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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.

Mossy cells (MCs) are a unique group of excitatory neurons in the hippocampus, a brain region important for emotion, learning, and memory. Due to the lack of a reliable method to isolate MCs from other cell types, how MCs integrate neural information and convey it to their synaptic targets for engaging a specific function are still unknown. Here, we report that MCs control the efficacy of spatial memory retrieval by synapsing directly onto local somatostatin-expressing (SST) cells. MC-SST synaptic transmission undergoes long-term potentiation (LTP), requiring Gria2-lacking Ca2+-permeable anti-α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor (Ca2+AR). A long noncoding RNA (Gria2I) is associated with Gria2 transcriptional repressors in SST cells. Silencing Gria2I induces Gria2 transcription, blocks LTP of MCs-SST synaptic transmission, and reduces the efficacy of memory retrieval. Thus, MCs directly and functionally innervate local SST neurons, and this innervation controls the efficacy of spatial memory retrieval by Gria2I inhibition of Gria2 transcription.

Stroke activates microglia pro-inflammatory response that not only induces the early neuronal injuries but also causes the secondary brain infarction. Yet, the underlying mechanisms for how microglia become activated in stroke are still unknown. Here, using the next-generation of RNA sequencing we find a total of 778 genes increasingly expressed in brain of stroke mice. Of these, we identified Hmgb2 as a microglia pro-inflammatory mediator by promoting the transcription of Ctss. Inhibition of either Hmgb2 or Ctss blocks microglia pro-inflammatory response and protects against brain damages and improves the neurological functions of stroke mice. This study uncovers Hmgb2 and Ctss as the major microglia inflammatory response mediators in stroke and hence warrants the promising targets for stroke therapies.

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.

Death-associated protein kinase 1 (DAPK1), a Ca2+/calmodulin (CaM)-dependent serine/threonine protein kinase, plays important roles in diverse apoptosis pathways not only in tumor suppression but also in neuronal cell death. The requirement of DAPK1 catalytic activity for its proposed cell functions and the elevation of catalytic activity of DAPK1 in injured neurons in models of neurological diseases, such as ischemia and epilepsy, validate that DAPK1 can be taken as a potential therapeutic target in these diseases. Recent studies show that DAPK1-NR2B, DAPK1-DANGER, DAPK1-p53, and DAPK1-Tau are currently known pathways in stroke-induced cell death, and blocking these cascades in an acute treatment effectively reduces neuronal loss. In this review, we focus on the role of DAPK1 in neuronal cell death after stroke. We hope to provide exhaustive summaries of relevant studies on DAPK1 signals involved in stroke damage. Therefore, disrupting DAPK1-relevant cell death pathway could be considered as a promising therapeutic approach in stroke.

MgxZn1–xO thin films were deposited on fused quartz substrate by PLD method with Mg0.4Zn0.6O source target, and the effect of the substrate surface atom constitution and the migration characteristics of reactive atoms on crystal structure of the MgZnO thin films were studied. Under oxygen-deficient condition, MgxZn1–xO thin film deposited mainly along (200) orientation of cubic structure lattice at temperature below 350 °C because of the alternatively constituted substrate surface by Si and O atoms and the weak horizontal migration of reactive atoms, mix-constituted substrate surface(Si/O areas and O-rich areas) and the intense horizontal migration of reactive atoms introduced phase separation in MgxZn1–xO thin films deposited at higher temperature. Single cubic structure (200) Mg0.38Zn0.62O thin films was made at 300 °C with Zn composition over theoretical limit in bulk materials, the band gap of which reached 4.2 eV and the MgZnO thin film could detect 330 nm near-UV light. And the available UV range of...

High-resolution x -ray photoelectron spectroscopy (XPS) was employed to characterize the energy band alignment between TiO 2 /multilayer (ML)-MoS 2 . The TiO 2 film and ML-MoS 2 film was grown by an atomic layer deposition (ALD) and chemical vapor deposition (CVD), respectively. The effect of CHF 3 plasma treatment on the band alignment between TiO 2 /ML-MoS 2 was evaluated. It was found that the valence band offset (VBO) and a conduction band offset (CBO) of TiO 2 /ML-MoS 2 interface was changed from 2.28 eV to 2.51 eV, and from 0.28 eV to 0.51 eV, respectively for the sample with CHF 3 plasma treatment. With the CHF 3 plasma treatment, the down-shift of Mo 3d core level binding energy results in a bend-up of energy potential on the MoS 2 side, leading to 0.23 eV ΔE C difference between the control and the sample with CHF 3 plasma treatment, which is caused by the interfacial layer in rich of F element. The physics details of the band alignment at TiO 2 /ML-MoS 2 interface will provide a guide for the MoS 2 based electronic device design.

