Search

The hippocampus is a temporal lobe structure critical for cognition, such as learning, memory, and attention, as well as emotional responses. Hippocampal dysfunction can lead to persistent anxiety and/or depression. However, how millions of neurons in the hippocampus are molecularly and structurally organized to engage their divergent functions remains unknown. Here, we genetically target a subset of neurons expressing the coagulation factor c homolog (COCH) gene. COCH-expressing neurons or COCH neurons are topographically segregated in the distal region of the ventral CA3 hippocampus and express Mtf1 and Cacna1h. MTF1 activation of Cacna1h transcription in COCH neurons encodes the ability of COCH neurons to burst action potentials and cause social-stress-induced anxiety-like behaviors by synapsing directly with a subset of GABAergic inhibitory neurons in the lateral septum. Together, this study provides a molecular and circuitry-based framework for understanding how COCH neurons in the hippocampus are assembled to engage social behavior.

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.

Alzheimer's disease (AD), manifested by memory loss and a decline in cognitive functions, is the most prevalent neurodegenerative disease accounting for 60-80 % of dementia cases. But, to-date, there is no effective treatment available to slow or stop the progression of AD. Exosomes are small extracellular vesicles that carry constituents, such as functional messenger RNAs, non-coding RNAs, proteins, lipids, DNA, and other bioactive substances of their source cells. In the brain, exosomes are likely to be sourced by almost all cell types and involve in cell communication to regulate cellular functions. The yet, accumulated evidence on the roles of exosomes and their constituents in the AD pathological process suggests their significance as additional biomarkers and therapeutic targets for AD. This review summarizes the current reported research findings on exosomes roles in the pathogenesis, diagnosis, and treatment of AD.

Incidence of intracerebral hemorrhage (ICH) and brain iron accumulation increases with age. Excess iron accumulation in brain tissues post‐ICH induces oxidative stress and neuronal damage. However, the mechanisms underlying iron deregulation in ICH, especially in the aged ICH model have not been well elucidated. Ferroportin1 (Fpn) is the only identified nonheme iron exporter in mammals to date. In our study, we reported that Fpn was significantly upregulated in perihematomal brain tissues of both aged ICH patients and mouse model. Fpn deficiency induced by injecting an adeno‐associated virus (AAV) overexpressing cre recombinase into aged Fpn‐floxed mice significantly worsened the symptoms post‐ICH, including hematoma volume, cell apoptosis, iron accumulation, and neurologic dysfunction. Meanwhile, aged mice pretreated with a virus overexpressing Fpn showed significant improvement of these symptoms. Additionally, based on prediction of website tools, expression level of potential miRNAs in ICH tissues and results of luciferase reporter assays, miR‐124 was identified to regulate Fpn expression post‐ICH. Higher serum miR‐124 levels were correlated with poor neurologic scores of aged ICH patients. Administration of miR‐124 antagomir enhanced Fpn expression and attenuated iron accumulation in aged mice model. Both apoptosis and ferroptosis, but not necroptosis, were regulated by miR‐124/Fpn signaling manipulation. Our study demonstrated the critical role of miR‐124/Fpn signaling in iron metabolism and neuronal death post‐ICH in aged murine model. Thus, Fpn upregulation or miR‐124 inhibition might be promising therapeutic approachs for this disease., Brain iron accumulation following ICH induced secondary brain injury and neuronal death. However, the mechanisms underlying iron deregulation in aged ICH model is poorly understood. miR‐124/Fpn signaling was downregulated in aged ICH model mice and patients as a protection mechanism. Higher serum miR‐124 levels were correlated with poor neurologic scores of aged patients. Targeting miR‐124/Fpn signaling could reduce the iron accumulation post‐ICH in aged murine model, thus ameliorated hematoma volume, cell apoptosis and neurologic dysfunction through inhibiting apoptosis and ferroptosis.

To further improve the performance of all-inkjet-printing ZnO UV photodetector and maintain the advantages of inkjet printing technology, the inkjet printing Ag nanoparticles (NPs) were deposited on the inkjet printing ZnO UV photodetector for the first time. The inkjet printing Ag NPs can passivate the surface defects of ZnO and work as surface plasmons from the characterization of photoluminescence (PL), X-ray photoelectron spectroscopy (XPS), and finite difference time domain method (FDTD) simulation. The normalized detectivity (D*) of the Ag NP-modified detector reaches to 1.45 × 1010 Jones at 0.715 mW incident light power, which is higher than that of 5.72 × 109 Jones of the bare ZnO photodetector. The power-law relationship between the photocurrent and the incident light power of the Ag NP-modified ZnO detector is Ipc ∝ P2.34, which means the photocurrent is highly sensitive to the change of incident light power.

