXs) play important roles in regulating intracellular calcium, and accumulated data suggests that reduced NCX function, following aberrant proteolytic cleavage of these exchangers, may contribute to neurodegeneration. This review, characterizes the expression and activity of NCX as a prominent feature of AD brain, identifies the molecular mechanisms underlying the effects of NCX isoforms, and pinpoints the molecular determinants responsible for the effects of NCX. Our findings suggest that calpain mediates cleavage of NCX3 in AD brain and therefore that reduced NCX3 activity contributes to the sustained increases in intraneuronal calcium concentrations that are associated with caspase-12 activation and neuronal death in AD.

Zinc oxide (ZnO) films were deposited onto Si to form n-ZnO/p-Si heterojunctions. Under the illumination of by both ultraviolet (UV) light and sunlight, obvious photovoltaic behavior was observed. It was found that the conversion efficiency of the heterojunctions increased significantly with increasing thickness of the ZnO film, and the mechanism for light-harvesting in the heterojunctions is discussed. The results suggest that ZnO films may be helpful to increasing the harvesting of UV photons, thus decreasing the thermalization loss of UV energy in Si-based solar cells.

Owing to the low doping concentration of nitrogen and strong compensation of intrinsic donors, the attainment of highly conductive p-type ZnO films remains one of the largest challenges for the application of ZnO. An approach has been proposed to increase the doping concentration of nitrogen in ZnO by exposing the ZnO:N films in the ambient of nitrogen plasma periodically in this paper. Hall measurements and photoluminescence spectroscopy indicate that this approach is effective in improving the hole concentration in ZnO films. Under the optimized conditions, a p-type ZnO film with a hole concentration of 1.68 × 1018 cm−3 has been achieved.

Lasing action is realized in a ZnO/GaN heterojunction by employing a MgO interlayer. The MgO layer can confine electrons in the ZnO layer, while holes can pass through the MgO layer and enter into the n-ZnO layer from the p-GaN layer. The threshold of the lasing action is as low as 0.8 mA.

In this paper, we have prepared Schottky type ZnO metal–semiconductor–metal (MSM) ultraviolet (UV) detector. The structural, electrical, and optical measurements were carried out. The detector exhibited a peak responsivity of 0.337 A/W at 360 nm and the dark current was about 1 nA under 3 V bias. An ultraviolet–visible rejection ratio was obtained about more than four orders of magnitude from the fabricated detector. The 10–90% rise and fall time were 20 ns and 250 ns, respectively. We proposed that the detector had shown a gain, which was attributed to the trapping of hole carriers at the semiconductor–metal interface.

Ni thin films were electrodeposited on n-Si (100) substrate from the electrolytes containing Ni(CH 3 COO) 2 and CH 3 COONH 4 at room temperature. The scanning electron microscope images of the films reveals the uniform distribution of the nickel all over the substrate surface, which illustrates that the fine Ni films on large scales could be obtained through the method of electrodeposition. Vibrating sample magnetometer measurement with the applied field parallel to the surface shows obvious hysteresis loops of the magnetic thin films. The morphology and magnetism of the Ni thin films evolves with the deposition time increasing. The effect of deposition conditions on the properties of the Ni thin films is investigated.