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.

Volatile organic compounds (VOCs) monitoring is a vital need for many industrial and environmental air quality monitoring applications. We proposed and demonstrated a dual-cavity Fabry-Perot interferometric (DFPI) sensors fabricated by using a polarization maintaining fiber (PMF) immobilized with graphene, PMMA and graphene/PMMA composite for detection of various volatile gases. The optical properties of these materials changes when exposed to different VOCs, which proportionally leads to wavelength and power shift in an interference spectrum due to effective change in refractive index of graphene and swelling of PMMA, respectively. The experimental results are best fitted with models based on Langmuir adsorption isotherm and Hansen solubility parameters. This study focuses on insight into the physical/chemical interaction of volatile gases with versatile sensing materials along with new optical fiber configuration approach, which could be explored for remote detection and air quality monitoring.

Strain regulation as an effective way to enhance the photoelectric properties of two-dimensional (2D) transition metal dichalcogenides has been widely employed to improve the performance of photovoltaic devices. In this work, tensile strain was introduced in multilayer MoS 2 grown on GaN by depositing 3 nm of Al 2 O 3 on the surface. The temperature-dependent Raman spectrum shows that the thermal stability of MoS 2 is improved by Al 2 O 3 . Theoretical simulations confirmed the existence of tensile strain on MoS 2 covered with Al 2 O 3 , and the bandgap and electron effective mass of six layers of MoS 2 decreased due to tensile strain, which resulted in an increase of electron mobility. Due to the tensile strain effect, the photodetector with the Al 2 O 3 stress liner achieved better performance under the illumination of 365 nm wavelength, including a higher responsivity of 24.6 A/W, photoconductive gain of 520, and external quantum efficiency of 8381%, which are more than twice the corresponding values of photodetectors without Al 2 O 3 . Our work provides an effective technical way for improving the performance of 2D material photodetectors.

Perovskite mixed valence magnetic (La0.7Ba0.3MnO3) material is explored as a magneto-optical sensor by integrating onto the surface of an optical fiber. The guiding properties of core modes excited by the material cavity are modulated by the external magnetic field. The experimental results concluded that the device exhibits linear response to applied magnetic field strength in the range of 0–20 mT with the sensitivity of 228 pm/mT and resolution of 0.87 Oe. Blue-shift phenomenon has been observed in the interference pattern, when a magnetic field is applied. Such wavelength shift is attributed to the influences of magneto-optical properties on optical-wave propagation. The results reveal the feasibility of developing an index-tuneable magneto-optical sensor using perovskite magnetic material.

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.

Tauopathies are a class of neurodegenerative diseases that are characterized by pathological aggregation of tau protein, which is accompanied by synaptic disorders. However, the role of tau in endocytosis, a fundamental process in synaptic transmission, remains elusive. Here, we report that forced expression of human tau (hTau) in mouse cortical neurons impairs endocytosis by decreasing the level of the GTPase dynamin 1 via disruption of the miR‐132‐MeCP2 pathway; this process can also be detected in the brains of Alzheimer's patients and hTau mice. Our results provide evidence for a novel role of tau in the regulation of presynaptic function.

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

A high-performance solar-blind photodetector with a metal&ndash, semiconductor&ndash, metal structure was fabricated based on amorphous In-doped Ga2O3 thin films prepared at room temperature by radio frequency magnetron sputtering. The photodetector shows a high responsivity (18.06 A/W) at 235 nm with a fast rise time (4.9 &mu, s) and a rapid decay time (230 &mu, s). The detection range was broadened compared with an individual Ga2O3 photodetector because of In doping. In addition, the uneven In distribution at different areas in the film results in different resistances, which causes a quasi-Zener tunneling internal gain mechanism. The quasi-Zener tunneling internal gain mechanism has a positive impact on the fast response speed and high responsivity.