BackgroundWith coronavirus disease 2019 (Covid-19) ravaging the global, concern has been aroused whether discharged Covid-19 patients with reappeared positive nucleic acid test results are infected again.ObjectiveTo analyze the clinical characteristics of discharged Covid-19 patients with reappeared positive nucleic acid test results and to track clinical outcomes of them.MethodsWe extracted clinical data on 938 Covid-19 patients from Wuhan Union Hospital (West Branch), and we obtained information about residual symptoms and nucleic acid tests after discharge through follow-up study. We evaluated the relationship of clinical characteristics and reappeared positive results. Each patient had at least 44 days of follow-up.ResultsOf 938 discharged patients, a total of 58 (6.2%) had reappeared positive nucleic acid test results and 880 remain negative. Among patients over the age of 50, the factors we found to be associated with re-positive results were coronary artery disease (14.1%, vs. 5.5% among those without coronary artery disease; odds ratio, 2.81; 95% confidence interval [CI], 1.28 to 6.15), and hypertension (9.5%, vs. 4.9% among those without hypertension; odds ratio, 2.05; 95% CI, 1.10 to 3.82). As of May 11, 2020, 54 (93.1%) re-positive patients turned negative again while two patients remained positive, and two patients was lost to the second follow-up.ConclusionCoexisting diseases including coronary artery disease and hypertension were substantial risk factors for re-positive outcomes among patients over 50. And most re-positive patients tended to return negative eventually.

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.

In this paper, we have introduced the auxetic effect in black phosphorus (BP) analog Sb and achieved auxetic modulations in monolayer As and Sb via first-principles calculations. Compared with monolayer As, the monolayer Sb is phonon unstable. By applying uniaxial strain along each direction, we discovered zigzag-vertical reversibility on out-of-plane auxeticity, and the negative Poisson's ratios for monolayer As and Sb were simulated to be -0.125/-0.172 and -0.036/-0.063, respectively, by applying the strain along zigzag/vertical directions. The negative Poisson's ratio could be significantly manipulated by applying a vertical electric field as it can be increased up to 70.3% for monolayer As and decreased up to 55.6% for monolayer Sb. Such an intrinsic negative Poisson's ratio and electric field modulation could endow these monolayers with potential applications in auxetic optoelectronic devices, electrodes and sensors, leading to novel multi-functionalities.

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.

Recently, we have reported that dentate mossy cells (MCs) control memory precision via directly and functionally innervating local somatostatin (SST) inhibitory interneurons. Here, we report a discovery that dysfunction of synaptic transmission between MCs and SST cells causes memory imprecision in a mouse model of early Alzheimer's disease (AD). Single‐cell RNA sequencing reveals that miR‐128 that binds to a 3′UTR of STIM2 and inhibits STIM2 translation is increasingly expressed in MCs from AD mice. Silencing miR‐128 or disrupting miR‐128 binding to STIM2 evokes STIM2 expression, restores synaptic function, and rescues memory imprecision in AD mice. Comparable findings are achieved by directly engineering MCs with the expression of STIM2. This study unveils a key synaptic and molecular mechanism that dictates how memory maintains or losses its details and warrants a promising target for therapeutic intervention of memory decays in the early stage of AD., Memory is imprecise in an early stage of AD due to a selective degeneration of mossy cell synaptic transmission. MiR‐128 inhibition of STIM2 translation causes a selective degeneration of mossy cell synaptic transmission in an early stage of AD. Uncoupling miR‐128 binding to STIM2 induces STIM2 translation, restores mossy cell synaptic transmission, and rescues memory precision in AD mice.

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.

Dominance hierarchy is a fundamental phenomenon in grouped animals and human beings, however, the underlying regulatory mechanisms remain elusive. Here, we report that an antisense long non-coding RNA (lncRNA) of synapsin II, named as AtLAS, plays a crucial role in the regulation of social hierarchy. AtLAS is decreased in the prefrontal cortical excitatory pyramidal neurons of dominant mice; consistently, silencing or overexpression of AtLAS increases or decreases the social rank, respectively. Mechanistically, we show that AtLAS regulates alternative polyadenylation of synapsin II gene and increases synapsin 2b (syn2b) expression. Syn2b reduces AMPA receptor (AMPAR)-mediated excitatory synaptic transmission through a direct binding with AMPAR at the postsynaptic site via its unique C-terminal sequence. Moreover, a peptide disrupting the binding of syn2b with AMPARs enhances the synaptic strength and social ranks. These findings reveal a novel role for lncRNA AtLAS and its target syn2b in the regulation of social behaviors by controlling postsynaptic AMPAR trafficking.