Impairments of dendritic trees and spines have been found in many neurodegenerative diseases, including Alzheimer's disease (AD), in which the deficits of melatonin signal pathway were reported. Melatonin receptor 2 (MT2) is widely expressed in the hippocampus and mediates the biological functions of melatonin. It is known that melatonin application is protective to dendritic abnormalities in AD. However, whether MT2 is involved in the neuroprotection and the underlying mechanisms are not clear. Here, we first found that MT2 is dramatically reduced in the dendritic compartment upon the insult of oligomer Aβ. MT2 activation prevented the Aβ‐induced disruption of dendritic complexity and spine. Importantly, activation of MT2 decreased cAMP, which in turn inactivated transcriptional factor CCAAT/enhancer‐binding protein α(C/EBPα) to suppress miR‐125b expression and elevate the expression of its target, GluN2A. In addition, miR‐125b mimics fully blocked the protective effects of MT2 activation on dendritic trees and spines. Finally, injection of a lentivirus containing a miR‐125b sponge into the hippocampus of APP/PS1 mice effectively rescued the dendritic abnormalities and learning/memory impairments. Our data demonstrated that the cAMP‐C/EBPα/miR‐125b/GluN2A signaling pathway is important to the neuroprotective effects of MT2 activation in Aβ‐induced dendritic injuries and learning/memory disorders, providing a novel therapeutic target for the treatment of AD synaptopathy.

White light-emitting diode (LED) with effective energy conservation and long service life could be employed in numerous applications. In this study, the high-performance n-ZnO films were first prepared via pulsed laser deposition on p-GaN substrates and then the n-ZnO/p-GaN heterojunction LED was fabricated. This LED exhibits blue and yellow light emission, and their emission intensities can be tuned by adjustment of the fabrication parameters (e.g., oxygen pressure) and/or by introduction of a semi-insulating i-ZnO layer to form a p-GaN/i-ZnO/n-ZnO heterojunction. Thus, a facile approach has been proposed for the preparation of white LED.

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.

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.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 AUCIn the single-ascending-dose study, vicagrel was metabolized rapidly with the median tVicagrel 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 P2YCTR20150346, CTR20160379.

The hippocampus is divided into dorsal and ventral zones along its principal axis. The dorsal hippocampus is critical for learning and memory, yet the basic function of the ventral hippocampus remains elusive. Here we genetically manipulate a subset of excitatory neurons expressing the serotonin receptor 2c (Htr2c) in the ventral hippocampus. Genetically modified virus tracing reveals that these Htr2c cells establish monosynaptic excitatory connections with newly identified neurons in the Edinger-Westphal nucleus (EW), which directly innervate the medial prefrontal cortex. Inactivation of Htr2c cells impairs behavioral performance in a visual-detection task that demands attention, without affecting novel-object recognition, learning, or memory. This attention deficit was recapitulated by inhibition of EW cells and rescued by activation of EW cells or synaptic projections from Htr2c cells onto EW cells. This study uncovers a synaptic pathway for control of attention.

Olfactory dysfunction is recognized as a potential risk factor for Alzheimer's disease (AD). We have reported previously that olfactory deprivation by olfactory bulbectomy (OBX) induced Alzheimer's-like pathological changes and behavioral abnormalities. However, the acute OBX model undergoes surgical-induced brain parenchyma loss and unexpected massive hemorrhage so that it cannot fully mimic the progressive olfactory loss and neurodegeneration in AD. Here, we employed the mice loss of cyclic nucleotide-gated channel alpha 2 (Cnga2) which is critical for olfactory sensory transduction, to investigate the role of olfactory dysfunction in AD pathological process. We found that impaired learning and memory abilities, loss of dendrite spines, as well as decrement of synaptic proteins were displayed in Cnga2 knockout mice. Moreover, Aβ overproduction, tau hyperphosphorylation, and somatodendritic translocation were also found in Cnga2 knockout mice. Our findings suggest that progressive olfactory loss leads to Alzheimer's-like behavior abnormities and pathological changes.

Effect of temperature on crystal and optical characteristics of MgZnO thin films by PLD method was studied. MgZnO thin film that contained cubic ZnO on the surface was made at lower temperature, which could absorb UV light ranged from 230 to 300 nm. This curious phenomenon is reason from the vertical separation of Zn atoms from cubic structure MgZnO lattice through vertical migration under vacuum condition during growth process. And because the solid solubility of Zn atoms in cubic MgZnO increased with temperature, the cubic ZnO didn't form in MgZnO thin films deposited at higher temperature. The cubic ZnO could just exist through special separating out process during growth process, which would transformed gradually from cubic structure to hexagonal structure when annealed at temperature from 450 °C to 850 °C under atmospheric conditions.

The two estrogen receptors (ERs), ERα and ERβ, mediate the diverse biological functions of estradiol. Opposite effects of ERα and ERβ have been found in estrogen-induced cancer cell proliferation and differentiation as well as in memory-related tasks. However, whether these opposite effects are implicated in the pathogenesis of Alzheimer’s disease (AD) remains unclear. Here, we find that ERα and ERβ play contrasting roles in regulating tau phosphorylation, which is a pathological hallmark of AD. ERα increases the expression of miR-218 to suppress the protein levels of its specific target, protein tyrosine phosphatase α (PTPα). The downregulation of PTPα results in the abnormal tyrosine hyperphosphorylation of glycogen synthase kinase-3β (resulting in activation) and protein phosphatase 2A (resulting in inactivation), the major tau kinase and phosphatase. Suppressing the increased expression of miR-218 inhibits the ERα-induced tau hyperphosphorylation as well as the PTPα decline. In contrast, ERβ inhibits tau phosphorylation by limiting miR-218 levels and restoring the miR-218 levels antagonized the attenuation of tau phosphorylation by ERβ. These data reveal for the first time opposing roles for ERα and ERβ in AD pathogenesis and suggest potential therapeutic targets for AD.

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.

Mg 1− x Zn x O thin films were deposited under different pressures during the growth process, which is modulated by different Ar/O 2 flow ratio. When growth pressure increases, the growth orientation of MgZnO thin film changed from (200) to (111) because of the decrease in migration energy of reactive Mg, Zn and O atoms from MgZnO target material. The band gap of MgZnO thin films decreased when growth pressure increased from 2 Pa to 6 Pa, which is reason from more Zn atoms combined with O atoms in (111) orientation MgZnO crystal lattice in MgZnO thin film deposited at higher pressures. But when the growth pressure increased from 6 Pa to 7 Pa, the band gap value of MgZnO thin films increased because less Zn atoms than Mg atoms combined with O atoms in MgZnO crystal lattice at higher pressures with the same (111) orientation.

Purpose The aim of this study was to evaluate the bioequivalence of a generic product 70 mg alendronate sodium tablets with the reference product Fosamax® 70 mg tablet. Materials and methods A single-center, open-label, randomized, three-period, three-sequence, reference-replicated crossover study was performed in 36 healthy Chinese male volunteers under fasting conditions. In each study period, the volunteers received a single oral dose of the generic or reference product (70 mg). Blood samples were collected at pre-dose and up to 8 h after administration. The bioequivalence of the generic product to the reference product was assessed using the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) reference-scaled average bioequivalence (RSABE) methods. Results The average maximum concentrations (Cmax) of alendronic acid were 64.78±43.76, 56.62±31.95, and 60.15±37.12 ng/mL after the single dose of the generic product and the first and second doses of the reference product, respectively. The areas under the plasma concentration–time curves from time 0 to the last timepoint (AUC0–t) were 150.36±82.90, 148.15±85.97, and 167.11±110.87 h⋅ng/mL, respectively. Reference scaling was used because the within-subject standard deviations of the reference product (sWR) for Cmax and AUC0–t were all higher than the cutoff value of 0.294. The 95% upper confidence bounds were −0.16 and −0.17 for Cmax and AUC0–t, respectively, and the point estimates for the generic/reference product ratio were 1.08 and 1.00, which satisfied the RSABE acceptance criteria of the FDA. The 90% CIs for Cmax and AUC0–t were 90.35%–129.04% and 85.31%–117.15%, respectively, which were within the limits of the EMA for the bioequivalence of 69.84%–143.19% and 80.00%–125.00%. Conclusion The generic product was bioequivalent to the reference product in terms of the rate and extent of alendronate absorption after a single 70 mg oral dose under fasting conditions.