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

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.

SUMMARY Protein phosphatase 2A (PP2A) inhibition causes hy-perphosphorylation of tau and APP in Alzheimer’s disease (AD). However, the mechanisms underlying the downregulation of PP2A activity in AD brain remain unclear. We demonstrate that Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is overexpressed in AD brain. CIP2A-mediated PP2A inhibition drives tau/APP hyperphosphorylation and increases APP β-cleavage and Aβ production. Increase in CIP2A expression also leads to tau mislocalization to dendrites and spines and synaptic degeneration. In mice, injection of AAV-CIP2A to hippocampus induced AD-like cognitive deficits and impairments in long-term potentiation (LTP) and exacerbated AD pathologies in neurons. Indicative of disease exacerbating the feedback loop, we found that increased CIP2A expression and PP2A inhibition in AD brains result from increased Aβ production. In summary, we show that CIP2A overexpression causes PP2A inhibition and AD-related cellular pathology and cognitive deficits, pointing to CIP2A as a potential target for AD therapy., In Brief PP2A inactivation plays a key role in AD pathogenesis. Shentu et al. report that endogenous PP2A inhibitor CIP2A is upregulated in AD brains. CIP2A overexpression promotes β-cleavage of APP and tau hyperphosphorylation through PP2A inhibition, leading to impairments in synapse, hippocampal LTP, and memory., Graphical Abstract

Alzheimer's disease (AD) underlies dementia for millions of people worldwide with no effective treatment. The dementia of AD is thought stem from the impairments of the synapses because of their critical roles in cognition. Melatonin is a neurohormone mainly released by the pineal gland in a circadian manner and it regulates brain functions in various manners. It is reported that both the melatonin deficit and synaptic impairments are present in the very early stage of AD and strongly contribute to the progress of AD. In the mammalian brains, the effects of melatonin are mainly relayed by two of its receptors, melatonin receptor type 1a (MT1) and 1b (MT2). To have a clear idea on the roles of melatonin in synaptic impairments of AD, this review discussed the actions of melatonin and its receptors in the stabilization of synapses, modulation of long-term potentiation, as well as their contributions in the transmissions of glutamatergic, GABAergic and dopaminergic synapses, which are the three main types of synapses relevant to the synaptic strength. The synaptic protective roles of melatonin in AD treatment were also summarized. Regarding its protective roles against amyloid-β neurotoxicity, tau hyperphosphorylation, oxygenation, inflammation as well as synaptic dysfunctions, melatonin may be an ideal therapeutic agent against AD at early stage.

The effect of oxygen pressure on deposition orientation and the UV response characteristics of the β-Ga2O3 thin film by the Pulse Laser Deposition (PLD) method were studied. The β-Ga2O3 thin film deposited mainly along ( 2 ¯ 01 ) orientation at 0.5 Pa oxygen pressure, however it deposited more along (400) orientation when the oxygen pressure increased from 0.5 Pa to 2 Pa. The decrease in the migration energy of reactive Ga and O atoms from Ga2O3 target at higher oxygen pressure is the main reason for the change in the orientation of the β-Ga2O3 thin film. The β-Ga2O3 thin film that was constituted mainly by ( 2 ¯ 01 ) and (400) orientations β-Ga2O3 was made at 2 Pa, where the band gap of the β-Ga2O3 thin film is wider than the ( 2 ¯ 01 ) orientation ones deposited at smaller oxygen pressure, and the maximum response of the β-Ga2O3 thin film shifted considerably from 255 nm to 240 nm compared with ( 2 ¯ 01 ) orientation β-Ga2O3 thin film. Because the Idark of the UV detector based on the mix-orientation β-Ga2O3 thin film is just 2.53 nA under 25 V bias voltage, which is much smaller than that of the ( 2 ¯ 01 ) β-Ga2O3 based detector, the Iuv/Idark of the mix-orientation β-Ga2O3–based detector reached 2500 at 25 V bias voltage. This value is much higher than the ( 2 ¯ 01 ) β-Ga2O3–based detector both in our experiments and in reported results. Wider band gap (400) β-Ga2O3 and relative higher density of boundaries at the interfaces between (400) and ( 2 ¯ 01 ) β-Ga2O3 are the main reasons for the smaller Idark and the higher Iuv/Idark of the β-Ga2O3 UV detector deposited at 2 Pa. The β-Ga2O3 thin film deposited along multiple orientations at oxygen pressure over 2Pa, the UV response, and Iuv of the β-Ga2O3 thin films deposited at higher oxygen pressure was much smaller than the one deposited at 2 Pa, and the Iuv/Idark was also much smaller. In addition, the UV β-Ga2O3 detector that composed of both (400) and ( 2 ¯ 01 ) β-Ga2O3 showed similar response time (0.8 us) and much smaller decay time (80 us) compared with the ( 2 ¯ 01 ) β-Ga2O3–based detector, which was also much faster than the reported results. Therefore, when appropriate numbers of (400) β-Ga2O3 were mixed into the ( 2 ¯ 01 ) β-Ga2O3 thin film, the mix-orientation β-Ga2O3–based UV detector showed a much lower noise level, much higher signal/noise ratio, and much faster decay speed at shorter wavelength UV light compared with a single ( 2 ¯ 01 ) β-Ga2O3–based based UV detector.

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.

High quality (200) and (111) orientations cubic MgZnO thin films were made on (200) and (111) orientations MgO substrates separately under different condition with higher and lower migration energy of reactive atoms separately. The crystal quality of (111) orientation MgZnO thin film is higher than (200) one because of the stronger horizontal migration of atoms on (111) surface under high temperature condition, the surface of (200) orientation MgZnO thin film is smoother than (111) orientation one because of lower vertical growth speed of (200) MgZnO grains. The band gap of (111) orientation MgZnO thin film is smaller than (200) one because of more Zn atoms in (111) orientation MgZnO lattice than that in (200) ones. This paper gives an effective method to improve crystal quality of different orientation MgZnO thin film under different condition, which is meaningful in application of cubic MgZnO in different areas.

ZnO:Al (AZO) and a-Ga2O3 thin films were successively deposited on a sapphire substrate by magnetron sputtering and the photoelectric properties of AZO/a-Ga2O3 heterojunction vertical structure to solar blind ultraviolet light were investigated. The device shows a high photo-to-dark current ratio (2.2 × 103), low dark current (11.4 nA), large responsivity (67.26 A/W) and fast response and recovery times of 1.53 μs and 2.25 ms under 254 nm light illumination at 10 V. Additionally, the device exhibits an obvious self-powered effect with light-dark current ratio (183.3) and the responsivity (2.92 × 10−2 A/W) at 0 V. The high response is attributed to the separation of photogenerated electron-hole pairs due to built-in field in the depletion width of AZO and Ga2O3. The analysis shows that there exists a quasi-Zener tunneling internal gain mechanism, which increases the performance of the device. The comprehensive performance of the device implied a wide potential in optoelectronics applications.

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.

Long non-coding RNA (lncRNA) is a kind of non-coding RNA (ncRNA), with a length of 200 nt to 100 kb, that lacks a significant open reading frame (ORF) encoding a protein. lncRNAs are widely implicated in various physiological and pathological processes, such as epigenetic regulation, cell cycle regulation, cell differentiation regulation, cancer, and neurodegenerative diseases, through their interactions with chromatin, protein, and other RNAs. Numerous studies have suggested that lncRNAs are closely linked with the occurrence and development of a variety of diseases, especially neurodegenerative diseases, of which the etiologies are complicated and the underlying mechanisms remain elusive. Determining the roles of lncRNA in the pathogenesis of neurodegenerative diseases will not only deepen understanding of the physiological and pathological processes that occur in those diseases but also provide new ideas and solutions for their diagnosis and prevention. This review aims to highlight the progress of lncRNA research in the pathological and behavioral changes of neurodegenerative diseases. Specifically, we focus on how lncRNA dysfunctions are involved in the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

Aggregation of amyloid-β (Aβ) peptides, which are the cleavage products of amyloid precursor protein (APP), is a major pathological hallmark in the brain of Alzheimer's disease (AD). Now, we know little about the roles of APP translation in the disease progression of AD. Here, we show that BC1, a long noncoding RNA (lncRNA), is expressed in the brain of AD mice. BC1 induces APP mRNA translation via association with a fragile X syndrome protein (FMRP). Inhibition of BC1 or BC1-FMRP association in AD mice blocks aggregation of Aβ in the brain and protects against the spatial learning and memory deficits. Expression of exogenous BC1 in excitatory pyramidal neurons of mice induces Aβ peptides accumulation and the spatial learning and memory impairments. This study provides a novel mechanism underlying aggregation of Aβ peptides via BC1 induction of APP mRNA translation and hence warrants a promising target for AD therapy.