Cholinergic system is very important for many higher brain functions, including learning and memory. Cholinergic neurons, especially those in the basal forebrain, are specifically susceptible in some neurodegenerative diseases, such as in Alzheimer’s disease (AD). Here, we studied the cholinergic system lesion effects of five familial AD mutations in 5XFAD mice, a transgenic mouse model of AD. Although the cholinergic system has been studied in this mouse model, the cholinergic deficits in AD mice have never been systematically mapped in a whole-brain three-dimensional (3D) reconstruction. Using the 3D reconstruction technology combined with immunohistochemistry (3D-IHC) and design-based stereology, we comprehensively compared the differences of the cholinergic neurons and fibers between the 5XFAD mice and C57BL/6 control mice at different age. Here, we found that the lesion of cholinergic fibers occurred earlier than the cholinergic neuron loss in 5XFAD mice. The cholinergic fiber lesions in the AD mice started sequentially in amygdala, cortex, hippocampus, and then basal forebrain. However, the basal forebrain was the first brain region observed with cholinergic neuron loss at the age of 9 months in 5XFAD mice, whereas such phenomenon first occurred at the age of 15 months in C57BL/6 control mice. Moreover, using 3D reconstruction to compare the lesion of cholinergic system of aged 5XFAD and C57BL/6 control mice, it is intuitive to notice the pathologic regions and severity of lesion. Therefore, the 3D-IHC provides detailed overview of the cholinergic neurons in the whole mouse brain, which will contribute to the study of the developing and pathologic mouse brain.

Cholinergic system is very important for many higher brain functions, including learning and memory. Cholinergic neurons, especially those in the basal forebrain, are specifically susceptible in some neurodegenerative diseases, such as in Alzheimer's disease (AD). Here, we studied the cholinergic system lesion effects of five familial AD mutations in 5XFAD mice, a transgenic mouse model of AD. Although the cholinergic system has been studied in this mouse model, the cholinergic deficits in AD mice have never been systematically mapped in a whole-brain three-dimensional (3D) reconstruction. Using the 3D reconstruction technology combined with immunohistochemistry (3D-IHC) and design-based stereology, we comprehensively compared the differences of the cholinergic neurons and fibers between the 5XFAD mice and C57BL/6 control mice at different age. Here, we found that the lesion of cholinergic fibers occurred earlier than the cholinergic neuron loss in 5XFAD mice. The cholinergic fiber lesions in the AD mice started sequentially in amygdala, cortex, hippocampus, and then basal forebrain. However, the basal forebrain was the first brain region observed with cholinergic neuron loss at the age of 9 months in 5XFAD mice, whereas such phenomenon first occurred at the age of 15 months in C57BL/6 control mice. Moreover, using 3D reconstruction to compare the lesion of cholinergic system of aged 5XFAD and C57BL/6 control mice, it is intuitive to notice the pathologic regions and severity of lesion. Therefore, the 3D-IHC provides detailed overview of the cholinergic neurons in the whole mouse brain, which will contribute to the study of the developing and pathologic mouse brain.

The over-production of β-amyloid (Aβ) has been strongly correlated to neuronal dysfunction and altered synaptic plasticity in Alzheimer’s disease (AD). Accordingly, it has been proposed that disrupted synaptic transmission and neuronal network instability underlie memory failure that is evident in the early phases of AD. Homeostatic synaptic plasticity (HSP) serves to restrain neuronal activity within a physiological range. Therefore a disruption of this mechanism may lead to destabilization in synaptic and neural circuit function. Here, we report that during HSP by neuronal activity deprivation, application of Aβ results in an aberrant over-response of the up-regulation of AMPA receptor (AMPAR)-mediated synaptic currents and cell-surface AMPAR expression. In the visual cortex, in vivo HSP induced by visual deprivation shows a similar over-response following an Aβ local injection. Aβ increases the expression of GluA2-lacking, calcium permeable AMPARs (CP-AMPARs), which are required for the initiation, but not maintenance of HSP. Both GluA2-lacking and GluA2-containing AMPARs contribute to the Aβ-mediated over-scaling of HSP. We also find that Aβ induces the dissociation of HDAC1 from the miR124 transcription factor EVI1, leading to an up-regulation of miR124 expression and increased amount of CP-AMPARs. Thus, via aberrant stimulation of miR124 expression and biogenesis of CP-AMPARs, Aβ is able to induce an over response in HSP. This Aβ-mediated dysregulation in homeostatic plasticity may play an important role in the pathogenesis of altered neural function and memory deficits in the early stages of AD. Electronic supplementary material The online version of this article (doi:10.1186/s40478-016-0398-0) contains supplementary material, which is available to authorized users.