Choline acetyltransferase neurons in the vertical diagonal band of Broca (vChATs) degenerate in the early stage of Alzheimer’s disease (AD). Here, we report that vChATs directly innervate newly generated immature neurons (NGIs) in the dorsal hippocampus (dNGIs) of adult mice and regulate both the dNGIs survival and spatial pattern separation. In a mouse model that exhibits amyloid-β plaques similar to AD patients, cholinergic synaptic transmission, dNGI survival and spatial pattern separation are impaired. Activation of vChATs with theta burst stimulation (TBS) that alleviates the decay in cholinergic synaptic transmission effectively protects against spatial pattern separation impairments in the AD mice and this protection was completely abolished by inhibiting the dNGIs survival. Thus, the impairments of pattern separation-associated spatial memory in AD mice are in part caused by degeneration of cholinergic synaptic transmission that modulates the dNGIs survival., Cholinergic neurons in the diagonal band of Broca degenerate early in Alzheimer’s disease. Here the authors show that in healthy mice, these cholinergic inputs innervate newborn neurons in the hippocampus, and that loss of this innervation in an Alzheimer’s disease model leads to impairments in spatial memory.

The disadvantages of the low on/off current ratio (Ion/off) and high leakage current in ZnO-based thin-film transistors (TFTs) impede its development to realize industrial production for replacing Si-TFTs. In this work, we fabricated a high performance MgZnO/ZnO dual-active-layer TFTs (DAL-TFTs) through systematic optimize the synthesis conditions. The optimized Mg0.2Zn0.8O/ZnO TFTs presents high mobility of 21.1 cm2V−1s−1 with a high Ion/off of 1.5 × 108, which is much higher than that of ZnO-based TFTs. The results indicate that high carrier concentration ZnO close to the insulation layer ensures the excellent mobility of MgZnO/ZnO DAL-TFTs and low carrier concentration MgZnO layer can reduce the off-state current of the device, and increase the switching ratio of the device. Our results indicate the MgZnO/ZnO composite is a promising candidate for high performance TFTs and other electronic devices.

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.

Functional failure of tau contributes to age-dependent, iron-mediated neurotoxicity, and as iron accumulates in ischemic stroke tissue, we hypothesized that tau failure may exaggerate ischemia-reperfusion-related toxicity. Indeed, unilateral, transient middle cerebral artery occlusion (MCAO) suppressed hemispheric tau and increased iron levels in young (3-month-old) mice and rats. Wild-type mice were protected by iron-targeted interventions: ceruloplasmin and amyloid precursor protein ectodomain, as well as ferroptosis inhibitors. At this age, tau-knockout mice did not express elevated brain iron and were protected against hemispheric reperfusion injury following MCAO, indicating that tau suppression may prevent ferroptosis. However, the accelerated age-dependent brain iron accumulation that occurs in tau-knockout mice at 12 months of age negated the protective benefit of tau suppression against MCAO-induced focal cerebral ischemia-reperfusion injury. The protective benefit of tau knockout was revived in older mice by iron-targeting interventions. These findings introduce tau-iron interaction as a pleiotropic modulator of ferroptosis and ischemic stroke outcome.

Altered neurogenesis and disrupted expression of synaptic proteins in prefrontal cortex of SHANK3 -deficient non-human primate

Yifan Zhang,1 Xiaoyan Chen,1 Yunbiao Tang,2 Youming Lu,1 Lixia Guo,1 Dafang Zhong1 1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 2Department of Pharmacy, The General Hospital of Shenyang Military Region, Shenyang, People’s Republic of China 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® 70mg 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 (70mg). Blood samples were collected at pre-dose and up to 8h 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±110.87h·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. Keywords: alendronate sodium, pharmacokinetics, highly variable drug, reference-scaled average bioequivalence

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.

Background Herpes simplex virus type 1 strain 129 (H129) has represented a promising anterograde neuronal circuit tracing tool, which complements the existing retrograde tracers. However, the current H129 derived tracers are multisynaptic, neither bright enough to label the details of neurons nor capable of determining direct projection targets as monosynaptic tracer. Methods Based on the bacterial artificial chromosome of H129, we have generated a serial of recombinant viruses for neuronal circuit tracing. Among them, H129-G4 was obtained by inserting binary tandemly connected GFP cassettes into the H129 genome, and H129-ΔTK-tdT was obtained by deleting the thymidine kinase (TK) gene and adding tdTomato coding gene to the H129 genome. Then the obtained viral tracers were tested in vitro and in vivo for the tracing capacity. Results H129-G4 is capable of transmitting through multiple synapses, labeling the neurons by green florescent protein, and visualizing the morphological details of the labeled neurons. H129-ΔTK-tdT neither replicates nor spreads in neurons alone, but transmits to and labels the postsynaptic neurons with tdTomato in the presence of complementary expressed TK from a helper virus. H129-ΔTK-tdT is also capable to map the direct projectome of the specific neuron type in the given brain regions in Cre transgenic mice. In the tested brain regions where circuits are well known, the H129-ΔTK-tdT tracing patterns are consistent with the previous results. Conclusions With the assistance of the helper virus complimentarily expressing TK, H129-ΔTK-tdT replicates in the initially infected neuron, transmits anterogradely through one synapse, and labeled the postsynaptic neurons with tdTomato. The H129-ΔTK-tdT anterograde monosynaptic tracing system offers a useful tool for mapping the direct output in neuronal circuitry. H129-G4 is an anterograde multisynaptic tracer with a labeling signal strong enough to display the details of neuron morphology. Electronic supplementary material The online version of this article (doi:10.1186/s13024-017-0179-7) contains supplementary material, which is available to authorized users.

Immediately following ischemia, glutamate accumulates in the extracellular space and results in extensive stimulation of its receptors including N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors. A large amount of Ca2+ influx directly through the receptor-gated ion channels which leads to Ca2+ overload and triggers several downstream lethal reactions. As a result, cell dies via apoptosis or necrosis, or both. Death-associated protein kinase 1 (DAPK1) physically and functionally interacts with the NMDA receptor GluN2B subunit at extra-synaptic sites and this interaction acts as a central mediator for stroke damage. The goal of this study is to explore an effective strategy in the treatment of stroke with a molecular genetic manipulation to interrupt DAPK1-GluN2B interaction. We generated a mutant strain of mice with the conditional deletion of GluN2B C-terminal tail consisting of amino acids 886-1269 in the forebrain excitatory neurons (the GluN2B mutant mice) and tested the protective effects of this mutation in stroke damages. GluN2B mutation effectively disrupted the DAPK1-GluN2B interaction and inhibited extra-synaptic NMDA receptor currents without affecting synaptic NMDA receptor channel activity in the central neurons. GluN2B mutation protected against stroke damages both in vitro and in vivo and hence improved behavioral performance. Disruption of the DAPK1-GluN2B interaction is therapeutically effective against stroke damages.

Histone deacetylase 2 (HDAC2) plays a major role in the epigenetic regulation of gene expression. Previous studies have shown that HDAC2 expression is strongly increased in Alzheimer’s disease (AD), a major neurodegenerative disorder and the most common form of dementia. Moreover, previous studies have linked HDAC2 to Aβ overproduction in AD; however, its involvement in tau pathology and other memory-related functions remains unclear. Here, we show that increased HDAC2 levels strongly correlate with phosphorylated tau in a mouse model of AD. HDAC2 overexpression induced AD-like tau hyperphosphorylation and aggregation, which were accompanied by a loss of dendritic complexity and spine density. The ectopic expression of HDAC2 resulted in the deacetylation of the hepatocyte nuclear factor 4α (HNF-4A) transcription factor, which disrupted its binding to the miR-101b promoter. The suppression of miR-101b caused an upregulation of its target, AMP-activated protein kinase (AMPK). The introduction of miR-101b mimics or small interfering RNAs (siRNAs) against AMPK blocked HDAC2-induced tauopathy and dendritic impairments in vitro. Correspondingly, miR-101b mimics or AMPK siRNAs rescued tau pathology, dendritic abnormalities, and memory deficits in AD mice. Taken together, the current findings implicate the HDAC2/miR-101/AMPK pathway as a critical mediator of AD pathogenesis. These studies also highlight the importance of epigenetics in AD and provide novel therapeutic targets.

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.

MSM structure UV detectors were fabricated on mixed-phase MgZnO thin films with (200) cubic MgZnO/hexagonal MgZnO and (111) cubic MgZnO/hexagonal MgZnO interfaces by PLD method. Under 25 V bias voltage, the maximum responsivity of the mix-phase MgZnO based detector with (002) cubic MgZnO/hexagonal MgZnO interfaces reached 8 A/W at 256 nm because of 3809% internal gain of the detector at solar-blind UV light, which is two order of magnitude bigger than the detector with (111) cubic MgZnO/hexagonal MgZnO interfaces. The higher density of interface states between (200) cubic and hexagonal MgZnO grains in the mix-phase MgZnO thin film is main reason for its big internal gain and high solar-blind UV response. The Idark of the mixed-phase MgZnO based detector with (111) cubic MgZnO/hexagonal MgZnO interfaces is much smaller and the Ilight/Idark of which is higher because of the higher interfaces barrier at (111) cubic MgZnO/hexagonal MgZnO interfaces, so the detector could effectively detect faint solar-blind UV signal more under strong noise background.