Quantitative analysis of H129-ΔTK-tdT monosynaptic tracing. Helper AAVs and H129-ΔTK-tdT were sequentially injected at VPM (a), nRT (b) or VTA (c) of wild type C57BL/6, PV-Cre or DAT-Cre mice respectively, as described in Fig.4-6. The brains’ corona slices were observed with an interval of 120 μM (every 4 slices), and the amounts of the labeled cell at the indicated brain regions were counted. The starter cells at the injection site were detected at Day32 as tdTomato and GFP co-expressing neurons (opened circle, each circle represents one mouse), and the tdTomato positive neurons at other brain regions were observed at Day 32 (filled triangle, each circle represents one mouse). (PDF 109 kb)

Anterograde transmission of H129-G4 from retina to CNS (a) Schema of the simplified mouse visual pathway. LGN, lateral geniculate nucleus; LP, lateral posterior thalamic nucleus; SC, superior colliculus; V1 and V2, primary and secondary visual cortex. (b-d) H129-G4 tracing from retina. H129-G4 was injected into the right retina of wild-type C57BL/6 mice, and images were obtained at 6 dpi. Representative images at LGN, LP (b) and visual cortex (c) are shown. Selected regions are magnified correspondingly, and representative single neurons are presented (d). (PDF 1100Â kb)

H129-ΔTK-tdT alone in various brain regions. (a) Parameters for H129-ΔTK-tdT injection. (b-g) Representative labeling results. H129-ΔTK-tdT was injected into the indicated brain regions of wild type C57BL/6 as listed in the table (a), and the brains were perfused at 10 dpi. The coronal brain slice throughout the brain were observed after staining for NeuN (blue), GFAP (green) and tdTomato (red). Representative images of upstream and downstream region of the injection sites are shown. The white arrows indicated the injection sites. The neurons in the upstream brain region labeled by virus terminal invasion are indicated by the white arrowheads (e3). OB, olfactory bulb; Pir, piriform cortex; MOE, main olfactory epithelium; M1, primary motor cortex; DG, dentate gyrus; LEC, lateral entorhinal cortex; LGN, lateral geniculate nucleus; V1, primary visual cortex; VTA, ventral tegmental area; LDTg, laterodorsal tegmental nucleus. (PDF 2370 kb)

Absence of labeled cells upstream of nRT-PV neurons. H129-Î TK-tdT and AAV-DIO-TK-GFP were injected into the nRT of PV-Cre mice as shown in Fig.5. The animals were perfused Day 32, and the coronal brain slices throughout the entire brains were observed. The representative images of S1, the upstream region of nRT, are shown. (PDF 929Â kb)

In vitro replication of the H129-ΔTK-tdT. To determine the growth property of H129-ΔTK-tdT which lacks TK, fetal mouse hippocampal and cortical neurons (Neuron) or Vero cells were infected with H129-ΔTK-tdT or the TK competent strain H129-tdT at an MOI of 0.02. At the indicated time point, virus titers in the cell culture were determined by standard plaque forming assay. Shown is the representative data from 3 independent experiments, and presented as the Mean ± SD from triplicates. (PDF 183 kb)

The microfluidic plate (a) The schematic structure diagram of the microfluidic system. (b) Axons through the microchannels. Freshly isolated fetal mouse hippocampal and cortical neurons were seeded into one chamber of the microfluidic plate, and cultured for 7 days with positive hydrostatic pressure in the soma chamber. Then the plate was disassembled and stained with antibodies against Tau and Map2. Shown is the representative image from 3 plates. (c) Pre- and post-synaptic markers in the afferent chamber. Neurons were sequentially plated into both chambers at Day 1 and Day 5 respectively, and cultured for additional 7 days with positive hydrostatic pressure in the efferent chamber. The plate was disassembled on Day 12 and stained for pre-synaptic marker synaptophysin (SYP) and post-synaptic marker PSD-95. The nuclei were counterstain with Hoechst dye. Shown is the representative image from 3 plates. (d) No inter-compartment leakage between the chambers. Vero cells were cultured in one chamber with positive hydrostatic pressure, and H129-G4 was added into the opposite chamber to a final concentration of 2.5 × 109 pfu/ml. The GFP signal in the Vero cell culture chamber was monitored, and show is the representative image at 72 hpi. (PDF 676 kb)