We investigated the thermal properties of few-layer Mo0.5W0.5S2 using a series of samples with different kinds of capping layers. Temperature-dependent Raman measurements were conducted in the range of 300–500 K, with power-dependent measurements also carried out. It indicated, for the few-layer Mo0.5W0.5S2, the temperature coefficients of the WS2-like E12g mode, MoS2-like E12g mode and A1g mode were −0.0155 cm−1/K, −0.0146 cm−1/K, and −0.0130 cm−1/K, respectively. And the thermal conductivity was estimated to be 44.8 W/mK. Moreover, the Mo0.5W0.5S2 samples coated with capping layers (ZrO2, HfO2) both showed a better thermal stability and a larger thermal conductivity than the one without. The results revealed that the capping layer should be an important factor in the thermal property. Keywords: Mo0.5W0.5S2, TMDs, Thermal properties, High temperature, Capping layers, Raman

We demonstrate the direct formation of c-axis oriented crystalline IGZO thin films at room temperature by magnetron sputtering. The influence of processing parameters such as oxygen partial pressure, post-annealing temperature and channel thickness on the electrical performance of IGZO films and thin-film transistors (TFTs) was intensively investigated. The as-deposited crystalline IGZO TFTs exhibited a mobility of 4.49 cm2 V−1 s−1 and an on/off ratio of 2.08 × 107. For the annealed device, a high mobility of 10.51 cm2 V−1 s−1, a subthreshold swing of 0.672 V decade−1, a threshold voltage of 0.38 V, as well as an on/off current ratio of ∼108 are achieved with an annealing temperature of 400 °C. These results present a significant step towards the development of high-performance TFTs using oriented crystalline IGZO.

Excitatory pyramidal neurons in the entorhinal cortical layer II region (ECIIPN) form functional excitatory synapses with CA1 parvalbumin inhibitory neurons (CA1PV) and undergo selective degeneration in the early stages of Alzheimer's disease (AD). Here, we show that death-associated protein kinase 1 (DAPK1) is selectively activated in ECIIPNof AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECIIPN-CA1PVsynaptic loss and improves spatial learning and memory in AD mice. This study demonstrates that activation of DAPK1 in ECIIPNcontributes to a memory loss in AD and hence warrants a promising target for the treatment of AD.SIGNIFICANCE STATEMENTOur recent study reported that excitatory pyramidal neurons in the entorhinal cortical layer II region (ECIIPN) target to CA1 parvalbumin-type inhibitory neurons (CA1PV) at a direct pathway and are one of the most vulnerable brain cells that are selectively degenerated in the early stage of Alzheimer's disease (AD). Our present study shows that death-associated protein kinase 1 (DAPK1) is selectively activated in ECIIPNof AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECIIPN-CA1PVsynaptic loss and improves spatial learning and memory in the early stage of AD. These data not only demonstrate a crucial molecular event for synaptic degeneration but also provide a therapeutic target for the treatment of AD.

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.

MicroRNAs have been implicated in diverse physiological and pathological processes. We previously reported that aberrant microRNA-124 (miR-124)/non-receptor-type protein phosphatase 1 (PTPN1) signaling plays an important role in the synaptic disorders associated with Alzheimer's disease (AD). In this study, we further investigated the potential role of miR-124/PTPN1 in the tau pathology of AD. We first treated the mice with intra-hippocampal stereotactic injections. Then, we used quantitative real-time reverse transcription PCR (qRT-PCR) to detect the expression of microRNAs. Western blotting was used to measure the level of PTPN1, the level of tau protein, the phosphorylation of tau at AD-related sites, and alterations in the activity of glycogen synthase kinase 3β (GSK-3β) and protein phosphatase 2 (PP2A). Immunohistochemistry was also used to detect changes in tau phosphorylation levels at AD-related sites and somadendritic aggregation. Soluble and insoluble tau protein was separated by 70% formic acid (FA) extraction to examine tau solubility. Finally, behavioral experiments (including the Morris water maze, fear conditioning, and elevated plus maze) were performed to examine learning and memory ability and emotion-related behavior. We found that artificially replicating the abnormalities in miR-124/PTPN1 signaling induced AD-like tau pathology in the hippocampus of wild-type mice, including hyperphosphorylation at multiple sites, insolubility and somadendritic aggregation, as well as learning/memory deficits. We also found that disruption of miR-124/PTPN1 signaling was caused by the loss of RE1-silencing transcription factor protein, which can be initiated by Aβ insults or oxidative stress, as observed in the brains of P301S mice. Correcting the deregulation of miR-124/PTPN1 signaling rescued the tau pathology and learning/memory impairments in the P301S mice. We also found that miR-124/PTPN1 abnormalities induced activation of glycogen synthase kinase 3 (GSK-3) and inactivation of protein phosphatase 2A (PP2A) by promoting tyrosine phosphorylation, implicating an imbalance in tau kinase/phosphatase. Thus, targeting the miR-124/PTPN1 signaling pathway is a promising therapeutic strategy for AD.