Invasion and transmission of H129-G4 in the VPM-S1 circuit. (a) Simplified schema of the VPM-S1 circuit. VPM, ventral posteromedial thalamic nucleus; nRT, nucleus of reticular thalamus; S1, primary somatosensory cortex; IV, V and VI, layer 4, 5 and 6 of the cortex. (b) Representative tracing results of H129-G4 in VPM-S1 circuit. H129-G4 (1 × 106 pfu in 200 nl) was injected into the VPM of wild-type C57BL/6 mice together with Alexa Fluor 594-conjugated CTB (CTB, red). The animals were perfused at the indicated time points, and representative images of the coronal brain slice at the VPM-S1 regions are shown. The boxed areas are magnified and presented in the right panel. The layers of the S1 cortex were determined according to NeuN staining and indicated by the dotted lines. (PDF 503 kb)

Terminal invasion of H129-G4 in vitro (a) Dose related incidence of H129-G4 terminal invasion. Fetal mouse hippocampal and cortical neurons were cultured as described above, H129-G4 was added to the terminal chamber at the indicated final concentrations, and GFP signal was monitored daily. Representative images at 48 hpi from 3 plates at each concentration group are shown. The labeled neurons are indicated with the dotted boxes and magnified in the lower panels. Scale bar = 100 μm. (b) Census of H129-G4 terminal invasion. Hippocampal and cortical neurons, trigeminal ganglion (TG) and dorsal root ganglion neurons (DRG) were cultured in microfluidic plates at the indicated cell amount. H129-G4 was added to the axonal terminal chamber at different final concentrations, and the GFP positive neurons in each plate were counted. Data were from 3 plates under each condition, and results are presented as mean ± SD. (c) Terminal invasion of VSV. Similarly, VSV-GFP was added into the terminal chamber of hippocampal and cortical neurons to a final concentration of 1 × 107 pfu/ml. The representative image from 3 plates at 48 hpi is shown. Scale bar = 100 μm. (PDF 429 kb)

Invasion and transmission of H129-G4 in the visual pathway. Different amount of H129-G4 was injected into the left LGN (a) or V1 (b) of wild-type C57BL/6 mice together with CTB, respectively. The animals were perfused at the indicated time points, and the coronal brain slices throughout the entire brains were observed. Representative images at V1, LGN and retinas are presented. (PDF 1400Â kb)

In this paper, photoluminescence (PL) of ZnO thin films prepared on c-Al2O3 substrates by the pulsed laser deposition (PLD) method at different O2 partial pressures is investigated. For all samples, a narrow ultraviolet (UV) emission and a broad visible emission can be observed at room-temperature (RT). With increasing O2 partial pressures from 0.2 to 5 Pa, the intensity ratio of the UV to visible emissions increases, and the energy positions of the UV emission band shift to the high energy side. It is noted that the visible part includes two emission bands of green luminescence (GL) and yellow luminescence (YL), in which the GL emission is strong at low oxygen pressure and the YL emission becomes dominant at high O2 partial pressures. The temperature-dependent PL spectra show that the UV emission is composed of two bands labeled FX and FA. The dependences and possible assignments of these PL bands are briefly discussed.

Necrosis and apoptosis are two distinct types of mechanisms that mediate ischemic injury. But a signaling point of convergence between them has yet to be identified. Here, we show that activated death-associated protein kinase 1 (DAPK1), phosphorylates p53 at serine-23 (pS23) via a direct binding of DAPK1 death domain (DAPK1DD) to the DNA binding motif of p53 (p53DM). We uncover that thepS23acts as a functional version of p53 and mediates necrotic and apoptotic neuronal death; in the nucleus,pS23induces the expression of proapoptotic genes, such asBax, whereas in the mitochondrial matrix,pS23triggers necrosis via interaction with cyclophilin D (CypD) in cultured cortical neurons from mice. Deletion of DAPK1DD (DAPK1DDΔ) or application of Tat-p53DM that interrupts DAPK1–p53 interaction blocks these dual pathways ofpS23actions in mouse cortical neurons. Thus, the DAPK1–p53 interaction is a signaling point of convergence of necrotic and apoptotic pathways and is a desirable target for the treatment of ischemic insults.