Alzheimer’s disease (AD) is characterized by chronic progressive cognitive deterioration frequently accompanied by psychopathological symptoms, including changes in personality and social isolation, which severely reduce quality of life. Currently, no viable therapies or present-day drugs developed for the treatment of AD symptoms are able to slow or reverse AD progression or prevent the advance of neurodegeneration. As such, non-drug alternatives are currently being tested, including deep brain stimulation (DBS). DBS is an established therapy for several neurological and psychiatric indications, such as movement disorders. Studies assessing DBS for other disorders have also found improvements in cognitive function, providing the impetus for clinical trials on DBS for AD. Targets of DBS in AD clinical trials and animal model studies include the fornix, entorhinal cortex (EC), nucleus basalis of Meynert (NBM), and vertical limb of diagonal band (VDB). However, there is still no comprehensive theory explaining the effects of DBS on AD symptoms or a consensus on which targets provide optimal benefits. This article reviews the anatomy of memory circuits related to AD, as well as studies on DBS rescue of AD in these circuits and the possible therapeutic mechanisms.

We report the fabrication of gallium oxide (GaOx) thin films by a novel polymer-assisted deposition (PAD) method. The influence and mechanism of postannealing temperature (200-800 °C) on the formation and properties of GaOx thin films are investigated by complementary characterization analyses. The results indicate that solution-deposited GaOx experiences the elimination of organic residuals as well as the transformation of amorphous GaOx to crystalline GaOx with the increase in annealing temperature. High-quality GaOx could be achieved with a smooth surface, wide band gap, and decent dielectric performance. Moreover, the solution-processed In2O3 thin-film transistors based on optimized GaOx dielectrics demonstrate outstanding electrical performance, including a low operating voltage of 5 V, a mobility of 3.09 cm2 V-1 s-1, an on/off current ratio of 1.8 × 105, and a subthreshold swing of 0.18 V dec-1. Our study suggests that GaOx achieved by PAD shows great potential for further low-cost and high-performance optoelectronic applications.

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.

The present study aimed to identify microRNAs (miRNAs) that are involved in neuropathic pain and predict their corresponding roles in the pathogenesis and development process of neuropathic pain. The rat model of neuropathic pain caused by spared nerve injury (SNI) was established in Sprague-Dawley male rats, followed by small RNA sequencing of the L3–L6 dorsal root ganglion. Real-time PCR was performed to validate the differently expressed miRNAs. Functional verification was performed by intrathecally injecting the animals with miRNA agomir. A total of 72 differentially expressed miRNAs were identified in the SNI rats, including 33 upregulated and 39 downregulated miRNAs. The results of qPCR further verified the expression levels of rno-miR-6215 (P=0.015), rno-miR-1224 (P=0.030), rno-miR-1249 (P=0.038), and rno-miR-488-3p (P=0.048), which were all significantly downregulated in the SNI rats compared to the control ones. The majority of differentially expressed miRNAs were associated with phosphorylation, intracellular signal transduction, and cell death. Target prediction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses suggested that these differentially expressed miRNAs targeted genes that are related to axon guidance, focal adhesion, and Ras and Wnt signaling pathways. Moreover, miR-1224 agomir significantly alleviated SNI-induced neuropathic pain. The current findings provide new insights into the role of miRNAs in the pathogenesis of neuropathic pain.

High-performance ultraviolet (UV) detectors with both high responses and fast speeds are hard to make on homogeneous crystal semiconductor materials. Here, the UV response characteristics of mixed-phase MgZnO thin films with different internal structure distributions are studied. The mixed-phase MgZnO-based detector with the given crystal composition has a high response at both deep UV light (96 A W−1 at 240 nm) and near UV light (80 A W−1 at 335 nm). Meanwhile, because of the quasi-tunneling breakdown mechanism within the device, the high-response UV detector also shows a fast response speed (tr = 0.11 μs) and recovery speed (td1 = 26 μs) at deep UV light, which is much faster than both low-response mixed-phase MgZnO-based UV detectors with other structure constitutions and reported high-response UV devices on homogenous crystal materials. The Idark of the device is just 4.27 pA under a 5 V bias voltage, so the signal-to-noise ratio of the device reached 23852 at 5.5 uW cm−2 235 nm UV light. The new quasi-tunneling breakdown mechanism is observed in some mixed-phase MgZnO thin films that contain both c-MgZnO and h-MgZnO parts, which introduce a high response, signal-to-noise ratio, and fast speed into mixed-phase MgZnO-based UV detectors at weak deep UV light.